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  1. Nerve growth factor improves visual loss in childhood optic gliomas: a randomized, double-blind, phase II clinical trial.

    PubMed

    Falsini, Benedetto; Chiaretti, Antonio; Rizzo, Daniela; Piccardi, Marco; Ruggiero, Antonio; Manni, Luigi; Soligo, Marzia; Dickmann, Anna; Federici, Matteo; Salerni, Annabella; Timelli, Laura; Guglielmi, Gaspare; Lazzareschi, Ilaria; Caldarelli, Massimo; Galli-Resta, Lucia; Colosimo, Cesare; Riccardi, Riccardo

    2016-02-01

    Paediatric optic pathway gliomas are low-grade brain tumours characterized by slow progression and invalidating visual loss. Presently there is no strategy to prevent visual loss in this kind of tumour. This study evaluated the effects of nerve growth factor administration in protecting visual function in patients with optic pathway glioma-related visual impairment. A prospective randomized double-blind phase II clinical trial was conducted in 18 optic pathway glioma patients, aged from 2 to 23 years, with stable disease and severe visual loss. Ten patients were randomly assigned to receive a single 10-day course of 0.5 mg murine nerve growth factor as eye drops, while eight patients received placebo. All patients were evaluated before and after treatment, testing visual acuity, visual field, visual-evoked potentials, optic coherence tomography, electroretinographic photopic negative response, and magnetic resonance imaging. Post-treatment evaluations were repeated at 15, 30, 90, and 180 days Brain magnetic resonance imaging was performed at baseline and at 180 days. Treatment with nerve growth factor led to statistically significant improvements in objective electrophysiological parameters (electroretinographic photopic negative response amplitude at 180 days and visual-evoked potentials at 30 days), which were not observed in placebo-treated patients. Furthermore, in patients in whom visual fields could still be measured, visual field worsening was only observed in placebo-treated cases, while three of four nerve growth factor-treated subjects showed significant visual field enlargement. This corresponded to improved visually guided behaviour, as reported by the patients and/or the caregivers. There was no evidence of side effects related to nerve growth factor treatment. Nerve growth factor eye drop administration appears a safe, easy and effective strategy for the treatment of visual loss associated with optic pathway gliomas. PMID:26767384

  2. Antiretroviral effect of lovastatin on HIV-1-infected individuals without highly active antiretroviral therapy (The LIVE study): a phase-II randomized clinical trial

    PubMed Central

    Montoya, Carlos J; Jaimes, Fabian; Higuita, Edwin A; Convers-Páez, Sandra; Estrada, Santiago; Gutierrez, Francisco; Amariles, Pedro; Giraldo, Newar; Peñaloza, Cristina; Rugeles, Maria T

    2009-01-01

    Background Highly active antiretroviral therapy produces a significant decrease in HIV-1 replication and allows an increase in the CD4 T-cell count, leading to a decrease in the incidence of opportunistic infections and mortality. However, the cost, side effects and complexity of antiretroviral regimens have underscored the immediate need for additional therapeutic approaches. Statins exert pleiotropic effects through a variety of mechanisms, among which there are several immunoregulatory effects, related and unrelated to their cholesterol-lowering activity that can be useful to control HIV-1 infection. Methods/design Randomized, double-blinded, placebo controlled, single-center, phase-II clinical trial. One hundred and ten chronically HIV-1-infected patients, older than 18 years and naïve for antirretroviral therapy (i.e., without prior or current management with antiretroviral drugs) will be enrolled at the outpatient services from the most important centres for health insurance care in Medellin-Colombia. The interventions will be lovastatin (40 mg/day, orally, for 12 months; 55 patients) or placebo (55 patients). Our primary aim will be to determine the effect of lovastatin on viral replication. The secondary aim will be to determine the effect of lovastatin on CD4+ T-cell count in peripheral blood. As tertiary aims we will explore differences in CD8+ T-cell count, expression of activation markers (CD38 and HLA-DR) on CD4 and CD8 T cells, cholesterol metabolism, LFA-1/ICAM-1 function, Rho GTPases function and clinical evolution between treated and not treated HIV-1-infected individuals. Discussion Preliminary descriptive studies have suggested that statins (lovastatin) may have anti HIV-1 activity and that their administration is safe, with the potential effect of controlling HIV-1 replication in chronically infected individuals who had not received antiretroviral medications. Considering that there is limited clinical data available on this topic, all these

  3. A Multicenter, Phase II, Randomized, Noncomparative Clinical Trial of Radiation and Temozolomide with or without Vandetanib in Newly Diagnosed Glioblastoma Patients

    PubMed Central

    Lee, Eudocia Q.; Kaley, Thomas J.; Duda, Dan G.; Schiff, David; Lassman, Andrew B.; Wong, Eric T.; Mikkelsen, Tom; Purow, Benjamin W.; Muzikansky, Alona; Ancukiewicz, Marek; Huse, Jason T.; Ramkissoon, Shakti; Drappatz, Jan; Norden, Andrew D.; Beroukhim, Rameen; Weiss, Stephanie E.; Alexander, Brian M.; McCluskey, Christine S.; Gerard, Mary; Smith, Katrina H.; Jain, Rakesh K.; Batchelor, Tracy T.; Ligon, Keith L.; Wen, Patrick Y.

    2016-01-01

    Purpose Vandetanib, a tyrosine kinase inhibitor of KDR (VEGFR2), EGFR, and RET, may enhance sensitivity to chemotherapy and radiation. We conducted a randomized, noncomparative, phase II study of radiation (RT) and temozolomide with or without vandetanib in patients with newly diagnosed glioblastoma (GBM). Experimental Design We planned to randomize a total of 114 newly diagnosed GBM patients in a ratio of 2:1 to standard RT and temozolomide with (76 patients) or without (38 patients) vandetanib 100 mg daily. Patients with age ≥ 18 years, Karnofsky performance status (KPS) ≥ 60, and not on enzyme-inducing antiepileptics were eligible. Primary end-point was median overall survival (OS) from the date of randomization. Secondary endpoints included median progression-free survival (PFS), 12-month PFS, and safety. Correlative studies included pharmacokinetics as well as tissue and serum biomarker analysis. Results The study was terminated early for futility based on the results of an interim analysis. We enrolled 106 patients (36 in the RT/temozolomide arm and 70 in the vandetanib/RT/temozolomide arm). Median OS was 15.9 months [95% confidence interval (CI), 11.0–22.5 months] in the RT/temozolomide arm and 16.6 months (95% CI, 14.9–20.1 months) in the vandetanib/RT/temozolomide (log-rank P = 0.75). Conclusions The addition of vandetanib at a dose of 100 mg daily to standard chemoradiation in patients with newly diagnosed GBM or gliosarcoma was associated with potential pharmacodynamic biomarker changes and was reasonably well tolerated. However, the regimen did not significantly prolong OS compared with the parallel control arm, leading to early termination of the study. PMID:25910950

  4. Randomized Phase II Trials: A Long-term Investment With Promising Returns

    PubMed Central

    Sharma, Manish R.; Stadler, Walter M.

    2011-01-01

    Given the multitude of novel anticancer drugs and the limited resources available to study them, phase II trials should identify drugs with the highest probability of succeeding in subsequent phase III trials. Currently, single-arm phase II trial results are interpreted relative to historical control subjects, introducing selection bias and confounding that may limit the validity of the conclusions. The rate of success (defined as a statistically significant difference between arms) in phase III oncology trials is only 40%, suggesting that current phase II trials are insufficiently informative. However, simulation studies suggest that randomized phase II trials would have lower error rates and greater predictive power for phase III results. Randomized phase II trials may also be more informative than single-arm phase II trials because of the hypotheses being tested, the variety of possible endpoints, and the opportunities for biomarker discovery. There are a wide variety of randomized phase II designs that can be used, including the randomized discontinuation design, the delayed-start design, adaptive (Bayesian) designs, selection designs, and phase II/III designs. The barriers to widespread adoption of randomized phase II trials include time to completion, sample size considerations, and ethical concerns, but none are insurmountable. We conclude that randomized phase II trials are a worthy investment considering finite patient and financial resources and should be the rule rather than the exception for evaluating novel therapies in oncology. PMID:21709274

  5. Comparison between nedaplatin and cisplatin plus docetaxel combined with intensity-modulated radiotherapy for locoregionally advanced nasopharyngeal carcinoma: a multicenter randomized phase II clinical trial

    PubMed Central

    Tang, Chunyuan; Wu, Fang; Wang, Rensheng; Lu, Heming; Li, Guisheng; Liu, Meilian; Zhu, Haisheng; Zhu, Jinxian; Zhang, Yong; Hu, Kai

    2016-01-01

    Nasopharyngeal carcinoma (NPC) is highly incident in southern China. Metastasis is the major cause of death in NPC patients. Concurrent chemoradiotherapy (CCRT) has been accepted as standard in the treatment of patients with locoregionally advanced nasopharyngeal carcinoma (NPC). However, induction chemotherapy (IC) also has benefits in this disease, especially in the patients with certain high-risk factors such as bulky and/or extensive nodal disease. It has been presented that adding IC to CCRT might be a reasonable approach and need more work to confirm. The optimal chemotherapeutic regimen combined with radiotherapy has not been determined so far. It is important to explore high effective and low toxic chemotherapy for the patients. In the multicenter prospective study, 223 patients with locoregionally advanced untreated NPC were randomized into experimental group and control group. The patients received two cycles of induction chemotherapy (IC) with docetaxel (DOC) plus nedaplatin (NDP) in experimental group every 3 weeks, followed by IMRT concurrent with weekly NDP for six cycles, and NDP was replaced by cisplatin (CDDP) in control group. More patients in experimental group could receive full courses of IC and concurrent chemoradiotherapy (CCRT) (P=0.013). There was no significant difference between the two groups in the percentage of reduction of GTVnx and GTVnd after IC (P=0.207 and P=0.107) and CR rate three months after completion of chemoradiotherapy (P=0.565 and P=0.738). With a mean follow-up of 35.1 months, no statistically significant difference in the 3-year OS, LRFS, RRFS, DMFS, and PFS was found. During IC, more patients suffered vomiting in control group (P=0.001). During CCRT, grade 3/4 neutropenia/thrombocytopenia were more common in experimental group (P=0.028 and P=0.035); whereas, severe anemia and vomiting were more common in control group (P=0.0001 and P=0.023). In conclusions, patients with locoregionally advanced NPC showed good

  6. A Phase II/III Randomized, Placebo-Controlled, Double-Blind Clinical Trial of Ginger (Zingiber officinale) for Nausea Caused by Chemotherapy for Cancer: A Currently Accruing URCC CCOP Cancer Control Study.

    PubMed

    Hickok, Jane T; Roscoe, Joseph A; Morrow, Gary R; Ryan, Julie L

    2007-09-01

    Despite the widespread use of 5-HT3 receptor antagonist antiemetics such as ondansetron and granistron, up to 70% of patients with cancer receiving highly emetogenic chemotherapy agents experience postchemotherapy nausea and vomiting. Delayed postchemotherapy nausea (nausea that occurs >/= 24 hours after chemotherapy administration) and anticipatory nausea (nausea that develops before chemotherapy administration, in anticipation of it) are poorly controlled by currently available antiemetic agents. Scientific studies suggest that ginger (Zingiber officinale) might have beneficial effects on nausea and vomiting associated with motion sickness, surgery, and pregnancy. In 2 small studies of patients with cancer receiving chemotherapy, addition of ginger to standard antiemetic medication further reduced the severity of postchemotherapy nausea. This article describes a phase II/III randomized, dose-finding, placebo-controlled, double-blind clinical trial to assess the efficacy of ginger for nausea associated with chemotherapy for cancer. The study is currently being conducted by private practice oncology groups that are funded by the National Cancer Institute's Community Clinical Oncology Program and affiliated with the University of Rochester Cancer Center Community Clinical Oncology Program Research Base. PMID:18632524

  7. Inhaled Nitric Oxide as an Adjunctive Treatment for Cerebral Malaria in Children: A Phase II Randomized Open-Label Clinical Trial

    PubMed Central

    Mwanga-Amumpaire, Juliet; Carroll, Ryan W.; Baudin, Elisabeth; Kemigisha, Elisabeth; Nampijja, Dorah; Mworozi, Kenneth; Santorino, Data; Nyehangane, Dan; Nathan, Daniel I.; De Beaudrap, Pierre; Etard, Jean-François; Feelisch, Martin; Fernandez, Bernadette O.; Berssenbrugge, Annie; Bangsberg, David; Bloch, Kenneth D.; Boum, Yap; Zapol, Warren M.

    2015-01-01

    Background. Children with cerebral malaria (CM) have high rates of mortality and neurologic sequelae. Nitric oxide (NO) metabolite levels in plasma and urine are reduced in CM. Methods. This randomized trial assessed the efficacy of inhaled NO versus nitrogen (N2) as an adjunctive treatment for CM patients receiving intravenous artesunate. We hypothesized that patients treated with NO would have a greater increase of the malaria biomarker, plasma angiopoietin-1 (Ang-1) after 48 hours of treatment. Results. Ninety-two children with CM were randomized to receive either inhaled 80 part per million NO or N2 for 48 or more hours. Plasma Ang-1 levels increased in both treatment groups, but there was no difference between the groups at 48 hours (P = not significant [NS]). Plasma Ang-2 and cytokine levels (tumor necrosis factor-α, interferon-γ, interleukin [IL]-1β, IL-6, IL-10, and monocyte chemoattractant protein-1) decreased between inclusion and 48 hours in both treatment groups, but there was no difference between the groups (P = NS). Nitric oxide metabolite levels—blood methemoglobin and plasma nitrate—increased in patients treated with NO (both P < .05). Seven patients in the N2 group and 4 patients in the NO group died. Five patients in the N2 group and 6 in the NO group had neurological sequelae at hospital discharge. Conclusions. Breathing NO as an adjunctive treatment for CM for a minimum of 48 hours was safe, increased blood methemoglobin and plasma nitrate levels, but did not result in a greater increase of plasma Ang-1 levels at 48 hours. PMID:26309894

  8. A single blind randomized controlled clinical trial of mexiletine in amyotrophic lateral sclerosis: Efficacy and safety of sodium channel blocker phase II trial.

    PubMed

    Shibuya, Kazumoto; Misawa, Sonoko; Kimura, Hideki; Noto, Yu-Ichi; Sato, Yasunori; Sekiguchi, Yukari; Iwai, Yuta; Mitsuma, Satsuki; Beppu, Minako; Watanabe, Keisuke; Fujimaki, Yumi; Tsuji, Yukiko; Shimizu, Toshio; Mizuno, Toshiki; Nakagawa, Masanori; Sawaguchi, Kyoko; Hanaoka, Hideki; Kuwabara, Satoshi

    2015-01-01

    Fasciculations are characteristic features of amyotrophic lateral sclerosis (ALS), and suggest motor nerve hyperexcitability. Recent reports have shown that an increase in persistent nodal sodium current is associated with shorter survival in ALS patients. This objective of this trial is to study the efficacy and safety of mexiletine, a sodium channel blocker, for ALS. Sixty eligible participants were randomly allocated (1:1) to riluzole 100 mg or riluzole plus mexiletine 300 mg. The primary endpoint was change in the revised ALS functional rating scale (ALSFRS-R) scores during six months. We also monitored strength-duration time constant (SDTC, a measure of persistent sodium current) in median motor axons. Results showed that during six months of treatment, changes in the ALSFRS-R score and SDTC were -7.0 ± 7.1 and -0.04 ± 0.1, respectively, in the riluzole group and -6.9 ± 6.4 and 0.04 ± 0.1, respectively, in the mexiletine group (p = 0.96 and 0.049). Adverse events amounted 20% in the riluzole and 33% in the mexiletine groups. In conclusion, the results suggest that daily 300 mg mexiletine has no effects on axonal sodium current and ALSFRS-R deterioration in ALS. We have to attempt another trial using a higher dose of mexiletine or other agents to suppress sodium currents and ALS progression in the future. PMID:25960085

  9. A randomized Phase II trial of systemic chemotherapy with and without trastuzumab followed by surgery in HER2-positive advanced gastric or esophagogastric junction adenocarcinoma with extensive lymph node metastasis: Japan Clinical Oncology Group study JCOG1301 (Trigger Study).

    PubMed

    Kataoka, Kozo; Tokunaga, Masanori; Mizusawa, Junki; Machida, Nozomu; Katayama, Hiroshi; Shitara, Kohei; Tomita, Toshihiko; Nakamura, Kenichi; Boku, Narikazu; Sano, Takeshi; Terashima, Masanori; Sasako, Mitsuru

    2015-11-01

    Pre-operative chemotherapy with S-1 plus cisplatin is considered to be acceptable as one of the standard treatment options for gastric cancer patients with extensive lymph node metastases in Japan. Addition of trastuzumab to chemotherapy is shown to be effective for HER2-positive advanced gastric cancer patients, and we have commenced a randomized Phase II trial in March 2015 to evaluate S-1 plus cisplatin plus trastuzumab compared with S-1 plus cisplatin alone in the neoadjuvant setting for HER2-positive gastric cancer patients with ELM, which are followed by adjuvant chemotherapy with S-1 for 1 year. A total of 130 patients will be accrued from 41 Japanese institutions over 3 years. The primary endpoint is overall survival. The secondary endpoints are progression-free survival, response rate of pre-operative chemotherapy, proportion of patients with R0 resection, proportion of patients who complete the pre-operative chemotherapy and surgery, proportion of patients who complete the protocol treatment including post-operative chemotherapy, pathological response rate and adverse events. This trial has been registered in the UMIN Clinical Trials Registry as UMIN 000016920.

  10. Adaptive two-stage designs in phase II clinical trials.

    PubMed

    Banerjee, Anindita; Tsiatis, Anastasios A

    2006-10-15

    Two-stage designs have been widely used in phase II clinical trials. Such designs are desirable because they allow a decision to be made on whether a treatment is effective or not after the accumulation of the data at the end of each stage. Optimal fixed two-stage designs, where the sample size at each stage is fixed in advance, were proposed by Simon when the primary outcome is a binary response. This paper proposes an adaptive two-stage design which allows the sample size at the second stage to depend on the results at the first stage. Using a Bayesian decision-theoretic construct, we derive optimal adaptive two-stage designs; the optimality criterion being minimum expected sample size under the null hypothesis. Comparisons are made between Simon's two-stage fixed design and the new design with respect to this optimality criterion. PMID:16479547

  11. Cabozantinib in Patients With Advanced Prostate Cancer: Results of a Phase II Randomized Discontinuation Trial

    PubMed Central

    Smith, David C.; Smith, Matthew R.; Sweeney, Christopher; Elfiky, Aymen A.; Logothetis, Christopher; Corn, Paul G.; Vogelzang, Nicholas J.; Small, Eric J.; Harzstark, Andrea L.; Gordon, Michael S.; Vaishampayan, Ulka N.; Haas, Naomi B.; Spira, Alexander I.; Lara, Primo N.; Lin, Chia-Chi; Srinivas, Sandy; Sella, Avishay; Schöffski, Patrick; Scheffold, Christian; Weitzman, Aaron L.; Hussain, Maha

    2013-01-01

    Purpose Cabozantinib (XL184) is an orally bioavailable tyrosine kinase inhibitor with activity against MET and vascular endothelial growth factor receptor 2. We evaluated the activity of cabozantinib in patients with castration-resistant prostate cancer (CRPC) in a phase II randomized discontinuation trial with an expansion cohort. Patients and Methods Patients received 100 mg of cabozantinib daily. Those with stable disease per RECIST at 12 weeks were randomly assigned to cabozantinib or placebo. Primary end points were objective response rate at 12 weeks and progression-free survival (PFS) after random assignment. Results One hundred seventy-one men with CRPC were enrolled. Random assignment was halted early based on the observed activity of cabozantinib. Seventy-two percent of patients had regression in soft tissue lesions, whereas 68% of evaluable patients had improvement on bone scan, including complete resolution in 12%. The objective response rate at 12 weeks was 5%, with stable disease in 75% of patients. Thirty-one patients with stable disease at week 12 were randomly assigned. Median PFS was 23.9 weeks (95% CI, 10.7 to 62.4 weeks) with cabozantinib and 5.9 weeks (95% CI, 5.4 to 6.6 weeks) with placebo (hazard ratio, 0.12; P < .001). Serum total alkaline phosphatase and plasma cross-linked C-terminal telopeptide of type I collagen were reduced by ≥ 50% in 57% of evaluable patients. On retrospective review, bone pain improved in 67% of evaluable patients, with a decrease in narcotic use in 56%. The most common grade 3 adverse events were fatigue (16%), hypertension (12%), and hand-foot syndrome (8%). Conclusion Cabozantinib has clinical activity in men with CRPC, including reduction of soft tissue lesions, improvement in PFS, resolution of bone scans, and reductions in bone turnover markers, pain, and narcotic use. PMID:23169517

  12. Evaluation of immunogenicity and safety of the new tetanus-reduced diphtheria (Td) vaccines (GC1107) in healthy Korean adolescents: a phase II, double-blind, randomized, multicenter clinical trial.

    PubMed

    Rhim, Jung-Woo; Lee, Kyung-Yil; Kim, Sang-Yong; Kim, Jong-Hyun; Kim, Hyun-Hee; Kim, Hwang Min; Choi, Young-Youn; Ma, Sang-Hyuk; Kim, Dong-Ho; Ahn, Dong Ho; Kang, Jin-Han

    2013-04-01

    This phase II clinical trial was conducted to compare the immunogenicity and safety of a newly developed tetanus-reduced diphtheria (Td) vaccine (GC1107-T5.0 and GC1107-T7.5) and control vaccine. This study was also performed to select the proper dose of tetanus toxoid in the new Td vaccines. Healthy adolescents aged between 11 and 12 yr participated in this study. A total of 130 subjects (44 GC1107-T5.0, 42 GC1107-T7.5 and 44 control vaccine) completed a single dose of vaccination. Blood samples were collected from the subjects before and 4 weeks after the vaccination. In this study, all subjects (100%) in both GC1107-T5.0 and GC1107-T7.5 groups showed seroprotective antibody levels (≥ 0.1 U/mL) against diphtheria or tetanus toxoids. After the vaccination, the geometric mean titer (GMT) against diphtheria was significantly higher in Group GC1107-T5.0 (6.53) and GC1107-T7.5 (6.11) than in the control group (3.96). The GMT against tetanus was 18.6 in Group GC1107-T5.0, 19.94 in GC1107-T7.5 and 19.01 in the control group after the vaccination. In this study, the rates of local adverse reactions were 67.3% and 59.1% in GC1107-T5.0 and GC1107-7.5, respectively. No significant differences in the number of adverse reactions, prevalence and degree of severity of the solicited and unsolicited adverse reactions were observed among the three groups. Thus, both newly developed Td vaccines appear to be safe and show good immunogenicity. GC1107-T5.0, which contains relatively small amounts of tetanus toxoid, has been selected for a phase III clinical trial.

  13. Phase II clinical trials on Investigational drugs for the Treatment of Pancreatic Cancers

    PubMed Central

    Kim, Edward J.; Semrad, Thomas J.; Bold, Richard J.

    2015-01-01

    Introduction Despite some recent advances in treatment options, pancreatic cancer remains a devastating disease with poor outcomes. In a trend contrary to most malignancies, both incidence and mortality continue to rise due to pancreatic cancer. The majority of patients present with advanced disease and there are no treatment options for this stage that have demonstrated a median survival greater than 1 year. As the penultimate step prior to phase III studies involving hundreds of patients, phase II clinical trials provide an early opportunity to evaluate the efficacy of new treatments that are desperately needed for this disease. Areas Covered This review covers the results of published phase II clinical trials in advanced pancreatic adenocarcinoma published within the past 5 years. The treatment results are framed in the context of the current standards of care and the historic challenge of predicting phase III success from phase II trial results. Expert opinion Promising therapies remain elusive in pancreatic cancer based on recent phase II clinical trial results. Optimization and standardization of clinical trial design in the phase II setting, with consistent incorporation of biomarkers, is needed to more accurately identify promising therapies that warrant phase III evaluation. PMID:25809274

  14. Randomized Phase II Trial of Lyophilized Strawberries in Patients with Dysplastic Precancerous Lesions of the Esophagus

    PubMed Central

    Chen, Tong; Yan, Fei; Qian, Jiaming; Guo, Mingzhou; Zhang, Hongbing; Tang, Xiaofei; Chen, Fang; Stoner, Gary D.; Wang, Xiaomin

    2016-01-01

    Dysplasia is a histologic precursor of esophageal squamous cell carcinoma (SCC). We previously showed that dietary freeze-dried, or lyophilized, strawberry powder inhibits N-nitrosomethylbenzylamine-induced SCC in the rat esophagus. On the basis of this observation, we conducted a randomized (noncomparative) phase II trial in China to investigate the effects of two doses of freeze-dried strawberries in patients with esophageal dysplastic lesions in a high-risk area for esophageal cancer. We randomly assigned 75 patients identified by endoscopy to have dysplastic esophageal premalignant lesions to receive freeze-dried strawberry powder at either 30 g/d (37 patients) or 60 g/d (38 patients) for six months; the powder was mixed with water and drunk. After six months, we assessed the changes in histologic grade of these lesions (primary endpoint) in a blinded fashion. The dose of 30 g/d, did not significantly affect histology or any other measured parameter. The dose of 60 g/d, however, reduced the histologic grade of dysplastic premalignant lesions in 29 (80.6%) of the 36 patients at this dose who were evaluated for histology (P < 0.0001). The strawberry powder was well tolerated, with no toxic effects or serious adverse events. Strawberries (60 g/d) also reduced protein expression levels of inducible nitric oxide synthase (iNOS) by 79.5% (P < 0.001), cyclooxygenase-2 (COX-2) by 62.9% (P < 0.001), phospho-nuclear factor kappa B (NFκB)-p65 (pNFκB-p65) by 62.6% (P < 0.001), and phospho-S6 (pS6) by 73.2% (P < 0.001). Freeze-dried strawberries (60 g/d) also significantly inhibited the Ki-67 labeling index by 37.9% (P = 0.023). Our present results indicate the potential of freeze-dried strawberry powder for preventing human esophageal cancer, supporting further clinical testing of this natural agent in this setting. PMID:22135048

  15. Web-based data management for a phase II clinical trial in ALS.

    PubMed

    Buchsbaum, Richard; Kaufmann, Petra; Barsdorf, Alexandra I; Arbing, Rachel; Montes, Jacqueline; Thompson, John L P

    2009-01-01

    The objective was to report on the creation, features and performance of a web-based data management system for a two-stage phase II randomized clinical trial of Co-Enzyme Q10 in ALS. We created a relatively comprehensive web-based data system that provided electronic data entry; patient management utilities; adverse event reporting, safety monitoring, and invoice generation; and standardized coding for medications and adverse events. In stage 1, clinical sites submitted 7207 forms reporting on 105 patients followed for 10 months. Less than 0.7% of submitted forms contained errors. At the time of the delivery of the analysis data set, only four errors remained unresolved. Data were available quickly, with a median time from event to data posting of two days. The data set was locked and the analysis data set produced nine days after the final patient visit. A survey of trial personnel yielded generally positive feedback, with 75% of respondents wishing to use a similar system in the future. Given sufficient resources, a comprehensive web-based data management system can meet the need for clean, available data in clinical trials in ALS and similar diseases, and can contribute significantly to their efficient execution. PMID:19922127

  16. Optimal and minimax three-stage designs for phase II oncology clinical trials.

    PubMed

    Chen, Kun; Shan, Michael

    2008-01-01

    The common objective of oncology phase II trials is to evaluate the anti-tumor activity of a new agent and to determine whether the new drug warrants further investigation. For cancer drugs that significantly shrink tumors, response (CR and PR) rate is usually the primary endpoint in cancer phase II trials for testing H(0): Por=P(1), where P(0) and P(1) are response rates which does not or does warrant further investigation given the rate of false positive (alpha) and false negative (beta). Multiple-stage designs including two-stage and three-stage have been developed by several authors. For example, Simon's optimal two-stage design [Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials 1989;10:1-10], Ensign et al. optimal three-stage design with restriction at the first stage [Ensign LG, Gehan EA, Kamen DS, Thall PF. An optimal three-stage design for phase II clinical trials. Stat Med 1994;13:1727-1736], Chen's optimal three-stage design without any restriction [Chen TT. Optimal three-stage designs for phase II clinical trials. Stat Med 1997;16:2701-2711], etc. However, all the above designs only early terminate a trial due to lack of activity of the study drug. Fleming's multiple-stage design [Fleming TR. One-sample multiple testing procedure for phase II clinical trials. Biometrics 1982;38:143-151] allows early stopping for either sufficient activity or lack of activity. But his design does not attempt to optimize its efficiency. We extend Chen's [Chen TT. Optimal three-stage designs for phase II clinical trials Stat Med 1997;16:2701-2711] design and propose an optimal and a minimax design for three-stage cancer phase II trials which allows early stopping under both hypotheses. The design is optimal in the sense that the average sample number (ASN) is minimized under P=P(0). The minimax design minimizes the maximal sample size (N) and then given this value of N minimizes the average sample number under P=P(0

  17. Phase II randomized clinical trial evaluating neoadjuvant chemotherapy regimens with weekly paclitaxel or eribulin followed by doxorubicin and cyclophosphamide in women with locally advanced HER2-negative breast cancer: NSABP Foundation Study FB-9.

    PubMed

    Abraham, Jame; Robidoux, André; Tan, Antoinette R; Limentani, Steven; Sturtz, Keren; Shalaby, Ibrahim; Alcorn, Hope; Buyse, Marc E; Wolmark, Norman; Jacobs, Samuel A

    2015-07-01

    Locally advanced breast cancer (LABC) is a good setting in which to monitor response to neoadjuvant chemotherapy, to downsize the tumor (which facilitates breast-conserving surgery), and to test newer agents in untreated patients. Eribulin (E) has shown activity in patients who have undergone previous taxane, anthracycline, and capecitabine treatment. We aimed to evaluate the neoadjuvant use of E followed by doxorubicin and cyclophosphamide (AC) in patients with HER2-negative LABC, using as a control a randomized group of women who received weekly paclitaxel (WP). Fifty women with LABC were accrued January-August 2013. Patients were randomized (1:2) to receive either WP (N = 19) for 12 treatments or E (N = 31) every 3 weeks for 4 cycles followed by AC every 3 weeks for 4 cycles before surgery. 17/19 patients who took WP and 25/30 who took E completed all cycles. Patients were evaluated by clinical examination and breast MRI at baseline and after completion of E or WP. Surgical pCR in breast and lymph nodes was determined by a local pathologist following chemotherapy. Forty-nine patients received ≥1 dose of neoadjuvant chemotherapy and are included in this analysis. Forty-eight underwent surgery; one had disease that was inoperable (on E) and is included as no-pCR patient. 17/19 of these patients who took WP completed 12 doses; 28/30 on E completed 4 cycles. Six discontinued treatment on WP, E, or AC. Both treatments were well tolerated. pCR on WP = 5/19(26 %) and on E = 5/30(17 %). Both regimens were equally well tolerated with no unexpected toxicities. pCR did not suggest higher activity with E than with other standard regimens in these LABC patients.

  18. Flexible designs for phase II comparative clinical trials involving two response variables.

    PubMed

    Bersimis, S; Sachlas, A; Papaioannou, T

    2015-01-30

    The aim of phase II clinical trials is to determine whether an experimental treatment is sufficiently promising and safe to justify further testing. The need for reduced sample size arises naturally in phase II clinical trials owing to both technical and ethical reasons, motivating a significant part of research in the field during recent years, while another significant part of the research effort is aimed at more complex therapeutic schemes that demand the consideration of multiple endpoints to make decisions. In this paper, our attention is restricted to phase II clinical trials in which two treatments are compared with respect to two dependent dichotomous responses proposing some flexible designs. These designs permit the researcher to terminate the clinical trial when high rates of favorable or unfavorable outcomes are observed early enough requiring in this way a small number of patients. From the mathematical point of view, the proposed designs are defined on bivariate sequences of multi-state trials, and the corresponding stopping rules are based on various distributions related to the waiting time until a certain number of events appear in these sequences. The exact distributions of interest, under a unified framework, are studied using the Markov chain embedding technique, which appears to be very useful in clinical trials for the sample size determination. Tables of expected sample size and power are presented. The numerical illustration showed a very good performance for these new designs.

  19. A randomized phase II study of pomegranate extract for men with rising PSA following initial therapy for localized prostate cancer

    PubMed Central

    Paller, CJ; Ye, X; Wozniak, PJ; Gillespie, BK; Sieber, PR; Greengold, RH; Stockton, BR; Hertzman, BL; Efros, MD; Roper, RP; Liker, HR; Carducci, MA

    2012-01-01

    BACKGROUND Pomegranate juice has been associated with PSA doubling time (PSADT) elongation in a single-arm phase II trial. This study assesses biological activity of two doses of pomegranate extract (POMx) in men with recurrent prostate cancer, using changes in PSADT as the primary outcome. METHODS This randomized, multi-center, double-blind phase II, dose-exploring trial randomized men with a rising PSA and without metastases to receive 1 or 3 g of POMx, stratified by baseline PSADT and Gleason score. Patients (104) were enrolled and treated for up to 18 months. The intent-to-treat (ITT) population was 96% white, with median age 74.5 years and median Gleason score 7. This study was designed to detect a 6-month on-study increase in PSADT from baseline in each arm. RESULTS: Overall, median PSADT in the ITT population lengthened from 11.9 months at baseline to 18.5 months after treatment (P<0.001). PSADT lengthened in the low-dose group from 11.9 to 18.8 months and 12.2 to 17.5 months in the high-dose group, with no significant difference between dose groups (P =0.554). PSADT increases >100% of baseline were observed in 43% of patients. Declining PSA levels were observed in 13 patients (13%). In all, 42% of patients discontinued treatment before meeting the protocol-definition of PSA progression, or 18 months, primarily due to a rising PSA. No significant changes occurred in testosterone. Although no clinically significant toxicities were seen, diarrhea was seen in 1.9% and 13.5% of patients in the 1- and 3-g dose groups, respectively. CONCLUSIONS POMx treatment was associated with ≥6 month increases in PSADT in both treatment arms without adverse effects. The significance of this on-study slowing of PSADT remains unclear, reinforcing the need for placebo-controlled studies in this patient population. PMID:22689129

  20. Resampling the N9741 Trial to Compare Tumor Dynamic Versus Conventional End Points in Randomized Phase II Trials

    PubMed Central

    Sharma, Manish R.; Gray, Elizabeth; Goldberg, Richard M.; Sargent, Daniel J.; Karrison, Theodore G.

    2015-01-01

    Purpose The optimal end point for randomized phase II trials of anticancer therapies remains controversial. We simulated phase II trials by resampling patients from N9741, a randomized phase III trial of chemotherapy regimens for metastatic colorectal cancer, and compared the power of various end points to detect the superior therapy (FOLFOX [infusional fluorouracil, leucovorin, and oxaliplatin] had longer overall survival than both IROX [irinotecan plus oxaliplatin] and IFL [irinotecan and bolus fluorouracil plus leucovorin]). Methods Tumor measurements and progression-free survival (PFS) data were obtained for 1,471 patients; 1,002 had consistently measured tumors and were resampled (5,000 replicates) to simulate two-arm, randomized phase II trials with α = 0.10 (one sided) and 20 to 80 patients per arm. End points included log ratio of tumor size at 6, 12, and 18 weeks relative to baseline; time to tumor growth (TTG), estimated using a nonlinear mixed-effects model; and PFS. Arms were compared using rank sum tests for log ratio and TTG and a log-rank test for PFS. Results For FOLFOX versus IFL, TTG and PFS had similar power, with both exceeding the power of log ratio at 18 weeks; for FOLFOX versus IROX, TTG and log ratio at 18 weeks had similar power, with both exceeding the power of PFS. The best end points exhibited > 80% power with 60 to 80 patients per arm. Conclusion TTG is a powerful end point for randomized phase II trials of cytotoxic therapies in metastatic colorectal cancer; it was either comparable or superior to PFS and log ratio at 18 weeks. Additional studies will be needed to clarify the potential of TTG as a phase II end point. PMID:25349295

  1. Raising the bar for enthusiasm when looking at results of randomized phase II trials-the case of sunitinib in small-cell lung cancer.

    PubMed

    Di Maio, Massimo; Bironzo, Paolo; Scagliotti, Giorgio Vittorio

    2016-02-01

    With the advent of targeted agents, randomized phase II trials designed with explicit comparative intent, to allow a better interpretation of the results obtained with experimental treatment, have become a common approach for anti-cancer drug development. In the Cancer and Leukemia Group B (CALGB) 30504 randomized phase II trial, patients with extensive-stage small-cell lung cancer (SCLC), without progression after four to six cycles of standard chemotherapy with cisplatin or carboplatin plus etoposide, were randomized to sunitinib or placebo, until disease progression. Primary endpoint of the study was progression-free survival (PFS), and the results were formally positive [hazard ratio (HR) 0.62; one-sided P=0.02]. However, the prognosis of patients with extensive-stage SCLC is particularly bad, and even a relevant relative benefit (i.e., an encouraging HR) will likely correspond to a debatable absolute benefit: the difference in median PFS between patients treated with sunitinib and patients assigned to control arm was slightly higher than 1.5 months. Is this difference in median PFS big enough to predict a clinically relevant benefit in overall survival? Unfortunately, we do not know. From a "clinical" point of view, is this small absolute improvement in PFS relevant enough to further invest in the strategy? Probably not, also considering the absence of known predictive factors. If the results of the phase II trial had been really promising, the subsequent phase III study should have been promptly conducted, but this was not the case. It seems that, this time, the bar for enthusiasm was already raised in the phase II setting.

  2. Does Early Postsurgical Temozolomide Plus Concomitant Radiochemotherapy Regimen Have Any Benefit in Newly-diagnosed Glioblastoma Patients? A Multi-center, Randomized, Parallel, Open-label, Phase II Clinical Trial

    PubMed Central

    Mao, Ying; Yao, Yu; Zhang, Li-Wei; Lu, Yi-Cheng; Chen, Zhong-Ping; Zhang, Jian-Min; Qi, Song-Tao; You, Chao; Wang, Ren-Zhi; Yang, Shu-Yuan; Zhang, Xiang; Wang, Ji-Sheng; Chen, Ju-Xiang; Yang, Qun-Ying; Shen, Hong; Li, Zhi-Yong; Wang, Xiang; Ma, Wen-Bin; Yang, Xue-Jun; Zhen, Hai-Ning; Zhou, Liang-Fu

    2015-01-01

    Background: The radiochemotherapy regimen concomitantly employing temozolomide (TMZ) chemotherapy and radiotherapy (RT) 4 weeks after surgery, followed by 6 cycles of TMZ is a common treatment for glioblastoma (GBM). However, its median overall survival (OS) is only 14.6 months. This study was to explore the effectiveness and safety of early TMZ chemotherapy between surgery and chemoradiotherapy plus the standard concomitant radiochemotherapy regimen. Methods: A randomized, parallel group, open-label study of 99 newly diagnosed GBM patients was conducted at 10 independent Chinese neurosurgical departments from June 2008 to June 2012. Patients were treated with concomitant radiochemotherapy regimen plus early postsurgical temozolomide (early TMZ group) or standard concomitant radiochemotherapy regimen (control group). Overall response was assessed based on objective tumor assessments, administration of corticosteroid and neurological status test. Hematological, biochemical, laboratory, adverse event (AE), and neurological condition were measured for 24 months of follow-up. The primary efficacy endpoint of this study was overall survival (OS). The secondary endpoint was progression free survival (PFS). Results: The median OS time in the early TMZ group was 17.6 months, compared with 13.2 months in the control group (log-rank test P = 0.021). In addition, the OS rate in the early TMZ group was higher at 6, 12, and 18 months than in the control group, respectively (P < 0.05). The median PFS time was 8.7 months in the early TMZ group and 10.4 months in the control group (log-rank test P = 0.695). AEs occurred in 29 (55.8%) and 31(73.8%) patients respectively in early and control groups, including nausea (15.4% vs. 33.3%), vomiting (7.7% vs. 28.6%), fever (7.7% vs. 11.9%), and headache (3.8% vs. 23.8%). Only 30.8% and 33.3% were drug-related, respectively. Conclusions: Addition of TMZ chemotherapy in the early break of the standard concomitant radiochemotherapy regimen

  3. A randomized Phase II clinical study of combining panitumumab and bevacizumab, plus irinotecan, 5-fluorouracil, and leucovorin (FOLFIRI) compared with FOLFIRI alone as second-line treatment for patients with metastatic colorectal cancer and KRAS mutation

    PubMed Central

    Liu, Yuguo; Luan, Lijuan; Wang, Xingli

    2015-01-01

    Background This study investigated the efficacy and safety of a new treatment strategy of combining panitumumab and bevacizumab, plus irinotecan, 5-fluorouracil, and leucovorin (FOLFIRI) versus FOLFIRI alone as second-line chemotherapy for metastatic colorectal cancer (mCRC) patients with known V-Ki-ras2 Kirsten rat sarcoma viral oncogene (KRAS) mutation status. Methods Patients with mCRC who had known KRAS tumor status and unsuccessful previous oxaliplatin-based chemotherapy were included in the study. They were randomly assigned to two groups to receive panitumumab and bevacizumab plus FOLFIRI, or FOLFIRI alone. In panitumumab and bevacizumab plus FOLFIRI group, patients were given 4 mg/kg panitumumab and bevacizumab plus FOLFIRI every 2 weeks. Results In all, 65 patients were assigned to panitumumab and bevacizumab plus FOLFIRI group, and 77 to FOLFIRI alone group. For WT KRAS patients, the median progression-free survival (PFS) was 5.7 months (95% confidence interval [CI], 2.4–7.5 months) for panitumumab and bevacizumab plus FOLFIRI and 3.8 months (95% CI, 3.0–6.7 months) for FOLFIRI alone; median overall survival (OS) was 15.2 months (95% CI, 8.9–19.7 months) for panitumumab and bevacizumab plus FOLFIRI and 11.0 months (95% CI, 8.2–15.4 months) for FOLFIRI alone. For MU KRAS patients, median PFS was 5.1 months (95% CI, 2.7–10.2 months) for panitumumab and bevacizumab plus FOLFIRI and 4.1 months (95% CI, 2.5–8.4 months) for FOLFIRI alone; median OS was 12.8 months (95% CI, 7.8–15.8 months) for panitumumab and bevacizumab plus FOLFIRI and 10.5 months (95% CI, 6.1–15.3 months) for FOLFIRI alone. Grade 3 and 4 adverse events were associated with panitumumab and bevacizumab plus FOLFIRI but tolerable among patients. Conclusion Patients with mCRC can be safely and efficiently treated with second-line chemotherapy of combining panitumumab and bevacizumab plus FOLFIRI, despite their KRAS mutation status. PMID:25999741

  4. A modified varying-stage adaptive phase II/III clinical trial design.

    PubMed

    Dong, Gaohong; Vandemeulebroecke, Marc

    2016-07-01

    Conventionally, adaptive phase II/III clinical trials are carried out with a strict two-stage design. Recently, a varying-stage adaptive phase II/III clinical trial design has been developed. In this design, following the first stage, an intermediate stage can be adaptively added to obtain more data, so that a more informative decision can be made. Therefore, the number of further investigational stages is determined based upon data accumulated to the interim analysis. This design considers two plausible study endpoints, with one of them initially designated as the primary endpoint. Based on interim results, another endpoint can be switched as the primary endpoint. However, in many therapeutic areas, the primary study endpoint is well established. Therefore, we modify this design to consider one study endpoint only so that it may be more readily applicable in real clinical trial designs. Our simulations show that, the same as the original design, this modified design controls the Type I error rate, and the design parameters such as the threshold probability for the two-stage setting and the alpha allocation ratio in the two-stage setting versus the three-stage setting have a great impact on the design characteristics. However, this modified design requires a larger sample size for the initial stage, and the probability of futility becomes much higher when the threshold probability for the two-stage setting gets smaller. Copyright © 2016 John Wiley & Sons, Ltd.

  5. Sorafenib plus hepatic arterial infusion chemotherapy with cisplatin versus sorafenib for advanced hepatocellular carcinoma: randomized phase II trial

    PubMed Central

    Ikeda, M.; Shimizu, S.; Sato, T.; Morimoto, M.; Kojima, Y.; Inaba, Y.; Hagihara, A.; Kudo, M.; Nakamori, S.; Kaneko, S.; Sugimoto, R.; Tahara, T.; Ohmura, T.; Yasui, K.; Sato, K.; Ishii, H.; Furuse, J.; Okusaka, T.

    2016-01-01

    Background Sorafenib (Sor) is acknowledged as a standard therapy for advanced hepatocellular carcinoma (HCC). This trial was conducted to evaluate the effect of addition of hepatic arterial infusion chemotherapy with cisplatin (SorCDDP) to Sor for the treatment of advanced HCC. Patients and methods We conducted a multicenter open-labeled randomized phase II trial in chemo-naïve patients with advanced HCC with Child-Pugh scores of 5–7. Eligible patients were randomly assigned 2:1 to receive SorCDDP (sorafenib: 400 mg bid; cisplatin: 65 mg/m2, day 1, every 4–6 weeks) or Sor (400 mg bid). The primary end point was overall survival. Results A total of 108 patients were randomized (Sor, n = 42; SorCDDP, n = 66). The median survival in the Sor and SorCDDP arms were 8.7 and 10.6 months, respectively [stratified hazard ratio (95% confidence interval), 0.60 (0.38–0.96), P = 0.031]. The median time to progression and the response rate were, respectively, 2.8 months and 7.3% in the Sor arm and 3.1 months and 21.7% in the SorCDDP arm. The adverse events were more frequent in the SorCDDP arm than in the Sor arm, but well-tolerated. Conclusion SorCDDP yielded favorable overall survival when compared with Sor in patients with advanced HCC. Clinical Trial registration UMIN-CTR (http://www.umin.ac.jp/ctr/index-j.htm), identification number: UMIN000005703. PMID:27573564

  6. Statistical Issues for Design and Analysis of Single-Arm Multi-Stage Phase II Cancer Clinical Trials

    PubMed Central

    Jung, Sin-Ho

    2015-01-01

    Summary Phase II trials have been very widely conducted and published every year for cancer clinical research. In spite of the fast progress in design and analysis methods, single-arm two-stage design is still the most popular for phase II cancer clinical trials. Because of their small sample sizes, statistical methods based on large sample approximation are not appropriate for design and analysis of phase II trials. As a prospective clinical research, the analysis method of a phase II trial is predetermined at the design stage and it is analyzed during and at the end of the trial as planned by the design. The analysis method of a trial should be matched with the design method. For two-stage single arm phase II trials, Simon's method has been the standards for choosing an optimal design, but the resulting data have been analyzed and published ignoring the two-stage design aspect with small sample sizes. In this article, we review analysis methods that exactly get along with the exact two-stage design method. We also discuss some statistical methods to improve the existing design and analysis methods for single-arm two-stage phase II trials. PMID:25749311

  7. SU-E-J-35: Clinical Performance Evaluation of a Phase II Proton CT Scanner

    SciTech Connect

    Mandapaka, A; Ghebremedhin, A; Farley, D; Giacometti, V; Vence, N; Bashkirov, V; Patyal, B; Schulte, R; Plautz, T; Zatserklyaniy, A; Johnson, R; Sadrozinski, H

    2014-06-01

    Purpose: To develop the methodology to evaluate the clinical performance of a Phase II Proton CT scanner Methods: Range errors on the order of 3%-5% constitute a major uncertainty in current charged particle treatment planning based on Hounsfield Unit (HU)-relative stopping power (RSP) calibration curves. Within our proton CT collaboration, we previously developed and built a Phase I proton CT scanner that provided a sensitive area of 9 cm (axial) × 18 cm (in-plane). This scanner served to get initial experience with this new treatment planning tool and to incorporate lessons learned into the next generation design. A Phase II scanner was recently completed and is now undergoing initial performance testing. It will increase the proton acquisition rate and provide a larger detection area of 9 cm x 36 cm. We are now designing a comprehensive evaluation program to test the image quality, imaging dose, and range uncertainty associated with this scanner. The testing will be performed along the lines of AAPM TG 66. Results: In our discussion of the evaluation protocol we identified the following priorities. The image quality of proton CT images, in particular spatial resolution and low-density contrast discrimination, will be evaluated with the Catphan600 phantom. Initial testing showed that the Catphan uniformity phantom did not provide sufficient uniformity; it was thus replaced by a cylindrical water phantom. The imaging dose will be tested with a Catphan dose module, and compared to a typical cone beam CT dose for comparable image quality. Lastly, we developed a dedicated dosimetry range phantom based on the CIRS pediatric head phantom HN715. Conclusion: A formal evaluation of proton CT as a new tool for proton treatment planning is an important task. The availability of the new Phase II proton CT scanner will allow us to perform this task. This research is supported by the National Institute of Biomedical Imaging and Bioengineering of the NIH under award number R01

  8. The Public Repository of Xenografts Enables Discovery and Randomized Phase II-like Trials in Mice.

    PubMed

    Townsend, Elizabeth C; Murakami, Mark A; Christodoulou, Alexandra; Christie, Amanda L; Köster, Johannes; DeSouza, Tiffany A; Morgan, Elizabeth A; Kallgren, Scott P; Liu, Huiyun; Wu, Shuo-Chieh; Plana, Olivia; Montero, Joan; Stevenson, Kristen E; Rao, Prakash; Vadhi, Raga; Andreeff, Michael; Armand, Philippe; Ballen, Karen K; Barzaghi-Rinaudo, Patrizia; Cahill, Sarah; Clark, Rachael A; Cooke, Vesselina G; Davids, Matthew S; DeAngelo, Daniel J; Dorfman, David M; Eaton, Hilary; Ebert, Benjamin L; Etchin, Julia; Firestone, Brant; Fisher, David C; Freedman, Arnold S; Galinsky, Ilene A; Gao, Hui; Garcia, Jacqueline S; Garnache-Ottou, Francine; Graubert, Timothy A; Gutierrez, Alejandro; Halilovic, Ensar; Harris, Marian H; Herbert, Zachary T; Horwitz, Steven M; Inghirami, Giorgio; Intlekoffer, Andrew M; Ito, Moriko; Izraeli, Shai; Jacobsen, Eric D; Jacobson, Caron A; Jeay, Sébastien; Jeremias, Irmela; Kelliher, Michelle A; Koch, Raphael; Konopleva, Marina; Kopp, Nadja; Kornblau, Steven M; Kung, Andrew L; Kupper, Thomas S; LaBoeuf, Nicole; LaCasce, Ann S; Lees, Emma; Li, Loretta S; Look, A Thomas; Murakami, Masato; Muschen, Markus; Neuberg, Donna; Ng, Samuel Y; Odejide, Oreofe O; Orkin, Stuart H; Paquette, Rachel R; Place, Andrew E; Roderick, Justine E; Ryan, Jeremy A; Sallan, Stephen E; Shoji, Brent; Silverman, Lewis B; Soiffer, Robert J; Steensma, David P; Stegmaier, Kimberly; Stone, Richard M; Tamburini, Jerome; Thorner, Aaron R; van Hummelen, Paul; Wadleigh, Martha; Wiesmann, Marion; Weng, Andrew P; Wuerthner, Jens U; Williams, David A; Wollison, Bruce M; Lane, Andrew A; Letai, Anthony; Bertagnolli, Monica M; Ritz, Jerome; Brown, Myles; Long, Henry; Aster, Jon C; Shipp, Margaret A; Griffin, James D; Weinstock, David M

    2016-04-11

    More than 90% of drugs with preclinical activity fail in human trials, largely due to insufficient efficacy. We hypothesized that adequately powered trials of patient-derived xenografts (PDX) in mice could efficiently define therapeutic activity across heterogeneous tumors. To address this hypothesis, we established a large, publicly available repository of well-characterized leukemia and lymphoma PDXs that undergo orthotopic engraftment, called the Public Repository of Xenografts (PRoXe). PRoXe includes all de-identified information relevant to the primary specimens and the PDXs derived from them. Using this repository, we demonstrate that large studies of acute leukemia PDXs that mimic human randomized clinical trials can characterize drug efficacy and generate transcriptional, functional, and proteomic biomarkers in both treatment-naive and relapsed/refractory disease. PMID:27070704

  9. Two Phase II randomized trials on the CRTh2 antagonist AZD1981 in adults with asthma

    PubMed Central

    Kuna, Piotr; Bjermer, Leif; Tornling, Göran

    2016-01-01

    Background Chemoattractant receptor-homologous molecule expressed on T helper type 2 (Th2) cell (CRTh2) receptor antagonists is being investigated for asthma. Objectives The aim of this study was to assess the effects of the CRTh2 receptor antagonist, AZD1981 (with/without inhaled corticosteroids [ICSs]), on lung function and asthma control. Patients and methods Adults aged 18–60 years were enrolled in two randomized, placebo-controlled, parallel-group trials (protocol number: D9830C00003 [study 1, n=209] and protocol number: D9830C00004 [study 2, n=510]). In study 1, patients with stable asthma (forced expiratory volume in 1 second [FEV1]: 65%−110%) were withdrawn from ICS (<400 µg/d) and randomized to AZD1981 1,000 mg twice daily (bid) or placebo. In study 2, patients with uncontrolled asthma (FEV1: 40%−85%) despite ICS therapy (≥500 µg/d) were randomized to 50 mg, 400 mg, or 1,000 mg bid AZD1981 or placebo. The primary efficacy variable for both trials was the change in morning peak expiratory flow after 4 weeks of treatment. Secondary variables included Asthma Control Questionnaire (ACQ-5) scores, FEV1 assessments, safety, and tolerability. In study 2, efficacy was also assessed according to atopic status. Results Following 4 weeks of treatment, there was a nonsignificant increase in morning peak expiratory flow on AZD1981 1,000 mg bid (9.5 L/min vs placebo, P=0.086 [study 1] and 12 L/min vs placebo, P=0.16 [study 2]). In study 2, all doses of AZD1981 provided significant improvements in ACQ-5 scores (0.26–0.3 units vs placebo, P=0.010–0.022); however, there was no dose–response relationship. Improved ACQ-5 scores and FEV1 were observed in the majority of atopic patients treated with AZD1981. AZD1981 was well tolerated across treatment groups. Conclusion Further research may be warranted in atopic patients to fully evaluate the clinical efficacy of AZD1981. PMID:27621597

  10. Two Phase II randomized trials on the CRTh2 antagonist AZD1981 in adults with asthma

    PubMed Central

    Kuna, Piotr; Bjermer, Leif; Tornling, Göran

    2016-01-01

    Background Chemoattractant receptor-homologous molecule expressed on T helper type 2 (Th2) cell (CRTh2) receptor antagonists is being investigated for asthma. Objectives The aim of this study was to assess the effects of the CRTh2 receptor antagonist, AZD1981 (with/without inhaled corticosteroids [ICSs]), on lung function and asthma control. Patients and methods Adults aged 18–60 years were enrolled in two randomized, placebo-controlled, parallel-group trials (protocol number: D9830C00003 [study 1, n=209] and protocol number: D9830C00004 [study 2, n=510]). In study 1, patients with stable asthma (forced expiratory volume in 1 second [FEV1]: 65%−110%) were withdrawn from ICS (<400 µg/d) and randomized to AZD1981 1,000 mg twice daily (bid) or placebo. In study 2, patients with uncontrolled asthma (FEV1: 40%−85%) despite ICS therapy (≥500 µg/d) were randomized to 50 mg, 400 mg, or 1,000 mg bid AZD1981 or placebo. The primary efficacy variable for both trials was the change in morning peak expiratory flow after 4 weeks of treatment. Secondary variables included Asthma Control Questionnaire (ACQ-5) scores, FEV1 assessments, safety, and tolerability. In study 2, efficacy was also assessed according to atopic status. Results Following 4 weeks of treatment, there was a nonsignificant increase in morning peak expiratory flow on AZD1981 1,000 mg bid (9.5 L/min vs placebo, P=0.086 [study 1] and 12 L/min vs placebo, P=0.16 [study 2]). In study 2, all doses of AZD1981 provided significant improvements in ACQ-5 scores (0.26–0.3 units vs placebo, P=0.010–0.022); however, there was no dose–response relationship. Improved ACQ-5 scores and FEV1 were observed in the majority of atopic patients treated with AZD1981. AZD1981 was well tolerated across treatment groups. Conclusion Further research may be warranted in atopic patients to fully evaluate the clinical efficacy of AZD1981.

  11. A Randomized Phase II Study of Linsitinib (OSI-906) Versus Topotecan in Patients With Relapsed Small-Cell Lung Cancer

    PubMed Central

    Otterson, Gregory A.; Dowlati, Afshin; Traynor, Anne M.; Horn, Leora; Owonikoko, Taofeek K.; Ross, Helen J.; Hann, Christine L.; Abu Hejleh, Taher; Nieva, Jorge; Zhao, Xiuhua; Schell, Michael; Sullivan, Daniel M.

