Latanoprostene Bunod 0.024% in Subjects With Open-angle Glaucoma or Ocular Hypertension: Pooled Phase 3 Study Findings.

PubMed

Weinreb, Robert N; Liebmann, Jeffrey M; Martin, Keith R; Kaufman, Paul L; Vittitow, Jason L

2018-01-01

To compare the diurnal intraocular pressure (IOP)-lowering effect of latanoprostene bunod (LBN) 0.024% with timolol maleate 0.5% in subjects with open-angle glaucoma (OAG) or ocular hypertension (OHT). Pooled analysis of two phase 3, randomized, multicenter, double-masked, parallel-group, noninferiority trials (APOLLO and LUNAR), each with open-label safety extension phases. Adults with OAG or OHT were randomized 2:1 to double-masked treatment with LBN once daily (qd) or timolol twice daily (bid) for 3 months followed by open-label LBN treatment for 3 (LUNAR) or 9 (APOLLO) months. IOP was measured at 8 AM, 12 PM, and 4 PM at week 2, week 6, and months 3, 6, 9, and 12. Of the 840 subjects randomized, 774 (LBN, n=523; timolol crossover to LBN, n=251) completed the efficacy phase, and 738 completed the safety extension phase. Mean IOP was significantly lower with LBN versus timolol at all 9 evaluation timepoints during the efficacy phase (P<0.001). A significantly greater proportion of LBN-treated subjects attained a mean IOP ≤18 mm Hg and IOP reduction ≥25% from baseline versus timolol-treated subjects (P<0.001). The IOP reduction with LBN was sustained through the safety phase; subjects crossed over from timolol to LBN experienced additional significant IOP lowering (P≤0.009). Both treatments were well tolerated, and there were no safety concerns with long-term LBN treatment. In this pooled analysis of subjects with OAG and OHT, LBN 0.024% qd provided greater IOP-lowering compared with timolol 0.5% bid and maintained lowered IOP through 12 months. LBN demonstrated a safety profile comparable to that of prostaglandin analogs.

Tofacitinib, an oral Janus kinase inhibitor, in patients from Mexico with rheumatoid arthritis: Pooled efficacy and safety analyses from Phase 3 and LTE studies.

PubMed

Burgos-Vargas, Ruben; Cardiel, Mario; Xibillé, Daniel; Pacheco-Tena, César; Pascual-Ramos, Virginia; Abud-Mendoza, Carlos; Mahgoub, Ehab; Rahman, Mahboob; Fan, Haiyun; Rojo, Ricardo; García, Erika; Santana, Karina

2017-05-25

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We characterized efficacy and safety of tofacitinib in Mexican patients from RA Phase 3 and long-term extension (LTE) studies. Data from Mexican patients with RA and an inadequate response to disease-modifying antirheumatic drugs (DMARDs) were taken from four Phase 3 studies (pooled across studies) and one open-label LTE study of tofacitinib. Patients received tofacitinib 5 or 10mg twice daily, adalimumab (one Phase 3 study) or placebo (four Phase 3 studies) as monotherapy or in combination with conventional synthetic DMARDs. Efficacy up to Month 12 (Phase 3) and Month 36 (LTE) was assessed by American College of Rheumatology 20/50/70 response rates, Disease Activity Score (erythrocyte sedimentation rate), and Health Assessment Questionnaire-Disability Index. Safety, including incidence rates (IRs; patients with events/100 patient-years) for adverse events (AEs) of special interest, was assessed throughout the studies. 119 and 212 Mexican patients were included in the Phase 3 and LTE analyses, respectively. Tofacitinib-treated patients in Phase 3 had numerically greater improvements in efficacy responses versus placebo at Month 3. Efficacy was sustained in Phase 3 and LTE studies. IRs for AEs of special interest were similar to those with tofacitinib in the global and Latin American RA populations. In Mexican patients from the tofacitinib global RA program, tofacitinib efficacy was demonstrated up to Month 12 in Phase 3 studies and Month 36 in the LTE study, with a safety profile consistent with tofacitinib global population. Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.

Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial.

PubMed

Hochhaus, A; Saglio, G; Hughes, T P; Larson, R A; Kim, D-W; Issaragrisil, S; le Coutre, P D; Etienne, G; Dorlhiac-Llacer, P E; Clark, R E; Flinn, I W; Nakamae, H; Donohue, B; Deng, W; Dalal, D; Menssen, H D; Kantarjian, H M

2016-05-01

In the phase 3 Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients (ENESTnd) study, nilotinib resulted in earlier and higher response rates and a lower risk of progression to accelerated phase/blast crisis (AP/BC) than imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP). Here, patients' long-term outcomes in ENESTnd are evaluated after a minimum follow-up of 5 years. By 5 years, more than half of all patients in each nilotinib arm (300 mg twice daily, 54%; 400 mg twice daily, 52%) achieved a molecular response 4.5 (MR(4.5); BCR-ABL⩽0.0032% on the International Scale) compared with 31% of patients in the imatinib arm. A benefit of nilotinib was observed across all Sokal risk groups. Overall, safety results remained consistent with those from previous reports. Numerically more cardiovascular events (CVEs) occurred in patients receiving nilotinib vs imatinib, and elevations in blood cholesterol and glucose levels were also more frequent with nilotinib. In contrast to the high mortality rate associated with CML progression, few deaths in any arm were associated with CVEs, infections or pulmonary diseases. These long-term results support the positive benefit-risk profile of frontline nilotinib 300 mg twice daily in patients with CML-CP.

The Long-Term Safety and Efficacy Follow-Up Study of Subjects Who Completed the Phase I Clinical Trial of Neurostem®-AD

ClinicalTrials.gov

2012-09-27

Alzheimer Disease; Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Delirium, Dementia, Amnestic, Cognitive Disorders; Mental Disorders

Secukinumab long-term safety experience: A pooled analysis of 10 phase II and III clinical studies in patients with moderate to severe plaque psoriasis.

PubMed

van de Kerkhof, Peter C M; Griffiths, Christopher E M; Reich, Kristian; Leonardi, Craig L; Blauvelt, Andrew; Tsai, Tsen-Fang; Gong, Yankun; Huang, Jiaqing; Papavassilis, Charis; Fox, Todd

2016-07-01

Secukinumab, a fully human anti-interleukin-17A monoclonal antibody, has demonstrated efficacy and safety in patients with moderate to severe plaque psoriasis. We reviewed safety data from the secukinumab psoriasis phase II/III program. Data were pooled from 10 phase II/III secukinumab psoriasis studies. Analysis included 3993 subjects; 3430 received secukinumab, representing 2725 subject-years (SYs) of exposure. Over 52 weeks, for secukinumab 300 mg, 150 mg, and etanercept, respectively, exposure-adjusted incidence rates (IRs) per 100 SYs were comparable across treatments for total adverse events (AEs; 236.1, 239.9, and 243.4, respectively); infections (91.1, 85.3, and 93.7, respectively); serious AEs (7.4, 6.8, and 7.0, respectively); serious infections (1.4, 1.1, and 1.4, respectively); malignant or unspecified tumors (0.77, 0.97, and 0.68, respectively); and adjudicated major adverse cardiovascular events (0.42, 0.35, and 0.34, respectively). AEs were not dose-related except for nonserious, mild/moderate, skin/mucosal candidiasis (IRs 3.55, 1.85, and 1.37 for secukinumab 300 mg, 150 mg, and etanercept, respectively). There was a limited number of patients in comparator groups and the exposure to placebo was short. Secukinumab had a favorable safety profile, had no meaningful difference between the 300- and 150-mg doses and, in terms of safety, was comparable to etanercept over 52 weeks in patients with moderate to severe plaque psoriasis. Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

Guselkumab for the treatment of moderate-to-severe plaque psoriasis.

PubMed

Yang, Eric J; Sanchez, Isabelle M; Beck, Kristen; Sekhon, Sahil; Wu, Jashin J; Bhutani, Tina

2018-04-01

Guselkumab is a human monoclonal antibody targeting the p19 subunit of IL-23 that has been approved for the treatment of adult patients with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. This medication blocks the IL-23/IL-17 axis, which has been implicated in playing a key role in the pathogenesis of psoriasis. Areas covered: This review outlines the pharmacologic properties, safety, and efficacy of guselkumab for the treatment of plaque psoriasis. Expert commentary: Guselkumab is the first IL-23 specific inhibitor to be approved for the treatment of plaque psoriasis. Phase II and III clinical trial results have demonstrated excellent safety and efficacy of guselkumab. IL-23 inhibitors may offer potential benefits over existing therapies for moderate-to-severe plaque psoriasis in terms of safety, frequency of administration, and efficacy. Long-term safety data will be critical in evaluating the role of guselkumab in the treatment of psoriasis.

Manned space flight nuclear system safety. Volume 3: Reactor system preliminary nuclear safety analysis. Part 2: Accident Model Document (AMD)

NASA Technical Reports Server (NTRS)

1972-01-01

The Accident Model Document is one of three documents of the Preliminary Safety Analysis Report (PSAR) - Reactor System as applied to a Space Base Program. Potential terrestrial nuclear hazards involving the zirconium hydride reactor-Brayton power module are identified for all phases of the Space Base program. The accidents/events that give rise to the hazards are defined and abort sequence trees are developed to determine the sequence of events leading to the hazard and the associated probabilities of occurence. Source terms are calculated to determine the magnitude of the hazards. The above data is used in the mission accident analysis to determine the most probable and significant accidents/events in each mission phase. The only significant hazards during the prelaunch and launch ascent phases of the mission are those which arise form criticality accidents. Fission product inventories during this time period were found to be very low due to very limited low power acceptance testing.

Long-term safety, efficacy, and tolerability of imidafenacin in the treatment of overactive bladder: a review of the Japanese literature

PubMed Central

Masumori, Naoya

2013-01-01

Imidafenacin is an antimuscarinic agent with high affinity for the M3 and M1 muscarinic receptor subtypes and low affinity for the M2 subtype, and is used to treat overactive bladder. Several animal studies have demonstrated that imidafenacin has organ selectivity for the bladder over the salivary glands, colon, heart, and brain. In Phase I studies in humans, the approximately 2.9-hour elimination half-life of imidafenacin was shorter than that of other antimuscarinics such as tolterodine and solifenacin. Imidafenacin was approved for clinical use in overactive bladder in Japan in 2007 after a randomized, double-blind, placebo-controlled Phase II study and a propiverine-controlled Phase III study conducted in Japanese patients demonstrated that imidafenacin 0.1 mg twice daily was clinically effective for treating overactive bladder and was not inferior to propiverine for reduction of episodes of incontinence, with a better safety profile than propiverine. Several short-term clinical studies have demonstrated that imidafenacin also improves sleep disorders, nocturia, and nocturia-related quality of life. In addition, it is speculated that addon therapy with imidafenacin is beneficial for men with benign prostatic hyperplasia whose overactive bladder symptoms are not controlled by alpha-1 adrenoceptor antagonists. No cognitive impairment or influence of imidafenacin on the QTc interval has been observed. Although there have been very few relevant long-term clinical studies, the available information suggests the long-term efficacy, safety, and tolerability of imidafenacin, with less frequent severe adverse events, such as dry mouth and constipation. In addition, imidafenacin can be used safely for a long time even for cognitively vulnerable elderly patients with symptoms of overactive bladder. Thus, it is highly likely that imidafenacin is safe, efficacious, and tolerable to control symptoms of overactive bladder even over the long term. However, it remains unknown if the practical effectiveness of imidafenacin is applicable to ethnic groups other than Japanese. PMID:23390360

Long-term treatment of Cushing's disease with pasireotide: 5-year results from an open-label extension study of a Phase III trial.

PubMed

Petersenn, S; Salgado, L R; Schopohl, J; Portocarrero-Ortiz, L; Arnaldi, G; Lacroix, A; Scaroni, C; Ravichandran, S; Kandra, A; Biller, B M K

2017-07-01

Treating hypercortisolism in patients with Cushing's disease after failed surgery often requires chronic medication, underlining the need for therapies with favourable long-term efficacy and safety profiles. In a randomised, double-blind study, 162 adult patients with persistent/recurrent or de novo Cushing's disease received pasireotide. Patients with mean urinary free cortisol at/below the upper limit of normal or clinical benefit at month 12 could continue receiving pasireotide during an open-ended, open-label phase, the outcomes of which are described herein. Sixteen patients received 5 years of pasireotide treatment. Among these, median (95% confidence interval) percentage change from baseline in mean urinary free cortisol was -82.6% (-89.0, -41.9) and -81.8% (-89.8, -67.4) at months 12 and 60. Eleven patients had mean urinary free cortisol ≤ upper limit of normal at month 60. Improvements in clinical signs were sustained during long-term treatment. The safety profile of pasireotide at 5 years was similar to that reported after 12 months. Fifteen of 16 patients experienced a hyperglycaemia-related adverse event; glycated haemoglobin levels were stable between months 6 and 60. Adverse events related to hyperglycaemia, bradycardia, gallbladder/biliary tract, and liver safety were most likely to first occur by month 6; adverse event severity did not tend to worsen over time. This represents the longest prospective trial of a medical therapy for Cushing's disease to date. A subset of patients treated with pasireotide maintained biochemical and clinical improvements for 5 years, with no new safety signals emerging. These data support the use of pasireotide as an effective long-term therapy for some patients with Cushing's disease.

Safety and Efficacy of a Halobetasol/Tazarotene Fixed Combination in the Treatment of Moderate-to-Severe Plaque Psoriasis: Results of two Phase 3 randomized controlled trials.

PubMed

Gold, Linda Stein; Lebwohl, Mark G; Sugarman, Jeffrey L; Pariser, David M; Lin, Tina; Martin, Gina; Pillai, Radhakrishnan; Israel, Robert; Ramakrishna, Tage

2018-03-31

Topical corticosteroids are the mainstay of psoriasis treatment; long-term safety concerns limit use. Combination with tazarotene may optimize efficacy, minimizing safety/tolerability concerns, In patients with moderate-to-severe plaque psoriasis treated with HP/TAZ lotion, improvement is noted within 2 weeks with few adverse effects observed after 8 weeks., HP/TAZ lotion may provide a realistic topical option for psoriasis management. Copyright © 2018. Published by Elsevier Inc.

An analysis of truck size and weight : phase I - safety.

DOT National Transportation Integrated Search

2013-11-01

Commercial motor vehicles carrying heavier loads or employing multiple trailers present significant concerns regarding the impact of their use in terms of increased accidents, accident severity and fatalities. In 2011, the most recent year for which ...

Reaction Mechanisms of Energetic Materials in the Condensed Phase: Long-term Aging, Munition Safety and Condensed-Phase Processes in Propellants and Explosives

DTIC Science & Technology

2009-03-31

Journal of the American Society for Mass Spectrometry, 2002. 13(2): p. 135- 143 . 7. Delcorte, A., P. Bertrand, and B.J. Garrison, Collision cascade and...TNCHP. 49, 50 The presence of the keto group in K6 appears to promote a more direct reaction to the gaseous decomposition products. Decomposition

Long-term safety and efficacy of a novel once-weekly oral trelagliptin as monotherapy or in combination with an existing oral antidiabetic drug in patients with type 2 diabetes mellitus: A 52-week open-label, phase 3 study.

PubMed

Inagaki, Nobuya; Sano, Hiroki; Seki, Yoshifumi; Kuroda, Shingo; Kaku, Kohei

2016-09-01

Trelagliptin is a novel once-weekly oral dipeptidyl peptidase-4 inhibitor for type 2 diabetes mellitus that was first approved in Japan. We evaluated long-term safety and efficacy of trelagliptin in Japanese patients with type 2 diabetes mellitus. This was a phase 3, multicenter, open-label study to evaluate long-term safety and efficacy of trelagliptin. Patients with type 2 diabetes mellitus inadequately controlled despite diet/exercise or treatment with one of the existing oral antidiabetic drugs along with diet/exercise received trelagliptin 100 mg orally once weekly for 52 weeks as monotherapy or combination therapies. The primary end-points were the safety variables, and the secondary end-points were glycosylated hemoglobin and fasting plasma glucose. A total of 680 patients received the following antidiabetic therapies: trelagliptin monotherapy (n = 248), combination with a sulfonylurea (n = 158), a glinide (n = 67), an α-glucosidase inhibitor (n = 65), a biguanide (n = 70), or a thiazolidinedione (n = 72). During the study, 79.8% of the patients experienced at least one adverse event for monotherapy, 87.3% for combination with a sulfonylurea, 77.6% for a glinide, 81.5% for an α-glucosidase inhibitor, 64.3% for a biguanide, and 84.7% for a thiazolidinedione, respectively. Most of the adverse events were mild or moderate. The change in glycosylated hemoglobin from baseline at the end of the treatment period was -0.74 to -0.25% for each therapy. Once-weekly oral trelagliptin provides well-tolerated long-term safety and efficacy in both monotherapy and combination therapies in Japanese patients with type 2 diabetes mellitus. © 2016 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.

Professional conceptualisation and accomplishment of patient safety in mental healthcare: an ethnographic approach

PubMed Central

2011-01-01

Background This study seeks to broaden current understandings of what patient safety means in mental healthcare and how it is accomplished. We propose a qualitative observational study of how safety is produced or not produced in the complex context of everyday professional mental health practice. Such an approach intentionally contrasts with much patient safety research which assumes that safety is achieved and improved through top-down policy directives. We seek instead to understand and articulate the connections and dynamic interactions between people, materials, and organisational, legal, moral, professional and historical safety imperatives as they come together at particular times and places to perform safe or unsafe practice. As such we advocate an understanding of patient safety 'from the ground up'. Methods/Design The proposed project employs a six-phase data collection framework in two mental health settings: an inpatient unit and a community team. The first four phases comprise multiple modes of focussed, unobtrusive observation of professionals at work, to enable us to trace the conceptualisation and enactment of safety as revealed in dialogue and narrative, use of artefacts and space, bodily activity and patterns of movement, and in the accomplishment of specific work tasks. An interview phase and a social network analysis phase will subsequently be conducted to offer comparative perspectives on the observational data. This multi-modal and holistic approach to studying patient safety will complement existing research, which is dominated by instrumentalist approaches to discovering factors contributing to error, or developing interventions to prevent or manage adverse events. Discussion This ethnographic research framework, informed by the principles of practice theories and in particular actor-network ideas, provides a tool to aid the understanding of patient safety in mental healthcare. The approach is novel in that it seeks to articulate an 'anatomy of patient safety' as it actually occurs, in terms of the networks of elements coalescing to enable the conceptual and material performance of safety in mental health settings. By looking at how patient safety happens or does not happen, this study will enable us to better understand how we might in future productively tackle its improvement. PMID:21569572

Drug safety evaluation of defibrotide.

PubMed

Richardson, Paul G; Corbacioglu, Selim; Ho, Vincent Trien-Vinh; Kernan, Nancy A; Lehmann, Leslie; Maguire, Craig; Maglio, Michelle; Hoyle, Margaret; Sardella, Marco; Giralt, Sergio; Holler, Ernst; Carreras, Enric; Niederwieser, Dietger; Soiffer, Robert

2013-01-01

Hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), is a potentially life-threatening complication of chemotherapeutic conditioning used in preparation for hematopoietic stem-cell transplantation (SCT). Defibrotide (DF) has been shown in Phase II and III trials to improve complete response in patients with severe VOD (sVOD). None of the articles, to date, provide a comprehensive review of the safety of DF in VOD and/or a range of other conditions. This article reviews current clinical findings on DF, primarily in terms of safety for use in treatment and prophylaxis of VOD, and relevant safety data for its use in other diseases. The literature review was conducted using a PubMed search with the fixed term 'defibrotide' in combination with ≥ 1 of 'safety', 'veno-occlusive disease' (with and without 'treatment', 'prevention'), 'oncology', 'myeloma', 'microangiopathy', 'anti-thrombotic' and 'peripheral vascular disorder'. Related articles from the EBMT and ASH conference websites were also included. DF was well tolerated in majority of the studies. The safety profile of DF is largely favourable with toxicities comparable to control populations in the setting of SCT complicated by sVOD.

Evaluating the Safety Profile of Non-Active Implantable Medical Devices Compared with Medicines.

PubMed

Pane, Josep; Coloma, Preciosa M; Verhamme, Katia M C; Sturkenboom, Miriam C J M; Rebollo, Irene

2017-01-01

Recent safety issues involving non-active implantable medical devices (NAIMDs) have highlighted the need for better pre-market and post-market evaluation. Some stakeholders have argued that certain features of medicine safety evaluation should also be applied to medical devices. Our objectives were to compare the current processes and methodologies for the assessment of NAIMD safety profiles with those for medicines, identify potential gaps, and make recommendations for the adoption of new methodologies for the ongoing benefit-risk monitoring of these devices throughout their entire life cycle. A literature review served to examine the current tools for the safety evaluation of NAIMDs and those for medicines. We searched MEDLINE using these two categories. We supplemented this search with Google searches using the same key terms used in the MEDLINE search. Using a comparative approach, we summarized the new product design, development cycle (preclinical and clinical phases), and post-market phases for NAIMDs and drugs. We also evaluated and compared the respective processes to integrate and assess safety data during the life cycle of the products, including signal detection, signal management, and subsequent potential regulatory actions. The search identified a gap in NAIMD safety signal generation: no global program exists that collects and analyzes adverse events and product quality issues. Data sources in real-world settings, such as electronic health records, need to be effectively identified and explored as additional sources of safety information, particularly in some areas such as the EU and USA where there are plans to implement the unique device identifier (UDI). The UDI and other initiatives will enable more robust follow-up and assessment of long-term patient outcomes. The safety evaluation system for NAIMDs differs in many ways from those for drugs, but both systems face analogous challenges with respect to monitoring real-world usage. Certain features of the drug safety evaluation process could, if adopted and adapted for NAIMDs, lead to better and more systematic evaluations of the latter.

Analysis of Wake VAS Benefits Using ACES Build 3.2.1: VAMS Type 1 Assessment

NASA Technical Reports Server (NTRS)

Smith, Jeremy C.

2005-01-01

The FAA and NASA are currently engaged in a Wake Turbulence Research Program to revise wake turbulence separation standards, procedures, and criteria to increase airport capacity while maintaining or increasing safety. The research program is divided into three phases: Phase I near term procedural enhancements; Phase II wind dependent Wake Vortex Advisory System (WakeVAS) Concepts of Operations (ConOps); and Phase III farther term ConOps based on wake prediction and sensing. The Phase III Wake VAS ConOps is one element of the Virtual Airspace Modelling and Simulation (VAMS) program blended concepts for enhancing the total system wide capacity of the National Airspace System (NAS). This report contains a VAMS Program Type 1 (stand-alone) assessment of the expected capacity benefits of Wake VAS at the 35 FAA Benchmark Airports and determines the consequent reduction in delay using the Airspace Concepts Evaluation System (ACES) Build 3.2.1 simulator.

A phase III, open-label, multicenter study to evaluate the safety and efficacy of long-term triple combination therapy with azilsartan, amlodipine, and hydrochlorothiazide in patients with essential hypertension.

PubMed

Rakugi, Hiromi; Shimizu, Kohei; Nishiyama, Yuya; Sano, Yuhei; Umeda, Yuusuke

2018-06-01

Patients with essential hypertension who are receiving treatment with an angiotensin II receptor blocker and a calcium channel blocker often develop inadequate blood pressure (BP) control and require the addition of a diuretic. This study aimed to evaluate the long-term safety and efficacy of a triple combination therapy with 20 mg azilsartan (AZL), 5 mg amlodipine (AML) and 12.5 mg hydrochlorothiazide (HCTZ). The phase III, open-label, multicenter study (NCT02277691) comprised a 4-week run-in period and 52-week treatment period. Patients with inadequate BP control despite AZL/AML therapy (n = 341) received 4 weeks' treatment with AZL/AML (combination tablet) + HCTZ (tablet) and 4 weeks' treatment with AZL/AML/HCTZ (combination tablet) in a crossover manner, followed by AZL/AML/HCTZ (combination tablet) from Week 8 of the treatment period up to Week 52. The primary and secondary endpoints were long-term safety and BP (office and home), respectively. Most adverse events (AEs) were mild or moderate in intensity, and no deaths or treatment-related serious AEs were reported. The triple therapy provided consistent BP-lowering effects in both office and home measurements. The triple combination therapy with AZL/AML/HCTZ was well tolerated and effective for 52 weeks in Japanese patients with essential hypertension.

Review of phase III trial data on IL-23 inhibitors tildrakizumab and guselkumab for psoriasis.

PubMed

Amin, M; Darji, K; No, D J; Wu, J J

2017-10-01

The development of monoclonal antibodies targeting IL-12 and IL-23 has enhanced the therapeutic options available for psoriasis patients. Recent research suggests that IL-23 alone plays a role in the pathogenesis of psoriasis. The objective was to review the phase III clinical trial data for the anti-IL-23 agents to evaluate the safety and efficacy profile of each agent. We reviewed the results of the phase III clinical trials for the anti-IL-23 agents tildrakizumab and guselkumab. The results of phase III trials on risankizumab have not yet been reported. By week 12, the proportion of patients reaching Psoriasis Area and Severity Index (PASI 75) was >60% among the most efficacious dose of each agent. The percentage of patients achieving PASI 90 at week 16 was the primary endpoint for the phase III trials for guselkumab, which was above 70%. The safety profiles of the agents were comparable, with the most commonly reported adverse events of nasopharyngitis and upper respiratory tract infections. The anti-IL-23 agents demonstrated a rapid clinical improvement that is similar or superior to the improvement seen with currently marketed IL-17 inhibitors with a favourable short-term safety profile. The results of the phase III trials support the notion that IL-23 is a potential target in psoriasis treatment. © 2017 European Academy of Dermatology and Venereology.

Chinese Herbal Therapy for the Treatment of Food Allergy

PubMed Central

Li, Xiu-Min

2014-01-01

Traditional Chinese medicine (TCM) has been widely used in China to treat various diseases for thousands of years. Given its reputed effectiveness, low cost, and favorable safety profile, TCM is attracting great interest in Western societies as a source of therapy for an array of illnesses, including allergies and asthma. Although food allergy has not been described in the TCM literature, a novel treatment for food allergy, named the food allergy herbal formula-2 (FAHF-2), was developed using TCM principles. Using a well-characterized murine model of peanut allergy, FAHF-2 has been shown to be highly effective in providing long-term protection against peanut-induced anaphylaxis, with a high safety margin. Phase 1 human trials have demonstrated the safety of FAHF-2 in food allergic individuals. Currently, a phase 2 trial examining efficacy of FAHF-2 is on-going. Other TCMs also show a potential for treating food allergies in preclinical studies. PMID:22581122

Tofacitinib, an oral Janus kinase inhibitor, for the treatment of chronic plaque psoriasis: Long-term efficacy and safety results from 2 randomized phase-III studies and 1 open-label long-term extension study.

PubMed

Papp, Kim A; Krueger, James G; Feldman, Steven R; Langley, Richard G; Thaci, Diamant; Torii, Hideshi; Tyring, Stephen; Wolk, Robert; Gardner, Annie; Mebus, Charles; Tan, Huaming; Luo, Yingchun; Gupta, Pankaj; Mallbris, Lotus; Tatulych, Svitlana

2016-05-01

Tofacitinib is an oral Janus kinase inhibitor being investigated for psoriasis. We sought to report longer-term tofacitinib efficacy and safety in patients with moderate to severe psoriasis. Data from 2 identical phase-III studies, Oral-treatment Psoriasis Trial Pivotal 1 and 2, were pooled with data from these patients in an ongoing open-label long-term extension study. Patients (n = 1861) were randomized 2:2:1 to tofacitinib 5 mg, 10 mg, or placebo twice daily (BID). At week 16, placebo patients were rerandomized to tofacitinib. Pivotal study participants could enroll into the long-term extension where they received tofacitinib at 10 mg BID for 3 months, after which dosing could be 5 or 10 mg BID. At week 28, the proportions of patients randomized to tofacitinib 5 and 10 mg BID achieving 75% or greater reduction in Psoriasis Area and Severity Index score from baseline were 55.6% and 68.8%, and achieving Physician Global Assessment of clear or almost clear were 54.7% and 65.9%. Efficacy was maintained in most patients through 24 months. Serious adverse events and discontinuations because of adverse events were reported in less than 11% of patients over 33 months of tofacitinib exposure. There was no dose comparison beyond week 52. Oral tofacitinib demonstrated sustained efficacy in patients with psoriasis through 2 years, with 10 mg BID providing greater efficacy than 5 mg BID. No unexpected safety findings were observed. Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

South Lake Tahoe Coordinated Transit System project : phase III evaluation report

DOT National Transportation Integrated Search

2000-03-01

Utah's basic highway information system is one of the most complete data base management systems found in any of the Highway Safety Information System (HSIS) States in terms of the number of files included in the system and the flexibility of output....

Anti-IL-23 Phase II Data for Psoriasis: A Review.

PubMed

Beroukhim, Kourosh; Danesh, Melissa J; Nguyen, Catherine; Austin, Annemieke; Koo, John; Levin, Ethan

2015-10-01

Monoclonal antibodies that target both Interleukin (IL)-12 and IL-23 have shown great efficacy in the treatment of psoriasis. Recent evidence suggests that IL-23 serves a more critical role than IL-12 in the pathogenesis of psoriasis, leading to the development of monoclonal antibodies that specifically target IL-23. We reviewed the results of the phase II clinical trials for the anti-IL-23 agents tildrakizumab and guselkumab, in order to assess the efficacy and safety profile of each agent. By week 16, the proportion of patients achieving Physician Global Assessment (PGA) score of clear (0) or minimal (1) and Psoriasis Area and Severity Index (PASI 75) was above 70% among the most efficacious dosage of each agent (P < 0.001 compared to placebo for all agents). The safety profiles of the agents were similar, with the most frequently reported adverse events of nasopharyngitis, upper respiratory infections, cough, and headache. The anti-IL-23 agents demonstrated a rapid clinical improvement and favorable short-term safety profile. The results of the phase II trials support IL-23 as an essential target in psoriasis treatment.

A phase 2, open-label, multicenter study of the long-term safety of siltuximab (an anti-interleukin-6 monoclonal antibody) in patients with multicentric Castleman disease.

PubMed

van Rhee, Frits; Casper, Corey; Voorhees, Peter M; Fayad, Luis E; van de Velde, Helgi; Vermeulen, Jessica; Qin, Xiang; Qi, Ming; Tromp, Brenda; Kurzrock, Razelle

2015-10-06

Multicentric Castleman disease (MCD) is a rare, systemic lymphoproliferative disorder driven by interleukin (IL)-6 overproduction. Siltuximab, an anti-IL-6 monoclonal antibody, has demonstrated durable tumor and symptomatic responses in a multinational, randomized, placebo-controlled study of MCD. This preplanned safety analysis was conducted to evaluate the long-term safety of siltuximab treatment among 19 patients with MCD who had stable disease or better and were enrolled in a phase-1 study and subsequent ongoing, open-label, phase-2 extension study. Dosing was 11 mg/kg administered intravenously every 3 weeks, per protocol, or every 6 weeks at the investigator's discretion. Safety monitoring focused on potential risks associated with the anti-IL-6 mechanism of action. Investigator-assessed disease control status was also documented. Median treatment duration for the 19 patients was 5.1 (range 3.4, 7.2) years, with 14 (74%) patients treated for >4 years. Grade-≥ 3 adverse events (AEs) reported in >1 patient included hypertension (n = 3) and nausea, cellulitis, and fatigue (n = 2 each). Grade-≥ 3 AEs at least possibly attributed to siltuximab were leukopenia, lymphopenia, and a serious AE of polycythemia (n = 1 each). Hypertriglyceridemia and hypercholesterolemia (total cholesterol) were reported in 8 and 9 patients, respectively. No disease relapses were observed, and 8 of 19 patients were able to switch to an every-6-week dosing schedule. All MCD patients in this extension study have received siltuximab for a prolonged duration (up to 7 years) without evidence of cumulative toxicity or treatment discontinuations and with few serious infections. All patients are alive, demonstrate sustained disease control, and continue to receive siltuximab.

Long-term safety and efficacy of dalfampridine for walking impairment in patients with multiple sclerosis: Results of open-label extensions of two Phase 3 clinical trials

PubMed Central

Goodman, Andrew D; Bethoux, Francois; Brown, Theodore R; Schapiro, Randall T; Cohen, Ron; Marinucci, Lawrence N; Henney, Herbert R

2015-01-01

Background: In Phase 3 double-blind trials (MS-F203 and MS-F204), dalfampridine extended release tablets 10 mg twice daily (dalfampridine-ER; prolonged-release fampridine in Europe; fampridine modified or sustained release elsewhere) improved walking speed relative to placebo in patients with multiple sclerosis (MS). Objectives: Evaluation of long-term safety and efficacy of dalfampridine-ER in open-label extensions (MS-F203EXT, MS-F204EXT). Methods: Patients received dalfampridine-ER 10 mg twice daily; and had Timed 25-Foot Walk (T25FW) assessments at 2, 14 and 26 weeks, and then every 6 months. Subjects were categorized as dalfampridine-ER responders or non-responders, based on their treatment response in the double-blind parent trials that assessed T25FW. Results: We had 269 patients enter MS-F203EXT and 154 patients complete it; for a maximum exposure of 5 years. We had 214 patients enter MS-F204EXT and 146 complete it; for a maximum exposure of 3.3 years. No new safety signals emerged and dalfampridine-ER tolerability was consistent with the double-blind phase. Improvements in walking speed were lost after dalfampridine-ER was discontinued in the parent trial, but returned by the 2-week assessment after re-initiation of the drug. Throughout the extensions, mean improvement in walking speed declined, but remained improved, among the double-blind responders as compared with non-responders. Conclusions: The dalfamipridine-ER safety profile was consistent with the parent trials. Although walking speed decreased over time, dalfampridine-ER responders continued to show improved walking speed, which was sustained compared with non-responders. PMID:25583832

Common Aperture Techniques for Imaging Electro-Optical Sensors (CATIES).

DTIC Science & Technology

1980-02-01

milliradians ) at the 5.33:1 zoom point. The zoom optics contain five elements with two moveable air -spaced doublets for accomplishing the zoom function...included in the electrical and optical design but due to funding limitations, system safety requirements during the testing phase and lack of long-term...determined during the system testing phase to be conducted by the Air Force. Limited electronic signal processing (split screen and video mix) was

Safety of inhaled glycopyrronium in patients with COPD: a comprehensive analysis of clinical studies and post-marketing data.

PubMed

D'Urzo, Anthony D; Kerwin, Edward M; Chapman, Kenneth R; Decramer, Marc; DiGiovanni, Robert; D'Andrea, Peter; Hu, Huilin; Goyal, Pankaj; Altman, Pablo

2015-01-01

Chronic use of inhaled anticholinergics by patients with chronic obstructive pulmonary disease (COPD) has raised long-term safety concerns, particularly cardiovascular. Glycopyrronium is a once-daily anticholinergic with greater receptor selectivity than previously available agents. We assessed the safety of inhaled glycopyrronium using data pooled from two analysis sets, involving six clinical studies and over 4,000 patients with COPD who received one of the following treatments: glycopyrronium 50 μg, placebo (both delivered via the Breezhaler device), or tiotropium 18 μg (delivered via the HandiHaler device). Data were pooled from studies that varied in their duration and severity of COPD of the patients (ie, ≤12 weeks duration with patients having moderate or severe COPD; and >1 year duration with patients having severe and very severe COPD). Safety comparisons were made for glycopyrronium vs tiotropium or placebo. Poisson regression was used to assess the relative risk for either active drug or placebo (and between drugs where placebo was not available) for assessing the incidence of safety events. During post-marketing surveillance (PMS), safety was assessed by obtaining reports from various sources, and disproportionality scores were computed using EMPIRICA. In particular, the cardiac safety of glycopyrronium during the post-marketing phase was evaluated. The overall incidence of adverse events and deaths was similar across groups, while the incidence of serious adverse events was numerically higher in placebo. Furthermore, glycopyrronium did not result in an increased risk of cerebro-cardiovascular events vs placebo. There were no new safety reports during the PMS phase that suggested an increased risk compared to results from the clinical studies. Moreover, the cardiac safety of glycopyrronium during the PMS phase was also consistent with the clinical data. The overall safety profile of glycopyrronium was similar to its comparators indicating no increase in the overall risk for any of the investigated safety end points.

Mindful Application of Aviation Practices in Healthcare.

PubMed

Powell-Dunford, Nicole; Brennan, Peter A; Peerally, Mohammad Farhad; Kapur, Narinder; Hynes, Jonny M; Hodkinson, Peter D

2017-12-01

Evidence supports the efficacy of incorporating select recognized aviation practices and procedures into healthcare. Incident analysis, debrief, safety brief, and crew resource management (CRM) have all been assessed for implementation within the UK healthcare system, a world leader in aviation-based patient safety initiatives. Mindful application, in which aviation practices are specifically tailored to the unique healthcare setting, show promise in terms of acceptance and long-term sustainment. In order to establish British healthcare applications of aviation practices, a PubMed search of UK authored manuscripts published between 2005-2016 was undertaken using search terms 'aviation,' 'healthcare,' 'checklist,' and 'CRM.' A convenience sample of UK-authored aviation medical conference presentations and UK-authored patient safety manuscripts were also reviewed. A total of 11 of 94 papers with UK academic affiliations published between 2005-2016 and relevant to aviation modeled healthcare delivery were found. The debrief process, incident analysis, and CRM are the primary practices incorporated into UK healthcare, with success dependent on cultural acceptance and mindful application. CRM training has gained significant acceptance in UK healthcare environments. Aviation modeled incident analysis, debrief, safety brief, and CRM training are increasingly undertaken within the UK healthcare system. Nuanced application, in which the unique aspects of the healthcare setting are addressed as part of a comprehensive safety approach, shows promise for long-term success. The patient safety brief and aviation modeled incident analysis are in earlier phases of implementation, and warrant further analysis.Powell-Dunford N, Brennan PA, Peerally MF, Kapur N, Hynes JM, Hodkinson PD. Mindful application of aviation practices in healthcare. Aerosp Med Hum Perform. 2017; 88(12):1107-1116.

Long-term (6 and 12 months) follow-up of two prospective, randomized, controlled phase III trials of photodynamic therapy with BF-200 ALA and methyl aminolaevulinate for the treatment of actinic keratosis

PubMed Central

Dirschka, T; Radny, P; Dominicus, R; Mensing, H; Brüning, H; Jenne, L; Karl, L; Sebastian, M; Oster-Schmidt, C; Klövekorn, W; Reinhold, U; Tanner, M; Gröne, D; Deichmann, M; Simon, M; Hübinger, F; Hofbauer, G; Krähn-Senftleben, G; Borrosch, F; Reich, K; Berking, C; Wolf, P; Lehmann, P; Moers-Carpi, M; Hönigsmann, H; Wernicke-Panten, K; Hahn, S; Pabst, G; Voss, D; Foguet, M; Schmitz, B; Lübbert, H; Szeimies, R-M

2013-01-01

Background Two phase III trials of photodynamic therapy (PDT) with BF-200 ALA, a recently approved nanoemulsion formulation of 5-aminolaevulinic acid (ALA) demonstrated high clearance rates in mild-to-moderate actinic keratosis (AK). The comparison to a registered methyl aminolaevulinate (MAL) cream demonstrated significantly superior total patient clearance rates. Objectives To evaluate long-term efficacy and safety of PDT for AK 6 and 12 months after the last PDT with BF-200 ALA, MAL or placebo. Methods The follow-up phase (FUP) was performed with patients of two phase III studies. Both studies compared BF-200 ALA with placebo, one of the studies additionally with MAL. Overall recurrence rates and various subgroups (light source, lesion severity, lesion location, complete responders after first PDT) were assessed 6 and 12 months after the last PDT. Results Recurrence rates were similar for BF-200 ALA and MAL, with a tendency to lower recurrence rates for BF-200 ALA. The proportion of patients who were fully cleared during PDT and remained completely clear for at least 12 months after PDT were 47% for BF-200 ALA (both studies) and 36% for MAL treatment. The subgroup that was illuminated with narrow wavelength LED lamps reached 69% and 53% for BF-200 ALA (both studies, respectively) and 41% for MAL. No safety concerns were reported. Conclusions The FUP data confirmed the high efficacy and safety of PDT with BF-200 ALA. The slightly lower recurrence rates after BF-200 ALA treatment compared with MAL treatment enhanced the better treatment outcome due to the significantly superior efficacy. PMID:23252768

Long-term (6 and 12 months) follow-up of two prospective, randomized, controlled phase III trials of photodynamic therapy with BF-200 ALA and methyl aminolaevulinate for the treatment of actinic keratosis.

PubMed

Dirschka, T; Radny, P; Dominicus, R; Mensing, H; Brüning, H; Jenne, L; Karl, L; Sebastian, M; Oster-Schmidt, C; Klövekorn, W; Reinhold, U; Tanner, M; Gröne, D; Deichmann, M; Simon, M; Hübinger, F; Hofbauer, G; Krähn-Senftleben, G; Borrosch, F; Reich, K; Berking, C; Wolf, P; Lehmann, P; Moers-Carpi, M; Hönigsmann, H; Wernicke-Panten, K; Hahn, S; Pabst, G; Voss, D; Foguet, M; Schmitz, B; Lübbert, H; Szeimies, R-M

2013-04-01

Two phase III trials of photodynamic therapy (PDT) with BF-200 ALA, a recently approved nanoemulsion formulation of 5-aminolaevulinic acid (ALA) demonstrated high clearance rates in mild-to-moderate actinic keratosis (AK). The comparison to a registered methyl aminolaevulinate (MAL) cream demonstrated significantly superior total patient clearance rates. To evaluate long-term efficacy and safety of PDT for AK 6 and 12 months after the last PDT with BF-200 ALA, MAL or placebo. The follow-up phase (FUP) was performed with patients of two phase III studies. Both studies compared BF-200 ALA with placebo, one of the studies additionally with MAL. Overall recurrence rates and various subgroups (light source, lesion severity, lesion location, complete responders after first PDT) were assessed 6 and 12 months after the last PDT. Recurrence rates were similar for BF-200 ALA and MAL, with a tendency to lower recurrence rates for BF-200 ALA. The proportion of patients who were fully cleared during PDT and remained completely clear for at least 12 months after PDT were 47% for BF-200 ALA (both studies) and 36% for MAL treatment. The subgroup that was illuminated with narrow wavelength LED lamps reached 69% and 53% for BF-200 ALA (both studies, respectively) and 41% for MAL. No safety concerns were reported. The FUP data confirmed the high efficacy and safety of PDT with BF-200 ALA. The slightly lower recurrence rates after BF-200 ALA treatment compared with MAL treatment enhanced the better treatment outcome due to the significantly superior efficacy. © 2012 Biofrontera Bioscience GmbH BJD © 2012 British Association of Dermatologists.

Toward a national core course in agricultural medicine and curriculum in agricultural safety and health: the "building capacity" consensus process.

PubMed

Rudolphi, Josie M; Donham, Kelley J

2015-01-01

ABSTRACT The agricultural industry poses specific hazards and risks to its workers. Since the 1970s, the University of Iowa has been establishing programs to educate rural health care and safety professionals who in turn provide education and occupational health and safety services to farm families and farm workers. This program has been well established in the state of Iowa as a program of Iowa's Center for Agricultural Safety and Health (I-CASH). However, the National 1989 Agriculture at Risk Report indicated there was a great need for agricultural medicine training beyond Iowa's borders. In order to help meet this need, Building Capacity: A National Resource of Agricultural Medicine Professionals was initiated as a project of the National Institute for Occupational Safety and Health (NIOSH)-funded Great Plains Center for Agricultural Health in 2006. Before the first phase of this project, a consensus process was conducted with a group of safety and health professionals to determine topics and learning objectives for the course. Over 300 students attended and matriculated the agricultural medicine course during first phase of the project (2007-2010). Beginning the second phase of the project (2012-2016), an expanded advisory committee (38 internationally recognized health and safety professionals) was convened to review the progress of the first phase, make recommendations for revisions to the required topics and competencies, and discuss updates to the second edition of the course textbook (Agricultural Medicine: Occupational and Environmental Health for the Health Professions). A formal consensus process was held and included an online survey and also a face-to-face meeting. The group was charged with the responsibility of developing the next version of this course by establishing best practices and setting an agenda with the long-term goal of developing a national course in agricultural medicine.

Analysis of WakeVAS Benefits Using ACES Build 3.2.1

NASA Technical Reports Server (NTRS)

Smith, Jeremy C.

2005-01-01

The FAA and NASA are currently engaged in a Wake Turbulence Research Program to revise wake turbulence separation standards, procedures, and criteria to increase airport capacity while maintaining or increasing safety. The research program is divided into three phases: Phase I near term procedural enhancements; Phase II wind dependent Wake Vortex Advisory System (WakeVAS) Concepts of Operations (ConOps); and Phase III farther term ConOps based on wake prediction and sensing. This report contains an analysis that evaluates the benefits of a closely spaced parallel runway (CSPR) Phase I ConOps, a single runway and CSPR Phase II ConOps and a single runway Phase III ConOps. A series of simulation runs were performed using the Airspace Concepts Evaluation System (ACES) Build 3.21 air traffic simulator to provide an initial assessment of the reduction in delay and cost savings obtained by the use of a WakeVAS at selected U.S. airports. The ACES simulator is being developed by NASA Ames Research Center as part of the Virtual Airspace Modelling and Simulation (VAMS) program.

Long-term safety and efficacy of abatacept in children with juvenile idiopathic arthritis.

PubMed

Ruperto, Nicolino; Lovell, Daniel J; Quartier, Pierre; Paz, Eliana; Rubio-Pérez, Nadina; Silva, Clovis A; Abud-Mendoza, Carlos; Burgos-Vargas, Ruben; Gerloni, Valeria; Melo-Gomes, Jose A; Saad-Magalhães, Claudia; Chavez-Corrales, J; Huemer, Christian; Kivitz, Alan; Blanco, Francisco J; Foeldvari, Ivan; Hofer, Michael; Horneff, Gerd; Huppertz, Hans-Iko; Job-Deslandre, Chantal; Loy, Anna; Minden, Kirsten; Punaro, Marilynn; Nunez, Alejandro Flores; Sigal, Leonard H; Block, Alan J; Nys, Marleen; Martini, Alberto; Giannini, Edward H

2010-06-01

We previously documented that abatacept was effective and safe in patients with juvenile idiopathic arthritis (JIA) who had not previously achieved a satisfactory clinical response with disease-modifying antirheumatic drugs or tumor necrosis factor blockade. Here, we report results from the long-term extension (LTE) phase of that study. This report describes the long-term, open-label extension phase of a double-blind, randomized, controlled withdrawal trial in 190 patients with JIA ages 6-17 years. Children were treated with 10 mg/kg abatacept administered intravenously every 4 weeks, with or without methotrexate. Efficacy results were based on data derived from the 153 patients who entered the open-label LTE phase and reflect >or=21 months (589 days) of treatment. Safety results include all available open-label data as of May 7, 2008. Of the 190 enrolled patients, 153 entered the LTE. By day 589, 90%, 88%, 75%, 57%, and 39% of patients treated with abatacept during the double-blind and LTE phases achieved responses according to the American College of Rheumatology (ACR) Pediatric 30 (Pedi 30), Pedi 50, Pedi 70, Pedi 90, and Pedi 100 criteria for improvement, respectively. Similar response rates were observed by day 589 among patients previously treated with placebo. Among patients who had not achieved an ACR Pedi 30 response at the end of the open-label lead-in phase and who proceeded directly into the LTE, 73%, 64%, 46%, 18%, and 5% achieved ACR Pedi 30, Pedi 50, Pedi 70, Pedi 90, and Pedi 100 responses, respectively, by day 589 of the LTE. No cases of tuberculosis and no malignancies were reported during the LTE. Pneumonia developed in 3 patients, and multiple sclerosis developed in 1 patient. Abatacept provided clinically significant and durable efficacy in patients with JIA, including those who did not initially achieve an ACR Pedi 30 response during the initial 4-month open-label lead-in phase.

Application of Satellite Based Augmentation Systems to Altitude Separation

NASA Astrophysics Data System (ADS)

Magny, Jean Pierre

This paper presents the application of GNSS1, or more precisely of Satellite Based Augmentation Systems (SBAS), to vertical separation for en-route, approach and landing operations. Potential improvements in terms of operational benefit and of safety are described for two main applications. First, vertical separation between en-route aircraft, which requires a system available across wide areas. SBAS (EGNOS, WAAS, and MSAS) are very well suited for this purpose before GNSS2 becomes available. And secondly, vertical separation from the ground during approach and landing, for which preliminary design principles of instrument approach procedures and safety issues are presented. Approach and landing phases are the subject of discussions within ICAO GNSS-P. En-route phases have been listed as GNSS-P future work and by RTCA for development of new equipments.

Secukinumab in the Treatment of Psoriasis and Psoriatic Arthritis: A Review of the Literature.

PubMed

Abrouk, M; Gandy, J; Nakamura, M; Lee, K; Brodsky, M; Singh, R; Zhu, H; Farahnik, B; Bhutani, T; Koo, J

2017-07-01

While there are several commercially available treatment options for psoriasis and psoriatic arthritis, there remains a large number of individuals who are refractory to current modalities. In the recent past, there has been increasing evidence that interleukin (IL)-17 plays a vital role in the pathophysiology of psoriasis. Preclinical, phase II, and phase III studies of secukinumab (Cosentyx®) targeting IL-17 and its receptor have thus far proved to be promising. We reviewed the results of phase II and phase III clinical trials for secukinumab in the treatment of psoriasis and psoriatic arthritis. Only published studies were considered in the present review. We also performed an English language literature search from January 2003 to September 2015 using PubMed with any of the following key words: (secukinumab OR AIN457) AND (psoriasis OR psoriatic arthritis). In our review of the literature, seven phase III and five phase II clinical trials, as well as open-label extension studies with unpublished findings were found. Results from phase III clinical trials indicated secukinumab to be efficacious and safe for the treatment of psoriasis and psoriatic arthritis according to Psoriasis Area and Severity Index (PASI) and American College of Rheumatology (ACR) scores. The safety profile of this agent was similar across all studies, with the most frequently reported adverse events of nasopharyngitis, upper respiratory infections, headache, and injection site reaction. Secukinumab demonstrates rapid and robust clinical improvement accompanied by a favorable short- term safety profile. The results of the phase III trials continue to reinforce the theory that the IL-17 pathway is an essential target in psoriasis and psoriatic arthritis treatment. Additional extension studies of lower level evidence are needed to further understand the safety profile of the drug.

Long-term safety of droxidopa in patients with symptomatic neurogenic orthostatic hypotension.

PubMed

Isaacson, Stuart; Vernino, Steven; Ziemann, Adam; Rowse, Gerald J; Kalu, Uwa; White, William B

2016-10-01

The long-term safety of droxidopa for the treatment of symptomatic neurogenic orthostatic hypotension in patients with Parkinson disease, pure autonomic failure, multiple system atrophy, or nondiabetic autonomic neuropathy was evaluated in a phase 3, multinational, open-label study in patients who previously participated in a double-blind, placebo-controlled clinical trial of droxidopa. A total of 350 patients received droxidopa 100 to 600 mg three times daily. Mean duration of droxidopa exposure was 363 days (range, 2-1133 days). Rates of serious adverse events (AEs), cardiac-related AEs, and supine hypertension were 24%, 5%, and 5%, respectively. Most AEs, including those of a cardiovascular nature, were not attributed by investigators to droxidopa. In this large cohort of patients with neurogenic orthostatic hypotension, droxidopa was well tolerated during long-term use. Copyright © 2016 The Author. Published by Elsevier Inc. All rights reserved.

Guidelines for the Clinical Evaluation of Psychoactive Drugs in Infants and Children.

ERIC Educational Resources Information Center

Food and Drug Administration (DHEW), Washington, DC.

These guidelines are intended to help those who design and conduct investigations of psychopharmacologic agents in children. A progression of studies in four phases is advocated. First, early short term studies should establish single and multiple dose safety baselines. Second, early pilot efficacy studies may be initiated jointly with longer…

Strategies to Minimize Risks and Exploitation in Phase One Trials on Healthy Subjects*

PubMed Central

Shamoo, Adil E.; Resnik, David B.

2014-01-01

Most of the literature on phase one trials has focused on ethical and safety issues in research on patients with advanced cancer, but this article focuses on healthy, adult subjects. The article makes six specific recommendations for protecting the rights and welfare of healthy subjects in phase one trials: 1) because phase one trials are short in duaration (usually 1 to 3 months), researchers should gather more data on the short-term and long-term risks of participation in phase one studies by healthy subjects; 2) researchers should develop strict inclusion/exclusion criteria that exclude unhealthy or vulnerable subjects, such as decisionally impaired people, in phase one studies; 3) subjects should not participate in more than one phase one study at the same time and should wait at least 30 days between participating in different studies; 4) researchers should develop a database to keep track of phase one participants; 5) subjects should be guaranteed a minimum wage equivalent to the equivalent type of unskilled labor, but there should be no upper limits on wages; and 6) subjects should be allowed to engage in collective bargaining with research sponsors. PMID:16754430

Strategies to minimize risks and exploitation in phase one trials on healthy subjects.

PubMed

Shamoo, Adil E; Resnik, David B

2006-01-01

Most of the literature on phase one trials has focused on ethical and safety issues in research on patients with advanced cancer, but this article focuses on healthy, adult subjects. The article makes six specific recommendations for protecting the rights and welfare of healthy subjects in phase one trials: 1) because phase one trials are short in duration (usually 1 to 3 months), researchers should gather more data on the short-term and long-term risks of participation in phase one studies by healthy subjects; 2) researchers should develop strict inclusion/exclusion criteria that exclude unhealthy or vulnerable subjects, such as decisionally impaired people, in phase one studies; 3) subjects should not participate in more than one phase one study at the same time and should wait at least 30 days between participating in different studies; 4) researchers should develop a database to keep track of phase one participants; 5) subjects should be guaranteed a minimum wage equivalent to the equivalent type of unskilled labor, but there should be no upper limits on wages; and 6) subjects should be allowed to engage in collective bargaining with research sponsors.

[Statement: Requirements for the assessment of surgical innovations].

PubMed

Seidel, Dörthe; Pieper, Dawid; Neugebauer, Edmund

2015-01-01

The term "innovation" refers to new products, but also to the process of developing and distributing new products and procedures. The operative disciplines are often associated with innovations because of their continuous, stepwise adaptation of daily practice to established procedures. Medical devices play a significant role in integrating surgical technology with surgical experience. The success of a surgical innovation and other invasive treatments does not only depend on the surgical procedure, but also on the context of the whole treatment process including the pre- and postoperative phase, the interaction of the surgical team and the setting. High standards have been set for the assessment of surgical innovations in terms of patient safety, efficacy and patient benefit, which will be discussed in the present paper. A stepwise approach to evaluation will be used, split into preclinical development, clinical development (feasibility and safety), evaluation phase (efficacy and patient benefit) and longtime surveillance. Our paper is based on the expert-based consented IDEAL approach as well as the consented recommendations of the European Association of Endoscopic Surgery (EAES). (As supplied by publisher). Copyright © 2015. Published by Elsevier GmbH.

Safety and patient outcomes with lubiprostone for up to 52 weeks in patients with irritable bowel syndrome with constipation.

PubMed

Chey, W D; Drossman, D A; Johanson, J F; Scott, C; Panas, R M; Ueno, R

2012-03-01

Irritable bowel syndrome with constipation (IBS-C) significantly decreases quality of life and the ability to perform daily living activities. To demonstrate the long-term safety, tolerability and patient outcomes of lubiprostone in patients with IBS-C. This extension study enrolled 522 IBS-C patients who had completed one of two randomised phase 3 studies. All enrolled patients received open-label lubiprostone orally for 36-weeks (8 mcg, twice daily). The primary objective was the assessment of long-term safety and tolerability, monitored via adverse events (AEs), laboratory parameters and vital signs. Additional outcome endpoints included monthly responder rates and patient evaluations of IBS-C symptom severity and impact on quality of life. The evaluable safety population comprised of 520 patients; 476 of which had patient reported outcome data available. The overall safety profile of lubiprostone during this study was similar to that observed in the preceding phase 3 studies. The most common AEs were diarrhoea (11.0%), nausea (11.0%), urinary tract infection (9.0%), sinusitis (9.0%) and abdominal distention (5.8%). Diarrhoea and nausea were the most common treatment-related AEs. No serious AEs were considered treatment-related. Seventeen patients discontinued due to a treatment-related AE, of which diarrhoea and nausea accounted for six (1.2%) and three (0.6%) respectively. For responder rates and patient-evaluated parameters (n = 476), all groups experienced significant improvements from baseline, with initial improvements maintained throughout the study. In patients with irritable bowel syndrome with constipation, lubiprostone 8 mcg twice daily was found to be safe and well tolerated over 9-13 months of treatment. © 2012 Blackwell Publishing Ltd.

Methylphenidate dose optimization for ADHD treatment: review of safety, efficacy, and clinical necessity

PubMed Central

Huss, Michael; Duhan, Praveen; Gandhi, Preetam; Chen, Chien-Wei; Spannhuth, Carsten; Kumar, Vinod

2017-01-01

Attention-deficit/hyperactivity disorder (ADHD) is a chronic psychiatric disorder characterized by hyperactivity and/or inattention and is often associated with a substantial impact on psychosocial functioning. Methylphenidate (MPH), a central nervous system stimulant, is commonly used for pharmacological treatment of adults and children with ADHD. Current practice guidelines recommend optimizing MPH dosage to individual patient needs; however, the clinical benefits of individual dose optimization compared with fixed-dose regimens remain unclear. Here we review the available literature on MPH dose optimization from clinical trials and real-world experience on ADHD management. In addition, we report safety and efficacy data from the largest MPH modified-release long-acting Phase III clinical trial conducted to examine benefits of dose optimization in adults with ADHD. Overall, MPH is an effective ADHD treatment with a good safety profile; data suggest that dose optimization may enhance the safety and efficacy of treatment. Further research is required to establish the extent to which short-term clinical benefits of MPH dose optimization translate into improved long-term outcomes for patients with ADHD. PMID:28740389

Methylphenidate dose optimization for ADHD treatment: review of safety, efficacy, and clinical necessity.

PubMed

Huss, Michael; Duhan, Praveen; Gandhi, Preetam; Chen, Chien-Wei; Spannhuth, Carsten; Kumar, Vinod

2017-01-01

Attention-deficit/hyperactivity disorder (ADHD) is a chronic psychiatric disorder characterized by hyperactivity and/or inattention and is often associated with a substantial impact on psychosocial functioning. Methylphenidate (MPH), a central nervous system stimulant, is commonly used for pharmacological treatment of adults and children with ADHD. Current practice guidelines recommend optimizing MPH dosage to individual patient needs; however, the clinical benefits of individual dose optimization compared with fixed-dose regimens remain unclear. Here we review the available literature on MPH dose optimization from clinical trials and real-world experience on ADHD management. In addition, we report safety and efficacy data from the largest MPH modified-release long-acting Phase III clinical trial conducted to examine benefits of dose optimization in adults with ADHD. Overall, MPH is an effective ADHD treatment with a good safety profile; data suggest that dose optimization may enhance the safety and efficacy of treatment. Further research is required to establish the extent to which short-term clinical benefits of MPH dose optimization translate into improved long-term outcomes for patients with ADHD.

Tofacitinib, an oral Janus kinase inhibitor, for the treatment of Latin American patients with rheumatoid arthritis: Pooled efficacy and safety analyses of Phase 3 and long-term extension studies.

PubMed

Radominski, Sebastião Cezar; Cardiel, Mario Humberto; Citera, Gustavo; Goecke, Annelise; Jaller, Juan Jose; Lomonte, Andrea Barranjard Vannucci; Miranda, Pedro; Velez, Patricia; Xibillé, Daniel; Kwok, Kenneth; Rojo, Ricardo; García, Erika Gabriela

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We assessed tofacitinib efficacy and safety in the Latin American (LA) subpopulation of global Phase 3 and long-term extension (LTE) studies. Data from LA patients with RA and inadequate response to disease-modifying antirheumatic drugs (DMARDs) were pooled across five Phase 3 studies. Phase 3 patients received tofacitinib 5 or 10mg twice daily (BID), adalimumab or placebo; patients in the single LTE study received tofacitinib 5 or 10mg BID; treatments were administered alone or with conventional synthetic DMARDs. Efficacy was reported up to 12 months (Phase 3) and 36 months (LTE) by American College of Rheumatology (ACR) 20/50/70 response rates, Disease Activity Score (DAS)28-4(erythrocyte sedimentation rate [ESR]) and Health Assessment Questionnaire-Disability Index (HAQ-DI). Incidence rates (IRs; patients with event/100 patient-years) of adverse events (AEs) of special interest were reported. The Phase 3 studies randomized 496 LA patients; the LTE study enrolled 756 LA patients from Phase 2 and Phase 3. In the Phase 3 studies, patients who received tofacitinib 5 and 10mg BID showed improvements vs placebo at Month 3 in ACR20 (68.9% and 75.7% vs 35.6%), ACR50 (45.8% and 49.7% vs 20.7%) and ACR70 (17.5% and 23.1% vs 6.9%) responses, mean change from baseline in HAQ-DI (-0.6 and -0.8 vs -0.3) and DAS28-4(ESR) score (-2.3 and -2.4 vs -1.4). The improvements were sustained up to Month 36 in the LTE study. In the Phase 3 studies, IRs with tofacitinib 5 and 10mg BID and placebo were 7.99, 6.57 and 9.84, respectively, for SAEs, and 3.87, 5.28 and 3.26 for discontinuation due to AEs. IRs of AEs of special interest in tofacitinib-treated LA patients were similar to the global population. In Phase 3 and LTE studies in LA patients with RA, tofacitinib demonstrated efficacy up to 36 months with a manageable safety profile up to 60 months, consistent with the overall tofacitinib study population. Copyright © 2016 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.

Long-term safety and tolerability of once-daily mesalamine granules in the maintenance of remission of ulcerative colitis.

PubMed

Lichtenstein, Gary R; Barrett, Andrew C; Bortey, Enoch; Paterson, Craig; Forbes, William P

2014-08-01

Ulcerative colitis (UC), a chronic, relapsing, and remitting inflammatory bowel disease, requires long-term treatment to maintain remission. In this study, the long-term safety and tolerability of mesalamine granules (MG) therapy was evaluated in the maintenance of UC remission. Previous prospective studies evaluating different oral mesalamine formulations have not exceeded a duration of 14 months. A phase 3, multicenter, 24-month, open-label extension study evaluating MG 1.5 g once daily in patients who achieved previous remission from mild to moderate UC was performed. Eligible patients had successfully participated in 1 of 2 previous 6-month double-blind, placebo-controlled trials or were new patients in remission. Safety assessments included monitoring of adverse events (AEs) and clinical laboratory tests. Risk of UC recurrence was assessed by the occurrence of UC-related AEs. Of the 393 patients enrolled (280 from the double-blind studies; 113 new patients), 388 were included in the safety population. The most common AEs included nasopharyngitis (13.9%), headache (11.6%), and diarrhea (10.8%), and the incidence of these events was generally lower in the MG group versus historical placebo group from the double-blind studies. Pancreatic, renal, and hepatic AEs occurred in 23 patients (5.9%). The risk of UC-related AEs was low and was maintained for 24 months during the open-label study. Once-daily MG has a favorable safety profile for the maintenance of remission for up to 2 years in patients with UC.

Immunogenicity and safety of a fully liquid aluminum phosphate adjuvanted Haemophilus influenzae type b PRP-CRM197-conjugate vaccine in healthy Japanese children: A phase III, randomized, observer-blind, multicenter, parallel-group study.

PubMed

Togashi, Takehiro; Mitsuya, Nodoka; Kogawara, Osamu; Sumino, Shuji; Takanami, Yohei; Sugizaki, Kayoko

2016-08-31

Broad use of monovalent Haemophilus influenzae type b (Hib) conjugate vaccines based on the capsular polysaccharide polyribosyl-ribitol phosphate (PRP), has significantly reduced invasive Hib disease burden in children worldwide, particularly in children aged <1year. In Japan, PRP conjugated to tetanus toxoid (PRP-T) vaccine has been widely used since the initiation of public funding programs followed by a routine vaccination designation in 2013. We compared the immunogenicity and safety of PRP conjugated to a non-toxic diphtheria toxin mutant (PRP-CRM197) vaccine with the PRP-T vaccine when administered subcutaneously to healthy Japanese children in a phase III study. Additionally, we evaluated the immunogenicity and safety profiles of a diphtheria-tetanus acellular pertussis (DTaP) combination vaccine when concomitantly administered with either PRP-CRM197 or PRP-T vaccines. The primary endpoint was the "long-term seroprotection rate", defined as the group proportion with anti-PRP antibody titers ⩾1.0μg/mL, after the primary series. Long-term seroprotection rates were 99.3% in the PRP-CRM197 group and 95.6% in the PRP-T group. The intergroup difference (PRP-CRM197 group - PRP-T group) was 3.7% (95% confidence interval: 0.099-7.336), demonstrating that PRP-CRM197 vaccine was non-inferior to PRP-T vaccine (p<0.0001). Furthermore, the "short-term seroprotection rate" (anti-PRP antibody titer ⩾0.15μg/mL) before booster vaccination was higher in the PRP-CRM197 group than in PRP-T. Concomitant administration of PRP-CRM197 vaccine with DTaP vaccine showed no differences in terms of immunogenicity compared with concomitant vaccination with PRP-T vaccine and DTaP vaccine. Although CRM197 vaccine had higher local reactogenicity, overall, both Hib vaccines had acceptable safety and tolerability profiles. The immunogenicity of PRP-CRM197 vaccine administered subcutaneously as a three-dose primary series in children followed by a booster vaccination 1year after the primary series induced protective levels of Hib antibodies with no safety or tolerability concerns. Registered on ClinicalTrials.gov: NCT01379846. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Solid-solid phase change thermal storage application to space-suit battery pack

NASA Astrophysics Data System (ADS)

Son, Chang H.; Morehouse, Jeffrey H.

1989-01-01

High cell temperatures are seen as the primary safety problem in the Li-BCX space battery. The exothermic heat from the chemical reactions could raise the temperature of the lithium electrode above the melting temperature. Also, high temperature causes the cell efficiency to decrease. Solid-solid phase-change materials were used as a thermal storage medium to lower this battery cell temperature by utilizing their phase-change (latent heat storage) characteristics. Solid-solid phase-change materials focused on in this study are neopentyl glycol and pentaglycerine. Because of their favorable phase-change characteristics, these materials appear appropriate for space-suit battery pack use. The results of testing various materials are reported as thermophysical property values, and the space-suit battery operating temperature is discussed in terms of these property results.

Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study.

PubMed

Long, G V; Flaherty, K T; Stroyakovskiy, D; Gogas, H; Levchenko, E; de Braud, F; Larkin, J; Garbe, C; Jouary, T; Hauschild, A; Chiarion-Sileni, V; Lebbe, C; Mandalà, M; Millward, M; Arance, A; Bondarenko, I; Haanen, J B A G; Hansson, J; Utikal, J; Ferraresi, V; Mohr, P; Probachai, V; Schadendorf, D; Nathan, P; Robert, C; Ribas, A; Davies, M A; Lane, S R; Legos, J J; Mookerjee, B; Grob, J-J

2017-07-01

Previous analysis of COMBI-d (NCT01584648) demonstrated improved progression-free survival (PFS) and overall survival (OS) with combination dabrafenib and trametinib versus dabrafenib monotherapy in BRAF V600E/K-mutant metastatic melanoma. This study was continued to assess 3-year landmark efficacy and safety after ≥36-month follow-up for all living patients. This double-blind, phase 3 study enrolled previously untreated patients with BRAF V600E/K-mutant unresectable stage IIIC or stage IV melanoma. Patients were randomized to receive dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily) or dabrafenib plus placebo. The primary endpoint was PFS; secondary endpoints were OS, overall response, duration of response, safety, and pharmacokinetics. Between 4 May and 30 November 2012, a total of 423 of 947 screened patients were randomly assigned to receive dabrafenib plus trametinib (n = 211) or dabrafenib monotherapy (n = 212). At data cut-off (15 February 2016), outcomes remained superior with the combination: 3-year PFS was 22% with dabrafenib plus trametinib versus 12% with monotherapy, and 3-year OS was 44% versus 32%, respectively. Twenty-five patients receiving monotherapy crossed over to combination therapy, with continued follow-up under the monotherapy arm (per intent-to-treat principle). Of combination-arm patients alive at 3 years, 58% remained on dabrafenib plus trametinib. Three-year OS with the combination reached 62% in the most favourable subgroup (normal lactate dehydrogenase and <3 organ sites with metastasis) versus only 25% in the unfavourable subgroup (elevated lactate dehydrogenase). The dabrafenib plus trametinib safety profile was consistent with previous clinical trial observations, and no new safety signals were detected with long-term use. These data demonstrate that durable (≥3 years) survival is achievable with dabrafenib plus trametinib in patients with BRAF V600-mutant metastatic melanoma and support long-term first-line use of the combination in this setting. © The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

ABP 980: promising trastuzumab biosimilar for HER2-positive breast cancer.

PubMed

Paplomata, Elisavet; Nahta, Rita

2018-03-01

Approval of the HER2-targeted antibody trastuzumab dramatically improved outcomes for patients with HER2-positive breast cancer. Multiple trastuzumab biosimilars, including ABP 980, are in clinical development. Biosimilars are not identical to the reference biologic, but exhibit equivalence and safety in analytical and clinical studies. Areas covered: A brief introduction to trastuzumab, overview of trastuzumab biosimilars, and detailed review of ABP 980 preclinical and clinical studies are included. We searched PubMed and 2016-2017 ASCO and ESMO conference proceedings for 'ABP 980' or 'trastuzumab biosimilar'. 'ABP 980 and breast cancer' or 'trastuzumab biosimilar and breast cancer' were used to search clinicaltrials.gov for phase III trials. Analytical studies of ABP 980 pharmacokinetics (PK) or pharmacodynamics (PD), phase I studies of ABP 980 safety and PK/PD, and phase III studies of clinical efficacy vs trastuzumab are included. Expert opinion: Questions remain regarding long-term impact of biosimilars on overall healthcare costs, insurance coverage of multiple approved biosimilars, and extensive clinical safety and efficacy follow-up. By producing a competitive market, trastuzumab biosimilars are anticipated to improve access to standard of care therapies, although real-world evidence remains to be obtained. Increased global access to HER2-targeted therapy may eventually alter the landscape of breast cancer and survival rates.

Twelve-month short-term safety and visual-acuity results from a multicentre prospective study of epiretinal strontium-90 brachytherapy with bevacizumab for the treatment of subfoveal choroidal neovascularisation secondary to age-related macular degeneration.

PubMed

Avila, M P; Farah, M E; Santos, A; Duprat, J P; Woodward, B W; Nau, J

2009-03-01

This study evaluated the short-term safety and feasibility of epiretinal strontium-90 brachytherapy delivered concomitantly with intravitreal bevacizumab for the treatment of subfoveal CNV due to AMD for 12 months. A 3-year follow-up is planned. In this prospective, non-randomised, multicentre study, 34 treatment-naïve patients with predominantly classic, minimally classic and occult subfoveal CNV lesions received a single treatment with 24 Gy beta radiation (strontium-90) and two injections of the anti-VEGF antibody bevacizumab. Adverse events were observed. BCVA was measured using standard ETDRS vision charts. Twelve months after treatment, no radiation-associated adverse events were observed. In the intent-to-treat (ITT) population, 91% of patients lost <3 lines (15 ETDRS letters) of vision at 12 months, 68% improved or maintained their BCVA at 12 months, and 38% gained >/=3 lines. The mean change in BCVA observed at month 12 was a gain of 8.9 letters. The safety and efficacy of intraocular, epiretinal brachytherapy delivered concomitantly with anti-VEGF therapy for the treatment of subfoveal CNV secondary to AMD were promising in this small study population. Long-term safety will be assessed for 3 years. This regimen is being evaluated in a large, multicentre, phase III study.

Overview of phase IV clinical trials for postmarket drug safety surveillance: a status report from the ClinicalTrials.gov registry.

PubMed

Zhang, Xinji; Zhang, Yuan; Ye, Xiaofei; Guo, Xiaojing; Zhang, Tianyi; He, Jia

2016-11-23

Phase IV trials are often used to investigate drug safety after approval. However, little is known about the characteristics of contemporary phase IV clinical trials and whether these studies are of sufficient quality to advance medical knowledge in pharmacovigilance. We aimed to determine the fundamental characteristics of phase IV clinical trials that evaluated drug safety using the ClinicalTrials.gov registry data. A data set of 19 359 phase IV clinical studies registered in ClinicalTrials.gov was downloaded. The characteristics of the phase IV trials focusing on safety only were compared with those evaluating both safety and efficacy. We also compared the characteristics of the phase IV trials in three major therapeutic areas (cardiovascular diseases, mental health and oncology). Multivariable logistic regression was used to evaluate factors associated with the use of blinding and randomisation. A total of 4772 phase IV trials were identified, including 330 focusing on drug safety alone and 4392 evaluating both safety and efficacy. Most of the phase IV trials evaluating drug safety (75.9%) had enrolment <300 with 96.5% <3000. Among these trials, 8.2% were terminated or withdrawn. Factors associated with the use of blinding and randomisation included the intervention model, clinical specialty and lead sponsor. Phase IV trials evaluating drug safety in the ClinicalTrials.gov registry were dominated by small trials that might not have sufficient power to detect less common adverse events. An adequate sample size should be emphasised for phase IV trials with safety surveillance as main task. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Efficacy and safety of tofacitinib in older and younger patients with rheumatoid arthritis.

PubMed

Curtis, Jeffrey R; Schulze-Koops, Hendrik; Takiya, Liza; Mebus, Charles A; Terry, Ketti K; Biswas, Pinaki; Jones, Thomas V

2017-01-01

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We evaluated the efficacy and safety of tofacitinib 5 or 10 mg twice daily (BID), in patients with moderate to severe RA, aged ≥65 and <65 years. Data were pooled from five Phase 3 trials and, separately, from two open-label long-term extension (LTE) studies (data cut-off April, 2012). Patients received tofacitinib, or placebo (Phase 3 only), with/without conventional synthetic DMARDs (mainly methotrexate). Clinical efficacy outcomes from Phase 3 studies were evaluated at Month 3. Safety evaluations using pooled Phase 3 data (Month 12) and pooled LTE data (Month 24) compared exposure-adjusted incidence rates (IRs; with 95% confidence intervals [CIs]), in older versus younger patients. In Phase 3 and LTE studies, 15.3% (475/3111) and 16.1% (661/4102) of patients, respectively, were aged ≥65 years. Consequently, exposure to tofacitinib was lower in older versus younger patients in Phase 3 (259.2 vs. 1554.9 patient years [pt-yrs]) and LTE (962.1 vs. 5071.7 pt-yrs) studies. Probability ratios for ACR responses and HAQ-DI improvement from baseline ≥0.22 (Month 3) favoured tofacitinib and were similar in older and younger patients, with overlapping CIs. IRs for SAEs and discontinuations due to AEs were generally numerically higher in older versus younger patients, irrespective of treatment. Older patients receiving tofacitinib 5 or 10 mg BID had a similar probability of ACR20 or ACR50 response and, due to comorbidities, a numerically higher risk of SAEs and discontinuations due to AEs compared with younger patients.

An In-home Advanced Robotic System to Manage Elderly Home-care Patients' Medications: A Pilot Safety and Usability Study.

PubMed

Rantanen, Pekka; Parkkari, Timo; Leikola, Saija; Airaksinen, Marja; Lyles, Alan

2017-05-01

We examined the safety profile and usability of an integrated advanced robotic device and telecare system to promote medication adherence for elderly home-care patients. There were two phases. Phase I aimed to verify under controlled conditions in a single nursing home (n = 17 patients) that no robotic malfunctions would hinder the device's safe use. Phase II involved home-care patients from 3 sites (n = 27) who were on long-term medication. On-time dispensing and missed doses were recorded by the robotic system. Patients' and nurses' experiences were assessed with structured interviews. The 17 nursing home patients had 457 total days using the device (Phase I; mean, 26.9 per patient). On-time sachet retrieval occurred with 97.7% of the alerts, and no medication doses were missed. At baseline, Phase II home-dwelling patients reported difficulty remembering to take their medicines (23%), and 18% missed at least 2 doses per week. Most Phase II patients (78%) lived alone. The device delivered and patients retrieved medicine sachets for 99% of the alerts. All patients and 96% of nurses reported the device was easy to use. This trial demonstrated the safety profile and usability of an in-home advanced robotic device and telecare system and its acceptability to patients and nurses. It supports individualized patient dosing schedules, patient-provider communications, and on-time, in-home medication delivery to promote adherence. Real time dose-by-dose monitoring and communication with providers if a dose is missed provide oversight generally not seen in home care. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Adapting and implementing an evidence-based sun-safety education program in rural Idaho, 2012.

PubMed

Cariou, Charlene; Gonzales, Melanie; Krebill, Hope

2014-05-08

Melanoma incidence and mortality rates in Idaho are higher than national averages. The importance of increased awareness of skin cancer has been cited by state and local organizations. St. Luke's Mountain States Tumor Institute (MSTI) prioritized educational outreach efforts to focus on the implementation of a skin cancer prevention program in rural Idaho. As a community cancer center, MSTI expanded cancer education services to include dedicated support to rural communities. Through this expansion, an MSTI educator sought to partner with a community organization to provide sun-safety education. MSTI selected, adapted, and implemented an evidence-based program, Pool Cool. The education program was implemented in 5 phases. In Phase I, we identified and recruited a community partner; in Phase 2, after thorough research, we selected a program, Pool Cool; in Phase 3, we planned the details of the program, including identification of desired short- and long-term outcomes and adaptation of existing program materials; in Phase 4, we implemented the program in summer 2012; in Phase 5, we assessed program sustainability and expansion. MSTI developed a sustainable partnership with Payette Municipal Pool, and in summer 2012, we implemented Pool Cool. Sun-safety education was provided to more than 700 young people aged 2 to 17 years, and educational signage and sunscreen benefitted hundreds of additional pool patrons. Community cancer centers are increasingly being asked to assess community needs and implement evidence-based prevention and screening programs. Clinical staff may become facilitators of evidence-based public health programs. Challenges of implementing evidence-based programs in the context of a community cancer centers are staffing, leveraging of resources, and ongoing training and support.

Adapting and Implementing an Evidence-Based Sun-Safety Education Program in Rural Idaho, 2012

PubMed Central

Gonzales, Melanie; Krebill, Hope

2014-01-01

Background Melanoma incidence and mortality rates in Idaho are higher than national averages. The importance of increased awareness of skin cancer has been cited by state and local organizations. St. Luke’s Mountain States Tumor Institute (MSTI) prioritized educational outreach efforts to focus on the implementation of a skin cancer prevention program in rural Idaho. Community Context As a community cancer center, MSTI expanded cancer education services to include dedicated support to rural communities. Through this expansion, an MSTI educator sought to partner with a community organization to provide sun-safety education. MSTI selected, adapted, and implemented an evidence-based program, Pool Cool. Methods The education program was implemented in 5 phases. In Phase I, we identified and recruited a community partner; in Phase 2, after thorough research, we selected a program, Pool Cool; in Phase 3, we planned the details of the program, including identification of desired short- and long-term outcomes and adaptation of existing program materials; in Phase 4, we implemented the program in summer 2012; in Phase 5, we assessed program sustainability and expansion. Outcome MSTI developed a sustainable partnership with Payette Municipal Pool, and in summer 2012, we implemented Pool Cool. Sun-safety education was provided to more than 700 young people aged 2 to 17 years, and educational signage and sunscreen benefitted hundreds of additional pool patrons. Interpretation Community cancer centers are increasingly being asked to assess community needs and implement evidence-based prevention and screening programs. Clinical staff may become facilitators of evidence-based public health programs. Challenges of implementing evidence-based programs in the context of a community cancer centers are staffing, leveraging of resources, and ongoing training and support. PMID:24809363

Safety and long-term immunological effects of CryJ2-LAMP plasmid vaccine in Japanese red cedar atopic subjects: A phase I study.

PubMed

Su, Yan; Romeu-Bonilla, Eliezer; Anagnostou, Athanasia; Fitz-Patrick, David; Hearl, William; Heiland, Teri

2017-12-02

Japanese Red Cedar (JRC) pollen induced allergy affects one third of Japanese and the development of effective therapies remains an unachieved challenge. We designed a DNA vaccine encoding CryJ2 allergen from the JRC pollen and Lysosomal Associated Membrane Protein 1 (LAMP-1) to treat JRC allergy. These Phase IA and IB trials assessed safety and immunological effects of the investigational CryJ2-LAMP DNA vaccine in both non-sensitive and sensitive Japanese expatriates living in Honolulu, Hawaii. In the Phase IA trial, 6 JRC non-sensitive subjects and 9 JRC and/or Mountain Cedar (MC) sensitive subjects were given 4 vaccine doses (each 4mg/1ml) intramuscularly (IM) at 14-day intervals. Nine JRC and/or MC sensitive subjects were given 4 doses (2 mg/0.5 ml) IM at 14-day intervals. The safety and functional biomarkers were followed for 132 d. Following this, 17 of 24 subjects were recruited into the IB trial and received one booster dose (2 mg/0.5 ml) IM approximately 300 d after the first vaccination dose to which they were randomized in the first phase of the trial. All safety endpoints were met and all subjects tolerated CryJ2-LAMP vaccinations well. At the end of the IA trial, 10 out of 12 JRC sensitive and 6 out of 11 MC sensitive subjects experienced skin test negative conversion, possibly related to the CryJ2-LAMP vaccinations. Collectively, these data suggested that the CryJ2-LAMP DNA vaccine is safe and may be immunologically effective in treating JRC induced allergy.

[Pain patients in street traffic. Do analgesics impair driving safety?].

PubMed

Sohn, W

2003-06-05

Analgesics--in particular when self-prescribed or taken over the long term--may have a negative effect on safety on the road. This applies not only to vehicle drivers, but also to cyclists and pedestrians. Psychotropic effects of analgesics of all three WHO categories play a major causal role. Impairments may take the form of sleepiness, impaired vision, giddiness, loss of muscular tone or cardiovascular reactions. On the other hand, untreated severe pain has a high risk potential, since it may reduce both cognitive and psychomotoric performance. During the stabilization phase or dose adjustment of opioids, the patient must cautioned not to drive, and particular care must be taken in patients on concomitant or long-term medication or drinking excessive alcohol. In the last resort, the prescription of an analgesic is an individual decision involving both physician and patient.

Analysis of nuclear waste disposal in space, phase 3. Volume 1: Executive summary of technical report

NASA Technical Reports Server (NTRS)

Rice, E. E.; Miller, N. E.; Yates, K. R.; Martin, W. E.; Friedlander, A. L.

1980-01-01

The objectives, approach, assumptions, and limitations of a study of nuclear waste disposal in space are discussed with emphasis on the following: (1) payload characterization; (2) safety assessment; (3) health effects assessment; (4) long-term risk assessment; and (5) program planning support to NASA and DOE. Conclusions are presented for each task.