    2016-01-01

    Lessons Learned Targeted therapy options for SCLC patients are limited; no agent, thus far, has resulted in a strategy promising enough to progress to phase III trials. Linsitinib, a potent insulin growth factor-1-receptor tyrosine kinase inhibitor, may be one agent with activity against SCLC. Despite lack of a reliable predictive biomarker in this disease, which may have partly contributed to the negative outcome reported here, linsitinib, although safe, showed no clinical activity in unselected, relapsed SCLC patients. Background. Treatment of relapsed small-cell lung cancer (SCLC) remains suboptimal. Insulin growth factor-1 receptor (IGF-1R) signaling plays a role in growth, survival, and chemoresistance in SCLC. Linsitinib is a potent IGF-1R tyrosine kinase inhibitor that potentially may be active against SCLC. Methods. In this phase II study, 8 eligible patients were randomly assigned in a 1:2 ratio to topotecan (1.5 mg/m2 intravenously or 2.3 mg/m2 orally, daily for 5 days for 4 cycles) or linsitinib (150 mg orally twice daily until progression). The primary endpoint was progression-free survival. Patients with relapsed SCLC, platinum sensitive or resistant, performance status (PS) 0–2, and adequate hematologic, renal, and hepatic function were enrolled. Patients with diabetes, cirrhosis, and those taking insulinotropic agents were excluded. Crossover to linsitinib was allowed at progression. Results. Fifteen patients received topotecan (8 resistant, 3 with PS 2) and 29 received linsitinib (16 resistant, 5 with PS 2). Two partial responses were observed with topotecan. Only 4 of 15 patients with topotecan and 1 of 29 with linsitinib achieved stable disease. Median progression-free survival was 3.0 (95% confidence interval [CI], 1.5–3.6) and 1.2 (95% CI, 1.1–1.4) months for topotecan and linsitinib, respectively (p = .0001). Median survival was 5.3 (95% CI, 2.2–7.6) and 3.4 (95% CI, 1.8–5.6) months for topotecan and linsitinib, respectively (p = .71

  12. Stereotactic Body Radiotherapy for Localized Prostate Cancer: Interim Results of a Prospective Phase II Clinical Trial

    SciTech Connect

    King, Christopher R. Brooks, James D.; Gill, Harcharan; Pawlicki, Todd; Cotrutz, Cristian; Presti, Joseph C.

    2009-03-15

    Purpose: The radiobiology of prostate cancer favors a hypofractionated dose regimen. We report results of a prospective Phase II clinical trial of stereotactic body radiotherapy (SBRT) for localized prostate cancer. Methods and Materials: Forty-one low-risk prostate cancer patients with 6 months' minimum follow-up received 36.25 Gy in five fractions of 7.25 Gy with image-guided SBRT alone using the CyberKnife. The early (<3 months) and late (>6 months) urinary and rectal toxicities were assessed using validated quality of life questionnaires (International Prostate Symptom Score, Expanded Prostate Cancer Index Composite) and the Radiation Therapy Oncology Group (RTOG) toxicity criteria. Patterns of prostate-specific antigen (PSA) response are analyzed. Results: The median follow-up was 33 months. There were no RTOG Grade 4 acute or late rectal/urinary complications. There were 2 patients with RTOG Grade 3 late urinary toxicity and none with RTOG Grade 3 rectal complications. A reduced rate of severe rectal toxicities was observed with every-other-day vs. 5 consecutive days treatment regimen (0% vs. 38%, p = 0.0035). A benign PSA bounce (median, 0.4 ng/mL) was observed in 12 patients (29%) occurring at 18 months (median) after treatment. At last follow-up, no patient has had a PSA failure regardless of biochemical failure definition. Of 32 patients with 12 months minimum follow-up, 25 patients (78%) achieved a PSA nadir {<=}0.4 ng/mL. A PSA decline to progressively lower nadirs up to 3 years after treatment was observed. Conclusions: The early and late toxicity profile and PSA response for prostate SBRT are highly encouraging. Continued accrual and follow-up will be necessary to confirm durable biochemical control rates and low toxicity profiles.

  13. Phase II clinical trial of pasireotide long-acting repeatable in patients with metastatic neuroendocrine tumors

    PubMed Central

    Cives, M; Kunz, P L; Morse, B; Coppola, D; Schell, M J; Campos, T; Nguyen, P T; Nandoskar, P; Khandelwal, V; Strosberg, J R

    2015-01-01

    Pasireotide long-acting repeatable (LAR) is a novel somatostatin analog (SSA) with avid binding affinity to somatostatin receptor subtypes 1, 2, 3 (SSTR1,2,3) and 5 (SSTR5). Results from preclinical studies indicate that pasireotide can inhibit neuroendocrine tumor (NET) growth more robustly than octreotide in vitro. This open-label, phase II study assessed the clinical activity of pasireotide in treatment-naïve patients with metastatic grade 1 or 2 NETs. Patients with metastatic pancreatic and extra-pancreatic NETs were treated with pasireotide LAR (60 mg every 4 weeks). Previous systemic therapy, including octreotide and lanreotide, was not permitted. Tumor assessments were performed every 3 months using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS), overall radiographic response rate (ORR), and safety. Twenty-nine patients were treated with pasireotide LAR (60 mg every 4 weeks) and 28 were evaluable for response. The median PFS was 11 months. The most favorable effect was observed in patients with low hepatic tumor burden, normal baseline chromogranin A, and high tumoral SSTR5 expression. Median OS has not been reached; the 30-month OS rate was 70%. The best radiographic response was partial response in one patient (4%), stable disease in 17 patients (60%), and progressive disease in ten patients (36%). Although grade 3/4 toxicities were rare, pasireotide LAR treatment was associated with a 79% rate of hyperglycemia including 14% grade 3 hyperglycemia. Although pasireotide appears to be an effective antiproliferative agent in the treatment of advanced NETs, the high incidence of hyperglycemia raises concerns regarding its suitability as a first-line systemic agent in unselected patients. SSTR5 expression is a potentially predictive biomarker for response. PMID:25376618

  14. A Phase II, Randomized, Controlled Trial of Acupuncture for Reduction of Postcolectomy Ileus

    PubMed Central

    Deng, Gary; Wong, W. Douglas; Guillem, Jose; Chan, Yi; Affuso, Theresa; Yeung, K. Simon; Coleton, Marci; Sjoberg, Daniel; Vickers, Andrew; Cassileth, Barrie

    2014-01-01

    Purpose. Postoperative ileus (POI) prolongs hospital stay and increases risk of postoperative complications. We conducted a randomized, sham-controlled trial to evaluate whether acupuncture reduces POI more effectively than sham acupuncture. Methods. Colon cancer patients undergoing elective colectomy were randomized to receive 30 min of true or sham acupuncture twice daily during their first 3 postoperative days. GI-3 (the later of the following two events: time that the patient first tolerated solid food, AND time that the patient first passed flatus OR a bowel movement) and GI-2 (the later of the following two events: time patient first tolerated solid food AND time patient first passed a bowel movement) were determined. Pain, nausea, vomiting, and use of pain medications were evaluated daily for the first 3 postoperative days. Results. Ninety patients were randomized. Eighty-one received the allocated intervention: 39 in the true acupuncture group and 42 in the sham acupuncture group, all evaluated for the primary endpoint. The mean time to GI-3 was 149 h [standard deviation (SD) 71 h] and 146 (SD 62 h) after surgery for the acupuncture group and the sham acupuncture group (difference between means −2 h; 95 % confidence interval −31, 26; p = 0.9). No significant differences were found between groups for secondary endpoints. Conclusions. True acupuncture as provided in this study did not reduce POI more significantly than sham acupuncture. The study was limited by a standard deviation much larger than expected, suggesting that a study with a larger sample size might be required. PMID:23188543

  15. Effects of laser immunotherapy on late-stage, metastatic breast cancer patients in a Phase II clinical trial

    NASA Astrophysics Data System (ADS)

    Ferrel, Gabriela L.; Zhou, Feifan; Li, Xiaosong; Hode, Tomas; Nordquist, Robert E.; Alleruzzo, Luciano; Chen, Wei R.

    2014-03-01

    Laser immunotherapy (LIT), a novel technique with a local intervention to induce systemic antitumor effects, was developed to treat metastatic cancers. The pre-clinical studies of LIT have shown its unique characteristics in generating a specific antitumor immunity in treating metastatic tumors in rats and mice. For late-stage, metastatic breast cancer patients, who were considered to be out of other available treatment options, we conducted a small Phase II clinical trial using LIT starting in 2009 in Lima, Peru. This Phase II study was closed in December of 2012, as acknowldged by the Ministry of Health (MOH) of Peur letter 438-2014-OGITT/INS dated March 5th, 2014. Ten patients were enrolled and received LIT in one or multiple 4-week treatment cycles. At the study closing date, four patients were alive and two of them remained cancer free. Here, following the successful conclusion of our Phase II study, we report the clinical effects of LIT on metastatic breast cancer patients. Specifically, we present the overall status of all the patients three years after the treatment and also the outcomes of two long-term surviving patients.

  16. Nimotuzumab combined with radiotherapy for esophageal cancer: preliminary study of a Phase II clinical trial

    PubMed Central

    Liang, Jun; E, Mingyan; Wu, Gang; Zhao, Lujun; Li, Xia; Xiu, Xia; Li, Ning; Chen, Bo; Hui, Zhouguang; Lv, Jima; Fang, Hui; Tang, Yu; Bi, Nan; Wang, Wenqing; Zhai, Yirui; Li, Tao; Chen, Dongfu; Zou, Shuangmei; Lu, Ning; Perez-Rodríguez, Rolando; Zheng, Junqi; Wang, Luhua

    2013-01-01

    Objective To determine the safety and therapeutic effects of nimotuzumab (h-R3) combined with radiotherapy in esophageal cancer. Methods This Phase II clinical trial involved 42 patients with stage II (inoperable or refused surgery) to stage IV (supraclavicular lymph node metastasis only) esophageal cancers treated between November 2008 and July 2010. All patients had squamous cell carcinomas, and all received three-dimensional conformal radiotherapy and 200 mg nimotuzumab per week during radiotherapy. Results There were 9, 25, and 8 patients with stage II, III and IV disease, respectively. All except two patients received 50–70 Gy radiation; 37 patients (88.1%) received more than five nimotuzumab doses. Grade III toxicities (21.4% of all adverse events) included esophagitis and gastrointestinal, dermatological and hematological toxicities. Complete response, partial response, stable disease, and progressive disease were observed in 0, 22 (52.4%), 17 (40.5%) and 3 (7.1%) patients at 1 month after the treatment. The epidermal growth factor receptor (EGFR) overexpression rate was 95.2%. After a median follow-up of 37 months, the median survival time (MST) was 14 months. The 2 year and 3 year overall survival (OS) rates were 33.3% and 26.2%, respectively. The median progression-free survival (PFS) time was 10 months. The 2 year and 3 year PFS rates were 24.5% and 22.1%, respectively. The MST in the 13 patients with (+++) EGFR expression (group A) and 7 patients with (++) EGFR expression (group B) was 15 and 11 months, respectively. The 2 year and 3 year OS rates were 46.2% and 38.5% in group A and 28.6% and 28.6% in group B, respectively (P = 0.405). Conclusion Although concurrent chemoradiotherapy was the standard care for locally advanced esophageal cancer, radiotherapy was the choice for those who were refused or could not tolerate chemoradiotherapy. Our study shows that nimotuzumab combined with radiotherapy was well tolerated in patients with esophageal cancer

  17. A Method for Utilizing Bivariate Efficacy Outcome Measures to Screen Regimens for Activity in 2-Stage Phase II Clinical Trials

    PubMed Central

    Rubinstein, Larry; Litwin, Samuel; Yothers, Greg

    2012-01-01

    Background Most phase II clinical trials utilize a single primary endpoint to determine the promise of a regimen for future study. However, many disorders manifest themselves in complex ways. For example, migraine headaches can cause pain, auras, photophobia, and emesis. Investigators may believe a drug is effective at reducing migraine pain and the severity of emesis during an attack. Nevertheless, they could still be interested in proceeding with development of the drug if it is effective against only one of these symptoms. Such a study would be a candidate for a clinical trial with co-primary endpoints. Purpose The purpose of the article is to provide a method for designing a 2-stage clinical trial with dichotomous co-primary endpoints of efficacy that has the ability to detect activity on either response measure with high probability when the drug is active on one or both measures, while at the same time rejecting the drug with high probability when there is little activity on both dimensions. The design enables early closure for futility and is flexible with regard to attained accrual. Methods The design is proposed in the context of cancer clinical trials where tumor response is used to assess a drug's ability to kill tumor cells and progression-free survival (PFS) status after a certain period is used to evaluate the drug's ability to stabilize tumor growth. Both endpoints are assumed to be distributed as binomial random variables, and uninteresting probabilities of success are determined from historical controls. Given the necessity of accrual flexibility, exhaustive searching algorithms to find optimum designs do not seem feasible at this time. Instead, critical values are determined for realized sample sizes using specific procedures. Then accrual windows are found to achieve a design's desired level of significance, probability of early termination (PET), and power. Results The design is illustrated with a clinical trial that examined bevacizumab in

  18. Ki-67 index guided selection of preoperative chemotherapy for HER2-positive breast cancer: a randomized phase II trial.

    PubMed

    Yamaguchi, Takeshi; Mukai, Hirofumi

    2012-12-01

    Changes in Ki-67 may be a useful predictor of efficacy for preoperative therapy in breast cancer. This randomized Phase II trial will compare standard preoperative chemotherapy comprising paclitaxel and trastuzumab with Ki-67 index guided preoperative chemotherapy in patients with human epidermal growth factor receptor 2-positive operable breast cancer. In the Ki-67 index guided therapy, paclitaxel and trastuzumab were administered initially and the Ki-67 index is evaluated from biopsied specimens after 2 weeks of preoperative chemotherapy. The subsequent chemotherapy regimen is modified according to changes in the Ki-67 index from the start of therapy. If the Ki-67 index is reduced as expected, paclitaxel and trastuzumab are continued. If the Ki-67 index is not reduced as expected, the chemotherapy regimen is changed to epirubicin, cyclophosphamide and trastuzumab. The primary endpoint is the rate of pathological complete response. The secondary endpoints are the objective response rate, disease-free survival and overall survival. Two hundred patients were planned to be accrued.

  19. A new adaptive design based on Simon's two-stage optimal design for phase II clinical trials.

    PubMed

    Jin, Hua; Wei, Zhen

    2012-11-01

    Phase II clinical trials are conducted to determine whether a new agent or drug regimen has sufficient promise in treating cancer to merit further testing in larger groups of patients. Both ethical and practical considerations often require early termination of phase II trials if early results clearly indicate that the new regimen is not active or worthy of further investigation. Simon's two-stage designs (1989) are common methods for conducting phase II studies investigating new cancer therapies. Banerjee and Tsiatis (2006) proposed an adaptive two-stage design which allows the sample size at the second stage to depend on the results at the first stage. Their design is more flexible than Simon's, but it is somewhat counter-intuitive: as the response in the first stage increases, the second-stage sample size increases till a certain point and then abruptly becomes zero. In this paper, based on Simon's two-stage optimal design, we propose a new adaptive one which depends on the first stage results using the restrict conditions the conditional type I error and the conditional power. Comparisons are made between Banerjee and Tsiatis' results and our new adaptive designs. PMID:22772088

  20. Statistical design in phase II clinical trials and its application in breast cancer.

    PubMed

    Perrone, Francesco; Di Maio, Massimo; De Maio, Ermelinda; Maione, Paolo; Ottaiano, Alessandro; Pensabene, Matilde; Di Lorenzo, Giuseppe; Lombardi, Alessandra Vernaglia; Signoriello, Giuseppe; Gallo, Ciro

    2003-05-01

    Several statistical designs for phase II studies have been proposed, but they are frequently misunderstood or not applied at all. In this review we describe the major characteristics of the available designs. To investigate the extent to which statistical designs were used in some recent phase II studies, and which designs were the most common, we did a survey of 145 trials involving treatment of breast cancer. Studies selected for the survey were published between 1995 and 1999 in one of seven specific oncology journals (all with impact factor consistently higher than 2). 94 of the studies (64.8%) did not have an identifiable statistical design. However, among the 51 studies with statistical design there was a notable heterogeneity in the type of design applied. We put together a list of factors associated with use of statistical design at univariate analysis. These factors included: referral to a previous phase I study, recent trial start date, private sponsorship, single-agent treatment, and multicentre organisation. Single-agent treatment (OR 2.35; 95% CI 1.01-5.51) and multicentre organisation (OR 3.24; 95% CI 1.47-7.15) were independently predictive of the presence of statistical design. Publication in journals with high impact factors and short intervals between the start of the study and publication were also correlated with statistical design.

  1. Phase II Randomized Controlled Trial of Combined Oral laxatives Medication for BOwel PREParation (COMBO-PREP study).

    PubMed

    Kim, Min Jung; Hong, Chang Won; Kim, Byung Chang; Park, Sung Chan; Han, Kyung Su; Joo, Jungnam; Oh, Jae Hwan; Sohn, Dae Kyung

    2016-02-01

    The combination of different laxatives at reduced volumes may benefit patients by enhancing efficacy for bowel cleansing and increasing tolerability. However, evidence regarding combined preparations is scarce. This study evaluated whether the combined preparations are associated with enhanced efficacy and tolerability. This randomized phase II study had a single-blind, parallel-arm design. Between December 2013 and September 2014, consecutive patients aged between 20 and 65 years and who required diagnostic colonoscopies were considered for inclusion. Patients were randomly allocated into 4 arms: sodium picosulfate and magnesium citrate (PMC) and polyethylene glycol (PEG) with ascorbic acid in a day-prior (PMC-PEG-DP), PMC and oral sodium phosphate (NaP) in a day-prior (PMC-NaP-DP), PMC and PEG with ascorbic acid in a split-dose (PMC-PEG-SD), and PMC and oral NaP in a split-dose (PMC-NaP-SD). Primary endpoint was the Aronchick scale, and Ottawa scale results by colon segment, patients' adverse gastrointestinal symptoms, and willingness to reuse the same agents were also recorded. Successful bowel preparation was defined as an "excellent" or "good" score on the Aronchick scale. A total of 236 patients were randomized and 229 patients received the planned colonoscopy. The rates of successful bowel preparation in the PMC-PEG-DP, PMC-NaP-DP, PMC-PEG-SD, and PMC-NaP-SD were 82.5%, 64.4%, 100%, and 100%, respectively. Excluding the failed PMC-NaP-DP group, all groups showed satisfactory rates of successful bowel preparation, and the mean Ottawa scores were significantly better in the PMC-PEG-SD and PMC-NaP-SD groups than in the PMC-PEG-DP group (P < 0.0001). The PMC-PEG-DP, PMC-NaP-DP, PMC-PEG-SD, and PMC-NaP-SD groups were similar in terms of rates of adverse gastrointestinal symptoms reported on a 5-point scale (P = 0.40) and willingness to reuse the same combined preparations (P = 0.55). PMC-PEG in a day-prior or split-dose and PMC-NaP in a split

  2. Phase II Randomized Controlled Trial of Combined Oral laxatives Medication for BOwel PREParation (COMBO-PREP study)

    PubMed Central

    Kim, Min Jung; Hong, Chang Won; Kim, Byung Chang; Park, Sung Chan; Han, Kyung Su; Joo, Jungnam; Oh, Jae Hwan; Sohn, Dae Kyung

    2016-01-01

    Abstract The combination of different laxatives at reduced volumes may benefit patients by enhancing efficacy for bowel cleansing and increasing tolerability. However, evidence regarding combined preparations is scarce. This study evaluated whether the combined preparations are associated with enhanced efficacy and tolerability. This randomized phase II study had a single-blind, parallel-arm design. Between December 2013 and September 2014, consecutive patients aged between 20 and 65 years and who required diagnostic colonoscopies were considered for inclusion. Patients were randomly allocated into 4 arms: sodium picosulfate and magnesium citrate (PMC) and polyethylene glycol (PEG) with ascorbic acid in a day-prior (PMC-PEG-DP), PMC and oral sodium phosphate (NaP) in a day-prior (PMC-NaP-DP), PMC and PEG with ascorbic acid in a split-dose (PMC-PEG-SD), and PMC and oral NaP in a split-dose (PMC-NaP-SD). Primary endpoint was the Aronchick scale, and Ottawa scale results by colon segment, patients’ adverse gastrointestinal symptoms, and willingness to reuse the same agents were also recorded. Successful bowel preparation was defined as an “excellent” or “good” score on the Aronchick scale. A total of 236 patients were randomized and 229 patients received the planned colonoscopy. The rates of successful bowel preparation in the PMC-PEG-DP, PMC-NaP-DP, PMC-PEG-SD, and PMC-NaP-SD were 82.5%, 64.4%, 100%, and 100%, respectively. Excluding the failed PMC-NaP-DP group, all groups showed satisfactory rates of successful bowel preparation, and the mean Ottawa scores were significantly better in the PMC-PEG-SD and PMC-NaP-SD groups than in the PMC-PEG-DP group (P < 0.0001). The PMC-PEG-DP, PMC-NaP-DP, PMC-PEG-SD, and PMC-NaP-SD groups were similar in terms of rates of adverse gastrointestinal symptoms reported on a 5-point scale (P = 0.40) and willingness to reuse the same combined preparations (P = 0.55). PMC-PEG in a day-prior or split-dose and PMC

  3. A Phase II, Randomized, Safety and Immunogenicity Trial of a Re-Derived, Live-Attenuated Dengue Virus Vaccine in Healthy Children and Adults Living in Puerto Rico.

    PubMed

    Bauer, Kristen; Esquilin, Ines O; Cornier, Alberto Santiago; Thomas, Stephen J; Quintero Del Rio, Ana I; Bertran-Pasarell, Jorge; Morales Ramirez, Javier O; Diaz, Clemente; Carlo, Simon; Eckels, Kenneth H; Tournay, Elodie; Toussaint, Jean-Francois; De La Barrera, Rafael; Fernandez, Stefan; Lyons, Arthur; Sun, Wellington; Innis, Bruce L

    2015-09-01

    This was a double-blind, randomized, controlled, phase II clinical trial, two dose study of re-derived, live-attenuated, tetravalent dengue virus (TDEN) vaccine (two formulations) or placebo in subjects 1-50 years of age. Among the 636 subjects enrolled, 331 (52%) were primed, that is, baseline seropositive to at least one dengue virus (DENV) type. Baseline seropositivity prevalence increased with age (10% [< 2 years], 26% [2-4 years], 60% [5-20 years], and 93% [21-50 years]). Safety profiles of TDEN vaccines were similar to placebo regardless of priming status. No vaccine-related serious adverse events (SAEs) were reported. Among unprimed subjects, immunogenicity (geometric mean antibody titers [GMT] and seropositivity rates) for each DENV increased substantially in both TDEN vaccine groups with at least 74.6% seropositive for four DENV types. The TDEN vaccine candidate showed an acceptable safety and immunogenicity profile in children and adults ranging from 1 to 50 years of age, regardless of priming status. ClinicalTrials.gov: NCT00468858.

  4. A Phase II, Randomized, Safety and Immunogenicity Trial of a Re-Derived, Live-Attenuated Dengue Virus Vaccine in Healthy Children and Adults Living in Puerto Rico

    PubMed Central

    Bauer, Kristen; Esquilin, Ines O.; Cornier, Alberto Santiago; Thomas, Stephen J.; Quintero del Rio, Ana I.; Bertran-Pasarell, Jorge; Morales Ramirez, Javier O.; Diaz, Clemente; Carlo, Simon; Eckels, Kenneth H.; Tournay, Elodie; Toussaint, Jean-Francois; De La Barrera, Rafael; Fernandez, Stefan; Lyons, Arthur; Sun, Wellington; Innis, Bruce L.

    2015-01-01

    This was a double-blind, randomized, controlled, phase II clinical trial, two dose study of re-derived, live-attenuated, tetravalent dengue virus (TDEN) vaccine (two formulations) or placebo in subjects 1–50 years of age. Among the 636 subjects enrolled, 331 (52%) were primed, that is, baseline seropositive to at least one dengue virus (DENV) type. Baseline seropositivity prevalence increased with age (10% [< 2 years], 26% [2–4 years], 60% [5–20 years], and 93% [21–50 years]). Safety profiles of TDEN vaccines were similar to placebo regardless of priming status. No vaccine-related serious adverse events (SAEs) were reported. Among unprimed subjects, immunogenicity (geometric mean antibody titers [GMT] and seropositivity rates) for each DENV increased substantially in both TDEN vaccine groups with at least 74.6% seropositive for four DENV types. The TDEN vaccine candidate showed an acceptable safety and immunogenicity profile in children and adults ranging from 1 to 50 years of age, regardless of priming status. ClinicalTrials.gov: NCT00468858. PMID:26175027

  5. Optimal blood sampling time windows for parameter estimation using a population approach: design of a phase II clinical trial.

    PubMed

    Chenel, Marylore; Ogungbenro, Kayode; Duval, Vincent; Laveille, Christian; Jochemsen, Roeline; Aarons, Leon

    2005-12-01

    The objective of this paper is to determine optimal blood sampling time windows for the estimation of pharmacokinetic (PK) parameters by a population approach within the clinical constraints. A population PK model was developed to describe a reference phase II PK dataset. Using this model and the parameter estimates, D-optimal sampling times were determined by optimising the determinant of the population Fisher information matrix (PFIM) using PFIM_ _M 1.2 and the modified Fedorov exchange algorithm. Optimal sampling time windows were then determined by allowing the D-optimal windows design to result in a specified level of efficiency when compared to the fixed-times D-optimal design. The best results were obtained when K(a) and IIV on K(a) were fixed. Windows were determined using this approach assuming 90% level of efficiency and uniform sample distribution. Four optimal sampling time windows were determined as follow: at trough between 22 h and new drug administration; between 2 and 4 h after dose for all patients; and for 1/3 of the patients only 2 sampling time windows between 4 and 10 h after dose, equal to [4 h-5 h 05] and [9 h 10-10 h]. This work permitted the determination of an optimal design, with suitable sampling time windows which was then evaluated by simulations. The sampling time windows will be used to define the sampling schedule in a prospective phase II study.

  6. Effects of treatment with an Hsp90 inhibitor in tumors based on 15 phase II clinical trials

    PubMed Central

    Wang, He; Lu, Mingjie; Yao, Mengqian; Zhu, Wei

    2016-01-01

    Heat shock protein (Hsp)90 serves as a chaperone protein that promotes the proper folding of proteins involved in a variety of signal transduction processes involved in cell growth. Hsp90 inhibitors, which inhibit the activity of critical client proteins, have emerged as the accessory therapeutic agents for multiple human cancer types. To better understand the effects of Hsp90 inhibitors in cancer treatment, the present study reviewed 15 published phase II clinical trials to investigate whether Hsp90 inhibitors will benefit patients with cancer. Information of complete response, partial response, stable disease, objective response and objective response rate was collected to evaluate clinical outcomes. Overall, Hsp90 inhibitors are effective against a variety of oncogene-addicted cancers, including those that have developed resistance to specific receptors.

  7. Randomized phase II trial of TEGAFIRI (tegafur/uracil, oral leucovorin, irinotecan) compared with FOLFIRI (folinic acid, 5-fluorouracil, irinotecan) in patients with unresectable/recurrent colorectal cancer.

    PubMed

    Shigeta, Kohei; Hasegawa, Hirotoshi; Okabayashi, Koji; Tsuruta, Masashi; Ishii, Yoshiyuki; Endo, Takashi; Ochiai, Hiroki; Kondo, Takayuki; Kitagawa, Yuko

    2016-08-15

    Irinotecan-based chemotherapy with bevacizumab is one of the first-line standard therapies for metastatic colorectal cancer (mCRC). TEGAFIRI (UFT/LV + irinotecan) is an irinotecan-based chemotherapy regimen. Currently, few clinical data regarding TEGAFIRI are available. This study evaluated the efficacy and safety of TEGAFIRI in Japanese patients with mCRC. This is a multicenter, randomized, phase II study. The major inclusion criteria were previously untreated patients with mCRC (age: 20-75 years, Eastern Cooperative Oncology Group performance status: 0-1). Eligible patients were randomly assigned (1:1) to receive either FOLFIRI ± bevacizumab or TEGAFIRI ± bevacizumab. The primary endpoint was progression-free survival (PFS). The secondary endpoints were response rate, overall survival, dose intensity and toxicity. From November 2007 to October 2011, 36 and 35 patients assigned to the FOLFIRI and TEGAFIRI groups were included in the primary analysis. No significant difference in PFS was observed between the groups {median PFS: TEGAFIRI 9.9 months [95% confidence interval (CI), 6.5-14.7], FOLFIRI 10.6 months [95% CI, 7.7-16.5]; Hazard ratio, 0.98, 95% CI, 0.57-1.66, p = 0.930}. The response rates in the FOLFIRI and TEGAFIRI groups were 56% and 66%, respectively. Relative dose intensity was similar between the groups. The most common Grade 3/4 adverse event was diarrhea (26%) in TEGAFIRI group and neutropenia (39%) in the FOLFIRI group. The results of the present study indicate that TEGAFIRI ± bevacizumab is an effective and tolerable first-line treatment regimen for mCRC. PMID:27061810

  8. Overall Survival Analysis of a Phase II Randomized Controlled Trial of a Poxviral-Based PSA-Targeted Immunotherapy in Metastatic Castration-Resistant Prostate Cancer

    PubMed Central

    Kantoff, Philip W.; Schuetz, Thomas J.; Blumenstein, Brent A.; Glode, L. Michael; Bilhartz, David L.; Wyand, Michael; Manson, Kelledy; Panicali, Dennis L.; Laus, Reiner; Schlom, Jeffrey; Dahut, William L.; Arlen, Philip M.; Gulley, James L.; Godfrey, Wayne R.

    2010-01-01

    Purpose Therapeutic prostate-specific antigen (PSA) –targeted poxviral vaccines for prostate cancer have been well tolerated. PROSTVAC-VF treatment was evaluated for safety and for prolongation of progression-free survival (PFS) and overall survival (OS) in a randomized, controlled, and blinded phase II study. Patients and Methods In total, 125 patients were randomly assigned in a multicenter trial of vaccination series. Eligible patients had minimally symptomatic castration-resistant metastatic prostate cancer (mCRPC). PROSTVAC-VF comprises two recombinant viral vectors, each encoding transgenes for PSA, and three immune costimulatory molecules (B7.1, ICAM-1, and LFA-3). Vaccinia-based vector was used for priming followed by six planned fowlpox-based vector boosts. Patients were allocated (2:1) to PROSTVAC-VF plus granulocyte-macrophage colony-stimulating factor or to control empty vectors plus saline injections. Results Eighty-two patients received PROSTVAC-VF and 40 received control vectors. Patient characteristics were similar in both groups. The primary end point was PFS, which was similar in the two groups (P = .6). However, at 3 years post study, PROSTVAC-VF patients had a better OS with 25 (30%) of 82 alive versus 7 (17%) of 40 controls, longer median survival by 8.5 months (25.1 v 16.6 months for controls), an estimated hazard ratio of 0.56 (95% CI, 0.37 to 0.85), and stratified log-rank P = .0061. Conclusion PROSTVAC-VF immunotherapy was well tolerated and associated with a 44% reduction in the death rate and an 8.5-month improvement in median OS in men with mCRPC. These provocative data provide preliminary evidence of clinically meaningful benefit but need to be confirmed in a larger phase III study. PMID:20100959

  9. Randomized phase II trial of hypofractionated proton versus carbon ion radiation therapy in patients with sacrococcygeal chordoma-the ISAC trial protocol

    PubMed Central

    2014-01-01

    Background Chordomas are relatively rare lesions of the bones. About 30% occur in the sacrococcygeal region. Surgical resection is still the standard treatment. Due to the size, proximity to neurovascular structures and the complex anatomy of the pelvis, a complete resection with adequate safety margin is difficult to perform. A radical resection with safety margins often leads to the loss of bladder and rectal function as well as motoric/sensoric dysfunction. The recurrence rate after surgery alone is comparatively high, such that adjuvant radiation therapy is very important for improving local control rates. Proton therapy is still the international standard in the treatment of chordomas. High-LET beams such as carbon ions theoretically offer biologic advantages in slow-growing tumors. Data of a Japanese study of patients with unresectable sacral chordoma showed comparable high control rates after hypofractionated carbon ion therapy only. Methods and design This clinical study is a prospective randomized, monocentric phase II trial. Patients with histologically confirmed sacrococcygeal chordoma will be randomized to either proton or carbon ion radiation therapy stratified regarding the clinical target volume. Target volume delineation will be carried out based on CT and MRI data. In each arm the PTV will receive 64 GyE in 16 fractions. The primary objective of this trial is safety and feasibility of hypofractionated irradiation in patients with sacrococygeal chordoma using protons or carbon ions in raster scan technique for primary or additive treatment after R2 resection. The evaluation is therefore based on the proportion of treatments without Grade 3–5 toxicity (CTCAE, version 4.0) up to 12 months after treatment and/or discontinuation of the treatment for any reason as primary endpoint. Local-progression free survival, overall survival and quality of life will be analyzed as secondary end points. Discussion The aim of this study is to confirm the toxicity

  10. Vaccination of castration-resistant prostate cancer patients with TroVax (MVA-5T4) in combination with docetaxel: a randomized phase II trial.

    PubMed

    Harrop, Richard; Chu, Franklin; Gabrail, Nashat; Srinivas, Sandy; Blount, Daniel; Ferrari, Anna

    2013-09-01

    The attenuated vaccinia virus, modified vaccinia Ankara, has been engineered to deliver the tumor antigen 5T4 (TroVax®). Here, we report results from a randomized open-label phase II trial in castration-resistant prostate cancer patients in which TroVax was administered in combination with docetaxel and compared against docetaxel alone. The aim was to recruit 80 patients (40 per arm), but the study was terminated early due to recruitment challenges. Therefore, this paper reports the comparative safety and immunological and clinical efficacy in 25 patients, 12 of whom were treated with TroVax plus docetaxel and 13 with docetaxel alone. 5T4-specific immune responses were monitored throughout the study. Clinical responses were assessed by measuring changes in tumor burden by CT and bone scan and by quantifying PSA concentrations. TroVax was well tolerated in all patients. Of 10 immunologically evaluable patients, 6 mounted 5T4-specific antibody responses. Patients treated with TroVax plus docetaxel showed a greater median progression-free survival of 9.67 months compared with 5.10 months for patients on the docetaxel alone arm (P = 0.097; HR = 0.31; 95% CI 0.08-1.24). Importantly, a pre-treatment biomarker previously demonstrated to predict 5T4 immune response and treatment benefit showed a strong association with 5T4 antibody response and a statistically significant association with progression-free survival in patients treated with TroVax plus docetaxel, but not docetaxel alone.

  11. Cancer immunotherapy: phase II clinical studies with TG4010 (MVA-MUC1-IL2).

    PubMed

    Acres, Bruce

    2007-09-01

    Vaccines are well known in the context of prevention of diseases caused by infectious agents. Current research is now aimed at using vaccines to manipulate the immune system to eliminate established diseases, including cancer. Several such immunotherapeutic vaccines are now in clinical trials and are beginning to show clinical benefit. TG4010 is one such vaccine. It incorporates the MUC1 antigen, which is overexpressed in the majority of cancers, into a non-propagative pox viral vector, MVA. A second gene, interleukin-2 is also incorporated into TG4010 as an immune stimulus. The vaccine has been tested in breast, kidney, prostate and lung cancers with encouraging results. PMID:17935281

  12. Cancer immunotherapy: phase II clinical studies with TG4010 (MVA-MUC1-IL2).

    PubMed

    Acres, Bruce

    2007-09-01

    Vaccines are well known in the context of prevention of diseases caused by infectious agents. Current research is now aimed at using vaccines to manipulate the immune system to eliminate established diseases, including cancer. Several such immunotherapeutic vaccines are now in clinical trials and are beginning to show clinical benefit. TG4010 is one such vaccine. It incorporates the MUC1 antigen, which is overexpressed in the majority of cancers, into a non-propagative pox viral vector, MVA. A second gene, interleukin-2 is also incorporated into TG4010 as an immune stimulus. The vaccine has been tested in breast, kidney, prostate and lung cancers with encouraging results.

  13. A randomized phase II efficacy and correlative studies of cetuximab with or without sorafenib in recurrent and/or metastatic head and neck squamous cell carcinoma

    PubMed Central

    Gilbert, Jill; Schell, Michael J.; Zhao, Xiuhua; Murphy, Barbara; Tanvetyanon, Tawee; Leon, Marino E.; Hayes, D. Neil; Haigentz, Missak; Saba, Nabil; Nieva, Jorge; Bishop, Justin; Sidransky, David; Ravi, Rajani; Bedi, Atul; Chung, Christine H.

    2015-01-01

    Introduction A combination of cetuximab and sorafenib in patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) were assessed for potential benefit. Material and Methods In a randomized phase II study, R/M HNSCC patients were treated with cetuximab 400mg/m2 IV on day 1 followed by 250mg/m2 IV weekly (Arm A), or cetuximab at the same dose/schedule plus sorafenib 400mg PO twice-a-day (Arm B). Each cycle was 21 days. Tumor p16 and HPV status, and plasma immunomodulatory cytokine levels were assessed. Results Of 55 patients enrolled (Arm A-27, Arm B-28), 52 patients received assigned treatments and 43 were evaluable for response. Overall response rate was 8% for both arms. Median overall survival (OS) and progression-free survival (PFS) were 9.0 and 3.0 months in Arm A, and 5.7 and 3.2 months in Arm B, respectively. Forty-four patients had tumors available for p16 staining (35-negative, 9-positive). Three of nine p16-positive tumors were also HPV positive. The p16-negative patients had significantly better PFS compared to the p16-positive patients (3.7 vs. 1.6 months; p-value: 0.03), regardless of study arms. Twenty-four plasma samples were tested for 12 cytokine levels and patients with higher TGFβ1 levels had inferior PFS compared to lower levels (1.9 vs. 4.7 months; adjusted p-value: 0.015), regardless of study arms. Conclusions A subset of R/M patients with p16-negative tumors or lower plasma TGFβ1 levels had longer PFS given the cetuximab-based therapy. However, both arms showed only modest response and sorafenib given with cetuximab did not demonstrate clinical benefit. PMID:25593015

  14. Neuroplastic Effects of Transcranial Direct Current Stimulation on Painful Symptoms Reduction in Chronic Hepatitis C: A Phase II Randomized, Double Blind, Sham Controlled Trial

    PubMed Central

    Brietzke, Aline P.; Rozisky, Joanna R.; Dussan-Sarria, Jairo A.; Deitos, Alicia; Laste, Gabriela; Hoppe, Priscila F. T.; Muller, Suzana; Torres, Iraci L. S.; Alvares-da-Silva, Mário R.; de Amorim, Rivadavio F. B.; Fregni, Felipe; Caumo, Wolnei

    2016-01-01

    Introduction: Pegylated Interferon Alpha (Peg-IFN) in combination with other drugs is the standard treatment for chronic hepatitis C infection (HCV) and is related to severe painful symptoms. The aim of this study was access the efficacy of transcranial direct current stimulation (tDCS) in controlling the painful symptoms related to Peg-IFN side effects. Materials and Methods: In this phase II double-blind trial, twenty eight (n = 28) HCV subjects were randomized to receive either 5 consecutive days of active tDCS (n = 14) or sham (n = 14) during 5 consecutive days with anodal stimulation over the primary motor cortex region using 2 mA for 20 min. The primary outcomes were visual analogue scale (VAS) pain and brain-derived neurotrophic factor (BDNF) serum levels. Secondary outcomes were the pressure-pain threshold (PPT), the Brazilian Profile of Chronic Pain: Screen (B-PCP:S), and drug analgesics use. Results: tDCS reduced the VAS scores (P < 0.003), with a mean pain drop of 56% (p < 0.001). Furthermore, tDCS was able to enhance BDNF levels (p < 0.01). The mean increase was 37.48% in the active group. Finally, tDCS raised PPT (p < 0.001) and reduced the B-PCP:S scores and analgesic use (p < 0.05). Conclusions: Five sessions of tDCS were effective in reducing the painful symptoms in HCV patients undergoing Peg-IFN treatment. These findings support the efficacy of tDCS as a promising therapeutic tool to improve the tolerance of the side effects related to the use of Peg-IFN. Future larger studies (phase III and IV trials) are needed to confirm the clinical use of the therapeutic effects of tDCS in such condition. Trial registration: Brazilian Human Health Regulator for Research with the approval number CAAE 07802012.0.0000.5327. PMID:26793047

  15. Dose-intensified chemotherapy alone or in combination with mogamulizumab in newly diagnosed aggressive adult T-cell leukaemia-lymphoma: a randomized phase II study.

    PubMed

    Ishida, Takashi; Jo, Tatsuro; Takemoto, Shigeki; Suzushima, Hitoshi; Uozumi, Kimiharu; Yamamoto, Kazuhito; Uike, Naokuni; Saburi, Yoshio; Nosaka, Kisato; Utsunomiya, Atae; Tobinai, Kensei; Fujiwara, Hiroshi; Ishitsuka, Kenji; Yoshida, Shinichiro; Taira, Naoya; Moriuchi, Yukiyoshi; Imada, Kazunori; Miyamoto, Toshihiro; Akinaga, Shiro; Tomonaga, Masao; Ueda, Ryuzo

    2015-06-01

    This multicentre, randomized, phase II study was conducted to examine whether the addition of mogamulizumab, a humanized anti-CC chemokine receptor 4 antibody, to mLSG15, a dose-intensified chemotherapy, further increases efficacy without compromising safety of patients with newly diagnosed aggressive adult T-cell leukaemia-lymphoma (ATL). Patients were assigned 1:1 to receive mLSG15 plus mogamulizumab or mLSG15 alone. The primary endpoint was the complete response rate (%CR); secondary endpoints included the overall response rate (ORR) and safety. The %CR and ORR in the mLSG15-plus-mogamulizumab arm (n = 29) were 52% [95% confidence interval (CI), 33-71%] and 86%, respectively; the corresponding values in the mLSG15 arm (n = 24) were 33% (95% CI, 16-55%) and 75%, respectively. Grade ≥ 3 treatment-emergent adverse events, including anaemia, thrombocytopenia, lymphopenia, leucopenia and decreased appetite, were observed more frequently (≥10% difference) in the mLSG15-plus-mogamulizumab arm. Several adverse events, including skin disorders, cytomegalovirus infection, pyrexia, hyperglycaemia and interstitial lung disease, were observed only in the mLSG15-plus-mogamulizumab arm. Although the combination strategy showed a potentially less favourable safety profile, a higher %CR was achieved, providing the basis for further investigation of this novel treatment for newly diagnosed aggressive ATL. This study was registered at ClinicalTrials.gov, identifier: NCT01173887. PMID:25733162

  16. Multi-Center Randomized Phase II Study Comparing Cediranib plus Gefitinib with Cediranib plus Placebo in Subjects with Recurrent/Progressive Glioblastoma

    PubMed Central

    Brown, Nicholas; McBain, Catherine; Nash, Stephen; Hopkins, Kirsten; Sanghera, Paul; Saran, Frank; Phillips, Mark; Dungey, Fiona; Clifton-Hadley, Laura; Wanek, Katharina; Krell, Daniel; Jeffries, Sarah; Khan, Iftekhar; Smith, Paul; Mulholland, Paul

    2016-01-01

    Background Cediranib, an oral pan-vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor, failed to show benefit over lomustine in relapsed glioblastoma. One resistance mechanism for cediranib is up-regulation of epidermal growth factor receptor (EGFR). This study aimed to determine if dual therapy with cediranib and the oral EGFR inhibitor gefitinib improved outcome in recurrent glioblastoma. Methods and Findings This was a multi-center randomized, two-armed, double-blinded phase II study comparing cediranib plus gefitinib versus cediranib plus placebo in subjects with first relapse/first progression of glioblastoma following surgery and chemoradiotherapy. The primary outcome measure was progression free survival (PFS). Secondary outcome measures included overall survival (OS) and radiologic response rate. Recruitment was terminated early following suspension of the cediranib program. 38 subjects (112 planned) were enrolled with 19 subjects in each treatment arm. Median PFS with cediranib plus gefitinib was 3.6 months compared to 2.8 months for cediranib plus placebo (HR; 0.72, 90% CI; 0.41 to 1.26). Median OS was 7.2 months with cediranib plus gefitinib and 5.5 months with cediranib plus placebo (HR; 0.68, 90% CI; 0.39 to 1.19). Eight subjects (42%) had a partial response in the cediranib plus gefitinib arm versus five patients (26%) in the cediranib plus placebo arm. Conclusions Cediranib and gefitinib in combination is tolerated in patients with glioblastoma. Incomplete recruitment led to the study being underpowered. However, a trend towards improved survival and response rates with the addition of gefitinib to cediranib was observed. Further studies of the combination incorporating EGFR and VEGF inhibition are warranted. Trial Registration ClinicalTrials.gov NCT01310855 PMID:27232884

  17. Efficacy and Safety of AmBisome in Combination with Sodium Stibogluconate or Miltefosine and Miltefosine Monotherapy for African Visceral Leishmaniasis: Phase II Randomized Trial

    PubMed Central

    Wasunna, Monique; Njenga, Simon; Balasegaram, Manica; Alexander, Neal; Omollo, Raymond; Edwards, Tansy; Dorlo, Thomas P. C.; Musa, Brima; Ali, Mohammed Hassan Sharaf; Elamin, Mohammed Yasein; Kirigi, George; Kip, Anke E.; Schoone, Gerard J.; Hailu, Asrat; Olobo, Joseph; Ellis, Sally; Kimutai, Robert; Wells, Susan; Khalil, Eltahir Awad Gasim; Strub Wourgaft, Nathalie; Alves, Fabiana; Musa, Ahmed

    2016-01-01

    Background SSG&PM over 17 days is recommended as first line treatment for visceral leishmaniasis in eastern Africa, but is painful and requires hospitalization. Combination regimens including AmBisome and miltefosine are safe and effective in India, but there are no published data from trials of combination therapies including these drugs from Africa. Methods A phase II open-label, non-comparative randomized trial was conducted in Sudan and Kenya to evaluate the efficacy and safety of three treatment regimens: 10 mg/kg single dose AmBisome plus 10 days of SSG (20 mg/kg/day), 10 mg/kg single dose AmBisome plus 10 days of miltefosine (2.5mg/kg/day) and miltefosine alone (2.5 mg/kg/day for 28 days). The primary endpoint was initial parasitological cure at Day 28, and secondary endpoints included definitive cure at Day 210, and pharmacokinetic (miltefosine) and pharmacodynamic assessments. Results In sequential analyses with 49–51 patients per arm, initial cure was 85% (95% CI: 73–92) in all arms. At D210, definitive cure was 87% (95% CI: 77–97) for AmBisome + SSG, 77% (95% CI 64–90) for AmBisome + miltefosine and 72% (95% CI 60–85) for miltefosine alone, with lower efficacy in younger patients, who weigh less. Miltefosine pharmacokinetic data indicated under-exposure in children compared to adults. Conclusion No major safety concerns were identified, but point estimates of definitive cure were less than 90% for each regimen so none will be evaluated in Phase III trials in their current form. Allometric dosing of miltefosine in children needs to be evaluated. Trial Registration The study was registered with ClinicalTrials.gov, number NCT01067443 PMID:27627654

  18. The SafeBoosC phase II clinical trial: an analysis of the interventions related with the oximeter readings

    PubMed Central

    Riera, Joan; Hyttel-Sorensen, Simon; Bravo, María Carmen; Cabañas, Fernando; López-Ortego, Paloma; Sanchez, Laura; Ybarra, Marta; Dempsey, Eugene; Greisen, Gorm; Austin, Topun; Claris, Olivier; Fumagalli, Monica; Gluud, Christian; Lemmers, Petra; Pichler, Gerhard; Plomgaard, Anne Mette; van Bel, Frank; Wolf, Martin; Pellicer, Adelina

    2016-01-01

    Background The SafeBoosC phase II randomised clinical trial recently demonstrated the benefits of a combination of cerebral regional tissue oxygen saturation (rStO2) by near-infrared spectroscopy (NIRS) and a treatment guideline to reduce the oxygen imbalance in extremely preterm infants. Aims To analyse rStO2-alarm-related clinical decisions and their heterogeneity in the NIRS experimental group (NIRS monitoring visible) and their impact on rStO2 and SpO2. Methods Continuous data from NIRS devices and the alarms (area under the curve of the rStO2 out of range had accumulated 0.2%h during 10 min), clinical data at discrete time points and interventions prompted by the alarms were recorded. Results Sixty-seven infants had data that fulfilled the requirements for this analysis. 1107 alarm episodes were analysed. The alarm triggered a treatment guideline intervention in 25% of the cases; the type of intervention chosen varied among clinical sites. More than 55% of alarms were not followed by an intervention (‘No action’); additionally, in 5% of alarms the rStO2 value apparently was considered non-reliable and the sensor was repositioned. The percentage of unresolved alarms at 30 min after ‘No action’ almost doubled the treatment guideline intervention (p<0.001). Changes in peripheral oxygen saturation (SpO2), were observed only after treatment guideline interventions. Conclusions This study shows that 25% of rStO2 alarms were followed by a clinical intervention determined by the treatment guideline. However, the rStO2 and SpO2 returned to normal ranges after the intervention, supporting the notion that decisions taken by the clinicians were appropriate. Trial registration number ClinicalTrial.gov NCT01590316. PMID:26645538

  19. Clinical Evidence of the Efficacy of a Mouthwash Containing Propolis for the Control of Plaque and Gingivitis: A Phase II Study

    PubMed Central

    Pereira, Elizete Maria Rita; da Silva, João Luís Duval Cândido; Silva, Fernando Freitas; De Luca, Mariana Passos; Ferreira, Efigênia Ferreira e; Lorentz, Telma Campos Medeiros; Santos, Vagner Rodrigues

    2011-01-01

    The aim of this study was to evidence the clinical efficacy of an alcohol-free mouthwash containing 5.0% (W/V) Brazilian green propolis (MGP 5%) for the control of plaque and gingivitis. Twenty five subjects, men and women aging between 18 and 60 years old (35 ± 9), were included in a clinical trials phase II study who had a minimum of 20 sound natural teeth, a mean plaque index of at least 1.5 (PI), and a mean gingival index of at least 1.0 (GI). They were instructed to rinse with 10 mL of mouthwash test for 1 minute, immediately after brushing in the morning and at night. After 45 and 90 days using mouthwash, the results showed a significant reduction in plaque and in gingival index when compared to samples obtained in baseline. These reductions were at 24% and 40%, respectively (P < .5). There were no important side effects in soft and hard tissues of the mouth. In this study, the MGP 5% showed evidence of its efficacy in reducing PI and GI. However, it is necessary to perform a clinical trial, double-blind, randomized to validate such effectiveness. PMID:21584253

  20. Clinical Evidence of the Efficacy of a Mouthwash Containing Propolis for the Control of Plaque and Gingivitis: A Phase II Study.

    PubMed

    Pereira, Elizete Maria Rita; da Silva, João Luís Duval Cândido; Silva, Fernando Freitas; De Luca, Mariana Passos; Ferreira, Efigênia Ferreira E; Lorentz, Telma Campos Medeiros; Santos, Vagner Rodrigues

    2011-01-01

    The aim of this study was to evidence the clinical efficacy of an alcohol-free mouthwash containing 5.0% (W/V) Brazilian green propolis (MGP 5%) for the control of plaque and gingivitis. Twenty five subjects, men and women aging between 18 and 60 years old (35 ± 9), were included in a clinical trials phase II study who had a minimum of 20 sound natural teeth, a mean plaque index of at least 1.5 (PI), and a mean gingival index of at least 1.0 (GI). They were instructed to rinse with 10 mL of mouthwash test for 1 minute, immediately after brushing in the morning and at night. After 45 and 90 days using mouthwash, the results showed a significant reduction in plaque and in gingival index when compared to samples obtained in baseline. These reductions were at 24% and 40%, respectively (P < .5). There were no important side effects in soft and hard tissues of the mouth. In this study, the MGP 5% showed evidence of its efficacy in reducing PI and GI. However, it is necessary to perform a clinical trial, double-blind, randomized to validate such effectiveness.

  1. TG1042 (Adenovirus-interferon-γ) in Primary Cutaneous B-cell Lymphomas: A Phase II Clinical Trial

    PubMed Central

    Dreno, Brigitte; Urosevic-Maiwald, Mirjana; Kim, Youn; Guitart, Joan; Duvic, Madeleine; Dereure, Olivier; Khammari, Amir; Knol, Anne-Chantal; Derbij, Anna; Lusky, Monika; Didillon, Isabelle; Santoni, Anne-Marie; Acres, Bruce; Bataille, Vincent; Chenard, Marie-Pierre; Bleuzen, Pascal; Limacher, Jean-Marc; Dummer, Reinhard

    2014-01-01

    Rational While a variety of registered therapies exist for Cutaneous T Cell Lymphoma, no such therapy is available for Cutaneous B Cell Therapy. In this context we performed a phase II, open label, multicenter, non-comparative study to evaluate the efficacy and safety of repeated intra-lesional administrations of TG1042 (adenovirus-interferon-γ) in patients with relapsing primary cutaneous B-cell lymphomas (CBCL). Method Thirteen patients have been enrolled and received intralesional injections of TG1042 containing 5×1010 viral particles into up to six lesions simultaneously. Injections were performed on days 1, 8 and 15 of each of four consecutive 28 day cycles. Results Eleven (85%) out of 13 enrolled patients showed an objective response after injections of TG1042. Seven patients (54%) exhibited complete and four (31%) displayed partial response. The median time to disease progression in the study population was 23.5 months (range 6.25 to 26+). Most commonly observed adverse events were minor to moderate flu-like symptoms, fatigue and injection site reactions. Conclusions Our study showed that treatment with TG1042 was associated with a clinical benefit in the majority of the patients with relapsing CBCL, including tumor regression, a clinically meaningful duration of response and a good treatment tolerance. Trial Registration www.clinicaltrials.gov NCT00394693 PMID:24586226

  2. Optimal adaptive two-stage designs for early phase II clinical trials.

    PubMed

    Shan, Guogen; Wilding, Gregory E; Hutson, Alan D; Gerstenberger, Shawn

    2016-04-15

    Simon's optimal two-stage design has been widely used in early phase clinical trials for Oncology and AIDS studies with binary endpoints. With this approach, the second-stage sample size is fixed when the trial passes the first stage with sufficient activity. Adaptive designs, such as those due to Banerjee and Tsiatis (2006) and Englert and Kieser (2013), are flexible in the sense that the second-stage sample size depends on the response from the first stage, and these designs are often seen to reduce the expected sample size under the null hypothesis as compared with Simon's approach. An unappealing trait of the existing designs is that they are not associated with a second-stage sample size, which is a non-increasing function of the first-stage response rate. In this paper, an efficient intelligent process, the branch-and-bound algorithm, is used in extensively searching for the optimal adaptive design with the smallest expected sample size under the null, while the type I and II error rates are maintained and the aforementioned monotonicity characteristic is respected. The proposed optimal design is observed to have smaller expected sample sizes compared to Simon's optimal design, and the maximum total sample size of the proposed adaptive design is very close to that from Simon's method. The proposed optimal adaptive two-stage design is recommended for use in practice to improve the flexibility and efficiency of early phase therapeutic development. PMID:26526165

  3. A randomized phase II study of cediranib alone versus cediranib in combination with dasatinib in docetaxel resistant, castration resistant prostate cancer patients

    PubMed Central

    Spreafico, Anna; Chi, Kim N.; Sridhar, Srikala S.; Smith, David C.; Carducci, Michael A.; Kavsak, Peter; Wong, Tracy S.; Wang, Lisa; Ivy, S. Percy; Mukherjee, Som Dave; Kollmannsberger, Christian K.; Sukhai, Mahadeo A.; Takebe, Naoko; Kamel-Reid, Suzanne; Siu, Lillian L.

    2014-01-01

    Summary Background Activation of the vascular endothelial growth factor receptor (VEGFR) and the oncogenic Src pathway has been implicated in the development of castration-resistant prostate cancer (CRPC) in preclinical models. Cediranib and dasatinib are multi-kinase inhibitors targeting VEGFR and Src respectively. Phase II studies of cediranib and dasatinib in CRPC have shown single agent activity. Methods Docetaxel-pretreated CRPC patients were randomized to arm A: cediranib alone (20 mg/day) versus arm B: cediranib (20 mg/day) plus dasatinib (100 mg/day) given orally on 4-week cycles. Primary endpoint was 12-week progression-free survival (PFS) as per the Prostate Cancer Clinical Trials Working Group (PCWG2). Patient reported outcomes were evaluated using Functional Assessment of Cancer Therapy- Prostate (FACT-P) and Present Pain Intensity (PPI) scales. Correlative studies of bone turnover markers (BTM), including bone alkaline phosphate (BAP) and serum beta-C telopeptide (B-CTx) were serially assayed. Results A total of 22 patients, 11 per arm, were enrolled. Baseline demographics were similar in both arms. Median number of cycles =4 in arm A (range 1–12) and 2 in arm B (range 1–9). Twelve-week PFS was 73 % in arm A versus 18 % in arm B (p=0.03). Median PFS in months (arm A versus B) was: 5.2 versus 2.6 (95 % CI: 1.9–6.5 versus 1.4-not reached). Most common grade 3 toxicities were hypertension, anemia and thrombocytopenia in arm A and hypertension, diarrhea and fatigue in arm B. One treatment-related death (retroperitoneal hemorrhage) was seen in arm A. FACT-P and PPI scores did not significantly change in either arm. No correlation between BTM and PFS was seen in either arm. Conclusions Although limited by small numbers, this randomized study showed that the combination of VEGFR and Src targeted therapy did not result in improved efficacy and may be associated with a worse outcome than VEGFR targeted therapy alone in patients with CRPC. PMID:24788563

  4. A Randomized, Double Blind, Placebo-Controlled, Multicenter Phase II Trial of Allisartan Isoproxil in Essential Hypertensive Population at Low-Medium Risk

    PubMed Central

    Li, Ying; Li, Xiao-hui; Huang, Zhi-jun; Yang, Guo-ping; Zhang, Guo-gang; Zhao, Shui-ping; Guo, Ying; Lu, Shi-juan; Ma, Jian-lin; Meng, Fan-bo; Chen, Ping; Yuan, Hong

    2015-01-01

    Background Angiotensin II receptor blockers (ARBs) is a well-tolerated class of antihypertensive agents, exhibiting effective antihypertensive and cardiovascular protective function. The objective of the study was to examine the efficacy and safety of Allisartan Isoproxil, a newly developed, selective, nonpeptide blocker of the angiotensin II type 1 receptor (AT1R), in essential hypertensive patients at low-medium risk. Methods and Findings A Phase II prospective, randomized, double-blind, placebo-controlled, multicenter trial comparing Allisartan Isoproxil 240mg versus placebo was conducted in essential hypertensive patients at low-medium risk at 8 sites in China. After a 2-week placebo baseline period, 275 patients received once-daily treatment with Allisartan Isoproxil 240mg or placebo randomly for 8 weeks. Systolic/diastolic blood pressure (SBP/DBP) was measured at week 2, 4 and 8. By the end of treatment, mean reductions from baseline of SBP and DBP in Allisartan Isoproxil and placebo groups were 14.5/10.4 and 8.3/7.7 mmHg, respectively (P<0.01). The rate of effective blood pressure control in Allisartan Isoproxil group was significantly higher than in placebo group at week 4 (61.3% vs 50.0%, P<0.05) and week 8 (67.2% vs 48.6%, P<0.01). In terms of safety and tolerability, there were no report of death and serious adverse event (SAE) in all subjects. There was no difference of frequency between two groups in adverse event (AE) and adverse drug reaction (ADR) (P>0.05). No one withdraw because of an ADR in two groups. 124 patients received additional 56 weeks treatment with Allisartan Isoproxil and 84 of them completed the study. The rate of effective BP control kept up to 80% since week 24. No significant clinical change was observed and ADRs were generally mild or moderate during the long-term study. Conclusions/Significance Allisartan Isoproxil 240mg was effective and safe for essential hypertension patients at low-medium risk. Trial Registration http

  5. A randomized phase II study of carboplatin plus pegylated liposomal doxorubicin versus carboplatin plus paclitaxel in platinum sensitive ovarian cancer patients: a Hellenic Cooperative Oncology Group study

    PubMed Central

    2010-01-01

    Background Platinum-based combinations are the standard second-line treatment for platinum-sensitive ovarian cancer (OC). This randomized phase II study was undertaken in order to compare the combination of carboplatin and pegylated liposomal doxorubicin (LD) with carboplatin and paclitaxel (CP) in this setting. Methods Patients with histologically confirmed recurrent OC, at the time of or more than 6 months after platinum-based chemotherapy, were randomized to six cycles of CP (carboplatin AUC5 + paclitaxel 175 mg/m2, d1q21) or CLD (carboplatin AUC5 + pegylated LD 45 mg/m2, d1q28). Results A total of 189 eligible patients (CP 96, CLD 93), with a median age of 63 years, median Performance Status (PS) 0 and a median platinum free interval (PFI) of 16.5 months, entered the study. Discontinuation due to toxicity was higher in the CP patients (13.5% versus 3%, P = 0.016). The overall response rate was similar: CP 58% versus CLD 51%, P = 0.309 (Complete Response; CR 34% versus 23%) and there was no statistical difference in time-to-progression (TTP) or overall survival (OS; TTP 10.8 months CP versus 11.8 CLD, P = 0.904; OS 29.4 months CP versus 24.7 CLD, P = 0.454). No toxic deaths were recorded. Neutropenia was the most commonly seen severe toxicity (CP 30% versus CLD 35%). More frequent in CLD were severe thrombocytopenia (11% versus 2%, P = 0.016), skin toxicity and Palmar-plantar erythrodysesthesia (PPE) grade 1-2 (38% versus 9%, P< 0.001), while grade 3 neurotoxicity and alopecia were higher in CP (7% versus 0%, P = 0.029, 20% versus 5%, P = 0.003). PS and PFI were independent prognostic factors for TTP and OS. Conclusions The combination of pegylated LD with carboplatin is effective, showing less neurotoxicity and alopecia than paclitaxel-carboplatin. It thus warrants a further phase III evaluation as an alternative treatment option for platinum-sensitive OC patients. Trial Registration Australian New Zealand Clinical Trials Registry: ACTRN12609000436279 PMID

  6. A Phase II Randomized Controlled Trial Comparing Safety, Procedure Time, and Cost of the PrePex™ Device to Forceps Guided Surgical Circumcision in Zimbabwe

    PubMed Central

    Tshimanga, Mufuta; Mangwiro, Tonderayi; Mugurungi, Owen; Xaba, Sinokuthemba; Murwira, Munyaradzi; Kasprzyk, Danuta; Montaño, Daniel E.; Nyamukapa, Daisy; Tambashe, Basile; Chatikobo, Pesanai; Gundidza, Patricia; Gwinji, Gerald

    2016-01-01

    Background The World Health Organization (WHO) and the Joint United Nations Program on HIV/AIDS promote MC (male circumcision) as a key HIV prevention strategy where HIV prevalence and incidence are high and MC prevalence is low. In Zimbabwe, to achieve the 1.26 million circumcisions needed to be performed by 2015 to achieve optimal MC coverage, a new approach was needed. The primary objective of the current trial was to assess the performance (safety, procedure time, and cost) of the PrePex device compared to forceps-guided surgical circumcision. Methods and Findings This Phase II, randomized, open-label trial in Zimbabwe involved healthy, non-circumcised adult male volunteers who were randomly assigned to the PrePex device (n = 160) or surgical arm (n = 80). Three doctors and 4 nurses, all certified on both circumcision methods, performed the procedures. The PrePex device procedure involves a plastic ring with a rubber O-ring that necrotizes the foreskin to facilitate easy and minimally invasive removal. Total procedure time was the primary endpoint. Adverse event (AE) data were also gathered for 90 days post-procedure. All 80 participants in the surgical arm and 158 participants in the PrePex arm achieved complete circumcision. The total procedure time for the PrePex device was approximately one-third of the total surgical procedure (4.8 minutes, Standard Deviation [SD]: 1.2 versus 14.6 minutes; SD: 4.2; p<0.00001). There were 2 AEs for 2 participants (rate of 1.3%, 95% Confidence Interval: 0.0025–4.53%), which were resolved with simple intervention. The AEs were device related, including 1 case of pain leading to device removal and 1 case of removal of the device. Conclusions The trial supports previous studies’ conclusions that the PrePex procedure is safe, quick, easy to apply, and effective in terms of procedure time as an alternative to traditional surgical circumcision. The PrePex device has great potential for use in overburdened health systems and in

  7. A phase II randomised clinical trial comparing cisplatin, paclitaxel and ifosfamide with cisplatin, paclitaxel and epirubicin in newly diagnosed advanced epithelial ovarian cancer: long-term survival analysis

    PubMed Central

    Fruscio, R; Colombo, N; Lissoni, A A; Garbi, A; Fossati, R; Ieda', N; Torri, V; Mangioni, C

    2008-01-01

    To test the feasibility and efficacy of epirubicin and ifosfamide added to first-line chemotherapy with cisplatin and paclitaxel in a phase II randomised clinical trial. Patients with histologically proven epithelial ovarian cancer were randomly assigned to receive first-line polychemotherapy with cisplatin/paclitaxel/epirubicin (CEP) or cisplatin/paclitaxel/ifosfamide (CIP) for six cycles every 21 days. Two hundred and eight patients were randomised between the two treatment arms and the median number of cycles per patient was six. Toxicity was predominantly haematological with both regimens; however, anaemia, leucopaenia, neutropaenic fever and use of granulocyte colony-stimulating factors and transfusion were significantly more frequent in the CIP treatment arm. Response rates were 85% (95% confidence interval (CI) 77–93%) in the CIP arm and 90% (95% CI 84–96%) in the CEP arm; complete response rates were 48 and 52%. After a median follow-up of 82 months, median overall survival (OS) was 51 and 65 months; 5-year survival rates were respectively 43 and 50%. In this clinical trial, both regimens showed good efficacy, but toxicity was heavier with the CIP regimen. Considering that more than 50% of patients were suboptimally debulked after the first surgery, OS seems to be longer than is commonly reported. This unexpected finding might be a consequence of the close surgical surveillance and aggressive chemotherapeutic approach. PMID:18253120

  8. Effect of Carbon Ion Radiotherapy for Sacral Chordoma: Results of Phase I-II and Phase II Clinical Trials

    SciTech Connect

    Imai, Reiko; Kamada, Tadashi; Tsuji, Hiroshi; Sugawara, Shinji; Serizawa, Itsuko; Tsujii, Hirohiko; Tatezaki, Shin-ichiro

    2010-08-01

    Purpose: To summarize the results of treatment for sacral chordoma in Phase I-II and Phase II carbon ion radiotherapy trials for bone and soft-tissue sarcomas. Patients and Methods: We performed a retrospective analysis of 38 patients with medically unresectable sacral chordomas treated with the Heavy Ion Medical Accelerator in Chiba, Japan between 1996 and 2003. Of the 38 patients, 30 had not received previous treatment and 8 had locally recurrent tumor after previous resection. The applied carbon ion dose was 52.8-73.6 Gray equivalents (median, 70.4) in a total of 16 fixed fractions within 4 weeks. Results: The median patient age was 66 years. The cranial tumor extension was S2 or greater in 31 patients. The median clinical target volume was 523 cm{sup 3}. The median follow-up period was 80 months. The 5-year overall survival rate was 86%, and the 5-year local control rate was 89%. After treatment, 27 of 30 patients with primary tumor remained ambulatory with or without supportive devices. Two patients experienced severe skin or soft-tissue complications requiring skin grafts. Conclusion: Carbon ion radiotherapy appears effective and safe in the treatment of patients with sacral chordoma and offers a promising alternative to surgery.

  9. Clinical Impact of the Temporal Relationship between Depression and Type 2 Diabetes: The Fremantle Diabetes Study Phase II

    PubMed Central

    Bruce, David G.; Davis, Wendy A.; Cetrullo, Violetta; Starkstein, Sergio E.; Davis, Timothy M. E.

    2013-01-01

    Background The clinical features of type 2 diabetes may differ depending on whether first depression episode precedes or follows the diagnosis of diabetes. Methods Type 2 patients from the observational community-based Fremantle Diabetes Study Phase II underwent assessment of lifetime depression using the Brief Lifetime Depression Scale (developed and validated for this study) supplemented by information on current depression symptoms (Patient Health Questionnaire, 9-item version) and use of antidepressants. Patients were categorized as never depressed (Group 1), having had depression before diabetes diagnosis (Group 2), diagnosed with depression and diabetes within 2 years of each other (Group 3) and having depression after diabetes diagnosis (Group 4). Results Of 1391 patients, 20.8% were assigned to Group 2, 6.0% to Group 3 and 14.5% to Group 4. In Group 2, depression occurred a median 15.6 years before diabetes onset at age 37.2±14.7 years. These patients had similar clinical characteristics to never depressed patients except for reduced self-care behaviours and having more symptomatic peripheral arterial disease. In Group 4, depression occurred a median 9.9 years after diabetes onset at age 59.8±13.0 years. These patients had long duration diabetes, poor glycaemic control, more intensive management and more diabetic complications. Group 4 patients had more current depression than Group 2 but were less likely to be receiving antidepressants. Conclusions/Interpretation The clinical features of depression and type 2 diabetes are heterogeneous depending on their temporal relationship. There may be corresponding differences in the pathogenesis of depression in diabetes that have implications for diagnosis and management. PMID:24324682

  10. Paclitaxel injection concentrate for nanodispersion versus nab-paclitaxel in women with metastatic breast cancer: a multicenter, randomized, comparative phase II/III study.

    PubMed

    Jain, Minish M; Gupte, Smita U; Patil, Shekhar G; Pathak, Anand B; Deshmukh, Chetan D; Bhatt, Niraj; Haritha, Chiramana; Govind Babu, K; Bondarde, Shailesh A; Digumarti, Raghunadharao; Bajpai, Jyoti; Kumar, Ravi; Bakshi, Ashish V; Bhattacharya, Gouri Sankar; Patil, Poonam; Subramanian, Sundaram; Vaid, Ashok K; Desai, Chirag J; Khopade, Ajay; Chimote, Geetanjali; Bapsy, Poonamalle P; Bhowmik, Shravanti

    2016-02-01

    Paclitaxel is widely used in the treatment of patients with metastatic breast cancer (MBC). Formulations of paclitaxel contain surfactants and solvents or albumin derived from human blood. The use of co-solvents such as polyoxyethylated castor oil is thought to contribute to toxicity profile and hypersensitivity reactions as well as leaching of plasticizers from polyvinyl chloride bags and infusion sets. Currently, nab-paclitaxel, an albumin-bound paclitaxel in nanometer range continues to be the preferred taxane formulation used in clinic. This study (CTRI/2010/091/001116) investigated the efficacy and tolerability of a polyoxyethylated castor oil- and albumin-free formulation of paclitaxel [paclitaxel injection concentrate for nanodispersion (PICN)] compared with nab-paclitaxel in women with refractory MBC. The current study was a multicenter, open-label, parallel-group, randomized, comparative phase II/III trial evaluating the efficacy and safety of PICN (260 mg/m(2) [n = 64] and 295 mg/m(2) [n = 58] every 3 weeks) compared with nab-paclitaxel (260 mg/m(2) every 3 weeks [n = 58]) in women 18 and 70 years old with confirmed MBC. Overall response rate (ORR) was assessed with imaging every 2 cycles. An independent analysis of radiologic data was performed for evaluable patients. Progression-free survival (PFS) was a secondary efficacy measure. Independent radiologist-assessed ORRs in the evaluable population of women aged ≥70 years were 35, 49, and 43 % in the PICN 260 mg/m(2), PICN 295 mg/m(2), and nab-paclitaxel 260 mg/m(2) arms, respectively. Median PFS in the evaluable population was 23, 35, and 34 weeks in the PICN 260 mg/m(2), PICN 295 mg/m(2), and nab-paclitaxel 260 mg/m(2) arms, respectively. Adverse events occurred in similar proportions of patients across treatment arms. Hypersensitivity reactions were not frequently observed with the clinical use of PICN across the treatment cohorts. In women with metastatic breast cancer, PICN at 260 and 295 mg/m(2

  11. Phase I/randomized phase II study of afatinib, an irreversible ErbB family blocker, with or without protracted temozolomide in adults with recurrent glioblastoma

    PubMed Central

    Reardon, David A.; Nabors, Louis B.; Mason, Warren P.; Perry, James R.; Shapiro, William; Kavan, Petr; Mathieu, David; Phuphanich, Surasak; Cseh, Agnieszka; Fu, Yali; Cong, Julie; Wind, Sven; Eisenstat, David D.

    2015-01-01

    Background This phase I/II trial evaluated the maximum tolerated dose (MTD) and pharmacokinetics of afatinib plus temozolomide as well as the efficacy and safety of afatinib as monotherapy (A) or with temozolomide (AT) vs temozolomide monotherapy (T) in patients with recurrent glioblastoma (GBM). Methods Phase I followed a traditional 3 + 3 dose-escalation design to determine MTD. Treatment cohorts were: afatinib 20, 40, and 50 mg/day (plus temozolomide 75 mg/m2/day for 21 days per 28-day cycle). In phase II, participants were randomized (stratified by age and KPS) to receive A, T or AT; A was dosed at 40 mg/day and T at 75 mg/m2 for 21 of 28 days. Primary endpoint was progression-free survival rate at 6 months (PFS-6). Participants were treated until intolerable adverse events (AEs) or disease progression. Results Recommended phase II dose was 40 mg/day (A) + T based on safety data from phase I (n = 32). Most frequent AEs in phase II (n = 119) were diarrhea (71% [A], 82% [AT]) and rash (71% [A] and 69% [AT]). Afatinib and temozolomide pharmacokinetics were unaffected by coadministration. Independently assessed PFS-6 rate was 3% (A), 10% (AT), and 23% (T). Median PFS was longer in afatinib-treated participants with epidermal growth factor receptor (EFGR) vIII-positive tumors versus EGFRvIII-negative tumors. Best overall response included partial response in 1 (A), 2 (AT), and 4 (T) participants and stable disease in 14 (A), 14 (AT), and 21 (T) participants. Conclusions Afatinib has a manageable safety profile but limited single-agent activity in unselected recurrent GBM patients. PMID:25140039

  12. Phase II clinical trials with time-to-event endpoints: Optimal two-stage designs with one-sample log-rank test

    PubMed Central

    Kwak, Minjung; Jung, Sin-Ho

    2014-01-01

    Summary Phase II clinical trials are often conducted to determine whether a new treatment is sufficiently promising to warrant a major controlled clinical evaluation against a standard therapy. We consider single-arm phase II clinical trials with right censored survival time responses where the ordinary one-sample logrank test is commonly used for testing the treatment efficacy. For planning such clinical trials this paper presents two-stage designs that are optimal in the sense that the expected sample size is minimized if the new regimen has low efficacy subject to constraints of the type I and type II errors. Two-stage designs which minimize the maximal sample size are also determined. Optimal and minimax designs for a range of design parameters are tabulated along with examples. PMID:24338995

  13. Phase II randomized, double-blind, placebo-controlled study of whole-brain irradiation with concomitant chloroquine for brain metastases

    PubMed Central

    2013-01-01

    Background and purpose Chloroquine (CLQ), an antimalarial drug, has a lysosomotropic effect associated with increased radiationsensibility, which is mediated by the leakage of hydrolytic enzymes, increased apoptosis, autophagy and increased oxidative stress in vitro. In this phase II study, we evaluated the efficacy and safety of radiosensibilization using CLQ concomitant with 30 Gray (Gy) of whole-brain irradiation (WBI) to treat patients with brain metastases (BM) from solid tumors. Methods Seventy-three eligible patients were randomized. Thirty-nine patients received WBI (30 Gy in 10 fractions over 2 weeks) concomitant with 150 mg of CLQ for 4 weeks (the CLQ arm). Thirty-four patients received the same schedule of WBI concomitant with a placebo for 4 weeks (the control arm). All the patients were evaluated for quality of life (QoL) using the EORTC Quality of Life (QoL) Questionnaire (EORTC QLQ-C30) (Mexican version) before beginning radiotherapy and one month later. Results The overall response rate (ORR) was 54% for the CLQ arm and 55% for the control arm (p=0.92). The progression-free survival of brain metastases (BMPFS) rates at one year were 83.9% (95% CI 69.4-98.4) for the CLQ arm and 55.1% (95% CI 33.6-77.6) for the control arm. Treatment with CLQ was independently associated with increased BMPFS (RR 0.31,95% CI [0.1-0.9], p=0.046).The only factor that was independently associated with increased overall survival (OS) was the presence of< 4 brain metastases (RR 1.9, 95% CI [1.12-3.3], p=0.017). WBI was associated with improvements in cognitive and emotional function but also with worsened nausea in both patients groups. No differences in QoL or toxicity were found between the study arms. Conclusion Treatment with CLQ plus WBI improved the control of BM (compared with the control arm) with no increase in toxicity; however, CLQ did not improve the RR or OS. A phase III clinical trial is warranted to confirm these findings. PMID:24010771

  14. Readability and Content Assessment of Informed Consent Forms for Phase II-IV Clinical Trials in China

    PubMed Central

    Wen, Gaiyan; Liu, Xinchun; Huang, Lihua; Shu, Jingxian; Xu, Nana; Chen, Ruifang; Huang, Zhijun; Yang, Guoping; Wang, Xiaomin; Xiang, Yuxia; Lu, Yao; Yuan, Hong

    2016-01-01

    Purpose To explore the readability and content integrity of informed consent forms (ICFs) used in China and to compare the quality of Chinese local ICFs with that of international ICFs. Methods The length, readability and content of 155 consent documents from phase II-IV drug clinical trials from the Third Xiangya Hospital Ethics Committee from November 2009 to January 2015 were evaluated. Reading difficulty was tested using a readability formula adapted for the Chinese language. An ICF checklist containing 27 required elements was successfully constructed to evaluate content integrity. The description of alternatives to participation was assessed. The quality of ICFs from different sponsorships were also compared. Results Among the 155 evaluable trials, the ICFs had a median length of 5286 words, corresponding to 7 pages. The median readability score was 4.31 (4.02–4.41), with 63.9% at the 2nd level and 36.1% at the 3rd level. Five of the 27 elements were frequently neglected. The average score for the description of alternatives to participation was 1.06, and 27.7% of the ICFs did not mention any alternatives. Compared with Chinese local ICFs, international ICFs were longer, more readable and contained more of the required elements (P < 0.05). Conclusion The ICFs used in China were difficult to read for most participants. These forms had poor description of alternatives to participation, and failed to provide a high degree of information disclosure, including an explanation of informed consent, follow-up processing of the data/sample, inclusion/exclusion criteria, double blinding, and unpredictable risks. International ICFs had better readability and content integrity than Chinese local ICFs. More efforts should thus be made to improve the quality of consent documents in China. PMID:27701471

  15. Randomized Phase II Trial of High-Dose Melatonin and Radiation Therapy for RPA Class 2 Patients With Brain Metastases (RTOG 0119)

    SciTech Connect

    Berk, Lawrence . E-mail: Berklb@moffitt.usf.edu; Berkey, Brian; Rich, Tyvin; Hrushesky, William; Gallagher, Michael; Kudrimoti, Mahesh; McGarry, Ronald C.; Suh, John; Mehta, Minesh

    2007-07-01

    Purpose: To determine if high-dose melatonin for Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) Class 2 patients with brain metastases improved survival over historical controls, and to determine if the time of day melatonin was given affected its toxicity or efficacy. RTOG 0119 was a phase II randomized trial for this group of patients. Methods and Materials: RTOG RPA Class 2 patients with brain metastases were randomized to 20 mg of melatonin, given either in the morning (8-9 AM) or in the evening (8-9 PM). All patients received radiation therapy (30 Gy in 10 fractions) in the afternoon. Melatonin was continued until neurologic deterioration or death. The primary endpoint was overall survival time. Neurologic deterioration, as reflected by the Mini-Mental Status Examination, was also measured. Results: Neither of the randomized groups had survival distributions that differed significantly from the historic controls of patients treated with whole-brain radiotherapy. The median survivals of the morning and evening melatonin treatments were 3.4 and 2.8 months, while the RTOG historical control survival was 4.1 months. Conclusions: High-dose melatonin did not show any beneficial effect in this group of patients.

  16. A phase II clinical trial of endoscopic submucosal dissection for early gastric cancer of undifferentiated type: Japan Clinical Oncology Group study JCOG1009/1010.

    PubMed

    Takizawa, Kohei; Takashima, Atsuo; Kimura, Aya; Mizusawa, Junki; Hasuike, Noriaki; Ono, Hiroyuki; Terashima, Masanori; Muto, Manabu; Boku, Narikazu; Sasako, Mitsuru; Fukuda, Haruhiko

    2013-01-01

    A Phase II clinical trial has been initiated to evaluate the efficacy and safety of endoscopic submucosal dissection for intramucosal (cT1a) gastric cancer of undifferentiated type. Patients with cT1a gastric cancer with undifferentiated-type adenocarcinoma are eligible for the study. The tumor size should be 2 cm or less without ulceration. The study will enroll a total of 325 patients from 51 institutions over a 4-year period. The primary endpoint is proportion of 5-year overall survival (% 5-year overall survival) in patients with undifferentiated dominant type. The secondary endpoints are overall survival, relapse-free survival, distant metastasis-free survival, % 5-year overall survival without either recurrence or gastrectomy, % en-bloc resection with endoscopic submucosal dissection, % pathological curative resection with endoscopic submucosal dissection, % 5-year overall survival in patients with differentiated dominant type, % 5-year overall survival in patients with pathologically curative resection with endoscopic submucosal dissection and adverse events.

  17. Superior efficacy of calcipotriene and betamethasone dipropionate aerosol foam versus ointment in patients with psoriasis vulgaris – A randomized phase II study

    PubMed Central

    Koo, John; Tyring, Stephen; Werschler, William P.; Bruce, Suzanne; Olesen, Martin; Villumsen, John; Bagel, Jerry

    2016-01-01

    Abstract Background: An aerosol foam formulation of fixed combination calcipotriene 0.005% (as hydrate; Cal) plus betamethasone dipropionate 0.064% (BD) was developed to improve psoriasis treatment. Objectives: To compare the efficacy and safety of Cal/BD aerosol foam with Cal/BD ointment after 4 weeks. Methods: In this Phase II, multicenter, investigator-blind, 4-week trial, adult patients with psoriasis vulgaris were randomized to Cal/BD aerosol foam, Cal/BD ointment, aerosol foam vehicle or ointment vehicle (3:3:1:1). The primary efficacy endpoint was the proportion of patients at week 4 who achieved treatment success (clear or almost clear with at least a two-step improvement) according to the physician’s global assessment of disease severity. Results: In total, 376 patients were randomized. At week 4, significantly more patients using Cal/BD aerosol foam achieved treatment success (54.6% versus 43.0% [ointment]; p = 0.025); mean modified (excluding the head, which was not treated) psoriasis area and severity index score was significantly different between Cal/BD aerosol foam and Cal/BD ointment (mean difference –0.6; p = 0.005). Rapid, continuous itch relief occurred with both active treatments. One adverse drug reaction was reported with Cal/BD aerosol foam (application site itch). Conclusions: Cal/BD aerosol foam demonstrates significantly greater efficacy and similar tolerability compared with Cal/BD ointment for psoriasis treatment. PMID:26444907

  18. A Phase II Randomized Trial Of Lycopene-Rich Tomato Extract Among Men With High-Grade Prostatic Intraepithelial Neoplasia

    PubMed Central

    Gann, Peter H.; Deaton, Ryan J.; Rueter, Erika Enk; van Breemen, Richard B.; Nonn, Larisa; Macias, Virgilia; Han, Misop; Ananthanarayanan, Viju

    2015-01-01

    Background A diverse body of evidence suggests that lycopene might inhibit prostate cancer development. We conducted a 6-month repeat biopsy randomized trial among men with HGPIN. Here we report results for serum lycopene, PSA and IGF proteins, histopathological review, and tissue markers for proliferation (MCM-2) and cell cycle inhibition (p27). Methods Participants consumed placebo or tomato extract capsules containing 30 mg/day lycopene. Pre- and post-treatment biopsies were immunostained and digitally scored. Serum lycopene was determined by LC-MS-MS. In secondary analyses, pathologists blindly reviewed each biopsy to score histological features. Results 58 men completed the trial. Serum lycopene increased 0.55 μmol/L with treatment and declined 0.29 μmol/L with placebo. We observed no meaningful differences in PSA, IGF-1 or IGFBP3 concentrations between groups, nor any differences in expression of MCM-2 or p27 in epithelial nuclei. Prevalences of cancer, HGPIN, atrophy or inflammation post-treatment were similar; however, more extensive atrophy and less extensive HGPIN was more common in the lycopene group. Conclusions Despite large differences in serum lycopene following intervention, no treatment effects were apparent on either the serum or benign tissue endpoints. Larger studies are warranted to determine whether changes observed in extent of HGPIN and focal atrophy can be replicated. PMID:26422197

  19. A Phase II Randomized Trial of Lycopene-Rich Tomato Extract Among Men with High-Grade Prostatic Intraepithelial Neoplasia.

    PubMed

    Gann, Peter H; Deaton, Ryan J; Rueter, Erika Enk; van Breemen, Richard B; Nonn, Larisa; Macias, Virgilia; Han, Misop; Ananthanarayanan, Viju

    2015-01-01

    A diverse body of evidence suggests that lycopene might inhibit prostate cancer development. We conducted a 6-mo repeat biopsy randomized trial among men with high-grade prostatic intraepithelial neoplasia (HGPIN). Here we report results for serum lycopene, prostate specific antigen (PSA) and insulin-like growth factor (IGF) proteins, histopathological review, and tissue markers for proliferation [minichromosome maintenance protein 2 (MCM-2)] and cell cycle inhibition (p27). Participants consumed placebo or tomato extract capsules containing 30 mg/day lycopene. Pre- and posttreatment biopsies were immunostained and digitally scored. Serum lycopene was determined by LC-MS-MS. In secondary analyses, pathologists blindly reviewed each biopsy to score histological features. Fifty-eight men completed the trial. Serum lycopene increased 0.55 μmol/L with treatment and declined 0.29 μmol/L with placebo. We observed no meaningful differences in PSA, IGF-1, or IGF binding protein 3 concentrations between groups, nor any differences in expression of MCM-2 or p27 in epithelial nuclei. Prevalences of cancer, HGPIN, atrophy, or inflammation posttreatment were similar; however, more extensive atrophy and less extensive HGPIN was more common in the lycopene group. Despite large differences in serum lycopene following intervention, no treatment effects were apparent on either the serum or benign tissue endpoints. Larger studies are warranted to determine whether changes observed in extent of HGPIN and focal atrophy can be replicated. PMID:26422197

  20. Bevacizumab and temozolomide versus temozolomide alone as neoadjuvant treatment in unresected glioblastoma: the GENOM 009 randomized phase II trial.

    PubMed

    Balana, Carmen; De Las Penas, Ramon; Sepúlveda, Juan Manuel; Gil-Gil, Miguel J; Luque, Raquel; Gallego, Oscar; Carrato, Cristina; Sanz, Carolina; Reynes, Gaspar; Herrero, Ana; Ramirez, Jose Luis; Pérez-Segura, Pedro; Berrocal, Alfonso; Vieitez, Jose Maria; Garcia, Almudena; Vazquez-Estevez, Sergio; Peralta, Sergi; Fernandez, Isaura; Henriquez, Ivan; Martinez-Garcia, Maria; De la Cruz, Juan Jose; Capellades, Jaume; Giner, Pilar; Villà, Salvador

    2016-05-01

    We sought to determine the impact of bevacizumab on reduction of tumor size prior to chemoradiotherapy in unresected glioblastoma patients. Patients were randomized 1:1 to receive temozolomide (TMZ arm) or temozolomide plus bevacizumab (TMZ + BEV arm). In both arms, neoadjuvant treatment was temozolomide (85 mg/m(2), days 1-21, two 28-day cycles), concurrent radiation plus temozolomide, and six cycles of adjuvant temozolomide. In the TMZ + BEV arm, bevacizumab (10 mg/kg) was added on days 1 and 15 of each neoadjuvant cycle and on days 1, 15 and 30 of concurrent treatment. The primary endpoint was investigator-assessed response to neoadjuvant treatment. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and the impact on outcome of MGMT methylation in tumor and serum. One hundred and two patients were included; 43 in the TMZ arm and 44 in the TMZ + BEV arm were evaluable for response. Results favored the TMZ + BEV arm in terms of objective response (3 [6.7 %] vs. 11 [22.9 %]; odds ratio 4.2; P = 0.04). PFS and OS were longer in the TMZ + BEV arm, though the difference did not reach statistical significance. MGMT methylation in tumor, but not in serum, was associated with outcome. More patients experienced toxicities in the TMZ + BEV than in the TMZ arm (P = 0.06). The combination of bevacizumab plus temozolomide is more active than temozolomide alone and may well confer benefit in terms of tumor shrinkage in unresected patients albeit at the expense of greater toxicity. PMID:26847813

  1. Simulating the contribution of a biospecimen and clinical data repository in a phase II clinical trial: A value of information analysis.

    PubMed

    Craig, Benjamin M; Han, Gang; Munkin, Murat K; Fenstermacher, David

    2016-08-01

    The potential contributions of a centralized data warehouse or repository in clinical research include the expedited accrual of subjects for phase II trials. Understanding the contribution of data warehouses that integrate clinical, biospecimen, and molecular data for the conduct of clinical trials is essential to inform private and public decisions on resource allocation and investment. We conducted a value of information analysis using data from recent trials at the Moffitt Cancer Center and simulated the potential reductions in trial size due to possible alternative scenarios of expedited accrual. In this study, we compared alternative data sets using a single model to assess value of information. Our findings suggest that the reductions in trial size range from 0% to 43%, depending on the amount of censoring in overall survival. The ability to expedite the accrual of patients for clinical trial studies using large data repositories that store data on inclusion/exclusion criteria and response to standard of care therapies demonstrated significant improvement in reducing the number of subjects needed to achieve similar end-results, as evaluated using value of information analysis with a limited number of parameters and a parsimonious model of overall survival.

  2. Efficacy and safety of thalidomide for the treatment of severe recurrent epistaxis in hereditary hemorrhagic telangiectasia: results of a prospective phase II clinical trial

    PubMed Central

    Invernizzi, Rosangela; Quaglia, Federica; Klersy, Caherine; Pagella, Fabio; Ornati, Federica; Chu, Francesco; Matti, Elina; Spinozzi, Giuseppe; Plumitallo, Sara; Grignani, Pierangela; Olivieri, Carla; Bastia, Raffaella; Bellistri, Francesca; Danesino, Cesare; Benazzo, Marco; Balduini, Carlo L

    2016-01-01

    Summary Background Hereditary hemorrhagic telangiectasia (HHT) is a genetic disease that leads to multiregional angiodysplasia. Severe recurrent epistaxis is the most common presentation, frequently leading to severe anemia. Multiple therapeutic approaches have been tried, but they are largely palliative with variable results.We aimed to assess the efficacy of thalidomide in reducing epistaxis in patients with HHT refractory to standard therapy. Methods HHT patients with severe recurrent epistaxis refractory to mini-invasive surgical procedures were included in an open label, phase II, prospective, non-randomized, single-centre study. Thalidomide was administered at a starting dose of 50 mg/day orally. In the event of no response, thalidomide dosage was increased by 50 mg/day every four weeks until response to a maximum dose of 200 mg/day. After response achievement, patients were treated for eight to16 additional weeks. Monthly follow-up was based on the epistaxis severity score and transfusion need, with adverse events being reported (ClinicalTrials.gov Identifier: NCT01485224). Findings Thirty-one patients, mean age 62∙6 (SD 11∙1) years, were enrolled (median follow-up 15∙9 months, 25th-75th 10∙1-22∙3). Treatment induced cessation of bleeding in three cases (9∙7%) and a significant decrease in all epistaxis parameters in 28 cases (90∙3%). Twenty-five patients (80∙7%) obtained remission with 50 mg/day of thalidomide, five (16∙1%) with 100 mg/day and one (3∙2%) with 150 mg/day. Treatment significantly increased hemoglobin levels (p<0∙001), and abolished or greatly decreased the transfusion need (p<0∙001).Only nonserious, grade I, adverse effects were observed, including constipation and drowsiness. Median time to relapse after the end of therapy was 6∙4 months. No correlation was found between genetic or clinical features and response to thalidomide or toxicity. Interpretation Low-dose thalidomide is safe and very effective in reducing

  3. A Phase II, Randomized, Safety and Immunogenicity Study of a Re-Derived, Live-Attenuated Dengue Virus Vaccine in Healthy Adults

    PubMed Central

    Thomas, Stephen J.; Eckels, Kenneth H.; Carletti, Isabelle; De La Barrera, Rafael; Dessy, Francis; Fernandez, Stefan; Putnak, Robert; Toussaint, Jean-Francois; Sun, Wellington; Bauer, Kristen; Gibbons, Robert V.; Innis, Bruce L.

    2013-01-01

    Two formulations of a new live tetravalent dengue virus (DENV) vaccine produced using re-derived master seeds from a precursor vaccine and that same precursor vaccine as a control were compared in a placebo-controlled, randomized, observer-blind, phase II trial of 86 healthy adults. Two vaccine doses were administered 6 months apart; a third dose was offered to a subset. Symptoms and signs of dengue-like illness reported after vaccination were mild to moderate, transient, and occurred with similar frequency among recipients of the new DENV vaccine and placebo, except for rash. Neither dengue nor vaccine-related serious adverse events were reported. The first DENV vaccine dose was moderately immunogenic; the second dose increased the potency and breadth of the neutralizing antibody response. Tetravalent response rates to the new formulations were 60% and 66.7% in unprimed subjects. A third dose did not increase tetravalent antibody rates. The new DENV vaccine candidates merit additional evaluation. PMID:23208878

  4. Randomized, placebo-controlled phase II trial of heat-killed Mycobacterium vaccae (Longcom batch) formulated as an oral pill (V7)

    PubMed Central

    Efremenko, Yuri V; Butov, Dmytro A; Prihoda, Natalia D; Zaitzeva, Svetlana I; Yurchenko, Larisa V; Sokolenko, Nina I; Butova, Tetyana S; Stepanenko, Anna L; Kutsyna, Galyna A; Jirathitikal, Vichai; Bourinbaiar, Aldar S

    2013-01-01

    One-month Phase II trial was conducted in 43 sputum smear-positive patients with pulmonary tuberculosis randomized into treatment (n = 22) and placebo (n = 21) arms to investigate the safety and efficacy of an orally-administered therapeutic TB vaccine (V7) containing 10 μg of heat-killed Mycobacterium vaccae provided by Longcom company. Immunotherapy and control groups comprised 8 newly diagnosed (1stDx TB; 18.6%), 6 re-treated (RTB; 14%), and 29 multidrug-resistant (MDR-TB; 67.4%) cases distributed at 5:4:13 and 3:2:16 ratios, respectively. Both arms received conventional TB drugs administered under directly observed therapy. The average weight gain in V7 arm was modest, but statistically significant (0.6 kg; p = 0.004), while placebo patients lost 0.1 kg (p = 0.77). Except defervescence and increased lymphocyte percentage, other secondary endpoints such as erythrocyte sedimentation rate (ESR), leukocyte counts and hemoglobin content were not significantly affected. In control patients only one secondary endpoint, ESR, has improved. After one month mycobacterial clearance in sputum smears was observed in 31.8% (p = 0.03) and 9.5% (p = 0.83) of patients on V7 and placebo. However, the difference between outcomes in two arms was below significance threshold (p = 0.07). Thus, larger population of patients with prolonged follow-up is required to support these preliminary findings. PMID:23782489

  5. Valproic Acid, a Histone Deacetylase Inhibitor, in Combination with Paclitaxel for Anaplastic Thyroid Cancer: Results of a Multicenter Randomized Controlled Phase II/III Trial

    PubMed Central

    Pugliese, Mariateresa; Gallo, Marco; Brignardello, Enrico; Milla, Paola; Orlandi, Fabio; Limone, Paolo Piero; Arvat, Emanuela; Boccuzzi, Giuseppe; Piovesan, Alessandro

    2016-01-01

    Anaplastic thyroid cancer (ATC) has a median survival less than 5 months and, to date, no effective therapy exists. Taxanes have recently been stated as the main drug treatment for ATC, and the histone deacetylase inhibitor valproic acid efficiently potentiates the effects of paclitaxel in vitro. Based on these data, this trial assessed the efficacy and safety of the combination of paclitaxel and valproic acid for the treatment of ATC. This was a randomized, controlled phase II/III trial, performed on 25 ATC patients across 5 centers in northwest Italy. The experimental arm received the combination of paclitaxel (80 mg/m2/weekly) and valproic acid (1,000 mg/day); the control arm received paclitaxel alone. Overall survival and disease progression, evaluated in terms of progression-free survival, were the primary outcomes. The secondary outcome was the pharmacokinetics of paclitaxel. The coadministration of valproic acid did not influence the pharmacokinetics of paclitaxel. Neither median survival nor median time to progression was statistically different in the two arms. Median survival of operated-on patients was significantly better than that of patients who were not operated on. The present trial demonstrates that the addition of valproic acid to paclitaxel has no effect on overall survival and disease progression of ATC patients. This trial is registered with EudraCT 2008-005221-11. PMID:27766105

  6. Immunogenicity and safety of a tetravalent dengue vaccine in healthy adults in India: A randomized, observer-blind, placebo-controlled phase II trial.

    PubMed

    Dubey, Anand Prakash; Agarkhedkar, Sharad; Chhatwal, Jugesh; Narayan, Arun; Ganguly, Satyabrata; Wartel, T Anh; Bouckenooghe, Alain; Menezes, Josemund

    2016-01-01

    Dengue is a mosquito-borne viral disease that is endemic in India. We evaluated the immunogenicity and safety of recombinant, live-attenuated, tetravalent dengue vaccine (CYD-TDV) in Indian adults. In this observer-blind, randomized, placebo-controlled, Phase II study, adults aged 18-45 years were randomized 2:1 to receive CYD-TDV or placebo at 0, 6 and 12 months in sub-cutaneous administration. Immunogenicity was assessed using a 50% plaque reduction neutralization test (PRNT50) at baseline and 28 days after each study injection. 189 participants were enrolled (CYD-TDV [n = 128]; placebo, [n = 61]). At baseline, seropositivity rates for dengue serotypes 1, 2, 3 and 4 ranged from 77.0% to 86.9%. Seropositivity rates for each serotype increased after each CYD-TDV injection with a more pronounced increase after the first injection. In the CYD-TDV group, geometric mean titres (GMTs) were 2.38 to 6.11-fold higher after the third injection compared with baseline but remained similar to baseline in the placebo group. In the CYD-TDV group, the GMTs were 1.66 to 4.95-fold higher and 9.23 to 24.6-fold higher after the third injection compared with baseline in those who were dengue seropositive and dengue seronegative, respectively. Pain was the most commonly reported solicited injection site reaction after the first injection in both the CYD-TDV (6.3%) and placebo groups (4.9%), but occurred less frequently after subsequent injections. No serious adverse events were vaccine-related, no immediate unsolicited adverse events, and no virologically-confirmed cases of dengue, were reported during the study. The immunogenicity and safety of CYD-TDV was satisfactory in both dengue seropositive and seronegative Indian adults. PMID:26291554

  7. Immunogenicity and safety of a tetravalent dengue vaccine in healthy adults in India: A randomized, observer-blind, placebo-controlled phase II trial.

    PubMed

    Dubey, Anand Prakash; Agarkhedkar, Sharad; Chhatwal, Jugesh; Narayan, Arun; Ganguly, Satyabrata; Wartel, T Anh; Bouckenooghe, Alain; Menezes, Josemund

    2016-01-01

    Dengue is a mosquito-borne viral disease that is endemic in India. We evaluated the immunogenicity and safety of recombinant, live-attenuated, tetravalent dengue vaccine (CYD-TDV) in Indian adults. In this observer-blind, randomized, placebo-controlled, Phase II study, adults aged 18-45 years were randomized 2:1 to receive CYD-TDV or placebo at 0, 6 and 12 months in sub-cutaneous administration. Immunogenicity was assessed using a 50% plaque reduction neutralization test (PRNT50) at baseline and 28 days after each study injection. 189 participants were enrolled (CYD-TDV [n = 128]; placebo, [n = 61]). At baseline, seropositivity rates for dengue serotypes 1, 2, 3 and 4 ranged from 77.0% to 86.9%. Seropositivity rates for each serotype increased after each CYD-TDV injection with a more pronounced increase after the first injection. In the CYD-TDV group, geometric mean titres (GMTs) were 2.38 to 6.11-fold higher after the third injection compared with baseline but remained similar to baseline in the placebo group. In the CYD-TDV group, the GMTs were 1.66 to 4.95-fold higher and 9.23 to 24.6-fold higher after the third injection compared with baseline in those who were dengue seropositive and dengue seronegative, respectively. Pain was the most commonly reported solicited injection site reaction after the first injection in both the CYD-TDV (6.3%) and placebo groups (4.9%), but occurred less frequently after subsequent injections. No serious adverse events were vaccine-related, no immediate unsolicited adverse events, and no virologically-confirmed cases of dengue, were reported during the study. The immunogenicity and safety of CYD-TDV was satisfactory in both dengue seropositive and seronegative Indian adults.

  8. Immunogenicity and safety of a tetravalent dengue vaccine in healthy adults in India: A randomized, observer-blind, placebo-controlled phase II trial

    PubMed Central

    Dubey, Anand Prakash; Agarkhedkar, Sharad; Chhatwal, Jugesh; Narayan, Arun; Ganguly, Satyabrata; Wartel, T Anh; Bouckenooghe, Alain; Menezes, Josemund

    2016-01-01

    Dengue is a mosquito-borne viral disease that is endemic in India. We evaluated the immunogenicity and safety of recombinant, live-attenuated, tetravalent dengue vaccine (CYD-TDV) in Indian adults. In this observer-blind, randomized, placebo-controlled, Phase II study, adults aged 18–45 years were randomized 2:1 to receive CYD-TDV or placebo at 0, 6 and 12 months in sub-cutaneous administration. Immunogenicity was assessed using a 50% plaque reduction neutralization test (PRNT50) at baseline and 28 days after each study injection. 189 participants were enrolled (CYD-TDV [n = 128]; placebo, [n = 61]). At baseline, seropositivity rates for dengue serotypes 1, 2, 3 and 4 ranged from 77.0% to 86.9%. Seropositivity rates for each serotype increased after each CYD-TDV injection with a more pronounced increase after the first injection. In the CYD-TDV group, geometric mean titres (GMTs) were 2.38 to 6.11-fold higher after the third injection compared with baseline but remained similar to baseline in the placebo group. In the CYD-TDV group, the GMTs were 1.66 to 4.95-fold higher and 9.23 to 24.6-fold higher after the third injection compared with baseline in those who were dengue seropositive and dengue seronegative, respectively. Pain was the most commonly reported solicited injection site reaction after the first injection in both the CYD-TDV (6.3%) and placebo groups (4.9%), but occurred less frequently after subsequent injections. No serious adverse events were vaccine-related, no immediate unsolicited adverse events, and no virologically-confirmed cases of dengue, were reported during the study. The immunogenicity and safety of CYD-TDV was satisfactory in both dengue seropositive and seronegative Indian adults. PMID:26291554

  9. Tumor volume measurement error using computed tomography imaging in a phase II clinical trial in lung cancer.

    PubMed

    Henschke, Claudia I; Yankelevitz, David F; Yip, Rowena; Archer, Venice; Zahlmann, Gudrun; Krishnan, Karthik; Helba, Brian; Avila, Ricardo

    2016-07-01

    To address the error introduced by computed tomography (CT) scanners when assessing volume and unidimensional measurement of solid tumors, we scanned a precision manufactured pocket phantom simultaneously with patients enrolled in a lung cancer clinical trial. Dedicated software quantified bias and random error in the [Formula: see text], and [Formula: see text] dimensions of a Teflon sphere and also quantified response evaluation criteria in solid tumors and volume measurements using both constant and adaptive thresholding. We found that underestimation bias was essentially the same for [Formula: see text], and [Formula: see text] dimensions using constant thresholding and had similar values for adaptive thresholding. The random error of these length measurements as measured by the standard deviation and coefficient of variation was 0.10 mm (0.65), 0.11 mm (0.71), and 0.59 mm (3.75) for constant thresholding and 0.08 mm (0.51), 0.09 mm (0.56), and 0.58 mm (3.68) for adaptive thresholding, respectively. For random error, however, [Formula: see text] lengths had at least a fivefold higher standard deviation and coefficient of variation than [Formula: see text] and [Formula: see text]. Observed [Formula: see text]-dimension error was especially high for some 8 and 16 slice CT models. Error in CT image formation, in particular, for models with low numbers of detector rows, may be large enough to be misinterpreted as representing either treatment response or disease progression.

  10. Tumor volume measurement error using computed tomography imaging in a phase II clinical trial in lung cancer.

    PubMed

    Henschke, Claudia I; Yankelevitz, David F; Yip, Rowena; Archer, Venice; Zahlmann, Gudrun; Krishnan, Karthik; Helba, Brian; Avila, Ricardo

    2016-07-01

    To address the error introduced by computed tomography (CT) scanners when assessing volume and unidimensional measurement of solid tumors, we scanned a precision manufactured pocket phantom simultaneously with patients enrolled in a lung cancer clinical trial. Dedicated software quantified bias and random error in the [Formula: see text], and [Formula: see text] dimensions of a Teflon sphere and also quantified response evaluation criteria in solid tumors and volume measurements using both constant and adaptive thresholding. We found that underestimation bias was essentially the same for [Formula: see text], and [Formula: see text] dimensions using constant thresholding and had similar values for adaptive thresholding. The random error of these length measurements as measured by the standard deviation and coefficient of variation was 0.10 mm (0.65), 0.11 mm (0.71), and 0.59 mm (3.75) for constant thresholding and 0.08 mm (0.51), 0.09 mm (0.56), and 0.58 mm (3.68) for adaptive thresholding, respectively. For random error, however, [Formula: see text] lengths had at least a fivefold higher standard deviation and coefficient of variation than [Formula: see text] and [Formula: see text]. Observed [Formula: see text]-dimension error was especially high for some 8 and 16 slice CT models. Error in CT image formation, in particular, for models with low numbers of detector rows, may be large enough to be misinterpreted as representing either treatment response or disease progression. PMID:27660808

  11. Early-stage squamous cell carcinoma of the oropharynx: Radiotherapy vs. Trans-Oral Robotic Surgery (ORATOR) – study protocol for a randomized phase II trial

    PubMed Central

    2013-01-01

    Background The incidence of oropharyngeal squamous cell carcinoma (OPSCC) has markedly increased over the last three decades due to newly found associations with human papillomavirus (HPV) infection. Primary radiotherapy (RT) is the treatment of choice for OPSCC at most centers, and over the last decade, the addition of concurrent chemotherapy has led to a significant improvement in survival, but at the cost of increased acute and late toxicity. Transoral robotic surgery (TORS) has emerged as a promising alternative treatment, with preliminary case series demonstrating encouraging oncologic, functional, and quality of life (QOL) outcomes. However, comparisons of TORS and RT in a non-randomized fashion are susceptible to bias. The goal of this randomized phase II study is to compare QOL, functional outcomes, toxicity profiles, and survival following primary RT (± chemotherapy) vs. TORS (± adjuvant [chemo] RT) in patients with OPSCC. Methods/Design The target patient population comprises OPSCC patients who would be unlikely to require chemotherapy post-resection: Tumor stage T1-T2 with likely negative margins at surgery; Nodal stage N0-2, ≤3 cm in size, with no evidence of extranodal extension on imaging. Participants will be randomized in a 1:1 ratio between Arm 1 (RT ± chemotherapy) and Arm 2 (TORS ± adjuvant [chemo] RT). In Arm 1, patients with N0 disease will receive RT alone, whereas N1-2 patients will receive concurrent chemoradiation. In Arm 2, patients will undergo TORS along with selective neck dissections, which may be staged. Pathologic high-risk features will be used to determine the requirement for adjuvant radiotherapy +/- chemotherapy. The primary endpoint is QOL score using the M.D. Anderson Dysphagia Inventory (MDADI), with secondary endpoints including survival, toxicity, other QOL outcomes, and swallowing function. A sample of 68 patients is required. Discussion This study, if successful, will provide a much-needed randomized

  12. Immunogenicity and safety of recombinant tetravalent dengue vaccine (CYD-TDV) in individuals aged 2-45 y: Phase II randomized controlled trial in Singapore.

    PubMed

    Leo, Yee Sin; Wilder-Smith, Anneliese; Archuleta, Sophia; Shek, Lynette P; Chong, Chia-Yin; Leong, Hoe Nam; Low, Chian Yong; Oh, May-Lin Helen; Bouckenooghe, Alain; Wartel, T Anh; Crevat, Denis

    2012-09-01

    This was a multicenter, blinded, Phase II study (NCT00880893) conducted in Singapore. The primary objectives were to evaluate the safety of a tetravalent dengue vaccine (TDV) comprising four recombinant, live, attenuated viruses (CYD-TDV) and the dengue virus serotype-specific antibody responses before and 28 d after each vaccination. Participants were randomized 3:1 to receive three doses of CYD-TDV or a control vaccine at 0, 6 and 12 mo. Control vaccine was placebo for the first dose (all ages) and for subsequent doses, licensed hepatitis-A for children (aged 2-11 y) or influenza vaccine for adolescents (12-17 y) and adults (18-45 y). Between April and October 2009, 317 children, 187 adolescents and 696 adults were enrolled. In all age groups, reactogenicity was higher after the first injection of CYD-TDV than after placebo control. Reactogenicity after subsequent CYD-TDV doses was no higher than after the first dose, and tended to be lower or similar to that seen after active control vaccination. Seropositivity rates and geometric mean neutralizing antibody titers (GMTs; 1/dil) against all four dengue virus serotypes increased in all age groups after each of the three CYD-TDV doses. Post-dose 3, 66.5% of all participants were seropositive to all four serotypes, and 87.2% were seropositive to ≥ 3 serotypes; GMTs for all participants ranged from 43.0 against dengue virus serotype 1 to 100 against dengue virus serotype 4. GMTs were higher in children than in adolescents. These results support the continued development of CYD-TDV for the prevention of dengue disease.

  13. Paclitaxel plus valproic acid versus paclitaxel alone as second- or third-line therapy for advanced gastric cancer: a randomized Phase II trial

    PubMed Central

    Fushida, Sachio; Kinoshita, Jun; Kaji, Masahide; Oyama, Katsunobu; Hirono, Yasuo; Tsukada, Tomoya; Fujimura, Takashi; Ohta, Tetsuo

    2016-01-01

    Background Weekly paclitaxel (wPTX) is the preferred second-line chemotherapy for gastric cancer in Japan. Histone deacetylase inhibitors have been shown to decrease proliferation through cell-cycle arrest, differentiation, and apoptosis in gastric cancer cells. One histone deacetylase inhibitor, valproic acid (VPA), also inhibits tumor growth by inducing apoptosis and enhances the efficacy of paclitaxel (PTX), shown in a murine gastric cancer model. This Phase II trial was designed to evaluate the benefits of adding VPA to wPTX in patients with gastric cancer refractory to first-line treatment with fluoropyrimidine. Patients and methods The patients were randomly assigned in a 1:1 ratio to receive PTX 80 mg/m2 intravenously on days 1, 8, and 15, every 4 weeks, or a dose of PTX plus VPA taken everyday at 7.5 mg/kg twice daily. Random assignment was carried out at the data center with a minimization method adjusted by the Eastern Cooperative Oncology Group performance status (0–1 vs 2), prior chemotherapy (first-line vs second-line), and measurable lesions (presence vs absence). The primary end point was the overall survival (OS) rate, and the secondary end points were the progression-free survival rate and safety analysis. Results Sixty-six patients were randomly assigned to receive wPTX (n=33) or wPTX plus VPA (n=33). The median OS was 9.8 months in the wPTX group and 8.7 months in the wPTX plus VPA group (hazard ratio 1.19; 95% CI 0.702–2.026; P=0.51). The median progression-free survival was 4.5 months in the wPTX group and 3.0 months in the wPTX plus VPA group (hazard ratio 1.29; 95% CI 0.753–2.211; P=0.35). Grade 3–4 adverse events were neutropenia (3.1%), pneumonia (1.6%), liver injury (1.6%), brain infarction (1.6%), and rupture of aorta (1.6%). Conclusion No statistically significant difference was observed between wPTX and wPTX plus VPA for OS. PMID:27524882

  14. Clinical, molecular and immune analysis of dabrafenib and trametinib in metastatic melanoma patients that progressed on BRAF inhibitor monotherapy: a phase II clinical trial

    PubMed Central

    Chen, Guo; McQuade, Jennifer L.; Panka, David J.; Hudgens, Courtney W.; Amin-Mansour, Ali; Mu, Xinmeng Jasmine; Bahl, Samira; Jane-Valbuena, Judit; Wani, Khalida M.; Reuben, Alexandre; Creasy, Caitlyn A.; Jiang, Hong; Cooper, Zachary A.; Roszik, Jason; Bassett, Roland L.; Joon, Aron Y.; Simpson, Lauren M.; Mouton, Rosalind D.; Glitza, Isabella C.; Patel, Sapna P.; Hwu, Wen-Jen; Amaria, Rodabe N.; Diab, Adi; Hwu, Patrick; Lazar, Alexander J.; Wargo, Jennifer A.; Garraway, Levi A.; Tetzlaff, Michael T.; Sullivan, Ryan J.; Kim, Kevin B.; Davies, Michael A.

    2016-01-01

    Importance Combined treatment with dabrafenib and trametinib (CombiDT) achieves clinical responses in only ~15% of BRAF inhibitor (BRAFi)-refractory metastatic melanoma patients, in contrast to the high activity observed in BRAFi-naïve patients. Identifying correlates of response and mechanisms of resistance in this population will facilitate clinical management and rational therapeutic development. Objective To determine correlates of benefit from CombiDT therapy in BRAFi-refractory metastatic melanoma patients. Design Single-center, single-arm prospective phase II study of CombiDT in patients with BRAFV600 metastatic melanoma resistant to BRAFi monotherapy conducted between September 2012 and October 2014. Setting University of Texas MD Anderson Cancer Center. Participants 28 patients were screened and 23 enrolled. Key eligibility criteria included: BRAFV600 metastatic melanoma, prior BRAFi monotherapy, measurable disease (RECIST 1.1), and accessible tumor for biopsy. Intervention Patients were treated with dabrafenib (150 mg twice daily) and trametinib (2 mg daily) continuously until disease progression or intolerance. All participants underwent a mandatory baseline biopsy, and optional biopsies were performed on-treatment and at progression. Whole-exome sequencing, RT-PCR for BRAF splicing, RNAseq and IHC were performed on tumor samples, and blood was analyzed for levels of circulating BRAFV600. Main outcome measures Primary endpoint was overall response rate (ORR). Progression-free survival (PFS) and overall survival (OS) were secondary clinical endpoints. Results Among evaluable patients, the confirmed ORR was 10%, disease control rate (DCR) was 45%, and median PFS was 13 weeks. Clinical benefit was associated with duration of prior BRAFi >6 months (DCR 73% vs. 11% for ≤6 months, p=0.02) and decrease in circulating BRAFV600 at day 8 of cycle 1 (DCR 75% vs. 18% for no decrease, p=0.015), but not by pre-treatment MAPK pathway mutations or activation. On

  15. Modeling of α/β for late rectal toxicity from a randomized phase II study: conventional versus hypofractionated scheme for localized prostate cancer

    PubMed Central

    Marzi, Simona; Saracino, Biancamaria; Petrongari, Maria G; Arcangeli, Stefano; Gomellini, Sara; Arcangeli, Giorgio; Benassi, Marcello; Landoni, Valeria

    2009-01-01

    Background Recently, the use of hypo-fractionated treatment schemes for the prostate cancer has been encouraged due to the fact that α/β ratio for prostate cancer should be low. However a major concern on the use of hypofractionation is the late rectal toxicity, it is important to be able to predict the risk of toxicity for alternative treatment schemes, with the best accuracy. The main purpose of this study is to evaluate the response of rectum wall to changes in fractionation and to quantify the α/β ratio for late rectal toxicity Methods 162 patients with localized prostate cancer, treated with conformal radiotherapy, were enrolled in a phase II randomized trial. The patients were randomly assigned to 80 Gy in 40 fractions over 8 weeks (arm A) or 62 Gy in 20 fractions over 5 weeks (arm B). The median follow-up was 30 months. The late rectal toxicity was evaluated using the Radiation Therapy Oncology Group (RTOG) scale. It was assumed ≥ Grade 2 (G2) toxicity incidence as primary end point. Fit of toxicity incidence by the Lyman-Burman-Kutcher (LKB) model was performed. Results The crude incidence of late rectal toxicity ≥ G2 was 14% and 12% for the standard arm and the hypofractionated arm, respectively. The crude incidence of late rectal toxicity ≥ G2 was 14.0% and 12.3% for the arm A and B, respectively. For the arm A, volumes receiving ≥ 50 Gy (V50) and 70 Gy (V70) were 38.3 ± 7.5% and 23.4 ± 5.5%; for arm B, V38 and V54 were 40.9 ± 6.8% and 24.5 ± 4.4%. An α/β ratio for late rectal toxicity very close to 3 Gy was found. Conclusion The ≥ G2 late toxicities in both arms were comparable, indicating the feasibility of hypofractionated regimes in prostate cancer. An α/β ratio for late rectal toxicity very close to 3 Gy was found. PMID:19689825

  16. Citalopram, a selective serotonin reuptake inhibitor: clinical antidepressive and long-term effect--a phase II study.