Interstate 80 freight corridor analysis : current freight traffic, trends and projections in special consideration of Wyoming policy-makers in planning, engineering, highway safety and enforcement.

DOT National Transportation Integrated Search

2008-12-01

"This report is the result of a two-part study intended to provide input to WYDOTs long-term planning process for the I-80 facility. The first phase of the study involved an on-the-ground freight survey of over 2,000 truckers traveling eastbound a...

Efficacy and safety of biological and targeted-synthetic DMARDs: a systematic literature review informing the 2016 update of the ASAS/EULAR recommendations for the management of axial spondyloarthritis

PubMed Central

Regel, Andrea; van der Heijde, Désirée; Braun, Jürgen; Baraliakos, Xenofon; Landewé, Robert; Van den Bosch, Filip; Falzon, Louise; Ramiro, Sofia

2017-01-01

Objectives To update the evidence for the efficacy and safety of (b)biological and (ts)targeted-synthetic disease-modifying anti-rheumatic drugs (DMARDs) in patients with axial spondyloarthritis (axSpA) to inform the 2016 update of the Assessment of SpondyloArthritis international Society/European League Against Rheumatism (ASAS/EULAR) recommendations for the management of axSpA. Methods Systematic literature review (2009–2016) for randomised controlled trials (RCT), including long-term extensions, strategy trials and observational studies (the latter was only for safety assessment and a comparator was required). Interventions were any bDMARD or tsDMARD. All relevant efficacy and safety outcomes were included. Results 76 papers and 24 abstracts fulfilled the inclusion criteria. Large treatment effects were found both in radiographic axSpA (r-axSpA) and non-radiographic axSpA (nr-axSpA) for all tumour necrosis factor inhibitors (TNFi) (NNT to achieve ASAS40 response ranged between 2.6–5.2 for r-axSpA and 2.3–5.4 for nr-axSpA). For nr-axSpA, efficacy was superior for those who had objective signs of inflammation (positive C reactive protein or inflammation on MRI-SI). Secukinumab 150 mg has shown efficacy in two phase 3 RCTs (NNT to achieve ASAS40 response: 3.4 and 4.0). Ustekinumab and tofacitinib have shown positive results in phase 2/proof-of-concept trials; trials with apremilast, rituximab, interleukin (IL)-6 antagonists and abatacept have failed their primary end points. New (unknown) safety signals were not found in the trials but long-term observational safety data for TNFi are still scarce. Conclusions New evidence supports the efficacy and safety of TNFi both in r-axSpA and nr-axSpA. Secukinumab is the first drug targeting the IL-17 pathway in r-axSpA that has shown efficacy. PMID:28176964

Patient safety reporting systems: sustained quality improvement using a multidisciplinary team and "good catch" awards.

PubMed

Herzer, Kurt R; Mirrer, Meredith; Xie, Yanjun; Steppan, Jochen; Li, Matthew; Jung, Clinton; Cover, Renee; Doyle, Peter A; Mark, Lynette J

2012-08-01

Since 1999, hospitals have made substantial commitments to health care quality and patient safety through individual initiatives of executive leadership involvement in quality, investments in safety culture, education and training for medical students and residents in quality and safety, the creation of patient safety committees, and implementation of patient safety reporting systems. At the Weinberg Surgical Suite at The Johns Hopkins Hospital (Baltimore), a 16-operating-room inpatient/outpatient cancer center, a patient safety reporting process was developed to maximize the usefulness of the reports and the long-term sustainability of quality improvements arising from them. A six-phase framework was created incorporating UHC's Patient Safety Net (PSN): Identify, report, analyze, mitigate, reward, and follow up. Unique features of this process included a multidisciplinary team to review reports, mitigate hazards, educate and empower providers, recognize the identifying/reporting individuals or groups with "Good Catch" awards, and follow up to determine if quality improvements were sustained over time. Good Catch awards have been given in recognition of 29 patient safety hazards identified since 2008; in each of these cases, an initiative was developed to mitigate the original hazard. Twenty-five (86%) of the associated quality improvements have been sustained. Two Good Catch award-winning projects--vials of heparin with an unusually high concentration of the drug that posed a potential overdose hazard and a rapid infusion device that resisted practitioner control--are described in detail. A multidisciplinary team's analysis and mitigation of hazards identified in a patient safety reporting process entailed positive recognition with a Good Catch award, education of practitioners, and long-term follow-up.

Tofacitinib, an Oral Janus Kinase Inhibitor: Pooled Efficacy and Safety Analyses in an Australian Rheumatoid Arthritis Population.

PubMed

Hall, Stephen; Nash, Peter; Rischmueller, Maureen; Bossingham, David; Bird, Paul; Cook, Nicola; Witcombe, David; Soma, Koshika; Kwok, Kenneth; Thirunavukkarasu, Krishan

2018-06-11

In Australia, there is an unmet need for improved treatments for rheumatoid arthritis (RA). Tofacitinib is an oral Janus kinase inhibitor for the treatment of RA. To provide an overview of key study outcomes for tofacitinib in Australian patients, we analyzed the efficacy and safety of tofacitinib in the Australian subpopulation of global RA phase III and long-term extension (LTE) studies. Data were pooled from the Australian subpopulation of four phase III studies and one LTE study (database not locked at cut-off date: January 2016). Patients in the phase III studies received tofacitinib 5 or 10 mg twice daily (BID), placebo (advancing to tofacitinib at months 3 or 6), or adalimumab, with background methotrexate or conventional synthetic disease-modifying antirheumatic drugs. Patients in the LTE study received tofacitinib 5 or 10 mg BID. Efficacy endpoints were American College of Rheumatology (ACR) 20/50/70 response rates, and change from baseline in the Disease Activity Score in 28 joints, erythrocyte sedimentation rate [DAS28-4(ESR)] and Health Assessment Questionnaire-Disability Index (HAQ-DI) scores. Safety endpoints included incidence of adverse events (AEs), serious AEs, and discontinuations due to AEs. AEs of special interest and laboratory parameters were analyzed in the LTE study. Across phase III studies (N = 100), ACR response rates and improvements in DAS28-4(ESR) and HAQ-DI scores were numerically greater with tofacitinib vs. placebo at month 3, and increased until month 12. The results were sustained in the LTE study (N = 99) after 60 months' observation. In general, the efficacy and safety profiles of tofacitinib were similar to those of the global RA population. In Australian patients with RA, tofacitinib therapy demonstrated sustained efficacy and consistent safety over ≥ 60 months' treatment. Pfizer Inc. TRIAL REGISTRATION NUMBERS (ALL CLINICALTRIALS.GOV): NCT00960440; NCT00847613; NCT00856544; NCT00853385; NCT00413699.

Pharmacotherapies for Obesity: Past, Current, and Future Therapies

PubMed Central

Ioannides-Demos, Lisa L.; Piccenna, Loretta; McNeil, John J.

2011-01-01

Past therapies for the treatment of obesity have typically involved pharmacological agents usually in combination with a calorie-controlled diet. This paper reviews the efficacy and safety of pharmacotherapies for obesity focusing on drugs approved for long-term therapy (orlistat), drugs approved for short-term use (amfepramone [diethylpropion], phentermine), recently withdrawn therapies (rimonabant, sibutamine) and drugs evaluated in Phase III studies (taranabant, pramlintide, lorcaserin and tesofensine and combination therapies of topiramate plus phentermine, bupropion plus naltrexone, and bupropion plus zonisamide). No current pharmacotherapy possesses the efficacy needed to produce substantial weight loss in morbidly obese patients. Meta-analyses support a significant though modest loss in bodyweight with a mean weight difference of 4.7 kg (95% CI 4.1 to 5.3 kg) for rimonabant, 4.2 kg (95% CI 3.6 to 4.8 kg) for sibutramine and 2.9 kg (95% CI 2.5 to 3.2 kg) for orlistat compared to placebo at ≥12 months. Of the Phase III pharmacotherapies, lorcaserin, taranabant, topiramate and bupropion with naltrexone have demonstrated significant weight loss compared to placebo at ≥12 months. Some pharmacotherapies have also demonstrated clinical benefits. Further studies are required in some populations such as younger and older people whilst the long term safety continues to be a major consideration and has led to the withdrawal of several drugs. PMID:21197148

A Two-Phase Pilot Study to Evaluate the Safety and Tolerability of an In Situ Polymerizing Collagen.

PubMed

Inglefield, Christopher; Rone-McCrate, Rebecca; Brooks, Robert; Zhu, Jiaxun; Grant, Sheila; DeVore, Dale P

2017-09-01

Demand for collagen-based fillers has declined primarily because of limited long-term clinical benefit and the introduction of hyaluronic acid compositions. In situ polymerizing collagen is a noncrosslinked solution of porcine collagen containing a collagenase shield that undergoes fibrillogenesis on injected into tissues forming a natural matrix. Conduct a prospective, single-center, dual-phase open-label study in 8 subjects to evaluate the safety, tolerability, and efficacy of the porcine collagen composition. In Phase I, potential hypersensitivity of the collagen composition was evaluated after skin testing in the back (men) or forearms of subjects (women). In Phase II, subjects showing no signs of hypersensitivity received collagen injections into the nasolabial area followed by evaluation at 1, 4, 8, and 12 weeks using the Global Aesthetic Improvement Scale. None of the subjects had signs of hypersensitivity and all continued in Phase II. The treating physician(s) reported no post-treatment adverse events. Improvement of the nasolabial fold was observed by the physicians and confirmed by assessment of high-resolution photographs and Global Aesthetic Improvement Scale scores over the 12-week treatment were maintained. In this pilot clinical study in situ polymerizing collagen was shown to be safe and effective throughout the 3-month study period.

Clinical feasibility of interactive motion-controlled games for stroke rehabilitation.

PubMed

Bower, Kelly J; Louie, Julie; Landesrocha, Yoseph; Seedy, Paul; Gorelik, Alexandra; Bernhardt, Julie

2015-08-02

Active gaming technologies, including the Nintendo Wii and Xbox Kinect, have become increasingly popular for use in stroke rehabilitation. However, these systems are not specifically designed for this purpose and have limitations. The aim of this study was to investigate the feasibility of using a suite of motion-controlled games in individuals with stroke undergoing rehabilitation. Four games, which utilised a depth-sensing camera (PrimeSense), were developed and tested. The games could be played in a seated or standing position. Three games were controlled by movement of the torso and one by upper limb movement. Phase 1 involved consecutive recruitment of 40 individuals with stroke who were able to sit unsupported. Participants were randomly assigned to trial one game during a single session. Sixteen individuals from Phase 1 were recruited to Phase 2. These participants were randomly assigned to an intervention or control group. Intervention participants performed an additional eight sessions over four weeks using all four game activities. Feasibility was assessed by examining recruitment, adherence, acceptability and safety in both phases of the study. Forty individuals (mean age 63 years) completed Phase 1, with an average session time of 34 min. The majority of Phase 1 participants reported the session to be enjoyable (93 %), helpful (80 %) and something they would like to include in their therapy (88 %). Sixteen individuals (mean age 61 years) took part in Phase 2, with an average of seven 26-min sessions over four weeks. Reported acceptability was high for the intervention group and improvements over time were seen in several functional outcome measures. There were no serious adverse safety events reported in either phase of the study; however, a number of participants reported minor increases in pain. A post-stroke intervention using interactive motion-controlled games shows promise as a feasible and potentially effective treatment approach. This paper presents important recommendations for future game development and research to further explore long-term adherence, acceptability, safety and efficacy. Australian and New Zealand Clinical Trials Registry ( ACTRN12613000220763 ).

Long-term safety and efficacy of deferasirox (Exjade®) for up to 5 years in transfusional iron-overloaded patients with sickle cell disease

PubMed Central

Vichinsky, Elliott; Bernaudin, Françoise; Forni, Gian Luca; Gardner, Renee; Hassell, Kathryn; Heeney, Matthew M; Inusa, Baba; Kutlar, Abdullah; Lane, Peter; Mathias, Liesl; Porter, John; Tebbi, Cameron; Wilson, Felicia; Griffel, Louis; Deng, Wei; Giannone, Vanessa; Coates, Thomas

2011-01-01

To date, there is a lack of long-term safety and efficacy data for iron chelation therapy in transfusion-dependent patients with sickle cell disease (SCD). To evaluate the long-term safety and efficacy of deferasirox (a once-daily oral iron chelator), patients with SCD completing a 1-year, Phase II, randomized, deferoxamine (DFO)-controlled study entered a 4-year extension, continuing to receive deferasirox, or switching from DFO to deferasirox. Average actual deferasirox dose was 19·4 ± 6·3 mg/kg per d. Of 185 patients who received at least one deferasirox dose, 33·5% completed the 5-year study. The most common reasons for discontinuation were withdrawal of consent (23·8%), lost to follow-up (9·2%) and adverse events (AEs) (7·6%). Investigator-assessed drug-related AEs were predominantly gastrointestinal [including nausea (14·6%), diarrhoea (10·8%)], mild-to-moderate and transient in nature. Creatinine clearance remained within the normal range throughout the study. Despite conservative initial dosing, serum ferritin levels in patients with ≥4 years deferasirox exposure significantly decreased by −591 μg/l (95% confidence intervals, −1411, −280 μg/l; P=0·027; n=67). Long-term deferasirox treatment for up to 5 years had a clinically acceptable safety profile, including maintenance of normal renal function, in patients with SCD. Iron burden was substantially reduced with appropriate dosing in patients treated for at least 4 years. PMID:21592110

Long-term safety and efficacy of deferasirox (Exjade) for up to 5 years in transfusional iron-overloaded patients with sickle cell disease.

PubMed

Vichinsky, Elliott; Bernaudin, Françoise; Forni, Gian Luca; Gardner, Renee; Hassell, Kathryn; Heeney, Matthew M; Inusa, Baba; Kutlar, Abdullah; Lane, Peter; Mathias, Liesl; Porter, John; Tebbi, Cameron; Wilson, Felicia; Griffel, Louis; Deng, Wei; Giannone, Vanessa; Coates, Thomas

2011-08-01

To date, there is a lack of long-term safety and efficacy data for iron chelation therapy in transfusion-dependent patients with sickle cell disease (SCD). To evaluate the long-term safety and efficacy of deferasirox (a once-daily oral iron chelator), patients with SCD completing a 1-year, Phase II, randomized, deferoxamine (DFO)-controlled study entered a 4-year extension, continuing to receive deferasirox, or switching from DFO to deferasirox. Average actual deferasirox dose was 19·4 ± 6·3 mg/kg per d. Of 185 patients who received at least one deferasirox dose, 33·5% completed the 5-year study. The most common reasons for discontinuation were withdrawal of consent (23·8%), lost to follow-up (9·2%) and adverse events (AEs) (7·6%). Investigator-assessed drug-related AEs were predominantly gastrointestinal [including nausea (14·6%), diarrhoea (10·8%)], mild-to-moderate and transient in nature. Creatinine clearance remained within the normal range throughout the study. Despite conservative initial dosing, serum ferritin levels in patients with ≥ 4 years deferasirox exposure significantly decreased by -591 μg/l (95% confidence intervals, -1411, -280 μg/l; P = 0·027; n = 67). Long-term deferasirox treatment for up to 5 years had a clinically acceptable safety profile, including maintenance of normal renal function, in patients with SCD. Iron burden was substantially reduced with appropriate dosing in patients treated for at least 4 years. © 2011 Blackwell Publishing Ltd.

Long-term safety of crisaborole ointment 2% in children and adults with mild to moderate atopic dermatitis.

PubMed

Eichenfield, Lawrence F; Call, Robert S; Forsha, Douglass W; Fowler, Joseph; Hebert, Adelaide A; Spellman, Mary; Stein Gold, Linda F; Van Syoc, Merrie; Zane, Lee T; Tschen, Eduardo

2017-10-01

Long-term topical treatment is often required for atopic dermatitis (AD), a chronic inflammatory skin disease. To assess the long-term safety results from a multicenter, open-label, 48-week safety study (AD-303) of patients (N = 517) ≥2 years of age with mild to moderate AD who continued crisaborole treatment, a topical phosphodiesterase-4 inhibitor, after completing a 28-day phase 3 pivotal study (AD-301, AD-302). Global disease severity was assessed in patients every 4 weeks, and if assessed as mild or greater, a 28-day treatment period with crisaborole applied twice daily was initiated. Adverse events (AEs), including treatment-emergent AEs (TEAEs), and serious AEs were analyzed. During the pivotal studies and AD-303, 65% of patients reported ≥1 TEAE, most of which were mild (51.2%) or moderate (44.6%) and considered unrelated to treatment (93.1%). The frequency and severity of TEAEs were consistent. The most frequently reported treatment-related AEs (overall, 10.2%) were dermatitis atopic (3.1%), application-site pain (2.3%), and application-site infection (1.2%). Nine patients (1.7%) discontinued the long-term study because of TEAEs. Long-term efficacy was not analyzed. Crisaborole ointment had a low frequency of treatment-related AEs over 48 weeks of treatment of patients with AD. Copyright © 2017 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

Dose-ranging phase 1 study of TMC120, a promising vaginal microbicide, in HIV-negative and HIV-positive female volunteers.

PubMed

Jespers, Vicky A; Van Roey, Jens M; Beets, Greet I; Buvé, Anne M

2007-02-01

To evaluate the short-term safety, tolerability, and systemic exposure of a vaginal microbicide gel containing the nonnucleoside reverse transcriptase inhibitor TMC120. Randomized, controlled, double-blind, phase 1 trial of a gel containing 3 different concentrations of TMC120 versus placebo. Of the 48 HIV-negative and 16 HIV-positive women enrolled, 52 women received active product. Participants applied the gel twice daily for 7 days and were assessed on 6 occasions. Colposcopic evaluation was performed before and after first gel application and on day 8. Laboratory safety assessments were carried out on all visits except day 7. Plasma levels of TMC120 were measured on days 1 and 7. All TMC120 concentrations were well tolerated, and there were no apparent differences in safety parameters. Four women (6%) had treatment-emergent mild cervical findings (petechiae in 3 women and erythema in 1 woman) of <5 mm. Plasma levels of TMC120 were quantifiable on day 1 in 7 (13%) participants and on day 7 in 39 (75%) participants using TMC120 gel. The TMC120 vaginal gel was well-tolerated in this short study by HIV-negative and HIV-positive women. The implications of the absorption of TMC120 should be studied further in expanded safety and effectiveness trials.

Moon manned missions radiation safety analysis

NASA Astrophysics Data System (ADS)

Tripathi, R. K.; Wilson, J. W.; de Anlelis, G.; Badavi, F. F.

An analysis is performed on the radiation environment found on the surface of the Moon, and applied to different possible lunar base mission scenarios. An optimization technique has been used to obtain mission scenarios minimizing the astronaut radiation exposure and at the same time controlling the effect of shielding, in terms of mass addition and material choice, as a mission cost driver. The optimization process has been realized through minimization of mass along all phases of a mission scenario, in terms of time frame (dates, transfer time length and trajectory, radiation environment), equipment (vehicles, in terms of shape, volume, onboard material choice, size and structure), location (if in space, on the surface, inside or outside a certain habitats), crew characteristics (number, gender, age, tasks) and performance required (spacecraft and habitat volumes), radiation exposure annual and career limit constraint (from NCRP 132), and implementation of the ALARA principle (shelter from the occurrence of Solar Particle Events). On the lunar surface the most important contribution to radiation exposure is given by background Galactic Cosmic Rays (GCR) particles, mostly protons, alpha particles, and some heavy ions, and by locally induced particles, mostly neutrons, created by the interaction between GCR and surface material and emerging from below the surface due to backscattering processes. In this environment manned habitats are to host future crews involved in the construction and/or in the utilization of moon based infrastructure. Three different kinds of lunar missions are considered in the analysis, Moon Base Construction Phase, during which astronauts are on the surface just to build an outpost for future resident crews, Moon Base Outpost Phase, during which astronaut crews are resident but continuing exploration and installation activities, and Moon Base Routine Phase, with long-term shifting resident crews. In each scenario various kinds of habitats, from very simple shelters to more complex bases, are considered in full detail (e.g., shape, thickness, materials, etc) with considerations of various shielding strategies. In this first analysis all the shape considered are cylindrical or composed of combination of cylinders. Moreover, a radiation safety analysis of more future possible habitats like lava tubes has been also performed.

Laser-based firing systems for prompt initiation of secondary explosives

NASA Technical Reports Server (NTRS)

Meeks, Kent D.; Setchell, Robert E.

1993-01-01

Motivated by issues of weapon safety and security, laser based firing systems for promptly initiating secondary explosives have been under active development at Sandia National Laboratories for more than four years. Such a firing system consists of miniaturized, Q-switched, solid-state laser, optical detonators, optical safety switches, and elements for splitting, coupling, and transmitting the laser output. Potential system applications pose significant challenges in terms of server mechanical and thermal environments and packaging constraints, while requiring clear demonstration of safety enhancements. The Direct Optical Initiation (DOI) Program at Sandia is addressing these challenges through progress development phases during which the design, fabrication, and testing of prototype hardware is aimed at more difficult application requirements. A brief history of the development program, and a summary of current and planned activities, will be presented.

Model Transformation for a System of Systems Dependability Safety Case

NASA Technical Reports Server (NTRS)

Murphy, Judy; Driskell, Steve

2011-01-01

The presentation reviews the dependability and safety effort of NASA's Independent Verification and Validation Facility. Topics include: safety engineering process, applications to non-space environment, Phase I overview, process creation, sample SRM artifact, Phase I end result, Phase II model transformation, fault management, and applying Phase II to individual projects.

Comprehensive long-term efficacy and safety of recombinant human alpha-mannosidase (velmanase alfa) treatment in patients with alpha-mannosidosis.

PubMed

Lund, Allan M; Borgwardt, Line; Cattaneo, Federica; Ardigò, Diego; Geraci, Silvia; Gil-Campos, Mercedes; De Meirleir, Linda; Laroche, Cécile; Dolhem, Philippe; Cole, Duncan; Tylki-Szymanska, Anna; Lopez-Rodriguez, Monica; Guillén-Navarro, Encarna; Dali, Christine I; Héron, Bénédicte; Fogh, Jens; Muschol, Nicole; Phillips, Dawn; Van den Hout, J M Hannerieke; Jones, Simon A; Amraoui, Yasmina; Harmatz, Paul; Guffon, Nathalie

2018-05-03

Long-term outcome data provide important insights into the clinical utility of enzyme replacement therapies. Such data are presented for velmanase alfa in the treatment of alpha-mannosidosis (AM). Patient data (n = 33; 14 adults, 19 paediatric) from the clinical development programme for velmanase alfa were integrated in this prospectively-designed analysis of long-term efficacy and safety. Patients who participated in the phase I/II or phase III trials and were continuing to receive treatment after completion of the trials were invited to participate in a comprehensive evaluation visit to assess long-term outcomes. Primary endpoints were changes in serum oligosaccharide and the 3-minute stair climb test (3MSCT). Mean (SD) treatment exposure was 29.3 (15.2) months. Serum oligosaccharide levels were significantly reduced in the overall population at 12 months (mean change: -72.7%, P < 0.001) and remained statistically significant at last observation (-62.8%, P < 0.001). A mean improvement of +9.3% in 3MSCT was observed at 12 months (P = 0.013), which also remained statistically significant at last observation (+13.8%, P = 0.004), with a more pronounced improvement detected in the paediatric subgroup. No treatment-emergent adverse events were reported leading to permanent treatment discontinuation. Patients treated with velmanase alfa experienced improvements in biochemical and functional measures that were maintained for up to 4 years. Long term follow-up is important and further supports the use of velmanase alfa as an effective and well-tolerated treatment for AM. Based on the currently available data set, no baseline characteristic can be predictive of treatment outcome. Early treatment during paediatric age showed better outcome in functional endpoints.

Technology demonstrator program for Space Station Environmental Control Life Support System

NASA Technical Reports Server (NTRS)

Adams, Alan M.; Platt, Gordon K.; Claunch, William C.; Humphries, William R.

1987-01-01

The main objectives and requirements of the NASA/Marshall Space Flight Center Technology Demonstration Program are discussed. The program consists of a comparative test and a 90-day manned system test to evaluate an Environmental Control and Life Support System (ECLSS). In the comparative test phase, 14 types of subsystems which perform oxygen and water reclamation functions are to be examined in terms of performance maintenance/service requirements, reliability, and safety. The manned chamber testing phase involves a four person crew using a partial ECLSS for 90 days. The schedule for the program and the program hardware requirements are described.

Firefighting Agent Research, Phase I

DTIC Science & Technology

2007-04-01

a variety of new challenges in terms of safety and environmental properties that were not considered historically in the development of new agents...systems continued to use protein foams because of low cost. These foams relied on hydrolyzed meat packing wastes (horns, hooves and blood) to... analogue . This illustrates how relatively poor parameters, such as those found in the MM2 force field, can produce qualitatively incorrect results

Use of asenapine as add-on therapy in the treatment of bipolar disorder: a comprehensive review and case series.

PubMed

Dell'Osso, Bernardo; Cremaschi, Laura; Palazzo, Maria Carlotta; Spagnolin, Gregorio; Cattaneo, Alma; Grancini, Benedetta; Maggi, Matteo; Altamura, Alfredo Carlo

2014-09-01

Several randomized controlled trials (RCTs), conducted in schizophrenic and bipolar patients, have documented the efficacy and tolerability of asenapine as monotherapy both for short- and long-term treatment. However, evidence on its augmentative use is more limited and related to the manic/mixed phase of bipolar disorder (BD). The present article reviews augmentative asenapine efficacy and safety/tolerability in the treatment of BD. It also includes some original cases of bipolar patients treated with add-on asenapine in the short- and long-term. To date, only a single RCT with manic/mixed patients with partial response to mood-stabilizer monotherapy supports the efficacy and safety/tolerability of augmentative asenapine to lithium/valproate, both in acute and long-term treatment. Additionally, two case reports confirm the overall effectiveness of augmentative asenapine to clozapine and valproate. Our case series, consisting of 4 bipolar patients treated with adjunctive asenapine to mood stabilizers and atypical antipsychotics - with treatment duration ranging from 1 to 14 months - provided clinical results that are consistent with literature data. Taken as a whole, available evidence seems to support the efficacy and safety of adjunctive asenapine in bipolar patients, though additional studies with active comparators are requested to confirm the current body of evidence.

Systematic Evaluation Program (SEP) at Rocky Flats Plant: An overview of practical management issues for evaluation of natural phenomena hazards

DOE Office of Scientific and Technical Information (OSTI.GOV)

Badwan, F.M.; Herring, K.S.

1993-08-01

Many of the buildings at the Rocky Flats Plant were designed and built before modern standards were developed, including standards for protection against extreme natural phenomenon such as tornadoes, earthquakes, and floods. The purpose of the SEP is to establish an integrated approach to assessing the design adequacy of specific high and moderate hazard Rocky Flats facilities from a safety perspective and to establish a basis for defining any needed facility improvements. The SEP is to be carried out in three Phases. In Phase 1, topics to be evaluated and an evaluation plan for each topic were developed. Any differencesmore » between Current Design Requirements (CDR) or acceptance criteria and the design of existing facilities, will be identified during Phase 2 and assessed using an integrated systematic approach during Phase 3. The integrated assessment performed during Phase 3 provides a process for evaluating the differences between existing facility design and CDRs so that decisions on corrective actions can be made on the basis of relative risk reduction and cost effectiveness. These efforts will ensure that a balanced and integrated level of safety is achieved for long-term operation of these buildings. Through appropriate selection of topics and identification of the structures, systems, and components to be evaluated, the SEP will address outstanding design issues related to the prevention and mitigation of design basis accidents, including those arising from natural phenomena. The objective of the SEP is not to bring these buildings into strict compliance with current requirements, but rather to ensure that an adequate level of safety is achieved in an economical fashion.« less

Long-term safety of tofacitinib for the treatment of rheumatoid arthritis up to 8.5 years: integrated analysis of data from the global clinical trials

PubMed Central

Cohen, Stanley B; Tanaka, Yoshiya; Mariette, Xavier; Curtis, Jeffrey R; Lee, Eun Bong; Nash, Peter; Winthrop, Kevin L; Charles-Schoeman, Christina; Thirunavukkarasu, Krishan; DeMasi, Ryan; Geier, Jamie; Kwok, Kenneth; Wang, Lisy; Riese, Richard; Wollenhaupt, Jürgen

2017-01-01

Objectives Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We report an integrated safety summary of tofacitinib from two phase I, nine phase II, six phase III and two long-term extension studies in adult patients with active RA. Methods Data were pooled for all tofacitinib-treated patients (data cut-off: 31 March 2015). Incidence rates (IRs; patients with event/100 patient-years) and 95% CIs are reported for adverse events (AEs) of interest. Results 6194 patients received tofacitinib for a total 19 406 patient-years' exposure; median exposure was 3.4 patient-years. IR (95% CI) for serious AEs was 9.4 (9.0 to 9.9); IR for serious infections was 2.7 (2.5 to 3.0). IR for (all) herpes zoster was 3.9 (3.6 to 4.2); IR for disseminated or multidermatomal herpes zoster was 0.3 (0.2 to 0.4). IR for opportunistic infections (excluding tuberculosis) was 0.3 (0.2 to 0.4) and was 0.2 (0.1 to 0.3) for tuberculosis. IR for malignancies (excluding non-melanoma skin cancer (NMSC)) was 0.9 (0.8 to 1.0); NMSC IR was 0.6 (0.5 to 0.7). IR for gastrointestinal perforations was 0.1 (0.1 to 0.2). Analysis of IR for serious infections, herpes zoster and malignancies by 6-month intervals did not reveal any notable increase in IR with longer-duration tofacitinib exposure. Conclusion This analysis of tofacitinib exposure up to 8.5 years allowed estimation of safety events with improved precision versus previous tofacitinib reports. AEs were generally stable over time; no new safety signals were observed compared with previous tofacitinib reports. Trial registration numbers NCT01262118, NCT01484561, NCT00147498, NCT00413660, NCT00550446, NCT00603512, NCT00687193, NCT01164579, NCT00976599, NCT01059864, NCT01359150, NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385, NCT01039688, NCT00413699, NCT00661661; Results. PMID:28143815

Imatinib mesylate in chronic myeloid leukemia: frontline treatment and long-term outcomes.

PubMed

Stagno, Fabio; Stella, Stefania; Spitaleri, Antonio; Pennisi, Maria Stella; Di Raimondo, Francesco; Vigneri, Paolo

2016-01-01

The tyrosine kinase inhibitor Imatinib Mesylate has dramatically improved the clinical outcome of chronic myeloid leukemia (CML) patients in the chronic phase of the disease, generating unprecedented rates of complete hematologic and cytogenetic responses and sustained reductions in BCR-ABL transcripts. Here, we present an overview on the efficacy and safety of Imatinib and describe the most important clinical studies employing this drug for the frontline treatment of chronic phase CML. We also discuss recent reports describing the long-term outcome of patients receiving Imatinib for their disease. The imminent availability of generic forms of Imatinib coupled with the approval of expensive second-generation tyrosine kinase inhibitors underlines an unmet need for early molecular parameters that may distinguish CML patients likely to benefit from the drug from those that should receive alternative forms of treatment.

Supporting and activating clinical governance development in Ireland: sharing our learning.

PubMed

Flynn, Maureen A; Burgess, Thora; Crowley, Philip

2015-01-01

The purpose of this paper is to present a description of the Irish national clinical governance development initiative and an evaluation of the initiative with the purpose of sharing the learning and proposing actions to activate structures and processes for quality and safety. The Quality and Patient Safety Division of the Health Service Executive established the initiative to counterbalance a possible focus on finances during the economic crisis in Ireland and bring attention to the quality of clinical care. A clinical governance framework for quality in healthcare in Ireland was developed to clearly articulate the fundamentals of clinical governance. The project plan involved three overlapping phases. The first was designing resources for practice; the second testing the implementation of the national resources in practice; and the third phase focused on gathering feedback and learning. Staff responded positively to the clinical governance framework. At a time when there are a lot of demands (measurement and scrutiny) the health services leads and responds well to focused support as they improve the quality and safety of services. Promoting the use of the term "governance for quality and safety" assisted in gaining an understanding of the more traditional term "clinical governance". The experience and outcome of the initiative informed the identification of 12 key learning points and a series of recommendations The initial evaluation was conducted at 24 months so at this stage it is not possible to assess the broader impact of the clinical governance framework beyond the action project hospitals. The single most important obligation for any health system is patient safety and improving the quality of care. The easily accessible, practical resources assisted project teams to lead changes in structures and processes within their services. This paper describes the fundamentals of the clinical governance framework which might serve as a guide for more integrative research endeavours on governance for quality and safety. Experience was gained in both the development of national guidance and their practical use in targeted action projects activating structures and processes that are a prerequisite to delivering safe quality services.

Pharmacogenomics in early-phase clinical development

PubMed Central

Burt, Tal; Dhillon, Savita

2015-01-01

Pharmacogenomics (PGx) offers the promise of utilizing genetic fingerprints to predict individual responses to drugs in terms of safety, efficacy and pharmacokinetics. Early-phase clinical trial PGx applications can identify human genome variations that are meaningful to study design, selection of participants, allocation of resources and clinical research ethics. Results can inform later-phase study design and pipeline developmental decisions. Nevertheless, our review of the clinicaltrials.gov database demonstrates that PGx is rarely used by drug developers. Of the total 323 trials that included PGx as an outcome, 80% have been conducted by academic institutions after initial regulatory approval. Barriers for the application of PGx are discussed. We propose a framework for the role of PGx in early-phase drug development and recommend PGx be universally considered in study design, result interpretation and hypothesis generation for later-phase studies, but PGx results from underpowered studies should not be used by themselves to terminate drug-development programs. PMID:23837482

Limited-scope probabilistic safety analysis for the Los Alamos Meson Physics Facility (LAMPF)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sharirli, M.; Rand, J.L.; Sasser, M.K.

1992-01-01

The reliability of instrumentation and safety systems is a major issue in the operation of accelerator facilities. A probabilistic safety analysis was performed or the key safety and instrumentation systems at the Los Alamos Meson Physics Facility (LAMPF). in Phase I of this unique study, the Personnel Safety System (PSS) and the Current Limiters (XLs) were analyzed through the use of the fault tree analyses, failure modes and effects analysis, and criticality analysis. Phase II of the program was done to update and reevaluate the safety systems after the Phase I recommendations were implemented. This paper provides a brief reviewmore » of the studies involved in Phases I and II of the program.« less

Limited-scope probabilistic safety analysis for the Los Alamos Meson Physics Facility (LAMPF)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sharirli, M.; Rand, J.L.; Sasser, M.K.

1992-12-01

The reliability of instrumentation and safety systems is a major issue in the operation of accelerator facilities. A probabilistic safety analysis was performed or the key safety and instrumentation systems at the Los Alamos Meson Physics Facility (LAMPF). in Phase I of this unique study, the Personnel Safety System (PSS) and the Current Limiters (XLs) were analyzed through the use of the fault tree analyses, failure modes and effects analysis, and criticality analysis. Phase II of the program was done to update and reevaluate the safety systems after the Phase I recommendations were implemented. This paper provides a brief reviewmore » of the studies involved in Phases I and II of the program.« less

Patient Safety Reporting Systems: Sustained Quality Improvement Using a Multidisciplinary Team and “Good Catch” Awards

PubMed Central

Herzer, Kurt R.; Mirrer, Meredith; Xie, Yanjun; Steppan, Jochen; Li, Matthew; Jung, Clinton; Cover, Renee; Doyle, Peter A.; Mark, Lynette J.

2014-01-01

Background Since 1999, hospitals have made substantial commitments to healthcare quality and patient safety through individual initiatives of executive leadership involvement in quality, investments in safety culture, education and training for medical students and residents in quality and safety, the creation of patient safety committees, and implementation of patient safety reporting systems. Cohesive quality and safety approaches have become comprehensive programs to identify and mitigate hazards that could harm patients. This article moves to the next level with an intense refocusing of attention on one of the individual components of a comprehensive program--the patient safety reporting system—with a goal of maximized usefulness of the reports and long-term sustainability of quality improvements arising from them. Methods A six-phase framework was developed to deal with patient safety hazards: identify, report, analyze, mitigate, reward, and follow up. Unique features of this process included a multidisciplinary team to review reports, mitigate hazards, educate and empower providers, recognize the identifying/reporting individuals or groups with “Good Catch” awards, and follow up to determine if quality improvements were sustained over time. Results To date, 29 patient safety hazards have gone through this process with “Good Catch” awards being granted at our institution. These awards were presented at various times over the past 4 years since the process began in 2008. Follow-up revealed that 86% of the associated quality improvements have been sustained over time since the awards were given. We present the details of two of these “Good Catch” awards: vials of heparin with an unusually high concentration of the drug that posed a potential overdose hazard and a rapid infusion device that resisted practitioner control. Conclusion A multidisciplinary team's analysis and mitigation of hazards identified in a patient safety reporting system, positive recognition with a “Good Catch” award, education of practitioners, and long-term follow-up resulted in an outcome of sustained quality improvement initiatives. PMID:22946251

IMPLEMENTATION OF DEFENSE NUCLEAR FACILITY SAFETY BOARD RECOMMENDATION 2000-2 AT WIPP

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jackson, K.; Wu, C.

2002-02-26

The Defense Nuclear Safeties Board (DNFSB) issued Recommendation 2000-2 on March 8, 2000, concerning the degrading conditions of vital safety systems, or systems important to nuclear safety, at DOE sites across the nation. The Board recommended that the DOE take action to assess the condition of its nuclear systems to ensure continued operational readiness of vital safety systems that are important for safely accomplishing the DOE's mission. To verify the readiness of vital safety systems, a two-phased approach was established. Phase I consisted of a qualitative assessment to approved criteria of the defined vital safety systems by operating contractor personnel,more » overseen by Federal field office personnel. Based on Phase I Assessment results, vital safety systems with significant deficiencies would be further assessed in Phase II, a more extensive quantitative assessment, by a contractor and Federal team, using a second set of criteria. In addition, Defense Nuclear Facility Safety Board Recommendation 2000-2 concluded that the degradation of confinement ventilation systems was of major concern, and issued a separate set of criteria to perform a Phase II Assessment on confinement ventilation systems.« less

Long-term safety and efficacy of tofogliflozin as add-on to insulin in patients with type 2 diabetes: Results from a 52-week, multicentre, randomized, double-blind, open-label extension, Phase 4 study in Japan (J-STEP/INS).

PubMed

Terauchi, Yasuo; Tamura, Masahiro; Senda, Masayuki; Gunji, Ryoji; Kaku, Kohei

2018-05-01

To evaluate the long-term safety and efficacy of tofogliflozin as an add-on treatment to insulin over 52 weeks. This 52-week, multicentre, Phase 4 study consisted of a 16-week, randomized, double-blind, placebo-controlled phase and a 36-week open label extension phase (NCT02201004). Japanese patients with type 2 diabetes mellitus, aged 20 to 75 years, with suboptimal glycaemic control (7.5%-10.5%) receiving insulin monotherapy (basal-bolus, bolus, premix [low and high] and basal) or receiving combination therapy with basal insulin and dipeptidyl peptidase-4 inhibitor were eligible for participation. Patients who received tofogliflozin throughout the study (52 weeks) were referred to as the 'tofo-tofo group' and patients who received placebo and tofogliflozin (36 weeks) were referred to as the 'pla-tofo group'. A total of 210 patients received treatment per randomization. Hypoglycaemia was the most common treatment-emergent adverse event (AE) (42.9% in the tofo-tofo group and 29.4% in the pla-tofo group). Patients reported genital infection, urinary tract infection, excessive urination and AEs related to volume depletion (2.1%, 2.1%, 7.1% and 10.0% of patients in the tofo-tofo group, and 0%, 1.5%, 2.9% and 7.4% of patients in the pla-tofo group, respectively). Mean HbA1c and body weight at baseline (mean changes ± standard error from baseline to Week 52) in the tofo-tofo and pla-tofo groups were 8.53% (-0.76% ± 0.077) and 8.40% (-0.73% ± 0.102); 68.84 kg (-1.52 kg ± 0.207) and 72.24 kg (-2.13 kg ± 0.313), respectively. This study demonstrates the safety and efficacy of tofogliflozin as add-on to insulin therapy in type 2 diabetes mellitus patients, offering a new therapeutic solution to diabetes management. © 2018 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Long‐term safety and efficacy of tofogliflozin as add‐on to insulin in patients with type 2 diabetes: Results from a 52‐week, multicentre, randomized, double‐blind, open‐label extension, Phase 4 study in Japan (J‐STEP/INS)

PubMed Central

Tamura, Masahiro; Senda, Masayuki; Gunji, Ryoji; Kaku, Kohei

2018-01-01

Aims To evaluate the long‐term safety and efficacy of tofogliflozin as an add‐on treatment to insulin over 52 weeks. Materials and methods This 52‐week, multicentre, Phase 4 study consisted of a 16‐week, randomized, double‐blind, placebo‐controlled phase and a 36‐week open label extension phase (NCT02201004). Japanese patients with type 2 diabetes mellitus, aged 20 to 75 years, with suboptimal glycaemic control (7.5%‐10.5%) receiving insulin monotherapy (basal‐bolus, bolus, premix [low and high] and basal) or receiving combination therapy with basal insulin and dipeptidyl peptidase‐4 inhibitor were eligible for participation. Patients who received tofogliflozin throughout the study (52 weeks) were referred to as the ‘tofo‐tofo group’ and patients who received placebo and tofogliflozin (36 weeks) were referred to as the ‘pla‐tofo group’. Results A total of 210 patients received treatment per randomization. Hypoglycaemia was the most common treatment‐emergent adverse event (AE) (42.9% in the tofo‐tofo group and 29.4% in the pla‐tofo group). Patients reported genital infection, urinary tract infection, excessive urination and AEs related to volume depletion (2.1%, 2.1%, 7.1% and 10.0% of patients in the tofo‐tofo group, and 0%, 1.5%, 2.9% and 7.4% of patients in the pla‐tofo group, respectively). Mean HbA1c and body weight at baseline (mean changes ± standard error from baseline to Week 52) in the tofo‐tofo and pla‐tofo groups were 8.53% (−0.76% ± 0.077) and 8.40% (−0.73% ± 0.102); 68.84 kg (−1.52 kg ± 0.207) and 72.24 kg (−2.13 kg ± 0.313), respectively. Conclusions This study demonstrates the safety and efficacy of tofogliflozin as add‐on to insulin therapy in type 2 diabetes mellitus patients, offering a new therapeutic solution to diabetes management. PMID:29316236

Fusion energy

NASA Astrophysics Data System (ADS)

1990-09-01

The main purpose of the International Thermonuclear Experimental Reactor (ITER) is to develop an experimental fusion reactor through the united efforts of many technologically advanced countries. The ITER terms of reference, issued jointly by the European Community, Japan, the USSR, and the United States, call for an integrated international design activity and constitute the basis of current activities. Joint work on ITER is carried out under the auspices of the International Atomic Energy Agency (IAEA), according to the terms of quadripartite agreement reached between the European Community, Japan, the USSR, and the United States. The site for joint technical work sessions is at the Max Planck Institute of Plasma Physics. Garching, Federal Republic of Germany. The ITER activities have two phases: a definition phase performed in 1988 and the present design phase (1989 to 1990). During the definition phase, a set of ITER technical characteristics and supporting research and development (R and D) activities were developed and reported. The present conceptual design phase of ITER lasts until the end of 1990. The objectives of this phase are to develop the design of ITER, perform a safety and environmental analysis, develop site requirements, define future R and D needs, and estimate cost, manpower, and schedule for construction and operation. A final report will be submitted at the end of 1990. This paper summarizes progress in the ITER program during the 1989 design phase.

Statewide traffic safety study phase I : review of current traffic safety research, practice, analytical procedures and databases.

DOT National Transportation Integrated Search

2005-05-01

This report synthesized the research findings of Phase I of the Statewide Traffic Safety Study of Louisiana, sponsored by the Louisiana Department of Transportation and Development. The objective of Phase I was to provide a comprehensive review of th...

RELAP5 Analysis of the Hybrid Loop-Pool Design for Sodium Cooled Fast Reactors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hongbin Zhang; Haihua Zhao; Cliff Davis

2008-06-01

An innovative hybrid loop-pool design for sodium cooled fast reactors (SFR-Hybrid) has been recently proposed. This design takes advantage of the inherent safety of a pool design and the compactness of a loop design to improve economics and safety of SFRs. In the hybrid loop-pool design, primary loops are formed by connecting the reactor outlet plenum (hot pool), intermediate heat exchangers (IHX), primary pumps and the reactor inlet plenum with pipes. The primary loops are immersed in the cold pool (buffer pool). Passive safety systems -- modular Pool Reactor Auxiliary Cooling Systems (PRACS) – are added to transfer decay heatmore » from the primary system to the buffer pool during loss of forced circulation (LOFC) transients. The primary systems and the buffer pool are thermally coupled by the PRACS, which is composed of PRACS heat exchangers (PHX), fluidic diodes and connecting pipes. Fluidic diodes are simple, passive devices that provide large flow resistance in one direction and small flow resistance in reverse direction. Direct reactor auxiliary cooling system (DRACS) heat exchangers (DHX) are immersed in the cold pool to transfer decay heat to the environment by natural circulation. To prove the design concepts, especially how the passive safety systems behave during transients such as LOFC with scram, a RELAP5-3D model for the hybrid loop-pool design was developed. The simulations were done for both steady-state and transient conditions. This paper presents the details of RELAP5-3D analysis as well as the calculated thermal response during LOFC with scram. The 250 MW thermal power conventional pool type design of GNEP’s Advanced Burner Test Reactor (ABTR) developed by Argonne National Laboratory was used as the reference reactor core and primary loop design. The reactor inlet temperature is 355 °C and the outlet temperature is 510 °C. The core design is the same as that for ABTR. The steady state buffer pool temperature is the same as the reactor inlet temperature. The peak cladding, hot pool, cold pool and reactor inlet temperatures were calculated during LOFC. The results indicate that there are two phases during LOFC transient – the initial thermal equilibration phase and the long term decay heat removal phase. The initial thermal equilibration phase occurs over a few hundred seconds, as the system adjusts from forced circulation to natural circulation flow. Subsequently, during long-term heat removal phase all temperatures evolve very slowly due to the large thermal inertia of the primary and buffer pool systems. The results clearly show that passive safety PRACS can effectively transfer decay heat from the primary system to the buffer pool by natural circulation. The DRACS system in turn can effectively transfer the decay heat to the environment.« less

Seeking Help From Police for Intimate Partner Violence: Applying a Relationship Phase Framework to the Exploration of Victims' Evolving Needs.

PubMed

Shearson, Kim M

2017-11-01

Intimate partner violence (IPV) is a pervasive social problem requiring multiple levels of intervention across sectors. Women experiencing IPV often seek assistance from police. Such help-seeking efforts are frequently perceived as problematic by both victims and police. A deeper understanding of victims' needs than is currently evident in the literature is needed to facilitate an appropriate, victim-centered police response across a diverse range of victim presentations. Applying a symbolic interactionist and feminist perspective and guided by a constructivist grounded theory approach, this qualitative study aimed to explore the application of Landenburger's model of entrapment in and recovery from violent relationships to understand victims' help-seeking needs when accessing police services. Semistructured interviews were conducted with 16 female victims residing in the culturally diverse Western metropolitan region of Melbourne, Australia. Fourteen victims participated in follow-up interviews. All victims primarily sought to stop the violence and hoped to find a powerful ally in police. Additional help-seeking needs were identified; subtle variations in victims' aspirations for safety, ego-support, and justice were found across the binding, enduring, disengaging, and recovery relationship phases. Victims progressed from focusing only on the immediate violent event during the binding phase to seeking to maintain long-term safety and exert their rights to protection and freedom from abuse in the recovery phase. While the operational response of police is dependent on level of violence and immediate concerns for victims' physical safety, victims' help-seeking aims are very much contingent upon their relationship phase and the associated strategies for managing the violence they use. In particular, this study provides insight into the needs of women in the enduring relationship phase, when factors such as diminished agency and low expectations of legal protection were found to constrain victims' help-seeking aspirations, sometimes eventuating in a cycle of chronic police intervention.

Payload Instrument Design Rules for Safe and Efficient Flight Operations

NASA Astrophysics Data System (ADS)

Montagnon, E.; Ferri, P.

2004-04-01

Payload operations are often being neglected in favour of optimisation of scientific performance of the instrument design. This has major drawbacks in terms of cost, safety, efficiency of operations and finally science return. By taking operational aspects into account in the early phases of the instrument design, with a minimum more cultural than financial or technological additional effort, many problems can be avoided or minimized, with significant benefits to be gained in the mission execution phases. This paper presents possible improvements based on the use of the telemetry and telecommand packet standard, proper sharing of autonomy functions between instrument and platform, and enhanced interface documents.

Oral Disease-Modifying Therapies for Multiple Sclerosis

PubMed Central

Kim, Woojun; Zandoná, Manuella Edler; Kim, Su-Hyun

2015-01-01

Classical multiple sclerosis (MS) treatments using first-line injectable drugs, although widely applied, remain a major concern in terms of therapeutic adherence and efficacy. New oral drugs recently approved for MS treatment represent significant advances in therapy. The oral route of administration clearly promotes patient satisfaction and increases therapeutic compliance. However, these drugs may also have safety and tolerability issues, and a thorough analysis of the risks and benefits is required. Three oral drugs have been approved by regulatory agencies for MS treatment: fingolimod, teriflunomide, and dimethyl fumarate. This article reviews the mechanisms of action, safety, and efficacy of these drugs and two other drugs that have yielded positive results in phase III trials: cladribine and laquinimod. PMID:25628732

Gonadotropin-releasing hormone antagonist in the management of prostate cancer.

PubMed

Debruyne, Frans M J

2004-01-01

Luteinizing hormone-releasing hormone (LHRH) agonist therapy to induce medical castration has become the most common form of hormonal therapy for advanced and metastatic prostate cancer. When treatment is started, LHRH agonists initially stimulate the release of LH, causing a surge in serum testosterone that can precipitate a "flare" phenomenon or worsening of disease, particularly in patients with bone metastatic disease. Gonadotropin-releasing hormone (GnRH) receptor antagonism represents a newer approach to medical castration. Abarelix is a pure GnRH receptor antagonist that is devoid of any LHRH agonist activity. Results from 1 phase II and 3 phase III clinical trials demonstrate that abarelix produces medical castration more quickly and without causing testosterone surge, as compared with LHRH agonists with or without a nonsteroidal antagonist. The safety profile in terms of adverse events is comparable between the 2 types of treatment, but the lack of testosterone surge with abarelix might confer a safety advantage by abolishing the risk of a disease flare.

A phased approach to clinical testing: criteria for progressing from Phase I to Phase II to Phase III studies.

PubMed

André, F E; Foulkes, M A

1998-01-01

The overall intent of clinical testing is to establish, in a series of phased studies, the clinical tolerance and acceptable "safety" of the candidate vaccine, as well as the type, level and persistence of the immune response after its inoculation, to a representative target population, according to a convenient administration schedule. The final stages involve the direct or indirect demonstration of protective efficacy, if possible in the population(s) for which the vaccine is intended. In addition, consistency of production must be demonstrated. At all these stages, the amount of prior information from preclinical and other studies affects and informs the objectives and design of subsequent studies. Progression from one testing phase to the next is dependent upon attaining the pre-set objectives of each series of studies. The precise objectives to be met will be decided on a case-by-case basis. The earliest assessments in humans (Phase I) involve evaluation of short-term clinical tolerance as measured by local and general reactogenicity, and gross assessments of immunogenicity, in a small number of highly selected individuals in an idealised situation. The selection of "optimal" dose and schedule are the result of further dose-ranging investigations (Phase II), involving more volunteers, with longer, more detailed follow-up assessments. It is at this stage that the accumulated evidence on its immunogenicity profile should be sufficient to assess whether or not the vaccine is worthy of further development. The next level of investigation (Phase III) aims to measure with greater precision the vaccine protective efficacy in the intended target population(s) by comparison of infection and/or disease attack rates in vaccine and placebo recipients. In consistency studies different production lots, manufactured at commercial scale, are tested to demonstrate consistency of manufacture. Additional bridging studies to establish similarity of lots at different production scales, or studies of the duration of the immunity conferred, are conducted in parallel with the progression of the studies in the different phases mentioned above. These latter types of studies are usually carried out concurrently with Phase III studies. This progression continues into the post-marketing period (Phase IV) with surveillance of long term efficacy and observational studies of possible rare adverse events to establish "safety" with more confidence. This paper examines, in general, the aims and designs of studies in each phase as an introduction to the more specific publications that follow.

Switching stable patients with schizophrenia from their oral antipsychotics to aripiprazole lauroxil: a post hoc safety analysis of the initial 12-week crossover period.

PubMed

Weiden, Peter J; Du, Yangchun; Liu, Chih-Chin; Stanford, Arielle D

2018-06-26

Switching antipsychotic medications is common in patients with schizophrenia who are experiencing persistent symptoms or tolerability issues associated with their current drug regimen. This analysis assessed the safety of switching from an oral antipsychotic to the long-acting injectable antipsychotic aripiprazole lauroxil (AL). This was a post hoc analysis of outpatients with schizophrenia who were prescribed an oral antipsychotic and who enrolled in an international, open-label, long-term (52-week) safety study of AL. The analysis focused on the first 3 injections of AL 882 mg over 12 weeks, divided into the immediate 4-week crossover period between the first and second AL injections (initiation phase) and the subsequent 8 weeks (stabilization phase). Patients were grouped by preswitch oral antipsychotic medication, and safety and clinical symptoms were assessed. In total, 190 patients had switched from one of the following oral antipsychotic medications: aripiprazole, conventional antipsychotics, risperidone/paliperidone, olanzapine, or quetiapine. The 12-week completion rate was high (92.1%) and similar across the different preswitch oral antipsychotic groups. Overall, adverse event (AE) rates experienced over 12 weeks were modest; no AEs were considered serious. The most common AEs in the initiation phase were injection site pain (5.8%), insomnia (5.8%), and akathisia (3.2%). No apparent relationship was observed between preswitch medication and early-onset AEs. Mean Positive and Negative Syndrome Scale total scores remained stable during this period across preswitch antipsychotic groups. Switching from an oral antipsychotic to AL was feasible in an outpatient setting for patients with schizophrenia, and the 12-week retention rate was favorable.

Saxagliptin for the treatment of diabetes - a focus on safety.

PubMed

Cernea, Simona; Cahn, Avivit; Raz, Itamar

2016-05-01

The safety of agents used to treat type 2 diabetes (T2D), a chronic disease requiring life-long intervention, is of particular interest. Saxagliptin is a potent and selective DPP-4 inhibitor that has emerged as a therapeutic option for T2D. Its safety was assessed in a development program of 20 phase 2/3 randomized clinical trials and in SAVOR-TIMI 53 trial that evaluated the cardiovascular outcomes. In order to capture any further safety signals, mainly in the long-term, a post-marketing safety surveillance is ongoing. This paper discusses the tolerability and safety profile of the agent, including cardiovascular, renal, pancreatic, hepatic and bone adverse events. Saxagliptin is a safe therapeutic option for patients with T2D, with low risk of hypoglycemia and good tolerability. It demonstrated cardiovascular safety (including in patients with pre-existing cardiovascular disease and/or HF) and safety with respect to all-cause mortality and adverse events of special interest. In SAVOR-TIMI53, saxagliptin was associated with an unexpected increased risk of HF hospitalization, mainly in the first 12 months; a mechanistic explanation for this has not been found. Further research needs to elucidate the effect of antidiabetic drugs on the heart, by including biomarkers and echocardiographic sub-studies within large outcome trials.

Long-term safety of human retinal progenitor cell transplantation in retinitis pigmentosa patients.

PubMed

Liu, Yong; Chen, Shao Jun; Li, Shi Ying; Qu, Ling Hui; Meng, Xiao Hong; Wang, Yi; Xu, Hai Wei; Liang, Zhi Qing; Yin, Zheng Qin

2017-09-29

Retinitis pigmentosa is a common genetic disease that causes retinal degeneration and blindness for which there is currently no curable treatment available. Vision preservation was observed in retinitis pigmentosa animal models after retinal stem cell transplantation. However, long-term safety studies and visual assessment have not been thoroughly tested in retinitis pigmentosa patients. In our pre-clinical study, purified human fetal-derived retinal progenitor cells (RPCs) were transplanted into the diseased retina of Royal College of Surgeons (RCS) rats, a model of retinal degeneration. Based on these results, we conducted a phase I clinical trial to establish the safety and tolerability of transplantation of RPCs in eight patients with advanced retinitis pigmentosa. Patients were studied for 24 months. After RPC transplantation in RCS rats, we observed moderate recovery of vision and maintenance of the outer nuclear layer thickness. Most importantly, we did not find tumor formation or immune rejection. In the retinis pigmentosa patients given RPC injections, we also did not observe immunological rejection or tumorigenesis when immunosuppressive agents were not administered. We observed a significant improvement in visual acuity (P < 0.05) in five patients and an increase in retinal sensitivity of pupillary responses in three of the eight patients between 2 and 6 months after the transplant, but this improvement did not appear by 12 months. Our study for the first time confirmed the long-term safety and feasibility of vision repair by stem cell therapy in patients blinded by retinitis pigmentosa. WHO Trial Registration, ChiCTR-TNRC-08000193 . Retrospectively registered on 5 December 2008.

Aviation Weather Information Communications Study (AWIN). Phase 1 and 2

NASA Technical Reports Server (NTRS)

Ball, J. W.; Herron, R. G.; Nozawa, E. T.; Thomas, E. A.; Witchey, R. D.

2000-01-01

This two part study examines the communication requirements to provide weather information in the cockpit as well as public and private communication systems available to address the requirements. Ongoing research projects combined with user needs for weather related information are used to identify and describe potential weather products that address decision support in three time frames: Far-Term Strategic, Near-Term Strategic and Tactical. Data requirements of these future products are identified and quantified. Communications systems and technologies available in the public as well as private sector are analyzed to identify potential solutions. Recommendations for further research identify cost, performance, and safety benefits to justify the investment. The study concludes that not all weather information has the same level of urgency to safety-of-flight and some information is more critical to one category of flight than another. Specific weather products need to be matched with communication systems with appropriate levels of reliability to support the criticality of the information. Available bandwidth for highly critical information should be preserved and dedicated to safety. Meanwhile, systems designed for in-flight-entertainment and other passenger/crew services could be used to support less critical information that is used only for planning and economic decision support.

The Development of the KSNP{sup +}, Areas of Improvements and Effects

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yang, J.Y.; Yang, J.S.; Yoon, K.S.

2004-07-01

The Korean Standard Nuclear Power Plant (KSNP) Improvement Program was launched in January 1998. The program formulated with three distinct phases to develop a new model of the KSNP{sup +} is a comprehensive program aiming at more economically competitive than its predecessors while the overall plant safety goal is not to be challenged. The first two phases have been carried out over four year period and the program now entered in its third phase of construction of commercial nuclear power plants of Shin-Kori 1 and 2 and Shin-Wolsong 1 and 2. In this paper, the description of the program focusingmore » on the areas of improvement and effects earned in terms of economic benefits are presented and major design improvements are introduced. (authors)« less

Effectiveness of high school safety belt instruction

DOT National Transportation Integrated Search

1982-12-01

The Effectiveness of High School Safety Belt Instruction was developed during a two-phased project. In Phase I, Focus Group Activities were conducted to determine whether audiovisual safety belt instructional materials assembled by the National Highw...

Immunogenicity, safety, and efficacy of abatacept administered subcutaneously with or without background methotrexate in patients with rheumatoid arthritis: results from a phase III, international, multicenter, parallel-arm, open-label study.

PubMed

Nash, Peter; Nayiager, Sauithree; Genovese, Mark C; Kivitz, Alan J; Oelke, Kurt; Ludivico, Charles; Palmer, William; Rodriguez, Cristian; Delaet, Ingrid; Elegbe, Ayanbola; Corbo, Michael

2013-05-01

To evaluate the impact of concomitant methotrexate (MTX) on subcutaneous (SC) abatacept immunogenicity, and to assess safety and efficacy. This phase III, open-label study had a 4-month short-term (ST) period and an ongoing long-term extension (LTE) period. Rheumatoid arthritis patients were stratified to receive SC abatacept (125 mg/week) with (combination) or without MTX (monotherapy), with no intravenous loading dose; patients receiving monotherapy could add MTX in the LTE period. Immunogenicity (percentage of anti-abatacept antibody-positive patients) was assessed. ST and LTE period data are reported, including efficacy through LTE month 14 and safety through LTE month 20. Ninety-six of 100 enrolled patients completed the ST period; 3.9% (combination) and 4.1% of patients (monotherapy) developed transient immunogenicity, and no patients were antibody positive at month 4. Serious adverse events (SAEs) were reported in 3.9% (combination) and 6.1% of patients (monotherapy); 5.9% (combination) and 8.2% of patients (monotherapy) experienced SC injection reactions, and all were mild in intensity. Mean 28-joint Disease Activity Score (DAS28) changes were -1.67 (95% confidence interval [95% CI] -2.06, -1.28; combination) and -1.94 (95% CI -2.46, -1.42; monotherapy) at month 4. Ninety patients entered and were treated in the LTE period; 83.3% (75 of 90) remained ongoing at month 24. One LTE-treated patient (1.1%) developed immunogenicity, 14.4% of patients experienced SAEs, and no SC injection reactions were reported. For patients entering the LTE period, mean DAS28 changes from baseline were -1.84 (95% CI -2.23, -1.34; combination) and -2.86 (95% CI -3.46, -2.27; monotherapy) at month 18. SC abatacept did not elicit immunogenicity associated with loss of safety or efficacy, either with or without MTX. Copyright © 2013 by the American College of Rheumatology.

Guideline for collection, analysis and presentation of safety data in clinical trials of vaccines in pregnant women.

PubMed

Jones, Christine E; Munoz, Flor M; Spiegel, Hans M L; Heininger, Ulrich; Zuber, Patrick L F; Edwards, Kathryn M; Lambach, Philipp; Neels, Pieter; Kohl, Katrin S; Gidudu, Jane; Hirschfeld, Steven; Oleske, James M; Khuri-Bulos, Najwa; Bauwens, Jorgen; Eckert, Linda O; Kochhar, Sonali; Bonhoeffer, Jan; Heath, Paul T

2016-12-01

Vaccination during pregnancy is increasingly being used as an effective approach for protecting both young infants and their mothers from serious infections. Drawing conclusions from published studies in this area can be difficult because of the inability to compare vaccine trial results across different studies and settings due to the heterogeneity in the definitions of terms used to assess the safety of vaccines in pregnancy and the data collected in such studies. The guidelines proposed in this document have been developed to harmonize safety data collection in all phases of clinical trials of vaccines in pregnant women and apply to data from the mother, fetus and infant. Guidelines on the prioritization of the data to be collected is also provided to allow applicability in various geographic, cultural and resource settings, including high, middle and low-income countries. Copyright © 2016. Published by Elsevier Ltd.

Guideline for collection, analysis and presentation of safety data in clinical trials of vaccines in pregnant women

PubMed Central

Jones, Christine E.; Munoz, Flor M.; Spiegel, Hans M.L.; Heininger, Ulrich; Zuber, Patrick L.F.; Edwards, Kathryn M.; Lambach, Philipp; Neels, Pieter; Kohl, Katrin S.; Gidudu, Jane; Hirschfeld, Steven; Oleske, James M.; Khuri-Bulos, Najwa; Bauwens, Jorgen; Eckert, Linda O.; Kochhar, Sonali; Bonhoeffer, Jan; Heath, Paul T.

2017-01-01

Vaccination during pregnancy is increasingly being used as an effective approach for protecting both young infants and their mothers from serious infections. Drawing conclusions from published studies in this area can be difficult because of the inability to compare vaccine trial results across different studies and settings due to the heterogeneity in the definitions of terms used to assess the safety of vaccines in pregnancy and the data collected in such studies. The guidelines proposed in this document have been developed to harmonize safety data collection in all phases of clinical trials of vaccines in pregnant women and apply to data from the mother, fetus and infant. Guidelines on the prioritization of the data to be collected is also provided to allow applicability in various geographic, cultural and resource settings, including high, middle and low-income countries. PMID:27481360

Deferasirox for managing iron overload in people with thalassaemia.

PubMed

Meerpohl, Joerg J; Antes, Gerd; Rücker, Gerta; Fleeman, Nigel; Motschall, Edith; Niemeyer, Charlotte M; Bassler, Dirk

2012-02-15

Thalassemia is a hereditary anaemia due to ineffective erythropoiesis. In particular, people with thalassaemia major develop secondary iron overload resulting from regular red blood cell transfusion. Iron chelation therapy is needed to prevent long-term complications.Both deferoxamine and deferiprone have been found to be efficacious. However, a systematic review of the effectiveness and safety of the new oral chelator deferasirox in people with thalassaemia is needed. To assess the effectiveness and safety of oral deferasirox in people with thalassaemia and secondary iron overload. We searched the Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register. We also searched MEDLINE, EMBASE, EBMR, Biosis Previews, Web of Science, Derwent Drug File, XTOXLINE and three trial registries: www.controlled-trials.com; www.clinicaltrials.gov; www.who.int./ictrp/en/. Date of the most recent searches of these databases: 24 June 2010.Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 03 November 2011. Randomised controlled trials comparing deferasirox with no therapy or placebo or with another iron chelating treatment. Two authors independently assessed risk of bias and extracted data. We contacted study authors for additional information. Four studies met the inclusion criteria.Two studies compared deferasirox to placebo or standard therapy of deferoxamine (n = 47). The placebo-controlled studies, a pharmacokinetic and a dose escalation study, showed that deferasirox leads to net iron excretion in transfusion-dependent thalassaemia patients. In these studies, safety was acceptable and further investigation in phase II and phase III trials was warranted.Two studies, one phase II study (n = 71) and one phase III study (n = 586) compared deferasirox to standard treatment with deferoxamine. Data suggest that a similar efficacy can be achieved depending on the ratio of doses of deferoxamine and deferasirox being compared; in the phase III trial, similar or superior efficacy for surrogate parameters of ferritin and liver iron concentration could only be achieved in the highly iron-overloaded subgroup at a mean ratio of 1 mg of deferasirox to 1.8 mg of deferoxamine corresponding to a mean dose of 28.2 mg/d and 51.6 mg/d respectively. Data on safety at the presumably required doses for effective chelation therapy are limited. Patient satisfaction was significantly better with deferasirox, while rate of discontinuations was similar for both drugs. Deferasirox offers an important alternative line of treatment for people with thalassaemia and secondary iron overload. Based on the available data, deferasirox does not seem to be superior to deferoxamine at the usually recommended ratio of 1 mg of deferasirox to 2 mg of deferoxamine. However, similar efficacy seems to be achievable depending on the dose and ratio of deferasirox compared to deferoxamine. Whether this will result in similar efficacy in the long run and will translate to similar benefits as has been shown for deferoxamine, needs to be confirmed. Data on safety, particularly on rare toxicities and long-term safety, are still limited.Therefore, we think that deferasirox should be offered as an alternative to all patients with thalassaemia who either show intolerance to deferoxamine or poor compliance with deferoxamine. In our opinion, data are still too limited to support the general recommendation of deferasirox as first-line treatment instead of deferoxamine. If a strong preference for deferasirox is expressed, it could be offered as first-line option to individual patients after a detailed discussion of the potential benefits and risks.

Improving traffic safety culture in Iowa : phase II.

DOT National Transportation Integrated Search

2013-07-01

Phase II of Improving Traffic Safety Culture in Iowa focuses on producing actions that will improve the traffic safety culture across the state, and involves collaboration among the three large public universities in Iowa: Iowa State University, Univ...

Safety performance of traffic phases and phase transitions in three phase traffic theory.

PubMed

Xu, Chengcheng; Liu, Pan; Wang, Wei; Li, Zhibin

2015-12-01

Crash risk prediction models were developed to link safety to various phases and phase transitions defined by the three phase traffic theory. Results of the Bayesian conditional logit analysis showed that different traffic states differed distinctly with respect to safety performance. The random-parameter logit approach was utilized to account for the heterogeneity caused by unobserved factors. The Bayesian inference approach based on the Markov Chain Monte Carlo (MCMC) method was used for the estimation of the random-parameter logit model. The proposed approach increased the prediction performance of the crash risk models as compared with the conventional logit model. The three phase traffic theory can help us better understand the mechanism of crash occurrences in various traffic states. The contributing factors to crash likelihood can be well explained by the mechanism of phase transitions. We further discovered that the free flow state can be divided into two sub-phases on the basis of safety performance, including a true free flow state in which the interactions between vehicles are minor, and a platooned traffic state in which bunched vehicles travel in successions. The results of this study suggest that a safety perspective can be added to the three phase traffic theory. The results also suggest that the heterogeneity between different traffic states should be considered when estimating the risks of crash occurrences on freeways. Copyright © 2015 Elsevier Ltd. All rights reserved.

Long-Term Safety and Efficacy of Enzyme Replacement Therapyfor Fabry Disease

PubMed Central

Wilcox, William R.; Banikazemi, Maryam; Guffon, Nathalie; Waldek, Stephen; Lee, Philip; Linthorst, Gabor E.; Desnick, Robert J.; Germain, Dominique P.

2004-01-01

Elsewhere, we reported the safety and efficacy results of a multicenter phase 3 trial of recombinant human α-galactosidase A (rh-αGalA) replacement in patients with Fabry disease. All 58 patients who were enrolled in the 20-wk phase 3 double-blind, randomized, and placebo-controlled study received subsequently 1 mg/kg of rh-αGalA (agalsidase beta, Fabrazyme, Genzyme Corporation) biweekly in an ongoing open-label extension study. Evidence of long-term efficacy, even in patients who developed IgG antibodies against rh-αGalA, included the continuously normal mean plasma globotriaosylceramide (GL-3) levels during 30 mo of the extension study and the sustained capillary endothelial GL-3 clearance in 98% (39/40) of patients who had a skin biopsy taken after treatment for 30 mo (original placebo group) or 36 mo (original enzyme-treated group). The mean serum creatinine level and estimated glomerular filtration rate also remained stable after 30–36 mo of treatment. Infusion-associated reactions decreased over time, as did anti-rh-αGalA IgG antibody titers. Among seroconverted patients, after 30–36 mo of treatment, seven patients tolerized (no detectable IgG antibody), and 59% had ⩾4-fold reductions in antibody titers. As of 30 mo into the extension trial, three patients were withdrawn from the study because of positive serum IgE or skin tests; however, all have been rechallenged successfully at the time of this report. Thus, enzyme replacement therapy for 30–36 mo with agalsidase beta resulted in continuously decreased plasma GL-3 levels, sustained endothelial GL-3 clearance, stable kidney function, and a favorable safety profile. PMID:15154115

Long-term safety and efficacy of enzyme replacement therapy for Fabry disease.

PubMed

Wilcox, William R; Banikazemi, Maryam; Guffon, Nathalie; Waldek, Stephen; Lee, Philip; Linthorst, Gabor E; Desnick, Robert J; Germain, Dominique P

2004-07-01

Elsewhere, we reported the safety and efficacy results of a multicenter phase 3 trial of recombinant human alpha -galactosidase A (rh-alpha GalA) replacement in patients with Fabry disease. All 58 patients who were enrolled in the 20-wk phase 3 double-blind, randomized, and placebo-controlled study received subsequently 1 mg/kg of rh-alpha GalA (agalsidase beta, Fabrazyme, Genzyme Corporation) biweekly in an ongoing open-label extension study. Evidence of long-term efficacy, even in patients who developed IgG antibodies against rh- alpha GalA, included the continuously normal mean plasma globotriaosylceramide (GL-3) levels during 30 mo of the extension study and the sustained capillary endothelial GL-3 clearance in 98% (39/40) of patients who had a skin biopsy taken after treatment for 30 mo (original placebo group) or 36 mo (original enzyme-treated group). The mean serum creatinine level and estimated glomerular filtration rate also remained stable after 30-36 mo of treatment. Infusion-associated reactions decreased over time, as did anti-rh- alpha GalA IgG antibody titers. Among seroconverted patients, after 30-36 mo of treatment, seven patients tolerized (no detectable IgG antibody), and 59% had > or =4-fold reductions in antibody titers. As of 30 mo into the extension trial, three patients were withdrawn from the study because of positive serum IgE or skin tests; however, all have been rechallenged successfully at the time of this report. Thus, enzyme replacement therapy for 30-36 mo with agalsidase beta resulted in continuously decreased plasma GL-3 levels, sustained endothelial GL-3 clearance, stable kidney function, and a favorable safety profile.

Long‐term effects of crizotinib in ALK‐positive tumors (excluding NSCLC): A phase 1b open‐label study

PubMed Central

Orlov, Sergey; Zhang, Li; Braiteh, Fadi; Huang, Huiqiang; Esaki, Taito; Horibe, Keizo; Ahn, Jin‐Seok; Beck, Joseph T.; Edenfield, William Jeffrey; Shi, Yuankai; Taylor, Matthew; Tamura, Kenji; Van Tine, Brian A.; Wu, Shang‐Ju; Paolini, Jolanda; Selaru, Paulina; Kim, Tae Min

2018-01-01

Abstract Crizotinib, an inhibitor of anaplastic lymphoma kinase (ALK), MET, and ROS1, is approved for treatment of patients with ALK‐positive or ROS1‐positive advanced non‐small‐cell lung cancer (NSCLC). However, ALK rearrangements are also implicated in other malignancies, including anaplastic large‐cell lymphoma and inflammatory myofibroblastic tumors (IMTs). In this ongoing, multicenter, single‐arm, open‐label phase 1b study (PROFILE 1013; NCT01121588), patients with ALK‐positive advanced malignancies other than NSCLC were to receive a starting dose of crizotinib 250 mg twice daily. Primary endpoints were safety and objective responses based on Response Evaluation Criteria in Solid Tumors version 1.1 or National Cancer Institute International Response Criteria. Forty‐four patients were enrolled (lymphoma, n = 18; IMT, n = 9; other tumors, n = 17). The objective response rate was 53% (95% confidence interval [CI], 28–77) for lymphoma, with 8 complete responses (CRs) and 1 partial response (PR); 67% (95% CI, 30–93) for IMTs, with 1 CR and 5 PRs; and 12% (95% CI, 2–36) for other tumors, with 2 PRs in patients affected by colon carcinoma and medullary thyroid cancer, respectively. The median duration of treatment was almost 3 years for patients with lymphoma and IMTs, with 2‐year progression‐free survival of 63% and 67%, respectively. The most common treatment‐related adverse events were diarrhea (45.5%) and vision disorders (45.5%), mostly grade 1. These findings indicate strong and durable activity of crizotinib in ALK‐positive lymphomas and IMTs. The safety profile was consistent with the known safety profile of crizotinib even with long‐term treatment. PMID:29352732

Comparison of solid-phase and eluate assays to gauge the ecotoxicological risk of organic wastes on soil organisms.

PubMed

Domene, Xavier; Alcañiz, Josep M; Andrés, Pilar

2008-02-01

Development of methodologies to assess the safety of reusing polluted organic wastes in soil is a priority in Europe. In this study, and coupled with chemical analysis, seven organic wastes were subjected to different aquatic and soil bioassays. Tests were carried out with solid-phase waste and three different waste eluates (water, methanol, and dichloromethane). Solid-phase assays were indicated as the most suitable for waste testing not only in terms of relevance for real situations, but also because toxicity in eluates was generally not representative of the chronic effects in solid-phase. No general correlations were found between toxicity and waste pollutant burden, neither in solid-phase nor in eluate assays, showing the inability of chemical methods to predict the ecotoxicological risks of wastes. On the contrary, several physicochemical parameters reflecting the degree of low organic matter stability in wastes were the main contributors to the acute toxicity seen in collembolans and daphnids.

Safety and tolerability of injectable lipid-lowering drugs: a review of available clinical data.

PubMed

Cicero, Arrigo F G; Tartagni, Elisa; Ertek, Sibel

2014-08-01

To answer the need of a better low-density lipoprotein (LDL) cholesterol control in statin-treated patients at high risk for cardiovascular disease, new injectable lipid-lowering drugs with innovative mechanisms of action are in advanced phase of development or have just been approved. Evolocumab and alirocumab are fully human monoclonal antibodies inhibiting the proprotein convertase subtilisin/kexin type 9 (PCSK9) that binds to hepatic LDL receptor and prevents it from normal recycling by targeting it for degradation. Mipomersen specifically binds to a segment of the human apolipoprotein B100 messenger RNA, blocking the translation of the gene product. Phase II (for evolocumab and alirocumab) and III (for evolocumab) trials show that PCSK9 inhibitors are equally well tolerated, with adverse events mainly limited to mild-to-moderate nasopharyngitis, injection-site pain, arthralgia and back pain. Mipomersen use is mainly associated to hepatosteatosis, increased transaminases (> 3 times the upper limit of normal), mild-to-moderate injection-site reactions and flu-like symptoms. PCSK9 inhibitors have demonstrated their good safety and tolerability in a large number of subjects with different clinical conditions, including statin-intolerance, enlarging their potential use in a broader range of patients. Further data on long-term mipomersen safety are required.

Effect of combination therapy with repaglinide and metformin hydrochloride on glycemic control in Japanese patients with type 2 diabetes mellitus.

PubMed

Kawamori, Ryuzo; Kaku, Kohei; Hanafusa, Toshiaki; Oikawa, Tatsuya; Kageyama, Shigeru; Hotta, Nigishi

2014-02-12

We investigated the efficacy and safety of repaglinide as an add-on therapy for Japanese patients with type 2 diabetes mellitus receiving metformin monotherapy (at a dose of 1,500 mg/day, mainly) in addition to diet and exercise. In the 16-week multicenter, placebo-controlled, randomized, double-blind, parallel-group trial (the phase III study), patients with type 2 diabetes mellitus with metformin monotherapy were randomly assigned to the repaglinide or placebo group. Thereafter, a 36-week, multicenter, uncontrolled, dose-titration method study was extended to a total duration of 52 weeks (the long-term study). The primary end-point of each study was a change in glycated hemoglobin (HbA1c) from baseline. After 16 weeks, mean reductions in HbA1c were significantly greater for the repaglinide group than for the placebo group (-0.98 ± 0.72% vs 0.13 ± 0.63%, P < 0.001). In the long-term study, the mean change in HbA1c was -0.76 ± 0.83%. The rate of adverse events was 60.6 and 50.0% in the repaglinide and placebo groups, respectively, in the phase III study, and 78.3% in the long-term study. Hypoglycemia was reported in 11.7, 0 and 13.3% of patients in the repaglinide group, placebo group and long-term study, respectively. Combination therapy with repaglinide and metformin resulted in an approximately 1% reduction in HbA1c at week 16 and in a significant long-term improvement in HbA1c at the end of the study. No safety problems were noted during the concomitant use of repaglinide and metformin. These studies were registered with JapicCTI (nos. JapicCTI-101202 and JapicCTI-101203).

Efficacy and safety of memantine in patients with moderate-to-severe Alzheimer's disease: results of a pooled analysis of two randomized, double-blind, placebo-controlled trials in Japan

PubMed Central

Nakamura, Yu; Kitamura, Shin; Homma, Akira; Shiosakai, Kazuhito; Matsui, Daiju

2014-01-01

Background: With the increase in the aging population, there is a pressing need to provide effective treatment options for individuals with Alzheimer's disease (AD). Memantine is an N-methyl-D-aspartate receptor antagonist used to treat AD in > 80 countries worldwide, and studies in the USA and Europe have shown it to be effective in improving language deficits; however, there are currently no data on language improvements in Japanese patients treated with memantine. Objectives: To clarify the efficacy and safety of memantine in Japanese outpatients with moderate to severe AD, using a pooled analysis of two multicenter randomized placebo-controlled trials, a phase 2 dose-finding study and a phase 3 study. Results: The final analysis comprised 633 patients (318 receiving memantine and 315 placebo). Memantine produced better outcomes in terms of Severe Impairment Battery-Japanese version, Clinician's Interview-Based Impression of Change plus-Japanese version, Behavioral Pathology in AD Rating Scale, and language scores, versus placebo. The overall incidence of adverse events and adverse reactions was similar between groups. Conclusion: In this pooled analysis of Japanese patients, memantine achieved better outcomes than placebo in terms of cognition, including attention, praxis, visuospatial ability and language, and behavioral and psychological symptoms, including activity disturbances and aggressiveness. PMID:24673497

Research safety vehicle program (Phase II) specification review. Volume II. Final technical report, Jul 1975--Nov 1976

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pugliese, S.M.

1977-02-01

In Phase I of the Research Safety Vehicle Program (RSV), preliminary design and performance specifications were developed for a mid-1980's vehicle that integrates crashworthiness and occupant safety features with material resource conservation, economy, and producibility. Phase II of the program focused on development of the total vehicle design via systems engineering and integration analyses. As part of this effort, it was necessary to continuously review the Phase I recommended performance specification in relation to ongoing design/test activities. This document contains the results of analyses of the Phase I specifications. The RSV is expected to satisfy all of the producibility andmore » safety related specifications, i.e., handling and stability systems, crashworthiness, occupant protection, pedestrian/cyclist protection, etc.« less

Long-term safety of tofacitinib for the treatment of rheumatoid arthritis up to 8.5 years: integrated analysis of data from the global clinical trials.

PubMed

Cohen, Stanley B; Tanaka, Yoshiya; Mariette, Xavier; Curtis, Jeffrey R; Lee, Eun Bong; Nash, Peter; Winthrop, Kevin L; Charles-Schoeman, Christina; Thirunavukkarasu, Krishan; DeMasi, Ryan; Geier, Jamie; Kwok, Kenneth; Wang, Lisy; Riese, Richard; Wollenhaupt, Jürgen

2017-07-01

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We report an integrated safety summary of tofacitinib from two phase I, nine phase II, six phase III and two long-term extension studies in adult patients with active RA. Data were pooled for all tofacitinib-treated patients (data cut-off: 31 March 2015). Incidence rates (IRs; patients with event/100 patient-years) and 95% CIs are reported for adverse events (AEs) of interest. 6194 patients received tofacitinib for a total 19 406 patient-years' exposure; median exposure was 3.4 patient-years. IR (95% CI) for serious AEs was 9.4 (9.0 to 9.9); IR for serious infections was 2.7 (2.5 to 3.0). IR for (all) herpes zoster was 3.9 (3.6 to 4.2); IR for disseminated or multidermatomal herpes zoster was 0.3 (0.2 to 0.4). IR for opportunistic infections (excluding tuberculosis) was 0.3 (0.2 to 0.4) and was 0.2 (0.1 to 0.3) for tuberculosis. IR for malignancies (excluding non-melanoma skin cancer (NMSC)) was 0.9 (0.8 to 1.0); NMSC IR was 0.6 (0.5 to 0.7). IR for gastrointestinal perforations was 0.1 (0.1 to 0.2). Analysis of IR for serious infections, herpes zoster and malignancies by 6-month intervals did not reveal any notable increase in IR with longer-duration tofacitinib exposure. This analysis of tofacitinib exposure up to 8.5 years allowed estimation of safety events with improved precision versus previous tofacitinib reports. AEs were generally stable over time; no new safety signals were observed compared with previous tofacitinib reports. NCT01262118, NCT01484561, NCT00147498, NCT00413660, NCT00550446, NCT00603512, NCT00687193, NCT01164579, NCT00976599, NCT01059864, NCT01359150, NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385, NCT01039688, NCT00413699, NCT00661661; Results. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Establishing research priorities for patient safety in emergency medicine: a multidisciplinary consensus panel.