    PubMed

    Pedersen, O L; Kragh-Sørensen, P; Bjerre, M; Overø, K F; Gram, L F

    1982-01-01

    In a phase II study the antidepressive effect of citalopram, a selective and potent serotonin reuptake inhibitor, was examined in 20 endogenously and three non-endogenously depressed hospitalized patients. Four endogenously depressed patients dropped out due to deterioration early in the treatment period. The remaining 19 patients completed a 4-6 week treatment schedule. Of 16 endogenously depressed patients 11 responded, one was a partial responder and four did not respond. Of three patients with non-endogenous depressions, two responded and one did not respond. No correlation between plasma citalopram concentration and therapeutic outcome was found. Fourteen patients were given maintenance treatment for 8-113 weeks. One patient developed depression when the dose was reduced from 60 to 40 mg and one patient became manic. After discontinuation of treatment seven patients had a depressive relapse and six of these who again were treated with citalopram responded completely. Side effect rating scores of symptoms usually associated with depression or treatment with tricyclic antidepressants declined during treatment. Three patients complained of increased need of sleep for a period after several weeks of treatment. Apart from an unspecific, transient rise in liver enzymes in two patients, detailed biochemical laboratory tests were all normal. There were no effects on blood pressure, pulse rate, orthostatic reaction, or electrocardiogram. One patient took an overdose of citalopram resulting in plasma levels about six times higher than the average therapeutic level, but there were no signs of severe toxicity. In particular no change in consciousness, electrocardiogram or blood pressure occurred. Pharmacokinetic variables such as dose schedule, steady state kinetics, and metabolism are discussed. PMID:6812140

  17. A Phase II Clinical Trial of CPI-613 in Patients with Relapsed or Refractory Small Cell Lung Carcinoma

    PubMed Central

    Pardee, Timothy S.; Petty, William J.; Bonomi, Marcelo; Alistar, Angela; Lamar, Zanetta S.; Isom, Scott; Chan, Michael D.; Miller, Antonius A.; Ruiz, Jimmy

    2016-01-01

    Background Small cell lung cancer (SCLC) is a common lung cancer which presents with extensive stage disease at time of diagnosis in two-thirds of patients. For treatment of advanced disease, traditional platinum doublet chemotherapy induces response rates up to 80% but with few durable responses. CPI-613 is a novel anti-cancer agent that selectively inhibits the altered form of mitochondrial energy metabolism in tumor cells. Methods We evaluated CPI-613 with a single-arm, open-label phase II study in patients with relapsed or refractory SCLC. CPI-613 was given at a dose of 3,000 mg/m2 on days 1 and 4 of weeks 1–3 of 4 week cycle. The primary outcome was response rate as assessed by CT imaging using RECIST v1.1 criteria. Secondary outcomes were progression-free survival (PFS), overall survival (OS), and toxicity. Twelve patients were accrued (median age 57yo) who had previously received between 1 and 4 lines of chemotherapy (median 1) for SCLC with a treatment-free interval of less than 60 days in 9 of the 12 patients. Results No complete or partial responses were seen. Ten patients (83%) progressed as best response and 2 (17%) were not evaluable for response. Median time to progression was 1.7 months (range 0.7 to 1.8 months). Eleven patients (92%) died with median overall survival of 4.3 months (range 1.2 to 18.2 months). The study was closed early due to lack of efficacy. Of note, three out of three patients who progressed after CPI-613 and were subsequently treated with standard topotecan then demonstrated treatment response with survival for 18.2, 7.4, and 5.1 months. We conducted laboratory studies which found synergy in-vitro for CPI-613 with topotecan. Conclusions Single agent CPI-613 had no efficacy in this study. Further study of CPI 613 in combination with a topoisomerase inhibitor is warranted. PMID:27732654

  18. Reactogenicity, safety and immunogenicity of a protein-based pneumococcal vaccine in Gambian children aged 2-4 years: A phase II randomized study.

    PubMed

    Odutola, A; Ota, M O; Ogundare, E O; Antonio, M; Owiafe, P; Worwui, A; Greenwood, B; Alderson, M; Traskine, M; Verlant, V; Dobbelaere, K; Borys, D

    2016-01-01

    Pneumococcal conjugate vaccines (PCVs) have been successful in preventing invasive pneumococcal disease but effectiveness has been challenged by replacement of vaccine serotypes with non-vaccine serotypes. Vaccines targeting common pneumococcal protein(s) found in most/all pneumococci may overcome this limitation. This phase II study assessed safety and immunogenicity of a new protein-based pneumococcal vaccine containing polysaccharide conjugates of 10 pneumococcal serotypes combined with pneumolysin toxoid(dPly) and pneumococcal histidine triad protein D(PhtD) (PHiD-CV/dPly/PhtD-30) in African children. 120 Gambian children (2-4 years, not previously vaccinated against Streptococcus pneumoniae) randomized (1:1) received a single dose of PHiD-CV/dPly/PhtD-30 or PCV13. Adverse events occurring over 4 d post-vaccination were reported, and blood samples obtained pre- and 1-month post-vaccination. Serious adverse events were reported for 6 months post-vaccination. Solicited local and systemic adverse events were reported at similar frequency in each group. One child (PHiD-CV/dPly/PhtD-30 group) reported a grade 3 local reaction to vaccination. Haematological and biochemical parameters seemed similar pre- and 1-month post-vaccination in each group. High pre-vaccination Ply and PhtD antibody concentrations were observed in each group, but only increased in PHiD-CV/dPly/PhtD-30 vaccinees one month post-vaccination. One month post-vaccination, for each vaccine serotype ≥96.2% of PHiD-CV/dPly/PhtD-30 vaccinees had serotype-specific polysaccharide antibody concentrations ≥0.20µg/mL except serotypes 6B (80.8%) and 23F (65.4%), and ≥94.1% had OPA titres of ≥8 except serotypes 1 (51.9%), 5 (38.5%) and 6B (78.0%), within ranges seen in PCV13-vaccinated children. A single dose of PHiD-CV/dPly/PhtD-30 vaccine, administered to Gambian children aged 2-4 y not previously vaccinated with a pneumococcal vaccine, was well-tolerated and immunogenic.

  19. Reactogenicity, safety and immunogenicity of a protein-based pneumococcal vaccine in Gambian children aged 2–4 years: A phase II randomized study

    PubMed Central

    Odutola, A; Ota, MO; Ogundare, EO; Antonio, M; Owiafe, P; Worwui, A; Greenwood, B; Alderson, M; Traskine, M; Verlant, V; Dobbelaere, K; Borys, D

    2016-01-01

    Pneumococcal conjugate vaccines (PCVs) have been successful in preventing invasive pneumococcal disease but effectiveness has been challenged by replacement of vaccine serotypes with non-vaccine serotypes. Vaccines targeting common pneumococcal protein(s) found in most/all pneumococci may overcome this limitation. This phase II study assessed safety and immunogenicity of a new protein-based pneumococcal vaccine containing polysaccharide conjugates of 10 pneumococcal serotypes combined with pneumolysin toxoid(dPly) and pneumococcal histidine triad protein D(PhtD) (PHiD-CV/dPly/PhtD-30) in African children. 120 Gambian children (2–4 years, not previously vaccinated against Streptococcus pneumoniae) randomized (1:1) received a single dose of PHiD-CV/dPly/PhtD-30 or PCV13. Adverse events occurring over 4 d post-vaccination were reported, and blood samples obtained pre- and 1-month post-vaccination. Serious adverse events were reported for 6 months post-vaccination. Solicited local and systemic adverse events were reported at similar frequency in each group. One child (PHiD-CV/dPly/PhtD-30 group) reported a grade 3 local reaction to vaccination. Haematological and biochemical parameters seemed similar pre- and 1-month post-vaccination in each group. High pre-vaccination Ply and PhtD antibody concentrations were observed in each group, but only increased in PHiD-CV/dPly/PhtD-30 vaccinees one month post-vaccination. One month post-vaccination, for each vaccine serotype ≥96.2% of PHiD-CV/dPly/PhtD-30 vaccinees had serotype-specific polysaccharide antibody concentrations ≥0.20µg/mL except serotypes 6B (80.8%) and 23F (65.4%), and ≥94.1% had OPA titres of ≥8 except serotypes 1 (51.9%), 5 (38.5%) and 6B (78.0%), within ranges seen in PCV13-vaccinated children. A single dose of PHiD-CV/dPly/PhtD-30 vaccine, administered to Gambian children aged 2–4 y not previously vaccinated with a pneumococcal vaccine, was well-tolerated and immunogenic. PMID:26618243

  20. [Three-year follow-up of 12 patients with prostate cancer treated with monthly degarelix in a phase II clinical trial].

    PubMed

    Hoshi, Senji; Hayashi, Natsuho; Yagi, Mayu; Ookubo, Teppei; Muto, Akinori; Sugano, Osamu; Numahata, Kenji; Bilim, Vladimir; Hoshi, Kiyotugu; Sasagawa, Isoji

    2014-01-01

    The efficacy and safety of degarelix, a luteinizing hormone-releasing hormone(LH-RH)antagonist, in patients with prostate cancer(PCa)were evaluated in a phase II, open-label, multicenter clinical trial. In this trial, a total of 13 patients were accrued at the Yamagata Prefectural Central Hospital from 2007 to 2008. The median age was 80 years(range, 65-85 years), and clinical stages were T1c, T2, T3, and T4 in 1, 4, 6, and 2 patients, respectively. Nodal(N)status was N0 in 9 patients and N1 in 4 patients. Distant metastases were absent(M0)in 12 patients and present(M1b)in 1 patient. The median prostate- specific antigen(PSA)level was 29.1 ng/mL(range, 6.3-427 ng/mL). All but one patient, who died of an unrelated cause, received a monthly dose(80 or 160mg)of degarelix for 12 months and were followed-up for 3 years. The PSA level declined in all patients. One patient died of an unrelated cause during the phase II trial. After completion of the phase II trial, 5 patients were treated with combined and rogen blockade(CAB)(leuprolide plus anti-androgen therapy), 2 patients were treated with single-agent leuprolide, 2 patients received single-agent bicalutamide, and 1 patient was followed-up without additional treatment. Radical prostatectomy was performed in 2 patients. Among the 5 patients treated with CAB, 2 died of metastatic cancer. CAB was effective in suppressing PSA levels in 3 patients. In 1 patient with T3aN1M1b PCa, colon cancer with lung metastases was detected during the follow-up period. Treatment with chemotherapy for colon cancer was effective in suppressing PSA levels for 12 months. In 1 patient with cT3aN1M0 PCa, the PSA level declined to <0.02 ng/mL, and a reduction in size of the prostate gland and metastatic lymph nodes was observed. This effect persisted for 3.5 years after the completion of the 12-month degarelix regimen, and no additional treatment was required.

  1. Expression of Heat Shock Protein 27 in Melanoma Metastases Is Associated with Overall Response to Bevacizumab Monotherapy: Analyses of Predictive Markers in a Clinical Phase II Study

    PubMed Central

    Schuster, Cornelia; Akslen, Lars A.; Straume, Oddbjørn

    2016-01-01

    The aim of this study was to identify potential predictive biomarkers in 35 patients with metastatic melanoma treated with anti-angiogenic bevacizumab monotherapy in a clinical phase II study. The immunohistochemical expression of various angiogenic factors in tissues from primary melanomas and metastases as well as their concentration in blood samples were examined. Strong expression of Heat Shock Protein 27 (HSP27) in metastases correlated significantly with complete or partial response to bevacizumab (p = 0.044). Furthermore, clinical benefit, i.e., complete or partial response or stable disease for at least 6 months, was more frequent in patients with strong expression of HSP27 in primary tumors (p = 0.046). Tissue expression of vascular endothelial growth factor (VEGF-A), its splicing variant VEGF165b or basic fibroblast growth factor (bFGF) did not correlate with response, and the concentration of HSP27, VEGF-A or bFGF measured in blood samples before treatment did not show predictive value. Further, microvessel density, proliferating microvessel density and presence of glomeruloid microvascular proliferations were assessed in sections of primary tumors and metastases. Microvessel density in primary melanomas was significantly higher in patients with clinical benefit than in non-responders (p = 0.042). In conclusion, our findings suggest that strong HSP27 expression in melanoma metastases predicts response to bevacizumab treatment. Trial Registration ClinicalTrials.gov NCT00139360 PMID:27166673

  2. Phase II clinical study of eribulin monotherapy in Japanese patients with metastatic breast cancer who had well-defined taxane resistance.

    PubMed

    Inoue, Kenichi; Saito, Tsuyoshi; Okubo, Katsuhiko; Kimizuka, Kei; Yamada, Hirofumi; Sakurai, Takashi; Ishizuna, Kazuo; Hata, Satoshi; Kai, Toshihiro; Kurosumi, Masafumi

    2016-06-01

    No clinical evidence on the efficacy and safety of eribulin monotherapy has been obtained by a prospective clinical study in patients with metastatic breast cancer (MBC) who had well-defined taxane resistance. The present Phase II, multicenter, single-arm, open-label study aimed to obtain the evidence. Japanese female patients, aged 33-74 years who had the metastasis of taxane-resistant and histopathologically confirmed breast cancer, received eribulin mesylate 1.4 mg/m(2) (equivalent to eribulin 1.23 mg/m(2) [expressed as free base]) as a 2- to 5-min intravenous infusion on days 1 and 8 of each 21-day cycle. The primary endpoint was the clinical benefit rate (CBR) [complete response (CR), partial response (PR), and long-term stable disease (LSD) ≥24 weeks]. A total of 51 patients underwent chemotherapy cycles (median 4; range 1-42 cycles). The CBR was 39.2 % (CR 2.0 %; PR 23.5 %; and LSD 13.7 %), and the rate of progressive disease was 49.0 %. The median progression-free survival and the median overall survival were 3.6 months [95 % confidence interval (CI) 2.6-4.6 months] and 11.7 months (95 % CI 9.2-14.2 months), respectively. Grade 3 or greater adverse events were leukopenia (23.5 %), neutropenia (35.3 %), anemia (5.9 %), and febrile neutropenia (7.8 %). The incidences of grade 3 and 4 peripheral sensory neuropathy were 2.0 and 0 %, respectively. Eribulin showed a clinically manageable tolerability profile by dose adjustments or symptomatic treatment. Eribulin was effective and well tolerated in heavily pretreated patients with MBC who had well-defined taxane resistance, thus providing a potential therapeutic option in the clinical settings. PMID:27125669

  3. Phase II Final Report

    SciTech Connect

    Schuknecht, Nate; White, David; Hoste, Graeme

    2014-09-11

    The SkyTrough DSP will advance the state-of-the-art in parabolic troughs for utility applications, with a larger aperture, higher operating temperature, and lower cost. The goal of this project was to develop a parabolic trough collector that enables solar electricity generation in the 2020 marketplace for a 216MWe nameplate baseload power plant. This plant requires an LCOE of 9¢/kWhe, given a capacity factor of 75%, a fossil fuel limit of 15%, a fossil fuel cost of $6.75/MMBtu, $25.00/kWht thermal storage cost, and a domestic installation corresponding to Daggett, CA. The result of our optimization was a trough design of larger aperture and operating temperature than has been fielded in large, utility scale parabolic trough applications: 7.6m width x 150m SCA length (1,118m2 aperture), with four 90mm diameter × 4.7m receivers per mirror module and an operating temperature of 500°C. The results from physical modeling in the System Advisory Model indicate that, for a capacity factor of 75%: The LCOE will be 8.87¢/kWhe. SkyFuel examined the design of almost every parabolic trough component from a perspective of load and performance at aperture areas from 500 to 2,900m2. Aperture-dependent design was combined with fixed quotations for similar parts from the commercialized SkyTrough product, and established an installed cost of $130/m2 in 2020. This project was conducted in two phases. Phase I was a preliminary design, culminating in an optimum trough size and further improvement of an advanced polymeric reflective material. This phase was completed in October of 2011. Phase II has been the detailed engineering design and component testing, which culminated in the fabrication and testing of a single mirror module. Phase II is complete, and this document presents a summary of the comprehensive work.

  4. A phase II randomized trial comparing standard and low dose rituximab combined with alemtuzumab as initial treatment of progressive chronic lymphocytic leukemia in older patients: a trial of the ECOG-ACRIN cancer research group (E1908).

    PubMed

    Zent, Clive S; Victoria Wang, Xin; Ketterling, Rhett P; Hanson, Curtis A; Libby, Edward N; Barrientos, Jacqueline C; Call, Timothy G; Chang, Julie E; Liu, Jane J; Calvo, Alejandro R; Lazarus, Hillard M; Rowe, Jacob M; Luger, Selina M; Litzow, Mark R; Tallman, Martin S

    2016-03-01

    Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) patients requiring initial therapy are often older and frailer and unsuitable candidates for standard chemoimmunotherapy regimens. Shorter duration combination monoclonal antibody (mAb) therapy using alemtuzumab and rituximab has been shown to be effective and tolerable treatment for CLL. Standard dose anti-CD20 mAb therapy causes loss of CD20 expression by surviving CLL cells, which can be minimized by decreasing the mAb dose. We report a randomized phase II clinical trial enrolling older (≥ 65 years) patients (median age 76 years, n = 31) with treatment naïve progressive CLL. Patients received 8-12 weeks of standard subcutaneous alemtuzumab with either intravenous standard (375 mg/m(2) weekly)(n = 16) or low dose (20 mg/m(2) 3x week)(n = 15) rituximab. This study was closed before full accrual because the manufacturer withdrew alemtuzumab for treatment of CLL. The overall response rate was 90% with an 45% complete response rate, median progression-free survival of 17.9 months and no significant differences in outcome between the low and standard dose rituximab arms. The major toxicities were cytopenia and infection with one treatment fatality caused by progressive multifocal leukoencephalopathy but no other opportunistic infections. Combination mAb therapy was effective and tolerable treatment for older and frailer patients with progressive CLL, achieving a high rate of complete remissions. These data support the role of mAb in therapy for less fit CLL patients and the further study of low dose higher frequency anti-CD20 mAb therapy as a potentially more effective use of anti-CD20 mAb in the treatment of CLL.

  5. Local Heat Application for the Treatment of Buruli Ulcer: Results of a Phase II Open Label Single Center Non Comparative Clinical Trial

    PubMed Central

    Vogel, Moritz; Bayi, Pierre F.; Ruf, Marie-Thérèse; Bratschi, Martin W.; Bolz, Miriam; Um Boock, Alphonse; Zwahlen, Marcel; Pluschke, Gerd; Junghanss, Thomas

    2016-01-01

    Background. Buruli ulcer (BU) is a necrotizing skin disease most prevalent among West African children. The causative organism, Mycobacterium ulcerans, is sensitive to temperatures above 37°C. We investigated the safety and efficacy of a local heat application device based on phase change material. Methods. In a phase II open label single center noncomparative clinical trial (ISRCTN 72102977) under GCP standards in Cameroon, laboratory confirmed BU patients received up to 8 weeks of heat treatment. We assessed efficacy based on the endpoints ‘absence of clinical BU specific features’ or ‘wound closure’ within 6 months (“primary cure”), and ‘absence of clinical recurrence within 24 month’ (“definite cure”). Results. Of 53 patients 51 (96%) had ulcerative disease. 62% were classified as World Health Organization category II, 19% each as category I and III. The average lesion size was 45 cm2. Within 6 months after completion of heat treatment 92.4% (49 of 53, 95% confidence interval [CI], 81.8% to 98.0%) achieved cure of their primary lesion. At 24 months follow-up 83.7% (41 of 49, 95% CI, 70.3% to 92.7%) of patients with primary cure remained free of recurrence. Heat treatment was well tolerated; adverse effects were occasional mild local skin reactions. Conclusions. Local thermotherapy is a highly effective, simple, cheap and safe treatment for M. ulcerans disease. It has in particular potential as home-based remedy for BU suspicious lesions at community level where laboratory confirmation is not available. Clinical Trials Registration. ISRCT 72102977. PMID:26486698

  6. Radiation Therapy Oncology Group 0247: A Randomized Phase II Study of Neoadjuvant Capecitabine and Irinotecan or Capecitabine and Oxaliplatin With Concurrent Radiotherapy for Patients With Locally Advanced Rectal Cancer

    SciTech Connect

    Wong, Stuart J.; Winter, Kathryn; Meropol, Neal J.; Anne, Pramila Rani; Kachnic, Lisa; Rashid, Asif; Watson, James C.; Mitchell, Edith; Pollock, Jondavid; Lee, Robert Jeffrey; Haddock, Michael; Erickson, Beth A.; Willett, Christopher G.

    2012-03-15

    Purpose: To evaluate the rate of pathologic complete response (pCR) and the toxicity of two neoadjuvant chemoradiotherapy (chemoRT) regimens for Stage T3-T4 rectal cancer in a randomized Phase II study. Methods and Materials: Patients with Stage T3 or T4 rectal cancer of <12 cm from the anal verge were randomized to preoperative RT (50.4 Gy in 1.8-Gy fractions) with concurrent capecitabine (1,200 mg/m{sup 2}/d Mondays through Friday) and irinotecan (50 mg/m{sup 2} weekly in four doses) (Arm 1) or concurrent capecitabine (1,650 mg/m{sup 2}/d Monday through Friday) and oxaliplatin (50 mg/m{sup 2} weekly in five doses) (Arm 2). Surgery was performed 4-8 weeks after chemoRT, and adjuvant chemotherapy 4-6 weeks after surgery. The primary endpoint was the pCR rate, requiring 48 evaluable patients per arm. Results: A total of 146 patients were enrolled. The protocol chemotherapy was modified because of excessive gastrointestinal toxicity after treatment of 35 patients; 96 were assessed for the primary endpoint-the final regimen described above. The patient characteristics were similar for both arms. After chemoRT, the rate of tumor downstaging was 52% and 60% and the rate of nodal downstaging (excluding N0 patients) was 46% and 40%, for Arms 1 and 2, respectively. The pCR rate for Arm 1 was 10% and for Arm 2 was 21%. For Arm 1 and 2, the preoperative chemoRT rate of Grade 3-4 hematologic toxicity was 9% and 4% and the rate of Grade 3-4 nonhematologic toxicity was 26% and 27%, respectively. Conclusions: Preoperative chemoRT with capecitabine plus oxaliplatin for distal rectal cancer has significant clinical activity (10 of 48 pCRs) and acceptable toxicity. This regimen is currently being evaluated in a Phase III randomized trial (National Surgical Adjuvant Breast and Bowel Project R04).

  7. Mature Results of the Ottawa Phase II Study of Intermittent Androgen-Suppression Therapy in Prostate Cancer: Clinical Predictors of Outcome

    SciTech Connect

    Malone, Shawn . E-mail: smalone@ottawahospital.on.ca; Perry, Gad; Eapen, Libni; Segal, Roanne; Gallant, Victor; Dahrouge, Simone; Crook, Juanita; Spaans, Johanna N.

    2007-07-01

    Purpose: To present the mature experience of a phase II trial of intermittent androgen suppression (IAS). Methods and Materials: Intermittent androgen-suppression therapy was initiated in prostate-cancer patients to delay hormone resistance and minimize potential side effects of androgen-deprivation therapy (ADT). Patients received cyclical periods of ADT and observation (off-treatment interval [OTI]). Androgen-deprivation therapy was reinitiated when the level of prostate-specific antigen (PSA) rose above 10 ng/ml, or for disease progression. Associations between clinical factors and eligibility for OTI were measured. Kaplan-Meier and Cox regression analyses were used to determine factors predicting the duration of OTIs. Results: Ninety-five patients completed 187 cycles of treatment. The median duration of OTIs was 8.5 months. Patients with higher PSA and metastatic disease were less likely to be eligible for the first OTI (p < 0.01). In multivariate analysis, patients with higher PSA and local relapse had significantly longer OTIs (p < 0.01) compared with metastatic patients. The median time to withdrawal from the study was 37 months. Conclusions: Intermittent androgen suppression appears to be a favorable treatment option for patients with biochemically (according to level of PSA) or locally recurrent prostate cancer with favorable long-term survival, a high probability of eligibility for OTIs, and durable OTIs.

  8. Randomized Phase II Trial of Erlotinib Alone or With Carboplatin and Paclitaxel in Patients Who Were Never or Light Former Smokers With Advanced Lung Adenocarcinoma: CALGB 30406 Trial

    PubMed Central

    Jänne, Pasi A.; Wang, Xiaofei; Socinski, Mark A.; Crawford, Jeffrey; Stinchcombe, Thomas E.; Gu, Lin; Capelletti, Marzia; Edelman, Martin J.; Villalona-Calero, Miguel A.; Kratzke, Robert; Vokes, Everett E.; Miller, Vincent A.

    2012-01-01

    Purpose Erlotinib is clinically effective in patients with non–small-cell lung cancer (NSCLC) who have adenocarcinoma, are never or limited former smokers, or have EGFR mutant tumors. We investigated the efficacy of erlotinib alone or in combination with chemotherapy in patients with these characteristics. Patients and Methods Patients with advanced NSCLC (adenocarcinoma) who were epidermal growth factor receptor tyrosine kinase inhibitor and chemotherapy naive never or light former smokers (smokers of > 100 cigarettes and ≤ 10 pack years and quit ≥ 1 year ago) were randomly assigned to continuous erlotinib or in combination with carboplatin and paclitaxel (ECP) for six cycles followed by erlotinib alone. The primary end point was progression-free survival (PFS). Tissue collection was mandatory. Results PFS was similar (5.0 v 6.6 months; P = .1988) in patients randomly assigned to erlotinib alone (arm A; n = 81) or to ECP (arm B; n = 100). EGFR mutation analysis was possible in 91% (164 of 181) of patients, and EGFR mutations were detected in 40% (51 of 128) of never smokers and in 42% (15 of 36) of light former smokers. In arm A, response rate (70% v 9%), PFS (14.1 v 2.6 months), and overall survival (OS; 31.3 v 18.1 month) favored EGFR-mutant patients. In arm B, response rate (73% v 30%), PFS (17.2 v 4.8 months), and OS (38.1 v 14.4 months) favored EGFR-mutant patients. Incidence of grades 3 to 4 hematologic (2% v 49%; P < .001) and nonhematologic (24% v 52%; P < .001) toxicity was greater in patients treated with ECP. Conclusion Erlotinib and erlotinib plus chemotherapy have similar efficacy in clinically selected populations of patients with advanced NSCLC. EGFR mutations identify patients most likely to benefit. PMID:22547605

  9. Sunitinib in relapsed or refractory diffuse large B-cell lymphoma: a clinical and pharmacodynamic phase II multicenter study of the NCIC Clinical Trials Group

    PubMed Central

    Buckstein, Rena; Kuruvilla, John; Chua, Neil; Lee, Christina; Macdonald, David A; Al-Tourah, Abdulwahab J; Foo, Alison H; Walsh, Wendy; Ivy, S Percy; Crump, Michael; Eisenhauer, Elizabeth A

    2011-01-01

    There are limited effective therapies for most patients with relapsed diffuse large B-cell lymphoma (DLBCL). We conducted a phase II trial of the multi-targeted vascular endothelial growth factor receptor (VEGFR) kinase inhibitor, sunitinib, 37.5 mg given orally once daily in adult patients with relapsed or refractory DLBCL. Of 19 enrolled patients, 17 eligible patients were evaluable for toxicity and 15 for response. No objective responses were seen and nine patients achieved stable disease (median duration 3.4 months). As a result, the study was closed at the end of the first stage. Grades 3—4 neutropenia and thrombocytopenia were observed in 29% and 35%, respectively. There was no relationship between change in circulating endothelial cell numbers (CECs) and bidimensional tumor burden over time. Despite some activity in solid tumors, sunitinib showed no evidence of response in relapsed/refractory DLBCL and had greater than expected hematologic toxicity. PMID:21463120

  10. Phase II, Randomized, Double-Blind, Multicenter Study Comparing the Safety and Pharmacokinetics of Tefibazumab to Placebo for Treatment of Staphylococcus aureus Bacteremia

    PubMed Central

    Weems, J. John; Steinberg, James P.; Filler, Scott; Baddley, John W.; Corey, G. Ralph; Sampathkumar, Priya; Winston, Lisa; John, Joseph F.; Kubin, Christine J.; Talwani, Rohit; Moore, Thomas; Patti, Joseph M.; Hetherington, Seth; Texter, Michele; Wenzel, Eric; Kelley, Violet A.; Fowler, Vance G.

    2006-01-01

    Tefibazumab (Aurexis), a humanized monoclonal antibody that binds to the surface-expressed adhesion protein clumping factor A, is under development as adjunctive therapy for serious Staphylococcus aureus infections. Sixty patients with documented S. aureus bacteremia (SAB) were randomized and received either tefibazumab at 20 mg/kg of body weight as a single infusion or a placebo in addition to an antibiotic(s). The primary objective of the study was determining safety and pharmacokinetics. An additional objective was to assess activity by a composite clinical end point (CCE). Baseline characteristics were evenly matched between groups. Seventy percent of infections were healthcare associated, and 57% had an SAB-related complication at baseline. There were no differences between the treatment groups in overall adverse clinical events or alterations in laboratory values. Two patients developed serious adverse events that were at least possibly related to tefibazumab; one hypersensitivity reaction was considered definitely related. The tefibazumab plasma half-life was 18 days. Mean plasma levels were <100 μg/ml by day 14. A CCE occurred in six patients (four placebo and two tefibazumab patients) and included five deaths (four placebo and one tefibazumab patient). Progression in the severity of sepsis occurred in four placebo and no tefibazumab patients. Tefibazumab was well tolerated, with a safety profile similar to those of other monoclonal antibodies. Additional trials are warranted to address the dosing range and efficacy of tefibazumab. PMID:16870768

  11. A Phase II Clinical Study of mFOLFOX6 Plus Bevacizumab as First-line Therapy for Japanese Advanced/Recurrent Colorectal Cancer Patients

    PubMed Central

    Nishina, Tomohiro; Takano, Yoshinao; Denda, Tadamichi; Yasui, Hisateru; Takeda, Koji; Ura, Takashi; Esaki, Taito; Okuyama, Yusuke; Kondo, Ken; Takahashi, Yasuo; Sugiyama, Yasuyuki; Muro, Kei

    2013-01-01

    Objective In Japan, there had been no prospective clinical studies conducted in terms of modified FOLFOX6 + bevacizumab therapy. We performed a post-marketing Phase II multicenter clinical study to examine the efficacy and safety of this regimen as first-line therapy for Japanese patients with advanced/recurrent colorectal cancer. Methods Bevacizumab (5 mg/kg) was administered intravenously, and then oxaliplatin (85 mg/m2) and levofolinate calcium (200 mg/m2) were infused intravenously over 2 h. Subsequently, a bolus dose of 5-fluorouracil (400 mg/m2) was injected, followed by infusion of 5-fluorouracil (2400 mg/m2) for 46 h. This regimen was repeated every 2 weeks until 24 cycles unless there was disease progression, unacceptable toxicity or patient refusal. The primary end point was the response rate. Results Among the 70 patients enrolled, two patients withdrew the study before treatment, and 68 patients were eligible for analysis of efficacy and safety. The response rate was 51.5% (95% confidence interval: 39.0–63.8%). The median progression-free survival and median overall survival time were 12.6 months (95% confidence interval: 10.4–14.5 months) and 28.5 months [95% confidence interval: 23.1 months–(not applicable)], respectively. There were no treatment-related deaths observed. The most common Grade 3 and 4 adverse events included neutropenia in 35.3% of the patients, peripheral neuropathy in 16.2% and hypertension in 16.2%. All adverse events were manageable and tolerable. The exploratory analysis of polymorphisms of three genes, ERCC1, XPD and GSTP1, did not show any trends in terms of correlation with the efficacy or safety of modified FOLFOX6 + bevacizumab therapy. Conclusions Modified FOLFOX6 + bevacizumab therapy was manageable and tolerable in Japanese patients, achieving a high response rate. PMID:23999770

  12. A Phase II Clinical Trial of Concurrent Helical Tomotherapy plus Cetuximab Followed by Adjuvant Chemotherapy with Cisplatin and Docetaxel for Locally Advanced Nasopharyngeal Carcinoma

    PubMed Central

    Zhang, Xinxin; Du, Lei; Zhao, Feifang; Wang, Qiuju; Yang, Shiming; Ma, Lin

    2016-01-01

    Purpose: The present clinical trial was designed to evaluate the efficacy and safety of concurrent helical tomotherapy (HT) with cetuximab followed by adjuvant chemotherapy with docetaxel and cisplatin (TP) in the treatment of patients with locoregionally advanced nasopharyngeal carcinoma. Materials and Methods: This phase II clinical trial included 43 patients with Stage III/IV LANC (33 Stage III and 10 Stage IV). The treatment consisted of concurrent HT with cetuximab (400 mg/m2 loading dose and weekly 250mg/m2), followed by four cycles of chemotherapy [docetaxel (70 mg/m2 on Day 1) and cisplatin (40 mg/m2 on Days 1 and 2 every 3 weeks). Side effects were evaluated with CTCAE criteria (Common Terminology Criteria for Adverse Events 3.0). Results: The median follow-up duration was 48.0 months [95% confidence interval (CI) 41.7-58.0 months], the 2-year locoregional failure-free rate (LFFR), progression-free survival (PFS), distant failure-free rate (DFFR) and overall survival (OS) were 95.2%, 79.1%, 88.1% and 93.0% respectively; the 3-year LFFR, DFFR, PFS and OS were 92.7%, 85.6%, 72.0% and 85.7% respectively. The most common grade 3 toxicities were oropharyngeal mucositis (81.4%) and RT-related dermatitis (7.0%). No patients had more than grade 3 radiation related toxicities and no patients required nasogastric feeding. One patient experienced grade 3 osteonecrosis at 18 months after treatment. Conclusions: Concurrent HT with cetuximab followed by adjuvant chemotherapy with TP is an effective strategy for the treatment of LANC with encouraging survival rates and minimal side effects. PMID:27019628

  13. A phase II randomized trial of induction chemotherapy versus no induction chemotherapy followed by preoperative chemoradiation in patients with esophageal cancer

    PubMed Central

    Ajani, J. A.; Xiao, L.; Roth, J. A.; Hofstetter, W. L.; Walsh, G.; Komaki, R.; Liao, Z.; Rice, D. C.; Vaporciyan, A. A.; Maru, D. M.; Lee, J. H.; Bhutani, M. S.; Eid, A.; Yao, J. C.; Phan, A. P.; Halpin, A.; Suzuki, A.; Taketa, T.; Thall, P. F.; Swisher, S. G.

    2013-01-01

    Background The contribution of induction chemotherapy (IC) before preoperative chemoradiation for esophageal cancer (EC) is not known. We hypothesized that IC would increase the rate of pathologic complete response (pathCR). Methods Trimodality-eligibile patients were randomized to receive no IC (Arm A) or IC (oxaliplatin/FU; Arm B) before oxaliplatin/FU/radiation. Surgery was attempted ∼5–6 weeks after chemoradiation. The pathCR rate, post-surgery 30-day mortality, overall survival (OS), and toxic effects were assessed. Bayesian methods and Fisher's exact test were used. Results One hundred twenty-six patients were randomized dynamically to balance the two arms for histology, baseline stage, gender, race, and age. Fifty-five patients in Arm A and 54 in Arm B underwent surgery. The median actuarial OS for all patients (54 deaths) was 45.62 months [95% confidence interval (CI), 27.63–NA], with median OS 45.62 months (95% CI 25.56–NA) in Arm A and 43.68 months (95% CI 27.63–NA) in Arm B (P = 0.69). The pathCR rate in Arm A was 13% (7 of 55) and 26% (14 of 54) in Arm B (two-sided Fisher's exact test, P = 0.094). Safety was similar in both arms. Conclusions These data suggest that IC produces non-significant increase in the pathCR rate and does not prolong OS. Further development of IC before chemoradiation may not be beneficial. Clinical trial no.: NCT 00525915 (www.clinicaltrials.gov). PMID:23975663

  14. Options Study - Phase II

    SciTech Connect

    R. Wigeland; T. Taiwo; M. Todosow; W. Halsey; J. Gehin

    2010-09-01

    The Options Study has been conducted for the purpose of evaluating the potential of alternative integrated nuclear fuel cycle options to favorably address the issues associated with a continuing or expanding use of nuclear power in the United States. The study produced information that can be used to inform decisions identifying potential directions for research and development on such fuel cycle options. An integrated nuclear fuel cycle option is defined in this study as including all aspects of the entire nuclear fuel cycle, from obtaining natural resources for fuel to the ultimate disposal of used nuclear fuel (UNF) or radioactive wastes. Issues such as nuclear waste management, especially the increasing inventory of used nuclear fuel, the current uncertainty about used fuel disposal, and the risk of nuclear weapons proliferation have contributed to the reluctance to expand the use of nuclear power, even though it is recognized that nuclear power is a safe and reliable method of producing electricity. In this Options Study, current, evolutionary, and revolutionary nuclear energy options were all considered, including the use of uranium and thorium, and both once-through and recycle approaches. Available information has been collected and reviewed in order to evaluate the ability of an option to clearly address the challenges associated with the current implementation and potential expansion of commercial nuclear power in the United States. This Options Study is a comprehensive consideration and review of fuel cycle and technology options, including those for disposal, and is not constrained by any limitations that may be imposed by economics, technical maturity, past policy, or speculated future conditions. This Phase II report is intended to be used in conjunction with the Phase I report, and much information in that report is not repeated here, although some information has been updated to reflect recent developments. The focus in this Options Study was to

  15. Efficacy Endpoints of RTOG 0247: A Randomized Phase II Study of Neoadjuvant Radiation Therapy Plus Concurrent Capecitabine and Irinotecan or Capecitabine and Oxaliplatin for Patients with Locally Advanced Rectal Cancer

    PubMed Central

    Wong, Stuart J.; Moughan, J.; Meropol, Neal J.; Anne, Pramila Rani; Kachnic, Lisa A.; Rashid, Asif; Watson, James C.; Mitchell, Edith P.; Pollock, Jondavid; Lee, R. Jeffrey; Haddock, Michael; Erickson, Beth A.; Willett, Christopher G.

    2015-01-01

    Purpose/Objectives Primary endpoint analysis of RTOG 0247 demonstrated preoperative RT with capecitabine plus oxaliplatin achieved a pCR pre-specified threshold (21%) to merit further study, whereas the RT with capecitabine plus irinotecan arm did not (10%). Secondary efficacy endpoints are reported here. Methods and Materials A randomized phase II trial evaluated preoperative RT (50.4 Gy in 1.8 Gy fractions) with two concurrent chemotherapy regimens: 1—capecitabine (1200 mg/m2/d M-F) plus irinotecan (50 mg/m2 /week × 4); and 2—capecitabine (1650 mg/m2/d M-F) plus oxaliplatin (50 mg/m2 /week × 5) for clinical T3 or T4 rectal cancer. Surgery was performed 4-8 weeks following chemoradiation, then 4-6 weeks later, adjuvant chemotherapy (oxaliplatin 85 mg/m2; leucovorin 400 mg/m2; 5FU 400 mg/m2; 5FU 2400 mg/m2) every 2 weeks × 9. Disease-free survival (DFS) and overall survival (OS) were estimated univariately by the Kaplan-Meier method. Local-regional failure (LRF), distant failure (DF), and second primary failure (SP) were estimated by the cumulative incidence method. No statistical comparisons were made between arms as each was evaluated individually. Results 104 patients (median age 57) were treated; characteristics were similar for both arms. Median follow-up for RT with capecitabine/irinotecan arm was 3.77 years and for RT with capecitabine/oxaliplatin arm was 3.97 years. Four-year DFS, OS, LRF, DF, and SP estimates for capecitabine/irinotecan arm are 68%, 85%, 16%, 24%, and 2%, respectively. The 4-year DFS, OS, LRF, DF, and SP failure estimates for capecitabine/oxaliplatin arm are 62%, 75%, 18%, 30%, and 6%, respectively. Conclusions Efficacy results for both arms are similar to other reported studies but suggest that pCR is an unsuitable surrogate for traditional survival metrics of clinical outcome. While it remains uncertain if the addition of a second cytotoxic agent enhances the effectiveness of fluorouracil plus RT, these results suggest further

  16. Impact of adjuvants on CD4(+) T cell and B cell responses to a protein antigen vaccine: Results from a phase II, randomized, multicenter trial.

    PubMed

    Leroux-Roels, Geert; Marchant, Arnaud; Levy, Jack; Van Damme, Pierre; Schwarz, Tino F; Horsmans, Yves; Jilg, Wolfgang; Kremsner, Peter G; Haelterman, Edwige; Clément, Frédéric; Gabor, Julian J; Esen, Meral; Hens, Annick; Carletti, Isabelle; Fissette, Laurence; Tavares Da Silva, Fernanda; Burny, Wivine; Janssens, Michel; Moris, Philippe; Didierlaurent, Arnaud M; Van Der Most, Robbert; Garçon, Nathalie; Van Belle, Pascale; Van Mechelen, Marcelle

    2016-08-01

    Immunogenicity and safety of different adjuvants combined with a model antigen (HBsAg) were compared. Healthy HBV-naïve adults were randomized to receive HBs adjuvanted with alum or Adjuvant Systems AS01B, AS01E, AS03A or AS04 at Days 0 and 30. Different frequencies of HBs-specific CD4+ T cells 14days post dose 2 but similar polyfunctionality profiles were induced by the different adjuvants with frequencies significantly higher in the AS01B and AS01E groups than in the other groups. Antibody concentrations 30days post-dose 2 were significantly higher in AS01B, AS01E and AS03A than in other groups. Limited correlations were observed between HBs-specific CD4+ T cell and antibody responses. Injection site pain was the most common solicited local symptom and was more frequent in AS groups than in alum group. Different adjuvants formulated with the same antigen induced different adaptive immune responses and reactogenicity patterns in healthy naïve adults. The results summary for this study (GSK study number 112115 - NCT# NCT00805389) is available on the GSK Clinical Study Register and can be accessed at www.gsk-clinicalstudyregister.com.

  17. Impact of adjuvants on CD4(+) T cell and B cell responses to a protein antigen vaccine: Results from a phase II, randomized, multicenter trial.

    PubMed

    Leroux-Roels, Geert; Marchant, Arnaud; Levy, Jack; Van Damme, Pierre; Schwarz, Tino F; Horsmans, Yves; Jilg, Wolfgang; Kremsner, Peter G; Haelterman, Edwige; Clément, Frédéric; Gabor, Julian J; Esen, Meral; Hens, Annick; Carletti, Isabelle; Fissette, Laurence; Tavares Da Silva, Fernanda; Burny, Wivine; Janssens, Michel; Moris, Philippe; Didierlaurent, Arnaud M; Van Der Most, Robbert; Garçon, Nathalie; Van Belle, Pascale; Van Mechelen, Marcelle

    2016-08-01

    Immunogenicity and safety of different adjuvants combined with a model antigen (HBsAg) were compared. Healthy HBV-naïve adults were randomized to receive HBs adjuvanted with alum or Adjuvant Systems AS01B, AS01E, AS03A or AS04 at Days 0 and 30. Different frequencies of HBs-specific CD4+ T cells 14days post dose 2 but similar polyfunctionality profiles were induced by the different adjuvants with frequencies significantly higher in the AS01B and AS01E groups than in the other groups. Antibody concentrations 30days post-dose 2 were significantly higher in AS01B, AS01E and AS03A than in other groups. Limited correlations were observed between HBs-specific CD4+ T cell and antibody responses. Injection site pain was the most common solicited local symptom and was more frequent in AS groups than in alum group. Different adjuvants formulated with the same antigen induced different adaptive immune responses and reactogenicity patterns in healthy naïve adults. The results summary for this study (GSK study number 112115 - NCT# NCT00805389) is available on the GSK Clinical Study Register and can be accessed at www.gsk-clinicalstudyregister.com. PMID:27236001

  18. Effect of leuprolide acetate on ovarian function after cyclophosphamide-doxorubicin-based chemotherapy in premenopausal patients with breast cancer: results from a phase II randomized trial.

    PubMed

    Song, Guiping; Gao, Hui; Yuan, Zhixiang

    2013-01-01

    Previous studies provided inconclusive evidence for the effectiveness of gonadotropin-releasing hormone analogue on ovarian function protection against chemotherapy-induced genotoxicity in premenopausal patients. This study was designed to examine the efficacy of leuprolide acetate on ovarian function preservation in patients with breast cancer. A total of 220 patients were recruited in this prospective clinical trial and were assigned randomly to receive cyclophosphamide-doxorubicin-based chemotherapy only or chemotherapy plus leuprolide acetate. Resumption of menses or premenopausal levels of both follicle-stimulating hormone (FSH) and estradiol (E2) within 12 months after the end of chemotherapy were considered as effective ovarian preservation. A total of 183 patients were considered evaluable (94 in chemotherapy-only group and 89 in chemotherapy plus leuprolide acetate group). At the end of follow-up, 27 patients in chemotherapy group and 15 in chemotherapy plus leuprolide acetate group resumed menses; seven patients in chemotherapy group and 14 in chemotherapy plus leuprolide acetate group restored premenopausal levels of FSH and E2. The median time to resume menses was 9.2 months for patients in chemotherapy plus leuprolide acetate group and was not reached in chemotherapy-only group. In addition, our results demonstrated that age and chemotherapy doses made no significant difference in the occurrence of premature menopause. The leuprolide acetate treatment simultaneously with cyclophosphamide-doxorubicin-based chemotherapy reduced the risk of developing premature menopause in premenopausal patients with breast cancer.

  19. Melatonin analgesia is associated with improvement of the descending endogenous pain-modulating system in fibromyalgia: a phase II, randomized, double-dummy, controlled trial

    PubMed Central

    2014-01-01

    Background Central disinhibition is a mechanism involved in the physiopathology of fibromyalgia. Melatonin can improve sleep quality, pain and pain threshold. We hypothesized that treatment with melatonin alone or in combination with amitriptyline would be superior to amitriptyline alone in modifying the endogenous pain-modulating system (PMS) as quantified by conditional pain modulation (CPM), and this change in CPM could be associated with serum brain-derived neurotrophic factor (BDNF). We also tested whether melatonin improves the clinical symptoms of pain, pain threshold and sleep quality. Methods Sixty-three females, aged 18 to 65, were randomized to receive bedtime amitriptyline (25 mg) (n = 21), melatonin (10 mg) (n = 21) or melatonin (10 mg) + amitriptyline (25 mg) (n = 21) for a period of six weeks. The descending PMS was assessed with the CPM-TASK. It was assessed the pain score on the Visual Analog Scale (VAS 0-100 mm), the score on Fibromyalgia Impact Questionnaire (FIQ), heat pain threshold (HPT), sleep quality and BDNF serum. Delta values (post- minus pre-treatment) were used to compare the treatment effect. The outcomes variables were collected before, one and six weeks after initiating treatment. Results Melatonin alone or in combination with amitriptyline reduced significantly pain on the VAS compared with amitriptyline alone (P < 0.01). The delta values on the VAS scores were-12.85 (19.93),-17.37 (18.69) and-20.93 (12.23) in the amitriptyline, melatonin and melatonin+amitriptyline groups, respectively. Melatonin alone and in combination increased the inhibitory PMS as assessed by the Numerical Pain Scale [NPS(0-10)] reduction during the CPM-TASK:-2.4 (2.04) melatonin + amitriptyline,-2.65 (1.68) melatonin, and-1.04 (2.06) amitriptyline, (P < 0.05). Melatonin + amitriptyline treated displayed better results than melatonin and amitriptyline alone in terms of FIQ and PPT improvement (P < 0.05, fort both

  20. A Proof of Concept, Phase II Randomized European Trial, on the Efficacy of ALF-5755, a Novel Extracellular Matrix-Targeted Antioxidant in Patients with Acute Liver Diseases

    PubMed Central

    Nalpas, Bertrand; Ichaï, Philippe; Jamot, Laure; Carbonell, Nicolas; Rudler, Marika; Mathurin, Philippe; Durand, François; Gerken, Guido; Manns, Michael; Trautwein, Christian; Larrey, Dominique; Radenne, Sylvie; Duvoux, Christophe; Leroy, Vincent; Bernuau, Jacques; Faivre, Jamila; Moniaux, Nicolas; Bréchot, Christian; Amouyal, Gilles; Amouyal, Paul; Samuel, Didier

    2016-01-01

    Objective No efficient medical treatment is available for severe acute hepatitis (SAH) except N-acetylcysteine for acetaminophen-induced acute liver failure. The human C-type lectin Reg3α, referred to as ALF-5755, improved survival in an animal model of acute liver failure and was well tolerated in a phase 1 trial in humans. We performed a phase 2a trial of ALF5755 in non-acetaminophen induced SAH. Design double-blind, randomized, placebo-controlled study. The primary end-point was the improvement in the coagulation protein synthesis assessed by the change of Prothrombin (PR) during the 72 hours following treatment initiation calculated as PRH0 minus PRH72 divided by 72 (PR slope H0H72). Intention to treat (ITT) and per-protocol (PP) analysis of the entire group and the Hepatitis B virus (HBV)/AIH (auto-immune hepatitis) sub-group were done separately. Results 57 patients were included. Twenty-eight received ALF-5755, 29 the placebo. Etiologies were: Hepatitis A (n = 10), HBV (n = 13), AIH (n = 9), drug-induced (n = 8), other (n = 17). On the whole group, nor the PR slope H0H72 (0.18±0.31 vs 0.25±0.32), nor the transplant-free survival rate at day 21 (75 vs 86%) differed between groups. Conversely, in the HBV-AIH subgroup, in which ALF was more severe, PR slope H0-H72 was higher in the ALF-5755 arm, the difference being significant in PP analysis (0.048±0.066 vs -0.040±0.099, p = 0.04); the median length of hospitalization was lower in the ALF-5755 group (8 vs 14 days, p = 0.02). Conclusion ALF-5755 was not efficient in a ITT analysis performed on the whole sample; however it led to a significant, although moderate, clinical benefit in a PP analysis of the sub-group of patients with HBV or AIH related SAH. As HBV is the major cause of SAH in Asia and Africa and AIH a growing cause, this study emphasizes the need to pursuit the evaluation of this novel medical treatment of SAH. Trial Registration ClinicalTrials.gov NCT01318525 PMID:26983031

  1. Randomized phase II study of pemetrexed/cisplatin with or without axitinib for non-squamous non-small-cell lung cancer

    PubMed Central

    2014-01-01

    Background The efficacy and safety of axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors 1, 2, and 3 in combination with pemetrexed and cisplatin was evaluated in patients with advanced non-squamous non–small-cell lung cancer (NSCLC). Methods Overall, 170 patients were randomly assigned to receive axitinib at a starting dose of 5-mg twice daily continuously plus pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 on day 1 of up to six 21-day cycles (arm I); axitinib on days 2 through 19 of each cycle plus pemetrexed/cisplatin (arm II); or pemetrexed/cisplatin alone (arm III). The primary endpoint was progression-free survival (PFS). Results Median PFS was 8.0, 7.9, and 7.1 months in arms I, II, and III, respectively (hazard ratio: arms I vs. III, 0.89 [P = 0.36] and arms II vs. III, 1.02 [P = 0.54]). Median overall survival was 17.0 months (arm I), 14.7 months (arm II), and 15.9 months (arm III). Objective response rates (ORRs) for axitinib-containing arms were 45.5% (arm I) and 39.7% (arm II) compared with 26.3% for pemetrexed/cisplatin alone (arm III). Gastrointestinal disorders and fatigue were frequently reported across all treatment arms. The most common all-causality grade ≥3 adverse events were hypertension in axitinib-containing arms (20% and 17%, arms I and II, respectively) and fatigue with pemetrexed/cisplatin alone (16%). Conclusion Axitinib in combination with pemetrexed/cisplatin was generally well tolerated. Axitinib combinations resulted in non-significant differences in PFS and numerically higher ORR compared with chemotherapy alone in advanced NSCLC. Trial registration ClinicalTrials.gov: NCT00768755 (October 7, 2008). PMID:24766732

  2. A randomized phase II study of S-1 plus oral leucovorin versus S-1 monotherapy in patients with gemcitabine-refractory advanced pancreatic cancer†

    PubMed Central

    Ueno, M.; Okusaka, T.; Omuro, Y.; Isayama, H.; Fukutomi, A.; Ikeda, M.; Mizuno, N.; Fukuzawa, K.; Furukawa, M.; Iguchi, H.; Sugimori, K.; Furuse, J.; Shimada, K.; Ioka, T.; Nakamori, S.; Baba, H.; Komatsu, Y.; Takeuchi, M.; Hyodo, I.; Boku, N.