PubMed

Plint, Amy C; Stang, Antonia S; Calder, Lisa A

2015-01-01

Patient safety in the context of emergency medicine is a relatively new field of study. To date, no broad research agenda for patient safety in emergency medicine has been established. The objective of this study was to establish patient safety-related research priorities for emergency medicine. These priorities would provide a foundation for high-quality research, important direction to both researchers and health-care funders, and an essential step in improving health-care safety and patient outcomes in the high-risk emergency department (ED) setting. A four-phase consensus procedure with a multidisciplinary expert panel was organized to identify, assess, and agree on research priorities for patient safety in emergency medicine. The 19-member panel consisted of clinicians, administrators, and researchers from adult and pediatric emergency medicine, patient safety, pharmacy, and mental health; as well as representatives from patient safety organizations. In phase 1, we developed an initial list of potential research priorities by electronically surveying a purposeful and convenience sample of patient safety experts, ED clinicians, administrators, and researchers from across North America using contact lists from multiple organizations. We used simple content analysis to remove duplication and categorize the research priorities identified by survey respondents. Our expert panel reached consensus on a final list of research priorities through an in-person meeting (phase 3) and two rounds of a modified Delphi process (phases 2 and 4). After phases 1 and 2, 66 unique research priorities were identified for expert panel review. At the end of phase 4, consensus was reached for 15 research priorities. These priorities represent four themes: (1) methods to identify patient safety issues (five priorities), (2) understanding human and environmental factors related to patient safety (four priorities), (3) the patient perspective (one priority), and (4) interventions for improving patient safety (five priorities). This study established expert, consensus-based research priorities for patient safety in emergency medicine. This framework could be used by researchers and health-care funders and represents an essential guiding step towards enhancing quality of care and patient safety in the ED.

Phase I therapeutic trial of the HIV-1 Tat protein and long term follow-up.

PubMed

Longo, Olimpia; Tripiciano, Antonella; Fiorelli, Valeria; Bellino, Stefania; Scoglio, Arianna; Collacchi, Barbara; Alvarez, Maria Josè Ruiz; Francavilla, Vittorio; Arancio, Angela; Paniccia, Giovanni; Lazzarin, Adriano; Tambussi, Giuseppe; Din, Chiara Tassan; Visintini, Raffaele; Narciso, Pasquale; Antinori, Andrea; D'Offizi, Gianpiero; Giulianelli, Marina; Carta, Maria; Di Carlo, Aldo; Palamara, Guido; Giuliani, Massimo; Laguardia, Maria Elena; Monini, Paolo; Magnani, Mauro; Ensoli, Fabrizio; Ensoli, Barbara

2009-05-26

A randomized, double blind, placebo-controlled phase I vaccine trial based on the native Tat protein was conducted in HIV-infected asymptomatic individuals. The vaccine was administered five times subcute with alum or intradermally without adjuvant at 7.5microg, 15microg or 30microg doses, respectively. The Tat vaccine was well tolerated both locally and systemically and induced and/or maintained Tat-specific T helper (Th)-1 T-cell responses and Th-2 responses in all subjects with a wide spectrum of functional anti-Tat antibodies, rarely seen in HIV-infected subjects. The data indicate the achievement of both the primary (safety) and secondary (immunogenicity) endpoints of the study.

Efficacy and safety of tadalafil 5 mg once daily in the treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia in men aged ≥75 years: integrated analyses of pooled data from multinational, randomized, placebo-controlled clinical studies.

PubMed

Oelke, Matthias; Wagg, Adrian; Takita, Yasushi; Büttner, Hartwig; Viktrup, Lars

2017-05-01

To assess efficacy and safety of tadalafil in men aged ≥75 years with lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH) and additional safety in men aged ≥75 years with erectile dysfunction (ED). We conducted an integrated analysis of 12 phase II-III randomized, double-blind and/or open-label extension studies to evaluate short-term (12-26 weeks) efficacy and short- and longer-term (42-52 weeks) safety in men aged <75 years vs men aged ≥75 years. All men received once-daily tadalafil 5 mg or placebo. The efficacy outcome was International Prostate Symptom Score (IPSS). Safety measurements included treatment-emergent adverse events (TEAEs), adverse events (AEs) leading to discontinuation, serious AEs (SAEs), and cardiovascular AEs. All analyses were intention-to-treat. Changes from baseline to efficacy endpoint and differences in changes between treatment groups were estimated as least-squares means using analysis of covariance models. Change in the mean IPSS was significantly different in men aged <75 years vs those aged ≥75 years across tadalafil and placebo groups (treatment-by-age interaction P = 0.034). Tadalafil was not statistically significantly better than placebo in men aged ≥75 years, but effect size varied between studies. Maintenance of efficacy with tadalafil was observed across age groups. Short-term tadalafil safety findings for men aged <75 vs ≥75 years included: TEAEs (52 [33.8%] vs 503 [30.1%]), AEs leading to discontinuation (3 [1.9%] vs 50 [3.0%]), SAEs (4 [2.6%] vs 15 [0.9%]) and cardiovascular AEs (4 [2.6%] vs 30 [1.8%]). Long-term tadalafil safety data did not reveal clinically relevant differences between age groups. Limitations include exclusion of men with serious co-existing conditions and limited sample sizes of men aged ≥75 years. Efficacy with once-daily tadalafil 5 mg in the treatment of LUTS/BPH differed between men aged <75 vs ≥75 years, with significant efficacy in the <75-year age group. The older age group had more concomitant diseases and used more drugs, which may have reduced efficacy. The small sample size precluded uni-/multivariate analyses to assess plausible interference from confounding factors. Tadalafil had a reassuring safety profile and no evidence of increased cardiovascular AEs in aging men. © 2016 The Authors BJU International © 2016 BJU International Published by John Wiley & Sons Ltd.

Rationale and Design of the ARREST Trial Investigating Mesenchymal Stem Cells in the Treatment of Small Abdominal Aortic Aneurysm.

PubMed

Wang, S Keisin; Green, Linden A; Gutwein, Ashley R; Drucker, Natalie A; Motaganahalli, Raghu L; Fajardo, Andres; Babbey, Clifford M; Murphy, Michael P

2018-02-01

Abdominal aortic aneurysms (AAAs) are a major source of morbidity and mortality despite continuing advances in surgical technique and care. Although the inciting factors for AAA development continue to be elusive, accumulating evidence suggests a significant periaortic inflammatory response leading to degradation and dilation of the aortic wall. Previous human trials have demonstrated safety and efficacy of mesenchymal stem cells (MSCs) in the treatment of inflammation-related pathologies such as rheumatoid arthritis, graft versus host disease, and transplant rejection. Therefore, herein, we describe the Aortic Aneurysm Repression with Mesenchymal Stem Cells (ARREST) trial, a phase I investigation into the safety of MSC infusion for patients with small AAA and the cells' effects on modulation of AAA-related inflammation. ARREST is a phase I, single-center, double-blind, randomized controlled trial (RCT) investigating infusion both dilute and concentrated MSCs compared to placebo in 36 small AAA (35-45 mm) patients. Subjects will be followed by study personnel for 12 months to ascertain incidence of adverse events, immune cell phenotype expression, peripheral cytokine profile, and periaortic inflammation. Maximum transverse aortic diameter will be assessed regularly for 5 years by a combination of computed tomography and duplex sonography. Four patients have thus far been enrolled, randomized, and treated per protocol. We anticipate the conclusion of the treatment phase within the next 24 months with ongoing long-term follow-up. ARREST will be pivotal in assessing the safety of MSC infusion and provide preliminary data on the ability of MSCs to favorably modulate the pathogenic AAA host immune response. The data gleaned from this phase I trial will provide the groundwork for a larger, phase III RCT which may provide the first pharmaceutical intervention for AAA. Copyright © 2017 Elsevier Inc. All rights reserved.

Crisaborole Ointment 2%: A Review in Mild to Moderate Atopic Dermatitis.

PubMed

Hoy, Sheridan M

2017-12-01

Crisaborole ointment 2% (Eucrisa™) is a novel, anti-inflammatory inhibitor of phosphodiesterase 4 (PDE4) that is available in the USA for the topical treatment of mild to moderate atopic dermatitis in patients aged ≥ 2 years. In two short-term (28 days), identically designed, multicentre, phase III studies in this patient population, topical therapy with crisaborole ointment 2% reduced disease severity and pruritus severity compared with vehicle, with the effect established early and sustained over the course of treatment. Improvements in the other signs of atopic dermatitis (erythema, exudation, excoriation, induration/papulation, and lichenification) were also seen. Crisaborole ointment 2% was generally well tolerated in the short-term studies, with its favorable safety profile maintained over the longer term (up to 52 weeks) in a multicentre, extension study. Most treatment-emergent adverse events (TEAEs) were of mild to moderate severity and considered unrelated to the study medication. Moreover, the incidence of application-site pain following short- and longer-term topical therapy with crisaborole ointment 2% was low. In conclusion, crisaborole ointment 2% is an effective and generally well tolerated new topical option for the management of mild to moderate atopic dermatitis in patients aged ≥ 2 years, with the potential to effectively treat this patient population over the longer term without the safety concerns associated with other current topical anti-inflammatory agents.

National Dam Safety Program. Brocton Reservoir (Inventory Number NY 785) , Lake Erie Basin, Chautauqua County, New York. Phase I Inspection Report

DTIC Science & Technology

1980-09-26

Inspection Report Brocton Reservoir National Dam Safety Program Lake Erie Basin, Chautauqua County, New York 6. PERFORMING ORG. REPORT NUMBER Inventory No...LAKE ERIE BASIN BROCTON RESERVOIR I ’CHAUTAUQUA COUNTY, NEW YORK I INVENTORY NO. N.Y. 785 PHASE I INSPECTION REPORT NATIONAL DAM SAFETY PROGRAMI. I...Drawings I I I I I I I I I I PHASE I INSPECTION REPORT NATIONAL DAM SAFETY PROGRAIM NAME OF DAM: Brocton Reservoir Inventory No. N.Y. 785 I STATE LOCATED

Fingolimod in relapsing multiple sclerosis: An integrated analysis of safety findings.

PubMed

Kappos, Ludwig; Cohen, Jeffrey; Collins, William; de Vera, Ana; Zhang-Auberson, Lixin; Ritter, Shannon; von Rosenstiel, Philipp; Francis, Gordon

2014-07-01

Fingolimod 0.5mg once daily is the first approved oral therapy for relapsing multiple sclerosis (MS). To report integrated long-term safety data from phase 2/3 fingolimod studies. Descriptive safety data are reported from the FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis (FREEDOMS) study, a 24-month, randomized, double-blind study comparing fingolimod 0.5mg and 1.25mg with placebo, and an All Studies group (patients who received fingolimod 0.5mg (n=1640) or 1.25-0.5mg (n=1776) in phase 2/3 studies and associated extensions). Relevant post-marketing experience, up to December 2011, is included. The incidence of adverse events (AEs) and serious AEs (SAEs) was similar with fingolimod and placebo in FREEDOMS. In the All Studies group, fingolimod 0.5mg was associated with transient, rarely symptomatic (0.5%), bradycardia and second-degree atrioventricular block on treatment initiation, minor blood pressure increases, frequent (9%) but generally asymptomatic liver enzyme elevations, and macular oedema (0.4%). The incidences of infections (including serious and herpes infections), malignancies, SAEs and treatment discontinuations due to AEs were similar with fingolimod 0.5mg and placebo. The safety profile of fingolimod has been well characterized in this large combined trial population. Although infrequent SAEs can occur, there is no increased risk of infections, malignancies or serious cardiovascular events versus placebo. Copyright © 2014. Published by Elsevier B.V.

Pre-Exposure Prophylaxis for HIV Prevention: Safety Concerns.

PubMed

Tetteh, Raymond A; Yankey, Barbara A; Nartey, Edmund T; Lartey, Margaret; Leufkens, Hubert G M; Dodoo, Alexander N O

2017-04-01

Available evidence supports the efficacy of pre-exposure prophylaxis (PrEP) in decreasing the incidence of human immunodeficiency virus (HIV) infection among high-risk individuals, especially when used in combination with other behavioural preventive methods. Safety concerns about PrEP present challenges in the implementation and use of PrEP. The aim of this review is to discuss safety concerns observed in completed clinical trials on the use of PrEP. We performed a literature search on PrEP in PubMed, global advocacy for HIV prevention (Aids Vaccine Advocacy Coalition) database, clinical trials registry " http://www.clinicaltrials.gov " and scholar.google, using combination search terms 'pre-exposure prophylaxis', 'safety concerns in the use of pre-exposure prophylaxis', 'truvada use as PrEP', 'guidelines for PrEP use', 'HIV pre-exposure prophylaxis' and 'tenofovir' to identify clinical trials and literature on PrEP. We present findings associated with safety issues on the use of PrEP based on a review of 11 clinical trials on PrEP with results on safety and efficacy as at April 2016. We also reviewed findings from routine real-life practice reports. The pharmacological intervention for PrEP was tenofovir disoproxil fumarate/emtricitabine in a combined form as Truvada ® or tenofovir as a single entity. Both products are efficacious for PrEP and seem to have a good safety profile. Regular monitoring is recommended to prevent long-term toxic effects. The main adverse effects observed with PrEP are gastrointestinal related; basically mild to moderate nausea, vomiting and diarrhea. Other adverse drug effects worth monitoring are liver enzymes, renal function and bone mineral density. PrEP as an intervention to reduce HIV transmission appears to have a safe benefit-risk profile in clinical trials. It is recommended for widespread use but adherence monitoring and real-world safety surveillance are critical in the post-marketing phase to ensure that the benefits observed in clinical trials are maintained in real-world use.

GB-InSAR monitoring and observational method for landslide emergency management: the Montaguto earthflow (AV, Italy)

NASA Astrophysics Data System (ADS)

Ferrigno, Federica; Gigli, Giovanni; Fanti, Riccardo; Intrieri, Emanuele; Casagli, Nicola

2017-06-01

On 10 March 2010, because of the heavy rainfall in the preceding days, the Montaguto landslide (Southern Italy) reactivated, affecting both state road 90 Delle Puglie and the Rome-Bari railway. A similar event occurred on May 2005 and on September 2009. As a result, the National Civil Protection Department (DPC) started an accurate monitoring and analysis program. A monitoring project using the GB-InSAR (ground-based interferometric synthetic aperture radar) system was emplaced to investigate the landslide kinematics, plan urgent safety measures for risk mitigation and design long-term stabilization work.Here, we present the GB-InSAR monitoring system results and its applications in the observational method (OM) approach. GB-InSAR is an established instrument for long-term campaigns aimed at early warning and monitoring during construction works. Our paper further develops these aspects in that it highlights how the OM based on the GB-InSAR technique can produce savings in terms of cost and time in engineering projects without compromising safety. This study focuses on the key role played by the monitoring activities during the design and planning activities, with special reference to the emergency phase.

For beginners in anaesthesia, self-training with an audiovisual checklist improves safety during anaesthesia induction: A prospective, randomised, controlled two-centre study.

PubMed

Beck, Stefanie; Reich, Christian; Krause, Dorothea; Ruhnke, Bjarne; Daubmann, Anne; Weimann, Jörg; Zöllner, Christian; Kubitz, Jens

2018-01-31

Beginners in residency programmes in anaesthesia are challenged because working environment is complex, and they cannot rely on experience to meet challenges. During this early stage, residents need rules and structures to guide their actions and ensure patient safety. We investigated whether self-training with an electronic audiovisual checklist app on a mobile phone would produce a long-term improvement in the safety-relevant actions during induction of general anaesthesia. During the first month of their anaesthesia residency, we randomised 26 residents to the intervention and control groups. The study was performed between August 2013 and December 2014 in two university hospitals in Germany. In addition to normal training, the residents of the intervention group trained themselves on well tolerated induction using the electronic checklist for at least 60 consecutive general anaesthesia inductions. After an initial learning phase, all residents were observed during one induction of general anaesthesia. The primary outcome was the number of safety items completed during this anaesthesia induction. Secondary outcomes were similar observations 4 and 8 weeks later. Immediately, and 4 weeks after the first learning phase, residents in the intervention group completed a significantly greater number of safety checks than residents in the control group 2.8 [95% confidence interval (CI) 0.4 to 5.1, P = 0.021, Cohen's d = 0.47] and 3.7 (95% CI 1.3 to 6.1, P = 0.003, Cohen's d = 0.61), respectively. The difference between the groups had disappeared by 8 weeks: mean difference in the number of safety checks at 8 weeks was 0.4, 95% CI -2.0 to 2.8, P = 0.736, Cohen's d = 0.07). The use of an audiovisual self-training checklists improves safety-relevant behaviour in the early stages of a residency training programme in anaesthesia.

One-year safety and efficacy study of bilastine treatment in Japanese patients with chronic spontaneous urticaria or pruritus associated with skin diseases.

PubMed

Yagami, Akiko; Furue, Masutaka; Togawa, Michinori; Saito, Akihiro; Hide, Michihiro

2017-04-01

A number of second-generation non-sedating antihistamines are used in clinical practices over the world. However, long-term safety and efficacy have not been proved high level evidence based medicine. We have performed an open-label, multicenter, phase III study to evaluate the long-term safety and efficacy of bilastine, a novel non-sedating H 1 -antihistamine for patients with chronic spontaneous urticaria (CSU) or pruritus associated with skin diseases (trial registration no. JapicCTI-142528). Patients aged 18-74 years were treated with bilastine 20 mg once daily for up to 52 weeks. Safety and tolerability were assessed on the basis of adverse events (AE), bilastine-related AE, laboratory tests and vital signs. Efficacy was assessed based on rash score, itch score, overall improvement and quality of life. One hundred and ninety-eight patients enrolled, 122 of whom (61.6%) completed the 52-week treatment period. AE were reported in 64.5% and bilastine-related AE in 2.5% of patients throughout the 52-week treatment period. All AE were mild to moderate in severity. AE associated with the nervous system occurred in 10 patients (5.1%) including seven patients (3.6%) with headache. Somnolence reported in two of these patients (1.0%) was related to bilastine. All efficacy variables improved during treatment with bilastine. In conclusion, long-term treatment with bilastine 20 mg once daily for 52 weeks is safe and well tolerated in Japanese patients with CSU or pruritus associated with skin diseases. Bilastine improved disease symptoms of both conditions early in treatment, and the efficacy was maintained throughout the treatment. © 2016 The Authors. The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.

Long-term efficacy and safety of mipomersen in patients with familial hypercholesterolaemia: 2-year interim results of an open-label extension.

PubMed

Santos, Raul D; Duell, P Barton; East, Cara; Guyton, John R; Moriarty, Patrick M; Chin, Wai; Mittleman, Robert S

2015-03-01

To evaluate the efficacy and safety of extended dosing with mipomersen in patients with familial hypercholesterolaemia (HC) taking maximally tolerated lipid-lowering therapy. A planned interim analysis of an ongoing, open-label extension trial in patients (n = 141) with familial HC receiving a subcutaneous injection of 200 mg mipomersen weekly plus maximally tolerated lipid-lowering therapy for up to 104 weeks. The mean changes in low-density lipoprotein cholesterol (LDL-C) from baseline to weeks 26 (n = 130), 52 (n = 111), 76 (n = 66), and 104 (n = 53) were -28, -27, -27, and -28%; and in apolipoprotein B -29, -28, -30, and -31%, respectively. Reductions in total cholesterol, non-high-density lipoprotein-cholesterol, and lipoprotein(a) were comparable with decreases in LDL-C and apolipoprotein B levels. Mean high-density lipoprotein cholesterol increased from baseline by 7 and 6% at weeks 26 and 52, respectively. The long-term safety profile of mipomersen was similar to that reported in the associated randomized placebo-controlled Phase 3 trials. Adverse events included injection site reactions and flu-like symptoms. There was an incremental increase in the median liver fat during the initial 6-12 months that appeared to diminish with continued mipomersen exposure beyond 1 year and returned towards baseline 24 weeks after last drug dose suggestive of adaptation. The median alanine aminotransferase level showed a similar trend over time. Long-term treatment with mipomersen for up to 104 weeks provided sustained reductions in all atherosclerotic lipoproteins measured and a safety profile consistent with prior controlled trials in these high-risk patient populations. CLINICALTRIALS.GOV: NCT00694109. © The Author 2013. Published by Oxford University Press on behalf of the European Society of Cardiology.

Long-term efficacy and safety of mipomersen in patients with familial hypercholesterolaemia: 2-year interim results of an open-label extension

PubMed Central

Santos, Raul D.; Duell, P. Barton; East, Cara; Guyton, John R.; Moriarty, Patrick M.; Chin, Wai; Mittleman, Robert S.

2015-01-01

Aims To evaluate the efficacy and safety of extended dosing with mipomersen in patients with familial hypercholesterolaemia (HC) taking maximally tolerated lipid-lowering therapy. Methods and results A planned interim analysis of an ongoing, open-label extension trial in patients (n = 141) with familial HC receiving a subcutaneous injection of 200 mg mipomersen weekly plus maximally tolerated lipid-lowering therapy for up to 104 weeks. The mean changes in low-density lipoprotein cholesterol (LDL-C) from baseline to weeks 26 (n = 130), 52 (n = 111), 76 (n = 66), and 104 (n = 53) were −28, −27, −27, and −28%; and in apolipoprotein B −29, −28, −30, and −31%, respectively. Reductions in total cholesterol, non-high-density lipoprotein-cholesterol, and lipoprotein(a) were comparable with decreases in LDL-C and apolipoprotein B levels. Mean high-density lipoprotein cholesterol increased from baseline by 7 and 6% at weeks 26 and 52, respectively. The long-term safety profile of mipomersen was similar to that reported in the associated randomized placebo-controlled Phase 3 trials. Adverse events included injection site reactions and flu-like symptoms. There was an incremental increase in the median liver fat during the initial 6–12 months that appeared to diminish with continued mipomersen exposure beyond 1 year and returned towards baseline 24 weeks after last drug dose suggestive of adaptation. The median alanine aminotransferase level showed a similar trend over time. Conclusion Long-term treatment with mipomersen for up to 104 weeks provided sustained reductions in all atherosclerotic lipoproteins measured and a safety profile consistent with prior controlled trials in these high-risk patient populations. Clinicaltrials.gov NCT00694109. PMID:24366918

Long-term safety and efficacy of adalimumab for intestinal Behçet's disease in the open label study following a phase 3 clinical trial.

PubMed

Inoue, Nagamu; Kobayashi, Kiyonori; Naganuma, Makoto; Hirai, Fumihito; Ozawa, Morio; Arikan, Dilek; Huang, Bidan; Robinson, Anne M; Thakkar, Roopal B; Hibi, Toshifumi

2017-07-01

Intestinal Behçet's disease (BD) is an immune-mediated inflammatory disorder. We followed up the patients and evaluated safety profile and effectiveness of adalimumab for the treatment of intestinal BD through 100 weeks rolled over from the 52 week clinical trial (NCT01243671). Patients initiated adalimumab therapy at 160 mg at week 0, followed by 80 mg at week 2, followed by 40 mg every other week until the end of the study. Long-term safety and all adverse events (AEs) were examined. The efficacy was assessed on the basis of marked improvement (MI) and complete remission (CR) using a composite efficacy index, which combined global gastrointestinal symptoms and endoscopic assessments. Twenty patients were enrolled in this study; 15 patients received adalimumab treatment until study completion. The incidence of AEs through week 100 was 544.4 events/100 person-years, which was comparable to the incidence through week 52 (560.4 events/100 person-years). No unexpected trend was observed and adalimumab was well tolerated. At weeks 52 and 100, 60.0% and 40.0% of patients showed MI, respectively, and 20.0% and 15.0% of patients showed CR, respectively. This report demonstrates 2 years safety and effectiveness of adalimumab in intestinal BD patients. Patients with intestinal BD refractory to conventional treatment receiving up to 2 years of adalimumab treatment demonstrated safety outcomes consistent with the known profile of adalimumab, and the treatment led to sustained reduction of clinical and endoscopic disease activity.

A uniform transit safety records system for the Commonwealth of Virginia.

DOT National Transportation Integrated Search

1981-01-01

This study was conceived as the first phase of a three-phase program to develop a safety data base for intracity bus transit. It involved reviewing the state of the art of general transportation safety management, examining the current intracity bus ...

An open-label study to evaluate the long-term safety and efficacy of lanadelumab for prevention of attacks in hereditary angioedema: design of the HELP study extension.

PubMed

Riedl, Marc A; Bernstein, Jonathan A; Craig, Timothy; Banerji, Aleena; Magerl, Markus; Cicardi, Marco; Longhurst, Hilary J; Shennak, Mustafa M; Yang, William H; Schranz, Jennifer; Baptista, Jovanna; Busse, Paula J

2017-01-01

Hereditary angioedema (HAE) is characterized by recurrent attacks of subcutaneous or submucosal edema. Attacks are unpredictable, debilitating, and have a significant impact on quality of life. Patients may be prescribed prophylactic therapy to prevent angioedema attacks. Current prophylactic treatments may be difficult to administer (i.e., intravenously), require frequent administrations or are not well tolerated, and breakthrough attacks may still occur frequently. Lanadelumab is a subcutaneously-administered monoclonal antibody inhibitor of plasma kallikrein in clinical development for prophylaxis of hereditary angioedema attacks. A Phase 1b study supported its efficacy in preventing attacks. A Phase 3, randomized, double-blind, placebo-controlled, parallel-arm study has been completed and an open-label extension is currently ongoing. The primary objective of the open-label extension is to evaluate the long-term safety of repeated subcutaneous administrations of lanadelumab in patients with type I/II HAE. Secondary objectives include evaluation of efficacy and time to first angioedema attack to determine outer bounds of the dosing interval. The study will also evaluate immunogenicity, pharmacokinetics/pharmacodynamics, quality of life, characteristics of breakthrough attacks, ease of self-administration, and safety/efficacy in patients who switch to lanadelumab from another prophylactic therapy. The open-label extension will enroll patients who completed the double-blind study ("rollover patients") and those who did not participate in the double-blind study ("non-rollover patients"), which includes patients who may or may not be currently using another prophylactic therapy. Rollover patients will receive a single 300 mg dose of lanadelumab on Day 0 and the second dose after the patient's first confirmed angioedema attack. Thereafter, lanadelumab will be administered every 2 weeks. Non-rollover patients will receive 300 mg lanadelumab every 2 weeks regardless of the first attack. All patients will receive their last dose on Day 350 (maximum of 26 doses), and will then undergo a 4-week follow-up. Prevention of attacks can reduce the burden of illness associated with HAE. Prophylactic therapy requires extended, repeated dosing and the results of this study will provide important data on the long-term safety and efficacy of lanadelumab, a monoclonal antibody inhibitor of plasma kallikrein for subcutaneous administration for the treatment of HAE. Trial registration NCT02741596.

Open-label, randomized, multicenter, phase III study to evaluate the safety and efficacy of benzoyl peroxide gel in long-term use in patients with acne vulgaris: A secondary publication.

PubMed

Kawashima, Makoto; Nagare, Toshitaka; Katsuramaki, Tsuneo

2017-06-01

An open-label, randomized, multicenter study was conducted to evaluate the safety and efficacy of long-term use of 2.5% and 5% benzoyl peroxide (BPO) gels administrated once daily for 52 weeks to Japanese patients with acne vulgaris. The efficacy of the study drugs was evaluated by counting inflammatory lesions and non-inflammatory lesions. Safety was evaluated based on adverse events, local skin tolerability scores and laboratory test values. In total, 458 subjects were included in the efficacy and safety analyses. The total lesion count, the efficacy end-point, was similarly changed both in the 2.5% and 5% BPO groups over the course of the study. The median rates of reduction from baseline to week 12 were approximately 65%. Thereafter, the counts were maintained at a reduced level without increasing until week 52. The median rates at week 52 were approximately 80%. Similar trends were observed for inflammatory and non-inflammatory lesion counts. Bacteriological evaluation indicated similar distribution of the minimum inhibitory concentration of each of the antibacterial drugs against Propionibacterium acnes between the values at baseline and at week 52, suggesting that long-term use did not result in changes in the drug sensitivity. The incidence of adverse events was 84.0% in the 2.5% BPO group and 87.2% in the 5% BPO group. Many of the adverse events occurred within the first month and were mild or moderate in severity and transient. The results suggest that both 2.5% and 5% BPO gels are effective and safe for long-term treatment of patients with acne vulgaris. © 2017 The Authors. The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.

Changes in Mipomersen Dosing Regimen Provide Similar Exposure With Improved Tolerability in Randomized Placebo‐Controlled Study of Healthy Volunteers

PubMed Central

Flaim, JoAnn D.; Grundy, John S.; Baker, Brenda F.; McGowan, Mary P.; Kastelein, John J. P.

2014-01-01

Background Mipomersen, an apolipoprotein B synthesis inhibitor, demonstrated significant reductions in low‐density lipoprotein (LDL) cholesterol, non‐high density lipoprotein cholesterol, and apolipoprotein B in 4 phase 3 studies at the FDA‐approved subcutaneous dose of 200 mg once weekly. Methods and Results A short‐term phase 1 study in healthy volunteers was conducted to evaluate the relative bioavailability, safety, and tolerability of mipomersen in 2 test dose regimens in reference to the 200 mg weekly dose regimen. Eighty‐four adults were randomized to 1 of 3 cohorts (30 mg once daily, 70 mg 3 times weekly, or 200 mg once weekly) and then mipomersen or placebo (3:1 ratio) for 3 weeks of treatment. Comparable mipomersen post‐distribution phase plasma concentrations were observed across the 3 dose regimens suggesting similar tissue exposure. Injection site reactions were reported, but did not lead to treatment discontinuation. The median incidence of these responses per injection was decreased by lowering the dose. Signals from a diverse panel of systemic inflammation markers were essentially indistinguishable between dose regimens and placebo treatment. The one exception was a modest transient post‐dose elevation of C‐reactive protein (CRP) in the mipomersen 200 mg weekly group. This elevation was not associated with an increase in other proinflammatory markers. Conclusions This study demonstrated a similar drug exposure and overall safety profile between the 3 dosing regimens. Exploratory assessment of a diverse panel of biomarkers found no indication of a systemic inflammatory response to mipomersen treatment. These results support assessment of alternative dose regimens in longer‐term studies. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01061814. PMID:24627419

Changes in mipomersen dosing regimen provide similar exposure with improved tolerability in randomized placebo-controlled study of healthy volunteers.

PubMed

Flaim, Joann D; Grundy, John S; Baker, Brenda F; McGowan, Mary P; Kastelein, John J P

2014-03-13

Mipomersen, an apolipoprotein B synthesis inhibitor, demonstrated significant reductions in low-density lipoprotein (LDL) cholesterol, non-high density lipoprotein cholesterol, and apolipoprotein B in 4 phase 3 studies at the FDA-approved subcutaneous dose of 200 mg once weekly. A short-term phase 1 study in healthy volunteers was conducted to evaluate the relative bioavailability, safety, and tolerability of mipomersen in 2 test dose regimens in reference to the 200 mg weekly dose regimen. Eighty-four adults were randomized to 1 of 3 cohorts (30 mg once daily, 70 mg 3 times weekly, or 200 mg once weekly) and then mipomersen or placebo (3:1 ratio) for 3 weeks of treatment. Comparable mipomersen post-distribution phase plasma concentrations were observed across the 3 dose regimens suggesting similar tissue exposure. Injection site reactions were reported, but did not lead to treatment discontinuation. The median incidence of these responses per injection was decreased by lowering the dose. Signals from a diverse panel of systemic inflammation markers were essentially indistinguishable between dose regimens and placebo treatment. The one exception was a modest transient post-dose elevation of C-reactive protein (CRP) in the mipomersen 200 mg weekly group. This elevation was not associated with an increase in other proinflammatory markers. This study demonstrated a similar drug exposure and overall safety profile between the 3 dosing regimens. Exploratory assessment of a diverse panel of biomarkers found no indication of a systemic inflammatory response to mipomersen treatment. These results support assessment of alternative dose regimens in longer-term studies. http://www.clinicaltrials.gov. Unique identifier: NCT01061814.

Safety Ellipse Motion with Coarse Sun Angle Optimization

NASA Technical Reports Server (NTRS)

Naasz, Bo

2005-01-01

The Hubble Space Telescope Robotic Servicing and De-orbit Mission (HRSDM) was t o be performed by the unmanned Hubble Robotic Vehicle (HRV) consisting of a Deorbit Module (DM), responsible for the ultimate disposal of Hubble Space Telescope (HST) at the end of science operations, and an Ejection Module (EM), responsible for robotically servicing the HST to extend its useful operational lifetime. HRSDM consisted of eight distinct phases, including: launch, pursuit, proximity operations, capture, servicing, EM jettison and disposal, science operations, and deorbit. The scope of this paper is limited to the Proximity Operations phase of HRSDM. It introduces a relative motion strategy useful for Autonomous Rendezvous and Docking (AR&D) or Formation Flying missions where safe circumnavigation trajectories, or close proximity operations (tens or hundreds of meters) are required for extended periods of time. Parameters and algorithms used to model the relative motion of HRV with respect to HST during the Proximity Operations phase of the HRSDM are described. Specifically, the Safety Ellipse (SE) concept, convenient parameters for describing SE motion, and a concept for initializing SE motion around a target vehicle to coarsely optimize sun and relative navigation sensor angles are presented. The effects of solar incidence angle variations on sun angle optimization, and the effects of orbital perturbations and navigation uncertainty on long term SE motion are discussed.

Etomidate anaesthesia by immersion in oriental fire-bellied toads (Bombina orientalis).

PubMed

d'Ovidio, D; Spadavecchia, C; Angeli, G; Adami, C

2015-10-01

The objective of the present study was to evaluate the efficacy and the safety of etomidate anaesthesia by immersion technique in Bombina orientalis. The study comprised two phases. The first phase was carried out to identify the etomidate concentration capable of producing anaesthetic induction, as well as surgical anaesthesia, in the toads. The second phase was aimed at testing that concentration in eight additional animals. Etomidate administered via immersion at a concentration of 37.5 mg/L produced effective anaesthesia in oriental fire-bellied toads. The average duration of surgical anaesthesia was 20 min. All the toads enrolled in the study survived the anaesthesia and long-term complications did not occur. However, undesired side-effects, namely itching, myoclonus and prolonged recovery, were noticed during the perianaesthetic period. The authors concluded that etomidate anaesthesia by immersion, at a concentration of 37.5 mg/L, is suitable in oriental fire-bellied toads and produces anaesthesia of a depth and duration that is sufficient to allow the completion of various experimental procedures, without resulting in lethal complications. However, the occurrence of undesired side-effects opens a debate on the safety of this anaesthetic technique, and imposes the need for further investigation prior to proposing the latter for routine laboratory practice. © The Author(s) 2015.

Long-term safety of once-daily, dual-release hydrocortisone in patients with adrenal insufficiency: a phase 3b, open-label, extension study

PubMed Central

Nilsson, Anna G; Bergthorsdottir, Ragnhildur; Burman, Pia; Dahlqvist, Per; Ekman, Bertil; Engström, Britt Edén; Ragnarsson, Oskar; Skrtic, Stanko; Wahlberg, Jeanette; Achenbach, Heinrich; Uddin, Sharif; Marelli, Claudio

2017-01-01

Objective To investigate the long-term safety and tolerability of a once-daily, dual-release hydrocortisone (DR-HC) tablet as oral glucocorticoid replacement therapy in patients with primary adrenal insufficiency (AI). Design Prospective, open-label, multicenter, 5-year extension study of DR-HC conducted at five university clinics in Sweden. Methods Seventy-one adult patients diagnosed with primary AI who were receiving stable glucocorticoid replacement therapy were recruited. Safety and tolerability outcomes included adverse events (AEs), intercurrent illness episodes, laboratory parameters and vital signs. Quality of life (QoL) was evaluated using generic questionnaires. Results Total DR-HC exposure was 328 patient-treatment years. Seventy patients reported 1060 AEs (323 per 100 patient-years); 85% were considered unrelated to DR-HC by the investigator. The most common AEs were nasopharyngitis (70%), fatigue (52%) and gastroenteritis (48%). Of 65 serious AEs reported by 32 patients (20 per 100 patient-years), four were considered to be possibly related to DR-HC: acute AI (n = 2), gastritis (n = 1) and syncope (n = 1). Two deaths were reported (fall from height and subarachnoid hemorrhage), both considered to be unrelated to DR-HC. From baseline to 5 years, intercurrent illness episodes remained relatively stable (mean 2.6–5.4 episodes per patient per year), fasting plasma glucose (0.7 mmol/L; P < 0.0001) and HDL cholesterol (0.2 mmol/L; P < 0.0001) increased and patient-/investigator-assessed tolerability improved. QoL total scores were unchanged but worsening physical functioning was recorded (P = 0.008). Conclusions In the first prospective study evaluating the long-term safety of glucocorticoid replacement therapy in patients with primary AI, DR-HC was well tolerated with no safety concerns observed during 5-year treatment. PMID:28292927

Selective estrogen receptor modulators in clinical practice: a safety overview.

PubMed

Ellis, Amanda J; Hendrick, Vicky M; Williams, Robert; Komm, Barry S

2015-06-01

Selective estrogen receptor (ER) modulators (SERMs) are a class of nonsteroidal compounds that interact with ERs, each with a distinct tissue-specific profile. Depending upon the degree of ER agonism/antagonism at the target tissue, SERMs show efficacy for various indications including osteoporosis, dyspareunia, and breast cancer, and are associated with safety risks. This review describes the safety profile of SERMs (tamoxifen, raloxifene, toremifene, bazedoxifene, lasofoxifene, and ospemifene) and fulvestrant (a pure ER antagonist) from Phase III trials, long-term extension studies, and active comparator studies. Tamoxifen, a first-generation SERM, is indicated for breast cancer prevention and treatment but is associated with serious safety concerns including endometrial cancer, venous thromboembolic events (VTE), and stroke. Toremifene, raloxifene, bazedoxifene, lasofoxifene, and ospemifene present generally improved, though distinctly different, safety profiles compared with tamoxifen, especially with endometrial cancer and stroke. However, the risk of VTE remains a concern for most SERMs. Each SERM presents a unique risk/benefit profile based on varying indications and tissue-specific ER agonist and antagonist effects, making careful patient selection and ongoing patient monitoring crucial aspects of treatment. Future research may focus on identifying new SERMs for endocrine-resistant and endocrine-responsive cancers and post-menopausal symptoms.

30 CFR 75.806 - Connection of single-phase loads.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Connection of single-phase loads. 75.806 Section 75.806 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR COAL MINE SAFETY AND HEALTH MANDATORY SAFETY STANDARDS-UNDERGROUND COAL MINES Underground High-Voltage Distribution...

Space-Based Range Safety and Future Space Range Applications

NASA Technical Reports Server (NTRS)

Whiteman, Donald E.; Valencia, Lisa M.; Simpson, James C.

2005-01-01

The National Aeronautics and Space Administration (NASA) Space-Based Telemetry and Range Safety (STARS) study is a multiphase project to demonstrate the performance, flexibility and cost savings that can be realized by using space-based assets for the Range Safety [global positioning system (GPS) metric tracking data, flight termination command and range safety data relay] and Range User (telemetry) functions during vehicle launches and landings. Phase 1 included flight testing S-band Range Safety and Range User hardware in 2003 onboard a high-dynamic aircraft platform at Dryden Flight Research Center (Edwards, California, USA) using the NASA Tracking and Data Relay Satellite System (TDRSS) as the communications link. The current effort, Phase 2, includes hardware and packaging upgrades to the S-band Range Safety system and development of a high data rate Ku-band Range User system. The enhanced Phase 2 Range Safety Unit (RSU) provided real-time video for three days during the historic Global Flyer (Scaled Composites, Mojave, California, USA) flight in March, 2005. Additional Phase 2 testing will include a sounding rocket test of the Range Safety system and aircraft flight testing of both systems. Future testing will include a flight test on a launch vehicle platform. This paper discusses both Range Safety and Range User developments and testing with emphasis on the Range Safety system. The operational concept of a future space-based range is also discussed.

Space-Based Range Safety and Future Space Range Applications

NASA Technical Reports Server (NTRS)

Whiteman, Donald E.; Valencia, Lisa M.; Simpson, James C.

2005-01-01

The National Aeronautics and Space Administration Space-Based Telemetry and Range Safety study is a multiphase project to demonstrate the performance, flexibility and cost savings that can be realized by using space-based assets for the Range Safety (global positioning system metric tracking data, flight termination command and range safety data relay) and Range User (telemetry) functions during vehicle launches and landings. Phase 1 included flight testing S-band Range Safety and Range User hardware in 2003 onboard a high-dynamic aircraft platform at Dryden Flight Research Center (Edwards, California) using the NASA Tracking and Data Relay Satellite System as the communications link. The current effort, Phase 2, includes hardware and packaging upgrades to the S-band Range Safety system and development of a high data rate Ku-band Range User system. The enhanced Phase 2 Range Safety Unit provided real-time video for three days during the historic GlobalFlyer (Scaled Composites, Mojave, California) flight in March, 2005. Additional Phase 2 testing will include a sounding rocket test of the Range Safety system and aircraft flight testing of both systems. Future testing will include a flight test on a launch vehicle platform. This report discusses both Range Safety and Range User developments and testing with emphasis on the Range Safety system. The operational concept of a future space-based range is also discussed.

Sortie laboratory, phase B technical summary. [design and operational requirements

NASA Technical Reports Server (NTRS)

1973-01-01

The design and operational requirements which evolved from Sortie Lab (SL) analysis are summarized. A source of requirements for systems is given along with experimental support for the SL, baseline. Basic design data covered include: configuration definition, mission analysis, experimental integration, safety, and logistics. A technical summary outlines characteristics which reflect the influence of the growth in SL capability and the results of the mission and operational analysis. Each of the selected areas is described in terms of objectives, equipment, operational concept, and support requirements.

Overall Control on Solid Rocket Motor Hazard Zone: Example of VEGA an Innovative Solution at System Level

NASA Astrophysics Data System (ADS)

Vertueux, M.

2013-09-01

The arrival of additional Space launch vehicles Soyouz and Vega in Guiana Space Center facilities faced a new ground range safety major question: The technical hazards assessment and management related to the preparation of these three launchers simultaneously with the same high level of safety. The objective of this publication is to highlight the new safety solutions that are applied in CSG to reduce the risk of self-propulsion of the stages of VEGA launcher. During all the preparation campaign of VEGA launch vehicle, the explosive risk due to the use of solid propellant is permanent. Uncontrolled propulsion of a solid rocket motor is capable of destruction of other important installations with catastrophic effects. This event could cause loss of human lives and great damages to the CSG launch site structures. Early in the space program development phases of VEGA, the risk of self- propulsion of solid rocket motors and the solutions to avoid the "domino effects" on neighboring facilities have been issued as one of the major concern in term of safety.

Safety of Tofacitinib in the Treatment of Rheumatoid Arthritis in Latin America Compared With the Rest of the World Population.

PubMed

Castañeda, Oswaldo M; Romero, Felix J; Salinas, Ariel; Citera, Gustavo; Mysler, Eduardo; Rillo, Oscar; Radominski, Sebastiao C; Cardiel, Mario H; Jaller, Juan J; Alvarez-Moreno, Carlos; Ponce de Leon, Dario; Castelli, Graciela; García, Erika G; Kwok, Kenneth; Rojo, Ricardo

2017-06-01

Rheumatoid arthritis (RA) is a chronic, autoimmune disease characterized by joint destruction. Tofacitinib is an oral Janus kinase inhibitor for the treatment of RA. This post hoc analysis assessed the safety of tofacitinib in Latin American (LA) patients with RA versus the Rest of World (RoW) population. Data were pooled from 14 clinical studies of tofacitinib: six Phase 2, six Phase 3 and two long-term extension studies. Incidence rates (IRs; patients with events/100 patient-years of treatment exposure) were calculated for safety events of special interest combined across tofacitinib doses. 95% confidence intervals (CI) for IRs were calculated using the maximum likelihood method. Descriptive comparisons were made between LA and RoW (excluding LA) populations. This analysis included data from 984 LA patients and 4687 RoW patients. IRs for safety events of special interest were generally similar between LA and RoW populations, with overlapping 95% CIs. IRs for discontinuation due to adverse events, serious infections, tuberculosis, all herpes zoster (HZ), serious HZ, malignancies (excluding non-melanoma skin cancer) and major adverse cardiovascular events were numerically lower for LA versus RoW patients; IR for mortality was numerically higher. No lymphoma was reported in the LA population versus eight cases in the RoW population. Exposure (extent and length) was lower in the LA population (2148.33 patient-years [mean = 2.18 years]) versus RoW (10515.68 patient-years [mean = 2.24 years]). This analysis of pooled data from clinical studies of tofacitinib in patients with RA demonstrates that tofacitinib has a consistent safety profile across LA and RoW patient populations.

Is mipomersen ready for clinical implementation? A transatlantic dilemma.

PubMed

Sjouke, Barbara; Balak, Deepak M W; Beuers, Ulrich; Ratziu, Vlad; Stroes, Erik S G

2013-08-01

Mipomersen has been approved by the US Food and Drug Administration as an orphan drug for patients with homozygous familial hypercholesterolemia (HoFH). In contrast, the European Medicines Agency advised negatively on the use of mipomersen. In this review, we discuss the efficacy and safety considerations for this discrepancy. On the basis of the results of clinical trials with mipomersen, safety concerns have been raised regarding cardiovascular risk reduction and development of hepatic steatosis. In addition, (long-term) tolerability concerns have been raised predominantly regarding injection site reactions. A pooled analysis of cardiovascular events in phase III trials with mipomersen did not provide evidence for either a positive or negative effect on cardiovascular disease. Although long-term studies with mipomersen are eagerly awaited, hepatic fat content appears to stabilize after 6-12 months notwithstanding continued mipomersen administration. HoFH is a disease with an unmet medical need for new lipid-lowering therapies. On the basis of a mean 2.9 mmol/l LDL-cholesterol reduction, mipomersen is expected to reduce cardiovascular risk in HoFH. Available evidence suggests that the fat accumulation associated with this treatment differs from steatohepatitis, which is a progressive and damaging liver disease. No evidence is available suggesting that injection site reactions because of mipomersen treatment will result in safety issues.

Orbital transfer vehicle concept definition and systems analysis study. Volume 11: Study extension 2 results

NASA Technical Reports Server (NTRS)

Willcockson, W. H.

1988-01-01

Work conducted in the second extension of the Phase A Orbit Transfer Vehicle Concept Definition and Systems Analysis Study is summarized. Four major tasks were identified: (1) define an initial OTV program consistent with near term Civil Space Leadership Initiative missions; (2) develop program evolution to long term advanced missions; (3) investigate the implications of current STS safety policy on an Aft Cargo Carrier based OTV; and (4) expand the analysis of high entry velocity aeroassist. An increased emphasis on the breath of OTV applications was undertaken to show the need for the program on the basis of the expansion of the nation's capabilities in space.

Effect of Mineral Dissolution/Precipitation and CO2 Exsolution on CO2 transport in Geological Carbon Storage.

PubMed

Xu, Ruina; Li, Rong; Ma, Jin; He, Di; Jiang, Peixue

2017-09-19

Geological carbon sequestration (GCS) in deep saline aquifers is an effective means for storing carbon dioxide to address global climate change. As the time after injection increases, the safety of storage increases as the CO 2 transforms from a separate phase to CO 2 (aq) and HCO 3 - by dissolution and then to carbonates by mineral dissolution. However, subsequent depressurization could lead to dissolved CO 2 (aq) escaping from the formation water and creating a new separate phase which may reduce the GCS system safety. The mineral dissolution and the CO 2 exsolution and mineral precipitation during depressurization change the morphology, porosity, and permeability of the porous rock medium, which then affects the two-phase flow of the CO 2 and formation water. A better understanding of these effects on the CO 2 -water two-phase flow will improve predictions of the long-term CO 2 storage reliability, especially the impact of depressurization on the long-term stability. In this Account, we summarize our recent work on the effect of CO 2 exsolution and mineral dissolution/precipitation on CO 2 transport in GCS reservoirs. We place emphasis on understanding the behavior and transformation of the carbon components in the reservoir, including CO 2 (sc/g), CO 2 (aq), HCO 3 - , and carbonate minerals (calcite and dolomite), highlight their transport and mobility by coupled geochemical and two-phase flow processes, and consider the implications of these transport mechanisms on estimates of the long-term safety of GCS. We describe experimental and numerical pore- and core-scale methods used in our lab in conjunction with industrial and international partners to investigate these effects. Experimental results show how mineral dissolution affects permeability, capillary pressure, and relative permeability, which are important phenomena affecting the input parameters for reservoir flow modeling. The porosity and the absolute permeability increase when CO 2 dissolved water is continuously injected through the core. The MRI results indicate dissolution of the carbonates during the experiments since the porosity has been increased after the core-flooding experiments. The mineral dissolution changes the pore structure by enlarging the throat diameters and decreasing the pore specific surface areas, resulting in lower CO 2 /water capillary pressures and changes in the relative permeability. When the reservoir pressure decreases, the CO 2 exsolution occurs due to the reduction of solubility. The CO 2 bubbles preferentially grow toward the larger pores instead of toward the throats or the finer pores during the depressurization. After exsolution, the exsolved CO 2 phase shows low mobility due to the highly dispersed pore-scale morphology, and the well dispersed small bubbles tend to merge without interface contact driven by the Ostwald ripening mechanism. During depressurization, the dissolved carbonate could also precipitate as a result of increasing pH. There is increasing formation water flow resistance and low mobility of the CO 2 in the presence of CO 2 exsolution and carbonate precipitation. These effects produce a self-sealing mechanism that may reduce unfavorable CO 2 migration even in the presence of sudden reservoir depressurization.

Efficacy and safety of tofacitinib in patients with active rheumatoid arthritis: review of key Phase 2 studies.

PubMed

Fleischmann, Roy; Kremer, Joel; Tanaka, Yoshiya; Gruben, David; Kanik, Keith; Koncz, Tamas; Krishnaswami, Sriram; Wallenstein, Gene; Wilkinson, Bethanie; Zwillich, Samuel H; Keystone, Edward

2016-12-01

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Here, the safety and efficacy data from five Phase 2 studies of tofacitinib in patients with RA are summarized. Tofacitinib 1-30 mg twice daily was investigated, as monotherapy and in combination with methotrexate, in patients with RA. Tofacitinib 20 mg once daily was investigated in one study. Tofacitinib 5 and 10 mg twice daily were selected for investigation in Phase 3 studies; therefore, the efficacy and safety of tofacitinib 5 and 10 mg twice daily in Phase 2 studies are the focus of this review. Tofacitinib ≥ 5 mg twice daily was efficacious in a dose-dependent manner, with statistically significant and clinically meaningful reductions in the signs and symptoms of RA and patient-reported outcomes. The safety profile was consistent across studies. The efficacy and safety profile of tofacitinib in Phase 2 studies supported its further investigation and the selection of tofacitinib 5 mg twice daily and tofacitinib 10 mg twice daily for evaluation in Phase 3 studies. © 2016 The Authors. International Journal of Rheumatic Diseases published by Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.

76 FR 10524 - Federal Motor Vehicle Safety Standards, Ejection Mitigation; Phase-In Reporting Requirements...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-02-25

... DEPARTMENT OF TRANSPORTATION National Highway Traffic Safety Administration 49 CFR Parts 571 and 585 [Docket No. NHTSA-2011-0004] RIN 2127-AK23 Federal Motor Vehicle Safety Standards, Ejection Mitigation; Phase-In Reporting Requirements; Incorporation by Reference Correction In rule document 2011-547...

Comprehensive assessment of the long-term safety of pirfenidone in patients with idiopathic pulmonary fibrosis

PubMed Central

Valeyre, Dominique; Albera, Carlo; Bradford, Williamson Z; Costabel, Ulrich; King, Talmadge E; Leff, Jonathan A; Noble, Paul W; Sahn, Steven A; du Bois, Roland M

2014-01-01

Background and objective Pirfenidone is an oral antifibrotic agent that is approved in several countries for the treatment of idiopathic pulmonary fibrosis (IPF). We performed a comprehensive analysis of safety across four clinical trials evaluating pirfenidone in patients with IPF. Methods All patients receiving pirfenidone 2403 mg/day in the Phase 3 CAPACITY studies (Studies 004 and 006) and all patients receiving at least one dose of pirfenidone in one of two ongoing open-label studies in patients with IPF (Studies 002 and 012) were selected for inclusion. Safety outcomes were evaluated from baseline until 28 days after the last dose of study drug. Results A total of 789 patients were included in the analysis. The median duration of exposure to pirfenidone was 2.6 years (range, 1 week–7.7 years), and the cumulative total exposure was 2059 person exposure years (PEY). Gastrointestinal and skin-related events were the most commonly reported adverse events; these were almost always mild to moderate in severity, and rarely led to treatment discontinuation. Elevations (>3× upper limit of normal) in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) occurred in 21/789 (2.7%) patients; the adjusted incidence of AST/ALT elevations was 1.7 per 100 PEY. Conclusions This comprehensive analysis of safety in a large cohort of IPF patients receiving pirfenidone for a total of 2059 PEY demonstrates that long-term treatment with pirfenidone is safe and generally well tolerated. PMID:24836849

Efficacy and Safety of Adalimumab in Moderately to Severely Active Cases of Ulcerative Colitis: A Meta-Analysis of Published Placebo-Controlled Trials

PubMed Central

Zhang, Zong Mei; Li, Wei; Jiang, Xue Liang

2016-01-01

Background/Aims To evaluate the efficacy and safety of adalimumab (ADA) in moderately to severely active ulcerative colitis (UC) patients who are unresponsive to traditional therapy. Methods Electronic databases, including the PubMed, Embase, and Cochrane databases, were searched to April 20, 2014. UC-related randomized controlled trials (RCTs) that compared ADA with placebo were eligible. Review Manager 5.1 was used for data analysis. Results This meta-analysis included three RCTs. ADA was considerably more effective compared with a placebo, and it increased the ratio of patients with clinical remission, clinical responses, mucosal healing and inflammatory bowel disease questionnaire responses in the induction and maintenance phases (p<0.05), as well as patients with steroid-free remission (p<0.05) during the maintenance phase. Clinical remission was achieved in a greater number of UC cases in the ADA 160/80/40 mg groups (0/2/4 week, every other week) compared with the placebo group at week 8 (p=0.006) and week 52 (p=0.0002), whereas the week 8 clinical remission rate was equivalent between the ADA 80/40 mg groups and the placebo group. Among the patients who received immunomodulators (IMM) at baseline, ADA was superior to the placebo in terms of inducing clinical remission (p=0.01). Between-group differences were not observed in terms of serious adverse events (p=0.61). Conclusions ADA, particularly at doses of 160/80/40 mg (0/2/4 week, every other week), is effective and safe in patients with moderate-to-severe UC who are unresponsive to traditional treatment. Concomitant IMM therapy may improve the short-term therapeutic efficacy of ADA. PMID:26780088

Efficacy and Safety of Adalimumab in Moderately to Severely Active Cases of Ulcerative Colitis: A Meta-Analysis of Published Placebo-Controlled Trials.

PubMed

Zhang, Zong Mei; Li, Wei; Jiang, Xue Liang

2016-03-01

To evaluate the efficacy and safety of adalimumab (ADA) in moderately to severely active ulcerative colitis (UC) patients who are unresponsive to traditional therapy. Electronic databases, including the PubMed, Embase, and Cochrane databases, were searched to April 20, 2014. UC-related randomized controlled trials (RCTs) that compared ADA with placebo were eligible. Review Manager 5.1 was used for data analysis. This meta-analysis included three RCTs. ADA was considerably more effective compared with a placebo, and it increased the ratio of patients with clinical remission, clinical responses, mucosal healing and inflammatory bowel disease questionnaire responses in the induction and maintenance phases (p<0.05), as well as patients with steroid-free remission (p<0.05) during the maintenance phase. Clinical remission was achieved in a greater number of UC cases in the ADA 160/80/40 mg groups (0/2/4 week, every other week) compared with the placebo group at week 8 (p=0.006) and week 52 (p=0.0002), whereas the week 8 clinical remission rate was equivalent between the ADA 80/40 mg groups and the placebo group. Among the patients who received immunomodulators (IMM) at baseline, ADA was superior to the placebo in terms of inducing clinical remission (p=0.01). Between-group differences were not observed in terms of serious adverse events (p=0.61). ADA, particularly at doses of 160/80/40 mg (0/2/4 week, every other week), is effective and safe in patients with moderate-to-severe UC who are unresponsive to traditional treatment. Concomitant IMM therapy may improve the short-term therapeutic efficacy of ADA.

French policy for managing the post-accident phase of a nuclear accident.

PubMed

Gallay, F; Godet, J L; Niel, J C

2015-06-01

In 2005, at the request of the French Government, the Nuclear Safety Authority (ASN) established a Steering Committee for the Management of the Post-Accident Phase of a Nuclear Accident or a Radiological Emergency, with the objective of establishing a policy framework. Under the supervision of ASN, this Committee, involving several tens of experts from different backgrounds (e.g. relevant ministerial offices, expert agencies, local information commissions around nuclear installations, non-governmental organisations, elected officials, licensees, and international experts), developed a number of recommendations over a 7-year period. First published in November 2012, these recommendations cover the immediate post-emergency situation, and the transition and longer-term periods of the post-accident phase in the case of medium-scale nuclear accidents causing short-term radioactive release (less than 24 h) that might occur at French nuclear facilities. They also apply to actions to be undertaken in the event of accidents during the transportation of radioactive materials. These recommendations are an important first step in preparation for the management of a post-accident situation in France in the case of a nuclear accident. © The Chartered Institution of Building Services Engineers 2014.

Exploratory double-blind, parallel-group, placebo-controlled extension study of edaravone (MCI-186) in amyotrophic lateral sclerosis.

PubMed

2017-10-01

Following the first phase III study of edaravone for amyotrophic lateral sclerosis (ALS), this extension study was performed to evaluate longer-term efficacy and safety. Patients given edaravone in the first 24-week phase III study (Cycles 1-6) were randomised to edaravone (E-E) or placebo (E-P) in the subsequent 24-week double-blind period (Cycles 7-12). Patients given placebo in phase III were switched to edaravone (P-E). Subsequently, all patients received edaravone for 12 weeks (Cycles 13-15). Efficacy endpoints included revised ALS Functional Rating Scale (ALSFRS-R) score. Analysis populations were the full analysis set (FAS) and the efficacy-expected subpopulation (EESP) defined by post-hoc analysis of the first phase III study. The least-squares mean and standard error of the intergroup difference (E-E vs. E-P) of change in the ALSFRS-R score from Cycles 7-12 was 1.16 ± 0.93 (p = 0.2176) in the FAS, and 1.85 ± 1.14 (p = 0.1127) in the EESP. The ALSFRS-R score changed almost linearly in the E-E group throughout Cycles 1-15 (60 weeks). The incidence of serious adverse events associated with ALS progression was higher in E-E than in E-P. Edaravone might have potential efficacy for up to 15 cycles when used to treat patients in the EESP with careful safety monitoring.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gougar, Hans

This document outlines the development of a high fidelity, best estimate nuclear power plant severe transient simulation capability that will complement or enhance the integral system codes historically used for licensing and analysis of severe accidents. As with other tools in the Risk Informed Safety Margin Characterization (RISMC) Toolkit, the ultimate user of Enhanced Severe Transient Analysis and Prevention (ESTAP) capability is the plant decision-maker; the deliverable to that customer is a modern, simulation-based safety analysis capability, applicable to a much broader class of safety issues than is traditional Light Water Reactor (LWR) licensing analysis. Currently, the RISMC pathway’s majormore » emphasis is placed on developing RELAP-7, a next-generation safety analysis code, and on showing how to use RELAP-7 to analyze margin from a modern point of view: that is, by characterizing margin in terms of the probabilistic spectra of the “loads” applied to systems, structures, and components (SSCs), and the “capacity” of those SSCs to resist those loads without failing. The first objective of the ESTAP task, and the focus of one task of this effort, is to augment RELAP-7 analyses with user-selected multi-dimensional, multi-phase models of specific plant components to simulate complex phenomena that may lead to, or exacerbate, severe transients and core damage. Such phenomena include: coolant crossflow between PWR assemblies during a severe reactivity transient, stratified single or two-phase coolant flow in primary coolant piping, inhomogeneous mixing of emergency coolant water or boric acid with hot primary coolant, and water hammer. These are well-documented phenomena associated with plant transients but that are generally not captured in system codes. They are, however, generally limited to specific components, structures, and operating conditions. The second ESTAP task is to similarly augment a severe (post-core damage) accident integral analyses code with high fidelity simulations that would allow investigation of multi-dimensional, multi-phase containment phenomena that are only treated approximately in established codes.« less

Topical retinoids in acne vulgaris: update on efficacy and safety.

PubMed

Thielitz, Anja; Gollnick, Harald

2008-01-01

Topical retinoids represent a mainstay of acne treatment because they expel mature comedones, reduce microcomedone formation, and exert anti-inflammatory effects. The first-generation retinoid tretinoin (all-trans retinoic acid) and the synthetic third-generation polyaromatics adapalene and tazarotene are approved for acne treatment by the US FDA, whereas topical tretinoin, isotretinoin (13-cis retinoic acid), and adapalene are accredited in Canada and Europe. Topical retinoids have a favorable safety profile distinct from the toxicity of their systemic counterparts. Local adverse effects, including erythema, dryness, itching, and stinging, occur frequently during the early treatment phase. Their impact varies with the vehicle formation, skin type, frequency and mode of application, use of moisturizers, and environmental factors such as sun exposure or temperature. The broad anti-acne activity and safety profile of topical retinoids justifies their use as first-line treatment in most types of non-inflammatory and inflammatory acne. They are also suitable as long-term medications, with no risk of inducing bacterial resistance, for maintenance of remission after cessation of initial combination therapy.

Results from a phase 1 study of nusinersen (ISIS-SMN(Rx)) in children with spinal muscular atrophy.

PubMed

Chiriboga, Claudia A; Swoboda, Kathryn J; Darras, Basil T; Iannaccone, Susan T; Montes, Jacqueline; De Vivo, Darryl C; Norris, Daniel A; Bennett, C Frank; Bishop, Kathie M

2016-03-08

To examine safety, tolerability, pharmacokinetics, and preliminary clinical efficacy of intrathecal nusinersen (previously ISIS-SMNRx), an antisense oligonucleotide designed to alter splicing of SMN2 mRNA, in patients with childhood spinal muscular atrophy (SMA). Nusinersen was delivered by intrathecal injection to medically stable patients with type 2 and type 3 SMA aged 2-14 years in an open-label phase 1 study and its long-term extension. Four ascending single-dose levels (1, 3, 6, and 9 mg) were examined in cohorts of 6-10 participants. Participants were monitored for safety and tolerability, and CSF and plasma pharmacokinetics were measured. Exploratory efficacy endpoints included the Hammersmith Functional Motor Scale Expanded (HFMSE) and Pediatric Quality of Life Inventory. A total of 28 participants enrolled in the study (n = 6 in first 3 dose cohorts; n = 10 in the 9-mg cohort). Intrathecal nusinersen was well-tolerated with no safety/tolerability concerns identified. Plasma and CSF drug levels were dose-dependent, consistent with preclinical data. Extended pharmacokinetics indicated a prolonged CSF drug half-life of 4-6 months after initial clearance. A significant increase in HFMSE scores was observed at the 9-mg dose at 3 months postdose (3.1 points; p = 0.016), which was further increased 9-14 months postdose (5.8 points; p = 0.008) during the extension study. Results from this study support continued development of nusinersen for treatment of SMA. This study provides Class IV evidence that in children with SMA, intrathecal nusinersen is not associated with safety or tolerability concerns. © 2016 American Academy of Neurology.

A trial of an all-terrain vehicle safety education video in a community-based hunter education program.

PubMed

Williams, Robert S; Graham, James; Helmkamp, James C; Dick, Rhonda; Thompson, Tonya; Aitken, Mary E

2011-01-01

All-terrain vehicle (ATV) injury is an increasingly serious problem, particularly among rural youth. There have been repeated calls for ATV safety education, but little study regarding optimal methods or content for such education. The purpose of this study was to determine if an ATV safety video was effective in increasing ATV safety knowledge when used in a community-based statewide hunter education program. During the baseline phase, surveys focusing on ATV safety were distributed to students in the Arkansas hunter safety program in 2006. In the intervention phase a year later, an ATV safety video on DVD was provided for use in required hunter education courses across Arkansas. The same survey was administered to hunter education students before and after the course. In the baseline phase, 1,641 precourse and 1,374 postcourse surveys were returned and analyzed. In the intervention phase, 708 precourse and 694 postcourse surveys were completed. Student knowledge of ATV safety after watching the video was higher than in preintervention classes. Knowledge of appropriate helmet usage increased from 95% to 98.8% (P < .0001). Awareness of the importance of not carrying a passenger behind the driver increased from 59.5% to 91.1% (P < .0001). Awareness of importance of hands-on ATV rider training increased from 82.1% to 92.4% (P < .0001). A brief ATV safety video used in a hunter education course increased ATV safety knowledge on most measures. A statewide hunter education program appears to be a useful venue for ATV safety education. © 2010 National Rural Health Association.

New obesity agents: lorcaserin and phentermine/topiramate.

PubMed

Fleming, Joshua W; McClendon, Katie S; Riche, Daniel M

2013-01-01

To evaluate the evidence for lorcaserin and phentermine/topiramate in the treatment of obesity. Literature was accessed through PubMed (June 1975-March 2013) using the search terms lorcaserin, phentermine, topiramate, or phenter mine/topiramate. Additionally, reference citations from publications identified were reviewed. Additional information was obtained from the Food and Drug Administration (FDA)-approved prescribing information and FDA briefing documents. English-language articles focusing on Phase 3 clinical trials for obesity were critiqued. Data from preclinical and Phase 1 and/or 2 trials are reported when appropriate. Six prospective Phase 3 trials were reviewed. Obesity has reached epidemic proportions, affecting more than one third of adults in the US. Two medication products, lorcaserin and phenter mine/topiramate, have recently received FDA approval as adjuncts to a reduced-calorie diet and increased physical activity among individuals with a body mass index greater than or equal to 30 kg/m(2) or greater than or equal to 27 kg/m(2) with an obesity-related comorbidity, such as hypertension, dyslipidemia, or diabetes. Lorcaserin is a selective serotonin 5-HT2C agonist that regulates food intake, while the combination of phentermine/topiramate causes appetite suppression and enhanced satiety. Three Phase 3 randomized, placebo-controlled trials reported approximately 75% and 45% of patients achieved greater than or equal to 5% weight loss with phentermine/topiramate and lorcaserin, respectively. With lifestyle modification, phentermine/topiramate appears most effective in terms of weight loss. Lorcaserin demonstrates moderate efficacy. Long-term cardiovascular outcomes studies are needed to confirm the safety and benefit of these new obesity agents.

Environmental Effects on Data Retention in Flash Cells

NASA Technical Reports Server (NTRS)

Katz, Rich; Flowers, David; Bergevin, Keith

2017-01-01

Flash technology is being utilized in fuzed munition applications and, based on the development of digital logic devices in the commercial world, usage of flash technology will increase. Antifuse technology, prevalent in non-volatile field programmable gate arrays (FPGAs), will eventually be phased out as new devices have not been developed for approximately a decade. The reliance on flash technology presents a long-term reliability issue for both DoD and NASA safety- and mission-critical applications. A thorough understanding of the data retention failure modes and statistics associated with Flash data retention is of vital concern to the fuze safety community. A key retention parameter for a flash cell is the threshold voltage (VTH), which is an indirect indicator of the amount of charge stored on the cells floating gate. This paper will present the results of our on-going tests: long-term storage at 150 C for a small population of devices, neutron radiation exposure, electrostatic discharge (ESD) testing, and the trends of large populations (over 300 devices for each condition) exposed to three difference temperatures: 25 C, 125 C, and 150 C.

Occupational Safety. Hygiene Safety. Pre-Apprenticeship Phase 1 Training.

ERIC Educational Resources Information Center

Lane Community Coll., Eugene, OR.

This self-paced student training module on hygiene safety is one of a number of modules developed for Pre-apprenticeship Phase 1 Training. Purpose of the module is to familiarize students with the different types of airborne contaminants--including noise--which may be health hazards and with the proper hygienic measures for dealing with them. The…

Occupational Safety. Hand Tools. Pre-Apprenticeship Phase 1 Training.

ERIC Educational Resources Information Center

Lane Community Coll., Eugene, OR.

This self-paced student training module on safety when using hand tools is one of a number of modules developed for Pre-apprenticeship Phase 1 Training. Purpose of the module is to teach students the correct safety techniques for operating common hand- and arm-powered tools, including selection, maintenance, technique, and uses. The module may…

Assessment of the short-term safety and tolerability of a quantified 80 % ethanol extract from the stem bark of Nauclea pobeguinii (PR 259 CT1) in healthy volunteers: a clinical phase I study.

PubMed

Mesia, Kahunu; Cimanga, Kanyanga; Tona, Lutete; Mampunza, Ma Miezi; Ntamabyaliro, Nsengi; Muanda, Tsobo; Muyembe, Tamfum; Totté, Jozef; Mets, Tony; Pieters, Luc; Vlietinck, Arnold

2011-01-01

The aim of this study was to evaluate the short-term safety and tolerability of an antimalarial herbal medicinal product (PR 259 CT1) consisting of a quantified 80 % ethanol extract from the stem bark of Nauclea pobeguinii when given orally to healthy adult male volunteers. The amount of the major alkaloid strictosamide in the extract was determined by a validated HPLC method and was shown to be 5.6 %. The herbal preparation was formulated in a gelatine capsule form containing 500 mg of PCR 259 CT1. A sample of 15 healthy male volunteers, selected using the Lot Quality Assurance of Sampling (LQAS) method, was eligible for inclusion after fulfillment of the inclusion criteria and clinical examination by a physician. The volunteers were treated in an outpatient clinic with a drug regimen of two 500 mg capsules three times daily (each eight hours) for seven days, during meals. Safety and tolerability were monitored clinically, haematologically, biochemically and by electrocardiographic (ECG) examination at days 0, 1, 3, 7 and 14. Adverse effects were recorded by self-reporting of the participants or by detection of abnormalities in clinical examinations by a physician. The oral administration of PR 259 CT1 at high doses of 2 × 500 mg/capsule/day for 7 days was found to induce no significant changes in the concentration levels of all investigated haematological, biochemical, electrocardiogram and vital sign parameters and physical characteristics after 14 days of treatment compared to those seen in the baseline data. The concentration levels of all evaluated parameters were within the normal limits as reported in the literature. All adverse events noted were mild and self-resolving including increase of appetite (33 %), headache (20 %) and nausea (20 %). Other minor side effects were insomnia, somnolence and asthenia (7 %). Thus, PR 259 CT1 presented a significant safety and tolerability in healthy volunteers to allow its further development by starting a phase II clinical trial. © Georg Thieme Verlag KG Stuttgart · New York.

Safety and immunogenicity of a novel quadrivalent meningococcal CRM-conjugate vaccine given concomitantly with routine vaccinations in infants.

PubMed

Klein, Nicola P; Reisinger, Keith S; Johnston, William; Odrljin, Tatjana; Gill, Christopher J; Bedell, Lisa; Dull, Peter

2012-01-01

In phase II studies, MenACWY-CRM elicited robust immunologic responses in young infants. We now present results from our pivotal phase III infant immunogenicity/safety study. In this open-label phase III study, we randomized full-term 2-month-old infants to 4 doses of MenACWY-CRM coadministered with routine vaccines at 2, 4, 6, and 12 months of age or with routine vaccines alone. We monitored for local and systemic reactions and serious adverse events among all study participants and evaluated for sufficiency of the immune responses to MenACWY-CRM through serum bactericidal activity assay with human complement. Bactericidal antibodies were present in 94% to 100% of subjects against each of the serogroups in MenACWY-CRM after the 4-dose series and were 67% to 97% after the first 3 doses. Geometric mean titers were higher after the fourth dose of MenACWY-CRM compared with a single dose of MenACWY-CRM at 12 months of age for all serogroups (range of ratios, 4.5-38). Responses to 3 doses of routine vaccines coadministered with MenACWY-CRM were noninferior to routine vaccinations alone, except for small differences in pneumococcal serotype 6B responses after dose 3 but not dose 4 and pertactin after dose 3. Inclusion of MenACWY-CRM did not affect the safety or reactogenicity profiles of the routine infant vaccine series. A 4-dose series of MenACWY-CRM was highly immunogenic and well tolerated in young infants, and it can be coadministered with routine infant vaccines. Substantial immunity was conferred after the first 3 doses administered at 2, 4, and 6 months of age.

Nintedanib: evidence for its therapeutic potential in idiopathic pulmonary fibrosis

PubMed Central

Inomata, Minoru; Nishioka, Yasuhiko; Azuma, Arata

2015-01-01

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with poor prognosis. The molecular mechanisms involved in the progression of IPF are not fully understood; however, the platelet-derived growth factor (PDGF)/PDGF receptor pathway is thought to play a critical role in fibrogenesis of the lungs. Other growth factors, including fibroblast growth factor and vascular endothelial growth factor, are also thought to contribute to the pathogenesis of pulmonary fibrosis. Nintedanib is an inhibitor of multiple tyrosine kinases, including receptors for PDGF, fibroblast growth factor, and vascular endothelial growth factor. In the Phase II TOMORROW trial, treatment with 150 mg of nintedanib twice daily showed a trend to slow the decline in lung function and significantly decrease acute exacerbations in patients with IPF, while showing an acceptable safety profile. The Phase III INPULSIS trials demonstrated a significant decrease in the annual rate of decline in forced vital capacity in IPF patients treated with 150 mg nintedanib twice daily. In the INPULSIS-2 trial, the time to the first acute exacerbation significantly increased in IPF patients who were treated with 150 mg of nintedanib twice daily. Pirfenidone, another antifibrotic drug, was shown to limit the decline in pulmonary function in patients with IPF in the ASCEND trial. Combination therapy with nintedanib and pirfenidone is anticipated, although further evaluation of its long-term safety is needed. There is limited evidence for the safety of the combination therapy although a Phase II trial conducted in Japan demonstrated that combination therapy with nintedanib and pirfenidone was tolerable for 1 month. Available antifibrotic agents (ie, pirfenidone and N-acetylcysteine) have limited efficacy as single therapies for IPF; therefore, further study of combination therapy with antifibrotic agents is needed. PMID:26346347

Albiglutide for the treatment of type 2 diabetes mellitus: An integrated safety analysis of the HARMONY phase 3 trials.

PubMed

Ahrén, Bo; Carr, Molly C; Murphy, Karen; Perkins, Christopher; Rendell, Marc; Mallory, Jason; Wilson, Timothy; Johnson, Susan

2017-04-01

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) stimulate the incretin system and lower glycaemic parameters in type 2 diabetes mellitus (T2DM). This analysis of clinical studies of up to 3years evaluated the safety of albiglutide, a GLP-1 RA, in people with T2DM. Integrated safety analysis included seven phase-3 T2DM studies of albiglutide compared with placebo and/or active comparators (a dipeptidyl peptidase-4 inhibitor, GLP-1 RA, insulin, sulphonylurea, and thiazolidinedione). Studies of 32months (HARMONY 7), 1year (HARMONY 6), and 3years (HARMONY 1-5), reported similar rates of adverse events (AEs) (84.8%, 82.3%), and serious AEs (13.1%, 12.9%) between albiglutide and all comparators, respectively. AEs that did not differ between the groups included symptomatic or severe hypoglycaemia as well as nausea (12.0%, 11.3%) and vomiting (5.3%, 4.7%) for albiglutide and all comparators, respectively. According to the Medical Dictionary for Regulatory Activities preferred terms, only diarrhoea (13.7%, 9.9%), injection-site reaction (9.0%, 2.0%), and peripheral oedema (4.5%, 6.8%) had at least 2% difference between the albiglutide and all-comparator groups. In a similar integrated analysis, pancreatitis occurred more often with albiglutide (0.3%, 0.1%). Renal and cardiac function did not differ between the two groups. In an integrated analysis of seven phase 3 clinical trials, albiglutide-treated patients experienced frequencies of AEs (including cardiovascular and renal) similar to the all-comparators group treated with other T2DM medications or placebo. Albiglutide treatment was associated with higher rates of diarrhoea and injection-site reactions, but not increased nausea and vomiting, versus all comparators. Copyright © 2017 Elsevier B.V. All rights reserved.

Rifaximin is safe and well tolerated for long-term maintenance of remission from overt hepatic encephalopathy.

PubMed

Mullen, Kevin D; Sanyal, Arun J; Bass, Nathan M; Poordad, Fred F; Sheikh, Muhammad Y; Frederick, R Todd; Bortey, Enoch; Forbes, William P

2014-08-01

Rifaximin is a gut-selective, oral antimicrobial agent shown to reduce the recurrence of overt hepatic encephalopathy (HE) and HE-related hospitalizations in a 6-month, randomized, controlled trial (RCT). We performed a phase 3, open-label maintenance study to assess the safety and rate of hospitalization with long-term rifaximin use. We conducted a 24-month, open-label maintenance study of rifaximin (550 mg, twice daily) in patients with HE who participated in the previous RCT of rifaximin or new patients enrolled from March 2007 to December 2010. Safety was assessed (adverse events, clinical laboratory parameters) for the integrated population of all patients, who were given rifaximin 550 mg twice daily (all-rifaximin population, N = 392). Safety and hospitalization data were compared between the group given placebo in the original RCT (n = 159) and those given rifaximin (n = 140). In the all-rifaximin population, the median exposure to rifaximin was 427.0 days (range, 2-1427 d), with 510.5 person-years of exposure. The profile and rate of adverse events with long-term rifaximin treatment were similar to those of the original RCT. There was no increase in the rate of infections, including with Clostridium difficile, or development of bacterial antibiotic resistance. Rates of hospitalizations with long-term rifaximin administration remained low: the HE-related hospitalization rate, normalized for exposure (0.21; all-rifaximin population), was similar to that of the rifaximin group in the original RCT (0.30), and lower than that for the placebo group (0.72). Long-term treatment (≥24 mo) with rifaximin (550 mg, twice daily) appears to provide a continued reduction in the rate of HE-related and all-cause hospitalization, without an increased rate of adverse events. ClinicalTrials.gov number: NCT00686920. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extension.

PubMed

Bone, Henry G; Wagman, Rachel B; Brandi, Maria L; Brown, Jacques P; Chapurlat, Roland; Cummings, Steven R; Czerwiński, Edward; Fahrleitner-Pammer, Astrid; Kendler, David L; Lippuner, Kurt; Reginster, Jean-Yves; Roux, Christian; Malouf, Jorge; Bradley, Michelle N; Daizadeh, Nadia S; Wang, Andrea; Dakin, Paula; Pannacciulli, Nicola; Dempster, David W; Papapoulos, Socrates

2017-07-01

Long-term safety and efficacy of osteoporosis treatment are important because of the chronic nature of the disease. We aimed to assess the long-term safety and efficacy of denosumab, which is widely used for the treatment of postmenopausal women with osteoporosis. In the multicentre, randomised, double-blind, placebo-controlled, phase 3 FREEDOM trial, postmenopausal women aged 60-90 years with osteoporosis were enrolled in 214 centres in North America, Europe, Latin America, and Australasia and were randomly assigned (1:1) to receive 60 mg subcutaneous denosumab or placebo every 6 months for 3 years. All participants who completed the FREEDOM trial without discontinuing treatment or missing more than one dose of investigational product were eligible to enrol in the open-label, 7-year extension, in which all participants received denosumab. The data represent up to 10 years of denosumab exposure for women who received 3 years of denosumab in FREEDOM and continued in the extension (long-term group), and up to 7 years for women who received 3 years of placebo and transitioned to denosumab in the extension (crossover group). The primary outcome was safety monitoring, comprising assessments of adverse event incidence and serious adverse event incidence, changes in safety laboratory analytes (ie, serum chemistry and haematology), and participant incidence of denosumab antibody formation. Secondary outcomes included new vertebral, hip, and non-vertebral fractures as well as bone mineral density (BMD) at the lumbar spine, total hip, femoral neck, and one-third radius. Analyses were done according to the randomised FREEDOM treatment assignments. All participants who received at least one dose of investigational product in FREEDOM or the extension were included in the combined safety analyses. All participants who enrolled in the extension with observed data were included in the efficacy analyses. The FREEDOM trial (NCT00089791) and its extension (NCT00523341) are both registered with ClinicalTrials.gov. Between Aug 3, 2004, and June 1, 2005, 7808 women were enrolled in the FREEDOM study. 5928 (76%) women were eligible for enrolment in the extension, and of these, 4550 (77%) were enrolled (2343 long-term, 2207 crossover) between Aug 7, 2007, and June 20, 2008. 2626 women (1343 long-term; 1283 crossover) completed the extension. The yearly exposure-adjusted participant incidence of adverse events for all individuals receiving denosumab decreased from 165·3 to 95·9 per 100 participant-years over the course of 10 years. Serious adverse event rates were generally stable over time, varying between 11·5 and 14·4 per 100 participant-years. One atypical femoral fracture occurred in each group during the extension. Seven cases of osteonecrosis of the jaw were reported in the long-term group and six cases in the crossover group. The yearly incidence of new vertebral fractures (ranging from 0·90% to 1·86%) and non-vertebral fractures (ranging from 0·84% to 2·55%) remained low during the extension, similar to rates observed in the denosumab group during the first three years of the FREEDOM study, and lower than rates projected for a virtual long-term placebo cohort. In the long-term group, BMD increased from FREEDOM baseline by 21·7% at the lumbar spine, 9·2% at total hip, 9·0% at femoral neck, and 2·7% at the one-third radius. In the crossover group, BMD increased from extension baseline by 16·5% at the lumbar spine, 7·4% at total hip, 7·1% at femoral neck, and 2·3% at one-third radius. Denosumab treatment for up to 10 years was associated with low rates of adverse events, low fracture incidence compared with that observed during the original trial, and continued increases in BMD without plateau. Amgen. Copyright © 2017 Elsevier Ltd. All rights reserved.

Safety Guided Design of Crew Return Vehicle in Concept Design Phase Using STAMP/STPA

NASA Astrophysics Data System (ADS)

Nakao, H.; Katahira, M.; Miyamoto, Y.; Leveson, N.