    2016-01-01

    Background We evaluated the efficacy and toxicity of adding oral leucovorin (LV) to S-1 when compared with S-1 monotherapy in patients with gemcitabine-refractory pancreatic cancer (PC). Patients and methods Gemcitabine-refractory PC patients were randomly assigned in a 1:1 ratio to receive S-1 at 40, 50, or 60 mg according to body surface area plus LV 25 mg, both given orally twice daily for 1 week, repeated every 2 weeks (SL group), or S-1 monotherapy at the same dose as the SL group for 4 weeks, repeated every 6 weeks (S-1 group). The primary end point was progression-free survival (PFS). Results Among 142 patients enrolled, 140 were eligible for efficacy assessment (SL: n = 69 and S-1: n = 71). PFS was significantly longer in the SL group than in the S-1 group [median PFS, 3.8 versus 2.7 months; hazard ratio (HR), 0.56; 95% confidence interval (CI), 0.37–0.85; P = 0.003]). The disease control rate was significantly higher in the SL group than in the S-1 group (91% versus 72%; P = 0.004). Overall survival (OS) was similar in both groups (median OS, 6.3 versus 6.1 months; HR, 0.82; 95% CI, 0.54–1.22; P = 0.463). After adjusting for patient background factors in a multivariate analysis, OS tended to be better in the SL group (HR, 0.71; 95% CI, 0.47–1.07; P = 0.099). Both treatments were well tolerated, although gastrointestinal toxicities were slightly more severe in the SL group. Conclusion The addition of LV to S-1 significantly improved PFS in patients with gemcitabine-refractory advanced PC, and a phase III trial has been initiated in a similar setting. Clinical trials number Japan Pharmaceutical Information Center: JapicCTI-111554. PMID:26681680

  3. EXpanding Treatment for Existing Neurological Disease (EXTEND): An Open-Label Phase II Clinical Trial of Hydroxyurea Treatment in Sickle Cell Anemia

    PubMed Central

    Little, Courtney R; Reid, Marvin E; Soares, Deanne P; Taylor-Bryan, Carolyn; Knight-Madden, Jennifer M; Stuber, Susan E; Badaloo, Asha V; Aldred, Karen; Wisdom-Phipps, Margaret E; Latham, Teresa; Ware, Russell E

    2016-01-01

    Background Cerebral vasculopathy in sickle cell anemia (SCA) begins in childhood and features intracranial arterial stenosis with high risk of ischemic stroke. Stroke risk can be reduced by transcranial doppler (TCD) screening and chronic transfusion therapy; however, this approach is impractical in many developing countries. Accumulating evidence supports the use of hydroxyurea for the prevention and treatment of cerebrovascular disease in children with SCA. Recently we reported that hydroxyurea significantly reduced the conversion from conditional TCD velocities to abnormal velocities; whether hydroxyurea can be used for children with newly diagnosed severe cerebrovascular disease in place of starting transfusion therapy remains unknown. Objective The primary objective of the EXpanding Treatment for Existing Neurological Disease (EXTEND) trial is to investigate the effect of open label hydroxyurea on the maximum time-averaged mean velocity (TAMV) after 18 months of treatment compared to the pre-treatment value. Secondary objectives include the effects of hydroxyurea on serial TCD velocities, the incidence of neurological and non-neurological events, quality of life (QOL), body composition and metabolism, toxicity and treatment response, changes to brain magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA), genetic and serologic markers of disease severity, and cognitive and pulmonary function. Methods This prospective Phase II trial will enroll children with SCA in Jamaica, between the ages of 2 and 17 years, with either conditional (170-199 cm/sec) or abnormal (≥ 200 cm/sec) TCD velocities. Oral hydroxyurea will be administered daily and escalated to the maximum tolerated dose (MTD). Participants will be seen in the Sickle Cell Unit (SCU) in Kingston, Jamaica monthly until achieving MTD, and then every 3 months. TCD will be performed every 6 months. Results Currently, 43 participants have been enrolled out of a projected 50. There was one

  4. Phase II study of first-line sagopilone plus prednisone in patients with castration-resistant prostate cancer: a phase II study of the Department of Defense Prostate Cancer Clinical Trials Consortium

    PubMed Central

    Beer, T M; Smith, D C; Hussain, A; Alonso, M; Wang, J; Giurescu, M; Roth, K; Wang, Y

    2012-01-01

    Background: Preclinical studies in prostate cancer (PC) models demonstrated the anti-tumour activity of the first fully synthetic epothilone, sagopilone. This is the first study to investigate the activity and safety of sagopilone in patients with metastatic castration-resistant PC (CRPC). Methods: Chemotherapy-naïve patients with metastatic CRPC received sagopilone (one cycle: 16 mg m−2 intravenously over 3 h q3w) plus prednisone (5 mg twice daily). The primary efficacy evaluation was prostate-specific antigen (PSA) response rate (⩾50% PSA reduction confirmed ⩾28 days apart). According to the Simon two-stage design, ⩾3 PSA responders were necessary within the first 13 evaluable patients for recruitment to continue until 46 evaluable patients were available. Results: In all, 53 patients received ⩾2 study medication cycles, with high compliance. Mean individual dose was 15.1±1.4 mg m−2 during initial six cycles, mean dose intensity 94±9%. The confirmed PSA response rate was 37%. Median overall progression-free survival was 6.4 months. The most commonly reported adverse events (>10% of patients) were peripheral neuropathy (94.3%), fatigue (54.7%) and pain in the extremities (47.2%). Sagopilone was associated with very little haematological toxicity. Conclusion: This study shows that first-line sagopilone has noteworthy anti-tumour activity and a clinically significant level of neuropathy for patients with metastatic chemotherapy-naïve CRPC. PMID:22850553

  5. Heat Shock Protein 70 (Hsp70) Peptide Activated Natural Killer (NK) Cells for the Treatment of Patients with Non-Small Cell Lung Cancer (NSCLC) after Radiochemotherapy (RCTx) – From Preclinical Studies to a Clinical Phase II Trial

    PubMed Central

    Specht, Hanno M.; Ahrens, Norbert; Blankenstein, Christiane; Duell, Thomas; Fietkau, Rainer; Gaipl, Udo S.; Günther, Christine; Gunther, Sophie; Habl, Gregor; Hautmann, Hubert; Hautmann, Matthias; Huber, Rudolf Maria; Molls, Michael; Offner, Robert; Rödel, Claus; Rödel, Franz; Schütz, Martin; Combs, Stephanie E.; Multhoff, Gabriele

    2015-01-01

    Heat shock protein 70 (Hsp70) is frequently overexpressed in tumor cells. An unusual cell surface localization could be demonstrated on a large variety of solid tumors including lung, colorectal, breast, squamous cell carcinomas of the head and neck, prostate and pancreatic carcinomas, glioblastomas, sarcomas and hematological malignancies, but not on corresponding normal tissues. A membrane (m)Hsp70-positive phenotype can be determined either directly on single cell suspensions of tumor biopsies by flow cytometry using cmHsp70.1 monoclonal antibody or indirectly in the serum of patients using a novel lipHsp70 ELISA. A mHsp70-positive tumor phenotype has been associated with highly aggressive tumors, causing invasion and metastases and resistance to cell death. However, natural killer (NK), but not T cells were found to kill mHsp70-positive tumor cells after activation with a naturally occurring Hsp70 peptide (TKD) plus low dose IL-2 (TKD/IL-2). Safety and tolerability of ex vivo TKD/IL-2 stimulated, autologous NK cells has been demonstrated in patients with metastasized colorectal and non-small cell lung cancer (NSCLC) in a phase I clinical trial. Based on promising clinical results of the previous study, a phase II randomized clinical study was initiated in 2014. The primary objective of this multicenter proof-of-concept trial is to examine whether an adjuvant treatment of NSCLC patients after platinum-based radiochemotherapy (RCTx) with TKD/IL-2 activated, autologous NK cells is clinically effective. As a mHsp70-positive tumor phenotype is associated with poor clinical outcome only mHsp70-positive tumor patients will be recruited into the trial. The primary endpoint of this study will be the comparison of the progression-free survival of patients treated with ex vivo activated NK cells compared to patients who were treated with RCTx alone. As secondary endpoints overall survival, toxicity, quality-of-life, and biological responses will be determined in both

  6. A randomized phase II trial of personalized peptide vaccine plus low dose estramustine phosphate (EMP) versus standard dose EMP in patients with castration resistant prostate cancer.

    PubMed

    Noguchi, Masanori; Kakuma, Tatsuyuki; Uemura, Hirotsugu; Nasu, Yasutomo; Kumon, Hiromi; Hirao, Yasuhiko; Moriya, Fukuko; Suekane, Shigetaka; Matsuoka, Kei; Komatsu, Nobukazu; Shichijo, Shigeki; Yamada, Akira; Itoh, Kyogo

    2010-07-01

    Personalized peptide vaccination (PPV) combined with chemotherapy could be a novel approach for many cancer patients. In this randomized study, we evaluated the anti-tumor effect and safety of PPV plus low-dose estramustine phosphate (EMP) as compared to standard-dose EMP for HLA-A2- or -A24-positive patients with castration resistant prostate cancer. Patients were randomized into groups receiving either PPV plus low-dose EMP (280 mg/day) or standard-dose EMP (560 mg/day). After disease progression, patients were switched to the opposite regime. The primary end point was progression-free survival (PFS). We randomly assigned 28 patients to receive PPV plus low-dose EMP and 29 patients to receive standard-dose EMP. Nineteen events in the PPV group and 20 events in the EMP group occurred during the first treatment. Median PFS for the first treatment was 8.5 months in the PPV group and 2.8 months in the EMP group with a hazard ratio (HR) of 0.28 (95% CI, 0.14-0.61; log-rank P = 0.0012), while there was no difference for median PFS for the second treatment. The HR for overall survival was 0.3 (95% CI, 0.1-0.91) in favor of the PPV plus low-dose EMP group (log-rank, P = 0.0328). The PPV plus low-dose EMP was well tolerated without major adverse effects and with increased levels of IgG and cytotoxic-T cell responses to the vaccinated peptides. PPV plus low-dose EMP was associated with an improvement in PSA-based PFS as compared to the standard-dose EMP alone.

  7. A phase II, randomized, controlled trial of S-adenosylmethionine in reducing serum alpha-fetoprotein (AFP) in patients with hepatitis C cirrhosis and elevated AFP

    PubMed Central

    Morgan, Timothy R.; Osann, Kathryn; Bottiglieri, Teodoro; Pimstone, Neville; Hoefs, John C.; Hu, Ke-Qin; Hassanein, Tarek; Boyer, Thomas D.; Kong, Lorene; Chen, Wen-Pin; Richmond, Ellen; Gonzalez, Rachel; Rodriguez, Luz M.; Meyskens, Frank L.

    2015-01-01

    In animal models of hepatocellular carcinoma (HCC), deficiency of S-adenosylmethionine (SAMe) increased the risk of HCC while administration of SAMe reduced HCC. The aim of this trial was to determine whether oral SAMe administration to patients with hepatitis C cirrhosis would decrease serum AFP level, a biomarker of HCC risk in hepatitis C. This was a prospective, randomized, placebo-controlled, double-blind trial of SAMe, up to 2.4 grams/day, for 24 weeks as compared with placebo among subjects with hepatitis C cirrhosis and a mildly elevated serum AFP. Primary outcome was change in AFP between baseline and week 24. Secondary outcomes included changes in routine tests of liver function and injury, other biomarkers of HCC risk, SAMe metabolites, markers of oxidative stress, and quality of life. 110 subjects were randomized and 87 (44 SAMe and 43 placebo) completed treatment. There was no difference in the change in AFP during 24 weeks among subjects receiving SAMe as compared with placebo. Changes in markers of liver function, liver injury, and hepatitis C viral level were not significantly different between groups. Similarly, SAMe did not change markers of oxidative stress or serum glutathione level. SAMe blood level increased significantly among subjects receiving SAMe. Changes in quality of life did not differ between groups. Overall, this trial did not find that SAMe treatment improved serum AFP in subjects with advanced hepatitis C cirrhosis and a mildly elevated AFP. SAMe did not improve tests of liver function or injury, or markers of oxidative stress or antioxidant potential. PMID:26130251

  8. Metformin intervention in obese non-diabetic patients with breast cancer: phase II randomized, double-blind, placebo-controlled trial.

    PubMed

    Ko, Kwang-Pil; Ma, Seung Hyun; Yang, Jae-Jeong; Hwang, Yunji; Ahn, Choonghyun; Cho, Young-Min; Noh, Dong-Young; Park, Byung-Joo; Han, Wonshik; Park, Sue K

    2015-09-01

    Previous observational studies have suggested that metformin in diabetes patients may reduce breast cancer risk more than the reductions from other anti-diabetes medications. This randomized, double-blind, placebo-controlled trial was performed to evaluate the efficacy of metformin for controlling physical and metabolic profiles related to prognosis and adverse events in non-diabetic breast cancer patients. Female breast cancer patients (N = 105), at least 6 months post-mastectomy, with obesity (≥25 kg/m(2)) and/or pre-diabetes (fasting blood sugar levels ≥100 mg/dL), were randomly assigned to three groups (placebo, metformin 500 mg, and metformin 1000 mg) stratified by tamoxifen use. A linear mixed model for repeated measurements among three groups and ANOVA for profile differences during 6 months of treatment were used for the intention-to-treat analysis. The metformin 1000 mg group had a significantly greater decline in glucose and HbA1c levels between treatment weeks 0 and 6 month (p = 0.008 and 0.009, respectively), and the declines increased with an increase in body mass index (BMI) level (p interaction with BMI = 0.007 and 0.067, respectively). A marginally significant different effect from the metformin 1000 mg treatment was detected for glucose and HbA1c levels (p interaction = 0.084 and 0.063, respectively) in the intention-to-treat analysis. Metformin 1000 mg treatment had a favorable effect on controlling glucose and HbA1C levels in obese non-diabetic breast cancer patients, indicating prognostic importance. Further trials are needed to elucidate the risk-benefit ratio of long-term use of metformin. PMID:26293146

  9. Immunogenicity and safety of tetravalent dengue vaccine in 2-11 year-olds previously vaccinated against yellow fever: randomized, controlled, phase II study in Piura, Peru.

    PubMed

    Lanata, Claudio F; Andrade, Teresa; Gil, Ana I; Terrones, Cynthia; Valladolid, Omar; Zambrano, Betzana; Saville, Melanie; Crevat, Denis

    2012-09-01

    In a randomized, placebo-controlled, monocenter, observer blinded study conducted in an area where dengue is endemic, we assessed the safety and immunogenicity of a recombinant, live, attenuated, tetravalent dengue vaccine candidate (CYD-TDV) in 2-11 year-olds with varying levels of pre-existing yellow-fever immunity due to vaccination 1-7 years previously. 199 children received 3 injections of CYD-TDV (months 0, 6 and 12) and 99 received placebo (months 0 and 6) or pneumococcal polysaccharide vaccine (month 12). One month after the third dengue vaccination, serotype specific neutralizing antibody GMTs were in the range of 178-190 (1/dil) (versus 16.7-38.1 in the control group), a 10-20 fold-increase from baseline, and 94% of vaccines were seropositive to all four serotypes (versus 39% in the control group). There were no vaccine-related SAEs. The observed reactogenicity profile was consistent with phase I studies, with severity grade 1-2 injection site pain, headache, malaise and fever most frequently reported and no increase after subsequent vaccinations. Virologically confirmed dengue cases were seen after completion of the 3 doses: 1 in the CYD-TDV group (N=199), and 3 in the control group (N=99). A 3-dose regimen of CYD-TDV had a good safety profile in 2-11 year olds with a history of YF vaccination and elicited robust antibody responses that were balanced against the four serotypes.

  10. ATON: results from a Phase II randomized trial of the B-cell-targeting agent atacicept in patients with optic neuritis.

    PubMed

    Sergott, Robert C; Bennett, Jeffrey L; Rieckmann, Peter; Montalban, Xavier; Mikol, Daniel; Freudensprung, Ulrich; Plitz, Thomas; van Beek, Johan

    2015-04-15

    The 36-week ATON study compared the efficacy and safety of atacicept with matching placebo in 34 patients with unilateral optic neuritis as a clinically isolated syndrome. Atacicept (150mg) was administered twice weekly for 4weeks (loading period), then once weekly for 32weeks. The ATON study was terminated prematurely by the sponsor when an independent Data and Safety Monitoring Board review observed increased multiple sclerosis (MS)-related disease activity in the atacicept arms of the concurrent ATAcicept in MS (ATAMS) study. Analysis of the prematurely terminated ATON study showed that the mean (standard deviation) change from baseline in retinal nerve fiber layer thickness at last observed value in the affected eye was -8.6 (10.1) μm in patients treated with atacicept (n=15) compared with -17.3 (15.2) μm in patients treated with placebo (n=16). In the atacicept treatment group, a higher proportion of patients converted to clinically definite MS during the double-blind period compared with placebo (35.3% [6/17] vs 17.6% [3/17]). Treatment-emergent adverse events were similar across both treatment groups in the double-blind period. A dichotomy emerged with more atacicept-treated patients converting to relapsing-remitting MS compared with placebo-treated patients, despite the same patients experiencing less axonal loss after an optic neuritis event.

  11. Key predictive factors for efficacy of axitinib in first-line metastatic renal cell carcinoma: subgroup analysis in Japanese patients from a randomized, double-blind phase II study

    PubMed Central

    Tomita, Yoshihiko; Fukasawa, Satoshi; Oya, Mototsugu; Uemura, Hirotsugu; Shinohara, Nobuo; Habuchi, Tomonori; Rini, Brian I.; Chen, Ying; Bair, Angel H.; Ozono, Seiichiro; Naito, Seiji; Akaza, Hideyuki

    2016-01-01

    Objectives To conduct Japanese subgroup analyses of a randomized, global Phase II study of axitinib with and without dose titration in first-line metastatic renal cell carcinoma and to explore predictive factors for axitinib efficacy in first-line metastatic renal cell carcinoma. Methods The data included 44 Japanese and 169 non-Japanese treatment-naïve patients with metastatic renal cell carcinoma. Patients received twice-daily axitinib 5 mg during a 4-week lead-in period. Patients who met the pre-defined randomization criteria were stratified by Eastern Cooperative Oncology Group performance status and randomly assigned (1:1) to axitinib or placebo titration. The primary endpoint was objective response rate; secondary endpoints included progression-free survival and safety. Predictive factors were analyzed using data from all patients. Results The objective response rate (95% confidence interval) was 66% (50–80%) vs. 44% (36–52%) in Japanese and non-Japanese patients, respectively. At the primary analysis, median progression-free survival could not be estimated for Japanese patients, and was 27.6 months (95% confidence interval: 16.6–33.2) in an updated analysis. Hypertension, diarrhea, hand–foot syndrome, dysphonia, hypothyroidism and proteinuria were common adverse events in Japanese patients. Due to a small number of randomized patients, effects of axitinib dose titration could not sufficiently be confirmed among Japanese patients. The multivariate analysis identified time from histopathological diagnosis to treatment and sum of the longest diameter for target lesion at baseline as independent predictive factors for progression-free survival. Conclusions Axitinib is effective and well tolerated as first-line metastatic renal cell carcinoma therapy in Japanese patients. Predictive factors for axitinib efficacy endpoints identified in this setting warrant further investigation. PMID:27572087

  12. A randomized phase II trial of azacitidine +/− epoetin-β in lower-risk myelodysplastic syndromes resistant to erythropoietic stimulating agents

    PubMed Central

    Thépot, Sylvain; Ben Abdelali, Raouf; Chevret, Sylvie; Renneville, Aline; Beyne-Rauzy, Odile; Prébet, Thomas; Park, Sophie; Stamatoullas, Aspasia; Guerci-Bresler, Agnes; Cheze, Stéphane; Tertian, Gérard; Choufi, Bachra; Legros, Laurence; Bastié, Jean Noel; Delaunay, Jacques; Chaury, Marie Pierre; Sanhes, Laurence; Wattel, Eric; Dreyfus, Francois; Vey, Norbert; Chermat, Fatiha; Preudhomme, Claude; Fenaux, Pierre; Gardin, Claude

    2016-01-01

    The efficacy of azacitidine in patients with anemia and with lower-risk myelodysplastic syndromes, if relapsing after or resistant to erythropoietic stimulating agents, and the benefit of combining these agents to azacitidine in this setting are not well known. We prospectively compared the outcomes of patients, all of them having the characteristics of this subset of lower-risk myelodysplastic syndrome, if randomly treated with azacitidine alone or azacitidine combined with epoetin-β. High-resolution cytogenetics and gene mutation analysis were performed at entry. The primary study endpoint was the achievement of red blood cell transfusion independence after six cycles. Ninety-eight patients were randomised (49 in each arm). Median age was 72 years. In an intention to treat analysis, transfusion independence was obtained after 6 cycles in 16.3% versus 14.3% of patients in the azacitidine and azacitidine plus epoetin-β arms, respectively (P=1.00). Overall erythroid response rate (minor and major responses according to IWG 2000 criteria) was 34.7% vs. 24.5% in the azacitidine and azacitidine plus epoetin-β arms, respectively (P=0.38). Mutations of the SF3B1 gene were the only ones associated with a significant erythroid response, 29/59 (49%) versus 6/27 (22%) in SF3B1 mutated and unmutated patients, respectively, P=0.02. Detection of at least one “epigenetic mutation” and of an abnormal single nucleotide polymorphism array profile were the only factors associated with significantly poorer overall survival by multivariate analysis. The transfusion independence rate observed with azacitidine in this lower-risk population, but resistant to erythropoietic stimulating agents, was lower than expected, with no observed benefit of added epoetin, (clinicaltrials.gov identifier: 01015352). PMID:27229713

  13. A randomized phase II trial of standard dose bevacizumab versus low dose bevacizumab plus lomustine (CCNU) in adults with recurrent glioblastoma

    PubMed Central

    Weathers, Shiao-Pei; Han, Xiaosi; Liu, Diane D.; Conrad, Charles A.; Gilbert, Mark R.; Loghin, Monica E.; O'Brien, Barbara J.; Penas-Prado, Marta; Puduvalli, Vinay K.; Tremont-Lukats, Ivo; Colen, Rivka R.; Yung, W. K. Alfred; de Groot, John F.

    2016-01-01

    Background Antiangiogenic therapy can rapidly reduce vascular permeability and cerebral edema but high doses of bevacizumab may induce selective pressure to promote resistance. This trial evaluated the efficacy of low dose bevacizumab in combination with lomustine (CCNU) compared to standard dose bevacizumab in patients with recurrent glioblastoma. Methods Patients (N = 71) with recurrent glioblastoma who previously received radiation and temozolomide were randomly assigned 1:1 to receive bevacizumab monotherapy (10 mg/kg) or low dose bevacizumab (5 mg/kg) in combination with lomustine (90 mg/m2). The primary end point was progression-free survival (PFS) based on a blinded, independent radiographic assessment of post-contrast T1-weighted and non-contrast T2/FLAIR weighted magnetic resonance imaging (MRI) using RANO criteria. Results For 69 evaluable patients, median PFS was not significantly longer in the low dose bevacizumab + lomustine arm (4.34 months, CI: 2.96-8.34) compared to the bevacizumab alone arm (4.11 months, CI: 2.69-5.55, p = 0.19). In patients with first recurrence, there was a trend towards longer median PFS time in the low dose bevacizumab + lomustine arm (4.96 months, CI: 4.17-13.44) compared to the bevacizumab alone arm (3.22 months CI: 2.5-6.01, p = 0.08). Conclusions The combination of low dose bevacizumab plus lomustine was not superior to standard dose bevacizumab in patients with recurrent glioblastoma. Although the study was not designed to exclusively evaluate patients at first recurrence, a strong trend towards improved PFS was seen in that subgroup for the combination of low dose bevacizumab plus lomustine. Further studies are needed to better identify such subgroups that may most benefit from the combination treatment. PMID:27406589

  14. Randomized multicenter phase II study of flavopiridol (alvocidib), cytarabine, and mitoxantrone (FLAM) versus cytarabine/daunorubicin (7+3) in newly diagnosed acute myeloid leukemia

    PubMed Central

    Zeidner, Joshua F.; Foster, Matthew C.; Blackford, Amanda L.; Litzow, Mark R.; Morris, Lawrence E.; Strickland, Stephen A.; Lancet, Jeffrey E.; Bose, Prithviraj; Levy, M. Yair; Tibes, Raoul; Gojo, Ivana; Gocke, Christopher D.; Rosner, Gary L.; Little, Richard F.; Wright, John J.; Doyle, L. Austin; Smith, B. Douglas; Karp, Judith E.

    2015-01-01

    Serial studies have demonstrated that induction therapy with FLAM [flavopiridol (alvocidib) 50 mg/m2 days 1–3, cytarabine 667 mg/m2/day continuous infusion days 6–8, and mitoxantrone (FLAM) 40 mg/m2 day 9] yields complete remission rates of nearly 70% in newly diagnosed poor-risk acute myeloid leukemia. Between May 2011–July 2013, 165 newly diagnosed acute myeloid leukemia patients (age 18–70 years) with intermediate/adverse-risk cytogenetics were randomized 2:1 to receive FLAM or 7+3 (cytarabine 100 mg/m2/day continuous infusion days 1–7 and daunorubicin 90 mg/m2 days 1–3), across 10 institutions. Some patients on 7+3 with residual leukemia on day 14 received 5+2 (cytarabine 100 mg/m2/day continuous infusion days 1–5 and daunorubicin 45 mg/m2 days 1–2), whereas patients on FLAM were not re-treated based on day 14 bone marrow findings. The primary objective was to compare complete remission rates between one cycle of FLAM and one cycle of 7+3. Secondary end points included safety, overall survival and event-free survival. FLAM led to higher complete remission rates than 7+3 alone (70% vs. 46%; P=0.003) without an increase in toxicity, and this improvement persisted after 7+3+/−5+2 (70% vs. 57%; P=0.08). There were no significant differences in overall survival and event-free survival in both arms but post-induction strategies were not standardized. These results substantiate the efficacy of FLAM induction in newly diagnosed AML. A phase III study is currently in development. This study is registered with clinicaltrials.gov identifier: 01349972. PMID:26022709

  15. Randomized multicenter phase II study of flavopiridol (alvocidib), cytarabine, and mitoxantrone (FLAM) versus cytarabine/daunorubicin (7+3) in newly diagnosed acute myeloid leukemia.

    PubMed

    Zeidner, Joshua F; Foster, Matthew C; Blackford, Amanda L; Litzow, Mark R; Morris, Lawrence E; Strickland, Stephen A; Lancet, Jeffrey E; Bose, Prithviraj; Levy, M Yair; Tibes, Raoul; Gojo, Ivana; Gocke, Christopher D; Rosner, Gary L; Little, Richard F; Wright, John J; Doyle, L Austin; Smith, B Douglas; Karp, Judith E

    2015-09-01

    Serial studies have demonstrated that induction therapy with FLAM [flavopiridol (alvocidib) 50 mg/m(2) days 1-3, cytarabine 667 mg/m(2)/day continuous infusion days 6-8, and mitoxantrone (FLAM) 40 mg/m(2) day 9] yields complete remission rates of nearly 70% in newly diagnosed poor-risk acute myeloid leukemia. Between May 2011-July 2013, 165 newly diagnosed acute myeloid leukemia patients (age 18-70 years) with intermediate/adverse-risk cytogenetics were randomized 2:1 to receive FLAM or 7+3 (cytarabine 100 mg/m(2)/day continuous infusion days 1-7 and daunorubicin 90 mg/m(2) days 1-3), across 10 institutions. Some patients on 7+3 with residual leukemia on day 14 received 5+2 (cytarabine 100 mg/m(2)/day continuous infusion days 1-5 and daunorubicin 45 mg/m(2) days 1-2), whereas patients on FLAM were not re-treated based on day 14 bone marrow findings. The primary objective was to compare complete remission rates between one cycle of FLAM and one cycle of 7+3. Secondary end points included safety, overall survival and event-free survival. FLAM led to higher complete remission rates than 7+3 alone (70% vs. 46%; P=0.003) without an increase in toxicity, and this improvement persisted after 7+3+/-5+2 (70% vs. 57%; P=0.08). There were no significant differences in overall survival and event-free survival in both arms but post-induction strategies were not standardized. These results substantiate the efficacy of FLAM induction in newly diagnosed AML. A phase III study is currently in development. This study is registered with clinicaltrials.gov identifier: 01349972.

  16. Standard Versus Continuous Administration of Capecitabine in Metastatic Breast Cancer (GEICAM/2009-05): A Randomized, Noninferiority Phase II Trial With a Pharmacogenetic Analysis

    PubMed Central

    Martínez, Noelia; Ramos, Manuel; Calvo, Lourdes; Lluch, Ana; Zamora, Pilar; Muñoz, Montserrat; Carrasco, Eva; Caballero, Rosalía; García-Sáenz, José Ángel; Guerra, Eva; Caronia, Daniela; Casado, Antonio; Ruíz-Borrego, Manuel; Hernando, Blanca; Chacón, José Ignacio; De la Torre-Montero, Julio César; Jimeno, María Ángeles; Heras, Lucía; Alonso, Rosario; De la Haba, Juan; Pita, Guillermo; Constenla, Manuel; González-Neira, Anna

    2015-01-01

    Background. The approved capecitabine regimen as monotherapy in metastatic breast cancer (MBC) is 1,250 mg/m2 twice daily for 2 weeks on and 1 week off (Cint). Dose modifications are often required because of severe hand-foot syndrome (HFS). We tested a continuous regimen with a lower daily dose but a similar cumulative dose in an attempt to reduce the severity of adverse events (AEs) while maintaining efficacy. Methods. We randomized 195 patients with HER-2/neu-negative MBC to capecitabine 800 mg/m2 twice daily throughout the 21-day cycle (Ccont) or to Cint to assess noninferiority in the percentage of patients free of progression at 1 year. Secondary endpoints included efficacy and safety. Associations between polymorphisms in capecitabine metabolism-related genes and drug response were assessed. Results. The percentage of patients free of progression at 1 year was 27.3% with Cint versus 25.3% with Ccont (difference of −2.0%; 95% confidence interval: −15.5% to 11.5%, exceeding the 15% deemed noninferior). Differences regarding other efficacy variables were also not found. Grade 3–4 HFS was the most frequent AE (41.1% in Cint vs. 42.3% in Ccont). Grade 3–4 neutropenia, thrombocytopenia, diarrhea, and stomatitis were more frequent with Cint. A 5′ untranslated region polymorphism in the carboxylesterase 2 gene was associated with HFS. One polymorphism in cytidine deaminase and two in thymidine phosphorylase were associated with survival. Conclusion. Our study was unable to show noninferiority with the continuous capecitabine regimen (Ccont) compared with the approved intermittent regimen (Cint). Further investigation is required to improve HFS. Polymorphisms in several genes might contribute to interindividual differences in response to capecitabine. PMID:25601966

  17. Randomized Phase II/III Trial Assessing Gemcitabine/ Carboplatin and Methotrexate/Carboplatin/Vinblastine in Patients With Advanced Urothelial Cancer “Unfit” for Cisplatin-Based Chemotherapy: Phase II—Results of EORTC Study 30986

    PubMed Central

    De Santis, Maria; Bellmunt, Joaquim; Mead, Graham; Kerst, J. Martijn; Leahy, Michael; Maroto, Pablo; Skoneczna, Iwona; Marreaud, Sandrine; de Wit, Ronald; Sylvester, Richard

    2009-01-01

    Purpose There is no standard treatment for patients with advanced urothelial cancer who are ineligible (“unfit”) for cisplatin-based chemotherapy (CHT). To compare the activity and safety of two CHT combinations in this patient group, a randomized phase II/III trial was conducted by the EORTC (European Organisation for Research and Treatment of Cancer). We report here the phase II results of the study. Patients and Methods CHT-naïve patients with measurable disease and impaired renal function (30 mL/min < glomerular filtration rate [GFR] < 60 mL/min) and/or performance status (PS) 2 were randomly assigned to receive either GC (gemcitabine 1,000 mg/m2 on days 1 and 8 and carboplatin area under the serum concentration-time curve [AUC] 4.5) for 21 days or M-CAVI (methotrexate 30 mg/m2 on days 1, 15, and 22; carboplatin AUC 4.5 on day 1; and vinblastine 3 mg/m2 on days 1, 15, and 22) for 28 days. End points of response and severe acute toxicity (SAT) were evaluated with respect to treatment group, renal function, PS, and Bajorin risk groups. Results Three of 178 patients who were ineligible or did not start treatment were excluded. SAT was reported in 13.6% of patients on GC and in 23% on M-CAVI. Overall response rates were 42% (37 of 88) for GC and 30% (26 of 87) for M-CAVI. Patients with PS 2 and GFR less than 60 mL/min and patients in Bajorin risk group 2 showed a response rate of only 26% and 20% and an SAT rate of 26% and 25%, respectively. Conclusion Both combinations are active in this group of unfit patients. However, patients with PS 2 and GFR less than 60 mL/min do not benefit from combination CHT. Alternative treatment modalities should be sought in this subgroup of poor-risk patients. PMID:19786668

  18. Randomized Phase II/III Trial Assessing Gemcitabine/Carboplatin and Methotrexate/Carboplatin/Vinblastine in Patients With Advanced Urothelial Cancer Who Are Unfit for Cisplatin-Based Chemotherapy: EORTC Study 30986

    PubMed Central

    De Santis, Maria; Bellmunt, Joaquim; Mead, Graham; Kerst, J. Martijn; Leahy, Michael; Maroto, Pablo; Gil, Thierry; Marreaud, Sandrine; Daugaard, Gedske; Skoneczna, Iwona; Collette, Sandra; Lorent, Julie; de Wit, Ronald; Sylvester, Richard

    2012-01-01

    Purpose This is the first randomized phase II/III trial comparing two carboplatin-based chemotherapy regimens in patients with urothelial cancer who are ineligible (“unfit”) for cisplatin chemotherapy. Patients and Methods The primary objective of the phase III part of this study was to compare the overall survival (OS) of chemotherapy-naive patients with measurable disease and an impaired renal function (glomerular filtration rate < 60 but > 30 mL/min) and/or performance score of 2 who were randomly assigned to receive either gemcitabine/carboplatin (GC) or methotrexate/carboplatin/vinblastine (M-CAVI). To detect an increase of 50% in median survival with GC compared with M-CAVI (13.5 v 9 months) based on a two-sided log-rank test at error rates α = .05 and β = .20, 225 patients were required. Secondary end points were overall response rate (ORR), progression-free survival (PFS), toxicity, and quality of life. Results In all, 238 patients were randomly assigned by 29 institutions over a period of 7 years. The median follow-up was 4.5 years. Best ORRs were 41.2% (36.1% confirmed response) for patients receiving GC versus 30.3% (21.0% confirmed response) for patients receiving M-CAVI (P = .08). Median OS was 9.3 months in the GC arm and 8.1 months in the M-CAVI arm (P = .64). There was no difference in PFS (P = .78) between the two arms. Severe acute toxicity (death, grade 4 thrombocytopenia with bleeding, grade 3 or 4 renal toxicity, neutropenic fever, or mucositis) was observed in 9.3% of patients receiving GC and 21.2% of patients receiving M-CAVI. Conclusion There were no significant differences in efficacy between the two treatment groups. The incidence of severe acute toxicities was higher for those receiving M-CAVI. PMID:22162575

  19. A Phase II Trial of Neoadjuvant Preoperative Chemoradiotherapy With S-1 Plus Irinotecan and Radiation in Patients With Locally Advanced Rectal Cancer: Clinical Feasibility and Response Rate

    SciTech Connect

    Sato, Takeo; Ozawa, Heita; Hatate, Kazuhiko; Onosato, Wataru; Naito, Masanori; Nakamura, Takatoshi; Ihara, Atsushi; Koizumi, Wasaburo; Hayakawa, Kazushige; Okayasu, Isao; Yamashita, Keishi; Watanabe, Masahiko

    2011-03-01

    Purpose: We aimed to validate our hypothesis that a preoperative chemoradiotherapy regimen with S-1 plus irinotecan is feasible, safe, and active for the management of locally advanced rectal cancer in a single-arm Phase II setting. Methods and Materials: Eligible patients had previously untreated, locally advanced rectal adenocarcinoma. Radiotherapy was administered in fractions of 1.8Gy/d for 25 days. S-1 was administered orally in a fixed daily dose of 80mg/m{sup 2} on Days 1 to 5, 8 to 12, 22 to 26, and 29 to 33. Irinotecan (80mg/m{sup 2}) was infused on Days 1, 8, 22, and 29. Four or more weeks after the completion of the treatment, total mesorectal excision with lateral lymph node dissection was performed. The primary endpoint was the rate of completing treatment in terms of feasibility. The secondary endpoints were the response rate and safety. Results: We enrolled 43 men and 24 women in the study. The number of patients who completed treatment was 58 (86.6%). Overall, 46 patients (68.7%) responded to treatment and 24 (34.7%) had a complete histopathologic response. Three patients had Grade 3 leukopenia, and another three patients had Grade 3 neutropenia. Diarrhea was the most common type of nonhematologic toxicity: 3 patients had Grade 3 diarrhea. Conclusions: A preoperative regimen of S-1, irinotecan, and radiotherapy to the rectum was feasible, and it appeared safe and effective in this nonrandomized Phase II setting. It exhibited a low incidence of adverse events, a high rate of completion of treatment, and an extremely high rate of pathologic complete response.

  20. Using quality of life measures in a Phase I clinical trial of noni in patients with advanced cancer to select a Phase II dose.

    PubMed

    Issell, Brian F; Gotay, Carolyn C; Pagano, Ian; Franke, Adrian A

    2009-01-01

    ABSTRACT. The purpose of this study was to determine a maximum tolerated dose of noni in cancer patients and whether an optimal quality of life-sustaining dose could be identified as an alternative way to select a dose for subsequent Phase II efficacy trials. Dose levels started at two capsules twice daily (2 g), the suggested dose for the marketed product, and were escalated by 2 g daily in cohorts of at least five patients until a maximum tolerated dose was found. Patients completed subscales of the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 quality of life (physical functioning, pain, and fatigue) the brief fatigue inventory (BFI), questionnaires at baseline and at approximately 4-week intervals. Blood and urine were collected at baseline and at approximately 4-week intervals for measurement of scopoletin. Fifty-one patients were enrolled at seven dose levels. The maximum tolerated dose was six capsules four times daily (12 g). Although no dose-limiting toxicity was found, seven of eight patients at the next level (14 g), withdrew due to the challenges of ingesting so many capsules. There were dose-related differences in self-reported physical functioning and pain and fatigue control. Overall, patients taking three or four capsules four times daily experienced better outcomes than patients taking lower or higher doses. Blood and urinary scopoletin concentrations related to noni dose. We concluded that it is feasible to use quality of life measures to select a Phase II dose. Three or four capsules four times daily (6-8 g) is recommended when controlling fatigue, pain, and maintaining physical function are the efficacies of interest. Scopoletin, a bioactive component of noni fruit extract, is measurable in blood and urine following noni ingestion and can be used to study the pharmacokinetics of noni in cancer patients.

  1. Chemotherapy With or Without Maintenance Sunitinib for Untreated Extensive-Stage Small-Cell Lung Cancer: A Randomized, Double-Blind, Placebo-Controlled Phase II Study—CALGB 30504 (Alliance)

    PubMed Central

    Ready, Neal E.; Pang, Herbert H.; Gu, Lin; Otterson, Gregory A.; Thomas, Sachdev P.; Miller, Antonius A.; Baggstrom, Maria; Masters, Gregory A.; Graziano, Stephen L.; Crawford, Jeffrey; Bogart, Jeffrey; Vokes, Everett E.

    2015-01-01

    Purpose To evaluate the efficacy of maintenance sunitinib after chemotherapy for small-cell lung cancer (SCLC). Patients and Methods The Cancer and Leukemia Group B 30504 trial was a randomized, placebo-controlled, phase II study that enrolled patients before chemotherapy (cisplatin 80 mg/m2 or carboplatin area under the curve of 5 on day 1 plus etoposide 100 mg/m2 per day on days 1 to 3 every 21 days for four to six cycles). Patients without progression were randomly assigned 1:1 to placebo or sunitinib 37.5 mg per day until progression. Cross-over after progression was allowed. The primary end point was progression-free survival (PFS) from random assignment for maintenance placebo versus sunitinib using a one-sided log-rank test with α = .15; 80 randomly assigned patients provided 89% power to detect a hazard ratio (HR) of 1.67. Results One hundred forty-four patients were enrolled; 138 patients received chemotherapy. Ninety-five patients were randomly assigned; 10 patients did not receive maintenance therapy (five on each arm). Eighty-five patients received maintenance therapy (placebo, n = 41; sunitinib, n = 44). Grade 3 adverse events with more than 5% incidence were fatigue (19%), decreased neutrophils (14%), decreased leukocytes (7%), and decreased platelets (7%) for sunitinib and fatigue (10%) for placebo; grade 4 adverse events were GI hemorrhage (n = 1) and pancreatitis, hypocalcemia, and elevated lipase (n = 1; all in same patient) for sunitinib and thrombocytopenia (n = 1) and hypernatremia (n = 1) for placebo. Median PFS on maintenance was 2.1 months for placebo and 3.7 months for sunitinib (HR, 1.62; 70% CI, 1.27 to 2.08; 95% CI, 1.02 to 2.60; one-sided P = .02). Median overall survival from random assignment was 6.9 months for placebo and 9.0 months for sunitinib (HR, 1.28; 95% CI, 0.79 to 2.10; one-sided P = .16). Three sunitinib and no placebo patients achieved complete response during maintenance. Ten (77%) of 13 patients evaluable after cross

  2. A randomized non-comparative phase II trial of cixutumumab (IMC-A12) or ramucirumab (IMC-1121B) plus mitoxantrone and prednisone in men with metastatic docetaxel-pretreated castration-resistant prostate cancer

    PubMed Central

    Hussain, Maha; Rathkopf, Dana; Liu, Glenn; Armstrong, Andrew; Kelly, Wm. Kevin; Ferrari, Anna; Hainsworth, John; Joshi, Adarsh; Hozak, Rebecca R.; Yang, Ling; Schwartz, Jonathan D.; Higano, Celestia S.

    2016-01-01

    Background Cixutumumab, a human monoclonal antibody (HuMAb), targets the insulin-like growth factor receptor. Ramucirumab is a recombinant HuMAb that binds to vascular endothelial growth factor receptor-2. A non-comparative randomized phase II study evaluated cixutumumab or ramucirumab plus mitoxantrone and prednisone (MP) in metastatic castration-resistant prostate cancer (mCRPC). Patients and Methods Men with progressive mCRPC during or after docetaxel therapy received mitoxantrone 12 mg/m2 on day 1 and prednisone 5 mg twice daily and were randomized 1:1 to receive either cixutumumab or ramucirumab 6 mg/kg intravenously weekly in a 21-day cycle. Primary endpoint was composite progression-free survival (cPFS). Secondary endpoints included safety, response, radiographic PFS, and overall survival (OS). Sample size was based on a 50% increase in median cPFS from 2.6 (MP) to 3.9 months (either combination). Results 132 men were treated (66 per arm). Median cPFS was 4.1 months (95% CI, 2.2–5.6) for cixutumumab and 6.7 months (95% CI, 4.5–8.3) for ramucirumab. Median time to radiographic progression was 7.5 months for cixutumumab and 10.2 months for ramucirumab, with a median OS of 10.8 and 13.0 months, respectively. Fatigue was the most frequent adverse event (AE). Incidence of most non-hematologic grade 3-4 AEs was <10% on both arms. Grade 3 cardiac dysfunction occurred in 7.6% of patients on ramucirumab. Conclusion Combinations of cixutumumab or ramucirumab plus MP were feasible and associated with moderate toxicities in docetaxel pretreated men with mCRPC. Of the two regimens, the ramucirumab regimen is worthy of further testing based on the observed cPFS relative to the historical control. PMID:26082390

  3. Randomized Phase II Study of Pemetrexed, Carboplatin, and Thoracic Radiation With or Without Cetuximab in Patients With Locally Advanced Unresectable Non–Small-Cell Lung Cancer: Cancer and Leukemia Group B Trial 30407

    PubMed Central

    Govindan, Ramaswamy; Bogart, Jeffrey; Stinchcombe, Thomas; Wang, Xiaofei; Hodgson, Lydia; Kratzke, Robert; Garst, Jennifer; Brotherton, Timothy; Vokes, Everett E.

    2011-01-01

    Purpose Cancer and Leukemia Group B conducted a randomized phase II trial to investigate two novel chemotherapy regimens in combination with concurrent thoracic radiation therapy (TRT). Patients and Methods Patients with unresectable stage III non–small-cell lung cancer (NSCLC) were randomly assigned to carboplatin (area under the curve, 5) and pemetrexed (500 mg/m2) every 21 days for four cycles and TRT (70 Gy; arm A) or the same treatment with cetuximab administered concurrent only with TRT (arm B). Patients in both arms received up to four cycles of pemetrexed as consolidation therapy. The primary end point was the 18-month overall survival (OS) rate; if the 18-month OS rate was ≥ 55%, the regimen(s) would be considered for further study. Results Of the 101 eligible patients enrolled (48 in arm A and 53 in arm B), 60% were male; the median age was 66 years (range, 32 to 81 years); 44% and 35% had adenocarcinoma and squamous carcinoma, respectively; and more patients enrolled onto arm A compared with arm B had a performance status of 0 (58% v 34%, respectively; P = .04). The 18-month OS rate was 58% (95% CI, 46% to 74%) in arm A and 54% (95% CI, 42% to 70%) in arm B. No significant difference in OS between patients with squamous and nonsquamous NSCLC was observed (P = .667). The toxicities observed were consistent with toxicities associated with concurrent chemoradiotherapy. Conclusion The combination of pemetrexed, carboplatin, and TRT met the prespecified criteria for further evaluation. This regimen should be studied further in patients with locally advanced unresectable nonsquamous NSCLC. PMID:21747084

  4. Ambovex® as a novel immunological modulator drug for the treatment of hepatocellular carcinoma (HCC) in the liver: a Phase II clinical trial

    PubMed Central

    Salama, Hosny; Ahmad, Hassan; Elchagea, Ismail; Zekri, Abdel Rahman; Medhat, Eman; Bahnassy, Abeer; Lange, Michael; Rabbat, Mohammed; de la Torre, Andrew N; Punamiya, Pravin

    2015-01-01

    Hepatocellular carcinoma (HCC) is a global public health problem, based on it being the fifth most common cancer and third leading cause of cancer-related mortality worldwide. The approved conventional treatment methods for HCC have shown life-threatening side effects with limited or negligible success, especially in multifocal HCC. As a consequence, new therapeutic approaches are being explored, including immunoregulatory molecules that may have the potential to treat or delay the progression of HCC. A novel pharmaceutical botanical drug – Ambovex®, an immune-modulator molecule – was tested to treat or delay the progress of HCC. We conducted a 6-month randomized clinical trial with an additional 3-month washing period (no treatment) to evaluate the safety and efficacy of low-dose Ambovex oral spray in treating patients with HCC. The clinical study involved a total of 40 patients, with 33 in the treatment group and seven in the control group. The α-fetoprotein (AFP) levels were measured every month and ultrasound scans were performed at time zero and every 2 months thereafter. Computed tomography (CT) scans were performed for patients in the treatment group. Ambovex proved to be safe, as there were no significant side effects although some patients found that the drug has unpleasant taste. AFP analysis showed a significant decrease in its level (α=0.05; 95% confidence interval) in the treatment group when compared to the control group at 3 months (P=0.0031) and at 6 months (P=0.007). The ultrasound results showed improvement in the treated group, as evidenced by a significant decrease in the lesion numbers and sizes. The lesions in 38% of treated patients decreased from multiple to single with major improvements; 35% of patients exhibited a decrease from multiple lesions to multiple lesions with minor improvements, whereas 27% had stabilized lesions. CT scans in the treated group showed significant improvement, as there was complete disappearance of the

  5. Concurrent Chemoradiotherapy Followed by Consolidation Chemotherapy With Bi-Weekly Docetaxel and Carboplatin for Stage III Unresectable, Non-Small-Cell Lung Cancer: Clinical Application of a Protocol Used in a Previous Phase II Study

    SciTech Connect

    Saitoh, Jun-Ichi; Saito, Yoshihiro; Kazumoto, Tomoko; Kudo, Shigehiro; Yoshida, Daisaku; Ichikawa, Akihiro; Sakai, Hiroshi; Kurimoto, Futoshi; Kato, Shingo; Shibuya, Kei

    2012-04-01

    Purpose: To assess the clinical applicability of a protocol evaluated in a previously reported phase II study of concurrent chemoradiotherapy followed by consolidation chemotherapy with bi-weekly docetaxel and carboplatin in patients with stage III, unresectable, non-small-cell lung cancer (NSCLC). Methods and Materials: Between January 2000 and March 2006, 116 previously untreated patients with histologically proven, stage III NSCLC were treated with concurrent chemoradiotherapy. Radiation therapy was administered in 2-Gy daily fractions to a total dose of 60 Gy in combination with docetaxel, 30 mg/m{sup 2}, and carboplatin at an area under the curve value of 3 every 2 weeks during and after radiation therapy. Results: The median survival time for the entire group was 25.5 months. The actuarial 2-year and 5-year overall survival rates were 53% and 31%, respectively. The 3-year cause-specific survival rate was 60% in patients with stage IIIA disease, whereas it was 35% in patients with stage IIIB disease (p = 0.007). The actuarial 2-year and 5-year local control rates were 62% and 55%, respectively. Acute hematologic toxicities of Grade {>=}3 severity were observed in 20.7% of patients, while radiation pneumonitis and esophagitis of Grade {>=}3 severity were observed in 2.6% and 1.7% of patients, respectively. Conclusions: The feasibility of the protocol used in the previous phase II study was reconfirmed in this series, and excellent treatment results were achieved.

  6. Harnessing Technology to Improve Clinical Trials: Study of Real-Time Informatics to Collect Data, Toxicities, Image Response Assessments, and Patient-Reported Outcomes in a Phase II Clinical Trial

    PubMed Central

    Pietanza, M. Catherine; Basch, Ethan M.; Lash, Alex; Schwartz, Lawrence H.; Ginsberg, Michelle S.; Zhao, Binsheng; Shouery, Marwan; Shaw, Mary; Rogak, Lauren J.; Wilson, Manda; Gabow, Aaron; Latif, Marcia; Lin, Kai-Hsiung; Wu, Qinfei; Kass, Samantha L.; Miller, Claire P.; Tyson, Leslie; Sumner, Dyana K.; Berkowitz-Hergianto, Alison; Sima, Camelia S.; Kris, Mark G.

    2013-01-01

    Purpose In clinical trials, traditional monitoring methods, paper documentation, and outdated collection systems lead to inaccuracies of study information and inefficiencies in the process. Integrated electronic systems offer an opportunity to collect data in real time. Patients and Methods We created a computer software system to collect 13 patient-reported symptomatic adverse events and patient-reported Karnofsky performance status, semi-automated RECIST measurements, and laboratory data, and we made this information available to investigators in real time at the point of care during a phase II lung cancer trial. We assessed data completeness within 48 hours of each visit. Clinician satisfaction was measured. Results Forty-four patients were enrolled, for 721 total visits. At each visit, patient-reported outcomes (PROs) reflecting toxicity and disease-related symptoms were completed using a dedicated wireless laptop. All PROs were distributed in batch throughout the system within 24 hours of the visit, and abnormal laboratory data were available for review within a median of 6 hours from the time of sample collection. Manual attribution of laboratory toxicities took a median of 1 day from the time they were accessible online. Semi-automated RECIST measurements were available to clinicians online within a median of 2 days from the time of imaging. All clinicians and 88% of data managers felt there was greater accuracy using this system. Conclusion Existing data management systems can be harnessed to enable real-time collection and review of clinical information during trials. This approach facilitates reporting of information closer to the time of events, and improves efficiency, and the ability to make earlier clinical decisions. PMID:23630218

  7. A Phase II Study of Sequential Capecitabine Plus Oxaliplatin Followed by Docetaxel Plus Capecitabine in Patients With Unresectable Gastric Adenocarcinoma: The TCOG 3211 Clinical Trial.

    PubMed

    Chen, Ming-Huang; Lin, Johnson; Hsiao, Chin-Fu; Shan, Yan-Shen; Chen, Yeu-Chin; Chen, Li-Tzong; Liu, Tsang-Wu; Li, Chung-Pin; Chao, Yee

    2016-01-01

    Fluorouracil and platinum are considered the standard treatment options for advanced gastric cancer. Docetaxel is also an effective agent and it shows no cross-resistance with fluorouracil and platinum. The combination treatment of docetaxel with fluorouracil and platinum has been explored, but it demonstrated intolerable toxicities. An alternative approach in the first-line treatment of gastric adenocarcinoma may be to use these agents sequentially. We aimed to evaluate the activity and safety profile of sequential chemotherapy with capecitabine plus oxaliplatin, followed by docetaxel plus capecitabine in the first-line treatment of unresectable gastric cancer.We conducted a phase II study of sequential first-line chemotherapy in advanced gastric cancer. Treatment consisted of 6 cycles of capecitabine plus oxaliplatin (capecitabine 1000 mg/m bid on days 1-10 and oxaliplatin 85 mg/m on day 1, every 2 weeks), followed by 4 cycles of docetaxel plus capecitabine (docetaxel 30 mg/m on days 1 and 8, capecitabine 825 mg/m bid on days 1-14, every 3 weeks). The primary end-point was the objective response rate.Fifty-one patients were enrolled: median age, 63 years; male/female: 37/14. The main grade 3 to 4 toxicities were a decreased absolute neutrophil count (25.4%), diarrhea (9.8%), and hand-foot syndrome (15.7%). The objective response rate was 61.7%. The median progression-free survival and overall survival were 8.6 and 11.0 months, respectively. Six patients (11.8%) received surgery after chemotherapy and 5 are still disease-free.This sequential treatment demonstrated feasibility with a favorable safety profile and produced encouraging results in terms of activity and efficacy. PMID:26817912

  8. IMATINIB 800MG DAILY INDUCES DEEPER MOLECULAR RESPONSES THAN IMATINIB 400MG DAILY: RESULTS OF SWOG S0325, AN INTERGROUP RANDOMIZED PHASE II TRIAL IN NEWLY DIAGNOSED CHRONIC PHASE CHRONIC MYELOID LEUKAEMIA

    PubMed Central

    Deininger, Michael W.; Kopecky, Kenneth J.; Radich, Jerald P.; Kamel-Reid, Suzanne; Stock, Wendy; Paietta, Elisabeth; Emanuel, Peter D.; Tallman, Martin; Wadleigh, Martha; Larson, Richard A.; Lipton, Jeffrey H.; Slovak, Marilyn L.; Appelbaum, Frederick R.; Druker, Brian J.

    2014-01-01

    The standard dose of imatinib for newly diagnosed patients with chronic phase chronic myeloid leukemia (CP-CML) is 400mg daily (IM400), but the optimal dose is unknown. This randomized phase II study compared the rates of molecular, haematologic and cytogenetic response to IM400 vs. imatinib 400mg twice daily (IM800) in 153 adult patients with CP-CML. Dose adjustments for toxicity were flexible to maximize retention on study. Molecular response (MR) at 12 months was deeper in the IM800 arm (4-log reduction of BCR-ABL1 mRNA: 25% vs. 10% of patients, P=0.038; 3-log reduction: 53% vs. 35%, P=0.049). During the first 12 months BCR-ABL1 levels in the IM800 arm were an average 2.9-fold lower than in the IM400 arm (P=0.010). Complete haematologic response was similar, but complete cytogenetic response was higher with IM800 (85% vs. 67%, P=0.040). Grade 3–4 toxicities were more common for IM800 (58% vs. 31%, P=0.0007), and were most commonly haematologic. Few patients have relapsed, progressed or died, but progression-free (P=0.048) and relapse-free (P=0.031) survival were superior for IM800. In newly diagnosed CP-CML patients, IM800 induced deeper molecular responses than IM400, with a trend for improved progression-free and overall survival, but was associated with more severe toxicity. PMID:24383843

  9. Oral liarozole in the treatment of patients with moderate/severe lamellar ichthyosis: results of a randomized, double-blind, multinational, placebo-controlled phase II/III trial

    PubMed Central

    Vahlquist, A; Blockhuys, S; Steijlen, P; van Rossem, K; Didona, B; Blanco, D; Traupe, H

    2014-01-01

    Summary Background Oral liarozole, a retinoic acid metabolism-blocking agent, may be an alternative to systemic retinoid therapy in patients with lamellar ichthyosis. Objective To demonstrate the efficacy and safety of once-daily oral liarozole in the treatment of moderate/severe lamellar ichthyosis. Methods This was a double-blind, multinational, parallel phase II/III trial (NCT00282724). Patients aged ≥ 14 years with moderate/severe lamellar ichthyosis [Investigator's Global Assessment (IGA) score ≥ 3] were randomized 3 : 3 : 1 to receive oral liarozole (75 or 150 mg) or placebo once daily for 12 weeks. Assessments included: IGA; a five-point scale for erythema, scaling and pruritus severity; Short Form-36 health survey; Dermatology Life Quality Index (DLQI); and safety parameters. The primary efficacy variable was response rate at week 12 (responder: ≥ 2-point decrease in IGA from baseline). Results Sixty-four patients were enrolled. At week 12, 11/27 (41%; liarozole 75 mg), 14/28 (50%; liarozole 150 mg) and one out of nine (11%; placebo) patients were responders; the difference between groups (liarozole 150 mg vs. placebo) was not significant (P = 0·056). Mean IGA and scaling scores decreased from baseline in both liarozole groups at weeks 8 and 12 vs. placebo; erythema and pruritus scores were similar between treatment groups. Improvement in DLQI score was observed in both liarozole groups. Treatment with liarozole for 12 weeks was well tolerated. Conclusions The primary efficacy variable did not reach statistical significance, possibly owing to the small sample size following premature termination. However, once-daily oral liarozole, 75 and 150 mg, improved scaling and DLQI and was well tolerated in patients with moderate/severe lamellar ichthyosis. PMID:24102348

  10. Randomized, Double-Blind, Phase II, Multicenter Study Evaluating the Safety/Tolerability and Efficacy of JNJ-Q2, a Novel Fluoroquinolone, Compared with Linezolid for Treatment of Acute Bacterial Skin and Skin Structure Infection ▿ †

    PubMed Central

    Covington, Paul; Davenport, J. Michael; Andrae, David; O'Riordan, William; Liverman, Lisa; McIntyre, Gail; Almenoff, June

    2011-01-01

    JNJ-Q2 is a fluoroquinolone with broad coverage including methicillin-resistant Staphylococcus aureus (MRSA). A double-blind, multicenter, phase II noninferiority study treated 161 patients for 7 to 14 days, testing the efficacy of JNJ-Q2 (250 mg, twice a day [BID]) versus linezolid (600 mg, BID) in patients with acute bacterial skin and skin structure infections (ABSSSI). The prespecified criterion for noninferiority was 15%. Primary intent-to-treat analysis was unable to declare noninferiority, as the risk difference lower bound of the 95% confidence interval between treatments was 19% at 36 to 84 h postrandomization for the composite end point of lesion assessment and temperature. Prespecified clinical cure rates 2 to 14 days after completion of therapy were similar (83.1% for JNJ-Q2 versus 82.1% for linezolid). Post hoc analyses revealed that JNJ-Q2 was statistically noninferior to linezolid (61.4% versus 57.7%, respectively; P = 0.024) based on the 2010 FDA guidance, which defines treatment success as lack of lesion spread and afebrile status within 48 to 72 h postrandomization. Despite evidence of systemic disease, <5% of patients presented with fever, suggesting fever is not a compelling surrogate measure of systemic disease resolution for this indication. Nausea and vomiting were the most common adverse events. Of the patients, 86% (104/121) had S. aureus isolated from the infection site; 63% of these were MRSA. The results suggest JNJ-Q2 shows promise as an effective treatment for ABSSSI, demonstrating (i) efficacy for early clinical response (i.e., lack of spread of lesions and absence of fever at 48 to 72 h), and (ii) cure rates for ABSSSI pathogens (especially MRSA) consistent with the historical literature. PMID:21947389

  11. [Accelerated partial breast irradiation with image-guided intensity-modulated radiotherapy following breast-conserving surgery - preliminary results of a phase II clinical study].