2012-01-01

In the concept development and design phase of a new space system, such as a Crew Vehicle, designers tend to focus on how to implement new technology. Designers also consider the difficulty of using the new technology and trade off several system design candidates. Then they choose an optimal design from the candidates. Safety should be a key aspect driving optimal concept design. However, in past concept design activities, safety analysis such as FTA has not used to drive the design because such analysis techniques focus on component failure and component failure cannot be considered in the concept design phase. The solution to these problems is to apply a new hazard analysis technique, called STAMP/STPA. STAMP/STPA defines safety as a control problem rather than a failure problem and identifies hazardous scenarios and their causes. Defining control flow is the essential in concept design phase. Therefore STAMP/STPA could be a useful tool to assess the safety of system candidates and to be part of the rationale for choosing a design as the baseline of the system. In this paper, we explain our case study of safety guided concept design using STPA, the new hazard analysis technique, and model-based specification technique on Crew Return Vehicle design and evaluate benefits of using STAMP/STPA in concept development phase.

Management of Ultimate Risk of Nuclear Power Plants by Source Terms - Lessons Learned from the Chernobyl Accident

DOE Office of Scientific and Technical Information (OSTI.GOV)

Genn Saji

2006-07-01

The term 'ultimate risk' is used here to describe the probabilities and radiological consequences that should be incorporated in siting, containment design and accident management of nuclear power plants for hypothetical accidents. It is closely related with the source terms specified in siting criteria which assures an adequate separation of radioactive inventories of the plants from the public, in the event of a hypothetical and severe accident situation. The author would like to point out that current source terms which are based on the information from the Windscale accident (1957) through TID-14844 are very outdated and do not incorporate lessonsmore » learned from either the Three Miles Island (TMI, 1979) nor Chernobyl accident (1986), two of the most severe accidents ever experienced. As a result of the observations of benign radionuclides released at TMI, the technical community in the US felt that a more realistic evaluation of severe reactor accident source terms was necessary. In this background, the 'source term research project' was organized in 1984 to respond to these challenges. Unfortunately, soon after the time of the final report from this project was released, the Chernobyl accident occurred. Due to the enormous consequences induced by then accident, the one time optimistic perspectives in establishing a more realistic source term were completely shattered. The Chernobyl accident, with its human death toll and dispersion of a large part of the fission fragments inventories into the environment, created a significant degradation in the public's acceptance of nuclear energy throughout the world. In spite of this, nuclear communities have been prudent in responding to the public's anxiety towards the ultimate safety of nuclear plants, since there still remained many unknown points revolving around the mechanism of the Chernobyl accident. In order to resolve some of these mysteries, the author has performed a scoping study of the dispersion and deposition mechanisms of fuel particles and fission fragments during the initial phase of the Chernobyl accident. Through this study, it is now possible to generally reconstruct the radiological consequences by using a dispersion calculation technique, combined with the meteorological data at the time of the accident and land contamination densities of {sup 137}Cs measured and reported around the Chernobyl area. Although it is challenging to incorporate lessons learned from the Chernobyl accident into the source term issues, the author has already developed an example of safety goals by incorporating the radiological consequences of the accident. The example provides safety goals by specifying source term releases in a graded approach in combination with probabilities, i.e. risks. The author believes that the future source term specification should be directly linked with safety goals. (author)« less

Umbilical cord blood expansion with nicotinamide provides long-term multilineage engraftment.

PubMed

Horwitz, Mitchell E; Chao, Nelson J; Rizzieri, David A; Long, Gwynn D; Sullivan, Keith M; Gasparetto, Cristina; Chute, John P; Morris, Ashley; McDonald, Carolyn; Waters-Pick, Barbara; Stiff, Patrick; Wease, Steven; Peled, Amnon; Snyder, David; Cohen, Einat Galamidi; Shoham, Hadas; Landau, Efrat; Friend, Etty; Peleg, Iddo; Aschengrau, Dorit; Yackoubov, Dima; Kurtzberg, Joanne; Peled, Tony

2014-07-01

Delayed hematopoietic recovery is a major drawback of umbilical cord blood (UCB) transplantation. Transplantation of ex vivo-expanded UCB shortens time to hematopoietic recovery, but long-term, robust engraftment by the expanded unit has yet to be demonstrated. We tested the hypothesis that a UCB-derived cell product consisting of stem cells expanded for 21 days in the presence of nicotinamide and a noncultured T cell fraction (NiCord) can accelerate hematopoietic recovery and provide long-term engraftment. In a phase I trial, 11 adults with hematologic malignancies received myeloablative bone marrow conditioning followed by transplantation with NiCord and a second unmanipulated UCB unit. Safety, hematopoietic recovery, and donor engraftment were assessed and compared with historical controls. No adverse events were attributable to the infusion of NiCord. Complete or partial neutrophil and T cell engraftment derived from NiCord was observed in 8 patients, and NiCord engraftment remained stable in all patients, with a median follow-up of 21 months. Two patients achieved long-term engraftment with the unmanipulated unit. Patients transplanted with NiCord achieved earlier median neutrophil recovery (13 vs. 25 days, P < 0.001) compared with that seen in historical controls. The 1-year overall and progression-free survival rates were 82% and 73%, respectively. UCB-derived hematopoietic stem and progenitor cells expanded in the presence of nicotinamide and transplanted with a T cell-containing fraction contain both short-term and long-term repopulating cells. The results justify further study of NiCord transplantation as a single UCB graft. If long-term safety is confirmed, NiCord has the potential to broaden accessibility and reduce the toxicity of UCB transplantation. Clinicaltrials.gov NCT01221857. Gamida Cell Ltd.

Long pulse pumping behavior of a cryopump for the neutral beam injector

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chakrapani, Ch.; Sharma, S. K.; Chakraborty, A. K.

2007-01-15

This article presents studies on the long term pumping behavior of a cryopump. It is shown that the pumping speed does not deteriorate on a time scale of 4200 s for a gas load of 2.4x10{sup 5} torr l, corresponding to {approx}10{sup 6} ML of hydrogen. It has also been observed that the need for regeneration of the pump is dictated by the safety limits of operation rather than its pumping capability. No sudden boil off of the cryogen takes place during the regeneration phase.

Efficacy and safety of Postoperative Intravenous Parecoxib sodium Followed by ORal CElecoxib (PIPFORCE) post-total knee arthroplasty in patients with osteoarthritis: a study protocol for a multicentre, double-blind, parallel-group trial

PubMed Central

Zhuang, Qianyu; Bian, Yanyan; Wang, Wei; Jiang, Jingmei; Feng, Bin; Sun, Tiezheng; Lin, Jianhao; Zhang, Miaofeng; Yan, Shigui; Shen, Bin; Pei, Fuxing; Weng, Xisheng

2016-01-01

Introduction Total knee arthroplasty (TKA) has been regarded as a most painful orthopaedic surgery. Although many surgeons sequentially use parecoxib and celecoxib as a routine strategy for postoperative pain control after TKA, high quality evidence is still lacking to prove the effect of this sequential regimen, especially at the medium-term follow-up. The purpose of this study, therefore, is to evaluate efficacy and safety of postoperative intravenous parecoxib sodium followed by oral celecoxib in patients with osteoarthritis (OA) undergoing TKA. The hypothesis is that compared to placebo with opioids as rescue treatment, sequential use of parecoxib and celecoxib can achieve less morphine consumption over the postoperative 2 weeks, as well as better pain control, quicker functional recovery in the postoperative 6 weeks and less opioid-related adverse events during the 12-week recovery phase. Methods and analysis This study is designed as a multicentre, randomised, double-blind, parallel-group and placebo-controlled trial. The target sample size is 246. All participants who meet the study inclusion and exclusion criteria will be randomly assigned in a 1:1 ratio to either the parecoxib/celecoxib group or placebo group. The randomisation and allocation will be study site based. The study will consist of three phases: an initial screening phase; a 6-week double-blind treatment phase; and a 6-week follow-up phase. The primary end point is cumulative opioid consumption during 2 weeks postoperation. Secondary end points consist of the postoperative visual analogue scale score, knee joint function, quality of life, local skin temperature, erythrocyte sedimentation rate, C reactive protein, cytokines and blood coagulation parameters. Safety end points will be monitored too. Ethics and dissemination Ethics approval for this study has been obtained from the Ethics Committee, Peking Union Medical College Hospital, China (Protocol number: S-572) Study results will be available as published manuscripts and presentations at national and international meetings. Trial registration number NCT02198924. PMID:27609846

Efficacy and safety of Postoperative Intravenous Parecoxib sodium Followed by ORal CElecoxib (PIPFORCE) post-total knee arthroplasty in patients with osteoarthritis: a study protocol for a multicentre, double-blind, parallel-group trial.

PubMed

Zhuang, Qianyu; Bian, Yanyan; Wang, Wei; Jiang, Jingmei; Feng, Bin; Sun, Tiezheng; Lin, Jianhao; Zhang, Miaofeng; Yan, Shigui; Shen, Bin; Pei, Fuxing; Weng, Xisheng

2016-09-08

Total knee arthroplasty (TKA) has been regarded as a most painful orthopaedic surgery. Although many surgeons sequentially use parecoxib and celecoxib as a routine strategy for postoperative pain control after TKA, high quality evidence is still lacking to prove the effect of this sequential regimen, especially at the medium-term follow-up. The purpose of this study, therefore, is to evaluate efficacy and safety of postoperative intravenous parecoxib sodium followed by oral celecoxib in patients with osteoarthritis (OA) undergoing TKA. The hypothesis is that compared to placebo with opioids as rescue treatment, sequential use of parecoxib and celecoxib can achieve less morphine consumption over the postoperative 2 weeks, as well as better pain control, quicker functional recovery in the postoperative 6 weeks and less opioid-related adverse events during the 12-week recovery phase. This study is designed as a multicentre, randomised, double-blind, parallel-group and placebo-controlled trial. The target sample size is 246. All participants who meet the study inclusion and exclusion criteria will be randomly assigned in a 1:1 ratio to either the parecoxib/celecoxib group or placebo group. The randomisation and allocation will be study site based. The study will consist of three phases: an initial screening phase; a 6-week double-blind treatment phase; and a 6-week follow-up phase. The primary end point is cumulative opioid consumption during 2 weeks postoperation. Secondary end points consist of the postoperative visual analogue scale score, knee joint function, quality of life, local skin temperature, erythrocyte sedimentation rate, C reactive protein, cytokines and blood coagulation parameters. Safety end points will be monitored too. Ethics approval for this study has been obtained from the Ethics Committee, Peking Union Medical College Hospital, China (Protocol number: S-572) Study results will be available as published manuscripts and presentations at national and international meetings. NCT02198924. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

The role of the Pharmaceuticals and Medical Devices Agency and healthcare professionals in post-marketing safety.

PubMed

Mori, Kazuhiko; Watanabe, Meguru; Horiuchi, Naoya; Tamura, Atsushi; Kutsumi, Hiromu

2014-04-01

The development of drugs and medical devices is necessary for medical progress; however, safety measures need to be put in place to protect the health of the population. In order to ensure the safety of drugs and medical devices, it is important to determine measures for appropriate management of risks at any time during the development phase, the regulatory review and the post-marketing phase. Adverse events detected in clinical trials are limited due to the restricted numbers of patients enrolled in the trials. Therefore, it is almost impossible to predict rare serious adverse events during the post-marketing phase. The revised Pharmaceutical Affairs Act was established in Japan in November 20, 2013. The new act focuses on increased safety of drugs and medical devices. The Pharmaceuticals and Medical Devices Agency (PMDA) is the regulatory authority in Japan that promotes safety measures from the development phase through to the post-marketing phase. In the post-marketing phase, the PMDA collects information from the medical product companies and healthcare professionals, as well as instructing and advising them with regard to post-marketing safety measures for each drug and medical device. Since Japan has a national health insurance system, a new drug or a medical device is available throughout the country when the drug price or medical fee is listed in the National Health Insurance price list. Healthcare professionals in medical institutions must learn about the drugs and medical devices they handle, and should make an effort to maintain patient safety. The PMDA medi-navi is a very useful electronic mail delivery service that provides critical information for protecting patients from health hazards caused by adverse events. The 'risk management plan' is also important as it contains important information about safety profile and post-marketing measures of a new drug.

Safety and mobility impacts of winter weather : phase I.

DOT National Transportation Integrated Search

2011-08-01

Highway agencies spend millions of dollars to ensure safe and efficient winter travel. However, the effectiveness of winter weather maintenance practices on safety and mobility are somewhat difficult to quantify. : Phase I of this project investigate...

National Dam Safety Program. Lake Muskoday Dam (Inventory Number N.Y. 341) Delaware River Basin, Sullivan County, New York. Phase I Inspection Report,

DTIC Science & Technology

1981-09-14

DACW-51-81-C-0006 . PERFORMING ORGANIZATION NAME AND ADDRESS 10. PROGRAM ELEMENT PROJECT. TASK AREA & WORK UNIT NUMBERS ~ Flaherty-Giauara Associates...olie It neceary and Idontily b block number) Dam Safety National Dam Safety Program Visual Inspection Lake Muskoday Dam Hydrology, Structural Stability...DELAWARE RIVER BASIN LAKE MUSKODAY DAM SULLIVAN COUNTY, NEW YORK INVENTORY No.NY341 PHASE I INSPECTION REPORT NATIONAL DAM SAFETY PROGRAM J T C NEW YORK

Canada's Deep Geological Repository For Used Nuclear Fuel -The Geoscientific Site Evaluation Process

NASA Astrophysics Data System (ADS)

Hirschorn, S.; Ben Belfadhel, M.; Blyth, A.; DesRoches, A. J.; McKelvie, J. R. M.; Parmenter, A.; Sanchez-Rico Castejon, M.; Urrutia-Bustos, A.; Vorauer, A.

2014-12-01

The Nuclear Waste Management Organization (NWMO) is responsible for implementing Adaptive Phased Management, the approach selected by the Government of Canada for long-term management of used nuclear fuel generated by Canadian nuclear reactors. In May 2010, the NWMO published and initiated a nine-step site selection process to find an informed and willing community to host a deep geological repository for Canada's used nuclear fuel. The site selection process is designed to address a broad range of technical and social, economic and cultural factors. The suitability of candidate areas will be assessed in a stepwise manner over a period of many years and include three main steps: Initial Screenings; Preliminary Assessments; and Detailed Site Characterizations. The Preliminary Assessment is conducted in two phases. NWMO has completed Phase 1 preliminary assessments for the first eight communities that entered into this step. While the Phase 1 desktop geoscientific assessments showed that each of the eight communities contains general areas that have the potential to satisfy the geoscientific safety requirements for hosting a deep geological repository, the assessment identified varying degrees of geoscientific complexity and uncertainty between communities, reflecting their different geological settings and structural histories. Phase 2 activities will include a sequence of high-resolution airborne geophysical surveys and focused geological field mapping to ground-truth lithology and structural features, followed by limited deep borehole drilling and testing. These activities will further evaluate the site's ability to meet the safety functions that a site would need to ultimately satisfy in order to be considered suitable. This paper provides an update on the site evaluation process and describes the approach, methods and criteria that are being used to conduct the geoscientific Preliminary Assessments.

Efficacy, safety and risk of augmentation of rotigotine for treating restless legs syndrome.

PubMed

Inoue, Yuichi; Hirata, Koichi; Hayashida, Kenichi; Hattori, Nobutaka; Tomida, Takayuki; Garcia-Borreguero, Diego

2013-01-10

The present study aimed to examine the long-term efficacy and safety of rotigotine treatment for restless legs syndrome (RLS), as well as the rate of clinically significant augmentation, in a 1-year open-label study of Japanese subjects. Japanese patients with RLS who had been treated with rotigotine or placebo in a double-blind trial were enrolled in a 1-year, open-label, uncontrolled extension study and treated with rotigotine at a dose of up to 3 mg/24 h after an 8-week titration phase. Outcomes included International Restless Legs Syndrome Study Group rating scale (IRLS scale), Pittsburgh Sleep Quality Index (PSQI), safety, and investigator-/expert panel-assessed augmentation (including Augmentation Severity Rating Scale). Overall, 185 patients entered the open-label study and 133 completed the study. IRLS and PSQI total scores improved throughout the 52-week treatment period (IRLS, from 23.2±5.1 to 7.8±7.6 and PSQI, from 8.0±3.1 to 5.0±2.9). Treatment-emergent adverse events were mild to moderate in severity, and included application site reactions (52.4%) and nausea (28.6%). Clinically significant augmentation occurred in five patients (2.7%). These results indicate a good long-term efficacy of rotigotine for treating RLS, with a relatively low risk of clinically significant augmentation. Copyright © 2012 Elsevier Inc. All rights reserved.

Comprehensive assessment of the long-term safety of pirfenidone in patients with idiopathic pulmonary fibrosis.

PubMed

Valeyre, Dominique; Albera, Carlo; Bradford, Williamson Z; Costabel, Ulrich; King, Talmadge E; Leff, Jonathan A; Noble, Paul W; Sahn, Steven A; du Bois, Roland M

2014-07-01

Pirfenidone is an oral antifibrotic agent that is approved in several countries for the treatment of idiopathic pulmonary fibrosis (IPF). We performed a comprehensive analysis of safety across four clinical trials evaluating pirfenidone in patients with IPF. All patients receiving pirfenidone 2403 mg/day in the Phase 3 CAPACITY studies (Studies 004 and 006) and all patients receiving at least one dose of pirfenidone in one of two ongoing open-label studies in patients with IPF (Studies 002 and 012) were selected for inclusion. Safety outcomes were evaluated from baseline until 28 days after the last dose of study drug. A total of 789 patients were included in the analysis. The median duration of exposure to pirfenidone was 2.6 years (range, 1 week-7.7 years), and the cumulative total exposure was 2059 person exposure years (PEY). Gastrointestinal and skin-related events were the most commonly reported adverse events; these were almost always mild to moderate in severity, and rarely led to treatment discontinuation. Elevations (>3× upper limit of normal) in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) occurred in 21/789 (2.7%) patients; the adjusted incidence of AST/ALT elevations was 1.7 per 100 PEY. This comprehensive analysis of safety in a large cohort of IPF patients receiving pirfenidone for a total of 2059 PEY demonstrates that long-term treatment with pirfenidone is safe and generally well tolerated. © 2014 The Authors. Respirology published by Wiley Publishing Asia Pty Ltd on behalf of Asian Pacific Society of Respirology.

Obtaining Valid Safety Data for Software Safety Measurement and Process Improvement

NASA Technical Reports Server (NTRS)

Basili, Victor r.; Zelkowitz, Marvin V.; Layman, Lucas; Dangle, Kathleen; Diep, Madeline

2010-01-01

We report on a preliminary case study to examine software safety risk in the early design phase of the NASA Constellation spaceflight program. Our goal is to provide NASA quality assurance managers with information regarding the ongoing state of software safety across the program. We examined 154 hazard reports created during the preliminary design phase of three major flight hardware systems within the Constellation program. Our purpose was two-fold: 1) to quantify the relative importance of software with respect to system safety; and 2) to identify potential risks due to incorrect application of the safety process, deficiencies in the safety process, or the lack of a defined process. One early outcome of this work was to show that there are structural deficiencies in collecting valid safety data that make software safety different from hardware safety. In our conclusions we present some of these deficiencies.

Deep Borehole Disposal Safety Analysis.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Freeze, Geoffrey A.; Stein, Emily; Price, Laura L.

This report presents a preliminary safety analysis for the deep borehole disposal (DBD) concept, using a safety case framework. A safety case is an integrated collection of qualitative and quantitative arguments, evidence, and analyses that substantiate the safety, and the level of confidence in the safety, of a geologic repository. This safety case framework for DBD follows the outline of the elements of a safety case, and identifies the types of information that will be required to satisfy these elements. At this very preliminary phase of development, the DBD safety case focuses on the generic feasibility of the DBD concept.more » It is based on potential system designs, waste forms, engineering, and geologic conditions; however, no specific site or regulatory framework exists. It will progress to a site-specific safety case as the DBD concept advances into a site-specific phase, progressing through consent-based site selection and site investigation and characterization.« less

Airport baggage handling--where do human factors fit in the challenges that airports put on a baggage system?

PubMed

Lenior, O N M

2012-01-01

The challenges put on large baggage systems by airports can be summarized as: handling a high number of bags in a short period of time, in a limited space, with all sorts of disruptions, whilst complying with stringent regulation upon security, sustainability and health and safety. The aim of this company case study is to show in the different project phases--as indicated in the system ergonomic approach--how the human factors specialist can play a major part in tackling these challenges. By describing different projects in terms of scope, organization, human factors topics covered, phases and lessons learned, the importance of Human-Computer Interaction, automation as well as manual handling and work organization in baggage is addressed.

SSME digital control design characteristics

NASA Technical Reports Server (NTRS)

Mitchell, W. T.; Searle, R. F.

1985-01-01

To protect against a latent programming error (software fault) existing in an untried branch combination that would render the space shuttle out of control in a critical flight phase, the Backup Flight System (BFS) was chartered to provide a safety alternative. The BFS is designed to operate in critical flight phases (ascent and descent) by monitoring the activities of the space shuttle flight subsystems that are under control of the primary flight software (PFS) (e.g., navigation, crew interface, propulsion), then, upon manual command by the flightcrew, to assume control of the space shuttle and deliver it to a noncritical flight condition (safe orbit or touchdown). The problems associated with the selection of the PFS/BFS system architecture, the internal BFS architecture, the fault tolerant software mechanisms, and the long term BFS utility are discussed.

Safety and efficacy of elobixibat for chronic constipation: results from a randomised, double-blind, placebo-controlled, phase 3 trial and an open-label, single-arm, phase 3 trial.

PubMed

Nakajima, Atsushi; Seki, Mitsunori; Taniguchi, Shinya; Ohta, Akira; Gillberg, Per-Göran; Mattsson, Jan P; Camilleri, Michael

2018-05-24

A subset of patients with constipation has reduced colonic bile acid concentrations, which are associated with slow colonic transit. In a previous study, elobixibat, a locally acting ileal bile acid transporter inhibitor, accelerated colonic transit in Japanese patients with functional constipation. In this study, we aimed to determine the efficacy of elobixibat for short-term treatment of chronic constipation, and safety, patient satisfaction, and quality of life with long-term treatment. We did two phase 3 studies of patients aged 20-80 years in Japan with at least 6 months of chronic constipation, who satisfied Rome III criteria for functional constipation, including fewer than three spontaneous bowel movements per week. The first trial, including patients enrolled at 16 clinics, was a 2-week, randomised, double-blind, placebo-controlled study in which (after a 2-week run-in period) patients were randomly assigned (1:1) to either elobixibat 10 mg/day for 2 weeks or placebo. Randomisation was done with permuted block method (block size six) without stratification. Masking to treatment allocation was achieved with identical appearances of elobixibat and placebo, which were supplied in sealed, opaque containers. Group assignment was concealed from patients, investigators, and analysts. The second trial, including patients enrolled at 34 clinics or hospitals, was an open-label, 1-year study in which all patients received elobixibat; participants could titrate the dose to 5 mg/day or 15 mg/day, or maintain the 10 mg/day dose. In both studies, participants took the study drug as an oral tablet once per day before breakfast. The primary outcome of the 2-week randomised trial was the change from baseline (ie, last week of the 2-week run-in) in the frequency of spontaneous bowel movements during week 1 of treatment. The primary outcome of the 52-week open-label trial was safety (type, severity, and incidence of adverse drug reactions) at all times from treatment initiation. All efficacy analyses were based on the modified intention-to-treat (ITT) population without imputation for any missing data. Safety analyses included all patients who received at least one dose of study drug. These trials are registered with the Japan Pharmaceutical Information Center (numbers JapicCTI-153061 and JapicCTI-153062) and have been completed. Between Nov 4, 2015, and June 11, 2016, we assigned 133 patients to treatment in the 2-week randomised trial: 70 to elobixibat (69 included in the modified ITT and safety populations) and 63 to placebo. The frequency of spontaneous bowel movements per week during week 1 of treatment was greater with elobixibat (least-squares mean 6·4, 95% CI 5·3-7·6) than with placebo (1·7, 1·2-2·2), p<0·0001). Between Oct 31, 2015, and March 15, 2017, we allocated 341 patients to 52 weeks of elobixibat (340 included in the modified ITT and safety populations). 163 (48%) patients in the 52-week trial had an adverse drug reaction, the most common of which were mild gastrointestinal disorders (in 135 [40%] patients). Inguinal hernia was reported in one patient with elobixibat in the 52-week study as a moderate adverse drug reaction. The most common adverse drug reactions in both trials were mild abdominal pain (13 [19%] patients with elobixibat and one [2%] with placebo in the 2-week randomised trial, and 82 [24%] patients in the 52-week trial) and diarrhoea (nine [13%] patients with elobixibat and none with placebo in the 2-week randomised trial and 50 [15%] in the 52-week trial). Elobixibat resolved constipation in the short-term, and was well tolerated with both short-term and long-term treatment. The evidence supports the use of this novel approach to increase intracolonic concentrations of endogenous bile acid for the treatment of chronic constipation. EA Pharma and Mochida Pharmaceutical. Copyright © 2018 Elsevier Ltd. All rights reserved.

Long-Term Safety and Efficacy of Belimumab in Patients With Systemic Lupus Erythematosus: A Continuation of a Seventy-Six-Week Phase III Parent Study in the United States.

PubMed

Furie, Richard A; Wallace, Daniel J; Aranow, Cynthia; Fettiplace, James; Wilson, Barbara; Mistry, Prafull; Roth, David A; Gordon, David

2018-06-01

We undertook this US multicenter continuation study (GlaxoSmithKline study BEL112233; ClinicalTrials.gov identifier: NCT00724867) to assess long-term safety and efficacy of belimumab in patients with systemic lupus erythematosus (SLE) who completed the Study of Belimumab in Subjects with SLE 76-week trial (ClinicalTrials.gov identifier: NCT00410384). Patients continued to receive the same belimumab dose plus standard therapy; patients previously receiving placebo received 10 mg/kg belimumab. The primary outcome measure was long-term safety of belimumab (frequency of adverse events [AEs] and damage assessed using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index [SDI], evaluated every 48 weeks [1 study year]). Other assessments included the SLE Responder Index (SRI), flare rates (using the modified SLE Flare Index [SFI]), prednisone use, and B cell levels. Of 268 patients, 140 completed the study and 128 withdrew. The mean ± SD score on the Safety of Estrogens in Lupus Erythematosus National Assessment version of the SLE Disease Activity Index (SELENA-SLEDAI) at baseline was 7.8 ± 3.86. The mean ± SD SDI score increased by 0.4 ± 0.68 from its value at baseline (1.2 ± 1.51). The overall incidence of treatment-related and serious AEs remained stable or declined through study year 7. An SRI response was achieved by 41.9% and 75.6% of patients at the study year 1 and study year 7 midpoints, respectively. At the study year 7 midpoint, relative to baseline, 78.2% had achieved a ≥4-point reduction in the SELENA-SLEDAI score, 98.4% had no new British Isles Lupus Assessment Group (BILAG) A organ domain score and no more than 1 new BILAG B organ domain score, 93.7% had no worsening in the physician's global assessment of disease activity, 20.6% had experienced ≥1 severe SFI flare, the mean decrease in prednisone dose was 31.4%, and the median change in CD20+ B cell numbers was -83.2%. These long-term exposure results confirm the previously observed safety and efficacy profiles of belimumab in patients with SLE. © 2018 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.

Autologous Myoblast Transplantation for Oculopharyngeal Muscular Dystrophy: a Phase I/Iia Clinical Study

PubMed Central

Périé, Sophie; Trollet, Capucine; Mouly, Vincent; Vanneaux, Valérie; Mamchaoui, Kamel; Bouazza, Belaïd; Marolleau, Jean Pierre; Laforêt, Pascal; Chapon, Françoise; Eymard, Bruno; Butler-Browne, Gillian; Larghero, Jérome; St Guily, Jean Lacau

2014-01-01

Oculopharyngeal muscular dystrophy (OPMD) is a late-onset autosomal dominant genetic disease mainly characterized by ptosis and dysphagia. We conducted a phase I/IIa clinical study (ClinicalTrials.gov NCT00773227) using autologous myoblast transplantation following myotomy in adult OPMD patients. This study included 12 patients with clinical diagnosis of OPMD, indication for cricopharyngeal myotomy, and confirmed genetic diagnosis. The feasibility and safety end points of both autologous myoblast transplantation and the surgical procedure were assessed by videoendoscopy in addition to physical examinations. Potential therapeutic benefit was also assessed through videoendoscopy and videofluoroscopy of swallowing, quality of life score, dysphagia grade, and a drink test. Patients were injected with a median of 178 million myoblasts following myotomy. Short and long-term (2 years) safety and tolerability were observed in all the patients, with no adverse effects. There was an improvement in the quality of life score for all 12 patients, and no functional degradation in swallowing was observed for 10 patients. A cell dose-dependant improvement in swallowing was even observed in this study. This trial supports the hypothesis that a local injection of autologous myoblasts in the pharyngeal muscles is a safe and efficient procedure for OPMD patients. PMID:23831596

Safety of Bifidobacterium animalis subsp. lactis (B. lactis) strain BB-12-supplemented yogurt in healthy adults on antibiotics: a phase I safety study

USDA-ARS?s Scientific Manuscript database

Probiotics are live microorganisms that, when administered in sufficient doses, provide health benefits on the host. The United States Food and Drug Administration (FDA) requires phase I safety studies for probiotics when the intended use of the product is as a drug. The purpose of the study was to ...

A Fire Safety Certification System for Board and Care Operators and Staff. SBIR Phase II: Final Report.

ERIC Educational Resources Information Center

Walker, Bonnie L.

This report describes Phase II of a project which developed a system for delivering fire safety training to board and care providers who serve adults with developmental disabilities. Phase II focused on developing and pilot testing a "train the trainers" workshop for instructors and field testing the provider's workshop. Evaluation of…

Discussing Firearm Ownership and Access as Part of Suicide Risk Assessment and Prevention: "Means Safety" versus "Means Restriction".

PubMed

Stanley, Ian H; Hom, Melanie A; Rogers, Megan L; Anestis, Michael D; Joiner, Thomas E

2017-01-01

The goal of this study was to describe the relative utility of the terms "means safety" versus "means restriction" in counseling individuals to limit their access to firearms in the context of a mock suicide risk assessment. Overall, 370 participants were randomized to read a vignette depicting a clinical scenario in which managing firearm ownership and access was discussed either using the term "means safety" or "means restriction." Participants rated the term "means safety" as significantly more acceptable and preferable than "means restriction." Participants randomized to the "means safety" condition reported greater intentions to adhere to clinicians' recommendations to limit access to a firearm for safety purposes (F[1,367] = 7.393, p = .007, [Formula: see text]). The term "means safety" may be more advantageous than "means restriction" when discussing firearm ownership and access in clinical settings and public health-oriented suicide prevention efforts.

Efficacy and safety of mepivacaine compared with lidocaine in local anaesthesia in dentistry: a meta-analysis of randomised controlled trials.

PubMed

Su, Naichuan; Liu, Yan; Yang, Xianrui; Shi, Zongdao; Huang, Yi

2014-04-01

The objective of the study was to assess the efficacy and safety of mepivacaine compared with lidocaine used in local anaesthesia in dentistry. Medline, Cochrane Central Register of Controlled Trials, EMBASE, Chinese BioMedical Literature Database, China National Knowledge Infrastructure and WHO International Clinical Trials Registry Platform were searched electronically. Relevant journals and references of studies included were hand-searched for randomised controlled trials comparing mepivacaine with lidocaine in terms of efficacy and safety. Twenty-eight studies were included, of which 15 had low risk of bias and 13 had moderate risk of bias. In comparison with 2% lidocaine with 1:100,000 adrenaline, 3% mepivacaine showed a lower success rate (P = 0.05), a shorter onset time of pulpal anaesthesia (P = 0.0005), inferior pain control during injection phase and superior inhibition of heart rate increase (P < 0.0001). In contrast, 2% mepivacaine with 1:100,000 adrenaline gave a higher success rate (P < 0.00001), a similar onset time of pulpal anaesthesia (P = 0.34) and superior pain control during injection phase (P < 0.0001); 2% mepivacaine with 1:20,000 levonordefrin had the same success rate (P = 0.69) and similar onset time of pulpal anaesthesia (P = 0.90). In addition, 3% mepivacaine had shorter onset time (P = 0.004), same level of success rate (P = 0.28) and similar pain control during injection and postinjection compared with 2% lidocaine with 1:50,000 adrenaline. Given the efficacy and safety of the two solutions, 2% mepivacaine with vasoconstrictors is better than 2% lidocaine with vasoconstrictors in dental treatment. Meanwhile, 3% plain mepivacaine is better for patients with cardiac diseases. © 2014 FDI World Dental Federation.

Deep Brain Stimulation Targeting the Fornix for Mild Alzheimer Dementia (the ADvance Trial): A Two Year Follow-up Including Results of Delayed Activation.

PubMed

Leoutsakos, Jeannie-Marie S; Yan, Haijuan; Anderson, William S; Asaad, Wael F; Baltuch, Gordon; Burke, Anna; Chakravarty, M Mallar; Drake, Kristen E; Foote, Kelly D; Fosdick, Lisa; Giacobbe, Peter; Mari, Zoltan; McAndrews, Mary Pat; Munro, Cynthia A; Oh, Esther S; Okun, Michael S; Pendergrass, Jo Cara; Ponce, Francisco A; Rosenberg, Paul B; Sabbagh, Marwan N; Salloway, Stephen; Tang-Wai, David F; Targum, Steven D; Wolk, David; Lozano, Andres M; Smith, Gwenn S; Lyketsos, Constantine G

2018-06-09

Given recent challenges in developing new treatments for Alzheimer dementia (AD), it is vital to explore alternate treatment targets, such as neuromodulation for circuit dysfunction. We previously reported an exploratory Phase IIb double-blind trial of deep brain stimulation targeting the fornix (DBS-f) in mild AD (the ADvance trial). We reported safety but no clinical benefits of DBS-f versus the delayed-on (sham) treatment in 42 participants after one year. However, secondary post hoc analyses of the one-year data suggested a possible DBS-f benefit for participants≥65 years. To examine the long-term safety and clinical effects of sustained and delayed-on DBS-f treatment of mild AD after two years. 42 participants underwent implantation of DBS-f electrodes, with half randomized to active DBS-f stimulation (early on) for two years and half to delayed-on (sham) stimulation after 1 year to provide 1 year of active DBS-f stimulation (delayed on). We evaluated safety and clinical outcomes over the two years of the trial. DBS-f had a favorable safety profile with similar rates of adverse events across both trial phases (years 1 and 2) and between treatment arms. There were no differences between treatment arms on any primary clinical outcomes. However, post-hoc age group analyses suggested a possible benefit among older (>65) participants. DBS-f was safe. Additional study of mechanisms of action and methods for titrating stimulation parameters will be needed to determine if DBS has potential as an AD treatment. Future efficacy studies should focus on patients over age 65.

Improving titer while maintaining quality of final formulated drug substance via optimization of CHO cell culture conditions in low-iron chemically defined media.

PubMed

Xu, Jianlin; Rehmann, Matthew S; Xu, Xuankuo; Huang, Chao; Tian, Jun; Qian, Nan-Xin; Li, Zheng Jian

2018-04-01

During biopharmaceutical process development, it is important to improve titer to reduce drug manufacturing costs and to deliver comparable quality attributes of therapeutic proteins, which helps to ensure patient safety and efficacy. We previously reported that relative high-iron concentrations in media increased titer, but caused unacceptable coloration of a fusion protein during early-phase process development. Ultimately, the fusion protein with acceptable color was manufactured using low-iron media, but the titer decreased significantly in the low-iron process. Here, long-term passaging in low-iron media is shown to significantly improve titer while maintaining acceptable coloration during late-phase process development. However, the long-term passaging also caused a change in the protein charge variant profile by significantly increasing basic variants. Thus, we systematically studied the effect of media components, seed culture conditions, and downstream processing on productivity and quality attributes. We found that removing β-glycerol phosphate (BGP) from basal media reduced basic variants without affecting titer. Our goals for late-phase process development, improving titer and matching quality attributes to the early-phase process, were thus achieved by prolonging seed culture age and removing BGP. This process was also successfully scaled up in 500-L bioreactors. In addition, we demonstrated that higher concentrations of reactive oxygen species were present in the high-iron Chinese hamster ovary cell cultures compared to that in the low-iron cultures, suggesting a possible mechanism for the drug substance coloration caused by high-iron media. Finally, hypotheses for the mechanisms of titer improvement by both high-iron and long-term culture are discussed.

Nuclear risk analysis of the Ulysses mission

NASA Astrophysics Data System (ADS)

Bartram, Bart W.; Vaughan, Frank R.; Englehart, Richard W., Dr.

1991-01-01

The use of a radioisotope thermoelectric generator fueled with plutonium-238 dioxide on the Space Shuttle-launched Ulysses mission implies some level of risk due to potential accidents. This paper describes the method used to quantify risks in the Ulysses mission Final Safety Analysis Report prepared for the U.S. Department of Energy. The starting point for the analysis described herein is following input of source term probability distributions from the General Electric Company. A Monte Carlo technique is used to develop probability distributions of radiological consequences for a range of accident scenarios thoughout the mission. Factors affecting radiological consequences are identified, the probability distribution of the effect of each factor determined, and the functional relationship among all the factors established. The probability distributions of all the factor effects are then combined using a Monte Carlo technique. The results of the analysis are presented in terms of complementary cumulative distribution functions (CCDF) by mission sub-phase, phase, and the overall mission. The CCDFs show the total probability that consequences (calculated health effects) would be equal to or greater than a given value.

46 CFR 50.10-23 - Marine Safety Center.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 46 Shipping 2 2010-10-01 2010-10-01 false Marine Safety Center. 50.10-23 Section 50.10-23 Shipping... Definition of Terms Used in This Subchapter § 50.10-23 Marine Safety Center. The term Marine Safety Center refers to the Commanding Officer, U.S. Coast Guard Marine Safety Center, 1900 Half Street, SW., Suite...

Developing a patient-led electronic feedback system for quality and safety within Renal PatientView.

PubMed

Giles, Sally J; Reynolds, Caroline; Heyhoe, Jane; Armitage, Gerry

2017-03-01

It is increasingly acknowledged that patients can provide direct feedback about the quality and safety of their care through patient reporting systems. The aim of this study was to explore the feasibility of patients, healthcare professionals and researchers working in partnership to develop a patient-led quality and safety feedback system within an existing electronic health record (EHR), known as Renal PatientView (RPV). Phase 1 (inception) involved focus groups (n = 9) and phase 2 (requirements) involved cognitive walkthroughs (n = 34) and 1:1 qualitative interviews (n = 34) with patients and healthcare professionals. A Joint Services Expert Panel (JSP) was convened to review the findings from phase 1 and agree the core principles and components of the system prototype. Phase 1 data were analysed using a thematic approach. Data from phase 1 were used to inform the design of the initial system prototype. Phase 2 data were analysed using the components of heuristic evaluation, resulting in a list of core principles and components for the final system prototype. Phase 1 identified four main barriers and facilitators to patients feeding back on quality and safety concerns. In phase 2, the JSP agreed that the system should be based on seven core principles and components. Stakeholders were able to work together to identify core principles and components for an electronic patient quality and safety feedback system in renal services. Tensions arose due to competing priorities, particularly around anonymity and feedback. Careful consideration should be given to the feasibility of integrating a novel element with differing priorities into an established system with existing functions and objectives. © 2016 European Dialysis and Transplant Nurses Association/European Renal Care Association.

Research safety vehicle, Phase II. Volume I. Executive summary. Final report jul 75-dec 76

DOE Office of Scientific and Technical Information (OSTI.GOV)

Struble, D.

1976-12-01

Volume I summarizes the results of the Minicars Research Safety Vehicle Phase II program, as detailed in Volumes II and III. Phase I identified trends leading to the desired national social goals of the mid-1980's in vehicle crashworthiness, crash avoidance, damageability, pedestrian safety, fuel economy, emissions and cost, and characterized an RSV to satisfy them. In Phase II an RSV prototype was designed, developed and tested to demonstrate the feasibility of meeting these goals simultaneously. Although further refinement is necessary to assure operational validity, in all categories the results meet or exceed the most advanced performance specified by The Presidentialmore » Task Force on Motor Vehicle Goals beyond 1980.« less

Safety of the HPV Bivalent and Quadrivalent Vaccines During Pregnancy.

PubMed

Forinash, Alicia B; Yancey, Abigail M; Pitlick, Jamie M; Myles, Thomas D

2011-02-01

To evaluate the safety of the human papillomavirus (HPV) bivalent and quadrivalent vaccines in pregnancy. PubMed (1966-August 2010) was searched using the terms human papillomavirus, human papillomavirus vaccine, and pregnancy. References were reviewed for relevant information. All studies including humans that were published in English with data describing HPV vaccine administration in pregnancy were evaluated. Two combined analyses of 7 Phase 3 efficacy trials have retrospectively evaluated the safety of unintentional administration of either the bivalent (n = 1786) or quadrivalent (n = 2085) HPV vaccine during pregnancy. In addition, postmarketing pregnancy registry surveillance data (prospective, n = 787; retrospective, n = 76) for the quadrivalent HPV vaccine have been published. However, only 279 pregnancies from the studies and 90 pregnancies from the registry occurred within 30 days of receiving the vaccination. Overall, the vaccine does not appear to be associated with an increased risk of spontaneous abortion, fetal malformations, or adverse pregnancy outcomes beyond that found in the general population. Although the data are limited, neither HPV vaccine appears to be associated with an increased risk of adverse pregnancy outcomes. However, limitations of the data include small patient populations, minimal to no adjustments for factors known to influence pregnancy outcomes or malformations, and the majority of the available pregnancy data are from retrospective analysis of Phase 3 efficacy trials. Neither HPV vaccine should be routinely administered during pregnancy. If a pregnancy occurs midseries, the remaining vaccines should be given after pregnancy completion. Further studies are required to determine actual risk. © 2011 SAGE Publications.

Pediatric experience with mipomersen as adjunctive therapy for homozygous familial hypercholesterolemia.

PubMed

Raal, Frederick J; Braamskamp, Marjet J; Selvey, Sheryl L; Sensinger, Charlotte H; Kastelein, John J

2016-01-01

Homozygous familial hypercholesterolemia (HoFH) is a rare, inherited condition resulting in severely elevated low-density lipoprotein cholesterol levels (LDL-C) leading to premature cardiovascular disease and, often, death. Mipomersen is an antisense oligonucleotide that inhibits apolipoprotein B (apo B) synthesis, lowering LDL-C levels. Mipomersen has demonstrated efficacy in adult HoFH patients, possibly providing a therapeutic option for pediatric patients. Study objectives were to summarize mipomersen efficacy and safety in the pediatric cohort of a phase 3 randomized controlled trial (RCT) and subsequent open-label extension study (OLE). Seven patients aged 12-18 years were randomized to 200-mg mipomersen or placebo weekly (26 weeks) and received mipomersen in the OLE (52 or 104 weeks). Plasma LDL-C and apo B concentrations and adverse events were assessed. All pediatric patients completed the RCT and entered OLE. The 3 mipomersen patients in the RCT experienced mean reductions from baseline to RCT end of 42.7% and 46.1% for LDL-C and apo B, respectively. Of the 4 placebo patients, 3 responded well to mipomersen during OLE, with reductions in LDL-C of 26.5%-42.1%. Three patients completed OLE treatment, and 4 patients discontinued therapy due to adverse events. Lipid level fluctuations were observed and were likely due to poor compliance. Long-term mipomersen treatment was successful regarding efficacy parameters for pediatric HoFH patients. The safety profile was consistent with other phase 3 clinical trials. Long-term compliance was an issue. Measures supporting adherence should be encouraged. Copyright © 2016 Sanofi-Genzyme. Published by Elsevier Inc. All rights reserved.

Evaluating the Cardiovascular Safety of Nonsteroidal Anti-Inflammatory Drugs.

PubMed

Antman, Elliott M

2017-05-23

Some drugs used to treat noncardiovascular conditions may adversely impact the cardiovascular status of individuals both with and without known cardiovascular disease. When the US Food and Drug Administration judges the potential cardiovascular safety signal to be of sufficient concern, it may require the pharmaceutical manufacturer of the drug in question to conduct a postmarketing (phase 4) randomized controlled trial (RCT). Although historically many phase 4 RCTs focused on efficacy (using a superiority design), contemporary phase 4 RCTs often are focused on safety and use a noninferiority design. The choices made by investigators during the planning stage of a postmarketing phase 4 RCT dedicated to the evaluation of cardiovascular safety can influence the ability to compare the standard and test agents. Multiple factors reflecting the conduct of a phase 4 RCT for a general medical condition may influence interpretation of a cardiovascular safety signal. The higher the rates of failure to adhere to the protocol and dropout from the study, the greater the risk of bias. Trials evaluating the cardiovascular safety of nonsteroidal anti-inflammatory drugs (NSAIDs) when used for arthritis are difficult to conduct and even more challenging to interpret. Concerns include the comparison of drug regimens that do not provide comparable analgesic efficacy and problems with adherence to the protocol and retention in the study. On the basis of phase 4 RCTs of NSAIDs to date, it appears that a comparatively low dose of celecoxib administered to low-risk subjects is associated with approximately the same cardiovascular risk as NSAIDs with less cyclooxygenase-2 inhibitory activity, but at the cost of not controlling arthritic pain as effectively. © 2017 American Heart Association, Inc.

Safety Profile of Biologic Drugs in the Therapy of Ulcerative Colitis: A Systematic Review and Network Meta-Analysis.

PubMed

Moćko, Paweł; Kawalec, Paweł; Pilc, Andrzej

2016-08-01

We compared the safety profile of biologic drugs in patients with moderately to severely active ulcerative colitis (UC). A systematic literature search was performed using Medline (PubMed), Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) databases through February 9, 2016. We included randomized controlled trials (RCTs) that compared the safety of biologic drugs (infliximab, adalimumab, golimumab, and vedolizumab) with one another or with placebo in patients with UC. Two reviewers independently conducted the search and selection of studies and rated the risk of bias in each trial. The network meta-analysis (NMA) was conducted for an induction phase (6-8 weeks) and maintenance phase (52-54 weeks) with a Bayesian hierarchical random effects model in Aggregate Data Drug Information System (ADDIS) software. The PROSPERO registration number was CRD42016032607. Seven RCTs were included in the systematic review with NMA. In the case of the induction phase, the NMA could be conducted for the assessment of the relative safety profile of adalimumab, golimumab, and vedolizumab, and in the case of the maintenance phase of infliximab, adalimumab, golimumab, and vedolizumab. The methodological quality of the included RCTs was evaluated as low risk of bias, but high risk of bias in the case of attrition bias (incomplete outcome data) according to the Cochrane criteria. No significant differences were found in the rate of adverse events in patients treated with the reviewed biologics. Vedolizumab was most likely to have the most favorable safety profile in the induction phase as was infliximab for the maintenance phase. The assessment of the relative safety profile revealed no significant differences between the biologic drugs. Further studies are needed to confirm our findings including head-to-head comparisons between the analyzed biologics. © 2016 Pharmacotherapy Publications, Inc.

Preventing back injuries in hospital settings: the effects of video modeling on safe patient lifting by nurses.

PubMed

Nielsen, Don; Sigurdsson, Sigurdur O; Austin, John

2009-01-01

This study evaluated video scoring and feedback about scoring as a safety intervention among 6 nursing staff. The dependent variable was safety behavior on one-person transfers. Following baseline, 5 nursing staff participated in an information phase. A video scoring phase was then introduced for all 6. A feedback phase was added for 2 participants. All participants experienced treatment withdrawal. Information resulted in improvements for all 5 participants who received it. Further improvements were observed during video scoring for the 5 participants who improved following information. No improvements were observed for the participant who received only video scoring. Safety feedback further improved safety for the 2 participants who received it. However, participants' behavior returned to video scoring levels during withdrawal.

PREVENTING BACK INJURIES IN HOSPITAL SETTINGS: THE EFFECTS OF VIDEO MODELING ON SAFE PATIENT LIFTING BY NURSES

PubMed Central

Nielsen, Don; Sigurdsson, Sigurdur O; Austin, John

2009-01-01

This study evaluated video scoring and feedback about scoring as a safety intervention among 6 nursing staff. The dependent variable was safety behavior on one-person transfers. Following baseline, 5 nursing staff participated in an information phase. A video scoring phase was then introduced for all 6. A feedback phase was added for 2 participants. All participants experienced treatment withdrawal. Information resulted in improvements for all 5 participants who received it. Further improvements were observed during video scoring for the 5 participants who improved following information. No improvements were observed for the participant who received only video scoring. Safety feedback further improved safety for the 2 participants who received it. However, participants' behavior returned to video scoring levels during withdrawal. PMID:20190918

Safety and persistence of the humoral and cellular immune responses induced by 2 doses of an AS03-adjuvanted A(H1N1)pdm09 pandemic influenza vaccine administered to infants, children and adolescents: Two open, uncontrolled studies.

PubMed

Garcia-Sicilia, José; Arístegui, Javier; Omeñaca, Félix; Carmona, Alfonso; Tejedor, Juan C; Merino, José M; García-Corbeira, Pilar; Walravens, Karl; Bambure, Vinod; Moris, Philippe; Caplanusi, Adrian; Gillard, Paul; Dieussaert, Ilse

2015-01-01

In children, 2 AS03-adjuvanted A(H1N1)pdm09 vaccine doses given 21 days apart were previously shown to induce a high humoral immune response and to have an acceptable safety profile up to 42 days following the first vaccination. Here, we analyzed the persistence data from 2 open-label studies, which assessed the safety, and humoral and cell-mediated immune responses induced by 2 doses of this vaccine. The first study was a phase II, randomized trial conducted in 104 children aged 6-35 months vaccinated with the A(H1N1)pdm09 vaccine containing 1.9 µg haemagglutinin antigen (HA) and AS03B (5.93 mg tocopherol) and the second study, a phase III, non-randomized trial conducted in 210 children and adolescents aged 3-17 years vaccinated with the A(H1N1)pdm09 vaccine containing 3.75 µg HA and AS03A (11.86 mg tocopherol). Approximately one year after the first dose, all children with available data were seropositive for haemagglutinin inhibition and neutralising antibody titres, but a decline in geometric mean antibody titres was noted. The vaccine induced a cell-mediated immune response in terms of antigen-specific CD4(+) T-cells, which persisted up to one year post-vaccination. The vaccine did not raise any safety concern, though these trials were not designed to detect rare events. In conclusion, 2 doses of the AS03-adjuvanted A(H1N1)pdm09 vaccine at 2 different dosages had a clinically acceptable safety profile, and induced high and persistent humoral and cell-mediated immune responses in children aged 6-35 months and 3-17 years. These studies have been registered at www.clinicaltrials.gov NCT00971321 and NCT00964158.

Aripiprazole once-monthly as maintenance treatment for bipolar I disorder: a 52-week, multicenter, open-label study.

PubMed

Calabrese, Joseph R; Jin, Na; Johnson, Brian; Such, Pedro; Baker, Ross A; Madera, Jessica; Hertel, Peter; Ottinger, Jocelyn; Amatniek, Joan; Kawasaki, Hiroaki

2018-06-10

The long-acting injectable antipsychotic aripiprazole once-monthly 400 mg (AOM 400) was recently approved for maintenance treatment of bipolar I disorder (BP-I). The purpose of this study was to evaluate the safety, tolerability, and efficacy of AOM 400 as long-term maintenance treatment for BP-I. This open-label multicenter study evaluated the effectiveness of AOM 400 as maintenance treatment for BP-I by assessing safety and tolerability (primary objective) and efficacy (secondary objective). The study enrolled AOM 400-naive ("de novo") patients as well as AOM 400-experienced ("rollover") patients with BP-I from a lead-in randomized, placebo-controlled clinical trial that demonstrated the efficacy of AOM 400 in the maintenance treatment of BP-I (Calabrese et al. in J Clin Psychiatry 78:324-331, 2017). Safety variables included frequency and severity of treatment-emergent adverse events (TEAEs) and TEAEs resulting in study discontinuation. Efficacy was assessed by the proportion of patients maintaining stability throughout the maintenance phase, as well as mean changes from baseline in Young Mania Rating Scale (YMRS), Montgomery-Asberg Depression Rating Scale, and Clinical Global Impressions for Bipolar Disorder-Severity of Illness Scale (CGI-BP-S) total scores. Patient acceptability and tolerability of treatment was assessed using the Patient Satisfaction with Medication Questionnaire-Modified. Of 464 patients entering the maintenance phase, 379 (82%) were de novo and 85 (18%) were rollover. TEAEs were more common in de novo than rollover patients. The overall discontinuation rate due to TEAEs was 10.3% (48/464). Improvements in YMRS and CGI-BP-S total scores were maintained during the study, and the vast majority of both de novo (87.0%) and rollover (97.6%) patients maintained stability through their last visit. Overall, the need for rescue medication during the maintenance phase was minimal (< 10% of patients). Patient satisfaction levels were high, with both de novo and rollover patients rating the side effect burden of AOM 400 as greatly improved relative to previous medications. AOM 400 was safe, effective, and well tolerated by both de novo and AOM 400-experienced patients with BP-I for long-term maintenance treatment. Trial registration ClinicalTrials.gov, NCT01710709.

Towards a Usability and Error "Safety Net": A Multi-Phased Multi-Method Approach to Ensuring System Usability and Safety.

PubMed

Kushniruk, Andre; Senathirajah, Yalini; Borycki, Elizabeth

2017-01-01

The usability and safety of health information systems have become major issues in the design and implementation of useful healthcare IT. In this paper we describe a multi-phased multi-method approach to integrating usability engineering methods into system testing to ensure both usability and safety of healthcare IT upon widespread deployment. The approach involves usability testing followed by clinical simulation (conducted in-situ) and "near-live" recording of user interactions with systems. At key stages in this process, usability problems are identified and rectified forming a usability and technology-induced error "safety net" that catches different types of usability and safety problems prior to releasing systems widely in healthcare settings.

Osimertinib in Pretreated T790M-Positive Advanced Non-Small-Cell Lung Cancer: AURA Study Phase II Extension Component.

PubMed

Yang, James Chih-Hsin; Ahn, Myung-Ju; Kim, Dong-Wan; Ramalingam, Suresh S; Sequist, Lecia V; Su, Wu-Chou; Kim, Sang-We; Kim, Joo-Hang; Planchard, David; Felip, Enriqueta; Blackhall, Fiona; Haggstrom, Daniel; Yoh, Kiyotaka; Novello, Silvia; Gold, Kathryn; Hirashima, Tomonori; Lin, Chia-Chi; Mann, Helen; Cantarini, Mireille; Ghiorghiu, Serban; Jänne, Pasi A

2017-04-20

Purpose Osimertinib is an irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) selective for both EGFR-TKI sensitizing ( EGFRm) and T790M resistance mutations. AURA (NCT01802632) is a phase I/II clinical trial to determine the dose, safety, and efficacy of osimertinib. This article reports the results from the phase II extension component. Patients and Methods Patients with EGFR-TKI-pretreated EGFRm- and T790M-positive advanced non-small-cell lung cancer (NSCLC) received once-daily osimertinib 80 mg. T790M status was confirmed by central testing from a tumor sample taken after the most recent disease progression. Patients with asymptomatic, stable CNS metastases that did not require corticosteroids were allowed to enroll. The primary end point was objective response rate (ORR) by independent radiology assessment. Secondary end points were disease control rate, duration of response, progression-free survival (PFS), and safety. Patient-reported outcomes comprised an exploratory objective. Results In total, 201 patients received treatment, with a median treatment duration of 13.2 months at the time of data cutoff (November 1, 2015). In evaluable patients (n = 198), ORR was 62% (95% CI, 54% to 68%), and the disease control rate was 90% (95% CI, 85 to 94). Median duration of response in 122 responding patients was 15.2 months (95% CI, 11.3 to not calculable). Median PFS was 12.3 months (95% CI, 9.5 to 13.8). The most common possibly causally related adverse events (investigator assessed) were diarrhea (43%; grade ≥ 3, < 1%) and rash (grouped terms; 40%; grade ≥ 3, < 1%). Interstitial lung disease (grouped terms) was reported in eight patients (4%; grade 1, n = 2; grade 3, n = 3; grade 5, n = 3). Conclusion In patients with EGFRm T790M advanced NSCLC who progress after EGFR-TKI treatment, osimertinib provides a high ORR, encouraging PFS, and durable response.

46 CFR 50.10-23 - Marine Safety Center.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 46 Shipping 2 2014-10-01 2014-10-01 false Marine Safety Center. 50.10-23 Section 50.10-23 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) MARINE ENGINEERING GENERAL PROVISIONS Definition of Terms Used in This Subchapter § 50.10-23 Marine Safety Center. The term Marine Safety Center...

46 CFR 50.10-23 - Marine Safety Center.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 46 Shipping 2 2013-10-01 2013-10-01 false Marine Safety Center. 50.10-23 Section 50.10-23 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) MARINE ENGINEERING GENERAL PROVISIONS Definition of Terms Used in This Subchapter § 50.10-23 Marine Safety Center. The term Marine Safety Center...

46 CFR 50.10-23 - Marine Safety Center.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 46 Shipping 2 2011-10-01 2011-10-01 false Marine Safety Center. 50.10-23 Section 50.10-23 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) MARINE ENGINEERING GENERAL PROVISIONS Definition of Terms Used in This Subchapter § 50.10-23 Marine Safety Center. The term Marine Safety Center...

46 CFR 50.10-23 - Marine Safety Center.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 46 Shipping 2 2012-10-01 2012-10-01 false Marine Safety Center. 50.10-23 Section 50.10-23 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) MARINE ENGINEERING GENERAL PROVISIONS Definition of Terms Used in This Subchapter § 50.10-23 Marine Safety Center. The term Marine Safety Center...

No harm from five year ingestion of oats in coeliac disease

PubMed Central

Janatuinen, E K; Kemppainen, T A; Julkunen, R J K; Kosma, V-M; Mäki, M; Heikkinen, M; Uusitupa, M I J

2002-01-01

Background: Six to 12 months of ingestion of moderate amounts of oats does not have a harmful effect in adult patients with coeliac disease. As the safety of long term intake of oats in coeliac patients is not known, we continued our previous 6–12 month study for five years. Aim: To assess the safety of long term ingestion of oats in the diet of coeliac patients. Patients: In our previous study, the effects of a gluten free diet and a gluten free diet including oats were compared in a randomised trial involving 92 adult patients with coeliac disease (45 in the oats group, 47 in the control group). After the initial phase of 6–12 months, patients in the oats group were allowed to eat oats freely in conjunction with an otherwise gluten free diet. After five years, 35 patients in the original oats group (23 still on an oats diet) and 28 in the control group on a conventional gluten free diet were examined. Methods: Clinical and nutritional assessment, duodenal biopsies for conventional histopathology and histomorphometry, and measurement of antiendomysial, antireticulin, and antigliadin antibodies. Results: There were no significant differences between controls and those patients consuming oats with respect to duodenal villous architecture, inflammatory cell infiltration of the duodenal mucosa, or antibody titres after five years of follow up. In both groups histological and histomorphometric indexes improved equally with time. Conclusions: This study provides the first evidence of the long term safety of oats as part of a coeliac diet in adult patients with coeliac disease. It also appears that the majority of coeliac patients prefer oats in their diet. PMID:11839710

Long-term opioid treatment of chronic nonmalignant pain: unproven efficacy and neglected safety?

PubMed Central

Kissin, Igor

2013-01-01

Background For the past 30 years, opioids have been used to treat chronic nonmalignant pain. This study tests the following hypotheses: (1) there is no strong evidence-based foundation for the conclusion that long-term opioid treatment of chronic nonmalignant pain is effective; and (2) the main problem associated with the safety of such treatment – assessment of the risk of addiction – has been neglected. Methods Scientometric analysis of the articles representing clinical research in this area was performed to assess (1) the quality of presented evidence (type of study); and (2) the duration of the treatment phase. The sufficiency of representation of addiction was assessed by counting the number of articles that represent (1) editorials; (2) articles in the top specialty journals; and (3) articles with titles clearly indicating that the addiction-related safety is involved (topic-in-title articles). Results Not a single randomized controlled trial with opioid treatment lasting >3 months was found. All studies with a duration of opioid treatment ≥6 months (n = 16) were conducted without a proper control group. Such studies cannot provide the consistent good-quality evidence necessary for a strong clinical recommendation. There were profound differences in the number of addiction articles related specifically to chronic nonmalignant pain patients and to opioid addiction in general. An inadequate number of chronic pain-related publications were observed with all three types of counted articles: editorials, articles in the top specialty journals, and topic-in-title articles. Conclusion There is no strong evidence-based foundation for the conclusion that long-term opioid treatment of chronic nonmalignant pain is effective. The above identified signs indicating neglect of addiction associated with the opioid treatment of chronic nonmalignant pain were present. PMID:23874119

Long-term follow-up observation of the safety, immunogenicity, and effectiveness of Gardasil™ in adult women.

PubMed

Luna, Joaquin; Plata, Manuel; Gonzalez, Mauricio; Correa, Alfonso; Maldonado, Ivete; Nossa, Claudia; Radley, David; Vuocolo, Scott; Haupt, Richard M; Saah, Alfred

2013-01-01

Previous analyses from a randomized trial in women aged 24-45 have shown the quadrivalent HPV vaccine to be efficacious in the prevention of infection, cervical intraepithelial neoplasia (CIN) and external genital lesions (EGL) related to HPV 6/11/16/18 through 4 years. In this report we present long term follow-up data on the efficacy, safety and immunogenicity of the quadrivalent HPV vaccine in adult women. Follow-up data are from a study being conducted in 5 sites in Colombia designed to evaluate the long-term immunogenicity, effectiveness, and safety of the qHPV vaccine in women who were vaccinated at 24 to 45 years of age (in the original vaccine group during the base study [n = 684]) or 29 to 50 years of age (in the original placebo group during the base study [n = 651]). This analysis summarizes data collected as of the year 6 post-vaccination visit relative to day 1 of the base study (median follow-up of 6.26 years) from both the original base study and the Colombian follow-up. There were no cases of HPV 6/11/16/18-related CIN or EGL during the extended follow-up phase in the per-protocol population. Immunogenicity persists against vaccine-related HPV types, and no evidence of HPV type replacement has been observed. No new serious adverse experiences have been reported. Vaccination with qHPV vaccine provides generally safe and effective protection from HPV 6-, 11-, 16-, and 18-related genital warts and cervical dysplasia through 6 years following administration to 24-45 year-old women. Clinicaltrials.govNCT00090220.

Five year follow-up after a first booster vaccination against tick-borne encephalitis following different primary vaccination schedules demonstrates long-term antibody persistence and safety.

PubMed

Beran, Jiří; Xie, Fang; Zent, Olaf

2014-07-23

Long-term vaccination programs are recommended for individuals living in regions endemic for tick-borne encephalitis (TBE). Current recommendations suggest a first booster vaccine be administered 3 years after a conventional regimen or 12-18 months after a rapid regimen. However, the research supporting subsequent booster intervals is limited. The aim of this study was thus to evaluate the long-term persistence of TBE antibodies in adults and adolescents after a first booster dose with Encepur(®). A total of 323 subjects aged 15 years and over, who had received one of four different primary TBE vaccination series in a parent study, participated in this follow-up Phase IV trial. Immunogenicity and safety were assessed for up to five years after a first booster dose, which was administered three years after completion of the primary series. One subset of subjects was excluded from the booster vaccination since they had already received their booster prior to enrollment. For comparison, immune responses were still recorded for these subjects on Day 0 and on an annual basis until Year 5, but safety information was not collected. Following a booster vaccination, high antibody titers were recorded in all groups throughout the study. Neutralization test (NT) titers of ≥ 10 were noted in at least 94% of subjects at every time point post-booster (on Day 21 and through Years 1-5). These results demonstrated that a first booster vaccination following any primary immunization schedule results in high and long-lasting (>5 years) immune responses. These data lend support to the current belief that subsequent TBE booster intervals could be extended from the current recommendation. NCT00387634. Copyright © 2014 Elsevier Ltd. All rights reserved.

Short-Term Safety of Zoledronic Acid in Young Patients With Bone Disorders: An Extensive Institutional Experience.

PubMed

George, Sobenna; Weber, David R; Kaplan, Paige; Hummel, Kelly; Monk, Heather M; Levine, Michael A

2015-11-01

Zoledronic acid (ZA) is increasingly used in young patients with bone disorders. However, data related to the safety of ZA administration in this population are limited. The study aimed to characterize the short-term safety profile of ZA and identify risk factors for ZA-related adverse events (AEs) in young patients. This was a retrospective chart review of inpatients and outpatients less than 21 years old who received at least one ZA infusion between July 2010 and January 2014 at The Children's Hospital of Philadelphia. Eighty-one patients (56% male; median age, 12 y; age at first infusion, 0.5 to 20 y) with diverse skeletal disorders received a total of 204 infusions. The most common indications were osteoporosis (33% of cohort) and osteogenesis imperfecta (27.2%). The median ZA dose was 0.025 mg/kg (interquartile range, 0.025-0.05); the median dosing interval was 6 months (range, 1 to 25.6 mo). AEs were mild and more common after the first ZA infusion in patients with no previous bisphosphonate exposure: hypophosphatemia (25.2% of infusions), acute phase reactions (19.1%), and hypocalcemia (16.4%). Symptomatic hypocalcemia requiring iv calcium occurred after two infusions. ZA dose was significantly associated with hypophosphatemia, but not other AEs. Hypocalcemia was more common in patients with high bone turnover as assessed by preinfusion alkaline phosphatase levels. AEs were not associated with diagnosis, baseline serum calcium, or calcium/calcitriol supplementation. Acute AEs related to ZA infusion in youths are common, occur principally after the first ZA infusion in bisphosphonate-naive patients, and are typically mild and easily managed. Future prospective studies are needed to determine the potential long-term risks, as well as benefits, of ZA therapy in the pediatric population.

Long-Term Follow-up Observation of the Safety, Immunogenicity, and Effectiveness of Gardasil™ in Adult Women

PubMed Central

Luna, Joaquin; Plata, Manuel; Gonzalez, Mauricio; Correa, Alfonso; Maldonado, Ivete; Nossa, Claudia; Radley, David; Vuocolo, Scott; Haupt, Richard M.; Saah, Alfred

2013-01-01

Background Previous analyses from a randomized trial in women aged 24–45 have shown the quadrivalent HPV vaccine to be efficacious in the prevention of infection, cervical intraepithelial neoplasia (CIN) and external genital lesions (EGL) related to HPV 6/11/16/18 through 4 years. In this report we present long term follow-up data on the efficacy, safety and immunogenicity of the quadrivalent HPV vaccine in adult women. Methods Follow-up data are from a study being conducted in 5 sites in Colombia designed to evaluate the long-term immunogenicity, effectiveness, and safety of the qHPV vaccine in women who were vaccinated at 24 to 45 years of age (in the original vaccine group during the base study [n = 684]) or 29 to 50 years of age (in the original placebo group during the base study [n = 651]). This analysis summarizes data collected as of the year 6 post-vaccination visit relative to day 1 of the base study (median follow-up of 6.26 years) from both the original base study and the Colombian follow-up. Results There were no cases of HPV 6/11/16/18-related CIN or EGL during the extended follow-up phase in the per-protocol population. Immunogenicity persists against vaccine-related HPV types, and no evidence of HPV type replacement has been observed. No new serious adverse experiences have been reported. Conclusions Vaccination with qHPV vaccine provides generally safe and effective protection from HPV 6-, 11-, 16-, and 18-related genital warts and cervical dysplasia through 6 years following administration to 24–45 year-old women. Trial Registration Clinicaltrials.gov NCT00090220 PMID:24391768

10 Years of Car-2-X Communication - a Success Story?

NASA Astrophysics Data System (ADS)

Wischhof, Lars; Ebner, André

2012-05-01

For more than ten years, car-2-x communication has been a major topic of research in the scientific community and an important development focus for the automotive industry. First, this article takes a retrospective look at the evolution of car-2-x and the two different communication paradigms: decentralized car-2-car communication and centralized cellular solutions. Afterwards, a comparison of their technical advantages and limitations is presented, respectively. The result shows that in order to implement safety-relevant applications, car-2-car communication has strong advantages compared to cellular technologies but requires high market penetration. However, its introduction solely for safety applications is difficult since the required penetration will not be achieved until several years after initial deployment. Therefore, car-2-car communication must provide a benefit to the customer, even in the phase of market introduction. For this purpose, the article outlines an approach called SODAD (Segment-Oriented Data Abstraction and Dissemination). It offers a possibility to introduce decentralized vehicular applications with early customer benefit, in order to enable safety applications based on car-2-car communication on a long term.

Decommissioning of the Iraq former nuclear complex

DOE Office of Scientific and Technical Information (OSTI.GOV)

Abbas, Mohammed; Helou, Tuama; Ahmead, Bushra

2007-07-01

Available in abstract form only. Full text of publication follows: A number of sites in Iraq have some degree of radiological contamination and require decommissioning and remediation in order to ensure radiological safety. Many of these sites in Iraq are located at the nuclear research centre at Al Tuwaitha. The International Atomic Energy Agency (IAEA) Board of Governors has approved a project to assist the Government of Iraq in the evaluation and decommissioning of former facilities that used radioactive materials. The project is divided into three phases: Phase 1: collect and analyze all available data and conduct training of themore » Iraqi staff, Phase 2: develop a decommissioning and remediation plan, and Phase 3: implement field activities relating to decommissioning, remediation and site selection suitable for final disposal of waste. Four working groups have been established to complete the Phase 1 work and significant progress has been made in drafting a new nuclear law which will provide the legal basis for the licensing of the decommissioning of the former nuclear complex. Work is also underway to collect and analysis existing date, to prioritize future activities and to develop a waste management strategy. This will be a long-term and costly project. (authors)« less

Safety assessment tool for construction zone work phasing plans

DOT National Transportation Integrated Search

2016-05-01

The Highway Safety Manual (HSM) is the compilation of national safety research that provides quantitative methods for : analyzing highway safety. The HSM presents crash modification functions related to freeway work zone characteristics such as : wor...

Pirfenidone: an update on clinical trial data and insights from everyday practice.

PubMed

Kreuter, Michael

2014-03-01

Pirfenidone is an orally active, small molecule that inhibits synthesis of profibrotic and inflammatory mediators. It was approved for the treatment of adults with mild-to-moderate idiopathic pulmonary fibrosis in the European Union based on the results of two pivotal phase III, double-blind, randomised, placebo-controlled clinical trials (CAPACITY) demonstrating efficacy and safety, and supported by two Japanese clinical trials (SP2 and SP3). Currently, there is increasing interest in experience with pirfenidone in patients relating to the real-world setting. Following the publication of the CAPACITY clinical studies, additional analyses have been conducted to provide further support for pirfenidone in clinical practice, including a modified per-protocol analysis of the CAPACITY study population. New data from the RECAP extension study also provided longer term data for pirfenidone and promising continuation rates with treatment. Pirfenidone is also being evaluated in specialist centre cohorts providing important information on real-world efficacy and safety. Increasing experience with pirfenidone in everyday clinical practice is helping to establish \\expert guidance on the management of known adverse events, together with practical recommendations, to ensure adherence to treatment so that the possible longer term benefits of pirfenidone treatment in reducing lung function decline can be maximised.

Avacopan in the treatment of ANCA-associated vasculitis.

PubMed

Tesar, Vladimir; Hruskova, Zdenka

2018-05-08

ANCA-associated vasculitis (AAV) is a rare but potentially life-threatening disease. Currently used induction treatment (cyclophosphamide or rituximab with high-dose corticosteroids) has significantly improved outcome of AAV, but is associated with high toxicity. Alternative complement pathway activation was shown to play a role in the pathogenesis of AAV, thus providing rationale for the use of avacopan, a selective inhibitor of C5a receptor, in the treatment of AAV. Areas covered: Pharmacokinetic and pharmocodynamic properties of avacopan, clinical efficacy and safety and tolerability of avacopan in so far performed clinical trials in patients with AAV are reviewed and discussed. Expert opinion: Avacopan was shown to have at least similar efficacy compared to high dose corticosteroids in patients with active AAV with renal involvement, while there were no major safety issues reported. Replacement of corticosteroids should decrease the corticosteroid-related toxicity and improve long-term outcome of patients with AAV even though this still needs to be confirmed in a larger trial. Data on long-term outcome of avacopan-treated patients are currently lacking and will be eagerly awaited. In the future, avacopan could replace corticosteroids not only in the induction phase, but also in the maintenance treatment of AAV.

Biosimilar Monoclonal Antibodies for Inflammatory Bowel Disease: Current Comfort and Future Prospects.

PubMed

Gecse, Krisztina B; Lakatos, Péter L

2016-10-01

Biosimilars are biologic medicines that enter the market after a patent for an original reference product expires. The European Medicines Agency (EMA) developed a stringent legislation process for biosimilar monoclonal antibodies, whereby similarity to the reference medicinal product in terms of quality characteristics, biological activity, clinical safety and efficacy must be demonstrated. Biosimilar infliximab CT-P13 was the first biosimilar monoclonal antibody to receive EMA marketing authorization, and further biosimilar molecules are being developed. The phase I and III clinical trials were conducted in ankylosing spondylitis and rheumatoid arthritis, and the use of CT-P13 in inflammatory bowel disease (IBD) was extrapolated on the results of these trials. Medical professionals were initially concerned about the reversed engineering process, the novel legal framework and the lack of clinical data in IBD. Emerging real-world data have confirmed the similarities between CT-P13 and the reference product in terms of efficacy, safety and immunogenicity in IBD. The cost reduction represented by biosimilars promotes industry competition and improves treatment access with sustained quality of care. This article reviews the existing and emerging clinical data for CT-P13 and a future perspective on biosimilar use in IBD.

Holographic display system for restoration of sight to the blind

PubMed Central

Goetz, G A; Mandel, Y; Manivanh, R; Palanker, D V; Čižmár, T

2013-01-01

Objective We present a holographic near-the-eye display system enabling optical approaches for sight restoration to the blind, such as photovoltaic retinal prosthesis, optogenetic and other photoactivation techniques. We compare it with conventional LCD or DLP-based displays in terms of image quality, field of view, optical efficiency and safety. Approach We detail the optical configuration of the holographic display system and its characterization using a phase-only spatial light modulator. Main results We describe approaches to controlling the zero diffraction order and speckle related issues in holographic display systems and assess the image quality of such systems. We show that holographic techniques offer significant advantages in terms of peak irradiance and power efficiency, and enable designs that are inherently safer than LCD or DLP-based systems. We demonstrate the performance of our holographic display system in the assessment of cortical response to alternating gratings projected onto the retinas of rats. Significance We address the issues associated with the design of high brightness, near-the-eye display systems and propose solutions to the efficiency and safety challenges with an optical design which could be miniaturized and mounted onto goggles. PMID:24045579

Synthesis of the SRM Fragmentation Activities Performed within VEGA Program

NASA Astrophysics Data System (ADS)

Jarry, A.; Meyer-Lasalle, F.; Le Falc'her, D.

2013-09-01

In the frame of VEGA program and especially the first flight on February 13, 2013, safety was a major concern. The default of the launcher and its impact on the close range were amongst the development phase topics because of the propellant masses at stake and the surrounding inhabited environment. A task group composed of members from ESA, CNES and industrial partners involved was formed for this matter.All SRMs are equipped with destruction chains. While P80 (first stage) is functioning, the Zefiri remain unpressurized. A scenario was set stating that the activation of Zefiri cutting chord creates an ignited gap inside the propellant. This ought to propagate till the inner bore, driving the explosion of the motor.This scenario was studied through small scale tests and numerical simulation, providing confidence on the feasibility of the destruction of the SRMs as well as inputs in terms of safety delays.

Analysis of nuclear waste disposal in space, phase 3. Volume 2: Technical report

NASA Technical Reports Server (NTRS)

Rice, E. E.; Miller, N. E.; Yates, K. R.; Martin, W. E.; Friedlander, A. L.

1980-01-01

The options, reference definitions and/or requirements currently envisioned for the total nuclear waste disposal in space mission are summarized. The waste form evaluation and selection process is documented along with the physical characteristics of the iron nickel-base cermet matrix chosen for disposal of commercial and defense wastes. Safety aspects of radioisotope thermal generators, the general purpose heat source, and the Lewis Research Center concept for space disposal are assessed as well as the on-pad catastrophic accident environments for the uprated space shuttle and the heavy lift launch vehicle. The radionuclides that contribute most to long-term risk of terrestrial disposal were determined and the effects of resuspension of fallout particles from an accidental release of waste material were studied. Health effects are considered. Payload breakup and rescue technology are discussed as well as expected requirements for licensing, supporting research and technology, and safety testing.

Analysis of nuclear waste disposal in space, phase 3. Volume 2: Technical report

NASA Astrophysics Data System (ADS)

Rice, E. E.; Miller, N. E.; Yates, K. R.; Martin, W. E.; Friedlander, A. L.

1980-03-01

The options, reference definitions and/or requirements currently envisioned for the total nuclear waste disposal in space mission are summarized. The waste form evaluation and selection process is documented along with the physical characteristics of the iron nickel-base cermet matrix chosen for disposal of commercial and defense wastes. Safety aspects of radioisotope thermal generators, the general purpose heat source, and the Lewis Research Center concept for space disposal are assessed as well as the on-pad catastrophic accident environments for the uprated space shuttle and the heavy lift launch vehicle. The radionuclides that contribute most to long-term risk of terrestrial disposal were determined and the effects of resuspension of fallout particles from an accidental release of waste material were studied. Health effects are considered. Payload breakup and rescue technology are discussed as well as expected requirements for licensing, supporting research and technology, and safety testing.

Influences of pre-crash braking induced dummy - forward displacements on dummy behaviour during EuroNCAP frontal crashtest.

PubMed

Woitsch, Gernot; Sinz, Wolfgang

2014-01-01

Combination of active and passive safety systems is a future key to further improvement in vehicle safety. Autonomous braking systems are able to reduce collision speeds, and therefore severity levels significantly. Passengers change their position due to pre-impact vehicle motion, a fact, which has not yet been considered in common crash tests. For this paper, finite elements simulations of crash tests were performed to show that forward displacements due to pre-crash braking do not necessarily increase dummy load levels. So the influence of different pre-crash scenarios, all leading to equal closing speeds in the crash phase, are considered in terms of vehicle motion (pitching, deceleration) and restraint system configurations (belt load limiter, pretensioner). The influence is evaluated by dummy loads as well as contact risk between the dummy and the interior. Copyright © 2013 Elsevier Ltd. All rights reserved.

Maintenance of Clinical and Radiographic Benefit With Intravenous Golimumab Therapy in Patients With Active Rheumatoid Arthritis Despite Methotrexate Therapy: Week‐112 Efficacy and Safety Results of the Open‐Label Long‐Term Extension of a Phase III, Double‐Blind, Randomized, Placebo‐Controlled Trial

PubMed Central

Mendelsohn, Alan M.; Kim, Lilianne; Xu, Zhenhua; Leu, Jocelyn; Han, Chenglong; Lo, Kim Hung; Westhovens, Rene; Weinblatt, Michael E.

2015-01-01

Objective To evaluate the safety, efficacy, pharmacokinetics, immunogenicity, and radiographic progression through 2 years of treatment with intravenous (IV) golimumab plus methotrexate (MTX) in an open‐label extension of a phase III trial of patients with active rheumatoid arthritis (RA) despite MTX therapy. Methods In the phase III, double‐blind, randomized, placebo‐controlled GO‐FURTHER trial, 592 patients with active RA were randomized (2:1) to intravenous golimumab 2 mg/kg plus MTX (Group 1) or placebo plus MTX (Group 2) at weeks 0 and 4, then every 8 weeks thereafter; placebo patients crossed over to golimumab at week 16 (early escape) or week 24 (crossover). The final golimumab infusion was at week 100. Assessments included American College of Rheumatology 20%, 50%, 70% (ACR20, ACR50, ACR70) response criteria, 28‐joint count disease activity score using the C‐reactive protein level (DAS28‐CRP), physical function and quality of life measures, and changes in the modified Sharp/van der Heijde scores (SHS). Safety was monitored through week 112. Results In total, 486 patients (82.1%) continued treatment through week 100, and 68.1%, 43.8%, and 23.5% had an ACR20/50/70 response, respectively, at week 100. Clinical response and improvements in physical function and quality of life were generally maintained from week 24 through 2 years. Mean change from baseline to week 100 in SHS score was 0.74 in Group 1 and 2.10 in Group 2 (P = 0.005); progression from week 52 to week 100 was clinically insignificant in both groups. A total of 481 patients completed the safety followup through week 112; 79.1% had an adverse event, and 18.2% had a serious adverse event. Conclusion Clinical response to IV golimumab plus MTX was maintained through week 100. Radiographic progression following golimumab treatment was clinically insignificant between week 52 and week 100. No unexpected adverse events occurred through week 112, and the safety profile was consistent with anti–tumor necrosis factor therapy. PMID:25623393

Individuals with severely impaired vision can learn useful orientation and mobility skills in virtual streets and can use them to improve real street safety.

PubMed

Bowman, Ellen Lambert; Liu, Lei

2017-01-01

Virtual reality has great potential in training road safety skills to individuals with low vision but the feasibility of such training has not been demonstrated. We tested the hypotheses that low vision individuals could learn useful skills in virtual streets and could apply them to improve real street safety. Twelve participants, whose vision was too poor to use the pedestrian signals were taught by a certified orientation and mobility specialist to determine the safest time to cross the street using the visual and auditory signals made by the start of previously stopped cars at a traffic-light controlled street intersection. Four participants were trained in real streets and eight in virtual streets presented on 3 projection screens. The crossing timing of all participants was evaluated in real streets before and after training. The participants were instructed to say "GO" at the time when they felt the safest to cross the street. A safety score was derived to quantify the GO calls based on its occurrence in the pedestrian phase (when the pedestrian sign did not show DON'T WALK). Before training, > 50% of the GO calls from all participants fell in the DON'T WALK phase of the traffic cycle and thus were totally unsafe. 20% of the GO calls fell in the latter half of the pedestrian phase. These calls were unsafe because one initiated crossing this late might not have sufficient time to walk across the street. After training, 90% of the GO calls fell in the early half of the pedestrian phase. These calls were safer because one initiated crossing in the pedestrian phase and had at least half of the pedestrian phase for walking across. Similar safety changes occurred in both virtual street and real street trained participants. An ANOVA showed a significant increase of the safety scores after training and there was no difference in this safety improvement between the virtual street and real street trained participants. This study demonstrated that virtual reality-based orientation and mobility training could be as efficient as real street training in improving street safety in individuals with severely impaired vision.

Vocabulary of aerospace safety terms pertaining to cryogenic safety, fires, explosions, and structure failure

NASA Technical Reports Server (NTRS)

Pelouch, J. J., Jr.; Mandel, G.; Ordin, P. M.

1976-01-01

This vocabulary listing characterizes the contents of over 10,000 documents of the NASA Aerospace Safety Research and Data Institute's (ASRDI) safety engineering collection. The ASRDI collection is now one of the series accessible on the NASA RECON data base. There are approximately 6,300 postable terms that describe literature in the areas of cryogenic fluid safety, specifically hydrogen, oxygen, liquified natural gas; fire and explosion technology; and the mechanics of structural failure. To facilitate the proper selection of information nonpostable, related and array terms have been included in this listing.

Space transfer vehicle concepts and requirements. Volume 4: Summary of special studies

NASA Technical Reports Server (NTRS)

1993-01-01

Our final report for Phase 1 addressed the future space transportation needs and requirements based on the current assets, at the time, and their evolution through technology/advanced development using a path and schedule that supported the world leadership role of the United States in a responsible and realistic financial forecast. Always, and foremost, the recommendations placed high values on the safety and success of missions both manned and unmanned through a total quality management philosophy at Martin Marietta. The second phase of the STV contract involved the use of Technical Directives (TD) to provide short-term support for specialized tasks as required by the COTR. Three of these tasks were performed in parallel with Phase 1. These tasks were the Liquid Acquisition Experiment (LACE), Liquid Reorientation Experiment (LIRE), and Expert System for Design, Operation, and Technology Studies (ESDOTS). The results of these TD's were reported in conjunction with the Phase 1 Final Report. Cost analysis of existing launch systems has demonstrated a need for a new upper stage that will increase America's competitiveness in the global launch services market. To provide a growth path of future exploration class STV's, near-term low-cost upper stages featuring modularity, portability, scalability, and evolvability must be developed. These recommendations define a program that: leverages ongoing activities to establish a new development environment, develop technologies that benefit the entire life cycle of a system, and result in a scalable hardware platform that provides a growth path to future upper stages.

Patient-reported safety incidents in older patients with long-term conditions: a large cross-sectional study

PubMed Central

Panagioti, Maria; Blakeman, Thomas; Hann, Mark; Bower, Peter

2017-01-01

Background Increasing evidence suggests that patient safety is a serious concern for older patients with long-term conditions. Despite this, there is a lack of research on safety incidents encountered by this patient group. In this study, we sought to examine patient reports of safety incidents and factors associated with reports of safety incidents in older patients with long-term conditions. Methods The baseline cross-sectional data from a longitudinal cohort study were analysed. Older patients (n=3378 aged 65 years and over) with a long-term condition registered in general practices were included in the study. The main outcome was patient-reported safety incidents including availability and appropriateness of medical tests and prescription of wrong types or doses of medication. Binary univariate and multivariate logistic regression analyses were undertaken to examine factors associated with patient-reported safety incidents. Results Safety incidents were reported by 11% of the patients. Four factors were significantly associated with patient-reported safety incidents in multivariate analyses. The experience of multiple long-term conditions (OR=1.09, 95% CI 1.05 to 1.13), a probable diagnosis of depression (OR=1.36, 95% CI 1.06 to 1.74) and greater relational continuity of care (OR=1.28, 95% CI 1.08 to 1.52) were associated with increased odds for patient-reported safety incidents. Perceived greater support and involvement in self-management was associated with lower odds for patient-reported safety incidents (OR=0.95, 95% CI 0.93 to 0.97). Conclusions We found that older patients with multimorbidity and depression are more likely to report experiences of patient safety incidents. Improving perceived support and involvement of patients in their care may help prevent patient-reported safety incidents. PMID:28559454

Towards an International Classification for Patient Safety: key concepts and terms

PubMed Central

Runciman, William; Hibbert, Peter; Thomson, Richard; Van Der Schaaf, Tjerk; Sherman, Heather; Lewalle, Pierre

2009-01-01

Background Understanding the patient safety literature has been compromised by the inconsistent use of language. Objectives To identify key concepts of relevance to the International Patient Safety Classification (ICPS) proposed by the World Alliance For Patient Safety of the World Health Organization (WHO), and agree on definitions and preferred terms. Methods Six principles were agreed upon—that the concepts and terms should: be applicable across the full spectrum of healthcare; be consistent with concepts from other WHO Classifications; have meanings as close as possible to those in colloquial use; convey the appropriate meanings with respect to patient safety; be brief and clear, without unnecessary or redundant qualifiers; be fit-for-purpose for the ICPS. Results Definitions and preferred terms were agreed for 48 concepts of relevance to the ICPS; these were described and the relationships between them and the ICPS were outlined. Conclusions The consistent use of key concepts, definitions and preferred terms should pave the way for better understanding, for comparisons between facilities and jurisdictions, and for trends to be tracked over time. Changes and improvements, translation into other languages and alignment with other sets of patient safety definitions will be necessary. This work represents the start of an ongoing process of progressively improving a common international understanding of terms and concepts relevant to patient safety. PMID:19147597

Safety Effectiveness of Regulatory Headlight Signs in Wyoming - Phase 1 : Interim Report - Phase 2

DOT National Transportation Integrated Search

2016-01-01

Although Daytime Running Lights (DRLs) may have a significant impact on increasing vehicle conspicuity during different times of the day, their effect on overall safety is still up for debate. A recent study by the U.S. Department of Transportation (...

75 FR 13336 - Notice of Passenger Facility Charge (PFC) Approvals and Disapprovals

Federal Register 2010, 2011, 2012, 2013, 2014

2010-03-19

... Approved for Collection at Key West International Airport (EYW) and Use at EYW: Runway safety area design. Runway safety area construction. Approach clearing--design. Runway obstruction clearing--design. Runway obstruction clearing, phase II--construction. Noise implementation plan, phase 6--design. Noise implementation...

Effects of Testing Method on Stretch-Flangeability of Dual-Phase 980/1180 Steel Grades

NASA Astrophysics Data System (ADS)

Madrid, Mykal; Van Tyne, Chester J.; Sadagopan, Sriram; Pavlina, Erik J.; Hu, Jun; Clarke, Kester D.

2018-04-01

Challenging fuel economy and safety standards in the automotive industry have led to the need for materials with higher strength while maintaining levels of formability that meet component manufacturing requirements. Advanced high-strength steels, such as dual-phase steels with tensile strengths of 980 MPa and 1180 MPa, are of interest to address this need. Increasing the strength of these materials typically comes at the expense of ductility, which may result in problems when stamping parts with trimmed or sheared edges, as cracking at the sheared edge may occur at lower strains. Here, hole expansion tests were performed with different punch geometries (conical and flat-bottom) and different edge conditions (sheared and machined) to understand the effects of testing conditions on performance, and these results are discussed in terms of mechanical properties and microstructures.

Effects of Testing Method on Stretch-Flangeability of Dual-Phase 980/1180 Steel Grades

NASA Astrophysics Data System (ADS)

Madrid, Mykal; Van Tyne, Chester J.; Sadagopan, Sriram; Pavlina, Erik J.; Hu, Jun; Clarke, Kester D.

2018-06-01

Challenging fuel economy and safety standards in the automotive industry have led to the need for materials with higher strength while maintaining levels of formability that meet component manufacturing requirements. Advanced high-strength steels, such as dual-phase steels with tensile strengths of 980 MPa and 1180 MPa, are of interest to address this need. Increasing the strength of these materials typically comes at the expense of ductility, which may result in problems when stamping parts with trimmed or sheared edges, as cracking at the sheared edge may occur at lower strains. Here, hole expansion tests were performed with different punch geometries (conical and flat-bottom) and different edge conditions (sheared and machined) to understand the effects of testing conditions on performance, and these results are discussed in terms of mechanical properties and microstructures.

Confirmation of model-based dose selection for a Japanese phase III study of rivaroxaban in non-valvular atrial fibrillation patients.

PubMed

Kaneko, Masato; Tanigawa, Takahiko; Hashizume, Kensei; Kajikawa, Mariko; Tajiri, Masahiro; Mueck, Wolfgang

2013-01-01

This study was designed to confirm the appropriateness of the dose setting for a Japanese phase III study of rivaroxaban in patients with non-valvular atrial fibrillation (NVAF), which had been based on model simulation employing phase II study data. The previously developed mixed-effects pharmacokinetic/pharmacodynamic (PK-PD) model, which consisted of an oral one-compartment model parameterized in terms of clearance, volume and a first-order absorption rate, was rebuilt and optimized using the data for 597 subjects from the Japanese phase III study, J-ROCKET AF. A mixed-effects modeling technique in NONMEM was used to quantify both unexplained inter-individual variability and inter-occasion variability, which are random effect parameters. The final PK and PK-PD models were evaluated to identify influential covariates. The empirical Bayes estimates of AUC and C(max) from the final PK model were consistent with the simulated results from the Japanese phase II study. There was no clear relationship between individual estimated exposures and safety-related events, and the estimated exposure levels were consistent with the global phase III data. Therefore, it was concluded that the dose selected for the phase III study with Japanese NVAF patients by means of model simulation employing phase II study data had been appropriate from the PK-PD perspective.

Accelerating clinical development of HIV vaccine strategies: methodological challenges and considerations in constructing an optimised multi-arm phase I/II trial design.

PubMed

Richert, Laura; Doussau, Adélaïde; Lelièvre, Jean-Daniel; Arnold, Vincent; Rieux, Véronique; Bouakane, Amel; Lévy, Yves; Chêne, Geneviève; Thiébaut, Rodolphe

2014-02-26

Many candidate vaccine strategies against human immunodeficiency virus (HIV) infection are under study, but their clinical development is lengthy and iterative. To accelerate HIV vaccine development optimised trial designs are needed. We propose a randomised multi-arm phase I/II design for early stage development of several vaccine strategies, aiming at rapidly discarding those that are unsafe or non-immunogenic. We explored early stage designs to evaluate both the safety and the immunogenicity of four heterologous prime-boost HIV vaccine strategies in parallel. One of the vaccines used as a prime and boost in the different strategies (vaccine 1) has yet to be tested in humans, thus requiring a phase I safety evaluation. However, its toxicity risk is considered minimal based on data from similar vaccines. We newly adapted a randomised phase II trial by integrating an early safety decision rule, emulating that of a phase I study. We evaluated the operating characteristics of the proposed design in simulation studies with either a fixed-sample frequentist or a continuous Bayesian safety decision rule and projected timelines for the trial. We propose a randomised four-arm phase I/II design with two independent binary endpoints for safety and immunogenicity. Immunogenicity evaluation at trial end is based on a single-stage Fleming design per arm, comparing the observed proportion of responders in an immunogenicity screening assay to an unacceptably low proportion, without direct comparisons between arms. Randomisation limits heterogeneity in volunteer characteristics between arms. To avoid exposure of additional participants to an unsafe vaccine during the vaccine boost phase, an early safety decision rule is imposed on the arm starting with vaccine 1 injections. In simulations of the design with either decision rule, the risks of erroneous conclusions were controlled <15%. Flexibility in trial conduct is greater with the continuous Bayesian rule. A 12-month gain in timelines is expected by this optimised design. Other existing designs such as bivariate or seamless phase I/II designs did not offer a clear-cut alternative. By combining phase I and phase II evaluations in a multi-arm trial, the proposed optimised design allows for accelerating early stage clinical development of HIV vaccine strategies.

Identifying positively deviant elderly medical wards using routinely collected NHS Safety Thermometer data: an observational study.

PubMed

Baxter, Ruth; Taylor, Natalie; Kellar, Ian; Pye, Victoria; Mohammed, Mohammed A; Lawton, Rebecca

2018-02-16

The positive deviance approach seeks to identify and learn from exceptional performers. Although a framework exists to apply positive deviance within healthcare organisations, there is limited guidance to support its implementation. The approach has also rarely explored exceptional performance on broad outcomes, been implemented at ward level, or applied within the UK. This study develops and critically appraises a pragmatic method for identifying positively deviant wards using a routinely collected, broad measure of patient safety. A two-phased observational study was conducted. During phase 1, cross-sectional and temporal analyses of Safety Thermometer data were conducted to identify a discrete group of positively deviant wards that consistently demonstrated exceptional levels of safety. A group of matched comparison wards with above average performances were also identified. During phase 2, multidisciplinary staff and patients on the positively deviant and comparison wards completed surveys to explore whether their perceptions of safety supported the identification of positively deviant wards. 34 elderly medical wards within a northern region of England, UK. Multidisciplinary staff (n=161) and patients (n=188) clustered within nine positively deviant and comparison wards. Phase 1: A combination of analyses identified five positively deviant wards that performed best in the region, outperformed their organisation and performed consistently well over 12 months. Five above average matched comparator wards were also identified. Phase 2: Staff and patient perceptions of safety generally supported the identification of positively deviant wards using Safety Thermometer data, although patient perceptions of safety were less concordant with the routinely collected data. This study tentatively supports a pragmatic method of using routinely collected data to identify positively deviant elderly medical wards; however, it also highlights the various challenges that are faced when conducting the first stage of the positive deviance approach. UK Clinical Research Network Portfolio (reference-18050). © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Identifying positively deviant elderly medical wards using routinely collected NHS Safety Thermometer data: an observational study

PubMed Central

Taylor, Natalie; Kellar, Ian; Pye, Victoria; Mohammed, Mohammed A; Lawton, Rebecca

2018-01-01

Objective The positive deviance approach seeks to identify and learn from exceptional performers. Although a framework exists to apply positive deviance within healthcare organisations, there is limited guidance to support its implementation. The approach has also rarely explored exceptional performance on broad outcomes, been implemented at ward level, or applied within the UK. This study develops and critically appraises a pragmatic method for identifying positively deviant wards using a routinely collected, broad measure of patient safety. Design A two-phased observational study was conducted. During phase 1, cross-sectional and temporal analyses of Safety Thermometer data were conducted to identify a discrete group of positively deviant wards that consistently demonstrated exceptional levels of safety. A group of matched comparison wards with above average performances were also identified. During phase 2, multidisciplinary staff and patients on the positively deviant and comparison wards completed surveys to explore whether their perceptions of safety supported the identification of positively deviant wards. Setting 34 elderly medical wards within a northern region of England, UK. Participants Multidisciplinary staff (n=161) and patients (n=188) clustered within nine positively deviant and comparison wards. Results Phase 1: A combination of analyses identified five positively deviant wards that performed best in the region, outperformed their organisation and performed consistently well over 12 months. Five above average matched comparator wards were also identified. Phase 2: Staff and patient perceptions of safety generally supported the identification of positively deviant wards using Safety Thermometer data, although patient perceptions of safety were less concordant with the routinely collected data. Conclusions This study tentatively supports a pragmatic method of using routinely collected data to identify positively deviant elderly medical wards; however, it also highlights the various challenges that are faced when conducting the first stage of the positive deviance approach. Trial registration number UK Clinical Research Network Portfolio (reference-18050). PMID:29453303

A single-arm, multicenter, safety-monitoring, phase IV study of icotinib in treating advanced non-small cell lung cancer (NSCLC).

PubMed

Hu, Xingsheng; Han, Baohui; Gu, Aiqin; Zhang, Yiping; Jiao, Shun Chang; Wang, Chang-Li; He, Jintao; Jia, Xueke; Zhang, Li; Peng, Jiewen; Wu, Meina; Ying, Kejing; Wang, Junye; Ma, Kewei; Zhang, Shucai; You, Changxuan; Tan, Fenlai; Wang, Yinxiang; Ding, Lieming; Sun, Yan

2014-11-01

The phase 3 ICOGEN trial established the non-inferiority of icotinib to gefitinib in terms of progression-free survival (PFS) in non-small cell lung cancer (NSCLC) patients, and this led to the approval of icotinib for NSCLC by the China Food and Drug Administration. A phase 4 study was conducted to assess the safety and efficacy of icotinib in a broad range of patients with advanced NSCLC across China. This study retrospectively analyzed data from unresectable, recurrent, and/or advanced NSCLC patients who received oral icotinib 125 mg three times per day. The primary endpoint was safety. The secondary endpoints included objective response rate (ORR) and disease control rate (DCR), which were investigated overall and in subgroups such as patients with an EGFR mutation and elderly patients. Between August, 2011 and August, 2012, a total of 6087 advanced NSCLC patients were registered in this study, of which 5549 were evaluable for safety and tumor response. The median age was 63 years (range 21-95 years), and 1571 (28.3%) patients were over the age of 70. The majority of patients were non-smokers, and had adenocarcinoma and stage IV disease. The overall incidence of adverse drug reactions (ADRs) of any grade was 31.5%. The most common ADRs included rash (17.4%) and diarrhea (8.5%), and three patients experienced interstitial lung disease (ILD). The ORR and DCR were 30.0% and 80.6%, respectively, for the overall population, and 33.4% and 81.2%, 30.3% and 80.3%, and 30.4% and 89.3%, for first-line, second-line, and third-line or multiple line subsets, respectively. In 665 EGFR-mutated patients who were evaluable for tumor response, the ORR and DCR were 49.2% (327/665) and 92.3% (614/665), respectively. The data from over 6000 patients was consistent with the results of the ICOGEN study. Icotinib demonstrated a favorable toxicity profile and efficacy in the routine clinical setting. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Everolimus-eluting stents in interventional cardiology

PubMed Central

Townsend, Jacob C; Rideout, Phillip; Steinberg, Daniel H

2012-01-01

Bare metal stents have a proven safety record, but limited long-term efficacy due to in-stent restenosis. First-generation drug-eluting stents successfully countered the restenosis rate, but were hampered by concerns about their long-term safety. Second generation drug-eluting stents have combined the low restenosis rate of the first generation with improved long-term safety. We review the evolution of drug-eluting stents with a focus on the safety, efficacy, and unique characteristics of everolimus-eluting stents. PMID:22910420

Tofacitinib, an oral Janus kinase inhibitor, as monotherapy or with background methotrexate, in Japanese patients with rheumatoid arthritis: an open-label, long-term extension study.

PubMed

Yamanaka, Hisashi; Tanaka, Yoshiya; Takeuchi, Tsutomu; Sugiyama, Naonobu; Yuasa, Hirotoshi; Toyoizumi, Shigeyuki; Morishima, Yosuke; Hirose, Tomohiro; Zwillich, Samuel

2016-01-28

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. Here, tofacitinib safety and efficacy data from a long-term extension study in Japanese patients are presented. Study A3921041 was a multi-centre, open-label, long-term extension study that included Japanese patients who had participated in a prior Phase 2 or Phase 3 study of tofacitinib as monotherapy or with background methotrexate. Patients received tofacitinib 5 mg twice daily (BID) or tofacitinib 10 mg BID. Dose adjustment of tofacitinib during treatment period, and concomitant usage of disease-modifying antirheumatic drugs including methotrexate after week 12 were permitted. Primary endpoints were adverse events, laboratory parameters and vital signs. Secondary efficacy endpoints included American College of Rheumatology (ACR)20/50/70 response rates, Disease Activity Score (DAS)28-4(erythrocyte sedimentation rate (ESR))<2.6 response rate (DAS-defined remission) and Health Assessment Questionnaire-Disability Index (HAQ-DI) score. Safety and efficacy data were assessed throughout the study. A total of 486 patients were recruited and treated (1439.9 patient-years of exposure). 308 patients completed the study. Median (range) duration of treatment in this extension study was 1185 (5-2016) days. 476 patients (97.9 %) experienced adverse events; the majority of which (97.8 %) were of mild or moderate severity. The two most common treatment-emergent adverse events were nasopharyngitis (n = 293, 60.3 %) and herpes zoster (n = 94, 19.3 %). For all tofacitinib-treated patients, the incidence rate (patients with events per 100 patient-years) was 10.7 for serious adverse events, 3.3 for serious infections, 7.4 for herpes zoster (serious and non-serious) and 1.2 for malignancies (excluding non-melanoma skin cancer). Mean changes from baseline (start of the index study) in laboratory parameters were consistent with those seen in previously reported studies of tofacitinib. ACR20/50/70 response rates, DAS-defined remission rates and HAQ-DI scores were sustained through to study completion. Tofacitinib (with or without background methotrexate) demonstrated a stable safety profile and sustained efficacy in Japanese patients with active rheumatoid arthritis. The risk of herpes zoster appears to be higher in Japanese patients treated with tofacitinib than in the global population. Clinicaltrials.gov NCT00661661 . Registered 7 February 2008.

Phase 2 Randomized, Dose-Ranging Study of Oxymetazoline Cream for Treatment of Persistent Facial Erythema Associated With Rosacea.

PubMed

DuBois, Janet; Dover, Jeffrey S; Jones, Terry M; Weiss, Robert A; Berk, David R; Ahluwalia, Gurpreet

2018-03-01

Rosacea is a chronic dermatologic condition with limited treatment options. This phase 2 study evaluated the optimal oxymetazoline dosing regimen in patients with moderate to severe persistent facial erythema of rosacea. Patients were randomly assigned to oxymetazoline cream, 0.5%, 1.0%, or 1.5%, or vehicle, administered once daily (QD) or twice daily (BID) for 28 consecutive days. The primary efficacy endpoint was the proportion of patients with ≥2-grade improvement from baseline on the Clinician Erythema Assessment (CEA) and the Subject Self-Assessment of erythema (SSA-1) on day 28. Safety assessments included treatment-emergent adverse events and dermal tolerability. A total of 356 patients were treated (mean age, 50.0 years; 80.1% female). The proportions of patients achieving the primary endpoint were significantly higher with oxymetazoline 0.5% QD (P=0.049), 1.0% QD (P=0.006), 1.5% QD (P=0.012), 1.0% BID (P=0.021), and 1.5% BID (P=0.006) versus their respective vehicles. For both QD and BID dosing, the efficacy of oxymetazoline 1.0% was greater than the 0.5% dose and comparable to the 1.5% dose. Safety and application-site tolerability were similar across groups. Short-term treatment period. Oxymetazoline 1.0% QD provided the optimal dosing regimen and was selected for evaluation in phase 3 clinical studies. J Drugs Dermatol. 2018;17(3):308-316.

Vaccine safety evaluation: Practical aspects in assessing benefits and risks.

PubMed

Di Pasquale, Alberta; Bonanni, Paolo; Garçon, Nathalie; Stanberry, Lawrence R; El-Hodhod, Mostafa; Tavares Da Silva, Fernanda

2016-12-20

Vaccines are different from most medicines in that they are administered to large and mostly healthy populations including infants and children, so there is a low tolerance for potential risks or side-effects. In addition, the long-term benefits of immunisation in reducing or eliminating infectious diseases may induce complacency due to the absence of cases. However, as demonstrated in recent measles outbreaks in Europe and United States, reappearance of the disease occurs as soon as vaccine coverage falls. Unfounded vaccine scares such as those associating the combined measles-mumps-rubella vaccine with autism, and whole-cell pertussis vaccines with encephalopathy, can also have massive impacts, resulting in reduced vaccine uptake and disease resurgence. The safety assessment of vaccines is exhaustive and continuous; beginning with non-clinical evaluation of their individual components in terms of purity, stability and sterility, continuing throughout the clinical development phase and entire duration of use of the vaccine; including post-approval. The breadth and depth of safety assessments conducted at multiple levels by a range of independent organizations increases confidence in the rigour with which any potential risks or side-effects are investigated and managed. Industry, regulatory agencies, academia, the medical community and the general public all play a role in monitoring vaccine safety. Within these stakeholder groups, the healthcare professional and vaccine provider have key roles in the prevention, identification, investigation and management of adverse events following immunisation (AEFI). Guidelines and algorithms aid in determining whether AEFI may have been caused by the vaccine, or whether it is coincidental to it. Healthcare providers are encouraged to rigorously investigate AEFIs and to report them via local reporting processes. The ultimate objective for all parties is to ensure vaccines have a favourable benefit-risk profile. Copyright © 2016. Published by Elsevier Ltd.

Wireless Roadside Inspection Proof of Concept Test Final Report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Capps, Gary J; Franzese, Oscar; Knee, Helmut E

2009-03-01

The U.S. Department of Transportation (DOT) FMCSA commissioned the Wireless Roadside Inspection (WRI) Program to validate technologies and methodologies that can improve safety through inspections using wireless technologies that convey real-time identification of commercial vehicles, drivers, and carriers, as well as information about the condition of the vehicles and their drivers. It is hypothesized that these inspections will: -- Increase safety -- Decrease the number of unsafe commercial vehicles on the road; -- Increase efficiency -- Speed up the inspection process, enabling more inspections to occur, at least on par with the number of weight inspections; -- Improve effectiveness --more » Reduce the probability of drivers bypassing CMV inspection stations and increase the likelihood that fleets will attempt to meet the safety regulations; and -- Benefit industry -- Reduce fleet costs, provide good return-on-investment, minimize wait times, and level the playing field. The WRI Program is defined in three phases which are: Phase 1: Proof of Concept Test (POC) Testing of commercially available off-the-shelf (COTS) or near-COTS technology to validate the wireless inspection concept. Phase 2: Pilot Test Safety technology maturation and back office system integration Phase 3: Field Operational Test Multi-vehicle testing over a multi-state instrumented corridor This report focuses on Phase 1 efforts that were initiated in March, 2006. Technical efforts dealt with the ability of a Universal Wireless Inspection System (UWIS) to collect driver, vehicle, and carrier information; format a Safety Data Message Set from this information; and wirelessly transmit a Safety Data Message Set to a roadside receiver unit or mobile enforcement vehicle.« less

STS safety approval process for small self-contained payloads

NASA Technical Reports Server (NTRS)

Gum, Mary A.

1988-01-01

The safety approval process established by the National Aeronautics and Space Administration for Get Away Special (GAS) payloads is described. Although the designing organization is ultimately responsible for the safe operation of its payload, the Get Away Special team at the Goddard Space Flight Center will act as advisors while iterative safety analyses are performed and the Safety Data Package inputs are submitted. This four phase communications process will ultimately give NASA confidence that the GAS payload is safe, and successful completion of the Phase 3 package and review will clear the way for flight aboard the Space Transportation System orbiter.

Two-Year Safety and Efficacy Experience in Patients with Methotrexate-Resistant Active Rheumatoid Arthritis Treated with Etanercept and Conventional Disease-Modifying Anti-rheumatic Drugs in the Latin American Region.

PubMed

Machado, Daniel A; Guzman, Renato; Xavier, Ricardo M; Simon, Jesus A; Mele, Linda; Shen, Qi; Pedersen, Ronald; Kotak, Sameer; Vlahos, Bonnie

2016-01-01

Although long-term data are available from biologic studies in North American/European populations with rheumatoid arthritis (RA), long-term findings in Latin American RA populations are limited. To examine long-term safety/efficacy of etanercept, methotrexate, and/or other disease-modifying anti-rheumatic drugs (DMARDs) in Latin American patients with moderate-to-severe active RA. In the first phase of this open-label study, patients were randomized to etanercept 50 mg weekly plus methotrexate or conventional DMARD (hydroxychloroquine or sulfasalazine) plus methotrexate for 24 weeks. At the start of the second phase (week 24), investigators selected a treatment regimen that included any combination/dosage of etanercept, methotrexate, hydroxychloroquine, or sulfasalazine based on previous treatment response, preference, and local product labeling, and was continued for the 104-week extension. In the extension, in the group previously randomized to etanercept-plus-methotrexate therapy, etanercept was continued in 259/260 patients; methotrexate continued in 260/260; and hydroxychloroquine and sulfasalazine added in 8/260 and 3/260, respectively. In the group previously randomized to conventional DMARD-plus-methotrexate therapy, conventional DMARD was discontinued in 86/126 and etanercept added in 105/126. Among etanercept-exposed patients (total exposure, 798.1 patient-year [PY]), rates of adverse events, serious adverse events, and serious infections per PY were 1.7, 0.07, and 0.02 events per PY. In both groups, after treatment modification was permitted, clinical response rates and improvements in clinical/patient-reported outcomes from baseline were sustained to week 128. After investigators were permitted to modify treatment, etanercept was part of the treatment regimen in 95% of patients. Continuation or addition of etanercept in the 2-year extension resulted in a consistently good risk:benefit profile. Open-Label Study Comparing Etanercept to Conventional Disease Modifying Antirheumatic Drug (DMARD) Therapy; ClinicalTrials.gov, number NCT00848354; https://clinicaltrials.gov/ct2/show/NCT00848354.

Assessment of immunogenicity and safety following primary and booster immunisation with a CRM197 -conjugated Haemophilus influenzae type B vaccine in healthy Chinese infants.

PubMed

Jun, L; Yuguo, C; Zhiguo, W; Jinfeng, L; Huawei, M; Xiuhua, L; Yonggui, Z; Yanhua, X; Kong, Y; Hongtao, L; Yuliang, Z

2013-10-01

Invasive meningitis and pneumonia caused by Haemophilus influenzae type b (Hib) is an important cause of childhood mortality in countries where Hib vaccination is not routine. We evaluated the non-inferiority of a licensed Hib vaccine, PRP-CRM(197) compared with a second licensed Hib vaccine, PRP-T, following the recommended Chinese immunisation schedule for infants between 6 months and 1 year of age. In the first study phase, 6-12 month-old infants received two primary doses of either PRP-CRM(197) (n = 335) or PRP-T (n = 335) vaccine administered 1 month apart. In the second study phase 8 months later, the same children received a single booster dose of vaccine identical to that use for priming (PRP-CRM(197), n = 327; PRP-T, n = 333). Serum levels of anti-polyribosylribitol phosphate (PRP) antibodies were measured using enzyme-linked immunosorbent assay (ELISA). Non-inferiority of primary and booster doses was assessed in terms of percentages of subjects with anti-PRP antibody levels associated with providing short-term (≥ 0.15 μg/ml) and long-term (≥ 1.0 μg/ml) protection; the non-inferiority margin was set at -5%. PRP-CRM(197) was demonstrated to be non-inferior to PRP-T. Anti-PRP antibodies levels ≥ 0.15 μg/ml and ≥ 1.0 μg/ml were achieved by 97% of infants in the PRP-CRM(197) group and 98% of infants in the PRP-T group 1 month after primary immunisation, and by all subjects (100%) in both vaccine groups 1 month after booster administration. Safety profiles for both vaccines were similar; no serious adverse events, deaths or adverse events leading to withdrawal occurred during the study. PRP-CRM(197) was well-tolerated and immunologically non-inferior to a licensed comparator Hib vaccine in Chinese infants (Clinicaltrials.gov: NCT01044316 & NCT01226953). © 2013 John Wiley & Sons Ltd.

Long-term safety and efficacy of the novel β3 -adrenoreceptor agonist vibegron in Japanese patients with overactive bladder: A phase III prospective study.

PubMed

Yoshida, Masaki; Kakizaki, Hidehiro; Takahashi, Satoru; Nagai, Shinji; Kurose, Takafumi

2018-05-11

To evaluate the long-term safety and efficacy of vibegron 50 mg and 100 mg, a novel β 3 -adrenoreceptor agonist, in Japanese patients with overactive bladder. This was a 1-year, multicenter, open-label, non-controlled study. After a 1-week observation phase, patients were treated with vibegron for 52 weeks. When the efficacy was insufficient after an 8-week treatment with 50 mg, the dose was increased to 100 mg and maintained for an additional 44 weeks. Among a total of 169 patients receiving one or more doses of vibegron, 118 (69.8%) received vibegron 50 mg for 52 weeks, and the dose was increased to 100 mg in 51 (30.2%) patients. The incidence of drug-related adverse events was 18.1% (21/116) in the vibegron 50 mg group and 11.8% (6/51) in the vibegron 100 mg group. Most frequent drug-related adverse events were dry mouth (3.0%), residual urine volume increased (3.0%), constipation (2.4%) and cystitis (1.8%). Statistically significant changes in overactive bladder symptom variables (daily means of micturitions, urgency episodes, urgency incontinence episodes, incontinence episodes and night-time frequency) from baseline were observed at week 4 and maintained until week 52. The condition of patients who did not respond well to vibegron 50 mg was much improved by increasing the dose to 100 mg. Vibegron improved the quality of life, and the proportion of patients' satisfaction after the treatment with vibegron was high. Long-term (52-week) treatment with vibegron is safe, well-tolerated and effective in patients with overactive bladder. © 2018 The Authors. International Journal of Urology published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Urological Association.

Safety, resource use, and quality of life in paramount: a phase III study of maintenance pemetrexed versus placebo after induction pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer.

PubMed

Gridelli, Cesare; de Marinis, Filippo; Pujol, Jean-Louis; Reck, Martin; Ramlau, Rodryg; Parente, Barbara; Pieters, Thierry; Middleton, Gary; Corral, Jesus; Winfree, Katherine; Melemed, Symantha; Zimmermann, Anna; John, William; Beyrer, Julie; Chouaki, Nadia; Visseren-Grul, Carla; Paz-Ares, Luis G

2012-11-01

In a phase III, randomized, double-blind study (PARAMOUNT), maintenance pemetrexed demonstrated significant benefit in advanced non-small-cell lung cancer (NSCLC). We present safety, resource use, and quality of life (QoL) results. After four 21-day cycles of pemetrexed-cisplatin (N = 939), patients with advanced nonsquamous NSCLC, whose disease had not progressed and who had a performance status of 0/1, were randomized 2:1 (N = 539) to maintenance pemetrexed 500 mg/m plus best supportive care or placebo plus best supportive care every 21 days until disease progression or unacceptable toxicity. QoL was measured using the EuroQol 5-dimensional questionnaire (EQ-5D). Frequently reported grade 3 to 4 drug-related toxicities with maintenance pemetrexed versus placebo were anemia (4.5% versus 0.6%; p = 0.016), fatigue (4.2% versus 0.6%; p = 0.016), and neutropenia (3.6% versus 0.0%; p < 0.006). No significant differences in drug-related grade 3 to 5 toxicities were observed with long-term pemetrexed exposure (>6 cycles), except grade 3 to 4 neutropenia, which did not result in increased infections. Patients on maintenance pemetrexed required more transfusions (13.4% versus 5.0%; p = 0.003), granulocyte colony- or granulocyte-macrophage colony-stimulating factors (5.3% versus 0.0%; p <0.001), anti-infectives (25.3% versus 16.7%; p = 0.028), and hospitalizations because of study drug (8.4% versus 3.3%, p = 0.028) than placebo-treated patients did. No significant treatment-by-time interactions, overall treatment differences, or clinically relevant changes from baseline were observed in EQ-5D scores during treatment. Long-term use of continuation maintenance pemetrexed was well tolerated; resource use was low, corresponding with known pemetrexed toxicities. The EQ-5D results demonstrate that patients tolerate long-term maintenance pemetrexed without worsening QoL.

A long-term, phase 2, multicenter, randomized, open-label, comparative safety study of pomaglumetad methionil (LY2140023 monohydrate) versus atypical antipsychotic standard of care in patients with schizophrenia

PubMed Central

2013-01-01

Background We compared the time to discontinuation due to lack of tolerability over 24 weeks in patients suffering from schizophrenia treated with pomaglumetad methionil (LY2140023 monohydrate, the prodrug of metabotropic glutamate 2/3 receptor agonist, LY404039) or standard of care (SOC: olanzapine, risperidone, or aripiprazole). Methods Study HBBR was a multicenter, randomized, open-label study comparing the long-term safety and tolerability of LY2140023 with SOC for schizophrenia. Patients had moderate symptomatology with prominent negative symptoms and evidence of functional impairment. Those who met entry criteria were randomized to open-label treatment with either LY2140023 (target dose: 40 mg twice daily [BID]; n = 130) or SOC (n = 131). Results There was no statistically significant difference between LY2140023 and SOC for time to discontinuation due to lack of tolerability (primary objective; P = .184). The Kaplan-Meier estimates revealed comparable time to event profiles. Only 27% of LY2140023 and 45% of SOC patients completed the 24-week open-label, active treatment phase. Twenty-seven patients (20.8%) in the LY2140023 group and 15 patients (11.5%) in the SOC group discontinued due to lack of efficacy (P = .044). Twenty-three patients (17.7%) in the LY2140023 group and 19 patients (14.5%) in the SOC group discontinued due to adverse events (physician and subject decision combined, P = .505). The incidence of serious adverse events was comparable between groups. LY2140023-treated patients reported significantly more treatment-emergent adverse events of vomiting, agitation, and dyspepsia, while SOC-treated patients reported significantly more akathisia and weight gain. The incidence of treatment-emergent parkinsonism (P = .011) and akathisia (P = .029) was significantly greater in SOC group. Improvement in PANSS total score over the initial 6 to 8 weeks of treatment was similar between groups, but improvement was significantly greater in the SOC group at 24-week endpoint (P = .004). LY2140023 and SOC groups had comparable negative symptom improvement at 24-week endpoint (P = .444). Conclusion These data provide further evidence that the potential antipsychotic LY2140023 monohydrate, with a glutamatergic mechanism of action, may have a unique tolerability profile characterized by a low association with some adverse events such as extrapyramidal symptoms and weight gain that may characterize currently available dopaminergic antipsychotics. Trials registration A Long-term, Phase 2, Multicenter, Randomized, Open-label, Comparative Safety Study of LY2140023 Versus Atypical Antipsychotic Standard of Care in Patients with DSM-IV-TR Schizophrenia ClinicalTrials.gov identifier: NCT00845026. PMID:23694720

Long-term safety assessment of trench-type surface repository at Chernobyl, Ukraine - computer model and comparison with results from simplified models

DOE Office of Scientific and Technical Information (OSTI.GOV)

Haverkamp, B.; Krone, J.; Shybetskyi, I.

2013-07-01

The Radioactive Waste Disposal Facility (RWDF) Buryakovka was constructed in 1986 as part of the intervention measures after the accident at Chernobyl NPP (ChNPP). Today, the surface repository for solid low and intermediate level waste (LILW) is still being operated but its maximum capacity is nearly reached. Long-existing plans for increasing the capacity of the facility shall be implemented in the framework of the European Commission INSC Programme (Instrument for Nuclear Safety Co-operation). Within the first phase of this project, DBE Technology GmbH prepared a safety analysis report of the facility in its current state (SAR) and a preliminary safetymore » analysis report (PSAR) for a future extended facility based on the planned enlargement. In addition to a detailed mathematical model, also simplified models have been developed to verify results of the former one and enhance confidence in the results. Comparison of the results show that - depending on the boundary conditions - simplifications like modeling the multi trench repository as one generic trench might have very limited influence on the overall results compared to the general uncertainties associated with respective long-term calculations. In addition to their value in regard to verification of more complex models which is important to increase confidence in the overall results, such simplified models can also offer the possibility to carry out time consuming calculations like probabilistic calculations or detailed sensitivity analysis in an economic manner. (authors)« less

First update of the International Xenotransplantation Association consensus statement on conditions for undertaking clinical trials of porcine islet products in type 1 diabetes--Chapter 3: Porcine islet product manufacturing and release testing criteria.

PubMed

Rayat, Gina R; Gazda, Lawrence S; Hawthorne, Wayne J; Hering, Bernhard J; Hosking, Peter; Matsumoto, Shinichi; Rajotte, Ray V

2016-01-01

In the 2009 IXA consensus, the requirements for the quality and control of manufacturing of porcine islet products were based on the U.S. regulatory framework where the porcine islet products fall within the definition of somatic cell therapy under the statutory authority of the U.S. Food and Drug Administration (FDA). In addition, porcine islet products require pre-market approval as a biologic product under the Public Health Services Act and they meet the definition of a drug under the Federal Food, Drug, and Cosmetic Act (FD&C Act). Thus, they are subject to applicable provisions of the law and as such, control of manufacturing as well as reproducibility and consistency of porcine islet products, safety of porcine islet products, and characterization of porcine islet products must be met before proceeding to clinical trials. In terms of control of manufacturing as well as reproducibility and consistency of porcine islet products, the manufacturing facility must be in compliance with current Good Manufacturing Practices (cGMP) guidelines appropriate for the initiation of Phase 1/2 clinical trials. Sponsors intending to conduct a Phase 1/2 trial of islet xenotransplantation products must be able to demonstrate the safety of the product through the establishment of particular quality assurance and quality control procedures. All materials (including animal source and pancreas) used in the manufacturing process of the porcine islet products must be free of adventitious agents. The final porcine islet product must undergo tests for the presence of these adventitious agents including sterility, mycoplasma (if they are cultured), and endotoxin. Assessments of the final product must include the safety specifications mentioned above even if the results are not available until after release as these data would be useful for patient diagnosis and treatment if necessary. In addition, a plan of action must be in place for patient notification and treatment in case the sterility culture results are positive. In terms of the characterization of porcine islet products and product release criteria, the information on the porcine islet products should be acquired from a sample of the final product to be used for transplantation and must include the morphology of the islets, specific identity, purity, viability, and potency of the product. In addition, information on the quantity of the islet products should also be provided in a standardized fashion and this should be in terms of islet equivalents and/or cell numbers. The current consensus was created to provide guidelines that manufacturing facilities may find helpful in the manufacture of and the release criteria for porcine islet products including encapsulated islets and combined islet products. Our intent with the above recommendations is to provide a framework for individual porcine islet manufacturing facilities to ensure a high level of safety for the initiation of Phase 1/2 clinical trials on porcine islet xenotransplantation. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Lubiprostone: RU 0211, SPI 0211.

PubMed

2005-01-01

Lubiprostone [RU 0211, SPI 0211] is a bicyclic fatty acid that acts as a chloride channel opener, increasing intestinal water secretion. Lubiprostone, an orally-administered formulation, is one of a series of functional fatty acid compounds discovered by Dr Ryuji Ueno, and is currently undergoing development for the treatment of constipation, constipation-predominant irritable bowel syndrome (IBS-C) and postoperative ileus with Sucampo Pharmaceutical's. Lubiprostone activates a specific chloride channel (CLC2) on cells lining the gut, thereby naturally increasing intestinal fluid secretion. The increased fluid level softens the stool, promotes spontaneous bowel movements, and reduces abdominal discomfort/pain and bloating. The chloride channel is a protein that controls cell membrane transport of chloride ion. Lubiprostone acts on the ClC-2 chloride channel, which is located in the apical intestinal membrane. In November 2004, Takeda Pharmaceuticals entered into a collaboration and licensing agreement for Lubiprostone with Sucampo Pharmaceuticals for the treatment of chronic constipation and constipation-predominant Irritable Bowel Syndrome (c-IBS). Under the terms of the agreement, Takeda received the right to market the product in the US and Canada, while Sucampo reserved the co-promotion rights for these countries. Takeda's wholly-owned US subsidiary, Takeda Pharmaceuticals North America Inc., will sell lubiprostone once the product is approved by the US FDA. Takeda will also receive an option for marketing rights in other territories, including Japan and Europe. Takeda and Sucampo agreed on the exclusive manufacturing and supply of Lubiprostone by R-Tech Ueno, Ltd, a member of the Sucampo Group. Sucampo has the potential to receive up to dollar US 210 million in initial and milestone payments, some of which are contingent upon the successful achievement of several milestones. Takeda will fund a major part of development costs not only for chronic constipation and c-IBS, but also for other indications in the gastroenterology field. Takeda will make royalty payments to Sucampo after the product is launched. In May 2005, Sucampo received dollar US 20 million from Takeda Pharmaceutical as payment for achieving a development milestone of initiating a phase III clinical trial of lubiprostone to treat patients with constipation-predominant irritable bowel syndrome. Sucampo Pharmaceuticals submitted a new drug application (NDA) for lubiprostone to the FDA on 31 March 2005 for approval in the treatment of chronic idiopathic constipation (CIC) and associated symptoms in adults. Sucampo completed three long-term, open-label safety studies, which will support the NDA for lubiprostone, in treating constipation. Results from its second open-label safety study with lubiprostone were announced in February 2004, with the first two studies demonstrating long-term safety and sustained effectiveness in constipated subjects. In the US, the final phase III study for chronic constipation was completed in the fourth quarter of 2004. In November 2004, Sucampo announced completing a phase II safety and efficacy study of lubiprostone for the treatment of IBS-C. This study, which was initiated in April 2003, randomised 195 patients with documented IBS into four treatment groups (three doses of SPI 0211 and placebo) from 19 locations throughout the US.

Review of Issues Associated with Safe Operation and Management of the Space Shuttle Program

NASA Technical Reports Server (NTRS)

Johnstone, Paul M.; Blomberg, Richard D.; Gleghorn, George J.; Krone, Norris J.; Voltz, Richard A.; Dunn, Robert F.; Donlan, Charles J.; Kauderer, Bernard M.; Brill, Yvonne C.; Englar, Kenneth G.;

Adalimumab for treating childhood plaque psoriasis: a clinical trial evaluation.

PubMed

Di Lernia, Vito

2017-12-01

Most systemic therapies have not been systematically investigated in moderate to severe childhood plaque psoriasis. Evidence on the efficacy and safety of systemic treatments is limited and therapeutic guidelines are lacking. Recently adalimumab, a fully human monoclonal antibody that binds tumor necrosis factor (TNF)- alpha, was investigated in childhood psoriasis. Adalimumab is licensed for many inflammatory conditions including chronic plaque psoriasis in adults. Areas covered: A randomized phase III study published provided favourable efficacy and safety data of adalimumab in childhood psoriasis. The active comparator was methotrexate. After 16 weeks of treatment, a PASI 75 score was achieved in 58% of patients within the adalimumab 0.8 mg/kg group compared with 32% of patients within the methotrexate group. Safety data gave no evidence of drug-related serious adverse events and no organ toxicity. This is the first randomised controlled study of either adalimumab or methotrexate in children and adolescents with psoriasis. Expert opinion: The aforementioned trial was the first to provide clinical data on adalimumab's efficacy and safety in the short term when treating children and adolescents with psoriasis. Through the use of an active comparator, this study has opened the way for the future assessment of systemic therapies in children and adolescent with this condition.

Tenofovir alafenamide (TAF) treatment of HBV, what are the unanswered questions?

PubMed

Viganò, Mauro; Loglio, Alessandro; Grossi, Glenda; Lampertico, Pietro

2018-02-01

Tenofovir disoproxil fumarate (TDF), an ester prodrug of tenofovir (TFV), is one of the recommended drugs for chronic hepatitis B (CHB) patients. However, reduced kidney function and loss of bone mineral density have been reported in some CHB patients treated with TDF. Consequent to these safety issues, tenofovir alafenamide (TAF) [Vemlidy®], a phosphonate prodrug of TFV, was developed for the treatment of CHB patients. Areas covered: The favourable pharmacological profile of TAF allows a marked reduction in dosage (25 mg/day) thus reducing systemic exposure to tenofovir and improving the bone and renal safety, keeping however the same virological efficacy, compared to TDF 300 mg/day. In two ongoing 96-week phase III trials in mainly treatment-naive HBeAg-positive or -negative patients, TAF showed similar viral suppression but was associated with significantly higher alanine aminotransferase normalization rates and more favourable renal and bone safety compared to TDF. In a 48-week TAF switch study enrolling patients treated with TDF for 96 weeks, glomerular, tubular and bone safety parameters rapidly improved while virological suppression was maintained. Expert commentary: Waiting long-term large scale clinical practice studies aimed to confirm these advantages, TAF represents an helpful treatment option for both naïve and TDF-exposed CHB patients.

Adverse events and dropouts in Alzheimer's disease studies: what can we learn?

PubMed

Henley, David B; Sundell, Karen L; Sethuraman, Gopalan; Schneider, Lon S

2015-01-01

Interpreting Alzheimer's disease (AD) clinical trial (CT) outcomes is complicated by treatment dropouts and adverse events (AEs). In elderly participants, AE rates, dropouts, and deaths are important considerations as they may undermine the validity of clinical trials. Published discontinuation and safety data are limited. Safety data from 1054 placebo-treated participants in IDENTITY and IDENTITY-2, 76-week, Phase 3 AD studies conducted in 31 countries, were pooled, annualized, and summarized overall, by country and age group. Median age was 74.2 (interquartile range 67.9-79.5) years; 57.4% were female; and median observation time was 63.2 (interquartile range 41.6-77.4) weeks when study drug dosing was halted. Overall annualized rates for discontinuations, discontinuations due to AEs, serious adverse events (SAEs), and deaths were 21.6% (range 19.6%-24.0%), 8.2% (range 8.1%-8.3%), 12.0%, and 1.7%, respectively. AE and discontinuation rates varied by country and age groups. Fall, pneumonia, and atrial fibrillation AEs were more frequent in the oldest age group. These annualized placebo safety data provide insight into the course of enrolled patients with mild-to-moderate AD, and are useful in planning longer term trials and in monitoring safety. Copyright © 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

A psychometric evaluation of the Chinese version of the nursing home survey on patient safety culture.

PubMed

Lin, Shu-Yuan; Tseng, Wei Ting; Hsu, Miao-Ju; Chiang, Hui-Ying; Tseng, Hui-Chen

2017-12-01

To test the psychometric properties of the Chinese version of the Nursing Home Survey on Patient Safety Culture scale among staff in long-term care facilities. The Nursing Home Survey on Patient Safety Culture scale is a standard tool for safety culture assessment in nursing homes. Extending its application to different types of long-term care facilities and varied ethnic populations is worth pursuing. A national random survey. A total of 306 managers and staff completed the Chinese version of the Nursing Home Survey on Patient Safety Culture scale among 30 long-term care facilities in Taiwan. Content validity and construct validity were tested by content validity index (CVI) and principal axis factor analysis (PAF) with Promax rotation. Concurrent validity was tested through correlations between the scale and two overall rating items. Reliability was computed by intraclass correlation coefficient and Cronbach's α coefficients. Statistical analyses such as descriptive, Pearson's and Spearman's rho correlations and PAF were completed. Scale-level and item-level CVIs (0.91-0.98) of the Chinese version of the Nursing Home Survey on Patient Safety Culture scale were satisfactory. Four-factor construct and merged item composition differed from the Nursing Home Survey on Patient Safety Culture scale, and it accounted for 53% of variance. Concurrent validity was evident by existing positive correlations between the scale and two overall ratings of resident safety. Cronbach's α coefficients of the subscales and the Chinese version of the Nursing Home Survey on Patient Safety Culture scale ranged from .76-.94. The Chinese version of the Nursing Home Survey on Patient Safety Culture scale identified essential dimensions to reflect the important features of a patient safety culture in long-term care facilities. The researchers introduced the Chinese version of the Nursing Home Survey on Patient Safety Culture for safety culture assessment in long-term care facilities, but further testing of the reliability of the scale in a large Chinese sample and in different long-term care facilities was recommended. The Chinese version of the Nursing Home Survey on Patient Safety Culture scale was developed to increase the users' intention towards safety culture assessment. It can identify areas for improvement, understand safety culture changes over time and evaluate the effectiveness of interventions. © 2017 John Wiley & Sons Ltd.

Safety and tolerability of rifaximin for the treatment of irritable bowel syndrome without constipation: a pooled analysis of randomised, double-blind, placebo-controlled trials.

PubMed

Schoenfeld, P; Pimentel, M; Chang, L; Lembo, A; Chey, W D; Yu, J; Paterson, C; Bortey, E; Forbes, W P

2014-05-01

The efficacy of rifaximin, a nonsystemic, gut-targeted antibiotic for reducing non-constipation-predominant irritable bowel syndrome (non-C IBS) symptoms, has been demonstrated in one phase 2b and two phase 3 randomised, double-blind, placebo-controlled trials, but detailed data about rifaximin safety and tolerability during treatment and subsequent follow-up periods are lacking. To assess and determine the frequency of rifaximin and placebo adverse events (AEs) in phase 2b and phase 3 non-C IBS trials. A post hoc pooled safety analysis of the phase 2b (rifaximin 275, 550, and 1100 mg twice daily for 2 weeks; 550 mg twice daily for 4 weeks) and phase 3 (rifaximin 550 mg three times daily for 2 weeks) studies was performed. Data on treatment and post-treatment AEs were collected. Patients were followed up for 12 weeks and 10 weeks post-treatment in the phase 2b and phase 3 trials, respectively. Patients receiving rifaximin (n = 1103) and placebo (n = 829) had a similar incidence of drug-related AEs (12.1% vs. 10.7%), serious AEs (1.5% vs. 2.2%), drug-related AEs resulting in study discontinuation (0.8% vs. 0.8%), gastrointestinal-associated AEs (12.2% vs. 12.2%) and infection-associated AEs (8.5% vs. 9.5%). There were no cases of Clostridium difficile colitis or deaths. The safety and tolerability profile of rifaximin during treatment and post-treatment was comparable to placebo. Future research should define the safety and tolerability profile, including risk of C. difficile colitis and microbial antibiotic resistance, with repeated courses of rifaximin in patients with non-constipation-predominant irritable bowel syndrome (ClinicalTrials.gov: NCT00269412, NCT00731679, and NCT00724126). © 2014 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.

Effects of a multicentre teamwork and communication programme on patient outcomes: results from the Triad for Optimal Patient Safety (TOPS) project.

PubMed

Auerbach, Andrew D; Sehgal, Niraj L; Blegen, Mary A; Maselli, Judith; Alldredge, Brian K; Vittinghoff, Eric; Wachter, Robert M

2012-02-01

Improving communication between caregivers is an important approach to improving safety. To implement teamwork and communication interventions and evaluate their impact on patient outcomes. A prospective, interrupted time series of a three-phase a run-in period (phase 1), during which a training programme was given to providers and staff on each unit; phase 2, which focused on unit-based safety teams to identify and address care problems using skills from phase 1; and phase 3, which focused on engaging patients in communication efforts. General medical inpatient units at three northern California hospitals. Administrative data were collected from all adults admitted to the target units, and a convenience sample of patients interviewed during and after hospitalisation. Readmission, length of stay and patient reports of teamwork, problems with care, and overall satisfaction. 10 977 patients were admitted; 581 patients (5.3% of total sample) were interviewed in hospital, and 313 (2.9% overall, 53.8% of interviewed patients) completed 1-month surveys. No phase of the study was associated with adjusted differences in readmission or length of stay. The phase 2 intervention appeared to be associated with improvement in reports of whether physicians treated them with respect, whether nurses treated them with respect or understood their needs (p<0.05 for all). Interestingly, patients were more likely to perceive that an error took place with their care and agreed less that their caregivers worked well together as a team. No phase had a consistent impact on patient reports of care processes or overall satisfaction. Limitations The study lacks direct measures of patient safety. Efforts to simultaneously improve caregivers' ability to troubleshoot care and enhance communication may improve patients' perception of team functions, but may also increase patients' perception of safety gaps.

Deferasirox for the treatment of chronic iron overload in transfusional hemosiderosis.

PubMed

Shashaty, George; Frankewich, Raymond; Chakraborti, Tamal; Choudary, Jasti; Al-Fayoumi, Suliman; Kacuba, Alice; Castillo, Sonia; Robie-Suh, Kathy; Rieves, Dwaine; Weiss, Karen; Pazdur, Richard

2006-12-01

This report describes the Food and Drug Administration's review of data and analyses leading to the approval of the oral iron chelator, deferasirox for the treatment of chronic iron overload due to transfusional hemosiderosis. The FDA reviewed findings of a controlled, open-label, randomized multicenter phase III study of deferasirox vs. deferoxamine in 586 patients with beta-thalessemia and transfusional hemosiderosis. The study results as well as the results of the FDA review of chemistry, preclinical pharmacology, and supportive studies are described. Following 48 weeks of treatment in the phase III study, patients' liver iron concentrations (a key endpoint variable) had decreased an average of 2.4 mg of iron (Fe)/g dry weight (dw) and 2.9 mg Fe/g dw in the deferasirox and deferoxamine groups, respectively, despite continued blood transfusions in both cohorts. Deferasirox was associated with serum creatinine increases in approximately a third of patients. Common adverse events included gastrointestinal symptoms and skin rash. Other data provided supportive evidence of deferasirox safety and efficacy. The FDA granted deferasirox accelerated approval on November 2, 2005, for use in treating chronic iron overload due to transfusional hemosiderosis in patients > or =2 years of age. The sponsor must obtain clinical data demonstrating the drug's long-term safety and effectiveness.

Overall Survival Analysis From a Randomized Phase II Study of Axitinib With or Without Dose Titration in First-Line Metastatic Renal Cell Carcinoma.

PubMed

Rini, Brian I; Tomita, Yoshihiko; Melichar, Bohuslav; Ueda, Takeshi; Grünwald, Viktor; Fishman, Mayer N; Uemura, Hirotsugu; Oya, Mototsugu; Bair, Angel H; Andrews, Glen I; Rosbrook, Brad; Jonasch, Eric

2016-12-01

In a randomized phase II trial in metastatic renal cell carcinoma (mRCC), objective response rate was significantly higher with axitinib versus placebo titration (54% vs. 34%; 1-sided P = .019). Treatment-naive patients with mRCC (n = 213) received axitinib 5 mg twice per day (b.i.d.) for 4 weeks. Patients meeting dose titration criteria were randomized to receive axitinib 5 mg b.i.d. with axitinib or placebo titration (n = 56 each); 91 patients ineligible for randomization continued axitinib 5 mg b.i.d.; 10 discontinued before randomization. Median overall survival (95% confidence interval [CI]) was 42.7 months (24.7-not estimable) with axitinib titration versus 30.4 months (23.7-45.0) with placebo titration (stratified hazard ratio, 0.785; 95% CI, 0.485-1.272; 1-sided P = .162), and 41.6 months (95% CI, 33.0-not estimable) in nonrandomized patients. Safety data were consistent with previous reports. Median overall survival was numerically longer in patients with first-line mRCC who received axitinib versus placebo titration. No new safety signal was observed after long-term axitinib treatment in first-line mRCC. Copyright © 2016 Elsevier Inc. All rights reserved.

Effectiveness of two conventional methods for seismic retrofit of steel and RC moment resisting frames based on damage control criteria

NASA Astrophysics Data System (ADS)

Beheshti Aval, Seyed Bahram; Kouhestani, Hamed Sadegh; Mottaghi, Lida

2017-07-01

This study investigates the efficiency of two types of rehabilitation methods based on economic justification that can lead to logical decision making between the retrofitting schemes. Among various rehabilitation methods, concentric chevron bracing (CCB) and cylindrical friction damper (CFD) were selected. The performance assessment procedure of the frames is divided into two distinct phases. First, the limit state probabilities of the structures before and after rehabilitation are investigated. In the second phase, the seismic risk of structures in terms of life safety and financial losses (decision variables) using the recently published FEMA P58 methodology is evaluated. The results show that the proposed retrofitting methods improve the serviceability and life safety performance levels of steel and RC structures at different rates when subjected to earthquake loads. Moreover, these procedures reveal that financial losses are greatly decreased, and were more tangible by the application of CFD rather than using CCB. Although using both retrofitting methods reduced damage state probabilities, incorporation of a site-specific seismic hazard curve to evaluate mean annual occurrence frequency at the collapse prevention limit state caused unexpected results to be obtained. Contrary to CFD, the collapse probability of the structures retrofitted with CCB increased when compared with the primary structures.

Safety and tolerability of azilsartan medoxomil in subjects with essential hypertension: a one-year, phase 3, open-label study.

PubMed

Handley, Alison; Lloyd, Eric; Roberts, Andrew; Barger, Bruce

2016-01-01

This 56-week phase 3, open-label, treat-to-target study, involving 2 consecutive, non-randomized cohorts, evaluated the safety and tolerability of azilsartan medoxomil (AZL-M) in essential hypertension (mean baseline blood pressure [BP] 152/100 mmHg). All subjects (n = 669) initiated AZL-M 40 mg QD, force-titrated to 80 mg QD at week 4, if tolerated. From week 8, subjects could receive additional medications, starting with chlorthalidone (CLD) 25 mg QD (Cohort 1) or hydrochlorothiazide (HCTZ) 12.5-25 mg QD (Cohort 2), if required, to reach BP targets. Adverse events (AEs) were reported in 75.9% of subjects overall in the two cohorts (73.8% Cohort 1, 78.5% Cohort 2). The most common AEs were dizziness (14.3%), headache (9.9%) and fatigue (7.2%). Transient serum creatinine elevations were more frequent with add-on CLD. Clinic systolic/diastolic BP (observed cases at week 56) decreased by 25.2/18.4 mmHg (Cohort 1) and 24.2/17.9 mmHg (Cohort 2). These results demonstrate that AZL-M is well tolerated over the long term and provides stable BP improvements when used in a treat-to-target BP approach with thiazide-type diuretics.

Biological induced corrosion of materials II: New test methods and experiences from mir station

NASA Astrophysics Data System (ADS)

Klintworth, R.; Reher, H. J.; Viktorov, A. N.; Bohle, D.

1999-09-01

During previous long-term manned missions, more than 100 species of microorganisms have been identified on surfaces of materials (bacteria and fungi). Among them were potentially pathogenic ones (saprophytes) which are capable of active growth on artificial substrates, as well as technophilic bacteria and fungi causing damages (destruction and degradation) to various materials (metals and polymers), resulting in failures and disruptions in the functioning of equipment and hardware. Aboard a space vehicle some microclimatic parameters are optimal for microorganism growth: the atmospheric fluid condensate with its specific composition, chemical and/or antropogenic contaminants (human metobolic products, etc.) all are stimulating factors for the development of bacteria and mould fungi on materials of the interior and equipment of an orbital station during its operational phase(s). Especially Russian long-term missions (SALJUT, MIR) have demonstrated that uncontrolled interactions of microorganisms with materials will ultimately lead to the appearence of technological and medical risks, significantly influencing safety and reliability characteristics of individual as well as whole systems and/ or subsystems. For a first conclusion, it could be summarized, that countermeasures and anti-strategies focussing on Microbial Contamination Management (MCM) for the International Space Station (ISS, next long-term manned mission) at least require a new materials test approach. Our respective concept includes a combined age-ing/biocorrosion test sequence. It is represented here, as well as current status of MCM program, e.g. continuous monitoring (microbiological analyses), long-term disinfection, frequent cleaning methods, mathematical modeling of ISS, etc.

A Raman Lidar as Operational Tool for Long-Term Water Vapor, Temperature and Aerosol Profiling in the Swiss Meteorological Office

NASA Astrophysics Data System (ADS)

Simeonov, Dr; Dinoev, Dr; Serikov, Dr; Calpini, Dr; Bobrovnikov, Dr; Arshinov, Dr; Ristori, Dr; van den Bergh, Dr; Parlange, Dr

2010-09-01

To satisfy the rising demands on the quality and frequency of atmospheric water vapor, temperature and aerosol measurements used for numerical weather prediction models, climate change observations and special events (volcanoes, dust and smoke transport) monitoring, MeteoSwiss decided to implement a lidar at his main aerological station in Payerne. The instrument is narrow field of view, narrowband UV Raman lidar designed for continuous day and night operational profiling of tropospheric water vapor, aerosol and temperature The lidar was developed and built by the Swiss Federal Institute of Technology- Lausanne (EPFL) within a joint project with MeteoSwiss. To satisfy the requirements for operational exploitation in a meteorological network the lidar had to satisfy a number of criteria, the most important of which are: accuracy and precision, traceability of the measurement, long-term data consistency, long-term system stability, automated operation, requiring minimal maintenance by a technician, and eye safety. All this requirements were taken into account during the design phase of the lidar. After a ten months test phase of the lidar at Payerne it has been in regular operation since August 2008. Selected data illustrating interesting atmospheric phenomena captured by the lidar as well as long-term intercomparison with collocated microwave radiometer, GPS, radiosonding and an airborne DIAL will be presented and discussed. The talk will address also the technical availability, alignment and calibration stabilities of the instrument.

42 CFR 86.37 - Terms and conditions.

Code of Federal Regulations, 2014 CFR

2014-10-01

... Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES OCCUPATIONAL SAFETY AND HEALTH RESEARCH AND RELATED ACTIVITIES GRANTS FOR EDUCATION PROGRAMS IN OCCUPATIONAL SAFETY AND HEALTH Occupational Safety and Health Direct Traineeships § 86.37 Terms and conditions. All direct traineeship awards...

42 CFR 86.37 - Terms and conditions.

Code of Federal Regulations, 2010 CFR

2010-10-01

... Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES OCCUPATIONAL SAFETY AND HEALTH RESEARCH AND RELATED ACTIVITIES GRANTS FOR EDUCATION PROGRAMS IN OCCUPATIONAL SAFETY AND HEALTH Occupational Safety and Health Direct Traineeships § 86.37 Terms and conditions. All direct traineeship awards...

A randomised trial to evaluate the immunogenicity, reactogenicity, and safety of the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) co-administered with routine childhood vaccines in Singapore and Malaysia.

PubMed

Lim, Fong Seng; Koh, Mia Tuang; Tan, Kah Kee; Chan, Poh Chong; Chong, Chia Yin; Shung Yehudi, Yeo Wee; Teoh, Yee Leong; Shafi, Fakrudeen; Hezareh, Marjan; Swinnen, Kristien; Borys, Dorota

2014-10-02

The immunogenicity, reactogenicity, and safety of the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) co-administered with routine childhood vaccines were evaluated among infants from Singapore and Malaysia, where PHiD-CV has been licensed. In the primary vaccination phase, 298 infants from Singapore and 168 infants from Malaysia were randomised to receive the Phase III Clinical (Clin) or the Commercial (Com) lot of PHiD-CV at 2, 3, and 5 months of age. In the booster vaccination phase, 238 toddlers from Singapore received one dose of the PHiD-CV Commercial lot at 18-21 months of age. Immune responses to pneumococcal polysaccharides were measured using 22F-inhibition enzyme-linked immunosorbent assay (ELISA) and functional opsonophagocytic activity (OPA) assay and to protein D, using ELISA. Immune responses induced by primary vaccination with the PHiD-CV Commercial lot were non-inferior to the Phase III Clinical lot in terms of adjusted antibody geometric mean concentration (GMC) ratios for each vaccine pneumococcal serotype and protein D. For each vaccine pneumococcal serotype, ≥93.6% and ≥88.5% of infants from Malaysia and Singapore had post-primary vaccination antibody concentrations ≥0.2 μg/mL and OPA titres ≥8, in the Clin and Com groups, respectively. For each vaccine pneumococcal serotype, ≥60.8% and ≥98.2% of toddlers from Singapore had pre- and post-booster antibody concentrations ≥0.2 μg/mL, in the Clin and Com groups, respectively. All children, except one, had measurable anti-protein D antibodies and the primary and booster doses of the co-administered vaccines were immunogenic. The incidence of each grade 3 solicited symptom was ≤11.1% in both study phases. No serious adverse events considered causally related to vaccination were reported throughout the study. PHiD-CV given as three-dose primary vaccination to infants in Singapore and Malaysia and booster vaccination to toddlers in Singapore was shown to be immunogenic with a clinically acceptable-safety profile.This study has been registered at http://www.clinicaltrials.govNCT00808444 and NCT01119625.

High-intensity interval training in patients with coronary heart disease: Prescription models and perspectives.

PubMed

Ribeiro, Paula A B; Boidin, Maxime; Juneau, Martin; Nigam, Anil; Gayda, Mathieu

2017-01-01

Recently, high-intensity interval training (HIIT) has emerged as an alternative and/or complementary exercise modality to continuous aerobic exercise training (CAET) in CHD patients. However, the literature contains descriptions of many HIIT protocols with different stage durations, nature of recovery and intensities. In this review, we discuss the most recent forms of validated HIIT protocols in patients with coronary heart disease (CHD) and how to prescribe and use them during short- and long-term (phase II and III) cardiac rehabilitation programs. We also compare the superior and/or equivalent short- and long-term effects of HIIT versus CAET on aerobic fitness, cardiovascular function, and quality of life; their efficiency, safety, and tolerance; and exercise adherence. Short interval HIIT was found beneficial for CHD patients with lower aerobic fitness and would ideally be used in initiation and improvement stages. Medium and/or long interval HIIT protocols may be beneficial for CHD patients with higher aerobic fitness, and would be ideally used in the improvement and maintenance stages because of their high physiological stimulus. Finally, we propose progressive individualized models of HIIT programs (phase II to III) for patients with CHD and how to ideally use them according to the clinical status of patients and phase of the cardiac rehabilitation program. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Laboratory safety and the WHO World Alliance for Patient Safety.

PubMed

McCay, Layla; Lemer, Claire; Wu, Albert W

2009-06-01

Laboratory medicine has been a pioneer in the field of patient safety; indeed, the College of American Pathology first called attention to the issue in 1946. Delivering reliable laboratory results has long been considered a priority, as the data produced in laboratory medicine have the potential to critically influence individual patients' diagnosis and management. Until recently, most attention on laboratory safety has focused on the analytic stage of laboratory medicine. Addressing this stage has led to significant and impressive improvements in the areas over which laboratories have direct control. However, recent data demonstrate that pre- and post-analytical phases are at least as vulnerable to errors; to further improve patient safety in laboratory medicine, attention must now be focused on the pre- and post-analytic phases, and the concept of patient safety as a multi-disciplinary, multi-stage and multi-system concept better understood. The World Alliance for Patient Safety (WAPS) supports improvement of patient safety globally and provides a potential framework for considering the total testing process.

Phase II multi-institutional clinical trial on a new mixed beam RT scheme of IMRT on pelvis combined with a carbon ion boost for high-risk prostate cancer patients.

PubMed

Marvaso, Giulia; Jereczek-Fossa, Barbara A; Vischioni, Barbara; Ciardo, Delia; Giandini, Tommaso; Hasegawa, Azusa; Cattani, Federica; Carrara, Mauro; Ciocca, Mario; Bedini, Nice; Villa, Sergio; Morlino, Sara; Russo, Stefania; Zerini, Dario; Colangione, Sarah Pia; Panaino, Costanza Maria Vittoria; Fodor, Cristiana; Santoro, Luigi; Pignoli, Emanuele; Valvo, Francesca; Valdagni, Riccardo; De Cobelli, Ottavio; Orecchia, Roberto

2017-05-12

Definition of the optimal treatment schedule for high-risk prostate cancer is under debate. A combination of photon intensity modulated radiotherapy (IMRT) on pelvis with a carbon ion boost might be the optimal treatment scheme to escalate the dose on prostate and deliver curative dose with respect to normal tissue and quality of dose distributions. In fact, carbon ion beams offer the advantage to deliver hypofractionated radiotherapy (RT) using a significantly smaller number of fractions compared to conventional RT without increasing risks of late effects. This study is a prospective phase II clinical trial exploring safety and feasibility of a mixed beam scheme of carbon ion prostate boost followed by photon IMRT on pelvis. The study is designed to enroll 65 patients with localized high-risk prostate cancer at 3 different oncologic hospitals: Istituto Europeo di Oncologia, Fondazione IRCCS Istituto Nazionale dei Tumori, and Centro Nazionale di Adroterapia Oncologica. The primary endpoint is the evaluation of safety and feasibility with acute toxicity scored up to 1 month after the end of RT. Secondary endpoints are treatment early (3 months after the end of RT) and long-term tolerability, quality of life, and efficacy. The study is not yet recruiting; in silico studies are ongoing and we expect to start recruitment by 2017. The present clinical trial aims at improving the current treatment for high-risk prostate cancer, evaluating safety and feasibility of a new RT mixed-beam scheme including photons and carbon ions. Encouraging results are coming from carbon ion facilities worldwide on the treatment of different tumors including prostate cancers. Carbon ions combine physical properties allowing for high dose conformity and advantageous radiobiological characteristics. The proposed mixed beam treatment has the advantage to combine a photon high conformity standard of care IMRT phase with a hypofractionated carbon ion RT boost delivered in a short overall treatment time.

Long-Term Follow Up of Patients with Mild-to-Moderate Alzheimer's Disease Treated with Bapineuzumab in a Phase III, Open-Label, Extension Study.

PubMed

Salloway, Stephen P; Sperling, Reisa; Fox, Nick C; Sabbagh, Marwan N; Honig, Lawrence S; Porsteinsson, Anton P; Rofael, Hany; Ketter, Nzeera; Wang, Daniel; Liu, Enchi; Carr, Stephen; Black, Ronald S; Brashear, H Robert

2018-06-08

A 3-year extension of two Phase III parent studies of intravenous (IV) bapineuzumab in patients with mild-to-moderate Alzheimer's disease dementia (apolipoprotein (APOE) ɛ4 carriers and noncarriers) is summarized. The primary and secondary objectives were to evaluate the long-term safety, tolerability, and maintenance of efficacy of bapineuzumab. A multicenter study in patients who had participated in double-blind placebo-controlled parent studies. Patients enrolled in the extension study were assigned to receive IV infusions of bapineuzumab (0.5 or 1.0 mg/kg) every 13 weeks until termination but were blinded to whether they had received bapineuzumab or placebo in the parent studies. A total of 1,462 (688 were APOEɛ4 carriers and 774 were noncarriers) patients were enrolled. Extension-onset adverse events occurred in >81% of the patients in each dose group. Fall, urinary tract infection, agitation, and ARIA-E occurred in ≥10% of participants. The incidence proportion of ARIA-E was higher among carriers and noncarriers who received bapineuzumab for the first time in the extension study (11.8% and 5.4%, respectively) versus those who were previously exposed in the parent studies (5.1% and 1.3%, respectively). After 6 to 12 months exposure to bapineuzumab IV in the extension study, similar deterioration of cognition and function occurred with no significant differences between the dose groups. Infusion of bapineuzumab 0.5 or 1.0 mg/kg every 13 weeks for up to 3 years was generally well tolerated, with a safety and tolerability profile similar to that in previous studies.

Open-label, 9-month extension study investigating the uro-selective alpha-blocker silodosin in men with LUTS associated with BPH.

PubMed

Osman, Nadir I; Chapple, Christopher R; Tammela, Teuvo L; Eisenhardt, Andreas; Oelke, Matthias

2015-05-01

To evaluate the long-term safety (primary objective) and efficacy/impact on quality of life (QoL, secondary objectives) of silodosin 8 mg once daily in men with LUTS/BPH. Men who completed the 12-week double-blind study with silodosin 8 mg, tamsulosin 0.4 mg, or placebo were offered to continue with the 9-month open-label study during which all patients received silodosin 8 mg once daily. Safety was assessed by analysing vital signs, electrocardiograms, laboratory tests, and adverse events. Efficacy was evaluated with the International Prostate Symptom Score (IPSS), IPSS voiding and storage sub-scores, IPSS-QoL, and maximum urinary flow rate (Q max). A total of 500 patients (mean age 66 years) entered the 9-month open-label study. Treatment-emergent adverse events (TEAE) were experienced by 33.4% patients. Ejaculation dysfunction was the most common TEAE (9.0%) but led to study discontinuations in only 1.6% of patients. Dizziness without orthostatic hypotension occurred in 0.8%. A marked reduction in total IPSS (-2.7 ± 3.8) was documented at the first visit of this extension phase in patients having de novo silodosin compared with lesser improvement in patients previously treated with silodosin (-0.82 ± 4.2) or tamsulosin (-0.83 ± 3.8). Improvements were maintained throughout the open-label phase. QoL also improved, with the greatest improvement in de novo silodosin patients. No relevant changes in Q max occurred. Long-term treatment with silodosin was safe and efficacious. Abnormal ejaculation was the most common TEAE, but led to treatment discontinuation in only 1.6% of patients. Orthostatic hypotension was not seen, and only a few patients experienced dizziness.

Brief Report: Long-Term (96-Week) Efficacy and Safety After Switching From Tenofovir Disoproxil Fumarate to Tenofovir Alafenamide in HIV-Infected, Virologically Suppressed Adults

PubMed Central

Raffi, François; Orkin, Chloe; Clarke, Amanda; Slama, Laurence; Gallant, Joel; Daar, Eric; Henry, Keith; Santana-Bagur, Jorge; Stein, David K.; Bellos, Nicholaos; Scarsella, Anthony; Yan, Mingjin; Abram, Michael E.; Cheng, Andrew

2017-01-01

Abstract: In a double-blind, phase 3 trial, 663 HIV-infected, virologically suppressed adults were randomized to switch to tenofovir alafenamide (TAF; n = 333) vs. remain on tenofovir disoproxil fumarate (TDF; n = 330), each coformulated with emtricitabine (FTC), while continuing their third agent (boosted protease inhibitor or unboosted third agent). At week 96, 88.6% on FTC/TAF and 89.1% on FTC/TDF had HIV-1 RNA <50 copies per milliliter [adjusted difference −0.5% (95% confidence interval: −5.3 to 4.4%)]. Proteinuria, albuminuria, proximal renal tubular function, and bone mineral density improved after switching to TAF- from TDF-containing regimens. These longer-term data support FTC/TAF as a safe, well-tolerated, and durable nucleotide reverse transcriptase inhibitor backbone. PMID:28272164

Long-term immunogenicity and safety after a single dose of the quadrivalent meningococcal serogroups A, C, W, and Y tetanus toxoid conjugate vaccine in adolescents and adults: 5-year follow-up of an open, randomized trial.

PubMed

Borja-Tabora, Charissa Fay Corazon; Montalban, Cecilia; Memish, Ziad A; Boutriau, Dominique; Kolhe, Devayani; Miller, Jacqueline M; Van der Wielen, Marie

2015-10-06

Long-term protection against meningococcal disease is associated with persistence of post-vaccination antibodies at protective levels. We evaluated the bactericidal antibody persistence and safety of the quadrivalent meningococcal serogroups A, C, W and Y tetanus-toxoid conjugate vaccine (MenACWY-TT) and the meningococcal polysaccharide serogroups A, C, W, and Y vaccine (MenACWY-PS) up to 5 years post-vaccination. This phase IIb, open, randomized, controlled study conducted in the Philippines and Saudi Arabia consisted of a vaccination phase and a long-term persistence phase. Healthy adolescents and adults aged 11-55 years were randomized (3:1) to receive a single dose of MenACWY-TT (ACWY-TT group) or MenACWY-PS (Men-PS group). Primary and persistence results up to 3 years post-vaccination have been previously reported. Antibody responses against meningococcal serogroups A, C, W, and Y were assessed by a serum bactericidal antibody assay using rabbit complement (rSBA, cut-off titers 1:8 and 1:128) at Year 4 and Year 5 post-vaccination. Vaccine-related serious adverse events (SAEs) and cases of meningococcal disease were assessed up to Year 5. Of the 500 vaccinated participants, 404 returned for the Year 5 study visit (Total Cohort Year 5). For the Total Cohort Year 5, 71.6-90.0 and 64.9-86.3 % of MenACWY-TT recipients had rSBA titers ≥1:8 and ≥1:128, respectively, compared to 24.8-74.3 and 21.0-68.6 % of MenACWY-PS recipients. The rSBA geometric mean titers (GMTs) remained above the pre-vaccination levels in both treatment groups. Exploratory analyses suggested that both rSBA GMTs as well as the percentages of participants with rSBA titers above the cut-offs were higher in the ACWY-TT than in the Men-PS group for serogroups A, W and Y, with no apparent difference for MenC. No SAEs related to vaccination or cases of meningococcal disease were reported up to Year 5. These results suggest that a single dose of MenACWY-TT could protect at least 72 % of vaccinated adolescents and adults against meningococcal disease at least 5 years post-vaccination. ClinicalTrials.gov NCT00356369.

Deferasirox for managing transfusional iron overload in people with sickle cell disease.

PubMed

Meerpohl, Joerg J; Schell, Lisa K; Rücker, Gerta; Motschall, Edith; Fleeman, Nigel; Niemeyer, Charlotte M; Bassler, Dirk

2014-05-27

Sickle cell disease (SCD) is a group of genetic haemoglobin disorders, that occurs in about 2.2 per 1000 births worldwide. Increasingly, some people with SCD develop secondary iron overload due to occasional red blood cell transfusions or are on long-term transfusion programmes for e.g. secondary stroke prevention. Iron chelation therapy can prevent long-term complications.Deferoxamine and deferiprone have been found to be efficacious. However, questions exist about the effectiveness and safety of the newer oral chelator deferasirox. To assess the effectiveness and safety of oral deferasirox in people with SCD and secondary iron overload. We searched the Cystic Fibrosis & Genetic Disorders Group's Haemoglobinopathies Trials Register: date of most recent search:13 March 2014.We searched MEDLINE, Embase, Biosis Previews, Web of Science, Derwent Drug File, XTOXLINE, EBMR and The Cochrane Library, respectively; date of most recent searches: 02 August 2013.We searched four trial registries: www.controlled-trials.com; www.clinicaltrials.gov; www.who.int./ictrp/en/; www.drks.de; date of most recent searches: 03 June 2013. Randomised controlled trials comparing deferasirox with no therapy or placebo or with another iron chelating treatment schedule. Two authors independently assessed risk of bias and extracted data. We contacted the corresponding study authors for additional information. Two studies (with 203 and 212 people) comparing the efficacy and safety of deferasirox and deferoxamine after 12 months and 24 weeks, respectively, were included. The overall quality, according to GRADE, for the main outcomes was moderate to low. Only limited data were available on mortality and end-organ damage, although one study did assess mortality, relative risk 1.26 (95% confidence interval 0.05 to 30.41), the 24-week follow up was too short to allow us to draw firm conclusions. One study reported a relative risk of 1.26 for the incidence of type 2 diabetes mellitus (95% confidence interval 0.05 to 30.41). Serum ferritin reduction was significantly greater with deferoxamine, mean difference of change of 440.69 µg/l (95% confidence interval 11.73 to 869.64). Liver iron concentration (reported in one study) measured by superconduction quantum interference device showed no significant difference for the overall group of patients adjusted for transfusion category, mean difference -0.20 mg Fe/g dry weight (95% confidence interval -3.15 to 2.75).The occurrence of serious adverse events did not differ between drugs. Nausea, diarrhoea and rash occurred significantly more often in people treated with deferasirox, while adverse events of any kind were more often reported for patients treated with deferoxamine (one study). The mean increase of creatinine was also significantly higher with deferasirox, mean difference 3.24 (95% confidence interval 0.45 to 6.03). Long-term adverse events could not be measured in the included studies (follow up 52 weeks and 24 weeks). Patient satisfaction and the likelihood of continuing treatment, were significantly better with deferasirox. Deferasirox appears to be of similar efficacy to deferoxamine depending on depending on the appropriate ratio of doses of deferoxamine and deferasirox being compared. However, only limited evidence is available assessing the efficacy regarding patient-important outcomes. The short-term safety of deferasirox seems to be acceptable, however, follow up in the available studies was too short to assess long-term side effects. Long-term safety and efficacy data are available from a non-controlled extension phase not included in our review; however, no valid comparative conclusions can be drawn and future studies should assess comparatively long-term outcomes both for safety and efficacy.

Space-Based Telemetry and Range Safety Project Ku-Band and Ka-Band Phased Array Antenna

NASA Technical Reports Server (NTRS)

Whiteman, Donald E.; Valencia, Lisa M.; Birr, Richard B.

2005-01-01

The National Aeronautics and Space Administration Space-Based Telemetry and Range Safety study is a multiphase project to increase data rates and flexibility and decrease costs by using space-based communications assets for telemetry during launches and landings. Phase 1 used standard S-band antennas with the Tracking and Data Relay Satellite System to obtain a baseline performance. The selection process and available resources for Phase 2 resulted in a Ku-band phased array antenna system. Several development efforts are under way for a Ka-band phased array antenna system for Phase 3. Each phase includes test flights to demonstrate performance and capabilities. Successful completion of this project will result in a set of communications requirements for the next generation of launch vehicles.

Ku- and Ka-Band Phased Array Antenna for the Space-Based Telemetry and Range Safety Project

NASA Technical Reports Server (NTRS)

Whiteman, Donald E.; Valencia, Lisa M.; Birr, Richard B.

2005-01-01

The National Aeronautics and Space Administration Space-Based Telemetry and Range Safety study is a multiphase project to increase data rates and flexibility and decrease costs by using space-based communications assets for telemetry during launches and landings. Phase 1 used standard S-band antennas with the Tracking and Data Relay Satellite System to obtain a baseline performance. The selection process and available resources for Phase 2 resulted in a Ku-band phased array antenna system. Several development efforts are under way for a Ka-band phased array antenna system for Phase 3. Each phase includes test flights to demonstrate performance and capabilities. Successful completion of this project will result in a set of communications requirements for the next generation of launch vehicles.