    PubMed

    Mészáros, Norbert; Major, Tibor; Stelczer, Gábor; Zaka, Zoltán; Mózsa, Emõke; Fodor, János; Polgár, Csaba

    2015-06-01

    The purpose of the study was to implement accelerated partial breast irradiation (APBI) by means of image-guided intensity-modulated radiotherapy (IG-IMRT) following breast-conserving surgery (BCS) for low-risk early invasive breast cancer. Between July 2011 and March 2014, 60 patients with low-risk early invasive (St I-II) breast cancer who underwent BCS were enrolled in our phase II prospective study. Postoperative APBI was given by means of step and shoot IG-IMRT using 4 to 5 fields to a total dose of 36.9 Gy (9×4.1 Gy) using a twice-a-day fractionation. Before each fraction, series of CT images were taken from the region of the target volume using a kV CT on-rail mounted in the treatment room. An image fusion software was used for automatic image registration of the planning and verification CT images. Patient set-up errors were detected in three directions (LAT, LONG, VERT), and inaccuracies were adjusted by automatic movements of the treatment table. Breast cancer related events, acute and late toxicities, and cosmetic results were registered and analysed. At a median follow-up of 24 months (range 12-44) neither locoregional nor distant failure was observed. Grade 1 (G1), G2 erythema, G1 oedema, and G1 and G2 pain occurred in 21 (35%), 2 (3.3%), 23 (38.3%), 6 (10%) and 2 (3.3%) patients, respectively. No G3-4 acute side effects were detected. Among late radiation side effects G1 pigmentation, G1 fibrosis, and G1 fat necrosis occurred in 5 (8.3%), 7 (11.7%), and 2 (3.3%) patients, respectively. No ≥G2 late toxicity was detected. Excellent and good cosmetic outcome was detected in 45 (75%) and 15 (25%) patients. IG-IMRT is a reproducible and feasible technique for the delivery of APBI following conservative surgery for the treatment of low-risk, early-stage invasive breast carcinoma. Preliminary results are promising, early radiation side effects are minimal, and cosmetic results are excellent. PMID:26035158

  12. HCV1b genome evolution under selective pressure of the cyclophilin inhibitor alisporivir during the DEB-025-HCV-203 phase II clinical trial.

    PubMed

    Cuypers, Lize; Snoeck, Joke; Kerremans, Lien; Libin, Pieter; Crabbé, Raf; Van Dooren, Sonia; Vuagniaux, Grégoire; Vandamme, Anne-Mieke

    2016-10-01

    Major advances have revolutionized the HCV antiviral treatment field, with interferon-free combinations of direct-acting antivirals (DAAs) resulting into success rates of >90% for all HCV genotypes. Nevertheless, viral eradication at a global level stills remains challenging, stimulating the continued search for new affordable pan-genotypic drugs. To overcome selection of drug resistant variants, targeting host proteins can be an attractive mechanism of action. Alisporivir (Debio 025) is a potent pan-genotypic host-targeting antiviral agent, acting on cyclophilin A, which is necessary for HCV replication. The efficacy and safety of three different oral doses of alisporivir in combination with pegylated interferon-α2a given over a period of four weeks, was investigated in a randomized, double-blind and placebo-controlled phase IIa clinical trial, in 90 treatment-naïve subjects infected with chronic hepatitis C, wherefrom 58 HCV1b samples were selected for genetic sequencing purposes. Sequencing results were used to study the HCV genome for amino acid changes potentially related with selective pressure and resistance to alisporivir. By comparing baseline and on-treatment sequences, a large variation in proportion of amino acid changes was detected in all treatment arms. The NS5A variant D320E, which was previously identified during in vitro resistance selection and resulted in 3.6-fold reduced alisporivir susceptibility, emerged in two subjects in the alisporivir monotherapy arm. However, emergence of D320E appeared to be associated only with concurrent viral load rebound in one subject with 0.8log10IU/ml increase in HCV RNA. In general, for all datasets, low numbers of positions under positive selective pressure were observed, with no significant differences between naïve and treated sequences. Additionally, incomplete sequence information for some of the 22 patients and the low number of individuals per treatment arm, is limiting the power to assess the

  13. Phase II metabolism of benzene.

    PubMed Central

    Schrenk, D; Orzechowski, A; Schwarz, L R; Snyder, R; Burchell, B; Ingelman-Sundberg, M; Bock, K W

    1996-01-01

    The hepatic metabolism of benzene is thought to be a prerequisite for its bony marrow toxicity. However, the complete pattern of benzene metabolites formed in the liver and their role in bone marrow toxicity are not fully understood. Therefore, benzene metabolism was studied in isolated rodent hepatocytes. Rat hepatocytes released benzene-1,2-dihydrodiol, hydroquinone (HQ), catechol (CT), phenol (PH), trans-trans-muconic acid, and a number of phase II metabolites such as PH sulfate and PH glucuronide. Pretreatment of animals with 3-methylcholantrene (3-MC) markedly increased PH glucuronide formation while PH sulfate formation was decreased. Likewise, V79 cells transfected with the 3-MC-inducible rat UGT1.6 cDNA showed a considerable rate of PH and HQ glucuronidation. In addition to inducing glucuronidation of phenols, 3-MC treatment (reported to protect rats from the myelotoxicity of benzene) resulted in a decrease of hepatic CYP2E1. In contrast, pretreatment of rats with the CYP2E1-inducer isopropanol strongly enhanced benzene metabolism and the formation of phenolic metabolites. Mouse hepatocytes formed much higher amounts of HQ than rat hepatocytes and considerable amounts of 1,2,4-trihydroxybenzene (THB) sulfate and HQ sulfate. In conclusion, the protective effect of 3-MC in rats is probably due to a shift from the labile PH sulfate to the more stable PH glucuronide, and to a decrease in hepatic CYP2E1. The higher susceptibility of mice toward benzene may be related to the high rate of formation of the myelotoxic metabolite HQ and the semistable phase II metabolites HQ sulfate and THB sulfate. Images Figure 4. PMID:9118891

  14. Evaluation of safety and immunogenicity of HNVAC, an MDCK-based H1N1 pandemic influenza vaccine, in Phase I single centre and Phase II/III multi-centre, double-blind, randomized, placebo-controlled, parallel assignment studies.

    PubMed

    Basavaraj, V H; Sampath, G; Hegde, Nagendra R; Mohan, V Krishna; Ella, Krishna M

    2014-07-31

    The clinical evaluation of the MDCK-based H1N1 pandemic influenza vaccine HNVAC in adults aged 18-65 years is reported. In the Phase I randomized, double-blind, placebo-controlled, single-centre study, 160 subjects were parallelly assigned 3:1 to vaccine:placebo groups (n=60:20) with both the aluminium hydroxide adjuvanted and non-adjuvanted vaccine formulations. A single dose of both the formulations containing 15 μg of haemagglutinin protein showed minimal adverse reactions, the most common of which were pain at injection site (11.67%) and fever (10.00%). Both formulations produced 74-81% seroprotection (SRP: titre of ≥40), 67-70% seroconversion (SRC: four-fold increase in titres between days 0 and 21), and a four-fold increase in geometric mean titres (GMT). Aluminium hydroxide did not have a significant effect either on immunogenicity or on reactogenicity. Nevertheless, based on its recognized positive effects on the stability and immunogenicity of many vaccines, and its marginal benefit in both pre-clinical and Phase I studies of HNVAC, alum adjuvanted HNVAC was further tested in a staggered Phase II/III randomized, double-blind, placebo-controlled, multi-centre study of 200 and 195 subjects, respectively, parallelly assigned 4:1 to adjuvanted vaccine and placebo groups. In these studies, the most common adverse reactions were pain at injection site (6.88% and 5.77% in Stage 1 and Stage 2, respectively) and fever (7.50% and 7.05%, respectively), and a single dose resulted in 87-90% SRP, 85-86% SRC, and a nearly six-fold increase in GMT, meeting or exceeding licensing criteria. It is concluded that HNVAC is safe and immunogenic to adults of 18-65 years.

  15. Sample Exchange Evaluation (SEE) Report - Phase II

    SciTech Connect

    Winters, W.I.

    1994-09-28

    This report describes the results from Phase II of the Sample Exchange Evaluation (SEE) Program, a joint effort to compare analytical laboratory performance on samples from the Hanford Site`s high-level waste tanks. In Phase II, the program has been expanded to include inorganic constituents in addition to radionuclides. Results from Phase II that exceeded 20% relative percent difference criteria are identified.

  16. Clinical Research Methodology 3: Randomized Controlled Trials.

    PubMed

    Sessler, Daniel I; Imrey, Peter B

    2015-10-01

    Randomized assignment of treatment excludes reverse causation and selection bias and, in sufficiently large studies, effectively prevents confounding. Well-implemented blinding prevents measurement bias. Studies that include these protections are called randomized, blinded clinical trials and, when conducted with sufficient numbers of patients, provide the most valid results. Although conceptually straightforward, design of clinical trials requires thoughtful trade-offs among competing approaches-all of which influence the number of patients required, enrollment time, internal and external validity, ability to evaluate interactions among treatments, and cost.

  17. Geology of the Phase II System

    SciTech Connect

    Laney, R.; Laughlin, A. William

    1980-11-19

    This is a report on the analysis of EE-2 cuttings and thin sections, geologic characterization of the Phase II system, comparison with Phase 1, and geologic speculations and recommendations concerning Phase II. The EE-2 litholog has been included in the pocket.

  18. A Phase II clinical trial of a mixture of plasma-derived factor VIIa and factor X (MC710) in haemophilia patients with inhibitors: haemostatic efficacy, safety and pharmacokinetics/pharmacodynamics.

    PubMed

    Shirahata, A; Fukutake, K; Takamatsu, J; Shima, M; Hanabusa, H; Mugishima, H; Amano, K; Takedani, H; Tamashima, S; Matsushita, T; Tawa, A; Tanaka, I; Higasa, S; Kosaka, Y; Fujii, T; Sakai, M; Migita, M; Kawakami, K; Ohashi, Y; Saito, H

    2013-11-01

    MC710, a mixture of plasma-derived activated factor VII and factor X at a protein weight ratio of 1:10, is a novel bypassing agent for haemostasis in haemophilia patients with inhibitors. In a Phase II trial, we evaluated the haemostatic efficacy and safety of single doses of MC710, and investigated pharmacokinetic and pharmacodynamic parameters in nine joint bleeding episodes in six male haemophilia patients with inhibitors. This trial was a multi-centre, open-label, non-randomized study of two doses (60 and 120 μg kg(-1) as FVIIa dose), allowing the re-administration of different MC710 dosages to the same subjects. Haemostatic efficacy was assessed by evaluating reduction in pain and swelling, as well as increase in range of motion in a bleeding joint. The results of the study showed that in nine bleeding episodes, seven treatments were rated as 'excellent' or 'effective' according to investigator's rating system of efficacy at 8 h after administration. No serious or severe adverse events were observed after administration; furthermore, measurement of several diagnostic markers revealed no signs or symptoms of disseminated intravascular coagulation (DIC). The haemostatic potential of MC710 was confirmed at doses of 60 and 120 μg kg(-1) in this trial. MC710 is thus expected to be a safe and efficacious novel bypassing agent for controlling bleeding in haemophilia patients with inhibitors. PMID:23738888

  19. KRAS Mutation Status and Clinical Outcome of Preoperative Chemoradiation With Cetuximab in Locally Advanced Rectal Cancer: A Pooled Analysis of 2 Phase II Trials

    SciTech Connect

    Kim, Sun Young; Shim, Eun Kyung; Yeo, Hyun Yang; Baek, Ji Yeon; Hong, Yong Sang; Kim, Dae Yong; Kim, Tae Won; Kim, Jee Hyun; Im, Seock-Ah; Jung, Kyung Hae; Chang, Hee Jin

    2013-01-01

    Purpose: Cetuximab-containing chemotherapy is known to be effective for KRAS wild-type metastatic colorectal cancer; however, it is not clear whether cetuximab-based preoperative chemoradiation confers an additional benefit compared with chemoradiation without cetuximab in patients with locally advanced rectal cancer. Methods and Materials: We analyzed EGFR, KRAS, BRAF, and PIK3CA mutation status with direct sequencing and epidermal growth factor receptor (EGFR) and Phosphatase and tensin homolog (PTEN) expression status with immunohistochemistry in tumor samples of 82 patients with locally advanced rectal cancer who were enrolled in the IRIX trial (preoperative chemoradiation with irinotecan and capecitabine; n=44) or the ERBIRIX trial (preoperative chemoradiation with irinotecan and capecitabine plus cetuximab; n=38). Both trials were similarly designed except for the administration of cetuximab; radiation therapy was administered at a dose of 50.4 Gy/28 fractions and irinotecan and capecitabine were given at doses of 40 mg/m{sup 2} weekly and 1650 mg/m{sup 2}/day, respectively, for 5 days per week. In the ERBIRIX trial, cetuximab was additionally given with a loading dose of 400 mg/m{sup 2} on 1 week before radiation, and 250 mg/m{sup 2} weekly thereafter. Results: Baseline characteristics before chemoradiation were similar between the 2 trial cohorts. A KRAS mutation in codon 12, 13, and 61 was noted in 15 (34%) patients in the IRIX cohort and 5 (13%) in the ERBIRIX cohort (P=.028). Among 62 KRAS wild-type cancer patients, major pathologic response rate, disease-free survival and pathologic stage did not differ significantly between the 2 cohorts. No mutations were detected in BRAF exon 11 and 15, PIK3CA exon 9 and 20, or EGFR exon 18-24 in any of the 82 patients, and PTEN and EGFR expression were not predictive of clinical outcome. Conclusions: In patients with KRAS wild-type locally advanced rectal cancer, the addition of cetuximab to the chemoradiation with

  20. A Randomized, Double-Blind, Placebo-Controlled Phase II Trial Investigating the Safety and Immunogenicity of Modified Vaccinia Ankara Smallpox Vaccine (MVA-BN®) in 56-80-Year-Old Subjects

    PubMed Central

    Greenberg, Richard N.; Hay, Christine M.; Stapleton, Jack T.; Marbury, Thomas C.; Wagner, Eva; Kreitmeir, Eva; von Krempelhuber, Alfred; Young, Philip; Nichols, Richard; Meyer, Thomas P.; Weigl, Josef; Virgin, Garth; Arndtz-Wiedemann, Nathaly; Chaplin, Paul

    2016-01-01

    Background Modified Vaccinia Ankara MVA-BN® is a live, highly attenuated, viral vaccine under advanced development as a non-replicating smallpox vaccine. In this Phase II trial, the safety and immunogenicity of Modified Vaccinia Ankara MVA-BN® (MVA) was assessed in a 56–80 years old population. Methods MVA with a virus titer of 1 x 108 TCID50/dose was administered via subcutaneous injection to 56–80 year old vaccinia-experienced subjects (N = 120). Subjects received either two injections of MVA (MM group) or one injection of Placebo and one injection of MVA (PM group) four weeks apart. Safety was evaluated by assessment of adverse events (AE), focused physical exams, electrocardiogram recordings and safety laboratories. Solicited AEs consisted of a set of pre-defined expected local reactions (erythema, swelling, pain, pruritus, and induration) and systemic symptoms (body temperature, headache, myalgia, nausea and fatigue) and were recorded on a memory aid for an 8-day period following each injection. The immunogenicity of the vaccine was evaluated in terms of humoral immune responses measured with a vaccinia-specific enzyme-linked immunosorbent assay (ELISA) and a plaque reduction neutralization test (PRNT) before and at different time points after vaccination. Results Vaccinations were well tolerated by all subjects. No serious adverse event related to MVA and no case of myopericarditis was reported. The overall incidence of unsolicited AEs was similar in both groups. For both groups immunogenicity responses two weeks after the final vaccination (i.e. Visit 4) were as follows: Seroconversion (SC) rates (doubling of titers from baseline) in vaccine specific antibody titers measured by ELISA were 83.3% in Group MM and 82.8% in Group PM (difference 0.6% with 95% exact CI [-13.8%, 15.0%]), and 90.0% for Group MM and 77.6% for Group PM measured by PRNT (difference 12.4% with 95% CI of [-1.1%, 27.0%]). Geometric mean titers (GMT) measured by ELISA two weeks after

  1. Functional characterization and anti-cancer action of the clinical phase II cardiac Na+/K+ ATPase inhibitor istaroxime: in vitro and in vivo properties and cross talk with the membrane androgen receptor

    PubMed Central

    Alevizopoulos, Konstantinos; Dimas, Konstantinos; Papadopoulou, Natalia; Schmidt, Eva-Maria; Tsapara, Anna; Alkahtani, Saad; Honisch, Sabina; Prousis, Kyriakos C.; Alarifi, Saud; Calogeropoulou, Theodora

    2016-01-01

    Sodium potassium pump (Na+/K+ ATPase) is a validated pharmacological target for the treatment of various cardiac conditions. Recent published data with Na+/K+ ATPase inhibitors suggest a potent anti-cancer action of these agents in multiple indications. In the present study, we focus on istaroxime, a Na+/K+ ATPase inhibitor that has shown favorable safety and efficacy properties in cardiac phase II clinical trials. Our experiments in 22 cancer cell lines and in prostate tumors in vivo proved the strong anti-cancer action of this compound. Istaroxime induced apoptosis, affected the key proliferative and apoptotic mediators c-Myc and caspase-3 and modified actin cystoskeleton dynamics and RhoA activity in prostate cancer cells. Interestingly, istaroxime was capable of binding to mAR, a membrane receptor mediating rapid, non-genomic actions of steroids in prostate and other cells. These results support a multi-level action of Na+/K+ ATPase inhibitors in cancer cells and collectively validate istaroxime as a strong re-purposing candidate for further cancer drug development. PMID:27027435

  2. Multicenter phase II clinical trial of nilotinib for patients with imatinib-resistant or -intolerant chronic myeloid leukemia from the East Japan CML study group evaluation of molecular response and the efficacy and safety of nilotinib

    PubMed Central

    2014-01-01

    Background Nilotinib is a second-generation tyrosine kinase inhibitor that exhibits significant efficacy as first- or second-line treatment in patients with chronic myeloid leukemia (CML). We conducted a multicenter Phase II Clinical Trial to evaluate the safety and efficacy of nilotinib among Japanese patients with imatinib-resistant or -intolerant CML-chronic phase (CP) or accelerated phase (AP). Results We analyzed 49 patients (33 imatinib-resistant and 16 imatinib-intolerant) treated with nilotinib 400 mg twice daily. The major molecular response (MMR) rate was 47.8% at 12 months among 35 patients who did not demonstrate an MMR at study entry. Somatic BCR-ABL1 mutations (Y253H, I418V, and exon 8/9 35-bp insertion [35INS]) were detected in 3 patients at 12 months or upon discontinuation of nilotinib. Although 75.5% of patients were still being treated at 12 months, nilotinib treatment was discontinued because of progressing disease in 1 patient, insufficient effect in 2, and adverse events in 9. There was no statistically significant correlation between MMR and trough concentrations of nilotinib. Similarly, no correlation was observed between trough concentrations and adverse events, except for pruritus and hypokalemia. Hyperbilirubinemia was frequently observed (all grades, 51.0%; grades 2–4, 29%; grades 3–4, 4.1%). Hyperbilirubinemia higher than grade 2 was significantly associated with the uridine diphosphate glucuronosyltransferase (UGT)1A9 I399C/C genotype (P = 0.0086; Odds Ratio, 21.2; 95% Confidence Interval 2.2–208.0). Conclusions Nilotinib was efficacious and well tolerated by patients with imatinib-resistant or -intolerant CML-CP/AP. Hyperbilirubinemia may be predicted before nilotinib treatment, and may be controlled by reducing the daily dose of nilotinib in patients with UGT1A9 polymorphisms. Trial registration clinicaltrials.gov: UMIN000002201 PMID:24650752

  3. Centrifuge workers study. Phase II, completion report

    SciTech Connect

    Wooten, H.D.

    1994-09-01

    Phase II of the Centrifuge Workers Study was a follow-up to the Phase I efforts. The Phase I results had indicated a higher risk than expected among centrifuge workers for developing bladder cancer when compared with the risk in the general population for developing this same type of cancer. However, no specific agent could be identified as the causative agent for these bladder cancers. As the Phase II Report states, Phase I had been limited to workers who had the greatest potential for exposure to substances used in the centrifuge process. Phase II was designed to expand the survey to evaluate the health of all employees who had ever worked in Centrifuge Program Departments 1330-1339 but who had not been interviewed in Phase I. Employees in analytical laboratories and maintenance departments who provided support services for the Centrifuge Program were also included in Phase II. In December 1989, the Oak Ridge Associated Universities (ORAU), now known as Oak Ridge Institute for Science and Education (ORISE), was contracted to conduct a follow-up study (Phase II). Phase H of the Centrifuge Workers Study expanded the survey to include all former centrifuge workers who were not included in Phase I. ORISE was chosen because they had performed the Phase I tasks and summarized the corresponding survey data therefrom.

  4. Phase II, randomized, open, controlled study of AS03-adjuvanted H5N1 pre-pandemic influenza vaccine in children aged 3 to 9 years: follow-up of safety and immunogenicity persistence at 24 months post-vaccination

    PubMed Central

    Díez-Domingo, Javier; Baldó, José-María; Planelles-Catarino, Maria Victoria; Garcés-Sánchez, María; Ubeda, Isabel; Jubert–Rosich, Angels; Marès, Josep; Garcia-Corbeira, Pilar; Moris, Philippe; Teko, Maurice; Vanden Abeele, Carline; Gillard, Paul

    2015-01-01

    Background An AS03-adjuvanted H5N1 influenza vaccine elicited broad and persistent immune responses with an acceptable safety profile up to 6 months following the first vaccination in children aged 3–9 years. Methods In this follow-up of the Phase II study, we report immunogenicity persistence and safety at 24 months post-vaccination in children aged 3–9 years. The randomized, open-label study assessed two doses of H5N1 A/Vietnam/1194/2004 influenza vaccine (1·9 μg or 3·75 μg hemagglutinin antigen) formulated with AS03A or AS03B (11·89 mg or 5·93 mg tocopherol, respectively). Control groups received seasonal trivalent influenza vaccine. Safety was assessed prospectively and included potential immune-mediated diseases (pIMDs). Immunogenicity was assessed by hemagglutination-inhibition assay 12 and 24 months after vaccination; cross-reactivity and cell-mediated responses were also assessed. (NCT00502593). Results The safety population included 405 children. Over 24 months, five events fulfilled the criteria for pIMDs, of which four occurred in H5N1 vaccine recipients, including uveitis (n = 1) and autoimmune hepatitis (n = 1), which were considered to be vaccine-related. Overall, safety profiles of the vaccines were clinically acceptable. Humoral immune responses at 12 and 24 months were reduced versus those observed after the second dose of vaccine, although still within the range of those observed after the first dose. Persistence of cell-mediated immunity was strong, and CD4+ T cells with a TH1 profile were observed. Conclusions Two doses of an AS03-adjuvanted H5N1 influenza vaccine in children showed low but persistent humoral immune responses and a strong persistence of cell-mediated immunity, with clinically acceptable safety profiles up to 24 months following first vaccination. PMID:25652873

  5. SLUDGE BATCH 6 PHASE II FLOWSHEET SIMULATIONS

    SciTech Connect

    Koopman, D.; Best, D.

    2010-03-30

    Two Sludge Receipt and Adjustment Tank (SRAT) runs were used to demonstrate that a fairly wide window of acid stoichiometry was available for processing SB6 Phase II flowsheet simulant (Tank 40 simulant) while still meeting the dual goals of acceptable nitrate destruction and controlled hydrogen generation. Phase II was an intermediate flowsheet study for the projected composition of Tank 40 after transfer of SB6/Tank 51 sludge to the heel of SB5. The composition was based on August 2009 projections. A window of about 50% in total acid was found between acceptable nitrite destruction and excessive hydrogen generation.

  6. Randomized Phase II Study of Docetaxel plus Personalized Peptide Vaccination versus Docetaxel plus Placebo for Patients with Previously Treated Advanced Wild Type EGFR Non-Small-Cell Lung Cancer.

    PubMed

    Takayama, Koichi; Sugawara, Shunichi; Saijo, Yasuo; Maemondo, Makoto; Sato, Atsushi; Takamori, Shinzo; Harada, Taishi; Sasada, Tetsuro; Kakuma, Tatsuyuki; Kishimoto, Junji; Yamada, Akira; Noguchi, Masanori; Itoh, Kyogo; Nakanishi, Yoichi

    2016-01-01

    Objectives. To evaluate the efficacy and safety of personalized peptide vaccination (PPV) combined with chemotherapy for patients with previously treated advanced non-small-cell lung cancer (NSCLC). Patients and Methods. Previously treated PS0-1 patients with IIIB/IV EGFR (epidermal growth factor receptor) wild genotype NSCLC were randomly assigned to docetaxel (60 mg/m(2) on Day 1) plus PPV based on preexisting host immunity or docetaxel plus placebo. Docetaxel administration was repeated every 3 weeks until disease progression. Personalized peptides or placebo was injected subcutaneously weekly in the first 8 weeks and biweekly in subsequent 16 weeks. The primary efficacy endpoint was progression-free survival (PFS). Results. PPV related toxicity was grade 2 or less skin reaction. The median PFS for placebo arm and PPV arm was 52 days and 59 days, respectively. There was no significant difference between two arms by log-rank test (p = 0.42). Interestingly, PFS and overall survival (OS) in humoral immunological responder were significantly longer than those in nonresponder. Conclusion. PPV did not improve the survival in combination with docetaxel for previously treated advanced NSCLC. However, PPV may be efficacious for the humoral immunological responders and a further clinical investigation is needed. PMID:27274999

  7. Randomized phase II trial of docetaxel with or without PSA-TRICOM vaccine in patients with castrate-resistant metastatic prostate cancer: A trial of the ECOG-ACRIN cancer research group (E1809)

    PubMed Central

    McNeel, Douglas G; Chen, Yu-Hui; Gulley, James L; Dwyer, Alexander J; Madan, Ravi A; Carducci, Michael A; DiPaola, Robert S

    2015-01-01

    Anti-tumor vaccines have demonstrated efficacy in patients with castration-resistant metastatic prostate cancer. One vaccine, Prostvac-VF®, using a heterologous prime-boost strategy with vaccinia and fowlpox viral vectors encoding PSA, is currently being evaluated in a registration phase III multinational clinical trial. The current trial was planned to assess the clinical efficacy of this vaccine in patients with castration-resistant metastatic prostate cancer receiving subsequent docetaxel chemotherapy. 10 patients with metastatic castration-resistant prostate cancer, with a predicted survival of at least 18 months, were enrolled out of a planned 144 patients. Eight of 10 patients were treated and were randomized to receive docetaxel chemotherapy alone (Arm B, n = 2) versus treatment with Prostvac-VF (days 1, 15, 29, 43, 57) followed by docetaxel (Arm A, n = 6) chemotherapy beginning at month 3. The primary endpoint of the trial was overall survival, and secondary endpoints included time to radiographic progression and immunological response. The trial was opened within the Eastern Cooperative Oncology Group, but due to slow accrual was closed by CTEP after only 10 patients were enrolled within 13 months. Results: Presented here are the safety, clinical, and immunological results from 8 eligible patients who underwent treatment. Two of 6 patients treated on Arm A, with vaccine followed by docetaxel, had a >50% PSA response, with one of these patients experiencing a PSA decline during treatment with vaccine. Significant PSA-specific CD4+ and CD8+ T-cell responses and IgG antibody responses specific for PSA were not detected. The primary endpoint of overall survival cannot be assessed due to limited accrual. The lack of T-cell responses, even in this small cohort, suggests that further validation and development of immune biomarkers will be important for future studies. Other trials remain ongoing to evaluate the role of anti-tumor vaccination in sequence

  8. ADULTS: A RANDOMIZED CONTROLLED CLINICAL TRIAL

    PubMed Central

    Shah, Krupa N.; Majeed, Zahraa; Yoruk, Yilmaz B.; Yang, Hongmei; Hilton, Tiffany N.; McMahon, James M.; Hall, William J.; Walck, Donna; Luque, Amneris E.; Ryan, Richard M.

    2016-01-01

    Objective HIV-infected older adults (HOA) are at risk of functional decline. Interventions promoting physical activity that can attenuate functional decline and are easily translated into the HOA community are of high priority. We conducted a randomized, controlled clinical trial to evaluate whether a physical activity counseling intervention based on self-determination theory (SDT) improves physical function, autonomous motivation, depression and the quality of life (QOL) in HOA. Methods A total of 67 community-dwelling HOA with mild-to-moderate functional limitations were randomized to one of two groups: a physical activity counseling group or the usual care control group. We used SDT to guide the development of the experimental intervention. Outcome measures that were collected at baseline and final study visits included a battery of physical function tests, levels of physical activity, autonomous motivation, depression, and QOL. Results The study participants were similar in their demographic and clinical characteristics in both the treatment and control groups. Overall physical performance, gait speed, measures of endurance and strength, and levels of physical activity improved in the treatment group compared to the control group (p<0.05). Measures of autonomous regulation such as identified regulation, and measures of depression and QOL improved significantly in the treatment group compared to the control group (p<0.05). Across the groups, improvement in intrinsic regulation and QOL correlated with an improvement in physical function (p<0.05). Conclusion Our findings suggest that a physical activity counseling program grounded in SDT can improve physical function, autonomous motivation, depression, and QOL in HOA with functional limitations. PMID:26867045

  9. Safety and Efficacy of Atacicept in Combination With Rituximab for Reducing the Signs and Symptoms of Rheumatoid Arthritis: A Phase II, Randomized, Double‐Blind, Placebo‐Controlled Pilot Trial

    PubMed Central

    van Vollenhoven, R. F.; Wax, S.; Li, Y.; Tak, P. P.

    2015-01-01

    Objective To explore the safety and tolerability of atacicept in combination with rituximab in patients with active rheumatoid arthritis (RA) receiving rituximab re‐treatment. Methods In this randomized, double‐blind, placebo‐controlled pilot trial, 2 infusions (1,000 mg per infusion) of intravenous rituximab, given 2 weeks apart, were followed by once‐weekly subcutaneous injections of 150 mg atacicept or placebo for 25 weeks. Primary end points were the nature, incidence, and severity of adverse events (AEs). Secondary end points were the effects on peripheral blood B cells, disease activity biomarkers, and American College of Rheumatology 20% (ACR20), 50% (ACR50), and 70% (ACR70) response rates. Results Eighteen patients were randomized to receive atacicept and 9 to receive placebo. AEs occurred in 17 atacicept‐treated patients (94.4%) and in all 9 placebo‐treated patients (100%). There were no infection‐related serious adverse events. Hypersensitivity and injection site reactions were more common, and more patients withdrew due to AEs, in the atacicept group. Median reductions in Ig levels from baseline to week 32 were greater with atacicept (median change in IgG −31.2%, IgM −60.9%, and IgA −56.4%) than with placebo (median change in IgG −4.4%, IgM −15.9%, and IgA −8.2%). Peripheral B cell numbers remained low in all patients after rituximab‐mediated B cell depletion, limiting comparison of time to recovery between treatment groups. There were no between‐group differences in ACR20, ACR50, and ACR70 response rates. Conclusion In this exploratory trial, atacicept in combination with rituximab showed no new safety issues. Peripheral B cell counts remained too low to determine whether atacicept delayed B cell re‐expansion following rituximab‐mediated depletion. Despite clear biologic effects, adding atacicept to rituximab in patients with active RA was not associated with clinical benefit. PMID:26137975

  10. A randomized trial to compare the safety of rivaroxaban vs aspirin in addition to either clopidogrel or ticagrelor in acute coronary syndrome: The design of the GEMINI-ACS-1 phase II study.

    PubMed

    Povsic, Thomas J; Roe, Matthew T; Ohman, Erik Magnus; Steg, Philippe Gabriel; James, Stefan; Plotnikov, Alexei; Mundl, Hardi; Welsh, Robert; Bode, Christoph; Gibson, Charles Michael

    2016-04-01

    Dual antiplatelet therapy (DAPT), the combination of aspirin and a P2Y12 inhibitor, given for 12 months remains the standard of care after presentation with acute coronary syndrome (ACS) because it has been shown to be associated with a significant reduction in ischemic events compared with aspirin monotherapy. The factor Xa inhibitor rivaroxaban was shown to be associated with a significant reduction in the composite of cardiovascular death, myocardial infarction, and stroke, and resulted in a nominal reduction in cardiovascular death, when added to background DAPT in the ATLAS ACS 2-TIMI 51 trial; however, there was excessive bleeding with this "triple-therapy" approach. The combination of rivaroxaban with P2Y12 inhibition in a "dual-pathway" approach may be an effective therapeutic regimen for the treatment of ACS, given the known importance of P2Y12 inhibition after stenting and intriguing data that the combination of an anticoagulant with clopidogrel after stenting in patients with atrial fibrillation appears an attractive option to this patient population. GEMINI-ACS-1 is a prospective, randomized, double-dummy, double-blind, active-controlled trial that will assess the safety of dual antithrombotic therapy (rivaroxaban [2.5 mg twice daily] + P2Y12 inhibitor) as compared with DAPT (aspirin [100 mg] + P2Y12 inhibitor) within 10 days of an ACS event in 3,000 patients. Patients will be randomized in a 1:1 ratio stratified by intended P2Y12 inhibitor use (clopidogrel 75 mg daily or ticagrelor 90 mg twice daily), with 1500 patients expected in each P2Y12 inhibitor strata. The primary end point is Thrombolysis in Myocardial Infarction clinically significant bleeding (major, minor, or requiring medical attention). The exploratory efficacy determination will be a composite of cardiovascular death, myocardial infarction, ischemic stroke, and stent thrombosis. GEMINI-ACS-1 will assess the safety and feasibility of dual antithrombotic therapy with rivaroxaban and a P2Y

  11. Efficacy of a Community-Based Physical Activity Program KM2H2 for Stroke and Heart Attack Prevention among Senior Hypertensive Patients: A Cluster Randomized Controlled Phase-II Trial

    PubMed Central

    Gong, Jie; Chen, Xinguang; Li, Sijian

    2015-01-01

    Objective To evaluate the efficacy of the program Keep Moving toward Healthy Heart and Healthy Brain (KM2H2) in encouraging physical activities for the prevention of heart attack and stroke among hypertensive patients enrolled in the Community-Based Hypertension Control Program (CBHCP). Design Cluster randomized controlled trial with three waves of longitudinal assessments at baseline, 3 and 6 months post intervention. Setting Community-based and patient-centered self-care for behavioral intervention in urban settings of China. Participants A total of 450 participants diagnosed with hypertension from 12 community health centers in Wuhan, China were recruited, and were randomly assigned by center to receive either KM2H2 plus standard CBHCP care (6 centers and 232 patients) or the standard care only (6 centers and 218 patients). Intervention KM2H2 is a behavioral intervention guided by the Transtheoretical Model, the Model of Personalized Medicine and Social Capital Theory. It consists of six intervention sessions and two booster sessions engineered in a progressive manner. The purpose is to motivate and maintain physical activities for the prevention of heart attack and stroke. Outcome Measures Heart attack and stroke (clinically diagnosed, primary outcome), blood pressure (measured, secondary outcome), and physical activity (self-report, tertiary outcome) were assessed at the individual level during the baseline, 3- and 6-month post-intervention. Results Relative to the standard care, receiving KM2H2 was associated with significant reductions in the incidence of heart attack (3.60% vs. 7.03%, p < .05) and stroke (5.11% vs. 9.90%, p<0.05), and moderate reduction in blood pressure (-3.72mmHg in DBP and -2.92 mmHg in DBP) at 6-month post-intervention; and significant increases in physical activity at 3- (d = 0.53, 95% CI: 0.21, 0.85) and 6-month (d = 0.45, 95% CI: 0.04, 0.85) post-intervention, respectively. Conclusion The program KM2H2 is efficacious to reduce the

  12. Mutation-targeted therapy with sunitinib or everolimus in patients with advanced low-grade or intermediate-grade neuroendocrine tumours of the gastrointestinal tract and pancreas with or without cytoreductive surgery: protocol for a phase II clinical trial

    PubMed Central

    Neychev, Vladimir; Steinberg, Seth M; Cottle-Delisle, Candice; Merkel, Roxanne; Nilubol, Naris; Yao, Jianhua; Meltzer, Paul; Pacak, Karel; Marx, Stephen; Kebebew, Electron

    2015-01-01

    Introduction Finding the optimal management strategy for patients with advanced, metastatic neuroendocrine tumours (NETs) of the gastrointestinal tract and pancreas is a work in progress. Sunitinib and everolimus are currently approved for the treatment of progressive, unresectable, locally advanced or metastatic low-grade or intermediate-grade pancreatic NETs. However, mutation-targeted therapy with sunitinib or everolimus has not been studied in this patient population. Methods and analysis This prospective, open-label phase II clinical trial was designed to determine if mutation-targeting therapy with sunitinib or everolimus for patients with advanced low-grade or intermediate-grade NETs is more effective than historically expected results with progression-free survival (PFS) as the primary end point. Patients ≥18 years of age with progressive, low-grade or intermediate-grade locally advanced or metastatic NETs are eligible for this study. Patients will undergo tumour biopsy (if they are not a surgical candidate) for tumour genotyping. Patients will be assigned to sunitininb or everolimus based on somatic/germline mutations profile. Patients who have disease progression on either sunitinib or everolimus will crossover to the other drug. Treatment will continue until disease progression, unacceptable toxicity, or consent to withdrawal. Using the proposed criteria, 44 patients will be accrued within each treatment group during a 48-month period (a total of 88 patients for the 2 treatments), and followed for up to an additional 12 months (a total of 60 months from entry of the first patient) to achieve 80% power in order to test whether there is an improvement in PFS compared to historically expected results, with a 0.10 α level one-sided significance test. Ethics and dissemination The study protocol was approved by the institutional review board of the National Cancer Institute (NCI-IRB Number 15C0040; iRIS Reference Number 339636). The results will be

  13. A Wearable Proprioceptive Stabilizer (Equistasi®) for Rehabilitation of Postural Instability in Parkinson’s Disease: A Phase II Randomized Double-Blind, Double-Dummy, Controlled Study

    PubMed Central

    Volpe, Daniele; Giantin, Maria Giulia; Fasano, Alfonso

    2014-01-01

    Background Muscle spindles endings are extremely sensitive to externally applied vibrations, and under such circumstances they convey proprioceptive inflows to the central nervous system that modulate the spinal reflexes excitability or the muscle responses elicited by postural perturbations. The aim of this pilot study is to test the feasibility and effectiveness of a balance training program in association with a wearable proprioceptive stabilizer (Equistasi) that emits focal mechanical vibrations in patients with PD. Methods Forty patients with PD were randomly divided in two groups wearing an active or inactive device. All the patients received a 2-month intensive program of balance training. Assessments were performed at baseline, after the rehabilitation period (T1), and two more months after (T2). Posturographic measures were used as primary endpoint; secondary measures of outcome included the number of falls and several clinical scales for balance and quality of life. Results Both groups improved at the end of the rehabilitation period and we did not find significant between-group differences in any of the principal posturographic measures with the exception of higher sway area and limit of stability on the instrumental functional reach test during visual deprivation at T1 in the Equistasi group. As for the secondary outcome, we found an overall better outcome in patients enrolled in the Equistasi group: 1) significant improvement at T1 on Berg Balance Scale (+45.0%, p = .026), Activities-specific Balance Confidence (+83.7, p = .004), Falls Efficacy Scale (−33.3%, p = .026) and PDQ-39 (−48.8%, p = .004); 2) sustained improvement at T2 in terms of UPDRS-III, Berg Balance Scales, Time Up and Go and PDQ-39; 3) significant and sustained reduction of the falls rate. Conclusions This pilot trial shows that a physiotherapy program for training balance in association with focal mechanical vibration exerted by a wearable proprioceptive stabilizer

  14. A non-comparative randomized phase II study of two doses of ATN-224, a copper/zinc superoxide dismutase inhibitor, in patients with biochemically recurrent hormone-naïve prostate cancer

    PubMed Central

    Lin, Jianqing; Zahurak, Marianna; Beer, Tomasz M.; Ryan, Charles. J.; Wilding, George; Mathew, Paul; Morris, Michael; Callahan, Jennifer. A.; Gordon, Gilad; Reich, Steven D.; Carducci, Michael A.; Antonarakis, Emmanuel S.

    2011-01-01

    Objective ATN-224 (choline tetrathiomolybdate) is an oral Cu2+/Zn2+-superoxide dismutase 1 (SOD1) inhibitor with preclinical antitumor activity. We hypothesized that ATN-224 may induce antitumor effects as an antiangiogenic agent at low dose-levels while possessing direct antitumor activity at higher dose-levels. The objective of this study was to screen its clinical activity in patients with biochemically recurrent hormone-naïve prostate cancer. Methods Biochemically-recurrent prostate cancer patients with prostate specific antigen doubling times (PSADT) <12 months, no radiographic evidence of metastasis, and no hormonal therapy within 6 months (with serum testosterone levels >150 ng/dL) were eligible. ATN-224 was administered at two dose-levels, 300 mg (n=23) or 30 mg (n=24) daily, by way of randomization. PSA progression was defined as a ≥50% increase (and >5 ng/mL) in PSA from baseline or post-treatment nadir. Endpoints included the proportion of patients who were free of PSA progression at 24 weeks, changes in PSA slope/PSADT, and safety. The study was not powered to detect differences between the two treatment groups. Results At 24 weeks, 59% (95% CI 33–82%) of men in the low-dose arm and 45% (95% CI 17–77%) in the high-dose arm were PSA progression-free. Median PSA progression-free survival was 30 weeks (95% CI 21–40+) and 26 weeks (95% CI 24–39+) in the low-dose and high-dose groups, respectively. Pre- and on-treatment PSA kinetics analyses showed a significant mean PSA slope decrease (p=0.006) and a significant mean PSADT increase (p=0.032) in the low-dose arm only. Serum ceruloplasmin levels, a biomarker for ATN-224 activity, were lowered in the high-dose group, but did not correlate with PSA changes. Conclusions Low-dose ATN-224 (30 mg daily) may have biologic activity in men with biochemically-recurrent prostate cancer, as suggested by an improvement in PSA kinetics. However, the clinical significance of PSA kinetics changes in this patient

  15. HPTN 035 Phase II/IIb Randomized Safety and Effectiveness Study of the Vaginal Microbicides BufferGel and 0.5% PRO 2000 for the Prevention of Sexually Transmitted Infections in Women

    PubMed Central

    Guffey, M. Bradford; Richardson, Barbra; Husnik, Marla; Makanani, Bonus; Chilongozi, David; Yu, Elmer; Ramjee, Gita; Mgodi, Nyaradzo; Gomez, Kailazarid; Hillier, Sharon L.; Karim, Salim Abdool

    2014-01-01

    Objectives To estimate the effectiveness of candidate microbicides BufferGel and 0.5% PRO 2000 Gel (P) (PRO 2000) for prevention of non-ulcerative sexually transmitted infections (STIs). Methods Between 2005 and 2007, 3099 women were enrolled in HIV Prevention Trials Network (HPTN) protocol 035, a phase II/IIb evaluation of the safety and effectiveness of BufferGel and PRO 2000 for prevention of sexually transmitted infections, including Neisseria gonorrhoeae (GC), Chlamydia trachomatis (CT), and Trichomonas vaginalis (TV). Incidences of STIs were determined by study arm, and hazard ratios (HRs) of BufferGel and PRO 2000 versus placebo gel or no gel control groups were computed using discrete time Andersen-Gill proportional hazards model. Results The overall incidence rates were 1.6/100 person-years at risk (PYAR) for GC, 3.9/100 PYAR for CT, and 15.3/100 PYAR for TV. For BufferGel versus placebo gel, HRs were 0.99 (95% CI 0.49–2.00), 1.00 (95% CI 0.64–1.57), and 0.95 (95% CI 0.71–1.25) for prevention of GC, CT, and TV respectively. For PRO 2000, HRs were 1.66 (95% CI 0.90–3.06), 1.16 (95% CI 0.76–1.79), and 1.18 (95% CI 0.90–1.53) for prevention of GC, CT, and TV respectively. Conclusions The incidence of STIs was high during HPTN 035 despite provision of free condoms and comprehensive risk-reduction counselling, highlighting the need for effective STI prevention programmes in this population. Unfortunately, candidate microbicides BufferGel and PRO2000 had no protective effect against gonorrhoea, Chlamydia, or trichomoniasis. PMID:24898857

  16. Safety and Efficacy Assessment of Two New Leprosy Skin Test Antigens: Randomized Double Blind Clinical Study

    PubMed Central

    Rivoire, Becky L.; Groathouse, Nathan A.; TerLouw, Stephen; Neupane, Kapil Dev; Ranjit, Chaman; Sapkota, Bishwa Raj; Khadge, Saraswoti; Kunwar, Chatra B.; Macdonald, Murdo; Hawksworth, Rachel; Thapa, Min B.; Hagge, Deanna A.; Tibbals, Melinda; Smith, Carol; Dube, Tina; She, Dewei; Wolff, Mark; Zhou, Eric; Makhene, Mamodikoe; Mason, Robin; Sizemore, Christine; Brennan, Patrick J.

    2014-01-01

    Background New tools are required for the diagnosis of pre-symptomatic leprosy towards further reduction of disease burden and its associated reactions. To address this need, two new skin test antigens were developed to assess safety and efficacy in human trials. Methods A Phase I safety trial was first conducted in a non-endemic region for leprosy (U.S.A.). Healthy non-exposed subjects (n = 10) received three titrated doses (2.5 µg, 1.0 µg and 0.1 µg) of MLSA-LAM (n = 5) or MLCwA (n = 5) and control antigens [Rees MLSA (1.0 µg) and saline]. A randomized double blind Phase II safety and efficacy trial followed in an endemic region for leprosy (Nepal), but involved only the 1.0 µg (high dose) and 0.1 µg (low dose) of each antigen; Tuberculin PPD served as a control antigen. This Phase II safety and efficacy trial consisted of three Stages: Stage A and B studies were an expansion of Phase I involving 10 and 90 subjects respectively, and Stage C was then conducted in two parts (high dose and low dose), each enrolling 80 participants: 20 borderline lepromatous/lepromatous (BL/LL) leprosy patients, 20 borderline tuberculoid/tuberculoid (BT/TT) leprosy patients, 20 household contacts of leprosy patients (HC), and 20 tuberculosis (TB) patients. The primary outcome measure for the skin test was delayed type hypersensitivity induration. Findings In the small Phase I safety trial, reactions were primarily against the 2.5 µg dose of both antigens and Rees control antigen, which were then excluded from subsequent studies. In the Phase II, Stage A/B ramped-up safety study, 26% of subjects (13 of 50) showed induration against the high dose of each antigen, and 4% (2 of 50) reacted to the low dose of MLSA-LAM. Phase II, Stage C safety and initial efficacy trial showed that both antigens at the low dose exhibited low sensitivity at 20% and 25% in BT/TT leprosy patients, but high specificity at 100% and 95% compared to TB patients. The high dose of both antigens

  17. Relationship between HER2 expression and efficacy with first-line trastuzumab emtansine compared with trastuzumab plus docetaxel in TDM4450g: a randomized phase II study of patients with previously untreated HER2-positive metastatic breast cancer

    PubMed Central

    2014-01-01

    Introduction The purpose of this study was to retrospectively explore the relationship between human epidermal growth factor receptor 2 (HER2) messenger RNA (mRNA) expression and efficacy in patients receiving trastuzumab plus docetaxel (HT) or trastuzumab emtansine (T-DM1). Methods Patients with HER2-positive, locally advanced or metastatic breast cancer (MBC) were randomly assigned to HT (n = 70) or T-DM1 (n = 67). HER2 status was assessed locally using immunohistochemistry or fluorescence in situ hybridization and confirmed retrospectively by central testing. HER2 mRNA expression was assessed using quantitative reverse transcriptase polymerase chain reaction. Results HER2 mRNA levels were obtained for 116/137 patients (HT = 61; T-DM1 = 55). Median pretreatment HER2 mRNA was 8.9. The risk of disease progression in the overall population was lower with T-DM1 than with HT (hazard ratio (HR) = 0.59; 95% confidence interval (CI) 0.36 to 0.97). This effect was more pronounced in patients with HER2 mRNA ≥ median (HR = 0.39; 95% CI 0.18 to 0.85) versus < median (HR = 0.85; 95% CI 0.44 to 1.67). In the T-DM1 arm, median progression-free survival (PFS) was not reached in patients with HER2 mRNA ≥ median and was 10.6 months in patients with HER2 mRNA < median. In the HT arm, PFS was 8.8 versus 9.8 months in patients with HER2 mRNA ≥ median versus < median, respectively. The effect of HER2 mRNA expression on objective response rates was less pronounced. Conclusions This exploratory analysis suggests that while overall, patients with HER2-positive MBC show improved PFS with T-DM1 relative to HT, the effect is enhanced in patients with tumor HER2 mRNA ≥ median. Trial registration ClinicalTrials.gov NCT00679341 PMID:24887458

  18. A Tool for Predicting Regulatory Approval After Phase II Testing of New Oncology Compounds.

    PubMed

    DiMasi, J A; Hermann, J C; Twyman, K; Kondru, R K; Stergiopoulos, S; Getz, K A; Rackoff, W

    2015-11-01

    We developed an algorithm (ANDI) for predicting regulatory marketing approval for new cancer drugs after phase II testing has been conducted, with the objective of providing a tool to improve drug portfolio decision-making. We examined 98 oncology drugs from the top 50 pharmaceutical companies (2006 sales) that first entered clinical development from 1999 to 2007, had been taken to at least phase II development, and had a known final outcome (research abandonment or regulatory marketing approval). Data on safety, efficacy, operational, market, and company characteristics were obtained from public sources. Logistic regression and machine-learning methods were used to provide an unbiased approach to assess overall predictability and to identify the most important individual predictors. We found that a simple four-factor model (activity, number of patients in the pivotal phase II trial, phase II duration, and a prevalence-related measure) had high sensitivity and specificity for predicting regulatory marketing approval. PMID:26239772

  19. A Randomized Clinical Trial of Schinus terebinthifolius Mouthwash to Treat Biofilm-Induced Gingivitis

    PubMed Central

    Freires, Irlan de Almeida; Alves, Livia Araújo; Ferreira, Gabriela Lacet Silva; Jovito, Vanessa de Carvalho; de Castro, Ricardo Dias; Cavalcanti, Alessandro Leite

    2013-01-01

    Objectives. This study aimed to investigate the efficacy of a Schinus terebinthifolius (ST) mouthwash in reducing gingival inflammation levels (GI) and biofilm accumulation (BA) in children with gingivitis. Methods. This was a randomized, controlled, triple blind, and phase II clinical trial, with children aged 9–13 years (n = 27) presenting with biofilm-induced gingivitis. The sample was randomized into experimental (0.3125% ST, n = 14) and control (0.12% chlorhexidine/CHX, n = 13) groups. Products were masked as regards color, flavor and aroma. Intervention protocol consisted in supervised rinsing of 10 mL/day for 01 minute for 10 days. Gingival bleeding and simplified oral hygiene indexes were used to assess the efficacy variables, measured at baseline and after intervention by calibrated examiners. Data were statistically treated with paired t-test, unpaired t-test, and Wilcoxon and Mann-Whitney tests (α = .05). Results. It was found that both ST and CHX were able to significantly reduce GI levels after 10 days (P < 0.001) and there was no significant difference between them (P > 0.05). CHX was the only product able to significantly reduce BA after 10 days when compared to baseline (P < 0.05). Conclusion. ST mouthwash showed significant anti-inflammatory activity (equivalent to CHX), but it was not able to reduce biofilm accumulation. PMID:23843886

  20. Paclitaxel/carboplatin with or without sorafenib in the first-line treatment of patients with stage III/IV epithelial ovarian cancer: a randomized phase II study of the Sarah Cannon Research Institute.

    PubMed

    Hainsworth, John D; Thompson, Dana S; Bismayer, John A; Gian, Victor G; Merritt, William M; Whorf, Robert C; Finney, Lindsey H; Dudley, B Stephens

    2015-05-01

    This trial compared the efficacy and toxicity of standard first-line treatment with paclitaxel/carboplatin versus paclitaxel/carboplatin plus sorafenib in patients with advanced ovarian carcinoma. Patients with stage 3 or 4 epithelial ovarian cancer with residual measurable disease or elevated CA-125 levels after maximal surgical cytoreduction were randomized (1:1) to receive treatment with paclitaxel (175 mg/m(2) , 3 h infusion, day 1) and carboplatin (AUC 6.0, IV, day 1) with or without sorafenib 400 mg orally twice daily (PO BID). Patients were reevaluated for response after completing 6 weeks of treatment (two cycles); responding or stable patients received six cycles of paclitaxel/carboplatin. Patients receiving the sorafenib-containing regimen continued sorafenib (400 PO BID) for a total of 52 weeks. Eighty-five patients were randomized and received treatment.Efficacy was similar for patients receiving paclitaxel/carboplatin/sorafenib versus paclitaxel/carboplatin: overall response rates 69% versus 74%; median progression-free survival 15.4 versus 16.3 months; 2 year survival 76% versus 81%. The addition of sorafenib added substantially to the toxicity of the regimen; rash, hand-foot syndrome, mucositis, and hypertension were significantly more common in patients treated with sorafenib. The addition of sorafenib to standard paclitaxel/carboplatin did not improve efficacy and substantially increased toxicity in the first-line treatment of advanced epithelial ovarian cancer. Based on evidence from this study and other completed trials, sorafenib is unlikely to have a role in the treatment of ovarian cancer.

  1. The Long Valley Well: Phase II operations

    SciTech Connect

    Finger, J.T.

    1992-01-01

    Phase II of the Long Valley Exploratory Well was completed to a depth of 7588 feet in November 1991. The drilling comprised two sub-phases: (1) drilling 17-1/2 inch hole from the Phase I casing shoe at 2558 feet to a depth of 7130 feet, plugging back to 6826 feet, and setting 13-3/8 inch casing at 6825 feet, all during August--September 1991; and (2) returning in November to drill a 3.85-inch core hole deviated out of the previous wellbore at 6868 feet and extending to 7588 feet. Ultimate depth of the well is planned to be 20,000 feet, or at a bottomhole temperature of 500{degrees}C, whichever comes first. Total cost of this drilling phase was approximately $2.3 million, and funding was shared about equally between the California Energy Commission and the Department of Energy. Phase II scientific work will commence in July 1992 and will be supported by DOE Office of Basic Energy Sciences, DOE Geothermal Division, and other funding sources.

  2. The Long Valley Well - Phase II Operations

    SciTech Connect

    Finger, John T.

    1992-03-24

    Phase II of the Long Valley Exploratory Well was completed to a depth of 7588 feet in November 1991. The drilling comprised two sub-phases: (1) drilling 17-1/2 inch hole from the Phase I casing shoe at 2558 feet to a depth of 7130 feet, plugging back to 6826 feet, and setting 13-3/8 inch casing at 6825 feet, all during August-September 1991; and (2) returning in November to drill a 3.85-inch core hole deviated out of the previous wellbore at 6808 feet and extending to 7588 feet. Ultimate depth of the well is planned to be 20,000 feet, or at a bottomhole temperature of 500 C, whichever comes first. Total cost of this drilling phase was approximately $2.3 million, and funding was shared about equally between the California Energy Commission and the Department of Energy. Phase II scientific work will commence in July 1992 and will be supported by DOE Office of Basic Energy Sciences, DOE Geothermal Division, and other funding sources.

  3. An Ongoing Randomized Clinical Trial in Dysphagia

    ERIC Educational Resources Information Center

    Robbins, JoAnne; Hind, Jackie; Logemann, Jerilyn

    2004-01-01

    Most of us who have clinical practices firmly contend that the treatments we provide cause beneficial changes in the lives of our patients. Indeed, our clinical experience engenders strong convictions to the point of believing that withholding treatment creates ethical violations. Intellectually, however, we must recognize that the value of…

  4. Webcam Delivery of the Camperdown Program for Adolescents Who Stutter: A Phase II Trial

    ERIC Educational Resources Information Center

    Carey, Brenda; O'Brian, Sue; Lowe, Robyn; Onslow, Mark

    2014-01-01

    Purpose: This Phase II clinical trial examined stuttering adolescents' responsiveness to the Webcam-delivered Camperdown Program. Method: Sixteen adolescents were treated by Webcam with no clinic attendance. Primary outcome was percentage of syllables stuttered (%SS). Secondary outcomes were number of sessions, weeks and hours to maintenance,…

  5. Eugenia uniflora Dentifrice for Treating Gingivitis in Children: Antibacterial Assay and Randomized Clinical Trial.

    PubMed

    Jovito, Vanessa de Carvalho; Freires, Irlan Almeida; Ferreira, Danilo Augusto de Holanda; Paulo, Marçal de Queiroz; Castro, Ricardo Dias de

    2016-01-01

    School-age children are frequently at high risk for the onset of biofilm-dependent conditions, including dental caries and periodontal diseases. The objective of this study was to evaluate the clinical efficacy of a dentifrice containing Eugenia uniflora Linn. (Surinam cherry) extract versus a triclosan-based comparator in treating gingivitis in children aged 10-12 years. The in vitro antibacterial potential of the dentifrice was tested against oral pathogens (Streptococcus mutans, Streptococcus oralis and Lactobacillus casei). Then a phase-II clinical trial was conducted with 50 subjects aged 10-12 years, with clinical signs of gingivitis. The subjects were randomly assigned to the experimental group (n=25) and control group (n=25), in which participants used the experimental dentifrice and a triclosan-based fluoridated dentifrice (Colgate Total 12(r)), respectively. Clinical examinations assessed the presence of gingivitis (primary outcome) and biofilm accumulation (secondary outcome) using the Gingival-Bleeding Index (GBI) and Simplified Oral Hygiene Index (OHI-S), respectively, at baseline and after seven days of tooth brushing 3x/day. The data were analyzed using paired and unpaired t-test (GBI) and Wilcoxon and Mann-Whitney (OHI-S), with p≤0.05. The experimental dentifrice showed efficient antibacterial activity in vitro. In the clinical trial, a significant reduction in gingival bleeding was observed in both experimental and control groups (p<0.0001), with no statistical difference between them (p=0.178), although a small size effect was observed. Biofilm accumulation was only reduced in the control group (p=0.0039). In conclusion, E. uniflora dentifrice showed anti-gingivitis properties in children aged 10-12 years. Thus, it may be a potentially efficient and safe product to be used alternatively in preventive dental practice. PMID:27652698

  6. Eugenia uniflora Dentifrice for Treating Gingivitis in Children: Antibacterial Assay and Randomized Clinical Trial.

    PubMed

    Jovito, Vanessa de Carvalho; Freires, Irlan Almeida; Ferreira, Danilo Augusto de Holanda; Paulo, Marçal de Queiroz; Castro, Ricardo Dias de

    2016-01-01

    School-age children are frequently at high risk for the onset of biofilm-dependent conditions, including dental caries and periodontal diseases. The objective of this study was to evaluate the clinical efficacy of a dentifrice containing Eugenia uniflora Linn. (Surinam cherry) extract versus a triclosan-based comparator in treating gingivitis in children aged 10-12 years. The in vitro antibacterial potential of the dentifrice was tested against oral pathogens (Streptococcus mutans, Streptococcus oralis and Lactobacillus casei). Then a phase-II clinical trial was conducted with 50 subjects aged 10-12 years, with clinical signs of gingivitis. The subjects were randomly assigned to the experimental group (n=25) and control group (n=25), in which participants used the experimental dentifrice and a triclosan-based fluoridated dentifrice (Colgate Total 12(r)), respectively. Clinical examinations assessed the presence of gingivitis (primary outcome) and biofilm accumulation (secondary outcome) using the Gingival-Bleeding Index (GBI) and Simplified Oral Hygiene Index (OHI-S), respectively, at baseline and after seven days of tooth brushing 3x/day. The data were analyzed using paired and unpaired t-test (GBI) and Wilcoxon and Mann-Whitney (OHI-S), with p≤0.05. The experimental dentifrice showed efficient antibacterial activity in vitro. In the clinical trial, a significant reduction in gingival bleeding was observed in both experimental and control groups (p<0.0001), with no statistical difference between them (p=0.178), although a small size effect was observed. Biofilm accumulation was only reduced in the control group (p=0.0039). In conclusion, E. uniflora dentifrice showed anti-gingivitis properties in children aged 10-12 years. Thus, it may be a potentially efficient and safe product to be used alternatively in preventive dental practice.

  7. Efficacy and safety of cord blood-derived dendritic cells plus cytokine-induced killer cells combined with chemotherapy in the treatment of patients with advanced gastric cancer: a randomized Phase II study

    PubMed Central

    Mu, Ying; Wang, Wei-hua; Xie, Jia-ping; Zhang, Ying-xin; Yang, Ya-pei; Zhou, Chang-hui

    2016-01-01

    Background Cellular immunotherapy has been widely used in the treatment of solid tumors. However, the clinical application of cord blood-derived dendritic cells and cytokine-induced killer cells (CB-DC-CIK) for the treatment of gastric cancer has not been frequently reported. In this study, the efficacy and safety of CB-DC-CIK for the treatment of gastric cancer were evaluated both in vitro and in vivo. Methods The phenotypes, cytokines, and cytotoxicity of CB-DC-CIK were detected in vitro. Patients with advanced gastric cancer were divided into the following two groups: the experimental group (CB-DC-CIK combined with chemotherapy) and the control group (chemotherapy alone). The curative effects and immune function were compared between the two groups. Results First, the results showed that combination therapy significantly increased the overall disease-free survival rate (P=0.0448) compared with chemotherapy alone. The overall survival rate (P=0.0646), overall response rate (P=0.410), and disease control rate (P=0.396) were improved in the experimental group, but these changes did not reach statistical significance. Second, the percentage of T-cell subsets (CD4+, CD3−CD56+, and CD3+CD56+) and the levels of IFN-γ, TNF-α, and IL-2, which reflect immune function, were significantly increased (P<0.05) after immunotherapy. Finally, no serious side effects appeared in patients with gastric cancer after the application of cellular immunotherapy based on CB-DC-CIK. Conclusion CB-DC-CIK combined with chemotherapy is effective and safe for the treatment of patients with advanced gastric cancer. PMID:27524915

  8. Low Noise Borehole Triaxial Seismometer Phase II

    SciTech Connect

    Kerr, James D; McClung, David W

    2006-11-06

    This report describes the preliminary design and the effort to date of Phase II of a Low Noise Borehole Triaxial Seismometer for use in networks of seismic stations for monitoring underground nuclear explosions. The design uses the latest technology of broadband seismic instrumentation. Each parameter of the seismometer is defined in terms of the known physical limits of the parameter. These limits are defined by the commercially available components, and the physical size constraints. A theoretical design is proposed, and a preliminary prototype model of the proposed instrument has been built. This prototype used the sensor module of the KS2000. The installation equipment (hole locks, etc.) has been designed and one unit has been installed in a borehole. The final design of the sensors and electronics and leveling mechanism is in process. Noise testing is scheduled for the last quarter of 2006.

  9. Busted Butte Phase II Excavation Analysis

    SciTech Connect

    J.W. Keifer

    2000-11-29

    The purpose of this analysis is to provide an engineering excavation and ground support design for the Busted Butte phase II mine back. The analysis will apply engineering practices and previous proven design methods for pillar design and ground support in accordance with applicable Integrated Safety Management principles and functions. The scope of this analysis is limited to the Busted Butte Test Facility. The intended use of this analysis is to provide testing excavation boundaries, ground support and pillar design input to drawing(s) to support test operations implementation. This design activity has been prepared under ''Technical Work Plan For Test Facilities Design FY01 Work Activities'' (TWP) (CRWMS M&O 2000b). No deviations from the TWP have been necessary for this analysis.

  10. EIS issued for Unocal Phase II expansion

    SciTech Connect

    Not Available

    1986-09-01

    The draft Environmental Impact Statement discusses the impacts of construction and operation of an 80,000 barrels per day expansion of Union's completed Phase I oil shale project at Parachute Creek, Colorado. With the demise of the United States Synthetic Fuels Corporation, there is, of course, no chance that the project will proceed under current economic conditions. If and when the project is able to proceed, the EIS indicates that it would be possible without exceeding the allowable PSD increments for air quality. This paper describes the proposed Phase II, which includes a new room and pillar mine, new surface retorting facilities, water supply system, synthetic crude pipelines, retorted shale disposal systems, and associated housing, roads, and power supplies. Summaries of the environmental impacts are given.

  11. Robotic dry stripping of airframes - Phase II

    NASA Astrophysics Data System (ADS)

    Pauli, Robert A.; Wittenberg, Art M.

    1989-03-01

    This paper describes a program for the development of a dust-free closed-cycle robotic system for dry stripping of airframes, designed to insure dust-free work environment and reduce plastic-media loss, the contamination risk, and the media inventory requirement. Phase I of the program involved building a prototype of the proposed robotic arm and its dust enclosure to prove basic automation concepts, showing reasonable paint removal rate from a curved surface, and establishing that the process is dust-free and recovers plastic media in a closed-cycle fashion. This paper contains calculations on the effect of different blasting parameters in order to determine optimum values required for the completion of Phase I. Also presented is the progress achieved by the Phase II of the program, which is to prove the total concept by building the complete system and demonstrating its capability.

  12. Safety and Immunogenicity of Modified Vaccinia Ankara-Bavarian Nordic Smallpox Vaccine in Vaccinia-Naive and Experienced Human Immunodeficiency Virus-Infected Individuals: An Open-Label, Controlled Clinical Phase II Trial

    PubMed Central

    Overton, Edgar Turner; Stapleton, Jack; Frank, Ian; Hassler, Shawn; Goepfert, Paul A.; Barker, David; Wagner, Eva; von Krempelhuber, Alfred; Virgin, Garth; Meyer, Thomas Peter; Müller, Jutta; Bädeker, Nicole; Grünert, Robert; Young, Philip; Rösch, Siegfried; Maclennan, Jane; Arndtz-Wiedemann, Nathaly; Chaplin, Paul

    2015-01-01

    Background. First- and second-generation smallpox vaccines are contraindicated in individuals infected with human immunodeficiency virus (HIV). A new smallpox vaccine is needed to protect this population in the context of biodefense preparedness. The focus of this study was to compare the safety and immunogenicity of a replication-deficient, highly attenuated smallpox vaccine modified vaccinia Ankara (MVA) in HIV-infected and healthy subjects. Methods. An open-label, controlled Phase II trial was conducted at 36 centers in the United States and Puerto Rico for HIV-infected and healthy subjects. Subjects received 2 doses of MVA administered 4 weeks apart. Safety was evaluated by assessment of adverse events, focused physical exams, electrocardiogram recordings, and safety laboratories. Immune responses were assessed using enzyme-linked immunosorbent assay (ELISA) and a plaque reduction neutralization test (PRNT). Results. Five hundred seventy-nine subjects were vaccinated at least once and had data available for analysis. Rates of ELISA seropositivity were comparably high in vaccinia-naive healthy and HIV-infected subjects, whereas PRNT seropositivity rates were higher in healthy compared with HIV-infected subjects. Modified vaccinia Ankara was safe and well tolerated with no adverse impact on viral load or CD4 counts. There were no cases of myo-/pericarditis reported. Conclusions. Modified vaccinia Ankara was safe and immunogenic in subjects infected with HIV and represents a promising smallpox vaccine candidate for use in immunocompromised populations. PMID:26380340

  13. Treatment of primary Sjögren's syndrome with low-dose natural human interferon-alpha administered by the oral mucosal route: a phase II clinical trial. IFN Protocol Study Group.

    PubMed

    Ship, J A; Fox, P C; Michalek, J E; Cummins, M J; Richards, A B

    1999-08-01

    The purpose of this investigation was to examine the safety and efficacy of four dosages of natural human interferon-alpha (nHuIFN-alpha) delivered over a 12-week period orally in lozenges (150 IU and 450 IU, once [QD] or three times [TID] daily) compared to placebo in subjects with primary Sjögren's syndrome. This randomized, double-blinded clinical trial demonstrated that nHuIFN-alpha at a dose of 150 IU administered TID by oral lozenge significantly improved stimulated whole saliva output compared to placebo after 12 weeks of treatment. The 150 IU TID dose also was suggestive of benefit for 5 of 7 subjective measures of oral and ocular comfort. IFN lozenges demonstrated a good safety profile, with no serious adverse events found in any treatment group. There were no significant differences between the placebo and the four doses of IFN for adverse events by total number, organ system, severity, dropouts, and number judged to be related to treatment. In conclusion, these results demonstrated that the use of 150 IU IFN lozenges TID for 12 weeks in subjects with primary Sjögren's syndrome improved salivary output and decreased complaints of xerostomia without causing significant adverse medical events. PMID:10476942

  14. Long-Term Results of an RTOG Phase II Trial (00-19) of External-Beam Radiation Therapy Combined With Permanent Source Brachytherapy for Intermediate-Risk Clinically Localized Adenocarcinoma of the Prostate

    SciTech Connect

    Lawton, Colleen A.; Yan, Yan; Lee, W. Robert; Gillin, Michael; Firat, Selim; Baikadi, Madhava; Crook, Juanita; Kuettel, Michael; Morton, Gerald; Sandler, Howard

    2012-04-01

    Purpose: External-beam radiation therapy combined with low-doserate permanent brachytherapy are commonly used to treat men with localized prostate cancer. This Phase II trial was performed to document late gastrointestinal or genitourinary toxicity as well as biochemical control for this treatment in a multi-institutional cooperative group setting. This report defines the long-term results of this trial. Methods and Materials: All eligible patients received external-beam radiation (45 Gy in 25 fractions) followed 2-6 weeks later by a permanent iodine 125 implant of 108 Gy. Late toxicity was defined by the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer late radiation morbidity scoring scheme. Biochemical control was defined by the American Society for Therapeutic Radiology and Oncology (ASTRO) Consensus definition and the ASTRO Phoenix definition. Results: One hundred thirty-eight patients were enrolled from 20 institutions, and 131 were eligible. Median follow-up (living patients) was 8.2 years (range, 2.7-9.3 years). The 8-year estimate of late grade >3 genitourinary and/or gastrointestinal toxicity was 15%. The most common grade >3 toxicities were urinary frequency, dysuria, and proctitis. There were two grade 4 toxicities, both bladder necrosis, and no grade 5 toxicities. In addition, 42% of patients complained of grade 3 impotence (no erections) at 8 years. The 8-year estimate of biochemical failure was 18% and 21% by the Phoenix and ASTRO consensus definitions, respectively. Conclusion: Biochemical control for this treatment seems durable with 8 years of follow-up and is similar to high-dose external beam radiation alone or brachytherapy alone. Late toxicity in this multi-institutional trial is higher than reports from similar cohorts of patients treated with high-dose external-beam radiation alone or permanent low-doserate brachytherapy alone, perhaps suggesting further attention to strategies that limit doses to

  15. Assessment of function and quality of life in a phase II multi-institutional clinical trial of fractionated simultaneous in-field boost radiotherapy for patients with 1-3 metastases.

    PubMed

    Bauman, Glenn; Yartsev, Slav; Roberge, David; MacRae, Robert; Roa, Wilson; Panet-Raymond, Valerie; Masucci, Laura; Yaremko, Brian; D'Souza, David; Palma, David; Sexton, Tracy; Yu, Edward; Pantarotto, Jason R; Ahmad, Belal; Fisher, Barbara; Dar, A Rashid; Lambert, Carole; Pond, Gregory; Stitt, Larry; Tay, Keng Yeow; Rodrigues, George

    2016-07-01

    We examined functional outcomes and quality of life of whole brain radiotherapy (WBRT) with integrated fractionated stereotactic radiotherapy boost (FSRT) for brain metastases treatment. Eighty seven people with 1-3 brain metastases (54/87 lung primary, 42/87 single brain metastases) were enrolled on this Phase II trial of WBRT (30 Gy/10) + simultaneous FSRT, (60 Gy/10). Median overall follow-up and survival was 5.4 months, 6 month actuarial intra-lesional control was 78 %; only 1 patient exhibited grade 4 toxicity (worsened seizures); most treatment related toxicity was grade 1 or 2; 2/87 patients demonstrated asymptomatic radiation necrosis on follow-up imaging. Mean (Min-Max) baseline KPS, Mini Mental Status Exam (MMSE) and FACT-BR quality of life were 83 (70-100), 28 (21-30) and 143 (98-153). Lower baseline MMSE (but not KPS or FACT-Br) was associated with worse survival after adjusting for age, number of metastases, primary and extra-cranial disease status. Crude rates of deterioration (>10 points decrease from baseline for KPS and FACT-Br, MMSE fall to <27) ranged from 26 to 38 % for KPS, 32-59 % for FACT-Br and 0-16 % for MMSE depending on the time-point assessed with higher rates generally noted at earlier time points (≤6 months post-treatment). Using a linear mixed models analysis, significant declines from baseline were noted for KPS and FACT-Br (largest effects at 6 weeks to 3 months) with no significant change in MMSE. The effects on function and quality of life of this integrated treatment of WBRT + simultaneous FSRT were similar to other published series combining WBRT + radiosurgery.

  16. Phase II Final Scientific/Technical Report

    SciTech Connect

    Grigg, Reid; McPherson, Brian; Lee, Rober

    2011-08-01

    The Southwest Regional Partnership on Carbon Sequestration (SWP) one of seven regional partnerships sponsored by the U.S. Department of Energy (USDOE) carried out five field pilot tests in its Phase II Carbon Sequestration Demonstration effort, to validate the most promising sequestration technologies and infrastructure concepts, including three geologic pilot tests and two terrestrial pilot programs. This field testing demonstrated the efficacy of proposed sequestration technologies to reduce or offset greenhouse gas emissions in the region. Risk mitigation, optimization of monitoring, verification, and accounting (MVA) protocols, and effective outreach and communication were additional critical goals of these field validation tests. The program included geologic pilot tests located in Utah, New Mexico, Texas, and a region-wide terrestrial analysis. Each geologic sequestration test site was intended to include injection of a minimum of ~75,000 tons/year CO{sub 2}, with minimum injection duration of one year. These pilots represent medium- scale validation tests in sinks that host capacity for possible larger-scale sequestration operations in the future. These validation tests also demonstrated a broad variety of carbon sink targets and multiple value-added benefits, including testing of enhanced oil recovery and sequestration, enhanced coalbed methane production and a geologic sequestration test combined with a local terrestrial sequestration pilot. A regional terrestrial sequestration demonstration was also carried out, with a focus on improved terrestrial MVA methods and reporting approaches specific for the Southwest region.

  17. Monorail bridge conveyor. Phase II report

    SciTech Connect

    Gonski, J

    1982-04-30

    This report covers the second phase of a four-phase contract to develop and test a roof hung monorail bridge conveyor coal haulage system working behind a continuous miner. Phase II covers the fabrication and assembly of all the components in making up the Monoral Bridge Conveyor System. The original concept presented had to be analyzed before final design could proceed. The analysis revealed that 24 ft. long bridge conveyor segments were the optimum length; the suspension system must have the vertical hinge point between bridges, the impact point of the coal transfer point and the suspension point itself, coincidental. The propulsion system is such that each bridge is self propelled in order to minimize side loading on the monorail. The conveyor belt drive is simple since it only has to drive one single 24 ft. conveyor. The entire assembly of twelve conveyors has been pre-tested in our Murfreesboro, Tennessee, shop. The electric circuit proved successful to operate from a manual control or automatically, and successfully proved the cycle of sequential strating and stopping.

  18. Spray Forming Aluminum - Final Report (Phase II)

    SciTech Connect

    D. D. Leon

    1999-07-08

    The U.S. Department of Energy - Office of Industrial Technology (DOE) has an objective to increase energy efficient and enhance competitiveness of American metals industries. To support this objective, ALCOA Inc. entered into a cooperative program to develop spray forming technology for aluminum. This Phase II of the DOE Spray Forming Program would translate bench scale spray forming technology into a cost effective world class process for commercialization. Developments under DOE Cooperative Agreement No. DE-FC07-94ID13238 occurred during two time periods due to budgetary constraints; April 1994 through September 1996 and October 1997 and December 1998. During these periods, ALCOA Inc developed a linear spray forming nozzle and specific support processes capable of scale-up for commercial production of aluminum sheet alloy products. Emphasis was given to alloys 3003 and 6111, both being commercially significant alloys used in the automotive industry. The report reviews research performed in the following areas: Nozzel Development, Fabrication, Deposition, Metal Characterization, Computer Simulation and Economics. With the formation of a Holding Company, all intellectual property developed in Phases I and II of the Project have been documented under separate cover for licensing to domestic producers.

  19. MesoNAM Verification Phase II

    NASA Technical Reports Server (NTRS)

    Watson, Leela R.

    2011-01-01

    The 45th Weather Squadron Launch Weather Officers use the 12-km resolution North American Mesoscale model (MesoNAM) forecasts to support launch weather operations. In Phase I, the performance of the model at KSC/CCAFS was measured objectively by conducting a detailed statistical analysis of model output compared to observed values. The objective analysis compared the MesoNAM forecast winds, temperature, and dew point to the observed values from the sensors in the KSC/CCAFS wind tower network. In Phase II, the AMU modified the current tool by adding an additional 15 months of model output to the database and recalculating the verification statistics. The bias, standard deviation of bias, Root Mean Square Error, and Hypothesis test for bias were calculated to verify the performance of the model. The results indicated that the accuracy decreased as the forecast progressed, there was a diurnal signal in temperature with a cool bias during the late night and a warm bias during the afternoon, and there was a diurnal signal in dewpoint temperature with a low bias during the afternoon and a high bias during the late night.

  20. Small Business Innovation Research GRC Phase I, Phase II, and Post-Phase II Opportunity Assessment for 2015

    NASA Technical Reports Server (NTRS)

    Nguyen, Hung D.; Steele, Gynelle C.

    2016-01-01

    This report outlines the 2015 Small Business Innovation Research/Small Business Technology Transfer (SBIR/STTR) Phase I, Phase II, and Post-Phase II opportunity contract award results associated with NASA's Aeronautics Research Mission Directorate (ARMD), Human Exploration and Operations Mission Directorate (HEOMD), Science Mission Directorate (SMD), and Space Technology Mission Directorate (STMD) for NASA Glenn Research Center. The report also highlights the number of Phase I, Phase II, and Post-Phase II contracts awarded by mission directorate. The 2015 Phase I contract awards to companies in Ohio and their corresponding technologies are also discussed.

  1. Venlafaxine versus applied relaxation for generalized anxiety disorder: a randomized controlled study on clinical and electrophysiological outcomes.

    PubMed

    Zullino, Daniele; Chatton, Anne; Fresard, Emmanuelle; Stankovic, Miroslava; Bondolfi, Guido; Borgeat, François; Khazaal, Yasser

    2015-03-01

    Some components of generalized anxiety disorder, such as physical symptoms, are thought to reflect autonomic nervous system arousal. This study primarily assessed the relationships between psychophysiological and clinical measures using venlafaxine extended release or applied relaxation, and secondarily, the impact of combination treatment in patients not remitting after 8 weeks. Fifty-eight patients were randomly assigned to 8 weeks of treatment with either venlafaxine or applied relaxation (Phase I). Non-remitted patients received combination treatment for an additional 8 weeks (Phase II). Assessments included the Hamilton Anxiety Scale (HAM-A), Beck Depression Inventory, Penn State Worry Questionnaire and the Stroop Color-Word Task coupled with electrophysiological measures (skin conductance and frontalis electromyography (EMG)). In Phase 1, a time effect was found for the clinical and skin conductance measures. Thirteen patients from each group were in remission. In Phase 2, seven additional patients remitted. Baseline psychophysiological measures were not associated with baseline clinical variables or with clinical outcomes. Independently of treatment allocation, a reduction in frontal EMG values at week 4 was significantly associated with a decrease in HAM-A scores at week 8. At week 4, responders from the applied relaxation group had lower electrophysiological activity than the venlafaxine group. Baseline psychophysiological measures were not linked with clinical measures at study inclusion or with treatment response. Frontal EMG response at week 4 is a possible predictor of treatment response. Treatment combination enhances treatment response after initial failure. PMID:25464934

  2. 40 CFR 790.52 - Phase II test rule.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 33 2013-07-01 2013-07-01 false Phase II test rule. 790.52 Section 790.52 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) TOXIC SUBSTANCES CONTROL ACT... Modification of Test Rules § 790.52 Phase II test rule. (a) If EPA determines that the proposed study...

  3. 40 CFR 72.44 - Phase II repowering extensions.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... (CONTINUED) PERMITS REGULATION Acid Rain Compliance Plan and Compliance Options § 72.44 Phase II repowering... the requirements of paragraph (a)(1)(i) of this section may include in the unit's Phase II Acid Rain... authority shall issue the Acid Rain portion of the operating permit including: (A) The approved...

  4. 40 CFR 72.44 - Phase II repowering extensions.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... (CONTINUED) PERMITS REGULATION Acid Rain Compliance Plan and Compliance Options § 72.44 Phase II repowering... the requirements of paragraph (a)(1)(i) of this section may include in the unit's Phase II Acid Rain... authority shall issue the Acid Rain portion of the operating permit including: (A) The approved...

  5. 40 CFR 72.44 - Phase II repowering extensions.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... (CONTINUED) PERMITS REGULATION Acid Rain Compliance Plan and Compliance Options § 72.44 Phase II repowering... the requirements of paragraph (a)(1)(i) of this section may include in the unit's Phase II Acid Rain... authority shall issue the Acid Rain portion of the operating permit including: (A) The approved...

  6. 40 CFR 72.44 - Phase II repowering extensions.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... (CONTINUED) PERMITS REGULATION Acid Rain Compliance Plan and Compliance Options § 72.44 Phase II repowering... the requirements of paragraph (a)(1)(i) of this section may include in the unit's Phase II Acid Rain... authority shall issue the Acid Rain portion of the operating permit including: (A) The approved...

  7. Utility-based optimization of phase II/III programs.

    PubMed

    Kirchner, Marietta; Kieser, Meinhard; Götte, Heiko; Schüler, Armin

    2016-01-30

    Phase II and phase III trials play a crucial role in drug development programs. They are costly and time consuming and, because of high failure rates in late development stages, at the same time risky investments. Commonly, sample size calculation of phase III is based on the treatment effect observed in phase II. Therefore, planning of phases II and III can be linked. The performance of the phase II/III program crucially depends on the allocation of the resources to phases II and III by appropriate choice of the sample size and the rule applied to decide whether to stop the program after phase II or to proceed. We present methods for a program-wise phase II/III planning that aim at determining optimal phase II sample sizes and go/no-go decisions in a time-to-event setting. Optimization is based on a utility function that takes into account (fixed and variable) costs of the drug development program and potential gains after successful launch. The proposed methods are illustrated by application to a variety of scenarios typically met in oncology drug development.

  8. Phase II trials in heart failure: The role of cardiovascular imaging

    PubMed Central

    Shah, Sanjiv J.; Fonarow, Gregg C.; Gheorghiade, Mihai; Lang, Roberto M.

    2013-01-01

    The development of new therapies for heart failure (HF), especially acute HF, has proven to be quite challenging; and therapies evaluated in HF have greatly outnumbered treatments that are eventually successful in obtaining regulatory approval. Thus, the development of therapies for HF remains a vexing problem for pharmaceutical and device companies, clinical trialists, and health care professionals. Nowhere is this more apparent than in the phase II HF clinical trial, in which the goal is to determine whether an investigational agent should move forward to a phase III trial. Recent advancements in noninvasive cardiovascular imaging have allowed a new era of comprehensive phenotyping of cardiac structure and function in phase II HF trials. Besides using imaging parameters to predict success of subsequent phase III outcome studies, it is essential to also use imaging in phase II HF trials in a way that increases understanding of drug or device mechanism. Determination of the patients who would benefit most from a particular drug or device could decrease heterogeneity of phase III trial participants and lead to more successful HF clinical trials. In this review, we outline advantages and disadvantages of imaging various aspects of cardiac structure and function that are potential targets for therapy in HF, compare and contrast imaging modalities, provide practical advice for the use of cardiovascular imaging in drug development, and conclude with some novel uses of cardiac imaging in phase II HF trials. PMID:21742085

  9. BADD phase II: DDS information management architecture

    NASA Astrophysics Data System (ADS)

    Stephenson, Thomas P.; DeCleene, Brian T.; Speckert, Glen; Voorhees, Harry L.

    1997-06-01

    The DARPA Battlefield Awareness and Data Dissemination (BADD) Phase II Program will provide the next generation multimedia information management architecture to support the warfighter. One goal of this architecture is proactive dissemination of information to the warfighter through strategies such as multicast and 'smart push and pull' designed to minimize latency and make maximum use of available communications bandwidth. Another goal is to support integration of information from widely distributed legacy repositories. This will enable the next generation of battlefield awareness applications to form a common operational view of the battlefield to aid joint service and/or multi-national peacekeeping forces. This paper discusses the approach we are taking to realize such an architecture for BADD. Our architecture and its implementation, known as the Distributed Dissemination Serivces (DDS) are based on two key concepts: a global database schema and an intelligent, proactive caching scheme. A global schema provides a common logical view of the information space in which the warfighter operates. This schema (or subsets of it) is shared by all warfighters through a distributed object database providing local access to all relevant metadata. This approach provides both scalability to a large number of warfighters, and it supports tethered as well as autonomous operations. By utilizing DDS information integration services that provide transparent access to legacy databases, related information from multiple 'stovepipe' systems are now available to battlefield awareness applications. The second key concept embedded in our architecture is an intelligent, hierarchical caching system supported by proactive dissemination management services which push both lightweight and heavyweight data such as imagery and video to warfighters based on their information profiles. The goal of this approach is to transparently and proactively stage data which is likely to be requested by

  10. RANDOMIZED CONTROLLED CLINICAL TRIALS IN ORTHOPEDICS: DIFFICULTIES AND LIMITATIONS

    PubMed Central

    Malavolta, Eduardo Angeli; Demange, Marco Kawamura; Gobbi, Riccardo Gomes; Imamura, Marta; Fregni, Felipe

    2015-01-01

    Randomized controlled clinical trials (RCTs) are considered to be the gold standard for evidence-based medicine nowadays, and are important for directing medical practice through consistent scientific observations. Steps such as patient selection, randomization and blinding are fundamental for conducting a RCT, but some additional difficulties are presented in trials that involve surgical procedures, as is common in orthopedics. The aim of this article was to highlight and discuss some difficulties and possible limitations on RCTs within the field of surgery. PMID:27027037

  11. Comparative Evaluation of Commercially Available Freeze Dried Powdered Probiotics on Mutans Streptococci Count: A Randomized, Double Blind, Clinical Study

    PubMed Central

    Nagaraj, Anup; Ganta, Shravani; Sidiq, Mohsin; Pareek, Sonia; Vishnani, Preeti; Acharya, Siddharth; Singh, Kushpal

    2015-01-01

    Objectives: Probiotic approaches are being considered to eliminate pathogenic microorganisms and are an alternative and promising way to combat infections by using harmless bacteria to displace pathogenic microorganisms. The aim of this study was to evaluate the effectiveness of commercially available freeze dried powdered probiotics on mutans streptococci count among 12–15 year-old Indian schoolchildren. Materials and Methods: The study was conducted in two phases of in-vitro (phase I) and in-vivo (phase II) study, which was a double blind, randomized and placebo controlled clinical trial. A total of 33 schoolchildren between 12–15 years were included in the study. They were randomly allocated to three groups. Group A included 11 children using freeze dried Lactobacillus acidophilus, Bifidobacterium longum, Bifidobacterium bifidum and Bifidobacterium lactis. Group B included 11 children using freeze dried lactic acid bacillus only. Group C included 11 children using placebo powder. The study was conducted over a period of three weeks and examination and sampling of the subjects were done on days 0 (baseline), seven, 14 and 21. Results: For both the intervention groups A and B, statistically significant reduction (P<0.05) in salivary mutans streptococci counts was recorded up to the second week. Conclusion: Oral administration of probiotics showed a short-term effect on reduction of mutans streptococci count and showed a preventive role in caries development. PMID:27252756

  12. Randomization in clinical trials in orthodontics: its significance in research design and methods to achieve it.

    PubMed

    Pandis, Nikolaos; Polychronopoulou, Argy; Eliades, Theodore

    2011-12-01

    Randomization is a key step in reducing selection bias during the treatment allocation phase in randomized clinical trials. The process of randomization follows specific steps, which include generation of the randomization list, allocation concealment, and implementation of randomization. The phenomenon in the dental and orthodontic literature of characterizing treatment allocation as random is frequent; however, often the randomization procedures followed are not appropriate. Randomization methods assign, at random, treatment to the trial arms without foreknowledge of allocation by either the participants or the investigators thus reducing selection bias. Randomization entails generation of random allocation, allocation concealment, and the actual methodology of implementing treatment allocation randomly and unpredictably. Most popular randomization methods include some form of restricted and/or stratified randomization. This article introduces the reasons, which make randomization an integral part of solid clinical trial methodology, and presents the main randomization schemes applicable to clinical trials in orthodontics.

  13. High frequency chest wall oscillation for asthma and chronic obstructive pulmonary disease exacerbations: a randomized sham-controlled clinical trial

    PubMed Central

    2011-01-01

    Background High frequency chest wall oscillation (HFCWO) is used for airway mucus clearance. The objective of this study was to evaluate the use of HFCWO early in the treatment of adults hospitalized for acute asthma or chronic obstructive pulmonary disease (COPD). Methods Randomized, multi-center, double-masked phase II clinical trial of active or sham treatment initiated within 24 hours of hospital admission for acute asthma or COPD at four academic medical centers. Patients received active or sham treatment for 15 minutes three times a day for four treatments. Medical management was standardized across groups. The primary outcomes were patient adherence to therapy after four treatments (minutes used/60 minutes prescribed) and satisfaction. Secondary outcomes included change in Borg dyspnea score (≥ 1 unit indicates a clinically significant change), spontaneously expectorated sputum volume, and forced expired volume in 1 second. Results Fifty-two participants were randomized to active (n = 25) or sham (n = 27) treatment. Patient adherence was similarly high in both groups (91% vs. 93%; p = 0.70). Patient satisfaction was also similarly high in both groups. After four treatments, a higher proportion of patients in the active treatment group had a clinically significant improvement in dyspnea (70.8% vs. 42.3%, p = 0.04). There were no significant differences in other secondary outcomes. Conclusions HFCWO is well tolerated in adults hospitalized for acute asthma or COPD and significantly improves dyspnea. The high levels of patient satisfaction in both treatment groups justify the need for sham controls when evaluating the use of HFCWO on patient-reported outcomes. Additional studies are needed to more fully evaluate the role of HFCWO in improving in-hospital and post-discharge outcomes in this population. Trial Registration ClinicalTrials.gov: NCT00181285 PMID:21906390

  14. Maximizing return on socioeconomic investment in phase II proof-of-concept trials.

    PubMed

    Chen, Cong; Beckman, Robert A

    2014-04-01

    Phase II proof-of-concept (POC) trials play a key role in oncology drug development, determining which therapeutic hypotheses will undergo definitive phase III testing according to predefined Go-No Go (GNG) criteria. The number of possible POC hypotheses likely far exceeds available public or private resources. We propose a design strategy for maximizing return on socioeconomic investment in phase II trials that obtains the greatest knowledge with the minimum patient exposure. We compare efficiency using the benefit-cost ratio, defined to be the risk-adjusted number of truly active drugs correctly identified for phase III development divided by the risk-adjusted total sample size in phase II and III development, for different POC trial sizes, powering schemes, and associated GNG criteria. It is most cost-effective to conduct small POC trials and set the corresponding GNG bars high, so that more POC trials can be conducted under socioeconomic constraints. If δ is the minimum treatment effect size of clinical interest in phase II, the study design with the highest benefit-cost ratio has approximately 5% type I error rate and approximately 20% type II error rate (80% power) for detecting an effect size of approximately 1.5δ. A Go decision to phase III is made when the observed effect size is close to δ. With the phenomenal expansion of our knowledge in molecular biology leading to an unprecedented number of new oncology drug targets, conducting more small POC trials and setting high GNG bars maximize the return on socioeconomic investment in phase II POC trials. PMID:24526732

  15. Combined Analysis of Phase I and Phase II Data to Enhance the Power of Pharmacogenetic Tests.

    PubMed

    Tessier, A; Bertrand, J; Chenel, M; Comets, E

    2016-03-01

    We show through a simulation study how the joint analysis of data from phase I and phase II studies enhances the power of pharmacogenetic tests in pharmacokinetic (PK) studies. PK profiles were simulated under different designs along with 176 genetic markers. The null scenarios assumed no genetic effect, while under the alternative scenarios, drug clearance was associated with six genetic markers randomly sampled in each simulated dataset. We compared penalized regression Lasso and stepwise procedures to detect the associations between empirical Bayes estimates of clearance, estimated by nonlinear mixed effects models, and genetic variants. Combining data from phase I and phase II studies, even if sparse, increases the power to identify the associations between genetics and PK due to the larger sample size. Design optimization brings a further improvement, and we highlight a direct relationship between η-shrinkage and loss of genetic signal. PMID:27069775

  16. Samples of exact k-stage group sequential designs for Phase II and Pilot studies.

    PubMed

    Kepner, James L; Chang, Myron N

    2004-06-01

    That the test of H(0): p=p(0) versus H(1): p>p(0) can be based on a binomially distributed random variable is widely known among users of statistical methods. What is not generally known is that under certain very general conditions, it is possible to find an exact k-stage group sequential test whose total sample size is bounded above by the sample size for the single stage binomial test. That is, it is possible to find k-stage tests for detecting H(1) for which the sum of the sample sizes at each of the stages is bounded above by the sample size for the standard binomial test. This result is somewhat remarkable since the total sample size under the group sequential test setting can be strictly less than the sample size for the uniformly most powerful (UMP) one-stage binomial test. In other words, exact group sequential tests cannot only save the average sample size but can also save the maximum sample size when they are compared to the standard binomial test. In this paper, implications of existing theory are explored and a web application written by the authors is presented. No new theory is established. Applications are described and methods are demonstrated that use the web application to rapidly create efficient designs for Phase II and Pilot studies that put a minimum number of patients at risk and that facilitate the rapid progression through a scientific research agenda. While couched here in the context of clinical trials, the results may be used in any field of inquiry where inferences are made based on the size of a binomial random variable.

  17. Clinical and genomic analysis of a randomised phase II study evaluating anastrozole and fulvestrant in postmenopausal patients treated for large operable or locally advanced hormone-receptor-positive breast cancer

    PubMed Central

    Quenel-Tueux, Nathalie; Debled, Marc; Rudewicz, Justine; MacGrogan, Gaetan; Pulido, Marina; Mauriac, Louis; Dalenc, Florence; Bachelot, Thomas; Lortal, Barbara; Breton-Callu, Christelle; Madranges, Nicolas; de Lara, Christine Tunon; Fournier, Marion; Bonnefoi, Hervé; Soueidan, Hayssam; Nikolski, Macha; Gros, Audrey; Daly, Catherine; Wood, Henry; Rabbitts, Pamela; Iggo, Richard

    2015-01-01

    Background: The aim of this study was to assess the efficacy of neoadjuvant anastrozole and fulvestrant treatment of large operable or locally advanced hormone-receptor-positive breast cancer not eligible for initial breast-conserving surgery, and to identify genomic changes occurring after treatment. Methods: One hundred and twenty post-menopausal patients were randomised to receive 1 mg anastrozole (61 patients) or 500 mg fulvestrant (59 patients) for 6 months. Genomic DNA copy number profiles were generated for a subgroup of 20 patients before and after treatment. Results: A total of 108 patients were evaluable for efficacy and 118 for toxicity. The objective response rate determined by clinical palpation was 58.9% (95% CI=45.0–71.9) in the anastrozole arm and 53.8% (95% CI=39.5–67.8) in the fulvestrant arm. The breast-conserving surgery rate was 58.9% (95% CI=45.0–71.9) in the anastrozole arm and 50.0% (95% CI=35.8–64.2) in the fulvestrant arm. Pathological responses >50% occurred in 24 patients (42.9%) in the anastrozole arm and 13 (25.0%) in the fulvestrant arm. The Ki-67 score fell after treatment but there was no significant difference between the reduction in the two arms (anastrozole 16.7% (95% CI=13.3–21.0) before, 3.2% (95% CI=1.9–5.5) after, n=43; fulvestrant 17.1% (95%CI=13.1–22.5) before, 3.2% (95% CI=1.8–5.7) after, n=38) or between the reduction in Ki-67 in clinical responders and non-responders. Genomic analysis appeared to show a reduction of clonal diversity following treatment with selection of some clones with simpler copy number profiles. Conclusions: Both anastrozole and fulvestrant were effective and well-tolerated, enabling breast-conserving surgery in over 50% of patients. Clonal changes consistent with clonal selection by the treatment were seen in a subgroup of patients. PMID:26171933

  18. Phase II Clinical Trial of Intratumoral Application of TG1042 (Adenovirus-interferon-γ) in Patients With Advanced Cutaneous T-cell Lymphomas and Multilesional Cutaneous B-cell Lymphomas

    PubMed Central

    Dummer, Reinhard; Eichmüller, Stefan; Gellrich, Sylke; Assaf, Chalid; Dreno, Brigitte; Schiller, Meinhard; Dereure, Olivier; Baudard, Marion; Bagot, Martine; Khammari, Amir; Bleuzen, Pascal; Bataille, Vincent; Derbij, Anna; Wiedemann, Nicole; Waterboer, Tim; Lusky, Monika; Acres, Bruce; Urosevic-Maiwald, Mirjana

    2010-01-01

    Cutaneous lymphomas (CLs) are a heterogeneous group of lymphoproliferative disorders that are manageable by immunotherapy. Twenty-one patients were enrolled in a prospective open-label, dose-escalation multicenter study evaluating the effects of repeated TG1042 [adenovirus-interferon (IFN)-γ] intralesional injections in patients with primary CLs, of which 18 were of T-cell and 3 of B-cell type. Repeated intralesional therapy using TG1042 consistently results in local tumor regressions in about half of treated patients and one-third of patients also in regressions in noninjected distant lesions, likely reflecting the systemic immune activation after intralesional therapy. Treatment was well tolerated with few adverse events including injection site reactions, chills, lymphopenia, and fever. Immune monitoring in the peripheral blood demonstrated systemic immune activation and the induction of antibodies against tumor antigens in some patients without clear association with clinical responses. CLs, in particular B-cell lymphomas with high objective response rates, seem to be excellent targets for this type of immunotherapy. PMID:20372104

  19. Phase II study of PX-866 in recurrent glioblastoma

    PubMed Central

    Pitz, Marshall W.; Eisenhauer, Elizabeth A.; MacNeil, Mary V.; Thiessen, Brian; Easaw, Jacob C.; Macdonald, David R.; Eisenstat, David D.; Kakumanu, Ankineedu S.; Salim, Muhammad; Chalchal, Haji; Squire, Jeremy; Tsao, Ming Sound; Kamel-Reid, Suzanne; Banerji, Shantanu; Tu, Dongsheng; Powers, Jean; Hausman, Diana F.; Mason, Warren P.

    2015-01-01

    Background Glioblastoma (GBM) is the most aggressive malignancy of the central nervous system in adults. Increased activity of the phosphatidylinositol-3-OH kinase (PI3K) signal transduction pathway is common. We performed a phase II study using PX-866, an oral PI3K inhibitor, in participants with recurrent GBM. Methods Patients with histologically confirmed GBM at first recurrence were given oral PX-866 at a dose of 8 mg daily. An MRI and clinical exam were done every 8 weeks. Tissue was analyzed for potential predictive markers. Results Thirty-three participants (12 female) were enrolled. Median age was 56 years (range 35–78y). Eastern Cooperative Oncology Group performance status was 0–1 in 29 participants and 2 in the remainder. Median number of cycles was 1 (range 1–8). All participants have discontinued therapy: 27 for disease progression and 6 for toxicity (5 liver enzymes and 1 allergic reaction). Four participants had treatment-related serious adverse events (1 liver enzyme, 1 diarrhea, 2 venous thromboembolism). Other adverse effects included fatigue, diarrhea, nausea, vomiting, and lymphopenia. Twenty-four participants had a response of progression (73%), 1 had partial response (3%, and 8 (24%) had stable disease (median, 6.3 months; range, 3.1–16.8 months). Median 6-month progression-free survival was 17%. None of the associations between stable disease and PTEN, PIK3CA, PIK3R1, or EGFRvIII status were statistically significant. Conclusions PX-866 was relatively well tolerated. Overall response rate was low, and the study did not meet its primary endpoint; however, 21% of participants obtained durable stable disease. This study also failed to identify a statistically significant association between clinical outcome and relevant biomarkers in patients with available tissue. PMID:25605819

  20. Phase II study of the GPC3-derived peptide vaccine as an adjuvant therapy for hepatocellular carcinoma patients

    PubMed Central

    Sawada, Yu; Yoshikawa, Toshiaki; Ofuji, Kazuya; Yoshimura, Mayuko; Tsuchiya, Nobuhiro; Takahashi, Mari; Nobuoka, Daisuke; Gotohda, Naoto; Takahashi, Shinichiro; Kato, Yuichiro; Konishi, Masaru; Kinoshita, Taira; Ikeda, Masafumi; Nakachi, Kohei; Yamazaki, Naoya; Mizuno, Shoichi; Takayama, Tadatoshi; Yamao, Kenji; Uesaka, Katsuhiko; Furuse, Junji; Endo, Itaru; Nakatsura, Tetsuya

    2016-01-01

    ABSTRACT The recurrence rates of Hepatocellular carcinoma (HCC) are high, necessitating novel and effective adjuvant therapies. Therefore, we conducted a phase II study of glypican-3 (GPC3) peptide vaccine as an adjuvant therapy for HCC patients. Forty-one patients with initial HCC who had undergone surgery or radiofrequency ablation (RFA) were analyzed in this phase II, open-label, single-arm trial. Ten vaccinations were performed for 1 y after curative treatment. We also investigated case-control subjects, where selected patients treated surgically during the same period were analyzed. The expression of GPC3 in the available primary tumors was determined by immunohistochemical analysis. Six patients received RFA therapy while 35 received surgery. The recurrence rate tended to be lower in the 35 patients treated with surgery plus vaccination compared to 33 patients who underwent surgery alone (28.6% vs. 54.3% and 39.4% vs. 54.5% at 1 and 2 y, respectively; p = 0.346, 0.983). Twenty-five patients treated with surgery and vaccination had GPC3-positive tumors; the recurrence rate in this group was significantly lower compared to that in 21 GPC3-positive patients who received surgery only (24% vs. 48% and 52.4% vs. 61.9% at 1 and 2 y, respectively; p = 0.047, 0.387). The GPC3 peptide vaccine improved the 1-y recurrence rate in patients with GPC3-positive tumors. This study demonstrated that GPC3 expression by the primary tumor may be used as a biomarker in a putative larger randomized clinical trial to determine the efficacy of the GPC3-derived peptide vaccine. PMID:27467945

  1. Nine-year change in statistical design, profile, and success rates of Phase II oncology trials.

    PubMed

    Ivanova, Anastasia; Paul, Barry; Marchenko, Olga; Song, Guochen; Patel, Neerali; Moschos, Stergios J

    2016-01-01

    We investigated nine-year trends in statistical design and other features of Phase II oncology clinical trials published in 2005, 2010, and 2014 in five leading oncology journals: Cancer, Clinical Cancer Research, Journal of Clinical Oncology, Annals of Oncology, and Lancet Oncology. The features analyzed included cancer type, multicenter vs. single-institution, statistical design, primary endpoint, number of treatment arms, number of patients per treatment arm, whether or not statistical methods were well described, whether the drug was found effective based on rigorous statistical testing of the null hypothesis, and whether the drug was recommended for future studies.

  2. Statistical comparison of random allocation methods in cancer clinical trials.

    PubMed

    Hagino, Atsushi; Hamada, Chikuma; Yoshimura, Isao; Ohashi, Yasuo; Sakamoto, Junichi; Nakazato, Hiroaki

    2004-12-01

    The selection of a trial design is an important issue in the planning of clinical trials. One of the most important considerations in trial design is the method of treatment allocation and appropriate analysis plan corresponding to the design. In this article, we conducted computer simulations using the actual data from 2158 rectal cancer patients enrolled in the surgery-alone group from seven randomized controlled trials in Japan to compare the performance of allocation methods, simple randomization, stratified randomization and minimization in relatively small-scale trials (total number of two groups are 50, 100, 150 or 200 patients). The degree of imbalance in prognostic factors between groups was evaluated by changing the allocation probability of minimization from 1.00 to 0.70 by 0.05. The simulation demonstrated that minimization provides the best performance to ensure balance in the number of patients between groups and prognostic factors. Moreover, to achieve the 1 percentile for the p-value of chi-square test around 0.50 with respect to balance in prognostic factors, the allocation probability of minimization was required to be set to 0.95 for 50, 0.80 for 100, 0.75 for 150 and 0.70 for 200 patients. When the sample size was larger, sufficient balance could be achieved even if reducing allocation probability. The simulation using actual data demonstrated that unadjusted tests for the allocation factors resulted in conservative type I errors when dynamic allocation, such as minimization, was used. In contrast, adjusted tests for allocation factors as covariates improved type I errors closer to the nominal significance level and they provided slightly higher power. In conclusion, both the statistical and clinical validity of minimization was demonstrated in our study.

  3. Alberta Education Energy Conservation Project. Phase II: Internal Evaluation.

    ERIC Educational Resources Information Center

    Sundmark, Dana

    This report is based on the Alberta Education Energy Conservation Project - Phase II. The project was a follow-up to an earlier study, extending from June 1980 to June 1983, in which government funding and engineering manpower were used to conduct an energy management program in 52 selected pilot schools in 5 areas of the province. The report…

  4. Interservice Procedures for Instructional Systems Development. Phase II: Design.

    ERIC Educational Resources Information Center

    Branson, Robert K.; And Others

    The document is the second of a five-part series focusing in minute detail on the processes involved in the formulation of an instructional systems development (ISD) program for military interservice training that will adequately train individuals to do a particular job. Phase II, Design, is concerned with designing instructional materials based…

  5. Dialysis fistula or graft: the role for randomized clinical trials.

    PubMed

    Allon, Michael; Lok, Charmaine E

    2010-12-01

    The Fistula First Initiative has strongly encouraged nephrologists, vascular access surgeons, and dialysis units in the United States to make valiant efforts to increase fistula use in the hemodialysis population. Unfortunately, the rigid "fistula first" recommendations are not based on solid, current, evidence-based data and may be harmful to some hemodialysis patients by subjecting them to prolonged catheter dependence with its attendant risks of bacteremia and central vein stenosis. Once they are successfully cannulated for dialysis, fistulas last longer than grafts and require fewer interventions to maintain long-term patency for dialysis. However, fistulas have a much higher primary failure rate than grafts, require more interventions to achieve maturation, and entail longer catheter dependence, thereby leading to more catheter-related complications. Given the tradeoffs between fistulas and grafts, there is equipoise about their relative merits in patients with moderate to high risk of fistula nonmaturation. The time is right for definitive, large, multicenter randomized clinical trials to compare fistulas and grafts in various subsets of chronic kidney disease patients. Until the results of such clinical trials are known, the optimal vascular access for a given patients should be determined by the nephrologist and access surgeon by taking into account (1) whether dialysis has been initiated, (2) the patient's life expectancy, (3) whether the patient has had a previous failed vascular access, and (4) the likelihood of fistula nonmaturation. Careful clinical judgment should optimize vascular access outcomes and minimize prolonged catheter dependence among hemodialysis patients. PMID:21030576

  6. The conflict between randomized clinical trials and the therapeutic obligation.

    PubMed

    Gifford, F

    1986-11-01

    The central dilemma concerning randomized clinical trials (RCTs) arises out of some simple facts about causal methodology (RCTs are the best way to generate the reliable causal knowledge necessary for optimally-informed action) and a prima facie plausible principle concerning how physicians should treat their patients (always do what it is most reasonable to believe will be best for the patient). A number of arguments related to this in the literature are considered. Attempts to avoid the dilemma fail. Appeals to informed consent and mechanisms for minimizing the resulting harm are important for policy, but informed consent is problematic and mechanisms for minimization of harm do not address the dilemma. Appeals to some sort of contract model of justification are promising and illuminating.

  7. Prospective randomized clinical trial: single and weekly viscosupplementation

    PubMed Central

    Zóboli, Alejandro Agustin Carri; de Rezende, Márcia Uchôa; de Campos, Gustavo Constantino; Pasqualin, Thiago; Frucchi, Renato; de Camargo, Olavo Pires

    2013-01-01

    OBJECTIVE: To compare two different dosages of an intermediate molecular weight sodium hyaluronate (HA) (Osteonil®-TRB Pharma) assessing whether a single 6 ml application of this HA has the same effectiveness as the classical three-weekly 2 ml dose. METHODS: 108 patients with knee osteoarthritis were randomized into two groups of 54 patients each. The groups were designated "single" (S) and "weekly" (W). Patients in group S underwent a viscosupplementation procedure by application of only 6 ml of sodium hyaluronate and 1 ml triamcinolone hexacetonide. Patients in group W underwent the procedure of viscosupplementation through three applications with 2 ml sodium hyaluronate with a week interval between them, and the first application was also performed with the infiltration of 1 ml (20 mg) of Triamcinolone Hexacetonide. Both groups were assessed before, at one month and three months after application, by responding to the WOMAC, Lequesne, IKDC and VAS questionnaires. RESULTS: There was no statistical difference between the single application of 6 ml of sodium hyaluronate and classic application with three weekly injections. However, only the classical regime showed statistically significant improvement in baseline pain (WOMAC pain and VAS). CONCLUSION: Our results suggest that both application schemes improve application function, but the three-weekly regimen of 2 ml was more effective in reducing pain. Level of Evidence I, Prospective Randomized, Clinical Trial. PMID:24453681

  8. Fundamentals of randomized clinical trials in wound care: reporting standards.

    PubMed

    Brölmann, Fleur E; Eskes, Anne M; Sumpio, Bauer E; Mayer, Dieter O; Moore, Zena; Agren, Magnus S; Hermans, Michel; Cutting, Keith; Legemate, Dink A; Vermeulen, Hester; Ubbink, Dirk T

    2013-01-01

    In wound care research, available high-level evidence according to the evidence pyramid is rare, and is threatened by a poor study design and reporting. Without comprehensive and transparent reporting, readers will not be able to assess the strengths and limitations of the research performed. Randomized clinical trials (RCTs) are universally acknowledged as the study design of choice for comparing treatment effects. To give high-level evidence the appreciation it deserves in wound care, we propose a step-by-step reporting standard for comprehensive and transparent reporting of RCTs in wound care. Critical reporting issues (e.g., wound care terminology, blinding, predefined outcome measures, and a priori sample size calculation) and wound-specific barriers (e.g., large diversity of etiologies and comorbidities of patients with wounds) that may prevent uniform implementation of reporting standards in wound care research are addressed in this article. The proposed reporting standards can be used as guidance for authors who write their RCT, as well as for peer reviewers of journals. Endorsement and application of these reporting standards may help achieve a higher standard of evidence and allow meta-analysis of reported wound care data. The ultimate goal is to help wound care professionals make better decisions for their patients in clinical practice.

  9. An open multicenter comparative randomized clinical study on chitosan.

    PubMed

    Mo, Xiaohui; Cen, John; Gibson, Elaine; Wang, Robin; Percival, Steven L

    2015-01-01

    Chitosan, a natural polysaccharide derivate from chitin, offers a promising alternative biomaterial for use in wound dressings. In this work, the safety and efficacy of a next-generation KA01 chitosan wound dressing in facilitating the healing of nonhealing chronic wounds was studied. This open multicenter comparative prospective randomized clinical study was conducted at three medical centers in China. A total of 90 patients (45 in test group and 45 in control group) with unhealed chronic wounds including pressure ulcers, vascular ulcers, diabetic foot ulcers, and wounds with minor infections, or at risk of infection, were treated with the next generation chitosan wound dressing as the test article or traditional vaseline gauze as a control. Baseline assessments were undertaken with the primary end point being wound area reduction. The secondary end points included pain reduction (using the NRS11 pain scale) at dressing change, wound exudate levels, wound depth and duration of the treatment. After 4 weeks treatment, the wound area reduction was significantly greater in the test group (65.97 ± 4.48%) than the control group (39.95 ± 4.48%). The average pain level in the test group was 1.12 ± 0.23 and 2.30 ± 0.23 in the control group. The wound depth was also lower in the test group 0.30 ± 0.48 cm than the control group 0.54 ± 0.86 cm. The level of exudate fell and the dressing could be removed integrally in both the test and control groups. The mean duration of the test group was 27.31 ± 5.37 days and control group 27.09 ± 6.44 days. No adverse events were reported in either group. In conclusion this open multicenter comparative prospective randomized clinical study has provided compelling evidence that the next generation chitosan wound dressing can enhance wound progression towards healing by facilitating wound reepithelialization and reducing the patients pain level. Furthermore the dressing was shown to be clinically safe and effective in the management

  10. An open multicenter comparative randomized clinical study on chitosan.

    PubMed

    Mo, Xiaohui; Cen, John; Gibson, Elaine; Wang, Robin; Percival, Steven L

    2015-01-01

    Chitosan, a natural polysaccharide derivate from chitin, offers a promising alternative biomaterial for use in wound dressings. In this work, the safety and efficacy of a next-generation KA01 chitosan wound dressing in facilitating the healing of nonhealing chronic wounds was studied. This open multicenter comparative prospective randomized clinical study was conducted at three medical centers in China. A total of 90 patients (45 in test group and 45 in control group) with unhealed chronic wounds including pressure ulcers, vascular ulcers, diabetic foot ulcers, and wounds with minor infections, or at risk of infection, were treated with the next generation chitosan wound dressing as the test article or traditional vaseline gauze as a control. Baseline assessments were undertaken with the primary end point being wound area reduction. The secondary end points included pain reduction (using the NRS11 pain scale) at dressing change, wound exudate levels, wound depth and duration of the treatment. After 4 weeks treatment, the wound area reduction was significantly greater in the test group (65.97 ± 4.48%) than the control group (39.95 ± 4.48%). The average pain level in the test group was 1.12 ± 0.23 and 2.30 ± 0.23 in the control group. The wound depth was also lower in the test group 0.30 ± 0.48 cm than the control group 0.54 ± 0.86 cm. The level of exudate fell and the dressing could be removed integrally in both the test and control groups. The mean duration of the test group was 27.31 ± 5.37 days and control group 27.09 ± 6.44 days. No adverse events were reported in either group. In conclusion this open multicenter comparative prospective randomized clinical study has provided compelling evidence that the next generation chitosan wound dressing can enhance wound progression towards healing by facilitating wound reepithelialization and reducing the patients pain level. Furthermore the dressing was shown to be clinically safe and effective in the management

  11. Sargramostim plus Ipilimumab vs Ipilimumab Alone for Treatment of Metastatic Melanoma: A Randomized Clinical Trial

    PubMed Central

    Hodi, F. Stephen; Lee, Sandra; McDermott, David F.; Rao, Uma N.; Butterfield, Lisa H.; Tarhini, Ahmad A.; Leming, Philip; Puzanov, Igor; Shin, Donghoon; Kirkwood, John M.