Department of Defense Air Traffic Control and Airspace Management Systems

DTIC Science & Technology

1989-08-08

service. The potential near-term impacts of incompatible and non- interoperable systems on the Air Force are described in terms of safety and...impacts of incompatible and non-interoperable systems on the Air Force are described in terms of safety and operational effectiveness and probable...derogation of safety , from the standpoint of aircraft collision avoidance, is probable where service specific systems are operating in adjacent or

Individuals with severely impaired vision can learn useful orientation and mobility skills in virtual streets and can use them to improve real street safety

PubMed Central

Liu, Lei

2017-01-01

Virtual reality has great potential in training road safety skills to individuals with low vision but the feasibility of such training has not been demonstrated. We tested the hypotheses that low vision individuals could learn useful skills in virtual streets and could apply them to improve real street safety. Twelve participants, whose vision was too poor to use the pedestrian signals were taught by a certified orientation and mobility specialist to determine the safest time to cross the street using the visual and auditory signals made by the start of previously stopped cars at a traffic-light controlled street intersection. Four participants were trained in real streets and eight in virtual streets presented on 3 projection screens. The crossing timing of all participants was evaluated in real streets before and after training. The participants were instructed to say “GO” at the time when they felt the safest to cross the street. A safety score was derived to quantify the GO calls based on its occurrence in the pedestrian phase (when the pedestrian sign did not show DON’T WALK). Before training, > 50% of the GO calls from all participants fell in the DON’T WALK phase of the traffic cycle and thus were totally unsafe. 20% of the GO calls fell in the latter half of the pedestrian phase. These calls were unsafe because one initiated crossing this late might not have sufficient time to walk across the street. After training, 90% of the GO calls fell in the early half of the pedestrian phase. These calls were safer because one initiated crossing in the pedestrian phase and had at least half of the pedestrian phase for walking across. Similar safety changes occurred in both virtual street and real street trained participants. An ANOVA showed a significant increase of the safety scores after training and there was no difference in this safety improvement between the virtual street and real street trained participants. This study demonstrated that virtual reality-based orientation and mobility training could be as efficient as real street training in improving street safety in individuals with severely impaired vision. PMID:28445540

School Safety Study: Phase I.

ERIC Educational Resources Information Center

Arora, Alka

This report summarizes findings from a study concerned with Arizona school safety. The survey component highlights safety-related policy information across 300 schools; the interview component highlights school-safety perceptions of 64 staff across 16 schools. Various policies and programs that respond to internal and external threats to school…

Safety through Education and Training.

ERIC Educational Resources Information Center

Thorburn, S.

1990-01-01

Addresses the need for safety education as a continuous process through elementary and secondary phases of education in the context of human risk within modern society. Discusses the teaching of safety subjects in civil engineering curriculum. (YP)

Comparison of gamma-oryzanol contents in crude rice bran oils from different sources by various determination methods.

PubMed

Yoshie, Ayano; Kanda, Ayato; Nakamura, Takahiro; Igusa, Hisao; Hara, Setsuko

2009-01-01

Although there are various determination methods for gamma -oryzanol contained in rice bran oil by absorptiometry, normal-phase HPLC, and reversed-phase HPLC, their accuracies and the correlations among them have not been revealed yet. Chloroform-containing mixed solvents are widely used as mobile phases in some HPLC methods, but researchers have been apprehensive about its use in terms of safety for the human body and the environment.In the present study, a simple and accurate determination method was developed by improving the reversed-phase HPLC method. This novel HPLC method uses methanol/acetonitrile/acetic acid (52/45/3 v/v/v), a non-chlorinated solvent, as the mobile phase, and shows an excellent linearity (y = 0.9527x + 0.1241, R(2) = 0.9974) with absorptiometry. The mean relative errors among the existing 3 methods and the novel method, determined by adding fixed amounts of gamma-oryzanol into refined rice salad oil, were -4.7% for the absorptiometry, -6.8% for the existing normal-phase HPLC, +4.6% for the existing reversed-phase HPLC, and -1.6% for the novel reversed-phase HPLC method. gamma -Oryzanol content in 12 kinds of crude rice bran oils obtained from different sources were determined by the four methods. The mean content of those oils were 1.75+/-0.18% for the absorptiometry, 1.29+/-0.11% for the existing normal-phase HPLC, 1.51+/-0.10% for the existing reversed-phase HPLC, and 1.54+/-0.19% for the novel reversed-phase HPLC method.

Patient Safety Policy in Long-Term Care: A Research Protocol to Assess Executive WalkRounds to Improve Management of Early Warning Signs for Patient Safety.

PubMed

van Dusseldorp, Loes; Hamers, Hub; van Achterberg, Theo; Schoonhoven, Lisette

2014-07-15

At many hospitals and long-term care organizations (such as nursing homes), executive board members have a responsibility to manage patient safety. Executive WalkRounds offer an opportunity for boards to build a trusting relationship with professionals and seem useful as a leadership tool to pick up on soft signals, which are indirect signals or early warnings that something is wrong. Because the majority of the research on WalkRounds has been performed in hospitals, it is unknown how board members of long-term care organizations develop their patient safety policy. Also, it is not clear if these board members use soft signals as a leadership tool and, if so, how this influences their patient safety policies. The objective of this study is to explore the added value and the feasibility of WalkRounds for patient safety management in long-term care. This study also aims to identify how executive board members of long-term care organizations manage patient safety and to describe the characteristics of boards. An explorative before-and-after study was conducted between April 2012 and February 2014 in 13 long-term care organizations in the Netherlands. After implementing the intervention in 6 organizations, data from 72 WalkRounds were gathered by observation and a reporting form. Before and after the intervention period, data collection included interviews, questionnaires, and studying reports of the executive boards. A mixed-method analysis is performed using descriptive statistics, t tests, and content analysis. Results are expected to be ready in mid 2014. It is a challenge to keep track of ongoing development and implementation of patient safety management tools in long-term care. By performing this study in cooperation with the participating long-term care organizations, insight into the potential added value and the feasibility of this method will increase.

Safety profile of biologic drugs in the therapy of Crohn disease: A systematic review and network meta-analysis.

PubMed

Moćko, Paweł; Kawalec, Paweł; Pilc, Andrzej

2016-12-01

Crohn disease (CD) is an inflammatory bowel disease which occurs especially in developed countries of Western Europe and North America. The aim of the study was to compare the safety profile of biologic drugs in patients with CD. A systematic literature search was performed using PubMed, Embase, and CENTRAL databases, until April 27, 2016. We included randomized controlled trials (RCTs) that compared the safety of biologic drugs (infliximab, adalimumab, vedolizumab, certolizumab pegol, and ustekinumab) with one another or with placebo in patients with CD. The network meta-analysis (NMA) was conducted for an induction phase (6-10 weeks) and maintenance phase (52-56 weeks) with a Bayesian hierarchical random effects model in the ADDIS ® software. The PROSPERO registration number was CRD42016032606. Ten RCTs were included in the systematic review with NMA. In the case of the induction phase, the NMA could be conducted for the assessment of the relative safety profile of adalimumab, vedolizumab, certolizumab pegol, and ustekinumab, and in the case of the maintenance phase-of infliximab, adalimumab, and vedolizumab. There were no significant differences in the rate of adverse events in patients treated with biologics. Statistical analysis revealed that vedolizumab had the greatest probability of being the safest treatment in most endpoints in the induction phase and adalimumab-in the maintenance phase. No significant differences between the biologics in the relative safety profile analysis were observed. Further studies are needed to confirm our findings, including head-to-head comparisons between the analyzed biologics. Copyright © 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Photorefractive keratectomy (PRK) at 193 nm using an erodible mask: new developments and clinical progress

NASA Astrophysics Data System (ADS)

Gordon, Michael; Seiler, Theo; Carey, Joseph P.; Friedman, Marc D.; Johnsson, N. M. F.; King, Michael C.; Muller, David F.

1993-06-01

This paper reports on our progress using an erodible mask to perform photorefractive keratectomy (PRK) for the correction of myopic astigmatism. We describe modifications to the mask, the mask eye cup and the surgical microscope aimed at simplifying the procedure and improving the ergonomics of the hardware. We report the clinical results of the post-op exam for 20 patients who have undergone PRK for myopic astigmatism under a Phase IIA study. The results compare favorably with an earlier Phase IIA study for performing PRK with a computer-controlled iris. Most important, the clinical data show the absence of any significant corneal haze and no significant decrease in spectacle corrected visual acuity. Although more long term follow-up is needed, the preliminary results support the safety and effectiveness of using an erodible mask to perform PRK for myopic astigmatism.

29 CFR 1912a.3 - Terms of membership.

Code of Federal Regulations, 2013 CFR

2013-07-01

... Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) NATIONAL ADVISORY COMMITTEE ON OCCUPATIONAL SAFETY AND HEALTH § 1912a.3 Terms of membership... occupational safety and health professions, and of the public. Appointment of a member to the Committee for a...

29 CFR 1912a.3 - Terms of membership.

Code of Federal Regulations, 2014 CFR

2014-07-01

... Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) NATIONAL ADVISORY COMMITTEE ON OCCUPATIONAL SAFETY AND HEALTH § 1912a.3 Terms of membership... occupational safety and health professions, and of the public. Appointment of a member to the Committee for a...

29 CFR 1912a.3 - Terms of membership.

Code of Federal Regulations, 2010 CFR

2010-07-01

... Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) NATIONAL ADVISORY COMMITTEE ON OCCUPATIONAL SAFETY AND HEALTH § 1912a.3 Terms of membership... occupational safety and health professions, and of the public. Appointment of a member to the Committee for a...

Getting past first base: Going all the way with Cognitive Work Analysis.

PubMed

McIlroy, Rich C; Stanton, Neville A

2011-01-01

This paper reports the application of Cognitive Work Analysis (CWA) to the problem of communications planning in military aviation. Applications of CWA rarely get beyond the first one or two phases; this paper presents an analysis in which all five phases have been completed. The method offers a formative description of the system, defining the set of boundaries and constraints that shape system activity in terms of work domain, recurring activities, decision making, social organisation and worker competency requirements. It is an analysis that is well suited to environments in which the occurrence of unanticipated events can have serious implications for both safety and productivity. Communications planning in military aviation is such an environment. The outputs of the analysis provided an extensive and exhaustive description of the system, highlighting the uneven spread of activity, across actors involved in communications planning and across the situations in which planning can occur. In addition, a new method for informing worker competency requirements based on abstract functions rather than specific decision steps is proposed and discussed in terms of job design, interface design, and person specification. Copyright © 2010 Elsevier Ltd and The Ergonomics Society. All rights reserved.

Exposure to airborne asbestos in thermal power plants in Mongolia

PubMed Central

Damiran, Naransukh; Silbergeld, Ellen K; Frank, Arthur L; Lkhasuren, Oyuntogos; Ochir, Chimedsuren; Breysse, Patrick N

2015-01-01

Background: Coal-fired thermal power plants (TPPs) in Mongolia use various types of asbestos-containing materials (ACMs) in thermal insulation of piping systems, furnaces, and other products. Objective: To investigate the occupational exposure of insulation workers to airborne asbestos in Mongolian power plants. Methods: Forty-seven air samples were collected from four power plants in Mongolia during the progress of insulation work. The samples were analyzed by phase contrast microscopy (PCM) and transmission electron microscopy (TEM). Results: The average phase contrast microscopy equivalent (PCME) asbestos fiber concentration was 0.93 f/cm3. Sixteen of the 41 personal and one of the area samples exceeded the United States Occupational Safety and Health Administration (US OSHA) short-term exposure limit of 1.0 f/cm3. If it is assumed that the short-term samples collected are representative of full-shift exposure, then the exposures are approximately 10 times higher than the US OSHA 8-hour permissible exposure limit of 0.1 f/cm3. Conclusion: Power plant insulation workers are exposed to airborne asbestos at concentrations that exceed the US OSHA Permissible Exposure Limit. Action to mitigate the risks should be taken in Mongolia. PMID:25730489

Exposure to airborne asbestos in thermal power plants in Mongolia.

PubMed

Damiran, Naransukh; Silbergeld, Ellen K; Frank, Arthur L; Lkhasuren, Oyuntogos; Ochir, Chimedsuren; Breysse, Patrick N

2015-01-01

Coal-fired thermal power plants (TPPs) in Mongolia use various types of asbestos-containing materials (ACMs) in thermal insulation of piping systems, furnaces, and other products. To investigate the occupational exposure of insulation workers to airborne asbestos in Mongolian power plants. Forty-seven air samples were collected from four power plants in Mongolia during the progress of insulation work. The samples were analyzed by phase contrast microscopy (PCM) and transmission electron microscopy (TEM). The average phase contrast microscopy equivalent (PCME) asbestos fiber concentration was 0·93 f/cm(3). Sixteen of the 41 personal and one of the area samples exceeded the United States Occupational Safety and Health Administration (US OSHA) short-term exposure limit of 1·0 f/cm(3). If it is assumed that the short-term samples collected are representative of full-shift exposure, then the exposures are approximately 10 times higher than the US OSHA 8-hour permissible exposure limit of 0·1 f/cm(3). Power plant insulation workers are exposed to airborne asbestos at concentrations that exceed the US OSHA Permissible Exposure Limit. Action to mitigate the risks should be taken in Mongolia.

FCRD Transmutation Fuels Handbook 2015

DOE Office of Scientific and Technical Information (OSTI.GOV)

Janney, Dawn Elizabeth; Papesch, Cynthia Ann

2015-09-01

Transmutation of minor actinides such as Np, Am, and Cm in spent nuclear fuel is of international interest because of its potential for reducing the long-term health and safety hazards caused by the radioactivity of the spent fuel. One important approach to transmutation (currently being pursued by the DOE Fuel Cycle Research & Development Advanced Fuels Campaign) involves incorporating the minor actinides into U-Pu-Zr alloys, which can be used as fuel in fast reactors. It is, therefore, important to understand the properties of U-Pu-Zr alloys, both with and without minor actinide additions. In addition to requiring extensive safety precautions, alloysmore » containing U and Pu are difficult to study for numerous reasons, including their complex phase transformations, characteristically sluggish phase-transformation kinetics, tendency to produce experimental results that vary depending on the histories of individual samples, and sensitivity to contaminants such as oxygen in concentrations below a hundred parts per million. Many of the experimental measurements were made before 1980, and the level of documentation for experimental methods and results varies widely. It is, therefore, not surprising that little is known with certainty about U-Pu-Zr alloys, and that general acceptance of results sometimes indicates that there is only a single measurement for a particular property. This handbook summarizes currently available information about U, Pu, Zr, and alloys of two or three of these elements. It contains information about phase diagrams and related information (including phases and phase transformations); heat capacity, entropy, and enthalpy; thermal expansion; and thermal conductivity and diffusivity. In addition to presenting information about materials properties, it attempts to provide information about how well the property is known and how much variation exists between measurements. Although the handbook includes some references to publications about modeling, its primary focus is experimental data. Most of the data has been published elsewhere (although scattered throughout numerous references, some quite obscure); however, some data is presented here for the first time.« less

DARHT: INTEGRATION OF AUTHORIZATION BASIS REQUIREMENTS AND WORKER SAFETY

DOE Office of Scientific and Technical Information (OSTI.GOV)

D. A. MC CLURE; C. A. NELSON; R. L. BOUDRIE

2001-04-01

This document describes the results of consensus agreements reached by the DARHT Safety Planning Team during the development of the update of the DARHT Safety Analysis Document (SAD). The SAD is one of the Authorization Basis (AB) Documents required by the Department prior to granting approval to operate the DARHT Facility. The DARHT Safety Planning Team is lead by Mr. Joel A. Baca of the Department of Energy Albuquerque Operations Office (DOE/AL). Team membership is drawn from the Department of Energy Albuquerque Operations Office, the Department of Energy Los Alamos Area Office (DOE/LAAO), and several divisions of the Los Alamosmore » National Laboratory. Revision 1 of the DARHT SAD had been written as part of the process for gaining approval to operate the Phase 1 (First Axis) Accelerator. Early in the planning stage for the required update of the SAD for the approval to operate both Phase 1 and Phase 2 (First Axis and Second Axis) DARHT Accelerator, it was discovered that a conflict existed between the Laboratory approach to describing the management of facility and worker safety.« less

Pegvaliase for the treatment of phenylketonuria: Results of a long-term phase 3 clinical trial program (PRISM).

PubMed

Thomas, Janet; Levy, Harvey; Amato, Stephen; Vockley, Jerry; Zori, Roberto; Dimmock, David; Harding, Cary O; Bilder, Deborah A; Weng, Haoling H; Olbertz, Joy; Merilainen, Markus; Jiang, Joy; Larimore, Kevin; Gupta, Soumi; Gu, Zhonghua; Northrup, Hope

2018-05-01

Phenylketonuria (PKU) is caused by phenylalanine hydroxylase (PAH) deficiency that results in phenylalanine (Phe) accumulation. Pegvaliase, PEGylated recombinant Anabaena variabilis phenylalanine ammonia lyase (PAL), converts Phe to trans-cinnamic acid and ammonia, and is a potential enzyme substitution therapy to lower blood Phe in adults with PKU. Two Phase 3 studies, PRISM-1 and PRISM-2, evaluated the efficacy and safety of pegvaliase treatment using an induction, titration, and maintenance dosing regimen in adults with PKU. In PRISM-1, pegvaliase-naïve participants with blood Phe >600 μmol/L were randomized 1:1 to a maintenance dose of 20 mg/day or 40 mg/day of pegvaliase. Participants in PRISM-1 continued pegvaliase treatment in PRISM-2, a 4-part clinical trial that includes an ongoing, open-label, long-term extension study of pegvaliase doses of 5 mg/day to 60 mg/day. Of 261 participants who received pegvaliase treatment, 72.0% and 32.6% reached ≥12 months and ≥ 24 months of study treatment, respectively, and 65% are still actively receiving treatment. Mean (SD) blood Phe was 1232.7 (386.4) μmol/L at baseline, 564.5 (531.2) μmol/L at 12 months, and 311.4 (427) μmol/L at 24 months, a decrease from baseline of 51.1% and 68.7%, respectively. Within 24 months, 68.4% of participants achieved blood Phe ≤600 μmol/L, 60.7% of participants achieved blood Phe ≤360 μmol/L, below the upper limit recommended in the American College of Medical Genetics and Genomics PKU management guidelines, and 51.2% achieved blood Phe ≤120 μmol/L, below the upper limit of normal in the unaffected population. Improvements in neuropsychiatric outcomes were associated with reductions in blood Phe and were sustained with long-term pegvaliase treatment. Adverse events (AEs) were more frequent in the first 6 months of exposure (early treatment phase) than after 6 months of exposure (late treatment phase); 99% of AEs were mild or moderate in severity and 96% resolved without dose interruption or reduction. The most common AEs were arthralgia (70.5%), injection-site reaction (62.1%), injection-site erythema (47.9%), and headache (47.1%). Acute systemic hypersensitivity events consistent with clinical National Institute of Allergy and Infectious Diseases and the Food Allergy and Anaphylaxis Network anaphylaxis criteria were observed in 12 participants (17 events); of these, 6 participants remained on treatment. Acute systemic hypersensitivity events including potential events of anaphylaxis were not associated with immunoglobulin E, and all events resolved without sequelae. Results from the PRISM Phase 3 program support the efficacy of pegvaliase for the treatment of adults with PKU, with a manageable safety profile in most participants. The PRISM-2 extension study will continue to assess the long-term effects of pegvaliase treatment. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

TA 55 Reinvestment Project II Phase C Update Project Status May 23, 2017

DOE Office of Scientific and Technical Information (OSTI.GOV)

Giordano, Anthony P.

The TA-55 Reinvestment Project (TRP) II Phase C is a critical infrastructure project focused on improving safety and reliability of the Los Alamos National Laboratory (LANL) TA-55 Complex. The Project recapitalizes and revitalizes aging and obsolete facility and safety systems providing a sustainable nuclear facility for National Security Missions.

Early investigational tubulin inhibitors as novel cancer therapeutics.

PubMed

Nepali, Kunal; Ojha, Ritu; Lee, Hsueh-Yun; Liou, Jing-Ping

2016-08-01

Microtubules represent one of the most logical and strategic molecular targets amongst the current targets for chemotherapy, alongside DNA. In the past decade, tubulin inhibitors as cancer therapeutics have been an area of focus due to the improved understanding and biological relevance of microtubules in cellular functions. Fueled by the objective of developing novel chemotherapeutics and with the aim of establishing the benefits of tubulin inhibition, several clinical trials have been conducted with others ongoing. At present, the antitubulin development pipeline contains an armful of agents under clinical investigation. This review focuses on novel tubulin inhibitors as cancer therapeutics. The article covers the agents which have completed the phase II studies along with the agents demonstrating promising results in phase I studies. Countless clinical trials evaluating the efficacy, safety and pharmacokinetics of novel tubulin inhibitors highlights the scientific efforts being paid to establish their candidature as cancer therapeutics. Colchicine binding site inhibitors as vascular disrupting agents (VDAs) and new taxanes appear to be the most likely agents for future clinical interest. Numerous agents have demonstrated clinical benefits in terms of efficacy and survival in phase I and II studies. However conclusive benefits can only be ascertained on the basis of phase III studies.

Clobetasol propionate shampoo 0.05% is efficacious and safe for long-term control of moderate scalp psoriasis.

PubMed

Poulin, Yves; Papp, Kim; Bissonnette, Robert; Barber, Kirk; Kerrouche, Nabil; Villemagne, Hervé

2010-05-01

We evaluated in this study the efficacy and safety of an alternate regimen using clobetasol propionate 0.05% shampoo (CP shampoo) for long-term control of scalp psoriasis. Patients with moderate scalp psoriasis (Global Severity Score [GSS] of 3 on a 0-5 scale) first received CP shampoo once daily for 4 weeks. Patients with a GSS 2) occurred, patients received the 4-week daily CP shampoo treatment. Patients who had a GSS

Safety and Mission Assurance Knowledge Management Retention: Managing Knowledge for Successful Mission Operations

NASA Technical Reports Server (NTRS)

Johnson, Teresa A.

2006-01-01

Knowledge Management is a proactive pursuit for the future success of any large organization faced with the imminent possibility that their senior managers/engineers with gained experiences and lessons learned plan to retire in the near term. Safety and Mission Assurance (S&MA) is proactively pursuing unique mechanism to ensure knowledge learned is retained and lessons learned captured and documented. Knowledge Capture Event/Activities/Management helps to provide a gateway between future retirees and our next generation of managers/engineers. S&MA hosted two Knowledge Capture Events during 2005 featuring three of its retiring fellows (Axel Larsen, Dave Whittle and Gary Johnson). The first Knowledge Capture Event February 24, 2005 focused on two Safety and Mission Assurance Safety Panels (Space Shuttle System Safety Review Panel (SSRP); Payload Safety Review Panel (PSRP) and the latter event December 15, 2005 featured lessons learned during Apollo, Skylab, and Space Shuttle which could be applicable in the newly created Crew Exploration Vehicle (CEV)/Constellation development program. Gemini, Apollo, Skylab and the Space Shuttle promised and delivered exciting human advances in space and benefits of space in people s everyday lives on earth. Johnson Space Center's Safety & Mission Assurance team work over the last 20 years has been mostly focused on operations we are now beginning the Exploration development program. S&MA will promote an atmosphere of knowledge sharing in its formal and informal cultures and work processes, and reward the open dissemination and sharing of information; we are asking "Why embrace relearning the "lessons learned" in the past?" On the Exploration program the focus will be on Design, Development, Test, & Evaluation (DDT&E); therefore, it is critical to understand the lessons from these past programs during the DDT&E phase.

Dose‐finding methods for Phase I clinical trials using pharmacokinetics in small populations

PubMed Central

Zohar, Sarah; Lentz, Frederike; Alberti, Corinne; Friede, Tim; Stallard, Nigel; Comets, Emmanuelle

2017-01-01

The aim of phase I clinical trials is to obtain reliable information on safety, tolerability, pharmacokinetics (PK), and mechanism of action of drugs with the objective of determining the maximum tolerated dose (MTD). In most phase I studies, dose‐finding and PK analysis are done separately and no attempt is made to combine them during dose allocation. In cases such as rare diseases, paediatrics, and studies in a biomarker‐defined subgroup of a defined population, the available population size will limit the number of possible clinical trials that can be conducted. Combining dose‐finding and PK analyses to allow better estimation of the dose‐toxicity curve should then be considered. In this work, we propose, study, and compare methods to incorporate PK measures in the dose allocation process during a phase I clinical trial. These methods do this in different ways, including using PK observations as a covariate, as the dependent variable or in a hierarchical model. We conducted a large simulation study that showed that adding PK measurements as a covariate only does not improve the efficiency of dose‐finding trials either in terms of the number of observed dose limiting toxicities or the probability of correct dose selection. However, incorporating PK measures does allow better estimation of the dose‐toxicity curve while maintaining the performance in terms of MTD selection compared to dose‐finding designs that do not incorporate PK information. In conclusion, using PK information in the dose allocation process enriches the knowledge of the dose‐toxicity relationship, facilitating better dose recommendation for subsequent trials. PMID:28321893

Safety and mobility impacts of winter weather - phase 3.

DOT National Transportation Integrated Search

2014-09-01

Highway agencies spend millions of dollars to ensure safe and efficient winter travel. However, the effectiveness of winter-weather : maintenance practices on safety and mobility are somewhat difficult to quantify. Safety and Mobility Impacts of Wint...

Safety of vedolizumab in the treatment of Crohn's disease and ulcerative colitis.

PubMed

Hagan, Matilda; Cross, Raymond K

2015-01-01

Vedolizumab is the latest FDA-approved anti-integrin therapy for treatment of moderate-to-severe inflammatory bowel disease (IBD). The safety and efficacy of vedolizumab have been studied in short-term clinical trials. This paper reviews the safety profile of vedolizumab compared with other biologics. It also highlights the mechanism of action of the medication. We discuss the current position of vedolizumab in our current algorithm for IBD management and comment on future prospects of the drug. Vedolizumab appears to be a safe and effective option in the treatment of moderate-to-severe IBD in the short term. Long-term observational studies and post-marketing safety data are needed to ascertain the long-term efficacy and side effect profile.

Assessment of safety and efficacy of long-term treatment with combination lumacaftor and ivacaftor therapy in patients with cystic fibrosis homozygous for the F508del-CFTR mutation (PROGRESS): a phase 3, extension study.

PubMed

Konstan, Michael W; McKone, Edward F; Moss, Richard B; Marigowda, Gautham; Tian, Simon; Waltz, David; Huang, Xiaohong; Lubarsky, Barry; Rubin, Jaime; Millar, Stefanie J; Pasta, David J; Mayer-Hamblett, Nicole; Goss, Christopher H; Morgan, Wayne; Sawicki, Gregory S

2017-02-01

The 24-week safety and efficacy of lumacaftor/ivacaftor combination therapy was shown in two randomised controlled trials (RCTs)-TRAFFIC and TRANSPORT-in patients with cystic fibrosis who were aged 12 years or older and homozygous for the F508del-CFTR mutation. We aimed to assess the long-term safety and efficacy of extended lumacaftor/ivacaftor therapy in this group of patients in PROGRESS, the long-term extension of TRAFFIC and TRANSPORT. PROGRESS was a phase 3, parallel-group, multicentre, 96-week study of patients who completed TRAFFIC or TRANSPORT in 191 sites in 15 countries. Patients were eligible if they were at least 12 years old with cystic fibrosis and homozygous for the F508del-CFTR mutation. Exclusion criteria included any comorbidity or laboratory abnormality that, in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering the study drug to the participant, history of drug intolerance, and history of poor compliance with the study drug. Patients who previously received active treatment in TRANSPORT or TRAFFIC remained on the same dose in PROGRESS. Patients who had received placebo in TRANSPORT or TRAFFIC were randomly assigned (1:1) to receive lumacaftor (400 mg every 12 h)/ivacaftor (250 mg every 12 h) or lumacaftor (600 mg once daily)/ivacaftor (250 mg every 12 h). The primary outcome was to assess the long-term safety of combined therapy. The estimated annual rate of decline in percent predicted FEV 1 (ppFEV 1 ) in treated patients was compared with that of a matched registry cohort. Efficacy analyses were based on modified intention-to-treat, such that data were included for all patients who were randomly assigned and received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01931839. Between Oct 24, 2013, and April 7, 2016, 1030 patients from the TRANSPORT and TRAFFIC studies enrolled in PROGRESS, and 1029 received at least one dose of study drug. 340 patients continued treatment with lumacaftor 400 mg every 12 h/ivacaftor 250 mg every 12 h; 176 patients who had received placebo in the TRANSPORT or TRAFFIC studies initiated treatment with lumacaftor 400 mg every 12 h/ivacaftor 250 mg every 12 h, the commercially available dose, for which data are presented. The most common adverse events were infective pulmonary exacerbations, cough, increased sputum, and haemoptysis. Modest blood pressure increases seen in TRAFFIC and TRANSPORT were also observed in PROGRESS. For patients continuing treatment, the mean change from baseline in ppFEV 1 was 0·5 (95% CI -0·4 to 1·5) at extension week 72 and 0·5 (-0·7 to 1·6) at extension week 96; change in BMI was 0·69 (0·56 to 0·81) at extension week 72 and 0·96 (0·81 to 1·11) at extension week 96. The annualised pulmonary exacerbation rate in patients continuing treatment through extension week 96 (0·65, 0·56 to 0·75) remained lower than the placebo rate in TRAFFIC and TRANSPORT. The annualised rate of ppFEV 1 decline was reduced in lumacaftor/ivacaftor-treated patients compared with matched controls (-1·33, -1·80 to -0·85 vs -2·29, -2·56 to -2·03). The efficacy and safety profile of the lumacaftor 600 mg once daily/ivacaftor 250 mg every 12 h groups was generally similar to that of the lumacaftor 400 mg every 12 h/ivacaftor 250 mg every 12 h groups. The long-term safety profile of lumacaftor/ivacaftor combination therapy was consistent with previous RCTs. Benefits continued to be observed with longer-term treatment, and lumacaftor/ivacaftor was associated with a 42% slower rate of ppFEV 1 decline than in matched registry controls. Vertex Pharmaceuticals Incorporated. Copyright © 2017 Elsevier Ltd. All rights reserved.

NASA/Navy Benchmarking Exchange (NNBE). Volume 1. Interim Report. Navy Submarine Program Safety Assurance

NASA Technical Reports Server (NTRS)

2002-01-01

The NASA/Navy Benchmarking Exchange (NNBE) was undertaken to identify practices and procedures and to share lessons learned in the Navy's submarine and NASA's human space flight programs. The NNBE focus is on safety and mission assurance policies, processes, accountability, and control measures. This report is an interim summary of activity conducted through October 2002, and it coincides with completion of the first phase of a two-phase fact-finding effort.In August 2002, a team was formed, co-chaired by senior representatives from the NASA Office of Safety and Mission Assurance and the NAVSEA 92Q Submarine Safety and Quality Assurance Division. The team closely examined the two elements of submarine safety (SUBSAFE) certification: (1) new design/construction (initial certification) and (2) maintenance and modernization (sustaining certification), with a focus on: (1) Management and Organization, (2) Safety Requirements (technical and administrative), (3) Implementation Processes, (4) Compliance Verification Processes, and (5) Certification Processes.

15 CFR 971.422 - Safety at sea requirements.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 15 Commerce and Foreign Trade 3 2012-01-01 2012-01-01 false Safety at sea requirements. 971.422...: Terms, Conditions and Restrictions Terms, Conditions and Restrictions § 971.422 Safety at sea... and property at sea. These requirements will be established with reference to subpart G of this part. ...

15 CFR 971.422 - Safety at sea requirements.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 15 Commerce and Foreign Trade 3 2010-01-01 2010-01-01 false Safety at sea requirements. 971.422...: Terms, Conditions and Restrictions Terms, Conditions and Restrictions § 971.422 Safety at sea... and property at sea. These requirements will be established with reference to subpart G of this part. ...

15 CFR 971.422 - Safety at sea requirements.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 15 Commerce and Foreign Trade 3 2011-01-01 2011-01-01 false Safety at sea requirements. 971.422...: Terms, Conditions and Restrictions Terms, Conditions and Restrictions § 971.422 Safety at sea... and property at sea. These requirements will be established with reference to subpart G of this part. ...

15 CFR 971.422 - Safety at sea requirements.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 15 Commerce and Foreign Trade 3 2014-01-01 2014-01-01 false Safety at sea requirements. 971.422...: Terms, Conditions and Restrictions Terms, Conditions and Restrictions § 971.422 Safety at sea... and property at sea. These requirements will be established with reference to subpart G of this part. ...

15 CFR 971.422 - Safety at sea requirements.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 15 Commerce and Foreign Trade 3 2013-01-01 2013-01-01 false Safety at sea requirements. 971.422...: Terms, Conditions and Restrictions Terms, Conditions and Restrictions § 971.422 Safety at sea... and property at sea. These requirements will be established with reference to subpart G of this part. ...

Long-Term Outcomes of Elagolix in Women With Endometriosis: Results From Two Extension Studies.

PubMed

Surrey, Eric; Taylor, Hugh S; Giudice, Linda; Lessey, Bruce A; Abrao, Mauricio S; Archer, David F; Diamond, Michael P; Johnson, Neil P; Watts, Nelson B; Gallagher, J Chris; Simon, James A; Carr, Bruce R; Dmowski, W Paul; Leyland, Nicholas; Singh, Sukhbir S; Rechberger, Tomasz; Agarwal, Sanjay K; Duan, W Rachel; Schwefel, Brittany; Thomas, James W; Peloso, Paul M; Ng, Juki; Soliman, Ahmed M; Chwalisz, Kristof

2018-06-06

To evaluate the efficacy and safety of elagolix, an oral, nonpeptide gonadotropin-releasing hormone antagonist, over 12 months in women with endometriosis-associated pain. Elaris Endometriosis (EM)-III and -IV were extension studies that evaluated an additional 6 months of treatment after two 6-month, double-blind, placebo-controlled phase 3 trials (12 continuous treatment months) with two elagolix doses (150 mg once daily and 200 mg twice daily). Coprimary efficacy endpoints were the proportion of responders (clinically meaningful pain reduction and stable or decreased rescue analgesic use) based on average monthly dysmenorrhea and nonmenstrual pelvic pain scores. Safety assessments included adverse events, clinical laboratory tests, and endometrial and bone mineral density assessments. The power of Elaris EM-III and -IV was based on the comparison to placebo in Elaris EM-I and -II with an expected 25% dropout rate. Between December 28, 2012, and October 31, 2014 (Elaris EM-III), and between May 27, 2014, and January 6, 2016 (Elaris EM-IV), 569 participants were enrolled. After 12 months of treatment, Elaris EM-III responder rates for dysmenorrhea were 52.1% at 150 mg once daily (Elaris EM-IV=50.8%) and 78.1% at 200 mg twice daily (Elaris EM-IV=75.9%). Elaris EM-III nonmenstrual pelvic pain responder rates were 67.8% at 150 mg once daily (Elaris EM-IV=66.4%) and 69.1% at 200 mg twice daily (Elaris EM-IV=67.2%). After 12 months of treatment, Elaris EM-III dyspareunia responder rates were 45.2% at 150 mg once daily (Elaris EM-IV=45.9%) and 60.0% at 200 mg twice daily (Elaris EM-IV=58.1%). Hot flush was the most common adverse event. Decreases from baseline in bone mineral density and increases from baseline in lipids were observed after 12 months of treatment. There were no adverse endometrial findings. Long-term elagolix treatment provided sustained reductions in dysmenorrhea, nonmenstrual pelvic pain, and dyspareunia. The safety was consistent with reduced estrogen levels and no new safety concerns were associated with long-term elagolix use. ClinicalTrials.gov, NCT01760954 and NCT02143713.

Ten-year immune persistence and safety of the HPV-16/18 AS04-adjuvanted vaccine in females vaccinated at 15-55 years of age.

PubMed

Schwarz, Tino F; Galaj, Andrzej; Spaczynski, Marek; Wysocki, Jacek; Kaufmann, Andreas M; Poncelet, Sylviane; Suryakiran, Pemmaraju V; Folschweiller, Nicolas; Thomas, Florence; Lin, Lan; Struyf, Frank

2017-11-01

Women remain at risk of human papillomavirus (HPV) infection for most of their lives. The duration of protection against HPV-16/18 from prophylactic vaccination remains unknown. We investigated the 10-year immune response and long-term safety profile of the HPV-16/18 AS04-adjuvanted vaccine (AS04-HPV-16/18 vaccine) in females aged between 15 and 55 years at first vaccination. Females who received primary vaccination with three doses of AS04-HPV-16/18 vaccine in the primary phase-III study (NCT00196937) were invited to attend annual evaluations for long-term immunogenicity and safety. Anti-HPV-16/18 antibodies in serum and cervico-vaginal secretions (CVS) were measured using enzyme-linked immunosorbent assay (ELISA). Serious adverse events (SAEs) were recorded throughout the follow-up period. Seropositivity rates for anti-HPV-16 remained high (≥96.3%) in all age groups 10 years after first vaccination. It was found that 99.2% of 15-25-year olds remained seropositive for anti-HPV-18 compared to 93.7% and 83.8% of 26-45-year olds and 45-55-year olds, respectively. Geometric mean titers (GMT) remained above natural infection levels in all age groups. Anti-HPV-16 and anti-HPV-18 titers were at least 5.3-fold and 3.1-fold higher than titers observed after natural infection, respectively, and were predicted to persist above natural infection levels for ≥30 years in all age groups. At Year 10, anti-HPV-16/18 antibody titers in subjects aged 15-25 years remained above plateau levels observed in previous studies. Correlation coefficients for antibody titers in serum and CVS were 0.64 (anti-HPV-16) and 0.38 (anti-HPV-18). This study concluded that vaccinated females aged 15-55 years elicited sustained immunogenicity with an acceptable safety profile up to 10 years after primary vaccination, suggesting long-term protection against HPV. © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

To what extent can theory account for the findings of road safety evaluation studies?

PubMed

Elvik, Rune

2004-09-01

This paper proposes a conceptual framework that can be used to assess to what extent the findings of road safety evaluation research make sense from a theoretical point of view. The effects of road safety measures are modelled as passing through two causal chains. One of these, termed the engineering effect, refers to the intended effects of a road safety measure on a set of risk factors related to accident occurrence or injury severity. The engineering effect of road safety measures is modelled in terms of nine basic risk factors, one or more of which any road safety measure needs to influence in order to have the intended effect on accidents or injuries. The other causal chain producing the effects of road safety measures is termed the behavioural effect, and refers to road user behavioural adaptations to road safety measures. The behavioural effect is related to the engineering effect, in the sense that certain properties of the engineering effect of a road safety measure influence the likelihood that behavioural adaptation will occur. The behavioural effect of a road safety measure is modelled in terms of six factors that influence the likelihood that behavioural adaptation will occur. The nine basic risk factors representing the engineering effect of a road safety measure, and the six factors influencing the likelihood of behavioural adaptation can be used as checklists in assessing whether or not the findings of road safety evaluation studies make sense from a theoretical point of view. At the current state of knowledge, a more stringent evaluation of the extent to which theory can explain the findings of road safety evaluation studies is, in most cases, not possible. Copyright 2003 Elsevier Ltd.

Reducing death on the road: the effects of minimum safety standards, publicized crash tests, seat belts, and alcohol.

PubMed Central

Robertson, L S

1996-01-01

OBJECTIVES. Two phases of attempts to improve passenger car crash worthiness have occurred: minimum safety standards and publicized crash tests. This study evaluated these attempts, as well as changes in seat belt and alcohol use, in terms of their effect on occupant death and fatal crash rates. METHODS. Data on passenger car occupant fatalities and total involvement in fatal crashes, for 1975 through 1991, were obtained from the Fatal Accident Reporting System. Rates per mile were calculated through published sources on vehicle use by vehicle age. Regression estimates of effects of regulation, publicized crash tests, seat belt use and alcohol involvement were obtained. RESULTS. Substantial reductions in fatalities occurred in the vehicle model years from the late 1960s through most of the 1970s, when federal standards were applied. Some additional increments in reduced death rates, attributable to additional improved vehicle crashworthiness, occurred during the period of publicized crash tests. Increased seat belt use and reduced alcohol use also contributed significantly to reduced deaths. CONCLUSIONS. Minimum safety standards, crashworthiness improvements, seat belt use laws, and reduced alcohol use each contributed to a large reduction in passenger car occupant deaths. PMID:8561238

Filgotinib for the treatment of rheumatoid arthritis.

PubMed

Taylor, Peter C; Abdul Azeez, Maha; Kiriakidis, Serafim

2017-10-01

Biologics were the first targeted therapies for rheumatoid arthritis (RA), having in common high clinical efficacy. Being proteins, they are administered parenterally. The first oral targeted small molecules approved for RA are competitive inhibitors of the Janus kinase (JAK) enzyme family which mediate signalling for a cytokine subset important in RA pathogenesis. Areas covered: Several JAK inhibitors have been developed with differing selectivity for the four JAK enzymes with a view to generating oral, multi-cytokine inhibitors. Here we review the pharmacology and clinical trial data for efficacy and safety of filgotinib, an investigational selective JAK1 inhibitor. We contextualise the contemporary approach to RA management and substantial unmet needs that remain. Expert opinion: The selectivity of filgotinib for JAK1 may have theoretical advantages in terms of limiting toxicity. However, establishing whether this is so before larger numbers of patients are exposed in phase III and beyond in the real word setting, will be difficult. Filgotinib clinical trial data to date has been encouraging with rapid, sustained efficacy with promising safety and tolerability. We are likely to see an expanding choice of approved JAK inhibitors in the clinic but it may not be straightforward to distinguish safety and efficacy differences.

Designing "Real-World" trials to meet the needs of health policy makers at marketing authorization.

PubMed

Calvert, Melanie; Wood, John; Freemantle, Nick

2011-07-01

There is increasing interest in conducting "Real-World" trials that go beyond traditional assessment of efficacy and safety to examine market access and value for money questions before marketing authorization of a new pharmaceutical product or health technology. This commentary uses practical examples to demonstrate how high-quality evidence of the cost-effectiveness of an intervention may be gained earlier in the development process. Issues surrounding the design and analysis of "Real-World" trials to demonstrate relative cost-effectiveness early in the life of new technologies are discussed. The modification of traditional phase III trial designs, de novo trial designs, the combination of trial-based and epidemiological data, and the use of simulation model-based approaches to address reimbursement questions are described. Modest changes to a phase III trial protocol and case report form may be undertaken at the design stage to provide valid estimates of health care use and the benefits accrued; however, phase III designs often preclude "real-life" practice. Relatively small de novo trials may be used to address adherence to therapy or patient preference, although simply designed studies with active comparators enrolling large numbers of patients may provide evidence on long-term safety and rare adverse events. Practical examples demonstrate that it is possible to provide high-quality evidence of the cost-effectiveness of an intervention earlier in the development process. Payers and decision makers should preferentially adopt treatments with such evidence than treatments for which evidence is lacking or of lower quality. Copyright © 2011 Elsevier Inc. All rights reserved.

Obeticholic Acid

PubMed Central

Smith, Susan M.; Pegram, Angela H.

2017-01-01

Objective: To review the pharmacology, efficacy, and safety of obeticholic acid (OCA) and determine its clinical role relative to other agents in the treatment of patients with primary biliary cholangitis (PBC). Data Sources: A PubMed search (1946 to November 2016) was conducted using the terms INT-747, obeticholic acid, OCA, farnesoid X receptor agonists, FXR agonists, primary biliary cirrhosis, and primary biliary cholangitis. Study Selection and Data Extraction: Phase II and III studies evaluating the use of OCA in PBC patients were included in this review. Data Synthesis: OCA, a farnesoid X receptor (FXR) agonist, is indicated for adult patients with PBC in combination with ursodeoxycholic acid (UDCA) or as monotherapy if unable to tolerate UDCA. Two clinical trials were identified evaluating OCA for the treatment of PBC. Study end points utilized biochemical markers (alkaline phosphatase [ALP] and bilirubin). A phase II study (n = 165) to determine efficacy and safety of OCA at 3 different doses (10 mg, 25 mg, 50 mg) demonstrated statistically significant reductions in ALP (P < .0001 for all OCA groups versus placebo) after 12 weeks. A phase III trial (n = 217) assessed lower OCA doses (5 mg and 10 mg) with a longer study duration (12 months). Statistically significant differences (P < .001) between the 5 to 10 mg group (46%) and the 10 mg group (47%) compared to the placebo group (10%) were found. The primary adverse effect reported in both trials was pruritus. Conclusions: OCA is the first FXR agonist approved for the treatment of PBC. Ongoing research to evaluate clinical outcomes with OCA is currently underway.

Daunorubicin and Cytarabine Liposome in Newly Diagnosed Therapy-Related Acute Myeloid Leukemia (AML) or AML With Myelodysplasia-Related Changes.

PubMed

Kim, Miryoung; Williams, Sherry

2018-03-01

To evaluate the efficacy and safety of daunorubicin and cytarabine liposome in older adults with newly diagnosed therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC). A literature search of PubMed and MEDLINE (January 2017 to January 2018) was performed using the terms CPX-351, Vyxeos, daunorubicin and cytarabine liposome, and acute myeloid leukemia. Phase I, II, and III clinical trials evaluating the efficacy and safety of daunorubicin and cytarabine liposome were reviewed with a specific focus on its use in older patients with newly diagnosed AML. All peer-reviewed articles with clinically relevant information were evaluated for inclusion. The phase II trial demonstrated that daunorubicin and cytarabine liposome improved response rates (RR), but there was no difference in event-free survival and overall survival in the overall patient population. However, clinical benefit was most pronounced in secondary AML with an increased RR and survival. The phase III trial illustrated that daunorubicin and cytarabine liposome improved survival and RR with tolerable toxicity compared with standard 7 plus 3 (daunorubicin and cytarabine) in patients 60 to 75 years of age with t-AML or AML-MRC. More patients proceeded to a stem cell transplant, and 30-day and 60-day mortality was lower with daunorubicin and cytarabine liposome. Grade 3 to 5 toxicities were similar between the 2 groups, except daunorubicin and cytarabine liposome had prolonged cytopenia and a higher risk of hemorrhage. Daunorubicin and cytarabine liposome improves RR and survival, with tolerable toxicity in older patients with t-AML or AML-MRC.

Mipomersen as a potential adjunctive therapy for hypercholesterolemia.

PubMed

Patel, Neeraj; Hegele, Robert A

2010-10-01

Mipomersen, an antisense oligonucleotide directed against apolipoprotein B-100 (apoB), was investigated for its safety and efficacy in reducing low-density lipoprotein (LDL) cholesterol (C) as adjunctive treatment for patients with homozygous familial hypercholesterolemia (HoFH) in a Phase III, double-blind, randomized, controlled trial. HoFH patients are very rare in the general population (∼ 1:1,000,000) and have very high risk for cardiovascular events. HoFH patients respond poorly to statins and most other existing lipid-lowering therapies. Mipomersen (200 or 160 mg) administered subcutaneously to 34 HoFH patients for 26 weeks significantly reduced LDL-C by 24.7% from baseline. In addition, mipomersen lowered plasma lipoprotein (a). In most patients, mipomersen administration was most associated with injection-site reactions; influenza-like symptoms were also more common in mipomersen-treated patients. Four patients had elevated serum alanine aminotransferase (ALT) concentrations, one of whom also had a significant increase in intrahepatic triglyceride content. Another patient met the stopping rules for increased ALT concentrations. No patient developed steatohepatitis during the study. Thus, so far short-term data indicate that mipomersen is safe and effective as an adjunctive drug for lowering LDL-C. Despite these promising results, the longer-term safety and efficacy of mipomersen still needs to be determined.

USDOT guidance summary for connected vehicle deployments : safety management.

DOT National Transportation Integrated Search

2016-07-01

This document provides guidance material in regards to safety management plan for the CV Pilots DeploymentConcept Development Phase. This guidance provides key concepts and references in developing the SafetyManagement Plan in Task 4, lists relevant ...

Quieter Cars and the Safety of Blind Pedestrians: Phase 1.

DOT National Transportation Integrated Search

2010-04-01

The National Highway Traffic Safety Administration recognizes that quieter cars such as hybrid-electric vehicles in low-speed operation using their : electric motors, may introduce a safety issue for pedestrians who are blind. This study documents th...

National child safety seat distribution program evaluation

DOT National Transportation Integrated Search

1999-03-01

The National Child Safety Seat Distribution Program (NCSS) was a multi-year, multi-phase program intended to distribute $8 million in child safety seats to low-income and special needs children in all fifty states. Non-profit organizations that recei...

Assessment of air pollutant emissions from the Akrotiri landfill site (Chania, Greece).

PubMed

Chalvatzaki, E; Lazaridis, M

2010-09-01

Air pollutants emitted from landfills affect air quality, contribute to the greenhouse effect and may cause serious problems to human health under certain circumstances. The current study was focused on the determination of air emissions from the Akrotiri landfill site which is located in the Akrotiri area (Chania, Greece). The landfill consists of two phases, phase A (first phase) which is currently closed (operational between 2003 and 2007) and phase B (second phase, operation between 2007 and (foreseen) 2013). Three different emission models (the EPA LandGEM model, the triangular model and the stoichiometric model) were used for the quantification of emissions. The LandGEM 3.02 software was further adopted and used in conjunction with the long-term dispersion model ISC3-LT for the evaluation of the dispersion of gaseous chemical components from the landfill. The emission and meteorological conditions under which the models were applied were based on the worst-case emission scenario. Furthermore, the concentration of hydrogen sulfide, vinyl chloride and benzene were determined in and around the landfill site. The concentrations of hydrogen sulfide and benzene were calculated to be far below the limit value proposed by the World Health Organization (WHO) for human health safety. However, the vinyl chloride concentrations were above the WHO reference lifetime exposure health criteria for the phase B area.

Effect of Cystone® on urinary composition and stone formation over a one year period.

PubMed

Erickson, S B; Vrtiska, T J; Lieske, J C

2011-07-15

Kidney stones are a common problem for which inadequate prevention exists. We recruited ten recurrent kidney stone formers with documented calcium oxalate stones into a two phased study to assess safety and effectiveness of Cystone(®), an herbal treatment for prevention of kidney stones. The first phase was a randomized double-blinded 12 week cross over study assessing the effect of Cystone(®) vs. placebo on urinary supersaturation. The second phase was an open label one year study of Cystone(®) to determine if renal stone burden decreased, as assessed by quantitative and subjective assessment of CT. Results revealed no statistically significant effect of Cystone(®) on urinary composition short (6 weeks) or long (52 weeks) term. Average renal stone burden increased rather than decreased on Cystone(®). Therefore, this study does not support the efficacy of Cystone(®) to treat calcium oxalate stone formers. Future studies will be needed to assess effects on stone passage, or on other stone types. Copyright © 2011 Elsevier GmbH. All rights reserved.

A Fire Safety Certification System for Board and Care Operators and Staff. SBIR Phase I: Final Report.

ERIC Educational Resources Information Center

Walker, Bonnie L.

This report describes the development and pilot testing of a fire safety certification system for board and care operators and staff who serve clients with developmental disabilities. During Phase 1, training materials were developed, including a trainer's manual, a participant's coursebook a videotape, an audiotape, and a pre-/post test which was…

Risk of Myocardial Infarction in Patients with Long-Term Non-Vitamin K Antagonist Oral Anticoagulant Treatment.

PubMed

Tornyos, Adrienn; Kehl, Dániel; D'Ascenzo, Fabrizio; Komócsi, András

2016-01-01

The relative cardiovascular (CV) safety of oral anticoagulants continues to be debated, and in particular concerns for risk of myocardial infarction (MI) have been raised. We analyzed the risk of MI in patients treated long term with oral anticoagulants (vitamin K antagonists [VKA], direct thrombin inhibitors or activated X factor antagonist) for atrial fibrillation, deep vein thrombosis or pulmonary embolism using a network meta-analysis (NMA). Randomized, phase 3 trials comparing novel anticoagulants to VKA were searched. Information on study design and clinical outcomes was extracted. The primary end-point of the analysis was the occurrence of MI or acute coronary syndrome. A Bayesian multiple treatment analysis was performed using fixed-effect and random-effects modeling. Twelve trials including 100,524 randomized patients were analyzed. The odds for MI in NMA were worse with dabigatran when compared to VKA, rivaroxaban, apixaban, and edoxaban (OR: 0.66 CI: 0.49-0.87; OR: 0.56 CI: 0.38-0.82, OR: 0.59 CI 0.40-0.88, and OR: 0.71 CI: 0.50-1.0, respectively).The posterior probability of being the first best choice of treatment was 53.5% for rivaroxaban, 33.8% for apixaban, 9.5% for ximelagatran, 2.0% for edoxaban, 1.2% for VKA, and 0.007% for dabigatran. There is a considerable heterogeneity regarding CV safety among oral anticoagulants. Differences in risk of MI may influence the choice of treatment. Multiple treatment NMA found 29%-44% higher odds of MI with dabigatran supporting the concerns regarding its CV safety. Copyright © 2015 Elsevier Inc. All rights reserved.

Secukinumab provides sustained improvements in the signs and symptoms of active ankylosing spondylitis with high retention rate: 3-year results from the phase III trial, MEASURE 2.

PubMed

Marzo-Ortega, Helena; Sieper, Joachim; Kivitz, Alan; Blanco, Ricardo; Cohen, Martin; Delicha, Evie-Maria; Rohrer, Susanne; Richards, Hanno

2017-01-01

Secukinumab treatment has previously been shown to significantly improve the signs and symptoms of active ankylosing spondylitis (AS), with responses sustained through 2 years. Here, we report the long-term (3 years) efficacy and safety of secukinumab in the MEASURE 2 study. MEASURE 2 (NCT01649375) is a 5-year phase III, randomised, double-blind, double-dummy, parallel-group, placebo-controlled study to evaluate the efficacy, safety and tolerability of subcutaneous loading and maintenance dosing of secukinumab in adult subjects with active AS. Subjects were randomised to receive subcutaneous secukinumab 150 mg, 75 mg or placebo at baseline, weeks 1, 2 and 3 and every 4 weeks from week 4. At week 16, placebo-treated subjects were rerandomised to receive secukinumab 150/75 mg. Retention rates were high during weeks 16-156 and were 86% and 76% for secukinumab 150 and 75 mg, respectively. Secukinumab 150 mg provided sustained improvements in the Assessment of Spondyloarthritis International Society ASAS 20/40 response rates at week 156 (70.1%/60.9%) compared with week 52 (74.2%/57.0%); however, there was a slight decrease for secukinumab 75 mg (54.3%/37.0% vs 62.5%/43.2%, respectively). Sustained improvements were observed in all other end points, including Bath Ankylosing Spondylitis Disease Activity Index, AS Disease Activity Score with C reactive protein inactive disease, ASAS 5/6, Short Form-36 Physical Component Summary and ASAS partial remission. Clinical benefits were observed regardless of prior exposure to anti-tumour necrosis factor agents. The safety profile remained favourable and was consistent with previous reports. This study showed sustained improvement through 3 years in signs, symptoms and physical function in subjects with AS. Retention rates were high and secukinumab was well tolerated, with a favourable safety profile.

The safety of Lipistart, a medium-chain triglyceride based formula, in the dietary treatment of long-chain fatty acid disorders: a phase I study.

PubMed

MacDonald, Anita; Webster, Rachel; Whitlock, Matthew; Gerrard, Adam; Daly, Anne; Preece, Mary Anne; Evans, Sharon; Ashmore, Catherine; Chakrapani, Anupam; Vijay, Suresh; Santra, Saikat

2018-03-28

Children with long-chain fatty acid β-oxidation disorders (LCFAOD) presenting with clinical symptoms are treated with a specialist infant formula, with medium chain triglyceride (MCT) mainly replacing long chain triglyceride (LCT). It is essential that the safety and efficacy of any new specialist formula designed for LCFAOD be tested in infants and children. In an open-label, 21-day, phase I trial, we studied the safety of a new MCT-based formula (feed 1) in six well-controlled children (three male), aged 7-13 years (median 9 years) with LCFAOD (very long chain acyl CoA dehydrogenase deficiency [VLCADD], n=2; long chain 3-hydroxyacyl CoA dehydrogenase deficiency [LCHADD], n=2; carnitine acyl carnitine translocase deficiency [CACTD], n=2). Feed 1 (Lipistart; Vitaflo) contained 30% energy from MCT, 7.5% LCT and 3% linoleic acid and it was compared with a conventional MCT feed (Monogen; Nutricia) (feed 2) containing 17% energy from MCT, 3% LCT and 1.1% linoleic acid. Subjects consumed feed 2 for 7 days then feed 1 for 7 days and finally resumed feed 2 for 7 days. Vital signs, blood biochemistry, ECG, weight, height, food/feed intake and symptoms were monitored. Five subjects completed the study. Their median daily volume of both feeds was 720 mL (range 500-1900 mL/day). Feed 1 was associated with minimal changes in tolerance, free fatty acids (FFA), acylcarnitines, 3-hydroxybutyrate (3-HB), creatine kinase (CK), blood glucose, liver enzymes and no change in an electrocardiogram (ECG). No child complained of muscle pain or symptoms associated with LCFAOD on either feed. This is the first safety trial reported of an MCT formula specifically designed for infants and children with LCFAOD. In this short-term study, it appeared safe and well tolerated in this challenging group.

Efficacy and safety of selective glucocorticoid receptor modulators in comparison to glucocorticoids in arthritis, a systematic review.

PubMed

Safy, M; de Hair, M J H; Jacobs, J W G; Buttgereit, F; Kraan, M C; van Laar, J M

2017-01-01

Long-term treatment with glucocorticoids (GCs) plays an important role in the management of arthritis patients, although the efficacy/safety balance is unfavorable. Alternatives with less (severe) adverse effects but with good efficacy are needed. Selective GC receptor modulators (SGRMs) are designed to engage the GC receptor with dissociative characteristics: transactivation of genes, which is mainly responsible for unwanted effects, is less strong while trans-repression of genes, reducing inflammation, is maintained. It is expected that SGRMs thus have a better efficacy/safety balance than GCs. A systematic review providing an overview of the evidence in arthritis is lacking. To systematically review the current literature on efficacy and safety of oral SGRMs in comparison to GCs in arthritis. A search was performed in Medline, Embase and the Cochrane Library, from inception dates of databases until May 2017. Experimental studies involving animal arthritis models or human material of arthritis patients, as well as clinical studies in arthritis patients were included, provided they reported original data. All types of arthritis were included. Data was extracted on the SGRM studied and on the GC used as reference standard; the design or setting of the study was extracted as well as the efficacy and safety results. A total of 207 articles was retrieved of which 17 articles were eligible for our analysis. Two studies concerned randomized controlled trials (RCT), five studies were pre-clinical studies using human material, and 10 studies involved pre-clinical animal models (acute and/or chronic arthritis induced in mice or rats). PF-04171327, the only compound investigated in a clinical trial setting, had a better efficacy/safety balance compared to GCs: better clinical anti-inflammatory efficacy and similar safety. Studies assessing both efficacy and safety of SGRMs are scarce. There is limited evidence for dissociation of anti-inflammatory and metabolic effects of the SGRMs studied. Development of many SGRMs is haltered in a preclinical phase. One SGRM showed a better clinical efficacy/safety balance.

24 CFR 232.510 - Commitment and commitment fee.

Code of Federal Regulations, 2013 CFR

2013-04-01

... of Fire Safety Equipment Fees and Charges § 232.510 Commitment and commitment fee. (a) Issuance of... setting forth the terms and conditions upon which the fire safety loan will be insured. (b) Type of... installation of the fire safety equipment, as determined by the Secretary of HHS. (c) Term of commitment. (1...

24 CFR 232.510 - Commitment and commitment fee.

Code of Federal Regulations, 2012 CFR

2012-04-01

... of Fire Safety Equipment Fees and Charges § 232.510 Commitment and commitment fee. (a) Issuance of... setting forth the terms and conditions upon which the fire safety loan will be insured. (b) Type of... installation of the fire safety equipment, as determined by the Secretary of HHS. (c) Term of commitment. (1...

24 CFR 232.510 - Commitment and commitment fee.

Code of Federal Regulations, 2014 CFR

2014-04-01

... of Fire Safety Equipment Fees and Charges § 232.510 Commitment and commitment fee. (a) Issuance of... setting forth the terms and conditions upon which the fire safety loan will be insured. (b) Type of... installation of the fire safety equipment, as determined by the Secretary of HHS. (c) Term of commitment. (1...

Safety in earth orbit study. Volume 5: Space shuttle payloads: Safety requirements and guidelines on-orbit phase

NASA Technical Reports Server (NTRS)

1972-01-01

Safety requirements and guidelines are listed for the sortie module, upper stage vehicle, and space station for the earth orbit operations of the space shuttle program. The requirements and guidelines are for vehicle design, safety devices, warning devices, operational procedures, and residual hazards.

Lubiprostone increases spontaneous bowel movement frequency and quality of life in patients with chronic idiopathic constipation.

PubMed

Fukudo, Shin; Hongo, Michio; Kaneko, Hiroshi; Takano, Masahiro; Ueno, Ryuji

2015-02-01

Lubiprostone is an activator of the type 2 chloride channel that facilitates spontaneous bowel movement (SBM). We performed phase 3 studies to determine whether lubiprostone increases the frequency of SBM in patients with chronic idiopathic constipation (CIC) in Japan, and whether long-term administration of lubiprostone increases the quality of life of patients with CIC. We performed a randomized, double-blind, placebo-controlled, phase 3 trial of lubiprostone. Patients with CIC (n = 124) were assigned randomly to groups given placebo (n = 62) or lubiprostone (48 μg/day; n = 62) for 4 weeks. The primary efficacy end point was the change from baseline in the weekly average number of SBMs after 1 week of administration. In a long-term study of efficacy and safety, 209 patients with CIC were given lubiprostone (24 μg twice daily) for 48 weeks. Daily administration of lubiprostone induced a significantly greater change, from baseline, in the weekly average number of SBMs at week 1 (increase of 3.7 ± 2.8), compared with placebo (increase of 1.3 ± 1.8; P < .001). The frequency of SBMs during each week of the study period was significantly higher after subjects began receiving lubiprostone than at baseline (P < .0001 at all weeks). Long-term administration of lubiprostone significantly increased scores from the Short-Form health survey and irritable bowel syndrome quality-of-life questionnaire, compared with baseline. We did not observe any severe adverse reactions to lubiprostone. In phase 3 studies in Japan, lubiprostone increased the weekly average number of SBMs and increased the quality of life of patients with CIC. Clinical Trial Notification of the Japanese Regulatory Authorities: 20-3296 and 20-3300. Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.

Wyoming freight movement system vulnerabilities and ITS.

DOT National Transportation Integrated Search

2013-12-01

This report summarizes the work performed during the second phase of a two-phase : research project. The first phase focused on two main areas: freight safety and wind : vulnerability, and the identification of critical infrastructure. Phase I also t...

Twelve-Month Efficacy and Safety Data for the "Stress Incontinence Control, Efficacy and Safety Study": A Phase III, Multicenter, Prospective, Randomized, Controlled Study Treating Female Stress Urinary Incontinence Using the Vesair Intravesical Balloon.

PubMed

Winkler, Harvey; Jacoby, Karny; Kalota, Susan; Snyder, Jeffrey; Cline, Kevin; Robertson, Kaiser; Kahan, Randall; Green, Lonny; McCammon, Kurt; Rovner, Eric; Rardin, Charles

The "Stress Incontinence Control, Efficacy and Safety Study" (SUCCESS) is a phase III study of the Vesair Balloon in women with stress urinary incontinence who had failed conservative therapy, and either failed surgery, were not candidates for surgery, or chose not to have surgery. The safety and efficacy of the balloon at 12 months is reported for those participants in the treatment arm who elected to continue with the SUCCESS trial beyond the primary end point at 3 months. The SUCCESS trial is a multicenter, prospective, single-blinded, randomized, sham-controlled study. Participants were randomized on a 2.33:1 basis to either Vesair Balloon placement or placebo. The primary efficacy end point was a composite of both a greater than 50% reduction from baseline on 1-hour provocative pad weight test and an at least 10-point improvement in symptoms on the Incontinence Quality of Life questionnaire assessed at the 3-month study visit. Patients in the treatment arm who opted to continue in the trial were followed up prospectively up to 12 months. A total of 221 participants were randomized, including 157 in the treatment arm and 64 in the control arm. Sixty-seven participants in the treatment arm (42.7% of participants enrolled) were evaluated at 12 months, with 56.3% achieving the composite end point and 78.7% having greater than 50% reduction in pad weight from baseline in a per-protocol analysis. In an intent-to-treat analysis treating all participants who did not continue with the balloon as failures, 24% of the participants achieved the composite end point and 33.6% had a greater than 50% reduction in pad weight from baseline. Treatment-related adverse events in this group included dysuria (40.1%), gross hematuria (36.9%), and urinary tract infection (26.1%). In this phase III trial, symptom relief was maintained for those participants who continued therapy for 12 months. The balloon was found to be safe with no device- or procedure-related serious adverse events reported. Additional studies are warranted to determine which patient populations are more tolerant of the balloon and to assess the efficacy and safety of its longer-term use. Additional screening methods, including screening patients for balloon tolerability, are warranted to reduce participant withdrawals.

[Side effects of biologic therapies in psoriasis].

PubMed

Altenburg, A; Augustin, M; Zouboulis, C C

2018-04-01

The introduction of biologics has revolutionized the treatment of moderate to severe plaque psoriasis. Due to the continuous expansion of biological therapies for psoriasis, it is particularly important to acknowledge efficacy and safety of the compounds not only in clinical trials but also in long-term registry-based observational studies. Typical side effects and significant risks of antipsoriatic biologic therapies considering psoriatic control groups are presented. A selective literature search was conducted in PubMed and long-term safety studies of the psoriasis registries PsoBest, PSOLAR and BADBIR were evaluated. To assess the long-term safety of biologics, the evaluation of the course of large patient cohorts in long-term registries is of particular medical importance. Newer biologic drugs seem to exhibit a better safety profile than older ones.

Usability Methods for Ensuring Health Information Technology Safety: Evidence-Based Approaches. Contribution of the IMIA Working Group Health Informatics for Patient Safety.

PubMed

Borycki, E; Kushniruk, A; Nohr, C; Takeda, H; Kuwata, S; Carvalho, C; Bainbridge, M; Kannry, J

2013-01-01

Issues related to lack of system usability and potential safety hazards continue to be reported in the health information technology (HIT) literature. Usability engineering methods are increasingly used to ensure improved system usability and they are also beginning to be applied more widely for ensuring the safety of HIT applications. These methods are being used in the design and implementation of many HIT systems. In this paper we describe evidence-based approaches to applying usability engineering methods. A multi-phased approach to ensuring system usability and safety in healthcare is described. Usability inspection methods are first described including the development of evidence-based safety heuristics for HIT. Laboratory-based usability testing is then conducted under artificial conditions to test if a system has any base level usability problems that need to be corrected. Usability problems that are detected are corrected and then a new phase is initiated where the system is tested under more realistic conditions using clinical simulations. This phase may involve testing the system with simulated patients. Finally, an additional phase may be conducted, involving a naturalistic study of system use under real-world clinical conditions. The methods described have been employed in the analysis of the usability and safety of a wide range of HIT applications, including electronic health record systems, decision support systems and consumer health applications. It has been found that at least usability inspection and usability testing should be applied prior to the widespread release of HIT. However, wherever possible, additional layers of testing involving clinical simulations and a naturalistic evaluation will likely detect usability and safety issues that may not otherwise be detected prior to widespread system release. The framework presented in the paper can be applied in order to develop more usable and safer HIT, based on multiple layers of evidence.

Case Report: Successful Use of the Combination of Electroconvulsive Therapy and Clozapine in Treating Treatment-Resistant Schizophrenia and Catatonia in an Adult with Intellectual Disability.

PubMed

Desarkar, Pushpal; Blumberger, Daniel; Daskalakis, Zafiris Jeff

2018-04-25

There is paucity of empirical data regarding the use of either clozapine or electroconvulsive therapy (ECT) in the acute phase and maintenance treatment of schizophrenia in adults with intellectual disability. Herein we report the successful acute and long-term remission of psychotic symptoms and catatonia with the combination of clozapine and ECT in a 26-year-old female with moderate ID and treatment-resistant schizophrenia. To our knowledge, this is the first case example of the successful use of the combination of bilateral, standard-pulse ECT and clozapine in both acute and long-term treatment of treatment-resistant schizophrenia and catatonia in an adult with ID. Our report adds further support to the emerging evidence regarding the efficacy and safety of this combination in treatment-resistant schizophrenia.

Manned space flight nuclear system safety. Volume 3: Reactor system preliminary nuclear safety analysis. Part 2A: Accident model document, appendix

NASA Technical Reports Server (NTRS)

1972-01-01

The detailed abort sequence trees for the reference zirconium hydride (ZrH) reactor power module that have been generated for each phase of the reference Space Base program mission are presented. The trees are graphical representations of causal sequences. Each tree begins with the phase identification and the dichotomy between success and failure. The success branch shows the mission phase objective as being achieved. The failure branch is subdivided, as conditions require, into various primary initiating abort conditions.

External Quality Assessment beyond the analytical phase: an Australian perspective.

PubMed

Badrick, Tony; Gay, Stephanie; McCaughey, Euan J; Georgiou, Andrew

2017-02-15

External Quality Assessment (EQA) is the verification, on a recurring basis, that laboratory results conform to expectations for the quality required for patient care. It is now widely recognised that both the pre- and post-laboratory phase of testing, termed the diagnostic phases, are a significant source of laboratory errors. These errors have a direct impact on both the effectiveness of the laboratory and patient safety. Despite this, Australian laboratories tend to be focussed on very narrow concepts of EQA, primarily surrounding test accuracy, with little in the way of EQA programs for the diagnostic phases. There is a wide range of possibilities for the development of EQA for the diagnostic phases in Australia, such as the utilisation of scenarios and health informatics. Such programs can also be supported through advances in health information and communications technology, including electronic test ordering and clinical decision support systems. While the development of such programs will require consultation and support from the referring doctors, and their format will need careful construction to ensure that the data collected is de-identified and provides education as well as useful and informative data, we believe that there is high value in the development of such programs. Therefore, it is our opinion that all pathology laboratories should strive to be involved in an EQA program in the diagnostic phases to both monitor the diagnostic process and to identify, learn from and reduce errors and near misses in these phases in a timely fashion.

External Quality Assessment beyond the analytical phase: an Australian perspective

PubMed Central

Gay, Stephanie; McCaughey, Euan J.; Georgiou, Andrew

2017-01-01

External Quality Assessment (EQA) is the verification, on a recurring basis, that laboratory results conform to expectations for the quality required for patient care. It is now widely recognised that both the pre- and post-laboratory phase of testing, termed the diagnostic phases, are a significant source of laboratory errors. These errors have a direct impact on both the effectiveness of the laboratory and patient safety. Despite this, Australian laboratories tend to be focussed on very narrow concepts of EQA, primarily surrounding test accuracy, with little in the way of EQA programs for the diagnostic phases. There is a wide range of possibilities for the development of EQA for the diagnostic phases in Australia, such as the utilisation of scenarios and health informatics. Such programs can also be supported through advances in health information and communications technology, including electronic test ordering and clinical decision support systems. While the development of such programs will require consultation and support from the referring doctors, and their format will need careful construction to ensure that the data collected is de-identified and provides education as well as useful and informative data, we believe that there is high value in the development of such programs. Therefore, it is our opinion that all pathology laboratories should strive to be involved in an EQA program in the diagnostic phases to both monitor the diagnostic process and to identify, learn from and reduce errors and near misses in these phases in a timely fashion. PMID:28392728

Establishment and assessment of code scaling capability

NASA Astrophysics Data System (ADS)

Lim, Jaehyok

In this thesis, a method for using RELAP5/MOD3.3 (Patch03) code models is described to establish and assess the code scaling capability and to corroborate the scaling methodology that has been used in the design of the Purdue University Multi-Dimensional Integral Test Assembly for ESBWR applications (PUMA-E) facility. It was sponsored by the United States Nuclear Regulatory Commission (USNRC) under the program "PUMA ESBWR Tests". PUMA-E facility was built for the USNRC to obtain data on the performance of the passive safety systems of the General Electric (GE) Nuclear Energy Economic Simplified Boiling Water Reactor (ESBWR). Similarities between the prototype plant and the scaled-down test facility were investigated for a Gravity-Driven Cooling System (GDCS) Drain Line Break (GDLB). This thesis presents the results of the GDLB test, i.e., the GDLB test with one Isolation Condenser System (ICS) unit disabled. The test is a hypothetical multi-failure small break loss of coolant (SB LOCA) accident scenario in the ESBWR. The test results indicated that the blow-down phase, Automatic Depressurization System (ADS) actuation, and GDCS injection processes occurred as expected. The GDCS as an emergency core cooling system provided adequate supply of water to keep the Reactor Pressure Vessel (RPV) coolant level well above the Top of Active Fuel (TAF) during the entire GDLB transient. The long-term cooling phase, which is governed by the Passive Containment Cooling System (PCCS) condensation, kept the reactor containment system that is composed of Drywell (DW) and Wetwell (WW) below the design pressure of 414 kPa (60 psia). In addition, the ICS continued participating in heat removal during the long-term cooling phase. A general Code Scaling, Applicability, and Uncertainty (CSAU) evaluation approach was discussed in detail relative to safety analyses of Light Water Reactor (LWR). The major components of the CSAU methodology that were highlighted particularly focused on the scaling issues of experiments and models and their applicability to the nuclear power plant transient and accidents. The major thermal-hydraulic phenomena to be analyzed were identified and the predictive models adopted in RELAP5/MOD3.3 (Patch03) code were briefly reviewed.

National Dam Safety Program. Manalapan Lake Dam (NJ00293), Raritan River Basin, Manalapan Brook, Middlesex County, New Jersey. Phase I Inspection Report.

DTIC Science & Technology

1979-04-01

NJ00293 1. OOVT ACCESSION NO. 4. TITLE (and Submit) Phase I Inspection Report National Dan Safety Program Manalapan Lake Dam Middlesea County...ssthoriistioa of set, Fsblic Lsw M- Ss7 . k brlsf assasaasat of ths ssa’s csssltlss is giwaa is ths frost of ths rsaort. oa wlsssl iaasostlaa, svallsbla

National Dam Safety Program. Steeger Lake Dam (MO 11098), Upper Mississippi - Kaskaskia - St. Louis Basin, Jefferson County, Missouri. Phase 1 Inspection Report

DTIC Science & Technology

1980-11-01

MISSOURPI 6 311-0 FOR: U. S. ARMY ENGINEER DISTRICT, ST. LOUIS CORPS OF ENGGINEERS -, NOVE4BER 1980 HS-8011 PHASE I REPORT NATIONAL DAM SAFETY...if the dam should fail, there may be loss of life, serious damage to homes, or extensive damage to agricultural, industrial and commercial facilities

The anti-CD6 antibody itolizumab provides clinical benefit without lymphopenia in rheumatoid arthritis patients: results from a 6-month, open-label Phase I clinical trial.

PubMed

Rodríguez, P C; Prada, D M; Moreno, E; Aira, L E; Molinero, C; López, A M; Gómez, J A; Hernández, I M; Martínez, J P; Reyes, Y; Milera, J M; Hernández, M V; Torres, R; Avila, Y; Barrese, Y; Viada, C; Montero, E; Hernández, P

2018-02-01

Itolizumab is a humanized anti-CD6 monoclonal antibody (mAb) that has previously shown encouraging results, in terms of safety and positive clinical effects, in a 6-week monotherapy clinical trial conducted in rheumatoid arthritis (RA) patients. The current Phase I study evaluated the safety and clinical response for a longer treatment of 12 itolizumab intravenous doses in subjects with active RA despite previous disease-modifying anti-rheumatic drug (DMARD) therapy. Twenty-one subjects were enrolled into four dosage groups (0·1, 0·2, 0·4 and 0·8 mg/kg). Efficacy end-points including American College of Rheumatology (ACR)20, ACR50 and ACR70 response rates and disease activity score in 28 joints (DAS28) were monitored at baseline and at specific time-points during a 10-week follow-up period. Itolizumab was well tolerated up to the highest tested dose. No related serious adverse events were reported and most adverse events were mild. Remarkably, itolizumab treatment did not produce lymphopenia and, therefore, was not associated with infections. All patients achieved a clinical response (ACR20) at least once during the study. Eleven subjects (55%) achieved at least a 20% improvement in ACR just 1 week after the first itolizumab administration. The clinical response was observed from the beginning of the treatment and was sustained during 24 weeks. The efficacy profile of this 12-week treatment was similar to that of the previous study (6-week treatment). These results reinforce the safety profile of itolizumab and provide further evidence on the clinical benefit from the use of this anti-CD6 mAb in RA patients. © 2017 British Society for Immunology.

Secukinumab after anti-tumour necrosis factor-α therapy: a phase III study in active rheumatoid arthritis.

PubMed

Dokoupilová, E; Aelion, J; Takeuchi, T; Malavolta, N; Sfikakis, P P; Wang, Y; Rohrer, S; Richards, H B

2018-02-20

To assess the efficacy and safety of secukinumab in patients with rheumatoid arthritis (RA) who failed to respond to tumour necrosis factor- α (TNF-α) inhibitors. This phase III double-blind, double-dummy, placebo-controlled study (NCT01770379) randomized (1:1:1) patients to subcutaneous secukinumab 150 mg, secukinumab 75 mg, or placebo at baseline, weeks 1, 2, 3, and 4, and then every 4 weeks. American College of Rheumatology (ACR) 20 response at week 24 was the primary endpoint. Secondary outcomes included the 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP), Health Assessment Questionnaire Disability Index (HAQ-DI), and ACR50 at week 24. Long-term treatment was planned for 5 years. ACR20 response rates at week 24 for the secukinumab 150 mg and 75 mg groups were not statistically superior to placebo. None of the secondary endpoints was met for either secukinumab dose. Although not statistically significant, compared with placebo, numerically greater differences in least squares mean changes from baseline in HAQ-DI score and numerically higher ACR50 response rates were observed at week 24 in both secukinumab treatment groups. No new or unexpected adverse events were observed in this study compared with the large secukinumab safety database across psoriasis, psoriatic arthritis, ankylosing spondylitis, and other RA studies. Given that other second-line therapies have demonstrated efficacy in RA patients who failed to respond to TNF-α inhibitors, these findings may suggest that interleukin-17A inhibition with secukinumab does not provide additional benefit to these patients. This study further confirms the well-characterized safety profile of secukinumab.

Safety assessment for the postictal confusional phase following complex partial seizure.

PubMed

Tucker, C

1985-06-01

Misunderstanding of the postictal confusional state that follows the complex partial seizure has caused emotional and physical harm to patients. Concern about this phenomenon and its effects upon the patient prompted this study to explore, describe, and document one method of intervention to lessen these harmful effects. An evaluative descriptive research design was employed to assess patient safety during and after the postictal confusional phase following a complex partial seizure. A closed-structured questionnaire and participant observation were the methods used to collect data for this study. A Level of Safety Tool was specifically designed for this study.

Short-Term Safety of Zoledronic Acid in Young Patients With Bone Disorders: An Extensive Institutional Experience

PubMed Central

George, Sobenna; Weber, David R.; Kaplan, Paige; Hummel, Kelly; Monk, Heather M.

2015-01-01

Context: Zoledronic acid (ZA) is increasingly used in young patients with bone disorders. However, data related to the safety of ZA administration in this population are limited. Objective: The study aimed to characterize the short-term safety profile of ZA and identify risk factors for ZA-related adverse events (AEs) in young patients. Design, Setting, and Participants: This was a retrospective chart review of inpatients and outpatients less than 21 years old who received at least one ZA infusion between July 2010 and January 2014 at The Children's Hospital of Philadelphia. Results: Eighty-one patients (56% male; median age, 12 y; age at first infusion, 0.5 to 20 y) with diverse skeletal disorders received a total of 204 infusions. The most common indications were osteoporosis (33% of cohort) and osteogenesis imperfecta (27.2%). The median ZA dose was 0.025 mg/kg (interquartile range, 0.025–0.05); the median dosing interval was 6 months (range, 1 to 25.6 mo). AEs were mild and more common after the first ZA infusion in patients with no previous bisphosphonate exposure: hypophosphatemia (25.2% of infusions), acute phase reactions (19.1%), and hypocalcemia (16.4%). Symptomatic hypocalcemia requiring iv calcium occurred after two infusions. ZA dose was significantly associated with hypophosphatemia, but not other AEs. Hypocalcemia was more common in patients with high bone turnover as assessed by preinfusion alkaline phosphatase levels. AEs were not associated with diagnosis, baseline serum calcium, or calcium/calcitriol supplementation. Conclusion: Acute AEs related to ZA infusion in youths are common, occur principally after the first ZA infusion in bisphosphonate-naive patients, and are typically mild and easily managed. Future prospective studies are needed to determine the potential long-term risks, as well as benefits, of ZA therapy in the pediatric population. PMID:26308295

Safety and efficacy outcomes of long-term treatment up to 4 years with 5% lidocaine medicated plaster in patients with post-herpetic neuralgia.

PubMed

Sabatowski, Rainer; Hans, Guy; Tacken, Ingrid; Kapanadze, Sofia; Buchheister, Bettina; Baron, Ralf

2012-08-01

Prospective evaluation of the long-term efficacy and safety of the 5% lidocaine medicated plaster in patients with post-herpetic neuralgia (PHN). Patients with persisting pain for ≥3 months after acute herpes zoster and a baseline pain intensity of at least 4 on an 11-point numerical rating scale (NRS 0-10) were treated with 5% lidocaine medicated plasters for up to 5 years and monitored in regular intervals. Efficacy parameters are presented for the first 4 years and include patients' recall of pain relief (6-point verbal rating scale (VRS), clinical global impression of change (CGIC), patients' global impression of change PGIC), and the global evaluations of study medication. Safety parameters (clinical examination, skin evaluation, laboratory) and adverse events (AEs) were assessed at regular visits. KF10004/02. A total of 102 patients continuing from a 1 year main study period were included in an extension phase of up to 3 years. Ten patients (9.8%) dropped out due to lack of efficacy and 9 patients (8.8%) due to treatment-related AEs; 56 patients (54.9%) left the study for non-treatment-related reasons. Twenty-seven patients (26.4%) were still under treatment after a total treatment period of 4 years. On average, a pain relief of at least 4.3 (between moderate and a lot) was achieved throughout the study. At all visits the CGIC and the PGIC were much or very much improved in about 80% of patients. At the final visit, study medication was rated at least to be good by 91% of physicians and 89% of patients. Drug-related adverse events (DRAEs) were reported in 19 of 102 patients, mainly mild to moderate localized skin reactions. There were no hints for a reduced analgesic effect or an increase of DRAEs with long-term treatment. This study demonstrates that long-term treatment of ≥12 months with the 5% lidocaine medicated plaster is effective and well tolerated in PHN patients. These findings support the recommendations to use the 5% lidocaine medicated plaster as baseline therapy for localized neuropathic pain after herpes zoster infection (PHN).

Five major NASA health and safety issues

NASA Astrophysics Data System (ADS)

Gavert, Raymond B.

2000-01-01

The goal has been set to establish NASA as number one in safety in the nation. This includes Systems and Mission Safety as well as Occupational Safety for all NASA employees and contractors on and off the job. There are five major health and safety issues important in the pursuit of being number one and they are: (1) Radiation (2) Hearing (3) Habitability/Toxicology (4) Extravehicular Activity (EVA) (5) Stress. The issues have features of accumulated injury since NASA's future missions involve long time human presence in space i.e., International Space Station operations and Mars missions. The objective of this paper is to discuss these five issues in terms of controlling risks and enhancing health and safety. Safety metrics are discussed in terms of the overall goal of NASA to be number one in safety. .

Uterine cavity lavage: adding FISH to conventional cytogenetics for embryonic sexing and diagnosing common chromosomal aberrations.

PubMed

Ishai, D; Amiel, A; Diukman, R; Cogan, O; Lichtenstein, Z; Abramovici, H; Fejgin, M D

1995-10-01

This study was undertaken to examine the efficacy for early prenatal diagnosis of uterine cavity lavage at the level of the internal os and to assess the rate of maternal contamination. In phase I, uterine cavity lavage was performed in 38 women scheduled for pregnancy termination between 6 and 12 weeks. In addition to short- and long-term cultures, one-colour FISH (fluorescence in situ hybridization) with Y and X probes was used for fetal sexing. Two-colour FISH was used in all known male fetuses for the assessment of maternal contamination. In phase II, lavage was performed on 16 women. Fetal sex was diagnosed with direct labelled X and Y probes and common numerical chromosomal aberration was attempted with 18 and 21 direct labelled probes. Fetal sexing was successful in all cases in phases I and II. Out of 34 patients in which tissue was obtained, only FISH was done in six. Long-term cell cultures were successful in the other 28 cases, but complete karyotyping in 19 (56 per cent). No chromosomal aberration was found with the direct labelled probes 18 and 21 in FISH. Maternal contamination was assessed to be 5-10 per cent. This simple and easy-to-master technique is very effective in obtaining fetal cells early in pregnancy for genetic diagnosis, especially by FISH. However, the safety of the procedure must be tested in ongoing pregnancies.

Safety and hemostatic efficacy of fibrin pad in partial nephrectomy: Results of an open-label Phase I and a randomized, standard-of-care-controlled Phase I/II study

PubMed Central

2012-01-01

Background Bleeding severity, anatomic location, tissue characteristics, and visibility are common challenges encountered while managing intraoperative bleeding, and conventional hemostatic measures (suture, ligature, and cautery) may sometimes be ineffective or impractical. While topical absorbable hemostats (TAH) are useful hemostatic adjuvants, each TAH has associated disadvantages. Methods We evaluated the safety and hemostatic efficacy of a new advanced biologic combination product―fibrin pad―to potentially address some gaps associated with TAHs. Fibrin pad was assessed as adjunctive hemostat in open partial nephrectomy in single-center, open-label, Phase I study (N = 10), and as primary hemostat in multicenter, single-blind, randomized, standard-of-care (SOC)-controlled Phase I/II study (N = 7) in Israel. It was used to control mild-to-moderate bleeding in Phase I and also spurting arterial bleeding in Phase I/II study. Phase I study assessed safety and Phase I/II study, proportion of successes at 10 min following randomization, analyzed by Fisher exact tests at 5% significance level. Results Phase I (N = 10): All patients completed the study. Hemostasis was achieved within 3–4 min (average = 3.1 min) of a single application in all patients. Fibrin pad was found to be safe for human use, with no product-related adverse events reported. Phase I/II (N = 7): Hemostatic success at 10 min (primary endpoint) was achieved in 3/4 patients treated with fibrin pad versus 0/3 patients treated with SOC. No clinically significant change in laboratory or coagulation parameters was recorded, except a case of post-procedural hemorrhage with fibrin pad, which was considered serious and related to the fibrin pad treatment, and required re-operation. Although Data Safety Monitoring Board authorized trial continuation, the sponsor decided against proceeding toward an indication for primary treatment of severe arterial hemorrhage as a replacement for sutures. The study was suspended after 7/30 planned subjects were enrolled. Conclusions The first-in-man trial of fibrin pad demonstrated its safety and efficacy as an adjunctive hemostatic technique for mild-to-moderate bleeding in partial nephrectomy. The study also suggested that the product should not replace sutures or meticulous surgical techniques for the treatment of severe arterial hemorrhage. Trial registration Phase I/II trial, NCT00598130 PMID:23137020

Enzyme replacement therapy in classical infantile pompe disease: results of a ten-month follow-up study.

PubMed

Klinge, L; Straub, V; Neudorf, U; Voit, T

2005-02-01

Infantile Pompe disease (IPD) is a fatal, autosomal recessive muscle-wasting disorder. Due to a deficiency of the lysosomal enzyme acid alpha-glucosidase patients develop a generalized myopathy, diaphragmatic weakness, and cardiomyopathy leading to death usually within the first year of life. So far there is no therapy available. We report on the safety and efficacy of transgenically derived recombinant human precursor acid alpha-glucosidase (rhGAA) in a 10-month follow-up study in two children with IPD who previously completed a 48-week course of enzyme replacement therapy (ERT) with the same medication at the same dose in a phase II clinical trial. Under this therapy cardiac status and muscle strength had improved, leading to survival beyond the age of one year. These results, together with data from two other phase II clinical trials encouraged further evaluation of the long-term safety and efficacy of enzyme replacement therapy in patients with infantile-onset Pompe disease. During the 10-month follow-up period, ERT was well-tolerated and neither patient experienced a single infusion-associated reaction. The initial improvements in cardiac size and function, as measured by left ventricular mass index and the fractional shortening, were maintained in both patients, and a continued improvement of motor function, as measured by the Alberta infant motor scale, was observed.

CT-P13: design, development, and place in therapy

PubMed Central

Gabbani, Tommaso; Deiana, Simona; Annese, Vito

2017-01-01

The introduction of biological agents has revolutionized the management of many life-threatening and debilitating immune-mediated diseases. Because of the high cost of biological drugs and their patent expiration, the market has opened to biosimilar agents, copy versions of the originators, which can lead to reduced health care expenditure and increase treatment access worldwide. CT-P13 is the first biosimilar of infliximab (IFX) and has been approved for the same indications as its originator drug. It obtained regulatory approval by the European Medicines Agency in September 2013 and by the US Food and Drug Administration in April 2016. The Phase I and Phase III clinical trials conducted in ankylosing spondylitis and rheumatoid arthritis have demonstrated pharmacokinetic and efficacy equivalence with comparable safety and immunogenicity to IFX. For these reasons, the use of CT-P13 has been extrapolated also to inflammatory bowel disease. There have been some initial concerns regarding the use of CT-P13 in inflammatory bowel disease patients, because of the lack of randomized controlled trials. However, emerging real-world data have further confirmed the comparability between CT-P13 and its reference product in terms of efficacy, safety, and immunogenicity, in patients naïve to the anti-tumor necrosis factor alpha agents and after switching from IFX, and will be summarized in this review. PMID:28652703

NP001 regulation of macrophage activation markers in ALS: A phase I clinical and biomarker study

PubMed Central

MILLER, ROBERT G.; ZHANG, RONGZHEN; BLOCK, GILBERT; KATZ, JONATHAN; BAROHN, RICHARD; KASARSKIS, EDWARD; FORSHEW, DALLAS; GOPALAKRISHNAN, VIDHYA; MCGRATH, MICHAEL S.

2017-01-01

This is a phase I, placebo-controlled, single ascending dose safety and tolerability study of NP001 in patients with ALS. NP001 is a novel regulator of inflammatory macrophages and monocytes. As ALS progression is thought to be related to neuroinflammation, an additional objective of the study was to assess the effects of NP001 administration on monocyte activation markers. Thirty-two ALS patients were enrolled and received either placebo (eight) or one of four (six at each dose) ascending single i.v. doses (0.2, 0.8, 1.6 and 3.2 mg/kg NP001). Patients were monitored for safety, and blood monocyte immune activation markers CD16 and HLA-DR were assessed pre- and 24 h post-dosing. Changes from baseline were calculated. Results showed that NP001 was generally safe and well tolerated. Importantly, a single dose of NP001 caused a dose-dependent reduction in expression of monocyte CD16, a marker of monocyte activation/inflammation. Additionally, monocyte HLA-DR expression was also decreased in those patients with elevated values at baseline. In conclusion, these data indicate that NP001 has an acute effect on inflammatory monocytes in ALS patient blood. The potential for modulation of inflammation in the context of ALS disease progression will require further study with long-term follow-up. PMID:25192333

Controversies in fluid therapy: Type, dose and toxicity

PubMed Central

McDermid, Robert C; Raghunathan, Karthik; Romanovsky, Adam; Shaw, Andrew D; Bagshaw, Sean M

2014-01-01

Fluid therapy is perhaps the most common intervention received by acutely ill hospitalized patients; however, a number of critical questions on the efficacy and safety of the type and dose remain. In this review, recent insights derived from randomized trials in terms of fluid type, dose and toxicity are discussed. We contend that the prescription of fluid therapy is context-specific and that any fluid can be harmful if administered inappropriately. When contrasting ‘‘crystalloid vs colloid’’, differences in efficacy are modest but differences in safety are significant. Differences in chloride load and strong ion difference across solutions appear to be clinically important. Phases of fluid therapy in acutely ill patients are recognized, including acute resuscitation, maintaining homeostasis, and recovery phases. Quantitative toxicity (fluid overload) is associated with adverse outcomes and can be mitigated when fluid therapy based on functional hemodynamic parameters that predict volume responsiveness and minimization of non-essential fluid. Qualitative toxicity (fluid type), in particular for iatrogenic acute kidney injury and metabolic acidosis, remain a concern for synthetic colloids and isotonic saline, respectively. Physiologically balanced crystalloids may be the ‘‘default’’ fluid for acutely ill patients and the role for colloids, in particular hydroxyethyl starch, is increasingly unclear. We contend the prescription of fluid therapy is analogous to the prescription of any drug used in critically ill patients. PMID:24834399

Safety and tolerability of azilsartan medoxomil in subjects with essential hypertension: a one-year, phase 3, open-label study

PubMed Central

Handley, Alison; Lloyd, Eric; Roberts, Andrew; Barger, Bruce

2016-01-01

Abstract This 56-week phase 3, open-label, treat-to-target study, involving 2 consecutive, non-randomized cohorts, evaluated the safety and tolerability of azilsartan medoxomil (AZL-M) in essential hypertension (mean baseline blood pressure [BP] 152/100 mmHg). All subjects (n = 669) initiated AZL-M 40 mg QD, force-titrated to 80 mg QD at week 4, if tolerated. From week 8, subjects could receive additional medications, starting with chlorthalidone (CLD) 25 mg QD (Cohort 1) or hydrochlorothiazide (HCTZ) 12.5–25 mg QD (Cohort 2), if required, to reach BP targets. Adverse events (AEs) were reported in 75.9% of subjects overall in the two cohorts (73.8% Cohort 1, 78.5% Cohort 2). The most common AEs were dizziness (14.3%), headache (9.9%) and fatigue (7.2%). Transient serum creatinine elevations were more frequent with add-on CLD. Clinic systolic/diastolic BP (observed cases at week 56) decreased by 25.2/18.4 mmHg (Cohort 1) and 24.2/17.9 mmHg (Cohort 2). These results demonstrate that AZL-M is well tolerated over the long term and provides stable BP improvements when used in a treat-to-target BP approach with thiazide-type diuretics. PMID:26817604

A systematic review of dermal fillers for age-related lines and wrinkles.

PubMed

Sturm, Lana P; Cooter, Rodney D; Mutimer, Keith L; Graham, John C; Maddern, Guy J

2011-01-01

Dermal fillers are gaining popularity for rapid aesthetic improvement. Long-term efficacy and safety have not been well documented. The aim of this systematic review was to assess the safety and efficacy of injectable dermal fillers compared with other facial augmentation techniques for the management of age-related lines and wrinkles. Studies including patients receiving injectable semi-permanent or permanent dermal fillers for age-related lines and wrinkles were included in this review. Efficacy outcomes (including changes in skin thickness and patient satisfaction) and safety outcomes (including mortality, lumps and infections) were examined. Three randomized control trials and six case series were included. Permanent and semi-permanent dermal fillers improved subjective ratings of appearance and resulted in higher patient satisfaction than temporary fillers. Long-term efficacy appeared good in the few studies that reported it. Short-term safety appeared favourable. Lumps were reported in all but one study but received little follow-up. Long-term safety data were limited. The treatment of age-related lines and wrinkles with permanent and semi-permanent dermal fillers is more efficacious compared with temporary fillers in those studies that compared them. Case series evidence suggests that these fillers achieve their objective, which is to decrease the visible effects of age-related changes. These fillers appear at least as safe as temporary fillers in the short term in those studies that compared them. Long-term safety could not be determined. © 2010 The Authors. ANZ Journal of Surgery © 2010 Royal Australasian College of Surgeons.

Drug development: from concept to marketing!

PubMed

Tamimi, Nihad A M; Ellis, Peter

2009-01-01

Drug development is an expensive, long and high-risk business taking 10-15 years and is associated with a high attrition rate. It is driven by medical need, disease prevalence and the likelihood of success. Drug candidate selection is an iterative process between chemistry and biology, refining the molecular properties until a compound suitable for advancing to man is found. Typically, about one in a thousand synthesised compounds is ever selected for progression to the clinic. Prior to administration to humans, the pharmacology and biochemistry of the drug is established using an extensive range of in vitro and in vivo test procedures. It is also a regulatory requirement that the drug is administered to animals to assess its safety. Later-stage animal testing is also required to assess carcinogenicity and effects on the reproductive system. Clinical phases of drug development include phase I in healthy volunteers to assess primarily pharmacokinetics, safety and toleration, phase II in a cohort of patients with the target disease to establish efficacy and dose-response relationship and large-scale phase III studies to confirm safety and efficacy. Experience tells us that approximately only 1 in 10 drugs that start the clinical phase will make it to the market. Each drug must demonstrate safety and efficacy in the intended patient population and its benefits must outweigh its risks before it will be approved by the regulatory agencies. Strict regulatory standards govern the conduct of pre-clinical and clinical trials as well as the manufacturing of pharmaceutical products. The assessment of the new medicinal product's safety continues beyond the initial drug approval through post-marketing monitoring of adverse events. Copyright 2009 S. Karger AG, Basel.

Enforcing Job Safety; A Union View of OSHA

ERIC Educational Resources Information Center

Wood, Michael

1975-01-01

A primary shortcoming of the Occupational Safety and Health Act of 1970 is that it provides the employer with too many phases of postponement of responsibility. However, positive administrative action has included organized labor's entry into all levels of job safety and health activities. (MW)

Technical Guidance from the International Safety Framework for Nuclear Power Source Applications in Outer Space for Design and Development Phases

NASA Astrophysics Data System (ADS)

Summerer, Leopold

2014-08-01

In 2009, the International Safety Framework for Nuclear Power Source Applications in Outer Space [1] has been adopted, following a multi-year process that involved all major space faring nations in the frame of the International Atomic Energy Agency and the UN Committee on the Peaceful Uses of Outer Space. The safety framework reflects an international consensus on best practices. After the older 1992 Principles Relevant to the Use of Nuclear Power Sources in Outer Space, it is the second document at UN level dedicated entirely to space nuclear power sources.This paper analyses aspects of the safety framework relevant for the design and development phases of space nuclear power sources. While early publications have started analysing the legal aspects of the safety framework, its technical guidance has not yet been subject to scholarly articles. The present paper therefore focuses on the technical guidance provided in the safety framework, in an attempt to assist engineers and practitioners to benefit from these.

Safety and tolerability of Bifidobacterium longum subspecies infantis EVC001 supplementation in healthy term breastfed infants: a phase I clinical trial.

PubMed

Smilowitz, Jennifer T; Moya, Jackelyn; Breck, Melissa A; Cook, Chelsea; Fineberg, Annette; Angkustsiri, Kathleen; Underwood, Mark A

2017-05-30

Historically, bifidobacteria were the dominant intestinal bacteria in breastfed infants. Still abundant in infants in developing nations, levels of intestinal bifidobacteria are low among infants in developed nations. Recent studies have described an intimate relationship between human milk and a specific subspecies of Bifidobacterium, B. longum subsp. infantis (B. infantis), yet supplementation of breastfed, healthy, term infants with this organism, has not been reported. The IMPRINT Study, a Phase I clinical trial, was initiated to determine the safety and tolerability of supplementing breastfed infants with B. infantis (EVC001). Eighty mother-infant dyads were enrolled in either lactation support plus B. infantis supplementation (BiLS) or lactation support alone (LS). Starting with Day 7 postnatal, BiLS infants were fed 1.8-2.8 × 10 10  CFU B. infantis EVC001 daily in breast milk for 21 days. Mothers collected fecal samples, filled out health questionnaires, and kept daily logs about their infants' feeding and gastrointestinal symptoms from birth until Day 61 postnatal. Safety and tolerability were determined from maternal reports. There were no differences in the mean gestational age at birth, weight 1 and 2 months postnatal, and breast milk intake between groups. The mean Log 10 change in fecal Bifidobacterium from Day 6 to Day 28 was higher (p = 0.0002) for BiLS (6.6 ± 2.8 SD) than for LS infants (3.5 ± 3.5 SD). Daily stool number was higher (p < 0.005) for LS and lower (p < 0.05) for BiLS infants during supplementation than at Baseline. During supplementation, watery stools decreased and soft stools increased by 36% over baseline in BiLS infants (p < 0.05) with no significant changes in stool consistency for the LS infants. None of the safety and tolerability endpoints, including flatulence, bloody stool, body temperature, ratings of gastrointestinal symptoms, use of antibiotics or gas-relieving medications, infant colic, jaundice, number of illnesses, sick doctor visits, or diagnoses of eczema were different for the groups at any point. The B. infantis EVC001 supplement was safely consumed and well-tolerated. Stools were fewer and better formed in infants in the BiLS group compared with LS group. Adverse events were those expected in healthy infants and not different between groups. ClinicalTrials.gov NCT02457338 . Registered May 27, 2015.

Shuttle: forever young?

PubMed

Sietzen, Frank

2002-01-01

NASA has started a 4-phase program of upgrades designed to increase safety and extend use of the space shuttles through the year 2020. Phase I is aimed at improving vehicle safety and supporting the space station. Phase II is aimed at combating obsolescence and includes a checkout launch and control system and protection from micrometeoroids and orbital debris. Phase III is designed to expand or enhance the capabilities of the shuttle and includes development of an auxiliary power unit, avionics, a channel-wall nozzle, extended nose landing gear, long-life fuel cells, a nontoxic orbital maneuvering system/reaction control system, and a water membrane evaporator. Phase IV is aimed at design of system changes that would alter the shuttle mold line and configuration; projects include a five-segment solid rocket booster, liquid flyback boosters, and a crew escape module.

Analysis of pharmaceutical safety-related regulatory actions in Japan: do tradeoffs exist between safer drugs and launch delay?

PubMed

Yamada, Toru; Kusama, Makiko; Hirai, Yuka; Arnold, Frank; Sugiyama, Yuichi; Ono, Shunsuke

2010-12-01

Prediction and management of drug safety is a global regulatory issue. Safety-related regulatory actions (SRRAs) are taken mostly when unexpected adverse drug reactions occur. Currently, Japan is reconciled to delayed access to new drugs (ie, launch delay compared to Western countries), but may have been benefiting by free-riding on safety data accumulated in other countries prior to Japanese launch. To identify factors that are significantly associated with SRRAs, and to discuss the challenges that Japan might have to face with increasing access to new drugs. The SRRAs of 135 new drugs approved from January 2000 to December 2005 were analyzed to investigate association with launch lag, company and drug characteristics, market size, submission data, and regulatory status. SRRAs were measured in terms of the number of emergency safety information notifications and official safety instructions issued by the Japanese regulatory agency within 3 years after approval. A negative binomial distribution model was used for regression analysis. Longer launch lags and presence of drugs with similar modes of action were associated with fewer SRRAs. Bridging strategy showed increased SRRAs. No significant association was observed between SRRAs and the subject number in clinical data packages. Occurrence of SRRAs was varied among development strategy, preceding products, and regional regulations. The occurrence of SRRAs was associated with the accumulation of both foreign and domestic postmarketing evidence rather than with clinical trial data upon launch. Considering the paradigm shift to simultaneous global drug development and filing for regulatory approval, this study indicates the importance of intensive data collection in the early postmarketing phase and use of safety information in early markets. However, even if we would be sufficiently cautious about safety risks of new drugs, a population that enjoys first-in-class drugs probably has to bear the risks.

Long-term Immunogenicity of Elosulfase Alfa in the Treatment of Morquio A Syndrome: Results From MOR-005, a Phase III Extension Study.

PubMed

Long, Brian; Tompkins, Troy; Decker, Celeste; Jesaitis, Lynne; Khan, Shahid; Slasor, Peter; Harmatz, Paul; O'Neill, Charles A; Schweighardt, Becky

2017-01-01

Elosulfase alfa is an enzyme replacement therapy for the treatment of Morquio A syndrome (mucopolysaccharidosis IVA), a lysosomal storage disorder caused by a deficiency of the enzyme N-acetylgalactose-amine-6-sulfatase. We previously reported immunogenicity data from our 24-week placebo-controlled Phase III study, MOR-004. Here, we report the long-term immunogenicity profile of elosulfase alfa from MOR-005, the Phase III extension trial to assess potential correlations between antidrug antibodies and efficacy and safety profile outcomes throughout 120 weeks of treatment. The long-term immunogenicity of elosulfase alfa was evaluated in patients with Morquio A syndrome in an open-label extension study for a total of 120 weeks. All patients received 2.0 mg/kg elosulfase alfa either weekly or every other week before establishment of 2.0 mg/kg/wk as the recommended dose, at which time all patients received weekly treatment. Efficacy measures were compared with those from the MOR-004 baseline, enabling analysis of changes over 120 weeks. The primary efficacy measure was the change from baseline in 6-minute walk test. Secondary measures included changes from baseline in 3-minute stair climb test and normalized urine keratan sulfate, a pharmacodynamic metric. All patients treated with elosulfase alfa developed antidrug total antibodies (TAb) by week 24 of MOR-004. In the extension study, all patients, including those who had previously received placebo, were TAb positive by study week 36 (MOR-005 week 12). All patients remained TAb positive throughout the study, and TAb titers were similar across treatment groups at week 120. Nearly all patients tested positive for neutralizing antibodies (NAb) at least once, with incidence of NAb positivity peaking at 85.9% at study week 36, then steadily declining to 66.0% at study week 120. In all treatment groups, mean urine keratan sulfate remained below treatment-naive baseline despite the presence of antidrug antibodies. No relationship was observed between TAb titers or NAb positivity and changes in urine keratan sulfate, 6-minute walk test, or 3-minute stair climb test from baseline to week 120. No consistent associations were detected between antidrug antibodies and the occurrence of hypersensitivity adverse events or anaphylaxis over the course of the study. Immunogenicity results from this long-term study are consistent with previously reported 24-week results. Despite the sustained presence of antidrug antibodies, elosulfase alfa was well tolerated, and patients continued to benefit from treatment through week 120. No associations were detected between higher TAb titers or NAb positivity and reduced treatment effect or worsened safety profile measures. ClinicalTrials.gov identifier: NCT01415427. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Two-Year Safety and Efficacy Experience in Patients with Methotrexate-Resistant Active Rheumatoid Arthritis Treated with Etanercept and Conventional Disease-Modifying Anti-rheumatic Drugs in the Latin American Region

PubMed Central

Machado, Daniel A.; Guzman, Renato; Xavier, Ricardo M.; Simon, Jesus A.; Mele, Linda; Shen, Qi; Pedersen, Ronald; Kotak, Sameer; Vlahos, Bonnie

2016-01-01

Background: Although long-term data are available from biologic studies in North American/European populations with rheumatoid arthritis (RA), long-term findings in Latin American RA populations are limited. Objective: To examine long-term safety/efficacy of etanercept, methotrexate, and/or other disease-modifying anti-rheumatic drugs (DMARDs) in Latin American patients with moderate-to-severe active RA. Methods: In the first phase of this open-label study, patients were randomized to etanercept 50 mg weekly plus methotrexate or conventional DMARD (hydroxychloroquine or sulfasalazine) plus methotrexate for 24 weeks. At the start of the second phase (week 24), investigators selected a treatment regimen that included any combination/dosage of etanercept, methotrexate, hydroxychloroquine, or sulfasalazine based on previous treatment response, preference, and local product labeling, and was continued for the 104-week extension. Results: In the extension, in the group previously randomized to etanercept-plus-methotrexate therapy, etanercept was continued in 259/260 patients; methotrexate continued in 260/260; and hydroxychloroquine and sulfasalazine added in 8/260 and 3/260, respectively. In the group previously randomized to conventional DMARD-plus-methotrexate therapy, conventional DMARD was discontinued in 86/126 and etanercept added in 105/126. Among etanercept-exposed patients (total exposure, 798.1 patient-year [PY]), rates of adverse events, serious adverse events, and serious infections per PY were 1.7, 0.07, and 0.02 events per PY. In both groups, after treatment modification was permitted, clinical response rates and improvements in clinical/patient-reported outcomes from baseline were sustained to week 128. Conclusion: After investigators were permitted to modify treatment, etanercept was part of the treatment regimen in 95% of patients. Continuation or addition of etanercept in the 2-year extension resulted in a consistently good risk:benefit profile. Trial Registration: Open-Label Study Comparing Etanercept to Conventional Disease Modifying Antirheumatic Drug (DMARD) Therapy; ClinicalTrials.gov, number NCT00848354; https://clinicaltrials.gov/ct2/show/NCT00848354 PMID:27006728

Increasing the number of trained health and safety professionals in agricultural medicine: evaluation of the "building capacity" program, 2007-2013.

PubMed

Rudolphi, Josie M; Donham, Kelley J

2015-01-01

ABSTRACT The University of Iowa began training health care professionals to care for farmers' occupational health needs since 1974. In order to geographically expand this training to practicing health and safety professionals, the "Building Capacity: A National Resource of Agricultural Medicine Professionals" program was developed and launched in 2006. The model began in 1987 as a program of Iowa's Center for Agricultural Safety and Health. In 2006, with funding from the National Institute for Occupational Safety and Health (NIOSH), Great Plains Center for Agricultural Health (GPCAH), the program was expanded beyond the Iowa borders. The principal component of the program, the 40-hour course, Agricultural Medicine: Occupational and Environmental Health for Rural Health Professionals-the Core Course (AMCC) is now being offered to health and safety professionals in nine states in the United States, in Australia, and a modified version presented in Turkey. An initial paper evaluated the first phase of the program, years 2007-2010. This paper compares the first phase (2007-2010) with the second phase (2011-2013), which has involved over 500 health and safety professionals. This paper also describes evaluation of the course and changes resulting from the evaluation. Finally, this paper describes best practices for operating this program and makes recommendations for future courses, as well as other trainings within the field.

Use of a risk characterisation approach to contextualise the safety profile of new rheumatoid arthritis treatments: a case study using tofacitinib.

PubMed

Curtis, Jeffrey R; Zhang, Richard; Krishnaswami, Sriram; Anisfeld, Andrew; Chen, Yan; Strengholt, Sander; Chen, Connie; Geier, Jamie

2017-03-01

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). To characterise the relative safety profile of tofacitinib to biologic disease-modifying antirheumatic drugs (bDMARDs), the accrued patient-years (pt-yrs) of exposure needed in an RA clinical trial programme to detect a potential increase in risk of specific adverse events (AEs) was determined. This case study/framework was constructed on the pt-yrs' accrual within pooled phase (P)1, P2 and P3, as well as long-term extension, studies of tofacitinib in RA (March 2015 data-cut) and published AE incidence rates for bDMARDs. Sample size calculations were based on a Poisson distribution to estimate pt-yrs' exposure required for 90 % probability that the lower bound of the 95 % confidence interval for tofacitinib/bDMARD would be >1, assuming that tofacitinib rates were 1.2×/1.5×/2.0× greater than comparator rates. AE rates for bDMARDs were derived from sources intended to optimise similarity with the tofacitinib database in terms of baseline characteristics, study duration and follow-up. Based on the tofacitinib exposure accrued (19,406 pt-yrs), data were sufficient (90 % probability) to detect potential differences over external bDMARD comparator rates in serious infections (≥1.2×), malignancies (excluding non-melanoma skin cancer [NMSC]), NMSC, major adverse cardiovascular events (MACE) and lymphoma (each ≥1.5×), as well as opportunistic infections and gastrointestinal perforations (≥2×), should they exist. This risk characterisation approach can support the comparative safety of new RA medications. To date, tofacitinib safety appears similar to approved published data from bDMARDs with respect to serious infections, malignancies (excluding NMSC), NMSC, MACE, lymphoma, opportunistic infections and gastrointestinal perforations.

Long-term safety and efficacy of recombinant factor VIII Fc fusion protein (rFVIIIFc) in subjects with haemophilia A.

PubMed

Nolan, B; Mahlangu, J; Perry, D; Young, G; Liesner, R; Konkle, B; Rangarajan, S; Brown, S; Hanabusa, H; Pasi, K J; Pabinger, I; Jackson, S; Cristiano, L M; Li, X; Pierce, G F; Allen, G

2016-01-01

The safety, efficacy and prolonged half-life of recombinant factor VIII Fc fusion protein (rFVIIIFc) in previously treated patients with severe haemophilia A was demonstrated in the phase 3 A-LONG and Kids A-LONG studies. Here, we report interim safety and efficacy data from the rFVIIIFc extension study, ASPIRE (ClinicalTrials.gov #NCT01454739). Eligible subjects could enrol in ASPIRE upon completing A-LONG or Kids A-LONG. There were four treatment groups: individualized prophylaxis; weekly prophylaxis; modified prophylaxis (for subjects in whom optimal treatment could not be achieved with individualized or weekly prophylaxis); and episodic treatment. The primary endpoint was development of inhibitors. A total of 150 A-LONG subjects and 61 Kids A-LONG subjects enrolled in ASPIRE. As of the interim data cut (6 January 2014), the median time on study was 80.9 (A-LONG) and 23.9 (Kids A-LONG) weeks. The majority of subjects (A-LONG, 92.0%; Kids A-LONG, 57.4%) had ≥100 cumulative rFVIIIFc exposure days. No inhibitors were observed. Adverse events were generally consistent with those expected in the general haemophilia A population. Median annualized bleeding rates (ABRs) were low with individualized [A-LONG: 0.66; Kids A-LONG: 0.00 (<6 years old), 1.54 (6 to <12 years old)], weekly (A-LONG: 2.03) and modified (A-LONG: 1.97) prophylaxis. There was no change in prophylactic infusion frequency or total weekly prophylactic dose in the majority of subjects from A-LONG and Kids A-LONG. Interim data from ASPIRE confirm the long-term safety of rFVIIIFc and the maintenance of a low ABR with extended-interval prophylactic dosing in patients with severe haemophilia A. © 2015 The Authors. Haemophilia Published by John Wiley & Sons Ltd.

Erenumab (AMG 334) in episodic migraine: Interim analysis of an ongoing open-label study.

PubMed

Ashina, Messoud; Dodick, David; Goadsby, Peter J; Reuter, Uwe; Silberstein, Stephen; Zhang, Feng; Gage, Julia R; Cheng, Sunfa; Mikol, Daniel D; Lenz, Robert A

2017-09-19

To assess long-term safety and efficacy of anti-calcitonin gene-related peptide receptor erenumab in patients with episodic migraine (EM). Patients enrolled in a 12-week, double-blind, placebo-controlled clinical trial (NCT01952574) who continued in an open-label extension (OLE) study will receive erenumab 70 mg every 4 weeks for up to 5 years. This preplanned interim analysis, conducted after all participants had completed the 1-year open-label follow-up, evaluated changes in monthly migraine days (MMD), achievement of ≥50%, ≥75%, and 100% reductions, Headache Impact Test (HIT-6) score, Migraine-Specific Quality of Life (MSQ), Migraine Disability Assessment (MIDAS), and safety. Data reported as observed without imputation for missing data. Of 472 patients enrolled in the parent study, 383 continued in the OLE with a median exposure to erenumab of 575 days (range 28-822 days). Mean (SD) MMD were 8.8 (2.6) at parent study baseline, 6.3 (4.2) at week 12 (beginning of OLE), and 3.7 (4.0) at week 64 (mean change from baseline [reduction] of 5.0 days). At week 64, 65%, 42%, and 26% achieved ≥50%, ≥75%, and 100% reduction in MMD, respectively. Mean HIT-6 scores were 60.2 (6.3) at baseline and 51.7 (9.2) at week 64. MSQ and MIDAS improvements from baseline were maintained through week 64. Safety profiles during the OLE were similar to those in the double-blind phase, which overall were similar to placebo. One-year efficacy, supported by functional improvements and favorable safety and tolerability profiles, supports further investigation of erenumab as a preventive treatment in patients with EM. NCT01952574. This study provides Class IV evidence that for patients with episodic migraine, erenumab reduces long-term MMD and improves headache-related disability and migraine-specific quality of life. © 2017 American Academy of Neurology.

Comparison of Different Forms of Exercise Training in Patients With Cardiac Disease: Where Does High-Intensity Interval Training Fit?

PubMed

Gayda, Mathieu; Ribeiro, Paula A B; Juneau, Martin; Nigam, Anil

2016-04-01

In this review, we discuss the most recent forms of exercise training available to patients with cardiac disease and their comparison or their combination (or both) during short- and long-term (phase II and III) cardiac rehabilitation programs. Exercise training modalities to be discussed include inspiratory muscle training (IMT), resistance training (RT), continuous aerobic exercise training (CAET), and high-intensity interval training (HIIT). Particular emphasis is placed on HIIT compared or combined (or both) with other forms such as CAET or RT. For example, IMT combined with CAET was shown to be superior to CAET alone for improving functional capacity, ventilatory function, and quality of life in patients with chronic heart failure. Similarly, RT combined with CAET was shown to optimize benefits with respect to functional capacity, muscle function, and quality of life. Furthermore, in recent years, HIIT has emerged as an alternative or complementary (or both) exercise modality to CAET, providing equivalent if not superior benefits to conventional continuous aerobic training with respect to aerobic fitness, cardiovascular function, quality of life, efficiency, safety, tolerance, and exercise adherence in both short- and long-term training studies. Finally, short-interval HIIT was shown to be useful in the initiation and improvement phases of cardiac rehabilitation, whereas moderate- or longer-interval (or both) HIIT protocols appear to be more appropriate for the improvement and maintenance phases because of their high physiological stimulus. We now propose progressive models of exercise training (phases II-III) for patients with cardiac disease, including a more appropriate application of HIIT based on the scientific literature in the context of a multimodal cardiac rehabilitation program. Copyright © 2016 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

Development of the Oregon traffic safety data archive : phases 1 and 2.

DOT National Transportation Integrated Search

2012-03-01

"This report describes the preliminary work to develop the Oregon Traffic Safety Data Archive (OrTSDA). The mission of OrTSDA is to build : the knowledge base of traffic safety data in Oregon. The archive hopes to become a valuable traffic safe...

Motivation of employers to encourage their employees to use safety belts (Phase 1)

DOT National Transportation Integrated Search

1982-05-01

For the purpose of motivating employers to encourage their employees to use safety belts, a manual for employers, "The Profit in Safety Belts: A View for Employers", is developed. The manual brings to the attention of employers the various cost eleme...

Validation and application of Highway Safety Manual (Part D) and developing Florida CMF Manual, phase 2.

DOT National Transportation Integrated Search

2016-05-01

The Highway Safety Manual (HSM) Part D provides a comprehensive list of the effects of safety treatments : (countermeasures). These effects are quantified by crash modification factors (CMF) which are based on compilation : from past studies of the e...

Revenue sources for financing transportation safety activities in Virginia : phase two, state sources.

DOT National Transportation Integrated Search

1980-01-01

Senate Bill 85, an action of the 1978 General Assembly, amended the Code of Virginia to provide, in part, that the Division of Highway Safety be succeeded by the newly created Department of Transportation Safety effective July 1, 1978. In its Declara...

Long-term safety of tiotropium/olodaterol Respimat® in patients with moderate-to-very severe COPD and renal impairment in the TONADO® studies.

PubMed

LaForce, Craig; Derom, Eric; Bothner, Ulrich; Kloer, Isabel M; Trampisch, Matthias; Buhl, Roland

2018-01-01

The safety, lung function efficacy, and symptomatic benefits of combined tiotropium and olodaterol in patients with COPD were established in the 1-year TONADO ® studies (NCT01431274; NCT01431287). As tiotropium is predominantly excreted by the kidneys, the long-term safety profile of tiotropium/olodaterol was investigated in patients with renal impairment in a prespecified safety analysis of the TONADO studies. These were 2 replicate, randomized, double-blind, parallel-group, 52-week Phase III studies that assessed tiotropium/olodaterol compared with tiotropium or olodaterol alone (all via Respimat ® ) in patients with moderate-to-very severe COPD. In this analysis, renal impairment was defined as mild (creatinine clearance [CLcr] 60-89 mL/min), moderate (CLcr 30-59 mL/min) or severe (CLcr 15-29 mL/min). Adverse events (AEs) were pooled from both studies. Of 3,041 patients included in this analysis, 1,333 (43.8%) had mild, 404 (13.3%) had moderate, and 5 (0.2%) had severe renal impairment; these were distributed equally between treatment groups. Almost one-quarter of all treated patients (23.4%) had a history of cardiac disorder, 45.6% had hypertension, and 13.3% had glucose metabolism disorders, including diabetes. AEs with olodaterol, tiotropium, and tiotropium/olodaterol occurred in 75.1%, 70.8%, and 72.0% of patients with no renal impairment, 75.7%, 74.0%, and 73.3% with mild renal impairment, and 84.3%, 79.5%, and 79.7% with moderate renal impairment, respectively. There was no notable effect of renal impairment on the proportion of patients with an AE, and no differences were observed between tiotropium/olodaterol versus the monocomponents. There was no difference in the incidence of major adverse cardiac events, renal and urinary tract AEs, or potential anticholinergic effects with increasing severity of renal impairment. Over half the patients enrolled in the TONADO studies had renal impairment, and there was a high level of pre-existing cardiovascular comorbidity. The safety and tolerability of tiotropium/olodaterol is comparable to the monocomponents, irrespective of the level of renal impairment.

Consumer Understanding, Preferences, and Responses to Different Versions of Drug Safety Messages in the United States: A Randomized Controlled Trial.

PubMed

McCormack, Lauren; Craig Lefebvre, R; Bann, Carla; Taylor, Olivia; Rausch, Paula

2016-02-01

As part of its mission, the US Food and Drug Administration (FDA) communicates with the public regularly about the benefits and risks of prescription and over-the-counter (OTC) drugs. Effectively communicating risk, however, is a significant public health challenge. To better understand how different populations understand information communicated by the FDA about drug safety, we conducted a randomized experiment to examine comprehension and other measures of effectiveness of drug safety messages that occurred in a post-market surveillance phase. We used an Internet panel survey of 1244 consumers, of whom 58% used prescription drugs in the past year. Half of the sample panel was randomized to read a previous FDA Drug Safety Communication (DSC) with the drug name changed, and the other half was randomized to read a revised version of the same DSC. We examined how making certain modifications to the way drug risk information is communicated has an impact on comprehension and behavioral intentions, including the user's likelihood of discontinuing the drug. We also studied how comprehension varied by respondent characteristics, health literacy skills, risk perceptions, and trust in the message. Based on a five-item comprehension index, the revised version of the message was associated with significantly greater comprehension of the information relative to the standard version (63 vs 52% correct, p < 0.001). Significantly more respondents found the revised version to be clear (82 vs 73%, p < 0.000), while fewer in that group reported learning something new (78% vs 84%, p = 0.015). No significant differences emerged between the two groups in terms of the message being informative, convincing, or helpful. We found no significant differences between the two groups in terms of behavioral intentions, risk perception, and trust. We found that making plain language changes to the DSC significantly increased consumers' level of comprehension of its content, providing support for ongoing use and further exploration of these strategies in pharmacovigilance communication research. The study findings have important implications for future drug safety and other communication messages related to prescription drugs.

Nuclear safety for the space exploration initiative

NASA Technical Reports Server (NTRS)

Dix, Terry E.

1991-01-01

The results of a study to identify potential hazards arising from nuclear reactor power systems for use on the lunar and Martian surfaces, related safety issues, and resolutions of such issues by system design changes, operating procedures, and other means are presented. All safety aspects of nuclear reactor power systems from prelaunch ground handling to eventual disposal were examined consistent with the level of detail for SP-100 reactor design at the 1988 System Design Review and for launch vehicle and space transport vehicle designs and mission descriptions as defined in the 90-day Space Exploration Initiative (SEI) study. Information from previous aerospace nuclear safety studies was used where appropriate. Safety requirements for the SP-100 space nuclear reactor system were compiled. Mission profiles were defined with emphasis on activities after low earth orbit insertion. Accident scenarios were then qualitatively defined for each mission phase. Safety issues were identified for all mission phases with the aid of simplified event trees. Safety issue resolution approaches of the SP-100 program were compiled. Resolution approaches for those safety issues not covered by the SP-100 program were identified. Additionally, the resolution approaches of the SP-100 program were examined in light of the moon and Mars missions.

Safety and tolerability review of lorcaserin in clinical trials.

PubMed

Greenway, F L; Shanahan, W; Fain, R; Ma, T; Rubino, D

2016-10-01

Lorcaserin is a novel selective serotonin 2C receptor agonist indicated by the US Food and Drug Administration for chronic weight management in adults with obesity or overweight with ≥1 comorbidity. The safety and efficacy of lorcaserin were established during two Phase III clinical trials in patients without diabetes (BLOOM and BLOSSOM) and one Phase III clinical trial in patients with type 2 diabetes (BLOOM-DM). Headache was the most common adverse event experienced by patients during all Phase III trials. Additional adverse events occurring in >5% of patients receiving lorcaserin included dizziness, fatigue, nausea, dry mouth and constipation in patients without diabetes, and hypoglycaemia, back pain, cough and fatigue in patients with diabetes. In a pooled analysis of echocardiographic data collected during the three lorcaserin Phase III trials, the incidence of FDA-defined valvulopathy was similar in patients taking lorcaserin and the placebo. Here, the safety profile of lorcaserin at the FDA-approved dose of 10 mg twice daily is reviewed using data from the lorcaserin Phase III programme, with a focus on theoretical adverse events commonly associated with agonists of the serotonin receptor family. Based on the lorcaserin Phase III clinical trial data, lorcaserin is safe and well tolerated in the indicated patient populations. © 2016 World Obesity.

Optimal dose selection accounting for patient subpopulations in a randomized Phase II trial to maximize the success probability of a subsequent Phase III trial.

PubMed

Takahashi, Fumihiro; Morita, Satoshi

2018-02-08

Phase II clinical trials are conducted to determine the optimal dose of the study drug for use in Phase III clinical trials while also balancing efficacy and safety. In conducting these trials, it may be important to consider subpopulations of patients grouped by background factors such as drug metabolism and kidney and liver function. Determining the optimal dose, as well as maximizing the effectiveness of the study drug by analyzing patient subpopulations, requires a complex decision-making process. In extreme cases, drug development has to be terminated due to inadequate efficacy or severe toxicity. Such a decision may be based on a particular subpopulation. We propose a Bayesian utility approach (BUART) to randomized Phase II clinical trials which uses a first-order bivariate normal dynamic linear model for efficacy and safety in order to determine the optimal dose and study population in a subsequent Phase III clinical trial. We carried out a simulation study under a wide range of clinical scenarios to evaluate the performance of the proposed method in comparison with a conventional method separately analyzing efficacy and safety in each patient population. The proposed method showed more favorable operating characteristics in determining the optimal population and dose.

[Organisational responsibility versus individual responsibility: safety culture? About the relationship between patient safety and medical malpractice law].

PubMed

Hart, Dieter

2009-01-01

The contribution is concerned with the correlations between risk information, patient safety, responsibility and liability, in particular in terms of liability law. These correlations have an impact on safety culture in healthcare, which can be evaluated positively if--in addition to good quality of medical care--as many sources of error as possible can be identified, analysed, and minimised or eliminated by corresponding measures (safety or risk management). Liability influences the conduct of individuals and enterprises; safety is (probably) also a function of liability; this should also apply to safety culture. The standard of safety culture does not only depend on individual liability for damages, but first of all on strict enterprise liability (system responsibility) and its preventive effects. Patient safety through quality and risk management is therefore also an organisational programme of considerable relevance in terms of liability law.

A nationwide hospital survey on patient safety culture in Belgian hospitals: setting priorities at the launch of a 5-year patient safety plan.

PubMed

Vlayen, Annemie; Hellings, Johan; Claes, Neree; Peleman, Hilde; Schrooten, Ward

2012-09-01

To measure patient safety culture in Belgian hospitals and to examine the homogeneous grouping of underlying safety culture dimensions. The Hospital Survey on Patient Safety Culture was distributed organisation-wide in 180 Belgian hospitals participating in the federal program on quality and safety between 2007 and 2009. Participating hospitals were invited to submit their data to a comparative database. Homogeneous groups of underlying safety culture dimensions were sought by hierarchical cluster analysis. 90 acute, 42 psychiatric and 11 long-term care hospitals submitted their data for comparison to other hospitals. The benchmark database included 55 225 completed questionnaires (53.7% response rate). Overall dimensional scores were low, although scores were found to be higher for psychiatric and long-term care hospitals than for acute hospitals. The overall perception of patient safety was lower in French-speaking hospitals. Hierarchical clustering of dimensions resulted in two distinct clusters. Cluster I grouped supervisor/manager expectations and actions promoting safety, organisational learning-continuous improvement, teamwork within units and communication openness, while Cluster II included feedback and communication about error, overall perceptions of patient safety, non-punitive response to error, frequency of events reported, teamwork across units, handoffs and transitions, staffing and management support for patient safety. The nationwide safety culture assessment confirms the need for a long-term national initiative to improve patient safety culture and provides each hospital with a baseline patient safety culture profile to direct an intervention plan. The identification of clusters of safety culture dimensions indicates the need for a different approach and context towards the implementation of interventions aimed at improving the safety culture. Certain clusters require unit level improvements, whereas others demand a hospital-wide policy.

Therapy of Hypoparathyroidism With PTH(1–84): A Prospective Six Year Investigation of Efficacy and Safety

PubMed Central

Cusano, Natalie E.; Fan, Wen-Wei; Delgado, Yasmine; Zhang, Chengchen; Costa, Aline G.; Cremers, Serge; Dworakowski, Elzbieta; Bilezikian, John P.

2016-01-01

Context: Human recombinant (rh)PTH(1–84) was recently approved for the treatment of refractory hypoparathyroidism, based upon a short-term phase 3 clinical trial. Long-term data are needed, because no time limit was placed on the treatment period. Objective: We studied the effect of long-term rhPTH(1–84) treatment in hypoparathyroidism for up to 6 years. Design: Prospective open-label study. Setting: Referral center. Patients: A total of 33 subjects with hypoparathyroidism. Interventions: rhPTH(1–84) treatment was initiated at a starting dose of 100 μg every other day for 6 years. Due to the availability of new dosages during the 6-year time period of the study, the dose could be and was adjusted for most patients to a daily dosing regimen. Main Outcome Measures: Supplemental calcium and vitamin D requirements, serum and urinary calcium (monthly for 6 mo and then biannually), serum phosphorus, bone turnover markers, and bone mineral density (BMD) biannually. Results: Treatment with rhPTH(1–84) progressively reduced supplemental calcium requirements over 6 years by 53% (P < .0001) and 1,25-dihydroxyvitamin D requirements by 67% (P < .0001). Sixteen subjects (48%) were able to eliminate 1,25-dihydroxyvitamin D supplementation completely. Serum calcium concentration remained stable, and urinary calcium excretion fell. Lumbar spine BMD increased (3.8 ± 1%, P = .004) as did total hip BMD (2.4 ± 1%, P = .02), whereas femoral neck BMD remained stable and the distal one third radius decreased (−4.4 ±1%, P < .0001). Bone turnover markers increased significantly, reaching a 3-fold peak above baseline values at 1 year and subsequently declining but remaining higher than pretreatment values. Hypercalcemia was uncommon (12 episodes over 6 y; 2.5% of all values). Conclusions: Long-term, continuous therapy of hypoparathyroidism for 6 years with rhPTH(1–84) is associated with reductions in supplemental calcium and calcitriol requirements, stable serum calcium concentration, and reduced urinary calcium excretion. The safety profile remains good. These data represent the longest experience with the therapeutic use of PTH for any condition and demonstrate its long-term efficacy and safety in hypoparathyroidism. PMID:27144931

Research safety vehicle. Phase II. Volume II. comprehensive technical results. Final report July 1975--December 1976

DOE Office of Scientific and Technical Information (OSTI.GOV)

DiNapoli, N.; Fitzpatrick, M.; Strother, C.

1977-11-01

Phase I identified trends leading to the desired national social goals of the mid-1980's in vehicle crashworthiness, crash avoidance, damageability, pedestrian safety, fuel economy, emissions and cost, and characterized an RSV to satisfy them. In Phase II an RSV prototype was designed, developed and tested to demonstrate the feasibility of meeting these goals simultaneously. Although further refinement is necessary to assure operational validity, in all categories the results meet or exceed the most advanced performance specified by The Presidential Task Force on Motor Vehicle Goals beyond 1980.

Long-term treatment of epilepsy with everolimus in tuberous sclerosis

PubMed Central

Wilfong, Angus A.; Mays, Maxwell; Talley, Christina M.; Agricola, Karen; Tudor, Cindy; Capal, Jamie; Holland-Bouley, Katherine; Franz, David Neal

2016-01-01

Objective: To evaluate the long-term benefit and safety of everolimus for the treatment of medically refractory epilepsy in patients with tuberous sclerosis complex (TSC). Methods: Everolimus was titrated over 4 weeks and continued an additional 8 weeks in a prospective, open-label, phase I/II clinical trial design. Participants demonstrating initial benefit continued treatment until study completion (48 months). The primary endpoint was percentage of patients with a ≥50% reduction in seizure frequency compared to baseline. Secondary endpoints assessed absolute seizure frequency, adverse events (AEs), behavior, and quality of life. Results: Of the 20 participants who completed the initial study phase, 18 continued extended treatment. Fourteen of 18 (78%) participants completed the study, all but 1 of whom reported ≥50% reduction in seizure frequency at 48 months. All participants reported at least 1 AE, the vast majority (94%) of which were graded mild or moderate severity. Improvements in behavior and quality of life were also observed, but failed to achieve statistical significance at 48 months. Conclusions: Improved seizure control was maintained for 4 years in the majority of patients with TSC with medically refractory epilepsy treated with everolimus. Long-term treatment with everolimus is safe and well-tolerated in this population. Everolimus may be a therapeutic option for refractory epilepsy in TSC. Classification of evidence: This study provides Class IV evidence that for patients with TSC with medically refractory epilepsy everolimus improves seizure control. PMID:27815402

A randomized, phase 1/2 trial of the safety, tolerability, and immunogenicity of bivalent rLP2086 meningococcal B vaccine in healthy infants.

PubMed

Martinon-Torres, Federico; Gimenez-Sanchez, Francisco; Bernaola-Iturbe, Enrique; Diez-Domingo, Javier; Jiang, Qin; Perez, John L

2014-09-08

Neisseria meningitidis serogroup B (MnB) is a major cause of invasive meningococcal disease in infants. A conserved, surface-exposed lipoprotein, LP2086 (a factor H-binding protein [fHBP]), is a promising MnB vaccine target. A bivalent, recombinant vaccine targeting the fHBP (rLP2086) of MnB was developed. This phase 1/2 clinical study was designed to assess the immunogenicity, safety, and tolerability of a 4-dose series of the rLP2086 vaccine at 20-, 60-, 120-, or 200-μg dose levels in vaccine-naive infants when given with routine childhood vaccines. The study was to consist of two phases: a single-blind sentinel phase and an open-label full enrollment phase. During the sentinel phase, randomization of subjects to the next higher dose was delayed pending a 14-day safety review of dose 1 of the preceding dose cohort. The full enrollment phase was to occur after completion of the sentinel phase. Local reactions were generally mild and adverse events infrequent; however, after only 46 infants were randomized into the study, fever rates were 64% and 90% in subjects receiving one 20- or 60-μg rLP2086 dose, respectively. Most fevers were <39.0°C. Only 2 subjects in the 20-μg group and 1 subject in the 60-μg group experienced fevers >39.0°C; no fevers were >40.0°C. Due to these high fever rates, the study was terminated early. No immunogenicity data were collected. This report discusses the safety and acceptability of rLP2086 in infants after one 20- or 60-μg dose. Due to the high fever rate experienced in the 20- and 60-μg groups, rLP2086 in the current formulation may not be acceptable for infants. Copyright © 2014. Published by Elsevier Ltd.

Trauma-focused CBT for youth with complex trauma

PubMed Central

Mannarino, Anthony P.; Kliethermes, Matthew; Murray, Laura A.

2013-01-01

Objectives Many youth develop complex trauma, which includes regulation problems in the domains of affect, attachment, behavior, biology, cognition, and perception. Therapists often request strategies for using evidence-based treatments (EBTs) for this population. This article describes practical strategies for applying Trauma-Focused Cognitive Behavioral Therapy (TF-CBT) for youth with complex trauma. Methods TF-CBT treatment phases are described and modifications of timing, proportionality and application are described for youth with complex trauma. Practical applications include a) dedicating proportionally more of the model to the TF-CBT coping skills phase; b) implementing the TF-CBT Safety component early and often as needed throughout treatment; c) titrating gradual exposure more slowly as needed by individual youth; d) incorporating unifying trauma themes throughout treatment; and e) when indicated, extending the TF-CBT treatment consolidation and closure phase to include traumatic grief components and to generalize ongoing safety and trust. Results Recent data from youth with complex trauma support the use of the above TF-CBT strategies to successfully treat these youth. Conclusions The above practical strategies can be incorporated into TF-CBT to effectively treat youth with complex trauma. Practice implications Practical strategies include providing a longer coping skills phase which incorporates safety and appropriate gradual exposure; including relevant unifying themes; and allowing for an adequate treatment closure phase to enhance ongoing trust and safety. Through these strategies therapists can successfully apply TF-CBT for youth with complex trauma. PMID:22749612

Evaluation of Current Practice for Illumination at Roundabouts : Safety and Illumination of Roundabouts (Phase I)

DOT National Transportation Integrated Search

2016-03-01

This report is for the first phase of a two-phase research program to develop recommended practices for GDOT for lighting rural roundabouts. Phase I of the study was designed to improve our understanding of the relationship between roundabout illumin...

Safety assessment in plant layout design using indexing approach: implementing inherent safety perspective. Part 1 - guideword applicability and method description.

PubMed

Tugnoli, Alessandro; Khan, Faisal; Amyotte, Paul; Cozzani, Valerio

2008-12-15

Layout planning plays a key role in the inherent safety performance of process plants since this design feature controls the possibility of accidental chain-events and the magnitude of possible consequences. A lack of suitable methods to promote the effective implementation of inherent safety in layout design calls for the development of new techniques and methods. In the present paper, a safety assessment approach suitable for layout design in the critical early phase is proposed. The concept of inherent safety is implemented within this safety assessment; the approach is based on an integrated assessment of inherent safety guideword applicability within the constraints typically present in layout design. Application of these guidewords is evaluated along with unit hazards and control devices to quantitatively map the safety performance of different layout options. Moreover, the economic aspects related to safety and inherent safety are evaluated by the method. Specific sub-indices are developed within the integrated safety assessment system to analyze and quantify the hazard related to domino effects. The proposed approach is quick in application, auditable and shares a common framework applicable in other phases of the design lifecycle (e.g. process design). The present work is divided in two parts: Part 1 (current paper) presents the application of inherent safety guidelines in layout design and the index method for safety assessment; Part 2 (accompanying paper) describes the domino hazard sub-index and demonstrates the proposed approach with a case study, thus evidencing the introduction of inherent safety features in layout design.

Invasive Cortical Stimulation to Promote Recovery of Function After Stroke

PubMed Central

Plow, Ela B.; Carey, James R.; Nudo, Randolph J.; Pascual-Leone, Alvaro

2011-01-01

Background and Purpose Residual motor deficits frequently linger after stroke. Search for newer effective strategies to promote functional recovery is ongoing. Brain stimulation, as a means of directing adaptive plasticity, is appealing. Animal studies and Phase I and II trials in humans have indicated safety, feasibility, and efficacy of combining rehabilitation and concurrent invasive cortical stimulation. However, a recent Phase III trial showed no advantage of the combination. We critically review results of various trials and discuss the factors that contributed to the distinctive result. Summary of Review Regarding cortical stimulation, it is important to determine the (1) location of peri-infarct representations by integrating multiple neuroanatomical and physiological techniques; (2) role of other mechanisms of stroke recovery; (3) viability of peri-infarct tissue and descending pathways; (4) lesion geometry to ensure no alteration/displacement of current density; and (5) applicability of lessons generated from noninvasive brain stimulation studies in humans. In terms of combining stimulation with rehabilitation, we should understand (1) the principle of homeostatic plasticity; (2) the effect of ongoing cortical activity and phases of learning; and (3) that subject-specific intervention may be necessary. Conclusions Future cortical stimulation trials should consider the factors that may have contributed to the peculiar results of the Phase III trial and address those in future study designs. PMID:19359643

National Space Transportation System (NSTS) technology needs

NASA Technical Reports Server (NTRS)

Winterhalter, David L.; Ulrich, Kimberly K.

1990-01-01

The National Space Transportation System (NSTS) is one of the Nation's most valuable resources, providing manned transportation to and from space in support of payloads and scientific research. The NSTS program is currently faced with the problem of hardware obsolescence, which could result in unacceptable schedule and cost impacts to the flight program. Obsolescence problems occur because certain components are no longer being manufactured or repair turnaround time is excessive. In order to achieve a long-term, reliable transportation system that can support manned access to space through 2010 and beyond, NASA must develop a strategic plan for a phased implementation of enhancements which will satisfy this long-term goal. The NSTS program has initiated the Assured Shuttle Availability (ASA) project with the following objectives: eliminate hardware obsolescence in critical areas, increase reliability and safety of the vehicle, decrease operational costs and turnaround time, and improve operational capability. The strategy for ASA will be to first meet the mandatory needs - keep the Shuttle flying. Non-mandatory changes that will improve operational capability and enhance performance will then be considered if funding is adequate. Upgrade packages should be developed to install within designated inspection periods, grouped in a systematic approach to reduce cost and schedule impacts, and allow the capability to provide a Block 2 Shuttle (Phase 3).

How I use hydroxyurea to treat young patients with sickle cell anemia

PubMed Central

2010-01-01

Hydroxyurea has many characteristics of an ideal drug for sickle cell anemia (SCA) and provides therapeutic benefit through multiple mechanisms of action. Over the past 25 years, substantial experience has accumulated regarding its safety and efficacy for patients with SCA. Early proof-of-principle studies were followed by prospective phase 1/2 trials demonstrating efficacy in affected adults, then adolescents and children, and more recently infants and toddlers. The phase 3 National Heart, Lung and Blood Institute–sponsored Multicenter Study of Hydroxyurea trial proved clinical efficacy for preventing acute vaso-occlusive events in severely affected adults. Based on this cumulative experience, hydroxyurea has emerged as an important therapeutic option for children and adolescents with recurrent vaso-occlusive events; recent evidence documents sustained long-term benefits with prevention or reversal of chronic organ damage. Despite abundant evidence for its efficacy, however, hydroxyurea has not yet translated into effective therapy for SCA. Because many healthcare providers have inadequate knowledge about hydroxyurea, patients and families are not offered treatment or decline because of unrealistic fears. Limited support for hydroxyurea by lay organizations and inconsistent medical delivery systems also contribute to underuse. Although questions remain regarding its long-term risks and benefits, current evidence suggests that many young patients with SCA should receive hydroxyurea treatment. PMID:20223921

Mars transit vehicle thermal protection system: Issues, options, and trades

NASA Technical Reports Server (NTRS)

Brown, Norman

1986-01-01

A Mars mission is characterized by different mission phases. The thermal control of cryogenic propellant in a propulsive vehicle must withstand the different mission environments. Long term cryogenic storage may be achieved by passive or active systems. Passive cryo boiloff management features will include multilayer insulation, vapor cooled shield, and low conductance structural supports and penetrations. Active boiloff management incorporates the use of a refrigeration system. Key system trade areas include active verses passive system boiloff management (with respect to safety, reliability, and cost) and propellant tank insulation optimizations. Technology requirements include refrigeration technology advancements, insulation performance during long exposure, and cryogenic fluid transfer system for mission vehicle propellant tanking during vehicle buildip in LEO.

Experience Of Implementing The Integrated Management System In Manufacturing Companies In Slovakia

NASA Astrophysics Data System (ADS)

Lestyánszka Škůrková, Katarína; Kučerová, Marta; Fidlerová, Helena

2015-06-01

In corporate practice, the term of Integrated Management System means a system the aim of which is to manage an organization regarding the quality, environment, health and safety at work. In the first phase of the VEGA project No. 1/0448/13 "Transformation of ergonomics program into the company management structure through interaction and utilization QMS, EMS, HSMS", we focused on obtaining information about the way or procedure of implementing the integrated management systems in manufacturing companies in Slovakia. The paper considers characteristics of integrated management system, specifies the possibilities for successive integration of the management systems and also describes the essential aspects of the practical implementation of integrated management systems in companies in Slovakia.

[The state of the art on nutrition, food safety and food security].

PubMed

Bonaccorsi, Guglielmo; Lorini, Chiara; Porchia, Barbara Rita; Capecchi, Leonardo; Malavolti, Marcella; Aggazzotti, Gabriella

2014-01-01

In Italy, public health is experiencing a phase of crisis. A contraction of services and a staff reallocation have affected in particular Food Hygiene services. We explored Pubmed and Google Ngram Viewer© to define the state of the art of research in food and nutritional field from a quantitative point of view and we focused on some areas of interest in terms of improvement of professional practice. The Italian contribution to food and nutritional research is still limited. Our findings seem to demonstrate the need of an alliance between the world of research and Public Health services, so as to develop a sustainable and effective health system.

Timing of Formal Phase Safety Reviews for Large-Scale Integrated Hazard Analysis

NASA Technical Reports Server (NTRS)

Massie, Michael J.; Morris, A. Terry

2010-01-01

Integrated hazard analysis (IHA) is a process used to identify and control unacceptable risk. As such, it does not occur in a vacuum. IHA approaches must be tailored to fit the system being analyzed. Physical, resource, organizational and temporal constraints on large-scale integrated systems impose additional direct or derived requirements on the IHA. The timing and interaction between engineering and safety organizations can provide either benefits or hindrances to the overall end product. The traditional approach for formal phase safety review timing and content, which generally works well for small- to moderate-scale systems, does not work well for very large-scale integrated systems. This paper proposes a modified approach to timing and content of formal phase safety reviews for IHA. Details of the tailoring process for IHA will describe how to avoid temporary disconnects in major milestone reviews and how to maintain a cohesive end-to-end integration story particularly for systems where the integrator inherently has little to no insight into lower level systems. The proposal has the advantage of allowing the hazard analysis development process to occur as technical data normally matures.

THC:CBD spray and MS spasticity symptoms: data from latest studies.

PubMed

Rekand, Tiina

2014-01-01

New clinical experience with 9-delta-tetrahydocannabinol (THC) and cannabidiol (CBD) oromucosal spray (Sativex®) involving more than an additional 1,000 patients with MS spasticity (approximately 150 in clinical studies and 900 in post-marketing surveillance studies) have become available in 2013 and are reviewed. A randomized, placebo controlled long-term follow-up clinical trial with THC:CBD spray versus placebo demonstrated that it was not associated with cognitive decline, depression or significant mood changes after 12 months of treatment. Furthermore, in a prospective observational pilot study involving 33 patients (60% female) aged 33-68 years and a mean disease duration of 6.6 years, THC:CBD oromucosal spray did not adversely influence standard driving ability in patients with moderate to severe MS spasticity. Other new long term observational data about the use of THC:CBD oromucosal spray in clinical practice are available from patient registries in the UK, Germany and Spain. Findings to date reinforce the efficacy and safety observed in Phase III clinical trials. It is of interest that in practice average dosages used by patients tended to be lower than those reported in clinical studies (5-6.4 vs. >8 sprays/day), and effectiveness was maintained in the majority of patients. Importantly, no additional safety concerns were identified in the registry studies which included findings from patients who have been treated for prolonged periods (in the German/UK registry 45% of patients had >2 years exposure). Thus, these new data support a positive benefit-risk relationship for THC:CBD oromucosal spray during longer-term use. © 2014 S. Karger AG, Basel.

Long-term safety of ivermectin 1% cream vs azelaic acid 15% gel in treating inflammatory lesions of rosacea: results of two 40-week controlled, investigator-blinded trials.

PubMed

Stein Gold, Linda; Kircik, Leon; Fowler, Joseph; Jackson, J Mark; Tan, Jerry; Draelos, Zoe; Fleischer, Alan; Appell, Melanie; Steinhoff, Martin; Lynde, Charles; Sugarman, Jeffrey; Liu, Hong; Jacovella, Jean

2014-11-01

Papulopustular rosacea (PPR) is characterized by facial erythema and inflammatory lesions believed to be primarily caused by dysregulation of the innate immune system. More recent evidence also suggests that Demodex folliculorum mites may contribute to the etiology of PPR. Ivermectin (IVM) 1% cream is a novel topical treatment developed to treat PPR. Two phase 3 trials have demonstrated that IVM 1% cream was significantly better than vehicle at investigator global assessment (IGA) success rate and lesion reductions and that it was safe and well tolerated. Two 40-week extension studies of those trials were conducted to assess the long-term safety of IVM 1% cream vs azelaic acid (AzA) 15% gel. Subjects originally treated with IVM 1% continued on IVM 1% and those originally treated with vehicle switched to AzA 15% gel. IVM 1% cream was safe throughout the study with a lower incidence of related adverse events (AEs) compared to AzA 15% gel. No subjects in the IVM 1% cream group discontinued either study due to a related AE. IVM 1% also continued to be efficacious during the 40-week extension studies as the percentage of subjects with IGA scores of clear or almost clear was higher at the end of the study compared to baseline. The results of these 40-week extension studies support the use of IVM 1% cream as a long-term therapy for PPR as IVM 1% cream was shown to be safe and effective for up to 52 weeks of total treatment.

LANL seismic screening method for existing buildings

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dickson, S.L.; Feller, K.C.; Fritz de la Orta, G.O.

1997-01-01

The purpose of the Los Alamos National Laboratory (LANL) Seismic Screening Method is to provide a comprehensive, rational, and inexpensive method for evaluating the relative seismic integrity of a large building inventory using substantial life-safety as the minimum goal. The substantial life-safety goal is deemed to be satisfied if the extent of structural damage or nonstructural component damage does not pose a significant risk to human life. The screening is limited to Performance Category (PC) -0, -1, and -2 buildings and structures. Because of their higher performance objectives, PC-3 and PC-4 buildings automatically fail the LANL Seismic Screening Method andmore » will be subject to a more detailed seismic analysis. The Laboratory has also designated that PC-0, PC-1, and PC-2 unreinforced masonry bearing wall and masonry infill shear wall buildings fail the LANL Seismic Screening Method because of their historically poor seismic performance or complex behavior. These building types are also recommended for a more detailed seismic analysis. The results of the LANL Seismic Screening Method are expressed in terms of separate scores for potential configuration or physical hazards (Phase One) and calculated capacity/demand ratios (Phase Two). This two-phase method allows the user to quickly identify buildings that have adequate seismic characteristics and structural capacity and screen them out from further evaluation. The resulting scores also provide a ranking of those buildings found to be inadequate. Thus, buildings not passing the screening can be rationally prioritized for further evaluation. For the purpose of complying with Executive Order 12941, the buildings failing the LANL Seismic Screening Method are deemed to have seismic deficiencies, and cost estimates for mitigation must be prepared. Mitigation techniques and cost-estimate guidelines are not included in the LANL Seismic Screening Method.« less

Immunogenicity and safety of a novel MMR vaccine (live, freeze-dried) containing the Edmonston-Zagreb measles strain, the Hoshino mumps strain, and the RA 27/3 rubella strain: Results of a randomized, comparative, active controlled phase III clinical trial.

PubMed

Sood, Ashwani; Mitra, Monjori; Joshi, Himanshu Arvind; Nayak, Uma Siddhartha; Siddaiah, Prashanth; Babu, T Ramesh; Mahapatro, Samarendra; Sanmukhani, Jayesh; Gupta, Gaurav; Mittal, Ravindra; Glueck, Reinhard

2017-07-03

This phase III clinical trial was conducted to evaluate the immunogenicity and safety of the single-dose and multi-dose formulations of a novel MMR vaccine (live, freeze-dried) developed by M/s Cadila Healthcare Limited, India (Cadila MMR vaccine), containing the Hoshino mumps strain, compared to that of an existing MMR vaccine (live, freeze-dried) developed by M/s Serum Institute of India Limited, India (Serum MMR vaccine). These two vaccines have similar measles and rubella strains, but different mumps strains (Hoshino in Cadila MMR vaccine, and L-Zagreb in Serum MMR vaccine). Three hundred and twenty-eight subjects of either sex, aged 15-18 months, were randomized in a 2:1 ratio to receive either the Cadila or Serum MMR vaccine. Immunogenicity assessments (IgG antibodies against measles, mumps, and rubella viruses) were done at baseline and 42 d after vaccination. Solicited (local and systemic) and unsolicited adverse events were recorded for up to 42 d following vaccination. The Cadila MMR vaccine was found to be non-inferior to the Serum MMR vaccine in terms of end-of-study proportion of subjects seropositive for anti-measles antibodies (100.0% in both groups), anti-mumps antibodies (94.5% vs. 94.0%), and anti-rubella antibodies (95.5% vs. 91.0%). Both vaccines were well tolerated by all study participants; the most common adverse event reported in both groups was fever, followed by rash. The results of this phase III clinical trial show that the novel Cadila MMR vaccine is non-inferior to the Serum MMR vaccine.

Umbilical cord mesenchymal stromal cell transplantations: A systemic analysis of clinical trials.

PubMed

Can, Alp; Celikkan, Ferda Topal; Cinar, Ozgur

2017-12-01

The advances and success of umbilical cord-derived mesenchymal stromal cells (UC-MSCs) in experimental disease animal models have fueled the development of targeted therapies in humans. The therapeutic potential of allogeneic transplantation of UC-MSCs has been under examination since 2009. The purpose of this systematic analysis was to review the published results, limitations and obstacles for UC-MSC transplantation. An extensive search strategy was applied to the published literature, 93 peer-reviewed full-text articles and abstracts were found published by early August 2017 that investigated the safety, efficacy and feasibility of UC-MSCs in 2001 patients with 53 distinct pathologies including many systemic/local, acute/chronic conditions. Few data were extracted from the abstracts and/or Chinese-written articles (n = 7, 8%). Importantly, no long-term adverse effects, tumor formation or cell rejection were reported. All studies noted certain degrees of therapeutic benefit as evidenced by clinical symptoms and/or laboratory findings. Thirty-seven percent (n = 34) of studies were found published as a single case (n = 10; 11%) or 2-10 case reports (n = 24; 26%) with no control group. Due to the nature of many stem cell-based studies, the majority of patients also received conventional therapy regimens, which obscured the pure efficacy of the cells transplanted. Randomized, blind, phase 1/2 trials with control groups (placebo-controlled) showed more plausible results. Given that most UC-MSC trials are early phase, the internationally recognized cell isolation and preparation standards should be extended to future phase 2/3 trials to reach more convincing conclusions regarding the safety and efficacy of UC-MSC therapies. Copyright © 2017 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Three-Year Follow-Up of an Alectinib Phase I/II Study in ALK-Positive Non-Small-Cell Lung Cancer: AF-001JP.

PubMed

Tamura, Tomohide; Kiura, Katsuyuki; Seto, Takashi; Nakagawa, Kazuhiko; Maemondo, Makoto; Inoue, Akira; Hida, Toyoaki; Yoshioka, Hiroshige; Harada, Masao; Ohe, Yuichiro; Nogami, Naoyuki; Murakami, Haruyasu; Kuriki, Hiroshi; Shimada, Tadashi; Tanaka, Tomohiro; Takeuchi, Kengo; Nishio, Makoto

2017-05-10

Purpose Alectinib is an anaplastic lymphoma kinase (ALK) -specific kinase inhibitor that seems to be effective against non-small-cell lung cancer (NSCLC) with a variety of ALK mutations. The primary analysis of AF-001JP reported a promising overall response rate. To assess progression-free survival (PFS) and overall survival (OS), patients from the phase II part of AF-001JP were followed up for approximately 3 years. Patients and Methods Oral alectinib 300 mg was administered twice per day to patients with ALK inhibitor-naïve, ALK-positive NSCLC who had progressed after one or more regimens of previous chemotherapy. In this long-term follow-up, efficacy (PFS, OS), correlation between tumor shrinkage and PFS, safety of alectinib, and relief of cancer symptoms were evaluated. Results At the updated data cutoff (September 10, 2015; first patient in August 30, 2011, last patient in April 18, 2012), 25 of 46 phase II patients were still receiving alectinib. Disease progression was confirmed in 18 patients (39%); median PFS was not reached (3-year PFS rate, 62%; 95% CI, 45 to 75). Fourteen patients had brain metastases at baseline; of these, 6 remained in the study without CNS and systemic progression. Tumor shrinkage and PFS showed no correlation. The 3-year OS rate was 78% (13 events). The most common treatment-related adverse event (all grades) was increased blood bilirubin (36.2%). Most cancer symptoms were relieved early, and medication for symptoms was dramatically decreased during alectinib therapy. Conclusion Alectinib was effective in this 3-year follow-up with a favorable safety profile over a long administration period in ALK-positive NSCLC without previous ALK inhibitor treatment.

Three-Year Follow-Up of an Alectinib Phase I/II Study in ALK-Positive Non–Small-Cell Lung Cancer: AF-001JP

PubMed Central

Tamura, Tomohide; Kiura, Katsuyuki; Seto, Takashi; Nakagawa, Kazuhiko; Maemondo, Makoto; Inoue, Akira; Hida, Toyoaki; Yoshioka, Hiroshige; Harada, Masao; Ohe, Yuichiro; Nogami, Naoyuki; Murakami, Haruyasu; Kuriki, Hiroshi; Shimada, Tadashi; Tanaka, Tomohiro; Takeuchi, Kengo; Nishio, Makoto

2017-01-01

Purpose Alectinib is an anaplastic lymphoma kinase (ALK) –specific kinase inhibitor that seems to be effective against non–small-cell lung cancer (NSCLC) with a variety of ALK mutations. The primary analysis of AF-001JP reported a promising overall response rate. To assess progression-free survival (PFS) and overall survival (OS), patients from the phase II part of AF-001JP were followed up for approximately 3 years. Patients and Methods Oral alectinib 300 mg was administered twice per day to patients with ALK inhibitor–naïve, ALK-positive NSCLC who had progressed after one or more regimens of previous chemotherapy. In this long-term follow-up, efficacy (PFS, OS), correlation between tumor shrinkage and PFS, safety of alectinib, and relief of cancer symptoms were evaluated. Results At the updated data cutoff (September 10, 2015; first patient in August 30, 2011, last patient in April 18, 2012), 25 of 46 phase II patients were still receiving alectinib. Disease progression was confirmed in 18 patients (39%); median PFS was not reached (3-year PFS rate, 62%; 95% CI, 45 to 75). Fourteen patients had brain metastases at baseline; of these, 6 remained in the study without CNS and systemic progression. Tumor shrinkage and PFS showed no correlation. The 3-year OS rate was 78% (13 events). The most common treatment-related adverse event (all grades) was increased blood bilirubin (36.2%). Most cancer symptoms were relieved early, and medication for symptoms was dramatically decreased during alectinib therapy. Conclusion Alectinib was effective in this 3-year follow-up with a favorable safety profile over a long administration period in ALK-positive NSCLC without previous ALK inhibitor treatment. PMID:28296581

Long-term follow-up of a phase 2 study of oral teriflunomide in relapsing multiple sclerosis: safety and efficacy results up to 8.5 years

PubMed Central

Li, David K; Freedman, Mark S; Truffinet, Philippe; Benzerdjeb, Hadj; Wang, Dazhe; Bar-Or, Amit; Traboulsee, Anthony L; Reiman, Lucy E; O’Connor, Paul W

2012-01-01

Background: Teriflunomide, an oral disease-modifying therapy in development for patients with relapsing forms of multiple sclerosis (RMS), was well tolerated and effective in reducing magnetic resonance imaging (MRI) lesions in 179 RMS patients in a phase 2 36-week, placebo-controlled study. Methods: A total of 147 patients who completed the core study entered an open-label extension. Teriflunomide patients continued their assigned dose, and placebo patients were re-allocated to teriflunomide, 7 mg/day or 14 mg/day. An interim analysis was performed at a cut-off on January 8 2010. Results: The mean and median duration of study treatment, including both the core and extension phase, from baseline to the interim cut-off, was 5.6 years (standard deviation: 2.7 years) and 7.1 years (range: 0.05–8.5 years), respectively. Of 147 patients, 62 (42.2%) discontinued (19% due to treatment-emergent adverse events (TEAEs)). The most common TEAEs were mild infections, fatigue, sensory disturbances and diarrhoea. No serious opportunistic infections occurred, with no discontinuations due to infection. Asymptomatic alanine aminotransferase increases (≤3× upper limit of normal (ULN)) were common (7 mg, 64.2%; 14 mg, 62.1%); increases >3×ULN were similar across groups (7 mg, 12.3%; 14 mg, 12.1%). Mild decreases in neutrophil counts occurred; none led to discontinuation. The incidence of malignancies was comparable to that of the general population, and cases were not reminiscent of those observed in immunocompromised patients. Annualised relapse rates remained low, minimal disability progression was observed, with a dose-dependent benefit with teriflunomide 14 mg for several MRI parameters. Conclusion: Teriflunomide had a favourable safety profile for up to 8.5 years. PMID:22307384

Long-term efficacy and safety of ertugliflozin monotherapy in patients with inadequately controlled T2DM despite diet and exercise: VERTIS MONO extension study.

PubMed

Aronson, Ronnie; Frias, Juan; Goldman, Allison; Darekar, Amanda; Lauring, Brett; Terra, Steven G

2018-06-01

This phase III, multicentre, randomized study (ClinicalTrials.gov; NCT01958671) evaluated the efficacy and safety of ertugliflozin monotherapy in adults with inadequately controlled type 2 diabetes (glycated haemoglobin [HbA1c], 7.0% to 10.5% [53-91 mmol/mol]) despite diet and exercise. The 52-week study comprised a 26-week, double-blind, placebo-controlled period (Phase A) during which 461 participants received placebo, ertugliflozin 5 mg/d or ertugliflozin 15 mg/d. This was followed by a 26-week active-controlled period (Phase B) during which participants in the placebo group who had not received glycaemic rescue therapy had blinded metformin added. Results to Week 52 are reported. Because of the use of metformin in Phase B, no statistical comparisons of efficacy were made between the ertugliflozin and placebo/metformin groups at Week 52. The mean (standard error) change from baseline to Week 52 in HbA1c was -0.9% (0.1) and -1.0% (0.1) in the ertugliflozin 5 and 15 mg groups, respectively. The proportions of participants with HbA1c <7.0% at Week 52 were 25.6% and 28.5%, respectively. Ertugliflozin reduced fasting plasma glucose, body weight and systolic blood pressure (SBP). The incidence of genital mycotic infections (GMIs) in females was significantly higher in both ertugliflozin groups (5 mg, 26.9%; 15 mg, 29.0%) vs the placebo/metformin group (9.9%), and in males was significantly higher in the 15 mg group (7.8%) vs the placebo/metformin group (1.2%). Ertugliflozin was not associated with increased incidence of urinary tract infections, symptomatic hypoglycaemia or hypovolaemia adverse events compared with placebo/metformin. Ertugliflozin treatment over 52 weeks improved glycaemic control and reduced body weight and SBP, but increased GMIs. © 2018 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

The hypocholesterolemic effect of an antacid containing aluminum hydroxide.

PubMed

Sperber, A D; Henkin, Y; Zuili, I; Bearman, J E; Shany, S

1991-12-01

To evaluate the efficacy, safety, and hypocholesterolemic effect of an aluminum hydroxide-containing antacid in hypercholesterolemic individuals. A prospective, randomized, double-masked, placebo-controlled phase of 2 months' duration, followed by an open-design treatment phase of 2 months' duration and a washout phase of 2 months' duration. Family practice clinics of two rural communities (kibbutzim) in Israel. Fifty-six men and women with hypercholesterolemia (type IIa or IIb). Fifty individuals completed the study. After 2 months of dietary modification (low-fat, low-cholesterol diet), the participants were randomized into two matched groups. Group 1 (28 participants) was treated for 2 months with a chewable antacid tablet containing simethicone, magnesium hydroxide, and 113 mg of aluminum hydroxide per tablet, at a dose of two tablets four times daily. Group 2 (22 participants) was given a similar number of placebo tablets for 2 months. During the following 2 months, both groups received the antacid at the above dose. Lipoprotein levels were evaluated at baseline and every 2 months thereafter for 6 months. Compared with pretreatment levels, Group 1 experienced a decrease in low-density lipoprotein cholesterol (LDL-C) of 9.8% after 2 months (p less than 0.001) and 18.5% after 4 months (p less than 0.001). Compared with Group 2, the decrease in LDL-C in Group 1 was 6.2% at the end of the 2-month double-masked, placebo phase. Although the high-density lipoprotein cholesterol (HDL-C) was also reduced in Group 1 at the end of 4 months of therapy (10.2%), the HDL-C/LDL-C ratio increased by 13% during the same interval (p less than 0.05). The treatment was well tolerated, with minimal side effects. An aluminum hydroxide-containing antacid reduces LDL-C in hypercholesterolemic individuals. Although HDL-C was also reduced to a lesser extent, the overall atherogenic index was improved. Further studies should be conducted to evaluate the long-term safety and efficacy of antacids containing aluminum hydroxide in hypercholesterolemic patients.

Site Safety and Health Plan (Phase 3) for the treatability study for in situ vitrification at Seepage Pit 1 in Waste Area Grouping 7, Oak Ridge National Laboratory, Oak Ridge, TN

DOE Office of Scientific and Technical Information (OSTI.GOV)

Spalding, B.P.; Naney, M.T.

1995-06-01

This plan is to be implemented for Phase III ISV operations and post operations sampling. Two previous project phases involving site characterization have been completed and required their own site specific health and safety plans. Project activities will take place at Seepage Pit 1 in Waste Area Grouping 7 at ORNL, Oak Ridge, Tennessee. Purpose of this document is to establish standard health and safety procedures for ORNL project personnel and contractor employees in performance of this work. Site activities shall be performed in accordance with Energy Systems safety and health policies and procedures, DOE orders, Occupational Safety and Healthmore » Administration Standards 29 CFR Part 1910 and 1926; applicable United States Environmental Protection Agency requirements; and consensus standards. Where the word ``shall`` is used, the provisions of this plan are mandatory. Specific requirements of regulations and orders have been incorporated into this plan in accordance with applicability. Included from 29 CFR are 1910.120 Hazardous Waste Operations and Emergency Response; 1910.146, Permit Required - Confined Space; 1910.1200, Hazard Communication; DOE Orders requirements of 5480.4, Environmental Protection, Safety and Health Protection Standards; 5480.11, Radiation Protection; and N5480.6, Radiological Control Manual. In addition, guidance and policy will be followed as described in the Environmental Restoration Program Health and Safety Plan. The levels of personal protection and the procedures specified in this plan are based on the best information available from reference documents and site characterization data. Therefore, these recommendations represent the minimum health and safety requirements to be observed by all personnel engaged in this project.« less

A pilot hospital-school educational program to address teen motor vehicle safety.

PubMed

Unni, Purnima; Morrow, Stephen E; Shultz, Barbara L; Tian, Tina T

2013-10-01

Texting while driving has emerged as a significant distracted driving behavior among teenage drivers. A unique hospital-school collaborative pilot intervention (called "Be in the Zone" or "BITZ") was implemented to combat this growing problem. This intervention was hypothesized to lead to a decline in texting while driving among high school students. This collaborative intervention consisted of two separate phases. In Phase 1, small groups of high school student leaders participated in a half-day interactive educational session in a pediatric hospital. Pre- and post-follow-up surveys were administered to this group. In Phase 2, these same students took the lessons they learned from the hospital to plan and implement a yearlong peer-to-peer campaign that focused on a clear "no texting while driving" message at their schools. Two unannounced driver observations were conducted to evaluate the effectiveness of the pilot program. Sixty-one high school students participated in Phase 1. Self-reported texting while driving rates decreased significantly among the participants after Phase 1. Two schools were recruited to participate in Phase 2. Unannounced driver observations were conducted before the campaign and toward the end of the campaign. Postintervention, there was a significant decrease in the percentage of drivers who texted while driving. Preliminary results from this pilot program suggest that a strategy of combining hospital-school partnerships with a peer-driven educational approach can be effective in reducing texting while driving among teenagers in the short-term.

Transcranial focal electrical stimulation via tripolar concentric ring electrodes does not modify the short- and long-term memory formation in rats evaluated in the novel object recognition test

PubMed Central

Rogel-Salazar, G; Luna-Munguía, H; Stevens, KE; Besio, WG

2013-01-01

Noninvasive transcranial focal electrical stimulation (TFS) via tripolar concentric ring electrodes (TCREs) has been under development by Besio as an alternative/complementary therapy for seizure control. TFS has shown efficacy attenuating penicillin, pilocarpine, and pentylenetetrazole– induced acute seizures in rat models. This study evaluated the effects of TFS via TCREs on the memory formation of healthy rats as a safety test of TFS. The short and long-term memory formation was tested after the application of TFS using the novel object recognition (NOR) test. Independent groups were used: naïve, control (without TFS), and TFS (treated). Naïve, control, and stimulated groups spent more time investigating the new object than the familiar one during the test phase. TFS via TCREs given once does not modify the short- and long-term memory formation in rats in the NOR test. Results provide an important step towards a better understanding for the safe usage of TFS via TCREs. PMID:23419871

Long-term follow-up of HIV-1-infected adults who received the F4/AS01B HIV-1 vaccine candidate in two randomised controlled trials.

PubMed

Harrer, Thomas; Dinges, Warren; Roman, François

2018-05-03

This Phase I/II, open, long-term follow-up study was conducted in antiretroviral therapy (ART)-naïve (N = 212) and ART-treated (N = 19) human immunodeficiency virus 1 (HIV-1)-infected adults, who received an HIV-1 investigational vaccine (F4/AS01 B ) or placebo in two previous studies (NCT00814762 and NCT01218113). After a minimum of two years and a maximum of four years of follow-up post-vaccination per patient, no significant differences were observed between F4/AS01 B and placebo groups in terms of viral load, CD4 + T-cell count and incidence of specific clinical events. Vaccine-induced polyfunctional CD4 + T-cells persisted up to study end and no relevant vaccine-related safety events were reported in F4/AS01 B groups. This study has been registered at ClinicalTrials.gov (NCT01092611). Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

30 CFR 75.905 - Connection of single-phase loads.

Code of Federal Regulations, 2011 CFR

2011-07-01

... Alternating Current Circuits § 75.905 Connection of single-phase loads. [Statutory Provisions] Single-phase... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Connection of single-phase loads. 75.905 Section 75.905 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR COAL MINE...

30 CFR 75.905 - Connection of single-phase loads.

Code of Federal Regulations, 2010 CFR

2010-07-01

... Alternating Current Circuits § 75.905 Connection of single-phase loads. [Statutory Provisions] Single-phase... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Connection of single-phase loads. 75.905 Section 75.905 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR COAL MINE...

49 CFR 585.2 - Phase-in reports.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 49 Transportation 7 2010-10-01 2010-10-01 false Phase-in reports. 585.2 Section 585.2 Transportation Other Regulations Relating to Transportation (Continued) NATIONAL HIGHWAY TRAFFIC SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) PHASE-IN REPORTING REQUIREMENTS General § 585.2 Phase-in reports. Each report submitted to NHTSA...

A Review of Recent Advances Using Tocilizumab in the Treatment of Rheumatic Diseases.

PubMed

Rubbert-Roth, Andrea; Furst, Daniel E; Nebesky, Jan Michael; Jin, Angela; Berber, Erhan

2018-06-01

Tocilizumab (TCZ) is the first humanized anti-interleukin-6 (IL-6) receptor monoclonal antibody approved for the treatment of patients with rheumatoid arthritis (RA), Castleman's disease, polyarticular and systemic juvenile idiopathic arthritis, and, most recently, giant cell arteritis as well as for the treatment of chimeric antigen receptor T cell therapy-induced cytokine release syndrome. The global clinical development program for TCZ provides a wealth of clinical data on intravenous TCZ, and more recent studies in patients with RA have provided evidence characterizing the role of intravenous TCZ as monotherapy in early disease and led to the introduction of a subcutaneous formulation of TCZ. In addition, recently published open-label extension and observational studies continue to support the long-term efficacy and safety of TCZ in both clinical trial and real-world settings. Given the involvement of IL-6-mediated signaling in inflammatory disorders, TCZ is also being investigated in other immunological diseases. In particular, a phase 2 trial on the safety and efficacy of subcutaneous TCZ in adults with systemic sclerosis shows clinically relevant improvements in skin sclerosis and lung function in these patients. Another anti-IL-6 receptor agent, sarilumab, targeting the IL6 receptor alpha subunit, was recently approved for the treatment of patients with RA, although long-term data for this biologic are not yet published. In this article we review the placement of TCZ in current treatment guidelines; recent clinical trial data, including quality of life in patients with RA; recent updates to the TCZ safety profile; recent investigations of TCZ in other immunological diseases; and the clinical development of other novel IL-6-targeted agents.

Long-term follow-up of MCL patients treated with single-agent ibrutinib: updated safety and efficacy results.

PubMed

Wang, Michael L; Blum, Kristie A; Martin, Peter; Goy, Andre; Auer, Rebecca; Kahl, Brad S; Jurczak, Wojciech; Advani, Ranjana H; Romaguera, Jorge E; Williams, Michael E; Barrientos, Jacqueline C; Chmielowska, Ewa; Radford, John; Stilgenbauer, Stephan; Dreyling, Martin; Jedrzejczak, Wieslaw Wiktor; Johnson, Peter; Spurgeon, Stephen E; Zhang, Liang; Baher, Linda; Cheng, Mei; Lee, Dana; Beaupre, Darrin M; Rule, Simon

2015-08-06

Ibrutinib, an oral inhibitor of Bruton tyrosine kinase, is approved for patients with mantle cell lymphoma (MCL) who have received one prior therapy. We report the updated safety and efficacy results from the multicenter, open-label phase 2 registration trial of ibrutinib (median 26.7-month follow-up). Patients (N = 111) received oral ibrutinib 560 mg once daily, and those with stable disease or better could enter a long-term extension study. The primary end point was overall response rate (ORR). The median patient age was 68 years (range, 40-84), with a median of 3 prior therapies (range, 1-5). The median treatment duration was 8.3 months; 46% of patients were treated for >12 months, and 22% were treated for ≥2 years. The ORR was 67% (23% complete response), with a median duration of response of 17.5 months. The 24-month progression-free survival and overall survival rates were 31% (95% confidence interval [CI], 22.3-40.4) and 47% (95% CI, 37.1-56.9), respectively. The most common adverse events (AEs) in >30% of patients included diarrhea (54%), fatigue (50%), nausea (33%), and dyspnea (32%). The most frequent grade ≥3 infections included pneumonia (8%), urinary tract infection (4%), and cellulitis (3%). Grade ≥3 bleeding events in ≥2% of patients were hematuria (2%) and subdural hematoma (2%). Common all-grade hematologic AEs were thrombocytopenia (22%), neutropenia (19%), and anemia (18%). The prevalence of infection, diarrhea, and bleeding was highest for the first 6 months of therapy and less thereafter. With longer follow-up, ibrutinib continues to demonstrate durable responses and favorable safety in relapsed/refractory MCL. The trial is registered to www.ClinicalTrials.gov as #NCT01236391. © 2015 by The American Society of Hematology.

Fenoterol hydrobromide delivered via HFA-MDI or CFC-MDI in patients with asthma: a safety and efficacy comparison.

PubMed

Goldberg, J; Böhning, W; Schmidt, P; Freund, E

2000-10-01

The main objective of the study was to compare the long-term safety and tolerability of fenoterol hydrobromide delivered using a metered-dose inhaler formulated with the alternative propellant, hydrofluoroalkane 134a (HFA-MDI), with delivery using the currently available chlorofluorocarbon MDI (CFC-MDI; Berotec 100). A further objective was to compare the efficacy of fenoterol HFA-MDI with fenoterol CFC-MDI, using the pulmonary function parameters of forced expiratory volume in 1 sec (FEV1), forced vital capacity (FVC) and peak expiratory flow (PEF). Following a 2-week run-in phase, a 12-week, double-blind parallel group comparison was undertaken in 290 patients randomized on a 2:1 basis to two puffs of 100 microg fenoterol four times a day (HFA-MDI=197 patients; CFC-MDI=93 patients). A total of 236 patients in this multi-centre study completed the trial as planned. The overall incidence of adverse events (AEs) was similar in both groups (29.9% of HFA-MDI patients and 28% of CFC-MDI patients). Reports of respiratory disorder AEs were also comparable (21.8% HFA-MDI; 22.6% CFCMDI). End of study laboratory tests, ECG, pulse, blood pressure and physical examination showed no significant differences from pre-study baselines in either group and both treatments appeared to be well tolerated. Pre-dose FEV1 measurements taken at the three clinic visits were constant and increase in FEV1 at 5 and 30 min post-dose demonstrated equivalent efficacy for the two formulations. No difference between the two groups was observed in PEF or in the use of rescue medication. We conclude from these findings that the long-term safety and efficacy profile of fenoterol HFA-MDI is comparable to that of the fenoterol CFC-MDI.

National Dam Safety Program. Lipps Lake Dam (MO 30214). Mississippi - Kaskaskia - St. Louis Basin, Cape Girardeau County, Missouri. Phase I Inspection Report.

DTIC Science & Technology

1980-10-01

AD-A105 988 HOSKINSEWESTERN-SONOER EGGER INC LINCOLN NEM F/S 13/13 NATIONAL DA -M SAFETY PROGRAM. LI PS LAKE DAM (MO 3021 ). MISS! SS7 - TC(U...COMPLETING FORM i. REPORT NUMBER 12. GOVT ACCESSION NO. 3. RECIPIENT’S CATALOG NIOMBER 4. TITLE (and Subtitle) 5. TYPE OF REPORT & PERIOD COVERED Phase I Dam

Long-term efficacy and safety of ustekinumab for Crohn's disease through the second year of therapy.

PubMed

Sandborn, W J; Rutgeerts, P; Gasink, C; Jacobstein, D; Zou, B; Johanns, J; Sands, B E; Hanauer, S B; Targan, S; Ghosh, S; de Villiers, W J S; Colombel, J-F; Feagan, B G

2018-05-24

In Phase 3 studies of ustekinumab, a fully human monoclonal IL-12/23p40 antibody approved for moderate-to-severe Crohn's disease, patients entered a long-term extension after completing 8 weeks of induction and 44 weeks of maintenance treatment. Efficacy through 92 weeks and safety through 96 weeks of IM-UNITI maintenance are reported. UNITI-1 (TNF-antagonist failures) and UNITI-2 (conventional therapy failures) patients (N = 1281) entered IM-UNITI, including 397 ustekinumab intravenous induction responders randomised to subcutaneous ustekinumab 90 mg every 12 weeks, every 8 weeks, or placebo and 884 nonrandomised patients. Dose-adjustment to 90 mg every 8 weeks occurred in patients randomised to 90 mg every 12 weeks and placebo patients with loss of response (Weeks 8-32). All Week 44 completers could enter the long-term extension without further dose adjustment. Placebo patients discontinued following study unblinding. A total of 718 patients (all treated) entered the long-term extension (298 randomised and 420 not randomised). Overall, 86.5% (621/718) completed Week 96. The proportions of randomised patients in clinical remission were generally maintained from Week 44 through 92 in ustekinumab 90 mg every 12 weeks (77.4% to 72.6%), every 8 weeks (84.1% to 74.4%), and prior dose adjustment groups (63.4% to 53.5%). At Week 92, the proportions of patients in clinical remission were similar in the ustekinumab 90 mg every 12 weeks and every 8 weeks groups and lower in patients with prior dose adjustment. Proportions of patients in clinical remission at Week 92 for all treated every 8 weeks (64.4%) and every 12 weeks (64.3%) groups were lower than randomised every 8 weeks (74.4%) and every 12 weeks (72.6%) groups, but similarly maintained. Safety events (per hundred patient-years) were similar among all placebo and ustekinumab patients (Week 0-96), including adverse events (484.39 vs 447.76), serious adverse events (19.24 vs 18.82), and serious infections (4.09 vs 4.02). No dose effect was observed. Subcutaneous ustekinumab maintained clinical response and remission through Week 92. No new safety signals were observed. ClinicalTrials.gov number NCT01369355. © 2018 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.

Environmental, health, and safety issues of fuel cells in transportation. Volume 1: Phosphoric acid fuel-cell buses

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ring, S

1994-12-01

The U.S. Department of Energy (DOE) chartered the Phosphoric Acid Fuel-Cell (PAFC) Bus Program to demonstrate the feasibility of fuel cells in heavy-duty transportation systems. As part of this program, PAFC- powered buses are being built to meet transit industry design and performance standards. Test-bed bus-1 (TBB-1) was designed in 1993 and integrated in March 1994. TBB-2 and TBB-3 are under construction and should be integrated in early 1995. In 1987 Phase I of the program began with the development and testing of two conceptual system designs- liquid- and air-cooled systems. The liquid-cooled PAFC system was chosen to continue, throughmore » a competitive award, into Phase H, beginning in 1991. Three hybrid buses, which combine fuel-cell and battery technologies, were designed during Phase III. After completing Phase II, DOE plans a comprehensive performance testing program (Phase HI) to verify that the buses meet stringent transit industry requirements. The Phase III study will evaluate the PAFC bus and compare it to a conventional diesel bus. This NREL study assesses the environmental, health, and safety (EH&S) issues that may affect the commercialization of the PAFC bus. Because safety is a critical factor for consumer acceptance of new transportation-based technologies the study focuses on these issues. The study examines health and safety together because they are integrally related. In addition, this report briefly discusses two environmental issues that are of concern to the Environmental Protection Agency (EPA). The first issue involves a surge battery used by the PAFC bus that contains hazardous constituents. The second issue concerns the regulated air emissions produced during operation of the PAFC bus.« less

TITLE: Environmental, health, and safety issues offuel cells in transportation. Volume 1: Phosphoricacid fuel-cell buses

NASA Astrophysics Data System (ADS)

Ring, Shan

1994-12-01

The U.S. Department of Energy (DOE) chartered the Phosphoric Acid Fuel-Cell (PAFC) Bus Program to demonstrate the feasibility of fuel cells in heavy-duty transportation systems. As part of this program, PAFC- powered buses are being built to meet transit industry design and performance standards. Test-bed bus-1 (TBB-1) was designed in 1993 and integrated in March 1994. TBB-2 and TBB-3 are under construction and should be integrated in early 1995. In 1987 Phase 1 of the program began with the development and testing of two conceptual system designs- liquid- and air-cooled systems. The liquid-cooled PAFC system was chosen to continue, through a competitive award, into Phase H, beginning in 1991. Three hybrid buses, which combine fuel-cell and battery technologies, were designed during Phase 3. After completing Phase 2, DOE plans a comprehensive performance testing program (Phase H1) to verify that the buses meet stringent transit industry requirements. The Phase 3 study will evaluate the PAFC bus and compare it to a conventional diesel bus. This NREL study assesses the environmental, health, and safety (EH&S) issues that may affect the commercialization of the PAFC bus. Because safety is a critical factor for consumer acceptance of new transportation-based technologies the study focuses on these issues. The study examines health and safety together because they are integrally related. In addition, this report briefly discusses two environmental issues that are of concern to the Environmental Protection Agency (EPA). The first issue involves a surge battery used by the PAFC bus that contains hazardous constituents. The second issue concerns the regulated air emissions produced during operation of the PAFC bus.

Evaluation of an intelligent wheelchair system for older adults with cognitive impairments

PubMed Central

2013-01-01

Background Older adults are the most prevalent wheelchair users in Canada. Yet, cognitive impairments may prevent an older adult from being allowed to use a powered wheelchair due to safety and usability concerns. To address this issue, an add-on Intelligent Wheelchair System (IWS) was developed to help older adults with cognitive impairments drive a powered wheelchair safely and effectively. When attached to a powered wheelchair, the IWS adds a vision-based anti-collision feature that prevents the wheelchair from hitting obstacles and a navigation assistance feature that plays audio prompts to help users manoeuvre around obstacles. Methods A two stage evaluation was conducted to test the efficacy of the IWS. Stage One: Environment of Use – the IWS’s anti-collision and navigation features were evaluated against objects found in a long-term care facility. Six different collision scenarios (wall, walker, cane, no object, moving and stationary person) and three different navigation scenarios (object on left, object on right, and no object) were performed. Signal detection theory was used to categorize the response of the system in each scenario. Stage Two: User Trials – single-subject research design was used to evaluate the impact of the IWS on older adults with cognitive impairment. Participants were asked to drive a powered wheelchair through a structured obstacle course in two phases: 1) with the IWS and 2) without the IWS. Measurements of safety and usability were taken and compared between the two phases. Visual analysis and phase averages were used to analyze the single-subject data. Results Stage One: The IWS performed correctly for all environmental anti-collision and navigation scenarios. Stage Two: Two participants completed the trials. The IWS was able to limit the number of collisions that occurred with a powered wheelchair and lower the perceived workload for driving a powered wheelchair. However, the objective performance (time to complete course) of users navigating their environment did not improve with the IWS. Conclusions This study shows the efficacy of the IWS in performing with a potential environment of use, and benefiting members of its desired user population to increase safety and lower perceived demands of powered wheelchair driving. PMID:23924489

Failures to further developing orphan medicinal products after designation granted in Europe: an analysis of marketing authorisation failures and abandoned drugs.

PubMed

Giannuzzi, Viviana; Landi, Annalisa; Bosone, Enrico; Giannuzzi, Floriana; Nicotri, Stefano; Torrent-Farnell, Josep; Bonifazi, Fedele; Felisi, Mariagrazia; Bonifazi, Donato; Ceci, Adriana

2017-09-11

The research and development process in the field of rare diseases is characterised by many well-known difficulties, and a large percentage of orphan medicinal products do not reach the marketing approval.This work aims at identifying orphan medicinal products that failed the developmental process and investigating reasons for and possible factors influencing failures. Drugs designated in Europe under Regulation (European Commission) 141/2000 in the period 2000-2012 were investigated in terms of the following failures: (1) marketing authorisation failures (refused or withdrawn) and (2) drugs abandoned by sponsors during development.Possible risk factors for failure were analysed using statistically validated methods. This study points out that 437 out of 788 designations are still under development, while 219 failed the developmental process. Among the latter, 34 failed the marketing authorisation process and 185 were abandoned during the developmental process. In the first group of drugs (marketing authorisation failures), 50% reached phase II, 47% reached phase III and 3% reached phase I, while in the second group (abandoned drugs), the majority of orphan medicinal products apparently never started the development process, since no data on 48.1% of them were published and the 3.2% did not progress beyond the non-clinical stage.The reasons for failures of marketing authorisation were: efficacy/safety issues (26), insufficient data (12), quality issues (7), regulatory issues on trials (4) and commercial reasons (1). The main causes for abandoned drugs were efficacy/safety issues (reported in 54 cases), inactive companies (25.4%), change of company strategy (8.1%) and drug competition (10.8%). No information concerning reasons for failure was available for 23.2% of the analysed products. This analysis shows that failures occurred in 27.8% of all designations granted in Europe, the main reasons being safety and efficacy issues. Moreover, the stage of development reached by drugs represents a specific risk factor for failures. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Users perspectives on interactive distance technology enabling home-based motor training for stroke patients.

PubMed

Ehn, Maria; Hansson, Pär; Sjölinder, Marie; Boman, Inga-Lill; Folke, Mia; Sommerfeld, Disa; Borg, Jörgen; Palmcrantz, Susanne

2015-01-01

The aim of this work has been to develop a technical support enabling home-based motor training after stroke. The basis for the work plan has been to develop an interactive technical solution supporting three different groups of stroke patients: (1) patients with stroke discharged from hospital with support from neuro team; (2) patients with stroke whose support from neuro team will be phased out and (3) patients living with impaired motor functions long-term. The technology has been developed in close collaboration with end-users using a method earlier evaluated and described [12]. This paper describes the main functions of the developed technology. Further, results from early user-tests with end-users, performed to identify needs for improvements to be carried out during further technical development. The developed technology will be tested further in a pilot study of the safety and, usefulness of the technology when applied as a support for motor training in three different phases of the post-stroke rehabilitation process.

Development and 10-year history of a biosimilar: the example of Binocrit®

PubMed Central

Aapro, Matti; Krendyukov, Andriy; Höbel, Nadja; Seidl, Andreas; Gascón, Pere

2018-01-01

Patent expirations for several biological products have prompted the development of alternative versions, termed ‘biosimilars’, which have comparable quality, safety and efficacy to a licensed biological medicine (also referred to as the ‘reference’ medicine). The first biosimilars developed in oncology were the supportive-care agents filgrastim and epoetin. Binocrit® (HX575) is a biosimilar version of epoetin alfa, indicated in the oncology setting for the treatment of chemotherapy-induced anemia (CIA). The process for development and approval of Binocrit® as a biosimilar included extensive analytical characterization and comparison with the reference epoetin alfa. This was followed by a clinical development program comprising phase I pharmacokinetic/pharmacodynamic studies to show bioequivalence to the reference medicine and a confirmatory phase III study to confirm therapeutic effectiveness in CIA. Since its approval, Binocrit® has been extensively used and studied in real-world clinical practice. The accumulated data confirm that Binocrit® is an effective and well-tolerated option for the treatment of CIA in patients with cancer.

AN-2728, a PDE4 inhibitor for the potential topical treatment of psoriasis and atopic dermatitis.

PubMed

Nazarian, Rachel; Weinberg, Jeffrey M

2009-11-01

Cytokines are signaling molecules that are believed to be key factors in perpetuating the inflammatory process in psoriasis and atopic dermatitis. AN-2728, being developed by Anacor Pharmaceuticals Inc, is a topically administered, boron-containing, anti-inflammatory compound that inhibits PDE4 activity and thereby suppresses the release of TNFalpha, IL-12, IL-23 and other cytokines. At the time of publication, three phase Ib clinical trials, a IIa trial and a IIb trial of AN-2728 in patients with psoriasis had been completed; the compound was also undergoing phase II development for atopic dermatitis, but no data were available for this indication. AN-2728 was reported to be well tolerated and to demonstrate significant effects on markers of efficacy, with results that were comparable to positive controls. AN-2728 appears to have good therapeutic potential, although further and larger trials are required to assess the long-term safety and characterize the broad utility of this drug.

Role of Hyperkalemia in Heart Failure and the Therapeutic Use of Potassium Binders.

PubMed

Sarwar, Chaudhry M S; Bhagat, Aditi A; Anker, Stefan D; Butler, Javed

2017-01-01

Hyperkalemia can be a life-threatening disorder, especially for at-risk patients with heart failure, chronic kidney disease, with diabetes, and patients on certain drugs like renin-angiotensin-aldosterone system antagonists and mineralocorticoid receptor antagonists. There are limited therapeutic options available for hyperkalemia, and they have narrow effectiveness because of their unfavorable side effects profile in long-term and high cost utilization requiring inpatient care. Patiromersorbitex calcium and sodium zirconium cyclosilicate are novel potassium-lowering compounds for the treatment and prevention of hyperkalemia in at-risk population. These therapeutic agents have shown encouraging results in early phase II and phase III clinical trials. However, there is need to further study their efficacy and safety in heart failure population in order to establish their clinical use. The focus of this chapter will be to promote better understanding of potassium homeostasis in heart failure patients and the mechanistic overview of novel drugs, with emphasis on heart failure population.

Aircraft Wake Vortex Measurements at Denver International Airport

NASA Technical Reports Server (NTRS)

Dougherty, Robert P.; Wang, Frank Y.; Booth, Earl R.; Watts, Michael E.; Fenichel, Neil; D'Errico, Robert E.

2004-01-01

Airport capacity is constrained, in part, by spacing requirements associated with the wake vortex hazard. NASA's Wake Vortex Avoidance Project has a goal to establish the feasibility of reducing this spacing while maintaining safety. Passive acoustic phased array sensors, if shown to have operational potential, may aid in this effort by detecting and tracking the vortices. During August/September 2003, NASA and the USDOT sponsored a wake acoustics test at the Denver International Airport. The central instrument of the test was a large microphone phased array. This paper describes the test in general terms and gives an overview of the array hardware. It outlines one of the analysis techniques that is being applied to the data and gives sample results. The technique is able to clearly resolve the wake vortices of landing aircraft and measure their separation, height, and sinking rate. These observations permit an indirect estimate of the vortex circulation. The array also provides visualization of the vortex evolution, including the Crow instability.

Unmanned Aerial Systems (UAS): Evolving Trends

NASA Technical Reports Server (NTRS)

Kopardekar, Parimal

2015-01-01

Near-term Goal: Enable initial low-altitude airspace and UAS operations with demonstrated safety as early as possible, within 5 years; Long-term Goal: Accommodate increased UAS operations with highest safety, efficiency, and capacity as much autonomously as possible (10-15 years).

Alcohol & highway safety laws : a national overview.

DOT National Transportation Integrated Search

1980-02-01

The problems associated with alcohol and highway safety laws can be measured statistically in terms of the number of traffic deaths per day across the nation, or financially in terms of the billions of dollars in lost income from death and disability...

Safely Enabling Low-Altitude Airspace Operations

NASA Technical Reports Server (NTRS)

Kopardekar, Parimal

2015-01-01

Near-term Goal: Enable initial low-altitude airspace and UAS operations with demonstrated safety as early as possible, within 5 years. Long-term Goal: Accommodate increased UAS operations with highest safety, efficiency, and capacity as much autonomously as possible (10-15 years).

Safety of phase I clinical trials with monoclonal antibodies in Germany--the regulatory requirements viewed in the aftermath of the TGN1412 disaster.

PubMed

Liedert, B; Bassus, S; Schneider, C K; Kalinke, U; Löwer, J

2007-01-01

This review summarizes scientific, ethical and regulatory aspects of Phase I clinical trials with monoclonal antibodies. The current standard requirements for pre-clinical testing and for clinical study design are presented. The scientific considerations discussed herein are generally applicable, the view on legal requirements for clinical trials refer to the German jurisdiction only. The adverse effects associated with the TGN1412 Phase I trial indicate that the predictive value of pre-clinical animal models requires reevaluation and that, in certain cases, some issues of clinical trial protocols such as dose fixing may need refinement or redesign. Concrete safety measures, which have been proposed as a consequence of the TGN1412 event include introduction of criteria for high-risk antibodies, sequential inclusion of trial participants and implementation of pre-Phase I studies where dose calculation is based on the pre-clinical No Effect Level instead of the No Observed Adverse Effect Level. The recently established European clinical trials database (EUDRACT Database) is a further safety tool to expedite the sharing of relevant information between scientific authorities.

Effectiveness of safety belt warning and interlock systems

DOT National Transportation Integrated Search

1973-04-01

Rental cars in Fayetteville, N.C., were equipped with four seat belt and warning systems: (Phase I) detachable shoulder and lap belt, no warning system; (Phase II) detachable shoulder and lap belt, warning system (January 1, 1972 standard); (Phase II...

Live birth rates and safety profile using dydrogesterone for luteal phase support in assisted reproductive techniques

PubMed Central

Nadarajah, Ravichandran; Rajesh, Hemashree; Wong, Ker Yi; Faisal, Fazlin; Yu, Su Ling

2017-01-01

INTRODUCTION Assisted reproductive techniques (ARTs) result in a deficient luteal phase, requiring the administration of intramuscular, intravaginal or oral exogenous progesterone. Dydrogesterone, an oral retroprogesterone with good bioavailability, has been used in assisted reproductive cycles with outcomes that are comparable to those of vaginal or intramuscular progesterone. However, there are limited reviews on its use for luteal phase support in ARTs, in terms of pregnancy outcomes and associated fetal anomalies. This study aimed to review the live birth rates and associated fetal anomalies of women who were given dydrogesterone for luteal phase support in assisted reproductive cycles at a tertiary hospital in Singapore. METHODS This retrospective descriptive study included 1,050 women who underwent in vitro fertilisation/intracytoplasmic sperm injection at the Centre for Assisted Reproduction of Singapore General Hospital between 2000 and 2011. The women were given dydrogesterone for luteal phase support. The main outcome measures were rates of pregnancy, live birth, miscarriage and fetal anomalies. RESULTS The pregnancy and live birth rates were 34.7% and 27.7%, respectively. Among those who achieved pregnancy, 17.0% miscarried, 0.8% had ectopic pregnancies and 0.3% had molar pregnancies. Fetal anomalies were detected in 1.9% of pregnancies, all of which were terminated by choice. CONCLUSION Since the outcomes of dydrogesterone are comparable to those of intramuscular and vaginal progesterone, it is a reasonable option to provide luteal phase support for women who are uncomfortable with injections or vaginal insertions. Randomised controlled studies are needed to determine the optimal dosage of dydrogesterone for luteal phase support in ARTs. PMID:27090598

Review article: novel oral-targeted therapies in inflammatory bowel disease.

PubMed

White, J R; Phillips, F; Monaghan, T; Fateen, W; Samuel, S; Ghosh, S; Moran, G W

2018-06-01

There is a great unmet clinical need for efficacious, tolerable, economical and orally administrated drugs for the treatment of inflammatory bowel disease (IBD). New therapeutic avenues have become possible including the development of medications that target specific genetic pathways found to be relevant in other immune mediated diseases. To provide an overview of recent clinical trials for new generation oral targeted medications that may have a future role in IBD management. Pubmed and Medline searches were performed up to 1 March 2018 using keywords: "IBD", "UC", "CD", "inflammatory bowel disease" "ulcerative colitis", "Crohn's disease" in combination with "phase", "study", "trial" and "oral". A manual search of the clinical trial register, article reference lists, abstracts from meetings of Digestive Disease Week, United European Gastroenterology Week and ECCO congress were also conducted. In randomised controlled trials primary efficacy endpoints were met for tofacitinib (JAK 1/3 inhibitor-phase III), upadacitinib (JAK 1 inhibitor-phase II) and AJM300 (α4-integrin antagonist-phase II) in ulcerative colitis. Ozanimod (S1P receptor agonist-phase II) also demonstrated clinical remission. For Crohn's disease, filgotinib (JAK1 inhibitor-phase II) met primary endpoints and laquinimod (quinolone-3-carboxide small molecule-phase II) was also efficacious. Trials using mongersen (SMAD7 inhibitor) and vidofludimus (dihydroorotate dehydrogenase inhibitor) have been halted. This is potentially the start of an exciting new era in which multiple therapeutic options are at the disposal of physicians to treat IBD on an individualised basis. Head-to-head studies with existing treatments and longer term safety data are needed for this to be possible. © 2018 John Wiley & Sons Ltd.

Biosimilars: pharmacovigilance and risk management.

PubMed

Zuñiga, Leyre; Calvo, Begoña

2010-07-01

Biosimilars cannot be authorized based on the same requirements that apply to generic medicines. Despite the fact that the biosimilar and reference drug can show similar efficacy, the biosimilar may exhibit different safety profile in terms of nature, seriousness or incidence of adverse reactions. However, the data from pre-authorization clinical studies normally are insufficient to identify all potential differences. Therefore, clinical safety of similar biological medicinal products must be monitored closely on an ongoing basis during the post-approval phase including continued risk-benefit assessment. The biosimilar applicant must provide the European Medicines Agency (EMEA) with a risk management plan (EU-RMP) and pharmacovigilance programme with its application, including a description of the potential safety issues associated with the similar biological medicinal product that may be a result of differences in the manufacturing process from the reference biologic. The most critical safety concern relating to biopharmaceuticals (including biosimilars) is immunogenicity. Risk management applies scientifically based methodologies to identify, assess, communicate and minimise risk throughout a drug's life cycle so as to establish and maintain a favourable benefit-risk profile in patients. The risk management plan for biosimilars should focus on heightens the pharmacovigilance measures, identify immunogenicity risk and implement special post-marketing surveillance. Although International Nonproprietary Names (INNs) served as a useful tool in worldwide pharmacovigilance, for biologicals they should not be relied upon as the only means of product identification. Biologicals should always be commercialized with a brand name or the INN plus the manufacturer's name. (c) 2010 John Wiley & Sons, Ltd.

A randomized controlled trial investigating the safety and efficacy of aripiprazole in the long-term maintenance treatment of pediatric patients with irritability associated with autistic disorder.

PubMed

Findling, Robert L; Mankoski, Raymond; Timko, Karen; Lears, Katherine; McCartney, Theresa; McQuade, Robert D; Eudicone, James M; Amatniek, Joan; Marcus, Ronald N; Sheehan, John J

2014-01-01

To evaluate the efficacy and safety of aripiprazole versus placebo in preventing relapse of irritability symptoms associated with autistic disorder in pediatric patients. This multicenter, double-blind, randomized, placebo-controlled, relapse-prevention trial enrolled patients (6-17 years) who met the current Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DMS-IV-TR) criteria for autistic disorder and who also had serious behavioral problems (ie, tantrums, aggression, self-injurious behavior, or a combination of these behavioral problems) between March 2011 and June 2012. In phase 1, single-blind aripiprazole was flexibly dosed (2-15 mg/d) for 13-26 weeks. Patients with a stable response (≥ 25% decrease in Aberrant Behavior Checklist-irritability subscale score and a rating of "much improved" or "very much improved" on the Clinical Global Impressions-Improvement scale) for 12 consecutive weeks were randomized into phase 2 to continue aripiprazole or switch to placebo. Treatment was continued until relapse or up to 16 weeks. The primary end point was time from randomization to relapse. Eighty-five patients were randomized in phase 2. The difference in time to relapse between aripiprazole and placebo was not statistically significant (P = .097). Kaplan-Meier relapse rates at week 16 were 35% for aripiprazole and 52% for placebo (hazard ratio [HR] = 0.57; number needed to treat [NNT] = 6). The most common adverse events during phase 1 were weight increase (25.2%), somnolence (14.8%), and vomiting (14.2%); and, during phase 2 (aripiprazole vs placebo), they were upper respiratory tract infection (10.3% vs 2.3%), constipation (5.1% vs 0%), and movement disorder (5.1% vs 0%). In this study, there was no statistically significant difference between aripiprazole and placebo in time to relapse during maintenance therapy. However, the HR and NNT suggest some patients will benefit from maintenance treatment. Patients receiving aripiprazole should be periodically reassessed to determine the continued need for treatment. ClinicalTrials.gov identifier: NCT01227668. © Copyright 2014 Physicians Postgraduate Press, Inc.

Revenue sources for financing transportation safety activities in Virginia : phase three, feasibility of a surcharge on traffic fines.

DOT National Transportation Integrated Search

1981-01-01

Senate Bill 85, an action of the 1978 General Assembly, amended the Code of Virginia to provide, in part, that the Division of Highway Safety be succeeded by the newly created Department of Transportation Safety effective July 1, 1978. In its Declara...

The Washington State Task Force on Student Transportation Safety. Final Report.

ERIC Educational Resources Information Center

Washington State Legislature, Olympia.

Findings of a study conducted by the Washington State Task Force on Student Transportation Safety are presented in this report. The data-collection process involved four phases: meetings with experts in student transportation and pedestrian safety; public meetings, informational work sessions, and tours of problems areas; task force meetings; and…

Comprehensive Lifecycle for Assuring System Safety

NASA Technical Reports Server (NTRS)

Knight, John C.; Rowanhill, Jonathan C.

2017-01-01

CLASS is a novel approach to the enhancement of system safety in which the system safety case becomes the focus of safety engineering throughout the system lifecycle. CLASS also expands the role of the safety case across all phases of the system's lifetime, from concept formation to decommissioning. As CLASS has been developed, the concept has been generalized to a more comprehensive notion of assurance becoming the driving goal, where safety is an important special case. This report summarizes major aspects of CLASS and contains a bibliography of papers that provide additional details.

U18 : Traffic signal safety (phase B).

DOT National Transportation Integrated Search

2009-08-01

Efficiently scheduling traffic, particularly heavy vehicles, remains a key challenge in transportation engineering. This project has focused on the development of a novel trafficsignal-control methodology to improve the safety of heavy vehicles on...

Wireless roadside inspection phase II : final report : [technology brief].

DOT National Transportation Integrated Search

2014-04-01

The Federal Motor Carrier Safety Administration (FMCSA) Wireless Roadside Inspection (WRI) Program is demonstrating the feasibility and value of electronically assessing truck and motorcoach driver and vehicle safety. Electronic assessments (or WRIs)...

Autonomous Flight Safety System

NASA Technical Reports Server (NTRS)

Ferrell, Bob; Santuro, Steve; Simpson, James; Zoerner, Roger; Bull, Barton; Lanzi, Jim

2004-01-01

Autonomous Flight Safety System (AFSS) is an independent flight safety system designed for small to medium sized expendable launch vehicles launching from or needing range safety protection while overlying relatively remote locations. AFSS replaces the need for a man-in-the-loop to make decisions for flight termination. AFSS could also serve as the prototype for an autonomous manned flight crew escape advisory system. AFSS utilizes onboard sensors and processors to emulate the human decision-making process using rule-based software logic and can dramatically reduce safety response time during critical launch phases. The Range Safety flight path nominal trajectory, its deviation allowances, limit zones and other flight safety rules are stored in the onboard computers. Position, velocity and attitude data obtained from onboard global positioning system (GPS) and inertial navigation system (INS) sensors are compared with these rules to determine the appropriate action to ensure that people and property are not jeopardized. The final system will be fully redundant and independent with multiple processors, sensors, and dead man switches to prevent inadvertent flight termination. AFSS is currently in Phase III which includes updated algorithms, integrated GPS/INS sensors, large scale simulation testing and initial aircraft flight testing.

49 CFR 585.12 - Purpose.

Code of Federal Regulations, 2014 CFR

2014-10-01

..., DEPARTMENT OF TRANSPORTATION (CONTINUED) PHASE-IN REPORTING REQUIREMENTS Advanced Air Bag Phase-in Reporting... Traffic Safety Administration in determining whether a manufacturer has complied with the advanced air bag...

49 CFR 585.12 - Purpose.

Code of Federal Regulations, 2012 CFR

2012-10-01

..., DEPARTMENT OF TRANSPORTATION (CONTINUED) PHASE-IN REPORTING REQUIREMENTS Advanced Air Bag Phase-in Reporting... Traffic Safety Administration in determining whether a manufacturer has complied with the advanced air bag...

49 CFR 585.12 - Purpose.

Code of Federal Regulations, 2010 CFR

2010-10-01

..., DEPARTMENT OF TRANSPORTATION (CONTINUED) PHASE-IN REPORTING REQUIREMENTS Advanced Air Bag Phase-in Reporting... Traffic Safety Administration in determining whether a manufacturer has complied with the advanced air bag...

49 CFR 585.12 - Purpose.

Code of Federal Regulations, 2013 CFR

2013-10-01

..., DEPARTMENT OF TRANSPORTATION (CONTINUED) PHASE-IN REPORTING REQUIREMENTS Advanced Air Bag Phase-in Reporting... Traffic Safety Administration in determining whether a manufacturer has complied with the advanced air bag...

49 CFR 585.12 - Purpose.

Code of Federal Regulations, 2011 CFR

2011-10-01

..., DEPARTMENT OF TRANSPORTATION (CONTINUED) PHASE-IN REPORTING REQUIREMENTS Advanced Air Bag Phase-in Reporting... Traffic Safety Administration in determining whether a manufacturer has complied with the advanced air bag...

Clinical trial designs incorporating predictive biomarkers☆

PubMed Central

Renfro, Lindsay A.; Mallick, Himel; An, Ming-Wen; Sargent, Daniel J.; Mandrekar, Sumithra J.

2016-01-01

Development of oncologic therapies has traditionally been performed in a sequence of clinical trials intended to assess safety (phase I), preliminary efficacy (phase II), and improvement over the standard of care (phase III) in homogeneous (in terms of tumor type and disease stage) patient populations. As cancer has become increasingly understood on the molecular level, newer “targeted” drugs that inhibit specific cancer cell growth and survival mechanisms have increased the need for new clinical trial designs, wherein pertinent questions on the relationship between patient biomarkers and response to treatment can be answered. Herein, we review the clinical trial design literature from initial to more recently proposed designs for targeted agents or those treatments hypothesized to have enhanced effectiveness within patient subgroups (e.g., those with a certain biomarker value or who harbor a certain genetic tumor mutation). We also describe a number of real clinical trials where biomarker-based designs have been utilized, including a discussion of their respective advantages and challenges. As cancers become further categorized and/or reclassified according to individual patient and tumor features, we anticipate a continued need for novel trial designs to keep pace with the changing frontier of clinical cancer research. PMID:26827695

Preventive medicines: vaccination, prophylaxis of infectious diseases, disinfectants.

PubMed

Heininger, Ulrich

2011-01-01

Immunizations belong to the most successful interventions in medicine. Like other drugs, vaccines undergo long periods of pre-clinical development, followed by careful clinical testing through study Phases I, II, and III before they receive licensure. A successful candidate vaccine will move on to be an investigational vaccine to undergo three phases of pre-licensure clinical trials in a stepwise fashion before it can be considered for approval, followed by an optional fourth phase of post-marketing assessment. The overall risk-benefit assessment of a candidate vaccine is very critical in making the licensure decision for regulatory authorities, supported by their scientific committees. It includes analyses of immunogenicity, efficacy, reactogenicity or tolerability, and safety of the vaccine. Public trust in vaccines is a key to the success of immunization programs worldwide. Maintaining this trust requires knowledge of the benefits and scientific understanding of real or perceived risks of immunizations. Under certain circumstances, pre- or post-exposure passive immunization can be achieved by administration of immunoglobulines. In terms of prevention of infectious diseases, disinfection can be applied to reduce the risk of transmission of pathogens from patient to patient, health-care workers to patients, patients to health-care workers, and objects or medical devices to patients.

Quo Vadis Payload Safety?

NASA Technical Reports Server (NTRS)

Fodroci, Michael P.; Schwartz, MaryBeth

2008-01-01

As we complete the preparations for the fourth Hubble Space Telescope (HST) servicing mission, we note an anniversary approaching: it was 30 years ago in July that the first HST payload safety review panel meeting was held. This, in turn, was just over a year after the very first payload safety review, a Phase 0 review for the Tracking and Data Relay Satellite and its Inertial Upper Stage, held in June of 1977. In adapting a process that had been used in the review and certification of earlier Skylab payloads, National Aeronautics and Space Administration (NASA) engineers sought to preserve the lessons learned in the development of technical payload safety requirements, while creating a new process that would serve the very different needs of the new space shuttle program. Their success in this undertaking is substantiated by the fact that this process and these requirements have proven to be remarkably robust, flexible, and adaptable. Furthermore, the payload safety process has, to date, served us well in the critical mission of safeguarding our astronauts, cosmonauts, and spaceflight participants. Both the technical requirements and their interpretation, as well as the associated process requirements have grown, evolved, been streamlined, and have been adapted to fit multiple programs, including the International Space Station (ISS) program, the Shuttle/Mir program, and most recently the United States Constellation program. From its earliest days, it was anticipated that the payload safety process would be international in scope, and so it has been. European Space Agency (ESA), Japan Aerospace Exploration Agency (JAXA), German Space Agency (DLR), Canadian Space Agency (CSA), Russian Space Agency (RSA), and many additional countries have flown payloads on both the space shuttle and on the ISS. Our close cooperation and long-term working relationships have culminated in the franchising of the payload safety review process itself to our partners in ESA, which in turn will serve as a roadmap for extending the franchise to other Partners.

Dapoxetine for the treatment of premature ejaculation: results from a randomized, double-blind, placebo-controlled phase 3 trial in 22 countries.

PubMed

Buvat, Jacques; Tesfaye, Fisseha; Rothman, Margaret; Rivas, David A; Giuliano, François

2009-04-01

Dapoxetine is being developed for the on-demand treatment of premature ejaculation (PE). Previous clinical trials have demonstrated its safety and efficacy. To evaluate the long-term efficacy and safety of dapoxetine in men with PE. This randomized, double-blind, parallel-group, placebo-controlled, phase 3 trial, conducted in 22 countries, enrolled men (N=1162) > or = 18 yr of age who met the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision criteria for PE for > or = 6 mo, with an intravaginal ejaculatory latency time (IELT) < or = 2 min in > or = 75% of intercourse episodes at baseline. Dapoxetine 30 mg or dapoxetine 60 mg or placebo on demand (1-3 h before intercourse) for 24 wk. Stopwatch-measured IELT, Premature Ejaculation Profile (PEP), Clinical Global Impression (CGI) of change, adverse events (AEs). The study was completed by 618 men. Mean average IELT increased from 0.9 min at baseline (all groups) to 1.9 min, 3.2 min, and 3.5 min with placebo and dapoxetine 30 mg and dapoxetine 60 mg, respectively, at study end point; geometric mean IELT increased from 0.7 min at baseline to 1.1 min, 1.8 min, and 2.3 min, respectively, at study end point. All PEP measures and IELTs improved significantly with dapoxetine versus placebo at week 12 and week 24 (p<0.001 for all). The most common AEs were nausea, dizziness, diarrhea, and headache. AEs led to discontinuation in 1.3%, 3.9%, and 8.2% of subjects with placebo and dapoxetine 30 mg and dapoxetine 60 mg, respectively. Limitations of this study included the exclusion of men who were not in long-term monogamous relationships. Dapoxetine significantly improved all aspects of PE and was generally well tolerated in this broad population.

Nemolizumab in moderate-to-severe atopic dermatitis: Randomized, phase II, long-term extension study.

PubMed

Kabashima, Kenji; Furue, Masutaka; Hanifin, Jon M; Pulka, Grazyna; Wollenberg, Andreas; Galus, Ryszard; Etoh, Takafumi; Mihara, Ryosuke; Nakano, Miwa; Ruzicka, Thomas

2018-05-09

Nemolizumab, an anti-interleukin-31 receptor A monoclonal antibody, improved pruritus, dermatitis, and sleep in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments in a phase II, 12-week, randomized, double-blind, placebo-controlled study (Part A) (NCT01986933). To assess long-term efficacy and safety of nemolizumab injected subcutaneously every 4 weeks (Q4W) or every 8 weeks (Q8W) in a 52-week double-blind extension (Part B). During Part B, patients continued previous nemolizumab dose (0.1, 0.5, or 2.0 mg/kg Q4W or 2.0 mg/kg Q8W). Part B endpoints included percentage improvement from baseline in pruritus visual analogue scale (VAS) and dermatitis scores (including Eczema Area and Severity Index [EASI]). Overall, 216/264 patients completed Part A and 191 entered Part B; 131 completed Part B. In 153 patients randomized to nemolizumab in Part A, improvement from baseline in pruritus VAS was maintained/increased from Week 12 to 64, with greatest improvement in the 0.5-mg/kg Q4W group (percentage change from baseline at Week 64: -73.0, -89.6, -74.7, and -79.1 in the 0.1-, 0.5-, and 2.0-mg/kg Q4W and 2.0-mg/kg Q8W groups, respectively). Improvement from baseline in dermatitis scores was also maintained/increased to Week 64 (percent change in EASI score: -68.5, -75.8, -78.9, and -69.3 in the 0.1-, 0.5-, and 2.0-mg/kg Q4W and 2.0-mg/kg Q8W groups, respectively). Over 64 weeks, 83-89% had ≥1 adverse event, with no new safety concerns identified. Nemolizumab for up to 64 weeks was efficacious and, overall, well tolerated in patients with moderate-to-severe atopic dermatitis inadequately controlled by topical therapy. Copyright © 2018. Published by Elsevier Inc.

Safety and effectiveness of a single and repeat intramuscular injection of a GnRH vaccine (GonaCon™) in adult female domestic cats.

PubMed

Vansandt, L M; Kutzler, M A; Fischer, A E; Morris, K N; Swanson, W F

2017-04-01

Sterilization is a key strategy to reduce the number of domestic cats entering and killed in shelters each year. However, surgical sterilization is expensive and labour-intensive and cannot fully address the 70 million free-roaming cats estimated to exist in the United States. GonaCon™ is a gonadotropin-releasing hormone vaccine originally developed for use as a wildlife immunocontraceptive. An earlier formulation was tested in domestic cats and found to be safe and effective for long-term contraception. However, the current Environmental Protection Agency (EPA)-registered formulation consists of a different antigen-carrier protein and increased antigen concentration and has never been tested in cats. A pilot study was undertaken to evaluate the short-term safety of a single GonaCon immunization, assess the consequences of vaccinated cats receiving an accidental second GonaCon injection and determine the humoral immune response to immunization. During Phase 1, cats in Group A (n = 3) received a single intramuscular injection of GonaCon and Group B (n = 3) received a single intramuscular injection of saline. During Phase 2, Group A received a second GonaCon injection and Group B received their initial GonaCon injection. All cats developed GnRH antibodies within 30 days of vaccine administration. The endpoint titre (1:1,024,000) was similar among all cats, and levels remained high throughout the duration of the study. Four cats developed a sterile, painless, self-limiting mass at the site of injection. The mean number of days to mass development was 110.3 (range, 18-249 days). In conclusion, this preliminary study suggests that the EPA-registered GonaCon formulation is safe for continued testing in domestic cats, an accidental revaccination should not increase the risk of a vaccine reaction and the EPA-registered formulation effectively elicits a strong humoral immune response. © 2016 Blackwell Verlag GmbH.

Infliximab is superior to other biological agents for treatment of active ulcerative colitis: A meta-analysis.

PubMed

Mei, Wei-Qun; Hu, Hui-Zhen; Liu, Ying; Li, Zhi-Chen; Wang, Wei-Guo

2015-05-21

To compare the efficacy and safety of biological agents for the treatment of active ulcerative colitis (UC). PubMed, MEDLINE, EMBASE and the Cochrane library were searched to screen relevant articles from January 1996 to August 2014. The mixed treatment comparison meta-analysis within a Bayesian framework was performed using WinBUGS14 software. The proportions of patients reaching clinical response, clinical remission and mucosal healing in induction and maintenance phases were analyzed as efficacy indicators. Serious adverse events in maintenance phase were analyzed as safety indicators. The meta-analysis results showed that biological agents achieved better clinical response, clinical remission and mucosal healing than placebo. Indirect comparison indicated that in induction phase, infliximab was more effective than adalimumab in inducing clinical response (OR = 0.41, 95%CI: 0.29-0.57), clinical remission (OR = 0.33, 95%CI: 0.19-0.56) and mucosal healing (OR = 0.33, 95%CI: 0.19-0.56), and golimumab in inducing clinical response (OR = 0.66, 95%CI: 0.39-2.33) and mucosal healing (OR = 2.15, 95%CI: 1.18-4.22). No significant difference was found between placebo and biological agents regarding their safety. All biological agents were superior to placebo for UC treatment in both induction and maintenance phases with a similar safety profile, and infliximab had a better clinical effect than the other biological agents.

Safety, immunogenicity, and clinical outcomes in patients with Morquio A syndrome participating in 2 sequential open-label studies of elosulfase alfa enzyme replacement therapy (MOR-002/MOR-100), representing 5 years of treatment.

PubMed

Hendriksz, Christian; Santra, Saikat; Jones, Simon A; Geberhiwot, Tarekegn; Jesaitis, Lynne; Long, Brian; Qi, Yulan; Hawley, Sara M; Decker, Celeste

2018-04-01

Elosulfase alfa is an enzyme replacement therapy for Morquio A syndrome (mucopolysaccharidosis IVA), a multisystemic progressive lysosomal storage disorder. This report includes the primary treatment outcomes and immunogenicity profile of elosulfase alfa in patients with Morquio A syndrome from 2 sequential studies, MOR-002 (ClinicalTrials.govNCT00884949) and MOR-100 (NCT01242111), representing >5 years of clinical study data. MOR-002 was an open-label, single-arm phase 1/2 study that evaluated the pharmacokinetics, safety, immunogenicity, and preliminary efficacy of 3 sequential doses of elosulfase alfa (0.1, 1.0, and 2.0 mg/kg/week) in patients with Morquio A syndrome (n = 20) over 36 weeks, followed by an optional 36- to 48-week treatment period using elosulfase alfa 1.0 mg/kg once weekly (qw). During the 0.1 mg/kg dosing phase, 1 patient discontinued due to a type I hypersensitivity adverse event (AE), and that patient's sibling voluntarily discontinued in the absence of AEs. An additional patient discontinued due to recurrent infusion reactions during the 1.0 mg/kg continuation phase. The remaining 17 patients completed MOR-002 and enrolled in MOR-100, an open-label, long-term extension study that further evaluated safety and clinical outcomes with elosulfase alfa administered at 2.0 mg/kg qw. During the course of MOR-100, patients were given the option of receiving elosulfase alfa infusions at home with nursing assistance. Over the course of both studies, all patients experienced ≥1 AE and most patients experienced a drug-related AE, generally of mild or moderate severity. Hypersensitivity reactions reported as related to study drug occurred in 25% of patients. Thirteen patients who chose to receive infusions at home had the same tolerability and safety profile, as well as comparable compliance rates, as patients who chose to receive on-site infusions. All patients developed antibodies to elosulfase alfa. Positivity for neutralizing antibodies was associated with increased drug half-life and decreased drug clearance. Despite formation of antidrug-binding (total antidrug antibodies, TAb) and in vitro neutralizing antibodies (NAb) in all patients, these types of immunogenicity to elosulfase alfa were not correlated with safety or clinical outcomes. In contrast with the reported natural history of Morquio A, no trends toward decreasing endurance, respiratory function, or ability to perform activities of daily living were observed in this cohort over the 5-year period. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Expanding AirSTAR Capability for Flight Research in an Existing Avionics Design

NASA Technical Reports Server (NTRS)

Laughter, Sean A.

2012-01-01

The NASA Airborne Subscale Transport Aircraft Research (AirSTAR) project is an Unmanned Aerial Systems (UAS) test bed for experimental flight control laws and vehicle dynamics research. During its development, the test bed has gone through a number of system permutations, each meant to add functionality to the concept of operations of the system. This enabled the build-up of not only the system itself, but also the support infrastructure and processes necessary to support flight operations. These permutations were grouped into project phases and the move from Phase-III to Phase-IV was marked by a significant increase in research capability and necessary safety systems due to the integration of an Internal Pilot into the control system chain already established for the External Pilot. The major system changes in Phase-IV operations necessitated a new safety and failsafe system to properly integrate both the Internal and External Pilots and to meet acceptable project safety margins. This work involved retrofitting an existing data system into the evolved concept of operations. Moving from the first Phase-IV aircraft to the dynamically scaled aircraft further involved restructuring the system to better guard against electromagnetic interference (EMI), and the entire avionics wiring harness was redesigned in order to facilitate better maintenance and access to onboard electronics. This retrofit and harness re-design will be explored and how it integrates with the evolved Phase-IV operations.

Immunogenicity and safety of early vaccination with two doses of a combined measles-mumps-rubella-varicella vaccine in healthy Indian children from 9 months of age: a phase III, randomised, non-inferiority trial.

PubMed

Lalwani, Sanjay; Chatterjee, Sukanta; Balasubramanian, Sundaram; Bavdekar, Ashish; Mehta, Shailesh; Datta, Sanjoy; Povey, Michael; Henry, Ouzama

2015-09-11

This study (NCT00969436) compared the immunogenicity and safety of measles-mumps-rubella (MMR) followed by MMR+varicella (V) vaccines to (1) 2 doses of combined MMRV and (2) MMR followed by MMRV, in Indian children. Phase III, open, randomised, non-inferiority study. 6 tertiary care hospitals located in India. Healthy participants aged 9-10 months not previously vaccinated against/exposed to measles, mumps, rubella and varicella or without a history of these diseases. Participants were randomised (2:2:1) to receive 2 doses of either MMRV (MMRV/MMRV group) or MMR followed by MMRV (MMR/MMRV group) or MMR followed by MMR+V (MMR/MMR+V, control group) at 9 and 15 months of age. Antibody titres against measles, mumps and rubella were measured using ELISA and against varicella using an immunofluorescence assay. To demonstrate non-inferiority of the 2 vaccination regimens versus the control in terms of seroconversion rates, defined as a group difference with a lower bound of the 95% CI >-10% for each antigen, 43 days postdose 2. Parents/guardians recorded solicited local and general symptoms for a 4-day and 43-day period after each vaccine dose, respectively. Seroconversion rates postdose 1 ranged from 87.5% to 93.2% for measles, 83.3% to 86.1% for mumps and 98.7% to 100% for rubella across the 3 vaccine groups. The seroconversion rates postdose 2 were 100% for measles, mumps and rubella and at least 95.8% for varicella across the 3 vaccine groups. Non-inferiority of MMRV/MMRV and MMR/MMRV to MMR/MMR+V was achieved for all antigens, 43 days postdose 2. The 3 vaccination regimens were generally well tolerated in terms of solicited local and general symptoms. The immune responses elicited by the MMRV/MMRV and MMR/MMRV vaccination regimens were non-inferior to those elicited by the MMR/MMR+V regimen for all antigens. The 3 vaccination schedules also exhibited an acceptable safety profile in Indian children. NCT00969436. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Manned space flight nuclear system safety. Volume 3: Reactor system preliminary nuclear safety analysis. Part 3: Nuclear Safety Analysis Document (NSAD)

NASA Technical Reports Server (NTRS)

1972-01-01

Nuclear safety analysis as applied to a space base mission is presented. The nuclear safety analysis document summarizes the mission and the credible accidents/events which may lead to nuclear hazards to the general public. The radiological effects and associated consequences of the hazards are discussed in detail. The probability of occurrence is combined with the potential number of individuals exposed to or above guideline values to provide a measure of accident and total mission risk. The overall mission risk has been determined to be low with the potential exposure to or above 25 rem limited to less than 4 individuals per every 1000 missions performed. No radiological risk to the general public occurs during the prelaunch phase at KSC. The most significant risks occur from prolonged exposure to reactor debris following land impact generally associated with the disposal phase of the mission where fission product inventories can be high.

3S (Safeguards, Security, Safety) based pyroprocessing facility safety evaluation plan

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ku, J.H.; Choung, W.M.; You, G.S.

The big advantage of pyroprocessing for the management of spent fuels against the conventional reprocessing technologies lies in its proliferation resistance since the pure plutonium cannot be separated from the spent fuel. The extracted materials can be directly used as metal fuel in a fast reactor, and pyroprocessing reduces drastically the volume and heat load of the spent fuel. KAERI has implemented the SBD (Safeguards-By-Design) concept in nuclear fuel cycle facilities. The goal of SBD is to integrate international safeguards into the entire facility design process since the very beginning of the design phase. This paper presents a safety evaluationmore » plan using a conceptual design of a reference pyroprocessing facility, in which 3S (Safeguards, Security, Safety)-By-Design (3SBD) concept is integrated from early conceptual design phase. The purpose of this paper is to establish an advanced pyroprocessing hot cell facility design concept based on 3SBD for the successful realization of pyroprocessing technology with enhanced safety and proliferation resistance.« less

Novel licensure pathways for expeditious introduction of new tuberculosis vaccines: a discussion of the adaptive licensure concept.

PubMed

Rustomjee, Roxana; Lockhart, Stephen; Shea, Jacqueline; Fourie, P Bernard; Hindle, Zoë; Steel, Gavin; Hussey, Gregory; Ginsberg, Ann; Brennan, Michael J

2014-03-01

The ultimate goal of vaccine development is licensure of a safe and efficacious product that has a well-defined manufacturing process resulting in a high quality product. In general, clinical development and regulatory approval occurs in a linear, sequential manner: Phase 1 - safety, immunogenicity; Phase 2 - immunogenicity, safety, dose ranging and preliminary efficacy; Phase 3 - definitive efficacy, safety, lot consistency; and, following regulatory approval, Phase 4 - post-marketing safety and effectiveness. For candidate TB vaccines, where correlates of protection are not yet identified, phase 2 and 3 efficacy of disease prevention trials are, by necessity, very large. Each trial would span 2-5 years, with full licensure expected only after 1 or even 2 decades of development. Given the urgent unmet need for a new TB vaccine, a satellite discussion was held at the International African Vaccinology Conference in Cape Town, South Africa in November 2012, to explore the possibility of expediting licensure by use of an "adaptive licensure" process, based on a risk/benefit assessment that is specific to regional needs informed by epidemiology. This may be appropriate for diseases such as TB, where high rates of morbidity, mortality, particularly in high disease burden countries, impose an urgent need for disease prevention. The discussion focused on two contexts: licensure within the South African regulatory environment - a high burden country where TB vaccine efficacy trials are on-going, and licensure by the United States FDA --a well-resourced regulatory agency where approval could facilitate global licensure of a novel TB vaccine. Copyright © 2013. Published by Elsevier Ltd.

Vernakalant: RSD 1235, RSD-1235, RSD1235.

PubMed

2007-01-01

Vernakalant is an atrial-selective antiarrhythmic drug discovered by Cardiome Pharma (formerly Nortran Pharmaceuticals). Vernakalant may have potential in the treatment of atrial arrhythmias, including acute atrial fibrillation and atrial flutter. Vernakalant is a mixed sodium/potassium channel blocker and selectively blocks ion channels in the heart that are known to be active during episodes of atrial fibrillation. An IV formulation of vernakalant is awaiting registration in the US for the acute conversion of atrial fibrillation. Also, an oral formulation of the compound is in phase II clinical development as a chronic-use product for the maintenance of normal heart rhythm following termination of atrial fibrillation. Cardiome is seeking co-development partners for intravenous vernakalant in the treatment of atrial arrhythmia, atrial fibrillation and atrial flutter in Europe and Japan. In October 2003, Cardiome Pharma and Fujisawa Healthcare, the US subsidiary of Fujisawa Pharmaceutical Co., Ltd (now Astellas Pharma), executed a $US68 million strategic partnership agreement for the co-development of vernakalant. On 1 April 2005, Fujisawa merged with Yamanouchi to form Astellas Pharma. The partnership grants Astellas Pharma exclusive commercialisation rights for vernakalant. Under the terms of the agreement, Cardiome and Astellas Pharma will co-develop vernakalant as an intravenous formulation for the treatment of atrial fibrillation and atrial flutter for North American markets. Astellas Pharma will be financially responsible for 75% of all future clinical development costs, with Cardiome responsible for the remaining 25% of costs. Astellas Pharma will be responsible for the development plan, NDA application (and NDA re-submission costs) and registration, along with the commercial manufacturing, marketing and sale of vernakalant. Cardiome will manage the phase III trials ACT 1 and ACT 2 and will also be responsible for the continued manufacturing of clinical supplies of vernakalant. Cardiome will receive royalties on end-user sales of vernakalant reflective of Cardiome's 25% share of development costs and other financial considerations. Product rights to the IV formulation of vernakalant for markets outside of North America and world rights to the oral formulation of vernakalant for chronic atrial fibrillation are not included within the scope of this partnership. Cardiome intends to form future additional alliances for these product opportunities or maintain such opportunities for commercialisation on its own. Cardiome and Astellas amended their agreement for vernakalant in relation to the re-submission of the NDA with the US FDA. Under the terms of the new agreement, Astellas agreed to fund 100% of the costs associated with re-submission, including engagement and external consultants. Astellas also agreed to modify the timing of the $US10 million NDA milestone to the date of resubmission. In February 2005, Cardiome Pharma received a $US6 million milestone payment from its co-development partner, Fujisawa Healthcare Inc. This milestone payment was triggered by the successful completion of ACT 1.A pivotal phase II trial demonstrated in September 2002 that vernakalant rapidly and effectively terminated recent onset atrial fibrillation and the study met both primary and secondary study endpoints. Following discussions with the FDA, Cardiome initiated three separate phase III clinical trials in order to enable Cardiome to apply for marketing approval for vernakalant. In August 2003, Cardiome Pharma commenced patient dosing in its first phase III efficacy study of vernakalant for the acute treatment of atrial fibrillation. This initial study, called ACT 1 (Atrial fibrillation Conversion Trial 1), measured the safety and efficacy of vernakalant in 416 patients with atrial arrhythmias. The placebo-controlled study was carried out in 45 centers in the US, Canada and Scandinavia. The ACT 1 study included two substudies of 60 patients with atrial flutter and 119 patients with longer term atrial fibrillation. The primary efficacy endpoint was acute conversion of atrial arrhythmia to normal heart rhythm. Cardiome commenced its second phase III efficacy study in March 2004, known as ACT 2. The ACT 2 study in post-cardiac surgery (coronary artery bypass graft) patients with atrial fibrillation, evaluated the safety and efficacy of vernakalant (IV) in the termination of atrial arrhythmias in patients after cardiac surgery. Around 210 patients from 25 centres in the US, Canada and Europe were enrolled in this study. The primary efficacy endpoint was acute conversion of atrial arrhythmias to normal heart rhythm. The ACT 2 study is ongoing. The third phase III study, known as ACT 3 (Atrial arrhythmia Conversion Trial 3), was initiated by Cardiome Pharma in July 2004. In September 2005, Cardiome and Astellas reported that ACT 3 had been completed, achieving its primary endpoint, with over half of the 170 patients with recent-onset atrial fibrillation (AF) who received vernakalant intravenously converting to normal heart rhythm, compared with only 4% in the placebo group. The study was being conducted by co-development partner Astellas Pharma and measured the safety and efficacy of intravenous vernakalant in recent onset atrial arrhythmia patients. The placebo-controlled study was being carried out in 276 patients in more than 50 centres throughout the world.ACT 4, a phase III safety study evaluating safety of IV vernakalant in approximately 120 AF patients from 30 centres in the US, Canada and Europe, was initiated in October 2005. Results from this trial are expected to supplement trial results from the pivotal ACT 1 and 3 trials. This study is ongoing. Cardiome Pharma successfully completed phase I studies for its controlled-release oral formulation of vernakalant in 2005. The oral, controlled-release formulation of vernakalant is expected to help prevent or slow the recurrence of atrial fibrillation, and will be used as a follow-on therapy to intravenous vernakalant.

Degradation of cellulose under alkaline conditions: new insights from a 12 years degradation study.

PubMed

Glaus, Martin A; Van Loon, Luc R

2008-04-15

Cellulose degradation under alkaline conditions is of relevance to the mobility of many cations of the transition metal, lanthanide, and actinide series in the geosphere because strong complexants such as isosaccharinic acids, 3-deoxy-2-C-hydroxymethyl-D-erythro-pentonic acid (alpha-ISA) and 3-deoxy-2-C-hydroxymethyl-D-threo-pentonic acid (beta-ISA) may be formed. In the context of the long-term safety of cementitious repositories for low- and intermediate-level radioactive waste, where large amounts of cellulose may be present, the question of the time scales needed for the complete degradation of cellulose is important. The present paper reports the results of a 12 year study of the degradation of four different cellulosic materials (pure cellulose, tissue, cotton, paper) in an artificial cement pore water under anaerobic conditions at approximately 25 degrees C. The observed reaction characteristics can be divided into a fast reaction phase (2-3 years), dominated by the stepwise conversion of terminal glucose monomeric units to alpha-ISA and beta-ISA, and a very slow reaction phase during which the same products were found. The slow rate of the alkaline degradation of cellulose during this second reaction phase shows that previous kinetic models of cellulose degradation did not adequately describe the long-term behavior under alkaline conditions and need to be reassessed. It is postulated that a previously unknown mechanism by which crystalline or inaccessible reducing end groups of the polysaccharide chain become temporarily susceptible to alkaline attack is responsible for the slow rate of cellulose degradation.

Wireless roadside inspection phase II : final report.

DOT National Transportation Integrated Search

2014-03-01

The Federal Motor Carrier Safety Administration (FMCSA) Wireless Roadside Inspection (WRI) Program is demonstrating the feasibility and value of electronically assessing truck and motorcoach driver and vehicle safety at least 25 times more often than...

Efficacy and safety of tofacitinib for active rheumatoid arthritis with an inadequate response to methotrexate or disease-modifying antirheumatic drugs: a meta-analysis of randomized controlled trials

PubMed Central

Song, Gwan Gyu; Bae, Sang-Cheol

2014-01-01

Background/Aims The aim of this study was to assess the efficacy and safety of tofacitinib (5 and 10 mg twice daily) in patients with active rheumatoid arthritis (RA). Methods A systematic review of randomized controlled trials (RCTs) that examined the efficacy and safety of tofacitinib in patients with active RA was performed using the Medline, Embase, and Cochrane Controlled Trials Register databases as well as manual searches. Results Five RCTs, including three phase-II and two phase-III trials involving 1,590 patients, met the inclusion criteria. The three phase-II RCTs included 452 patients with RA (144 patients randomized to 5 mg of tofacitinib twice daily, 156 patients randomized to 10 mg of tofacitinib twice daily, and 152 patients randomized to placebo) who were included in this meta-analysis. The American College of Rheumatology 20% response rate was significantly higher in the tofacitinib 5- and 10-mg groups than in the control group (relative risk [RR], 2.445; 95% confidence interval [CI], 1.229 to 4.861; p = 0.011; and RR, 2.597; 95% CI, 1.514 to 4.455; p = 0.001, respectively). The safety outcomes did not differ between the tofacitinib 5- and 10-mg groups and placebo groups with the exception of infection in the tofacitinib 10-mg group (RR, 2.133; 95% CI, 1.268 to 3.590; p = 0.004). The results of two phase-III trials (1,123 patients) confirmed the findings in the phase-II studies. Conclusions Tofacitinib at dosages of 5 and 10 mg twice daily was found to be effective in patients with active RA that inadequately responded to methotrexate or disease-modifying antirheumatic drugs, and showed a manageable safety profile. PMID:25228842

Maximum tolerated dose evaluation of the AMPA modulator Org 26576 in healthy volunteers and depressed patients: a summary and method analysis of bridging research in support of phase II dose selection.

PubMed

Nations, Kari R; Bursi, Roberta; Dogterom, Peter; Ereshefsky, Larry; Gertsik, Lev; Mant, Tim; Schipper, Jacques

2012-09-01

A key challenge to dose selection in early central nervous system (CNS) clinical drug development is that patient tolerability profiles often differ from those of healthy volunteers (HVs), yet HVs are the modal population for determining doses to be investigated in phase II trials. Without clear tolerability data from the target patient population, first efficacy trials may include doses that are either too high or too low, creating undue risk for study participants and the development program overall. Bridging trials address this challenge by carefully investigating safety and tolerability in the target population prior to full-scale proof-of-concept trials. Org 26576 is an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor positive allosteric modulator that acts by modulating ionotropic AMPA-type glutamate receptors to enhance glutamatergic neurotransmission. In preparation for phase II efficacy trials in major depressive disorder (MDD), two separate phase I trials were conducted to evaluate safety, tolerability, and pharmacokinetics in HVs and in the target patient population. Both trials were randomized and placebo controlled, and included multiple rising-dose cohorts (HV range 100-400 mg bid; MDD range 100-600 mg bid). HVs (n = 36) and patients with MDD (n = 54) were dosed under similarly controlled conditions in an inpatient facility, HVs for up to 14 days and MDD patients for up to 28 days. Safety, tolerability, and pharmacokinetics were assessed frequently. Despite comparable pharmacokinetic profiles, the maximum tolerated dose (MTD) in depressed patients was 450 mg bid, twice the MTD established in HVs. No clinically relevant safety issues associated with Org 26576 were noted. This article presents safety, tolerability, and pharmacokinetic data from two different populations examined under similar dosing conditions. The important implications of such bridging work in phase II dose selection are discussed, as are study design and data interpretation challenges.

A novel integrated approach for the hazardous radioactive dust source terms estimation in future nuclear fusion power plants.

PubMed

Poggi, L A; Malizia, A; Ciparisse, J F; Gaudio, P

2016-10-01

An open issue still under investigation by several international entities working on the safety and security field for the foreseen nuclear fusion reactors is the estimation of source terms that are a hazard for the operators and public, and for the machine itself in terms of efficiency and integrity in case of severe accident scenarios. Source term estimation is a crucial key safety issue to be addressed in the future reactors safety assessments, and the estimates available at the time are not sufficiently satisfactory. The lack of neutronic data along with the insufficiently accurate methodologies used until now, calls for an integrated methodology for source term estimation that can provide predictions with an adequate accuracy. This work proposes a complete methodology to estimate dust source terms starting from a broad information gathering. The wide number of parameters that can influence dust source term production is reduced with statistical tools using a combination of screening, sensitivity analysis, and uncertainty analysis. Finally, a preliminary and simplified methodology for dust source term production prediction for future devices is presented.

Regulatory Anatomy: How "Safety Logics" Structure European Transplant Medicine.

PubMed

Hoeyer, Klaus

2015-07-01

This article proposes the term "safety logics" to understand attempts within the European Union (EU) to harmonize member state legislation to ensure a safe and stable supply of human biological material for transplants and transfusions. With safety logics, I refer to assemblages of discourses, legal documents, technological devices, organizational structures, and work practices aimed at minimizing risk. I use this term to reorient the analytical attention with respect to safety regulation. Instead of evaluating whether safety is achieved, the point is to explore the types of "safety" produced through these logics as well as to consider the sometimes unintended consequences of such safety work. In fact, the EU rules have been giving rise to complaints from practitioners finding the directives problematic and inadequate. In this article, I explore the problems practitioners face and why they arise. In short, I expose the regulatory anatomy of the policy landscape.

The comprehensive community-based traffic safety program : phase II, program assessment for District 2 and District 7, final report.

DOT National Transportation Integrated Search

1987-01-01

The program assessment phase was designed to identify community resources and address the recommendation, made in Phase I, that initial countermeasures should target the program areas of occupant protection, alcohol, selective enforcement, and pedest...

Changes of Geo-Runoff Components in Russian Arctic Rivers

NASA Astrophysics Data System (ADS)

Groisman, P. Y.; Georgiadi, A.; Kashutina, E.; Milyukova, I.

2017-12-01

Long-term phases of changes in naturalized components of the geo-runoff (streamflow, heat flow and suspended sediment yield) of Russian Arctic Rivers during the period of observation (from 1930-1940 till 2000s) were revealed on the basis of normalized cumulative curves. Their characteristics and the effects of impact of anthropogenic factors are evaluated. Since 1930-1940s till the beginning of the 21st century, the naturalized annual and seasonal river runoff in the largest river basins (Ob', Yenisei, Lena) was characterized by two main long-term phases of its changes. The phase of decreased runoff (since the 1930-1940s) was replaced in the 1970-1980s by a long-term phase of increased streamflow. The duration of phases was several decades and are characterized by significant runoff differences. In the long-term variations of the heat flow of the Ob, Yenisei, Lena, Northern Dvina and Pechora also were found two major long-term phases. The phase of the heat flow decrease, which began in 1930-1940-ies and lasted for 35-55 years, was replaced in 1970-1980 by 20-year phase of its increase (except the Yenisei, where this phase began in the late 1990s.) and has continued until now. Similar long-term phases are observed for river water temperature of considered rivers. Differences in heat flow reaches 20% during the phase of its increased and decreased values for the Northern Dvina and the Yenisei Rivers, but for other rivers they are not higher than 10%. Long-term changes of annual suspended sediment yield for the Yenisei and Lena Rivers are also characterized by two major long-term phases, which replaced each another in the 1970-1990. Differences in the suspended sediment yield during the increase and decrease phases reach 40% for Lena, whereas for Yenisei they are substantially less (10%). Anthropogenic factors (mainly water reservoirs) have significantly changed the characteristics of the long-term phases on the Yenisei River while their impact is not significant on other rivers. The long-term phases of decrease and increase of "conditionally natural" components of Arctic Rivers of Russia geo-runoff are closely associated with the indices zonal atmospheric air transport intensity.

Synthesis of a Novel Energetic Heterocyclic Oxidizer with Higher Energy and Lower Sensitivity (Phase 2) Final Report CRADA No. TC02125.0

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pagoria, P. F.; Racoveanu, A.

2017-09-08

This project was a continuation of work originally performed under a Phase 1 of the Small Business Technology Transfer (STIR). The success of the Phase 1 led to the award of a Phase 2 of the STIR. In Phase 1 of the STIR, the target energetic compound, 3,4-bis(4-nitro-l,2,5- oxadiazol-3yl)-1,2,5-oxadiazole-l-oxide (DNTF), was synthesized at the 5g scale and small-scale safety tests were performed. DNTF showed promising performance· and safety properties. DNTF was shown to be relatively insensitive while performing better than the current industry standard, H1vIX, in solid propellant formulations. Because of the successful research and development project involving PSI, LLNLmore » and Aerojet in Phase I of the STIR, the sponsors wanted to obtain larger quantities of DNTF for further testing.« less

Post hoc analysis of Japanese patients from the placebo-controlled PREVAIL trial of enzalutamide in patients with chemotherapy-naive, metastatic castration-resistant prostate cancer-updated results.

PubMed

Kimura, Go; Ueda, Takeshi

2017-03-01

A post hoc analysis of interim results from PREVAIL, a Phase III, double-blind, placebo-controlled trial of men with metastatic castration-resistant prostate cancer, demonstrated that the treatment effects, safety and pharmacokinetics of enzalutamide in Japanese patients were generally consistent with those of the overall population. A recent longer term analysis of PREVAIL demonstrated continued benefit of enzalutamide treatment over placebo. Here, we report results from a post hoc analysis of Japanese patients enrolled in PREVAIL at the prespecified number of deaths for the final analysis. In Japanese patients, enzalutamide reduced the risk of death by 35% (hazard ratio, 0.65; 95% confidence interval, 0.28-1.51) and the risk of investigator-assessed radiographic progression or death by 60% (hazard ratio, 0.40; 95% confidence interval, 0.18-0.90). These results show that treatment effects and safety in Japanese patients in the final analysis of PREVAIL continued to be generally consistent with those of the overall population. © The Author 2016. Published by Oxford University Press.

Post hoc analysis of Japanese patients from the placebo-controlled PREVAIL trial of enzalutamide in patients with chemotherapy-naive, metastatic castration-resistant prostate cancer—updated results

PubMed Central

Ueda, Takeshi

2017-01-01

Abstract A post hoc analysis of interim results from PREVAIL, a Phase III, double-blind, placebo-controlled trial of men with metastatic castration-resistant prostate cancer, demonstrated that the treatment effects, safety and pharmacokinetics of enzalutamide in Japanese patients were generally consistent with those of the overall population. A recent longer term analysis of PREVAIL demonstrated continued benefit of enzalutamide treatment over placebo. Here, we report results from a post hoc analysis of Japanese patients enrolled in PREVAIL at the prespecified number of deaths for the final analysis. In Japanese patients, enzalutamide reduced the risk of death by 35% (hazard ratio, 0.65; 95% confidence interval, 0.28–1.51) and the risk of investigator-assessed radiographic progression or death by 60% (hazard ratio, 0.40; 95% confidence interval, 0.18–0.90). These results show that treatment effects and safety in Japanese patients in the final analysis of PREVAIL continued to be generally consistent with those of the overall population. PMID:28003320

Safety profile of bilastine: 2nd generation H1-antihistamines.

PubMed

Scaglione, F

2012-12-01

Bilastine is a new H1 antagonist with no sedative side effects, no cardiotoxic effects, and no hepatic metabolism. In addition, bilastine has proved to be effective for the symptomatic treatment of allergic rhinoconjunctivitis and urticaria. Pharmacological studies have shown that bilastine is highly selective for the H1 receptor in both in vivo and in vitro studies, and with no apparent affinity for other receptors. The absorption of bilastine is fast, linear and dose-proportional; it appears to be safe and well tolerated at all doses levels in healthy population. Multiple administration of bilastine has confirmed the linearity of the kinetic parameters. The distribution in the brain is undetectable. The safety profile in terms of adverse effects is very similar to placebo in all Phase I, II and III clinical trials. Bilastine (20 mg), unlike cetirizine, does not increase alcohol effects on the CNS. Bilastine 20 mg does not increase the CNS depressant effect of lorazepam. Bilastine 20 mg is similar to placebo in the driving test. Therefore, it meets the current criteria for medication used in the treatment of allergic rhinitis and urticaria.

Corticotropin-releasing factor receptor-1 antagonism mitigates beta amyloid pathology and cognitive and synaptic deficits in a mouse model of Alzheimer's disease.

PubMed

Zhang, Cheng; Kuo, Ching-Chang; Moghadam, Setareh H; Monte, Louise; Campbell, Shannon N; Rice, Kenner C; Sawchenko, Paul E; Masliah, Eliezer; Rissman, Robert A

2016-05-01

Stress and corticotropin-releasing factor (CRF) have been implicated as mechanistically involved in Alzheimer's disease (AD), but agents that impact CRF signaling have not been carefully tested for therapeutic efficacy or long-term safety in animal models. To test whether antagonism of the type-1 corticotropin-releasing factor receptor (CRFR1) could be used as a disease-modifying treatment for AD, we used a preclinical prevention paradigm and treated 30-day-old AD transgenic mice with the small-molecule, CRFR1-selective antagonist, R121919, for 5 months, and examined AD pathologic and behavioral end points. R121919 significantly prevented the onset of cognitive impairment in female mice and reduced cellular and synaptic deficits and beta amyloid and C-terminal fragment-β levels in both genders. We observed no tolerability or toxicity issues in mice treated with R121919. CRFR1 antagonism presents a viable disease-modifying therapy for AD, recommending its advancement to early-phase human safety trials. Copyright © 2015 Alzheimer's Association. All rights reserved.