    2015-01-01

    Importance Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) blockade with ipilimumab prolongs survival in metastatic melanoma patients. CTLA-4 blockade and granulocyte-macrophage colony stimulating factor (GM-CSF) secreting tumor vaccine combinations demonstrate therapeutic synergy in pre-clinical models. A key issue is whether systemic GM-CSF synergizes with CTLA-4 blockade. Objective To compare the effect of sargramostim plus ipilimumab vs ipilimumab alone on overall survival in patients with metastatic melanoma. Design, Setting, and Participants A phase II randomized clinical trial was conducted in the United States by Eastern Cooperative Oncology Group between December 28, 2010 and July 28, 2011. Patients with unresectable stage III or IV melanoma, ≥one prior therapy, no CNS metastases, and ECOG performance status 0/1 were eligible. Interventions Patients were randomized to ipilimumab 10 mg/kilogram intravenously day 1 plus sargramostim 250 μg subcutaneously days 1-14 of 21 day cycles versus ipilimumab alone. Ipilimumab treatment included induction for four cycles followed by maintenance every fourth cycle. Main Outcomes and Measures Primary was comparison of the length of overall survival. Secondary was progression-free survival, response rate, safety, and tolerability. Results A total of 245 patients were treated. Median follow-up was 13.3 months (range; .03-19.9). Median overall survival for sargramostim plus ipilimumab was 17.5 months (95% CI; 14.9, not reached) compared to 12.7 months (95% CI; 10.0, not reached) for ipilimumab. One-year survival rate for sargramostim was 68.9% (95% CI; 60.6%, 85.5%) compared to 52.9% (95% CI; 43.6%, 62.2%) with ipilimumab (stratified logrank one-sided P=.01; mortality hazard ratio .64, one-sided 90% repeated CI (not applicable, .90)). A planned interim analysis was conducted at 69.8% (104 observed/ 149 planned deaths) information time. O'Brien-Fleming boundary was crossed for improvement in overall survival. There

  12. Urban Integrated Industrial Cogeneration Systems Analysis. Phase II final report

    SciTech Connect

    Not Available

    1984-01-01

    Through the Urban Integrated Industrial Cogeneration Systems Analysis (UIICSA), the City of Chicago embarked upon an ambitious effort to identify the measure the overall industrial cogeneration market in the city and to evaluate in detail the most promising market opportunities. This report discusses the background of the work completed during Phase II of the UIICSA and presents the results of economic feasibility studies conducted for three potential cogeneration sites in Chicago. Phase II focused on the feasibility of cogeneration at the three most promising sites: the Stockyards and Calumet industrial areas, and the Ford City commercial/industrial complex. Each feasibility case study considered the energy load requirements of the existing facilities at the site and the potential for attracting and serving new growth in the area. Alternative fuels and technologies, and ownership and financing options were also incorporated into the case studies. Finally, site specific considerations such as development incentives, zoning and building code restrictions and environmental requirements were investigated.

  13. Small Business Innovation Research, Post-Phase II Opportunity Assessment

    NASA Technical Reports Server (NTRS)

    Nguyen, Hung D.; Steele, Gynelle C.

    2015-01-01

    This report outlines current Small Business Innovation Research (SBIR) Post-Phase II opportunity contract award results for the SBIR technology program from 2007 to 2011 for NASA's Aeronautics Research Mission Directorate (ARMD), Human Exploration and Operations Mission Directorate (HEOMD), Science Mission Directorate (SMD), and Space Technology Mission Directorate (STMD). The report provides guidelines for incorporating SBIR technology into NASA programs and projects and provides a quantitative overview of the post-Phase II award patterns that correspond with each mission directorate at NASA Glenn Research Center (GRC). In recent years, one of NASA's goals has been to not only transfer SBIR technologies to commercial industries, but to ensure that NASA mission directorates incorporate SBIR technologies into their program and project activities. Before incorporating technologies into MD programs, it is important to understand each mission directorate structure because each directorate has different objectives and needs. The directorate program structures follow.

  14. Computerized Tool to Manage Dental Anxiety: A Randomized Clinical Trial.

    PubMed

    Tellez, M; Potter, C M; Kinner, D G; Jensen, D; Waldron, E; Heimberg, R G; Myers Virtue, S; Zhao, H; Ismail, A I

    2015-09-01

    Anxiety regarding dental and physical health is a common and potentially distressing problem, for both patients and health care providers. Anxiety has been identified as a barrier to regular dental visits and as an important target for enhancement of oral health-related quality of life. The study aimed to develop and evaluate a computerized cognitive-behavioral therapy dental anxiety intervention that could be easily implemented in dental health care settings. A cognitive-behavioral protocol based on psychoeducation, exposure to feared dental procedures, and cognitive restructuring was developed. A randomized controlled trial was conducted (N = 151) to test its efficacy. Consenting adult dental patients who met inclusion criteria (e.g., high dental anxiety) were randomized to 1 of 2 groups: immediate treatment (n = 74) or a wait-list control (n = 77). Analyses of covariance based on intention-to-treat analyses were used to compare the 2 groups on dental anxiety, fear, avoidance, and overall severity of dental phobia. Baseline scores on these outcomes were entered into the analyses as covariates. Groups were equivalent at baseline but differed at 1-mo follow-up. Both groups showed improvement in outcomes, but analyses of covariance demonstrated significant differences in dental anxiety, fear, avoidance, and overall severity of dental phobia in favor of immediate treatment at the follow-up assessment. Of the patients who met diagnostic criteria for phobia at baseline, fewer patients in the immediate treatment group continued to meet criteria for dental phobia at follow-up as compared with the wait-list group. A new computer-based tool seems to be efficacious in reducing dental anxiety and fear/avoidance of dental procedures. Examination of its effectiveness when administered in dental offices under less controlled conditions is warranted (ClinicalTrials.gov NCT02081365). PMID:26202996

  15. Snoezelen Room and Childbirth Outcome: A Randomized Clinical Trial

    PubMed Central

    Jamshidi Manesh, Mansoureh; Kalati, Mahnaz; Hosseini, Fatemeh

    2015-01-01

    Background: One of the strategies for a good outcome and pain free childbearing is to design the delivery room. Objectives: The aim of this study was to evaluate the effects of snoezelen room on childbearing outcome such as pain intensity, duration of labor, and perinea status in nulliparous women. Patients and Methods: This study was a randomized controlled clinical trial consists of 100 childbearing women. They were randomly divided into 2 groups. The experimental group went to snoezelen room when their cervix dilation was 4 cm, while the control group went to physiologic delivery room with the same cervix dilation. Results: The mean ± SD of VAS (Visual Analogue Scale) pain intensity of the experimental and control groups before the intervention were 5.1 ± 1.95 and 5.58 ± 1.62, respectively (P = 0.13). The mean ± SD of VAS pain intensity scores of the experimental and control groups after 3 hours spending in their assigned rooms were 5.26 ± 0.86 and 9.56 ± 1.48, respectively (P = 0.01). The mean ± SD of the first stage scores of the experimental and control groups were 6.95 ± 0.97 and 8.41 ± 0.67, respectively (P = 0.042). About 92% of participants’ intervention vs. 66% of control participants had perinea laceration (P = 0.041). Conclusions: According to the findings of the present study, distracting senses in snoezelen room decreases mother’s pain intensity, the length of labor, and incidence of episiotomy. PMID:26082849

  16. Continuous fiber ceramic composites. Phase II - Final report

    SciTech Connect

    Bird, James

    1997-10-31

    This report documents Atlantic Research Corporation's (ARC) Phase 11 effort on the Department of Energy's (DOE) Continuous Fiber Ceramic Composite (CFCC) program. This project is supported by the DOE cooperative agreement DE-FCO2-92CE40998. Such DOE support does not constitute an endorsement of the views expressed in this report. ARC'S CFCC Phase II effort began during October 1993 and was suspended in March of 1997 when, for business considerations, ARC closed the Amercom operation. This report covers progress from Phase II program inception through Amercom closure. ARC'S Phase II effort built upon the results of the Phase I Applications Assessment and Process Engineering developments to produce CFCC test components for end-user evaluation. Initially, the Phase 11 effort planned to develop and produce three CFCC components: CFCC compression rings for stationary diesel engines, CFCC hot gas fans for industrial furnace applications, and CFCC hot gas filters for current and advanced coal fired power cycles. As the program progressed, the development effort for the diesel engine piston rings was suspended. This decision was based on technical issues, cost factors and reduced program funding; the status of CFCC diesel engine piston ring development will be discussed in detail in section 2.2.1.

  17. Randomized controlled clinical trial to access efficacy and safety of miltefosine in the treatment of cutaneous leishmaniasis Caused by Leishmania (Viannia) guyanensis in Manaus, Brazil.

    PubMed

    Chrusciak-Talhari, Anette; Dietze, Reynaldo; Chrusciak Talhari, Carolina; da Silva, Roberto Moreira; Gadelha Yamashita, Ellen Priscila; de Oliveira Penna, Gerson; Lima Machado, Paulo Roberto; Talhari, Sinésio

    2011-02-01

    Miltefosine has been used in the treatment of several new world cutaneous leishmaniasis (CL) species with variable efficacy. Our study is the first evidence on its clinical efficacy in Leishmania (Viannia) guyanensis. In this phase II/III randomized clinical trial, 90 CL patients were randomly allocated (2:1) to oral miltefosine (2.5 mg/kg/day/28 days) (N = 60) or parenteral antimony (15-20 mg/Sb/kg/day/20 days) (N = 30) according to age groups: 2-12 y/o and 13-65 y/o. Patients were human immunodeficiency virus (HIV) noninfected parasitological proven CL without previous treatment. Definitive cure was accessed at 6 months follow-up visit. No severe adverse events occurred. Vomiting was the most frequent adverse event (48.3%) followed by nausea (8.6%) and diarrhea (6.7%). Cure rates were 71.4% (95% confidence interval [CI] = 57.8-82.7) and 53.6% (95% CI = 33.9-72.5) (P = 0.05) for miltefosine and antimonial, respectively. There were no differences in cure rates between age groups within the same treatment arms. Miltefosine was safe and relatively well tolerated and cure rate was higher than antimony.

  18. Effects of healing touch in clinical practice: a systematic review of randomized clinical trials.

    PubMed

    Anderson, Joel G; Taylor, Ann Gill

    2011-09-01

    Hands-on healing and energy-based interventions have been found in cultures throughout history around the world. These complementary therapies, rooted in ancient Eastern healing practices, are becoming mainstream. Healing Touch, a biofield therapy that arose in the nursing field in the late 1980s, is used in a variety of settings (i.e., pain centers, surgical settings, and private practices) with reported benefits (i.e., decreased anxiety, pain, and depressive behaviors; increased relaxation and a sense of well-being). However, clinical trial data concerning the effectiveness of Healing Touch have not been evaluated using a systematic, evidence-based approach. Thus, this systematic review is aimed at critically evaluating the data from randomized clinical trials examining the clinical efficacy of Healing Touch as a supportive care modality for any medical condition.

  19. 48 CFR 1852.219-81 - Limitation on subcontracting-SBIR Phase II program.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... subcontracting-SBIR Phase II program. 1852.219-81 Section 1852.219-81 Federal Acquisition Regulations System... CLAUSES Texts of Provisions and Clauses 1852.219-81 Limitation on subcontracting—SBIR Phase II program. As prescribed in 1819.7302(b), insert the following clause: Limitation on Subcontracting—SBIR Phase II...

  20. 48 CFR 1852.219-81 - Limitation on subcontracting-SBIR Phase II program.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... subcontracting-SBIR Phase II program. 1852.219-81 Section 1852.219-81 Federal Acquisition Regulations System... CLAUSES Texts of Provisions and Clauses 1852.219-81 Limitation on subcontracting—SBIR Phase II program. As prescribed in 1819.7302(b), insert the following clause: Limitation on Subcontracting—SBIR Phase II...

  1. Phase II Trial of Concurrent Sunitinib and Image-Guided Radiotherapy for Oligometastases

    PubMed Central

    Tong, Charles C. L.; Ko, Eric C.; Sung, Max W.; Cesaretti, Jamie A.; Stock, Richard G.; Packer, Stuart H.; Forsythe, Kevin; Genden, Eric M.; Schwartz, Myron; Lau, K. H. Vincent; Galsky, Matthew; Ozao-Choy, Junko; Chen, Shu-hsia; Kao, Johnny

    2012-01-01

    Background Preclinical data suggest that sunitinib enhances the efficacy of radiotherapy. We tested the combination of sunitinib and hypofractionated image-guided radiotherapy (IGRT) in a cohort of patients with historically incurable distant metastases. Methods Twenty five patients with oligometastases, defined as 1–5 sites of active disease on whole body imaging, were enrolled in a phase II trial from 2/08 to 9/10. The most common tumor types treated were head and neck, liver, lung, kidney and prostate cancers. Patients were treated with the recommended phase II dose of 37.5 mg daily sunitinib (days 1–28) and IGRT 50 Gy (days 8–12 and 15–19). Maintenance sunitinib was used in 33% of patients. Median follow up was 17.5 months (range, 0.7 to 37.4 months). Results The 18-month local control, distant control, progression-free survival (PFS) and overall survival (OS) were 75%, 52%, 56% and 71%, respectively. At last follow-up, 11 (44%) patients were alive without evidence of disease, 7 (28%) were alive with distant metastases, 3 (12%) were dead from distant metastases, 3 (12%) were dead from comorbid illness, and 1 (4%) was dead from treatment-related toxicities. The incidence of acute grade ≥ 3 toxicities was 28%, most commonly myelosuppression, bleeding and abnormal liver function tests. Conclusions Concurrent sunitinib and IGRT achieves major clinical responses in a subset of patients with oligometastases. Trial Registration ClinicalTrials.gov NCT00463060 PMID:22761653

  2. Prevalence and impact of correlative science in breast cancer phase II trials.

    PubMed

    Zhang, Tian; Schneider, Andrew; Hamilton, Erika P; Patel, Krish; Kamal, Arif H; Lyman, Gary H; Peppercorn, Jeffrey M

    2013-06-01

    Correlative science (CS) can potentially augment clinical trial results by identifying biomarkers of response and resistance to a novel intervention. We evaluated recently published breast cancer phase II trials (BP2T) to determine prevalence, characteristics, and outcomes of CS. Through Pubmed, we identified BP2T of systemic therapy published between June 2005 and June 2010. A study-specific abstraction tool recorded trial characteristics, CS endpoints, source of tissue, adequacy of samples, biopsy safety, and CS outcomes. BP2T authors were contacted to verify abstraction results. Results were abstracted from 298 eligible trials enrolling 18,782 patients, of which 81 (27.2 %) involved CS. Of these, 57 (70.4 %) included tissue with 16 (28 %) using optional research biopsies and 17 (30 %) requiring mandatory research biopsies. No trial addressed biopsy safety issues. Trials were more likely to include CS if they were: industry versus non-industry sponsored (33.7 % vs. 17.1 %, p = 0.0017), neoadjuvant versus metastatic setting (47 % vs. 21.2 %, p = 0.0001), or U.S. versus non-U.S. trials (37 % vs. 21 %, p = 0.005). A minority of phase II breast cancer trials include CS representing a missed opportunity to learn more from clinical research. When CS is included, consistent reporting of endpoints, feasibility, outcomes, and safety is needed.

  3. Physics Detector Simulation Facility Phase II system software description

    SciTech Connect

    Scipioni, B.; Allen, J.; Chang, C.; Huang, J.; Liu, J.; Mestad, S.; Pan, J.; Marquez, M.; Estep, P.

    1993-05-01

    This paper presents the Physics Detector Simulation Facility (PDSF) Phase II system software. A key element in the design of a distributed computing environment for the PDSF has been the separation and distribution of the major functions. The facility has been designed to support batch and interactive processing, and to incorporate the file and tape storage systems. By distributing these functions, it is often possible to provide higher throughput and resource availability. Similarly, the design is intended to exploit event-level parallelism in an open distributed environment.

  4. Microbial Dark Matter Phase II: Stepping deeper into unknown territory

    SciTech Connect

    Jarett, Jessica; Dunfield, Peter; Peura, Sari; Wielen, Paul van der; Hedlund, Brian; Elshahed, Mostafa; Kormas, Konstantinos; Stott, Andreas Teske8, Matt; Birkeland, Nils-Kare; Zhang, Chuanlun; Rengefors, Karin; Lindemann, Stephen; Ravin, Nikolai V.; Spear, John; Hallam, Steven; Crowe, Sean; Steele, Jillian; Goudeau, Danielle; Malmstrom, Rex; Kyrpides, Nikos; Stepanauskas, Ramunas; Woyke, Tanja

    2014-10-27

    Currently available microbial genomes are of limited phylogenetic breadth due to our historical inability to cultivate most microorganisms in the laboratory. The first phase of the Microbial Dark Matter project used single-cell genomics to sequence 201 single cells from uncultivated lineages, and was able to resolve new superphyla and reveal novel metabolic features in bacteria and archaea. However, many fundamental questions about the evolution and function of microbes remain unanswered, and many candidate phyla remain uncharacterized. Phase II of the Microbial Dark Matter project will target candidate phyla with no sequenced representatives at a variety of new sites using a combination of single-cell sequencing and shotgun metagenomics approaches.

  5. PWR steam generator chemical cleaning. Phase II. Final report

    SciTech Connect

    Not Available

    1980-01-01

    Two techniques believed capable of chemically dissolving the corrosion products in the annuli between tubes and support plates were developed in laboratory work in Phase I of this project and were pilot tested in Indian Point Unit No. 1 steam generators. In Phase II, one of the techniques was shown to be inadequate on an actual sample taken from an Indian Point Unit No. 2 steam generator. The other technique was modified slightly, and it was demonstrated that the tube/support plate annulus could be chemically cleaned effectively.

  6. Phase II study of lonidamine in metastatic breast cancer.

    PubMed Central

    Pronzato, P.; Amoroso, D.; Bertelli, G.; Conte, P. F.; Cusimano, M. P.; Ciottoli, G. B.; Gulisano, M.; Lionetto, R.; Rosso, R.

    1989-01-01

    Thirty patients with previously treated metastatic breast cancer were entered in a phase II study with oral lonidamine. Twenty-eight patients are evaluable for toxicity and 25 for response. A partial remission was obtained in four patients (16%) and disease stability in 11 (44%): 10 patients progressed (40%). Toxicity was acceptable, consisting mainly of myalgias (39% of patients) and asthenia (21.4%). No myelotoxicity was observed. The drug is active in previously treated metastatic breast cancer and, because of its peculiar pattern of action and toxicity, deserves to be evaluated in combination with cytotoxic chemotherapy. PMID:2930690

  7. A design of phase II cancer trials using total and complete response endpoints.

    PubMed

    Lu, Ying; Jin, Hua; Lamborn, Kathleen R

    2005-10-30

    Phase II clinical trials in oncology are used for initial evaluation of the therapeutic efficacy of a new treatment regimen. Simon's two-stage design based on total response (TR) rate is commonly used for such trials. Several authors have proposed alternative strategies to consider either response and toxicity or response and early progression. Because TR consists of both partial response (PR) and complete response (CR) and these two types of responses have different effects on subsequent patient outcome, Lin and Chen proposed a flexible design that is based on a weighted average of PR and CR rates as a way to recognize the differential significance of the two levels of response. Panageas and colleagues, on the other hand, used a trinomial model and direct search to consider a rejection region for PR and CR separately. In this paper, we reformat their hypotheses to assess efficacy based on TR and CR. A new two-stage optimum phase II trial design based on TR and CR is developed. We provide guides on searching the stopping and rejecting regions and on determining sample size. An example of a phase II trial for glioblastomas treatment is presented. In this trial, physicians would be interested in either stable disease (SD), PR, or CR as an indication of efficacy. However, because PR and CR rarely occur, observation of any PR or CR will lean towards acceptance of the treatment. Our design has the advantage of being close to the traditional Simon two-stage design while still having the flexibility to treat responses (PR and CR in this example) differently than SD.

  8. Random assignment in clinical trials: issues in planning (Infant Health and Development Program).

    PubMed

    Kraemer, H C; Fendt, K H

    1990-01-01

    Various options available for the randomization of subjects into groups in a clinical trial are discussed, emphasizing the issues of logistics given less focus in more mathematical treatments. We discuss advantages and disadvantages of total randomization, of Zelen-type randomization procedures, of Efron-type procedures vs more classical blocking procedures to control the balance between groups, and of Simon-Pocock-type procedures vs more classical stratification for controlling possible biases in prognostic factors. Finally, we discuss issues related to choice and implementation of randomization procedures. The discussion is illustrated with the processes of decision-making in a national collaborative randomized clinical trial, the Infant Health and Development Program.

  9. Hemiablative Focal Low Dose Rate Brachytherapy: A Phase II Trial Protocol

    PubMed Central

    Bucci, Joseph; Chin, Yaw Sinn; Malouf, David; Howie, Andrew; Enari, Komiti Ese

    2016-01-01

    Background The objective of focal brachytherapy (BT) is to provide effective prostate cancer control for low-risk disease but with reduced genitourinary, gastrointestinal and sexual side effects in a cost-effective way. Objective The aim of this study is to describe a phase II study examining technical and dosimetric feasibility and toxicity, quality of life changes, and local control with post-treatment biopsy outcomes in men with early stage low volume prostate cancer treated with focal iodine-125 seed BT. Methods The study design is a prospective, multicenter trial with a planned sample size of 20 patients including men with a minimum age of 60 years, a life expectancy estimated to be greater than 10 years, with low or low-tier intermediate risk prostate cancer, unilateral disease on the biopsy, and a Gleason score of ≤3+4 and <25% cores involved. The investigations specific for the study are multi-parametric magnetic resonance imaging (Mp-MRI) baseline, at 20 and 36 months to rule out high grade disease and a transperineal mapping biopsy (baseline and at 36 months) for more accurate patient selection. The hemigland region will receive 144 Gy. Standard normal tissue constraints will be considered as for a whole gland (WG) implant. Dosimetric parameters will be evaluated at day 30 after the implant. Toxicity and quality of life will be evaluated with international validated questionnaires focusing on urinary, rectal, sexual domain, and general health-related quality of life. The patients will complete this assessment at baseline and then approximately every 6 months after the implant up to 10 years. Results To date, one patient is involved in the trial. He underwent the pre-implant investigations which found bilateral disease. Therefore, a standard seed implant was performed. If the results from this trial provide evidence that the treatment is safe, feasible, and improves toxicity, funding will be sought to conduct a large, multicenter, randomized controlled

  10. A note on Harold S. Diehl, randomization, and clinical trials.

    PubMed

    Waller, L A

    1997-04-01

    Harold S. Diehl and coworkers published results from a remarkable trial on the efficacy of vaccines for the common cold in 1938. The original report states that patients were assigned to treatment and control groups "at random." Diehl's study has been referred to as one of the first instances of a randomized, double-blind, placebo-controlled trial. No description of a formal randomization scheme is given in the 1938 report and an unpublished paper of Diehl's suggests the use of alternate assignment in the study.

  11. {sup 129}I Interlaboratory comparison: phase I and phase II

    SciTech Connect

    Caffee, M W; Roberts, M L

    1999-09-30

    An interlaboratory comparison exercise for {sup 129}I was organized and conducted. Nine laboratories participated in the exercise to either a full or limited extent. In Phase I of the comparison, 11 samples were measured. The suite of samples contained both synthetic ''standard type'' materials (i.e., AgI) and environmental materials. The isotopic {sup 129}I/{sup 127}I ratios of the samples varied from 10{sup {minus}8} to 10{sup {minus}14}. In this phase, each laboratory was responsible for its own chemical preparation of the samples. In Phase I, the {sup 129}I AMS measurements for prepared AgI were in good agreement. However, large discrepancies were seen in {sup 129}I AMS measurements of environmental samples. Because of the large discrepancies seen in the Phase I {sup 129}I intercomparison, a subsequent study was conducted. In Phase II of the {sup 129}I intercomparison, three separate laboratories prepared AgI from two environmental samples (IAEA 375 soil and maples leaves). Each laboratory used its own chemical preparation method with each of the methods being distinctly different. The resulting six samples (two sets of three) were then re-distributed to the participating {sup 129}I AMS facilities and {sup 129}I/{sup 127}I ratios measured. Results and discussion of both the Phase I and Phase II interlaboratory comparison are presented.

  12. 129I interlaboratory comparison: phase I and phase II results

    SciTech Connect

    Roberts, M.I.; Caffee, M.W.; Proctor, I.D.

    1997-07-01

    An interlaboratory comparison exercise for 129I was organized and conducted. A total of nine laboratories participated in the exercise to either a full or limited extent. In Phase I of the comparison, a suite of 11 samples were measured. The suite of samples contained both synthetic `standard type` materials (i.e., AgI) and environmental materials. The isotopic 129I/127I ratios of the samples varied from 10`-8 to 10`-14. In this phase, each laboratory was responsible for its own chemical preparation of the environmental samples. The 129I AMS measurements obtained at different laboratories for prepared AgI were in good agreement. However, large discrepancies were seen in 129I AMS measurements of environmental samples. Because of the large discrepancies seen in the Phase I intercomparison, a subsequent study was conducted. In Phase II of the comparison, AgI was prepared from two environmental samples (IAEA 375 soil and maples leaves) by three separate laboratories. Each laboratory used its own chemical preparation method with each of the methods being distinctly different. The resulting six samples (two sets of three) were then redistributed to the participating 129I AMS facilities and 129I/127I ratios measured. Results and discussion of both the Phase I and Phase II interlaboratory comparison are presented.

  13. Mercury Oxidation via Catalytic Barrier Filters Phase II

    SciTech Connect

    Wayne Seames; Michael Mann; Darrin Muggli; Jason Hrdlicka; Carol Horabik

    2007-09-30

    In 2004, the Department of Energy National Energy Technology Laboratory awarded the University of North Dakota a Phase II University Coal Research grant to explore the feasibility of using barrier filters coated with a catalyst to oxidize elemental mercury in coal combustion flue gas streams. Oxidized mercury is substantially easier to remove than elemental mercury. If successful, this technique has the potential to substantially reduce mercury control costs for those installations that already utilize baghouse barrier filters for particulate removal. Completed in 2004, Phase I of this project successfully met its objectives of screening and assessing the possible feasibility of using catalyst coated barrier filters for the oxidation of vapor phase elemental mercury in coal combustion generated flue gas streams. Completed in September 2007, Phase II of this project successfully met its three objectives. First, an effective coating method for a catalytic barrier filter was found. Second, the effects of a simulated flue gas on the catalysts in a bench-scale reactor were determined. Finally, the performance of the best catalyst was assessed using real flue gas generated by a 19 kW research combustor firing each of three separate coal types.

  14. Randomized Phase III study of gemcitabine plus S-1 versus gemcitabine plus cisplatin in advanced biliary tract cancer: Japan Clinical Oncology Group Study (JCOG1113, FUGA-BT).

    PubMed

    Mizusawa, Junki; Morizane, Chigusa; Okusaka, Takuji; Katayama, Hiroshi; Ishii, Hiroshi; Fukuda, Haruhiko; Furuse, Junji

    2016-04-01

    A Phase II selection design trial was conducted to identify the most promising regimen for comparison with standard therapy in chemo-naive patients with unresectable or recurrent biliary tract cancer (JCOG0805). Gemcitabine plus S-1 therapy showed better efficacy than S-1 monotherapy with acceptable safety in JCOG0805 study. Based on this result, a randomized Phase III trial was started in May 2013 to confirm the non-inferiority of gemcitabine plus S-1 therapy relative to gemcitabine plus cisplatin therapy, which is the current standard treatment for chemo-naive patients with unresectable or recurrent biliary tract cancer. A total of 350 patients will be accrued from 32 Japanese institutions within 4 years. The primary endpoint is overall survival, while the secondary endpoints are progression-free survival, adverse events, serious adverse events, clinically significant adverse events, response rate and %planned dose. This trial has been registered with the UMIN Clinical Trials Registry (http://www.umin.ac.jp/ctr/index.htm) and the registration number is UMIN000010667.

  15. The need for thorough phase II studies in medicines development for Alzheimer's disease.

    PubMed

    Gray, Julian A; Fleet, David; Winblad, Bengt

    2015-10-26

    An important factor in the universal failure in phase III trials in mild to moderate Alzheimer's disease in the past decade is the lack of phase II clinical data prior to entering phase III, with common reliance on biomarker results alone. Conduction of two learn-confirm cycles according to the Sheiner model would allow go/no-go decision making to include reliable clinical efficacy data prior to conducting phase III and would likely bring the rate of late stage failure more into line with that of other neurological indications. In studies in earlier disease stages, combined phase IIB/III adaptive approaches merit consideration in view of the long timelines of each study, though advantages and disadvantages of this approach versus the classical development pathway still need careful assessment.

  16. PHASE II VAULT TESTING OF THE ARGONNE RFID SYSTEM

    SciTech Connect

    Willoner, T.; Turlington, R.; Koenig, R.

    2012-06-25

    The U.S. Department of Energy (DOE) (Environmental Management [EM], Office of Packaging and Transportation [EM-45]) Packaging and Certification Program (DOE PCP) has developed a Radio Frequency Identification (RFID) tracking and monitoring system, called ARG-US, for the management of nuclear materials packages during transportation and storage. The performance of the ARG-US RFID equipment and system has been fully tested in two demonstration projects in April 2008 and August 2009. With the strong support of DOE-SR and DOE PCP, a field testing program was completed in Savannah River Site's K-Area Material Storage (KAMS) Facility, an active Category I Plutonium Storage Facility, in 2010. As the next step (Phase II) of continued vault testing for the ARG-US system, the Savannah River Site K Area Material Storage facility has placed the ARG-US RFIDs into the 910B storage vault for operational testing. This latest version (Mark III) of the Argonne RFID system now has the capability to measure radiation dose and dose rate. This paper will report field testing progress of the ARG-US RFID equipment in KAMS, the operability and reliability trend results associated with the applications of the system, and discuss the potential benefits in enhancing safety, security and materials accountability. The purpose of this Phase II K Area test is to verify the accuracy of the radiation monitoring and proper functionality of the ARG-US RFID equipment and system under a realistic environment in the KAMS facility. Deploying the ARG-US RFID system leads to a reduced need for manned surveillance and increased inventory periods by providing real-time access to status and event history traceability, including environmental condition monitoring and radiation monitoring. The successful completion of the testing program will provide field data to support a future development and testing. This will increase Operation efficiency and cost effectiveness for vault operation. As the next step (Phase

  17. Methodological Aspects of the Phase II Study AFF006 Evaluating Amyloid-beta -Targeting Vaccine AFFITOPE® AD02 in Early Alzheimer’s Disease – Prospective Use of Novel Composite Scales

    PubMed Central

    Hendrix, S.; Ellison, N.; Stanworth, S.; Tierney, L.; Mattner, F.; Schmidt, W.; Dubois, B.; Schneeberger, A.

    2015-01-01

    items that were selected for the adapted cognitive scale (aADAS-cog) and had the highest weights were Word Recall, Word Recognition, and Orientation. Delayed Word Recall and Digit Cancellation were among the items excluded due to lack of improved sensitivity to decline. Highly weighted ADL items included in the adapted functional scale (aADCS-ADL) were using the telephone, traveling, preparing a meal/snack, selecting clothing, shopping and using appliances. Excluded items were primarily basic ADLs such as eating, walking, toileting and bathing. Comparisons between traditional scales and primary outcome adapted scales show improved sensitivity to group differences with the adapted scales in the phase II trial. Most of the improvement in the sensitivity of the aADAS-cog and the aADCS-ADL is due to a larger treatment difference observed rather than the improved sensitivity to decline in the comparison groups. CONCLUSION To our knowledge, this is the first study to prospectively use optimized scales as primary endpoints and to demonstrate the superior power of optimized scales and composites in early disease. Although it is possible that the treatment difference between randomized groups is due to a factor other than the treatment itself, for instance baseline imbalance, the improved power to detect these differences still argues in favor of the adapted scales. The issue of oversensitivity to detect treatment effects is controlled by selection of the alpha level for significance, and in our case will happen less than 5% of the time. Clinical relevance of the treatment difference should be assessed separately from statistical significance, and in this phase II study, is supported by significant or similar sizes of effect on function, behaviour and quality of life outcomes, which are important to patients and caregivers. PMID:26866015

  18. Small Business Innovation Research. Abstracts of Phase II awards, 2000

    SciTech Connect

    2000-12-01

    The SBIR program enables DOE to obtain effective, innovative solutions to important problems through the private sector, which has a commercial incentive to pursue the resulting technology and bring it to the marketplace. The growing number of awardees, many of them started in business in response to SBIR solicitations, is becoming a significant resource for the solution of high risk, high technology problems for the Department. As detailed below, this publication describes the technical efforts and commercialization possibilities for SBIR Phase II awards in Fiscal Year (FY) 2000. It is intended for the educated layman, and maybe of particular interest to potential investors who wish to get in on the ground floor of exciting opportunities.

  19. Advanced Simulation Capability for Environmental Management (ASCEM) Phase II Demonstration

    SciTech Connect

    Freshley, M.; Hubbard, S.; Flach, G.; Freedman, V.; Agarwal, D.; Andre, B.; Bott, Y.; Chen, X.; Davis, J.; Faybishenko, B.; Gorton, I.; Murray, C.; Moulton, D.; Meyer, J.; Rockhold, M.; Shoshani, A.; Steefel, C.; Wainwright, H.; Waichler, S.

    2012-09-28

    quality assurance. The Platform and HPC capabilities are being tested and evaluated for EM applications through a suite of demonstrations being conducted by the Site Applications Thrust. In 2010, the Phase I Demonstration focused on testing initial ASCEM capabilities. The Phase II Demonstration, completed in September 2012, focused on showcasing integrated ASCEM capabilities. For Phase II, the Hanford Site Deep Vadose Zone (BC Cribs) served as an application site for an end-to-end demonstration of ASCEM capabilities on a site with relatively sparse data, with emphasis on integration and linkages between the Platform and HPC components. Other demonstrations included in this Phase II report included addressing attenuation-based remedies at the Savannah River Site F-Area, to exercise linked ASCEM components under data-dense and complex geochemical conditions, and conducting detailed simulations of a representative waste tank. This report includes descriptive examples developed by the Hanford Site Deep Vadose Zone, the SRS F-Area Attenuation-Based Remedies for the Subsurface, and the Waste Tank Performance Assessment working groups. The integrated Phase II Demonstration provides test cases to accompany distribution of the initial user release (Version 1.0) of the ASCEM software tools to a limited set of users in 2013. These test cases will be expanded with each new release, leading up to the release of a version that is qualified for regulatory applications in the 2015 time frame.

  20. Preliminary Exploratory Study of Different Phase II Collimators

    SciTech Connect

    Lari, L.; Assmann, R.W.; Bertarelli, A.; Bracco, C.; Brugger, M.; Cerutti, F.; Dallocchio, A.; Ferrari, A.; Mauri, M.; Roesler, S.; Sarchiapone, L.; Vlachoudis, Vasilis; Doyle, J.E.; Keller, L.; Lundgren, S.A.; Markiewicz, Thomas W.; Smith, J.C.; Lari, L.; /LPHE, Lausanne

    2011-11-02

    The Large Hadron Collider (LHC) collimation system is installed and commissioned in different phases, following the natural evolution of the LHC performance. To improve cleaning efficiency towards the end of the low beta squeeze at 7TeV, and in stable physics conditions, it is foreseen to complement the 30 highly robust Phase I secondary collimators with low impedance Phase II collimators. At this stage, their design is not yet finalized. Possible options include metallic collimators, graphite jaws with a movable metallic foil, or collimators with metallic rotating jaws. As part of the evaluation of the different designs, the FLUKA Monte Carlo code is extensively used for calculating energy deposition and studying material damage and activation. This report outlines the simulation approach and defines the critical quantities involved.

  1. An easily customized, random allocation system using the minimization method for multi-institutional clinical trials.

    PubMed

    Kenjo, Y; Antoku, Y; Akazawa, K; Hanada, E; Kinukawa, N; Nose, Y

    2000-05-01

    In a randomized clinical trial, random allocation of patients to treatment groups should be done to balance in the distribution of prognostic factors. Random allocation in a multi-institutional randomized clinical trial is conducted by a coordinating center, independent of the medical institution the attending doctor uses for his/her practice. This study provides a sophisticated system for doing an exact random allocation of patients to treatment groups. The minimization method proposed by Pocock was applied to this system to balance the distribution of prognostic factors between two treatment groups, even when the number of registered patients is relatively small (S.J. Pocock, Allocation of patients to treatment in clinical trial, Biometrics 35 (1979) 183-197). Furthermore, Zelen's method is used to balance the number of patients allocated to the two groups within each institution (M. Zelen, The randomization and stratification of patients to clinical trials, J. Chron. Dis. 27 (1974) 365-375.). This system was created by the 'PERL&RSQUO; language for writing common gateway interface (CGI) script, and can therefore, be easily extended to include data entry function by attending doctors as well as the random allocation function. This system is being used effectively in thirteen multi-institutional randomized clinical trials for stomach, colon-rectum and breast cancers in Japan.

  2. A Randomized Clinical Trial of Smoking Cessation Treatments Provided in HIV Clinical Care Settings

    PubMed Central

    2013-01-01

    Introduction: Identifying successful smoking treatment interventions and methods of delivery is critical given the smoking rates among HIV-positive populations and the medical implications of smoking in this population. This study compared the efficacy of 3 smoking cessation interventions provided in HIV clinical treatment settings. Methods: Following a baseline assessment, 209 HIV-positive smokers were randomly assigned to 1 of 3 conditions in a parallel group design. Treatment conditions were individual counseling plus nicotine replacement treatment (NRT), a computer-based Internet smoking treatment plus NRT, and self-help plus NRT. Smoking status was determined at follow-up assessments completed at 12, 24, 36, and 52 weeks following treatment initiation. Results: Cessation rates ranged from 15% to 29%; however, no statistically significant differences in abstinence were found among the treatment conditions over time. Those employed, those who reported a greater desire to quit, or those with lower mood disturbance scores were more likely to achieve abstinence (p < .01). The number of cigarettes participants reported smoking in the 24hr prior to each assessment significantly declined over time (p < .001). Conclusions: Although we found no differences in abstinence rates across groups, the results indicate that integration of smoking cessation interventions is feasible in HIV clinical treatment settings, and cessation results are promising. The overall abstinence rates we report are comparable to those found in similar treatment studies across multiple populations. Further research is warranted. PMID:23430708

  3. Unbiased estimation in seamless phase II/III trials with unequal treatment effect variances and hypothesis-driven selection rules.

    PubMed

    Robertson, David S; Prevost, A Toby; Bowden, Jack

    2016-09-30

    Seamless phase II/III clinical trials offer an efficient way to select an experimental treatment and perform confirmatory analysis within a single trial. However, combining the data from both stages in the final analysis can induce bias into the estimates of treatment effects. Methods for bias adjustment developed thus far have made restrictive assumptions about the design and selection rules followed. In order to address these shortcomings, we apply recent methodological advances to derive the uniformly minimum variance conditionally unbiased estimator for two-stage seamless phase II/III trials. Our framework allows for the precision of the treatment arm estimates to take arbitrary values, can be utilised for all treatments that are taken forward to phase III and is applicable when the decision to select or drop treatment arms is driven by a multiplicity-adjusted hypothesis testing procedure. © 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd. PMID:27103068

  4. Unbiased estimation in seamless phase II/III trials with unequal treatment effect variances and hypothesis-driven selection rules.

    PubMed

    Robertson, David S; Prevost, A Toby; Bowden, Jack

    2016-09-30

    Seamless phase II/III clinical trials offer an efficient way to select an experimental treatment and perform confirmatory analysis within a single trial. However, combining the data from both stages in the final analysis can induce bias into the estimates of treatment effects. Methods for bias adjustment developed thus far have made restrictive assumptions about the design and selection rules followed. In order to address these shortcomings, we apply recent methodological advances to derive the uniformly minimum variance conditionally unbiased estimator for two-stage seamless phase II/III trials. Our framework allows for the precision of the treatment arm estimates to take arbitrary values, can be utilised for all treatments that are taken forward to phase III and is applicable when the decision to select or drop treatment arms is driven by a multiplicity-adjusted hypothesis testing procedure. © 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.

  5. Acupuncture for Vascular Dementia: A Pragmatic Randomized Clinical Trial

    PubMed Central

    Shi, Guang-Xia; Li, Qian-Qian; Yang, Bo-Feng; Liu, Yan; Guan, Li-Ping; Wu, Meng-Meng; Wang, Lin-Peng; Liu, Cun-Zhi

    2015-01-01

    In this trial, patients who agreed to random assignment were allocated to a randomized acupuncture group (R-acupuncture group) or control group. Those who declined randomization were assigned to a nonrandomized acupuncture group (NR-acupuncture group). Patients in the R-acupuncture group and NR-acupuncture group received up to 21 acupuncture sessions during a period of 6 weeks plus routine care, while the control group received routine care alone. Cognitive function, activities of daily living, and quality of life were assessed by mini-mental state examination (MMSE), Activities of Daily Living Scale (ADL), and dementia quality of life questionnaire (DEMQOL), respectively. All the data were collected at baseline, after 6-week treatment, and after 4-week follow-up. No significant differences of MMSE scores were observed among the three groups but pooled-acupuncture group had significant higher score than control group. Compared to control group, ADL score significantly decreased in NR-acupuncture group and pooled-acupuncture group. For DEMQOL scores, no significant differences were observed among the three groups, as well as between pooled-acupuncture group and control group. Additional acupuncture to routine care may have beneficial effects on the improvements of cognitive status and activities of daily living but have limited efficacy on health-related quality of life in VaD patients. PMID:26495416

  6. Exploratory, Phase II Controlled Trial of Shiunko Ointment Local Application Twice a Day for 4 Weeks in Ethiopian Patients with Localized Cutaneous Leishmaniasis

    PubMed Central

    Na-Bangchang, Kesara; Ahmed, Oumer; Hussein, Jemal; Hirayama, Kenji; Kongjam, Panida; Aseffa, Abraham; Karbwang, Juntra

    2016-01-01

    The clinical efficacy and safety of Shiunko ointment (phase II clinical trial) was investigated in 40 Ethiopian patients with cutaneous leishmaniasis. Patients were randomized to receive treatment with Shiunko ointment or placebo (n = 20, each), applied on the lesion twice a day for 4 weeks. Clinicoparasitological assessments were performed before treatment, weekly for 4 weeks, and then 4, 8, and 12 weeks after the end of treatment. A marked reduction in lesion size was observed on week 16 of treatment in the Shiunko compared with placebo group (69% and 22% reduction, resp.). The overall rate of lesion reduction during the four weeks of treatment was significantly faster in the Shiunko group. Shiunko provided significant effect on wound closure in patients with ulcerated lesion. The clinical efficacy and tolerability of Shiunko were comparable to placebo with regard to its clinicoparasitological response (cure rate and parasitological clearance). Results of this preliminary study may suggest that Shiunko could be useful as adjuvant or as complementary treatment, not as alternatives to current treatment. Its attractive action includes fast lesion healing with a significantly smaller lesion at week 16 of treatment compared with placebo. In addition, its action was promoted in ulcerative lesions. PMID:27195014

  7. Biomarker-Guided Adaptive Trial Designs in Phase II and Phase III: A Methodological Review

    PubMed Central

    Antoniou, Miranta; Jorgensen, Andrea L; Kolamunnage-Dona, Ruwanthi

    2016-01-01

    Background Personalized medicine is a growing area of research which aims to tailor the treatment given to a patient according to one or more personal characteristics. These characteristics can be demographic such as age or gender, or biological such as a genetic or other biomarker. Prior to utilizing a patient’s biomarker information in clinical practice, robust testing in terms of analytical validity, clinical validity and clinical utility is necessary. A number of clinical trial designs have been proposed for testing a biomarker’s clinical utility, including Phase II and Phase III clinical trials which aim to test the effectiveness of a biomarker-guided approach to treatment; these designs can be broadly classified into adaptive and non-adaptive. While adaptive designs allow planned modifications based on accumulating information during a trial, non-adaptive designs are typically simpler but less flexible. Methods and Findings We have undertaken a comprehensive review of biomarker-guided adaptive trial designs proposed in the past decade. We have identified eight distinct biomarker-guided adaptive designs and nine variations from 107 studies. Substantial variability has been observed in terms of how trial designs are described and particularly in the terminology used by different authors. We have graphically displayed the current biomarker-guided adaptive trial designs and summarised the characteristics of each design. Conclusions Our in-depth overview provides future researchers with clarity in definition, methodology and terminology for biomarker-guided adaptive trial designs. PMID:26910238

  8. 7 CFR 3403.8 - Proposal format for phase II applications.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... budget category must be included. (6) Organizational management information. Each Phase II awardee will..., financial statements or balance sheet) and report any changes in management or principals....

  9. 7 CFR 3403.8 - Proposal format for phase II applications.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... budget category must be included. (6) Organizational management information. Each Phase II awardee will..., financial statements or balance sheet) and report any changes in management or principals....

  10. 7 CFR 3403.8 - Proposal format for phase II applications.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... budget category must be included. (6) Organizational management information. Each Phase II awardee will..., financial statements or balance sheet) and report any changes in management or principals....

  11. Anti-IP-10 antibody (BMS-936557) for ulcerative colitis: a phase II randomised study

    PubMed Central

    Mayer, Lloyd; Sandborn, William J; Stepanov, Yuriy; Geboes, Karel; Hardi, Robert; Yellin, Michael; Tao, Xiaolu; Xu, Li An; Salter-Cid, Luisa; Gujrathi, Sheila; Aranda, Richard; Luo, Allison Y

    2014-01-01

    Objective Interferon-γ-inducible protein-10 (IP-10 or CXCL10) plays a role in inflammatory cell migration and epithelial cell survival and migration. It is expressed in higher levels in the colonic tissue and plasma of patients with ulcerative colitis (UC). This phase II study assessed the efficacy and safety of BMS-936557, a fully human, monoclonal antibody to IP-10, in the treatment of moderately-to-severely active UC. Design In this 8-week, phase II, double-blind, multicentre, randomised study, patients with active UC received placebo or BMS-936557 (10 mg/kg) intravenously every other week. The primary endpoint was the rate of clinical response at Day 57; clinical remission and mucosal healing rates were secondary endpoints. Post hoc analyses evaluated the drug exposure–response relationship and histological improvement. Results 109 patients were included (BMS-936557: n=55; placebo: n=54). Prespecified primary and secondary endpoints were not met; clinical response rate at Day 57 was 52.7% versus 35.2% for BMS-936557 versus placebo (p=0.083), and clinical remission and mucosal healing rates were 18.2% versus 16.7% (p=1.00) and 41.8% versus 35.2% (p=0.556), respectively. However, higher BMS-936557 steady-state trough concentration (Cminss) was associated with increased clinical response (87.5% vs 37.0% (p<0.001) for patients with Cminss 108–235 μg/ml vs placebo) and histological improvements (73.0% vs 41.0%; p=0.004). Infections occurred in 7 (12.7%) BMS-936557-treated patients and 3 (5.8%) placebo-treated patients. 2 (3.6%) BMS-936557 patients discontinued due to adverse events. Conclusions Anti-IP-10 antibody, BMS-936557, is a potentially effective therapy for moderately-to-severely active UC. Higher drug exposure correlated with increasing clinical response and histological improvement. Further dose–response studies are warranted. Clinical Trial Registration Number: ClinicalTrials.gov NCT00656890. PMID:23461895

  12. A Phase II Trial of Arc-Based Hypofractionated Intensity-Modulated Radiotherapy in Localized Prostate Cancer

    SciTech Connect

    Lock, Michael; Best, Lara; Wong, Eugene; Bauman, Glenn; D'Souza, David; Venkatesan, Varagur; Sexton, Tracy; Ahmad, Belal; Izawa, Jonathan; Rodrigues, George

    2011-08-01

    Purpose: To evaluate acute and late genitourinary (GU) and gastrointestinal (GI) toxicity and biochemical control of hypofractionated, image-guided (fiducial markers or ultrasound guidance), simplified intensity-modulated arc therapy for localized prostate cancer. Methods and Materials: This Phase II prospective clinical trial for T1a-2cNXM0 prostate cancer enrolled 66 patients who received 63.2 Gy in 20 fractions over 4 weeks. Fiducial markers were used for image guidance in 30 patients and daily ultrasound for the remainder. Toxicity was scored according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. Results: Median follow-up was 36 months. Acute Phase Grade 2 and 3 toxicity was 34% and 9% for GU vs. 25% and 10% for GI symptoms. One Grade 4 acute GI toxicity occurred in a patient with unrecognized Crohn's disease. Late Grade 2 and 3 toxicity for GU was 14% and 5%, and GI toxicity was 25% and 3%. One late GI Grade 4 toxicity was observed in a patient with significant comorbidities (anticoagulation, vascular disease). Acute GI toxicity {>=}Grade 2 was shown to be a predictor for late toxicity Grade {>=}2 (p < 0.001). The biochemical disease-free survival at 3 years was 95%. Conclusions: Hypofractionated simplified intensity-modulated arc therapy radiotherapy given as 63.2 Gy in 20 fractions demonstrated promising biochemical control rates; however, higher rates of acute Grade 3 GU and GI toxicity and higher late Grade 2 GU and GI toxicity were noted. Ongoing randomized controlled trials should ultimately clarify issues regarding patient selection and the true rate of severe toxicity that can be directly attributed to hypofractionated radiotherapy.

  13. Lunar Quest in Second Life, Lunar Exploration Island, Phase II

    NASA Astrophysics Data System (ADS)

    Ireton, F. M.; Day, B. H.; Mitchell, B.; Hsu, B. C.

    2010-12-01

    Linden Lab’s Second Life is a virtual 3D metaverse created by users. At any one time there may be 40,000-50,000 users on line. Users develop a persona and are seen on screen as a human figure or avatar. Avatars move through Second Life by walking, flying, or teleporting. Users form communities or groups of mutual interest such as music, computer graphics, and education. These groups communicate via e-mail, voice, and text within Second Life. Information on downloading the Second Life browser and joining can be found on the Second Life website: www.secondlife.com. This poster details Phase II in the development of Lunar Exploration Island (LEI) located in Second Life. Phase I LEI highlighted NASA’s LRO/LCROSS mission. Avatars enter LEI via teleportation arriving at a hall of flight housing interactive exhibits on the LRO/ LCROSS missions including full size models of the two spacecraft and launch vehicle. Storyboards with information about the missions interpret the exhibits while links to external websites provide further information on the mission, both spacecraft’s instrument suites, and related EPO. Other lunar related activities such as My Moon and NLSI EPO programs. A special exhibit was designed for International Observe the Moon Night activities with links to websites for further information. The sim includes several sites for meetings, a conference stage to host talks, and a screen for viewing NASATV coverage of mission and other televised events. In Phase II exhibits are updated to reflect on-going lunar exploration highlights, discoveries, and future missions. A new section of LEI has been developed to showcase NASA’s Lunar Quest program. A new exhibit hall with Lunar Quest information has been designed and is being populated with Lunar Quest information, spacecraft models (LADEE is in place) and kiosks. A two stage interactive demonstration illustrates lunar phases with static and 3-D stations. As NASA’s Lunar Quest program matures further

  14. Rooftop PV system. Final technical progress report, Phase II

    SciTech Connect

    1995-08-01

    Under this four-year PV:BONUS Program, ECD and United Solar are developing and demonstrating two new lightweight flexible building integrated Photovoltaic (BIPV) modules specifically designed as exact replacements for conventional asphalt shingles and standing seam metal roofing. These modules can be economically and aesthetically integrated into new residential and commercial buildings, and address the even larger roofing replacement market. The modules are designed to be installed by roofing contractors without special training which minimizes the installation and balance of system costs. The modules will be fabricated from high-efficiency, multiple-junction a-Si alloy solar cells developed by ECD and United Solar. Under the Phase I Program, which ended in March 1994, we developed two different concept designs for rooftop PV modules: (1) the United Solar overlapping (asphalt shingle replacement) shingle-type modules and (2) the ECD metal roof-type modules. We also developed a plan for fabricating, testing and demonstrating these modules. Candidate demonstration sites for our rooftop PV modules were identified and preliminary engineering designs for these demonstrations were developed; a marketing study plan was also developed. The major objectives of the Phase II Program, which started in June 1994 was (1) to develop, test, and qualify these new rooftop modules; (2) to develop mechanical and electrical engineering specifications for the demonstration projects; and (3) to develop a marketing/commercialization plan.

  15. Overview of SBIR Phase II Work on Hollow Graphite Fibers

    NASA Technical Reports Server (NTRS)

    Stallcup, Michael; Brantley, Lott W. (Technical Monitor)

    2001-01-01

    Ultra-Lightweight materials are enabling for producing space based optical components and support structures. Heretofore, innovative designs using existing materials has been the approach to produce lighter-weight optical systems. Graphite fiber reinforced composites, because of their light weight, have been a material of frequent choice to produce space based optical components. Hollow graphite fibers would be lighter than standard solid graphite fibers and, thus, would save weight in optical components. The Phase I SBIR program demonstrated it is possible to produce hollow carbon fibers that have strengths up to 4.2 GPa which are equivalent to commercial fibers, and composites made from the hollow fibers had substantially equivalent composite strengths as commercial fiber composites at a 46% weight savings. The Phase II SBIR program will optimize processing and properties of the hollow carbon fiber and scale-up processing to produce sufficient fiber for fabricating a large ultra-lightweight mirror for delivery to NASA. Information presented here includes an overview of the strength of some preliminary hollow fibers, photographs of those fibers, and a short discussion of future plans.

  16. Yakima River Basin Phase II Fish Screen Evaluations, 2002

    SciTech Connect

    Carter, Jessica A.; McMichael, Geoffrey A.; Chamness, Mickie A.

    2003-03-01

    In 2002, the Pacific Northwest National Laboratory evaluated 23 Phase II fish screen sites in the Yakima River Basin as part of a multi-year project for the Bonneville Power Administration on the effectiveness of fish screening devices. Pacific Northwest National Laboratory collected data to determine whether velocities in front of the screens and in the bypasses met National Marine Fisheries Service criteria to promote safe and timely fish passage and whether bypass outfall conditions allowed fish to safely return to the river. In addition, Pacific Northwest National Laboratory conducted underwater video surveys to evaluate the environmental and operational conditions of the screen sites with respect to fish passage. Based on evaluations in 2002, PNNL concluded that: (1) In general, water velocity conditions at the screen sites met fish passage criteria set by the National Marine Fisheries Service. (2) Conditions at most facilities would be expected to provide for safe juvenile fish passage. (3) Conditions at some facilities indicate that operation and/or maintenance should be modified to increase safe juvenile fish passage. (4) Automated cleaning brushes generally functioned properly; chains and other moving parts were typically well greased and operative. (5) Removal of sediment buildup and accumulated leafy and woody debris should be improved at some sites.

  17. Yakima River Basin Phase II Fish Screen Evaluations, 2003

    SciTech Connect

    Vucelick, Jessica A.; McMichael, Geoffrey A.; Chamness, Mickie A.

    2004-05-01

    In 2003, the Pacific Northwest National Laboratory (PNNL) evaluated 23 Phase II fish screen sites in the Yakima River Basin as part of a multi-year project for the Bonneville Power Administration on the effectiveness of fish screening devices. PNNL collected data to determine whether velocities in front of the screens and in the bypasses met the Nation Oceanic and Atmospheric Administration Fisheries (NOAA Fisheries, formerly the National Marine Fisheries Service (NMFS)) criteria to promote safe and timely fish passage. In addition, PNNL conducted underwater video surveys to evaluate the environmental and operational conditions of the screen sites with respect to fish passage. Based on evaluations in 2003, PNNL concluded that: (1) In general, water velocity conditions at the screen sites met fish passage criteria set by the National Oceanic and Atmospheric Administration Fisheries. (2) Conditions at most facilities would be expected to provide for safe juvenile fish passage. (3) Conditions at some facilities indicate that operation and/or maintenance should be modified to improve juvenile fish passage conditions. (4) Automated cleaning brushes generally functioned properly; chains and other moving parts were typically well greased and operative. (5) Removal of sediment buildup and accumulated leafy and woody debris could be improved at some sites.

  18. Easier Phase IIs: Recent Improvements to the Gemini User Tools

    NASA Astrophysics Data System (ADS)

    Miller, Bryan; Nuñez, A.

    2013-01-01

    During 2011 and 2012 Gemini Observatory undertook a significant project to improve the software tools used by investigators to propose for and prepare observations. The main goal was to make the definition of observation details (the Phase II process) easier and faster. The main initiatives included rewriting the observing proposal tool (Phase I Tool) and making several major improvements to the Observing Tool, including automatic settings for arc and flat exposures, automatic guide star selection for all instruments and wavefront sensors, and more complete initial template observations with capabilities for simultaneous editing of many observations. This poster explains these major changes as well as outlines future development plans. The Gemini Observatory is operated by the Association of Universities for Research in Astronomy, Inc., under a cooperative agreement with the NSF on behalf of the Gemini partnership: the National Science Foundation (United States), the Science and Technology Facilities Council (United Kingdom), the National Research Council (Canada), CONICYT (Chile), the Australian Research Council (Australia), Ministério da Ciência, Tecnologia e Inovação (Brazil), and Ministerio de Ciencia, Tecnología e Innovación Productiva (Argentina).

  19. Phase II trial of methotrexate in myasthenia gravis.

    PubMed

    Pasnoor, Mamatha; He, Jianghua; Herbelin, Laura; Dimachkie, Mazen; Barohn, Richard J

    2012-12-01

    Prednisone is a frequently used treatment for myasthenia gravis (MG) but it has numerous side effects. Methotrexate is a selective inhibitor of dihydrofolate reductase and lymphocyte proliferation and is an effective immuosuppressive medication for autoimmune diseases. Given the negative results of the mycophenolate mofetil study, search for an effective immunosuppressant drug therapy is ongoing. The objective is to determine if oral methotrexate is safe and effective for MG patients who take prednisone. We have initiated a randomized, double-blind, placebo-controlled multicenter trial of methotrexate versus placebo in patients taking at least 10 mg/day of prednisone at enrollment. The methotrexate dose is increased to 20 mg and the prednisone dose is adjusted per protocol during the study. Clinical and laboratory evaluations are performed monthly for 12 months, with the primary efficacy measure being the nine-month prednisone area under the curve (AUC) from months 3 to 12. Secondary outcome measures include MG outcomes, quality of life measures, and a polyglutamation biomarker assay. A total of 18 U.S. sites and 2 Canadian sites are participating, with 48 screened cases, 42 enrolled, with 19 still active in the study.

  20. Phase II trial of methotrexate in myasthenia gravis

    PubMed Central

    Pasnoor, Mamatha; He, Jianghua; Herbelin, Laura; Dimachkie, Mazen; Barohn, Richard J.

    2013-01-01

    Prednisone is a frequently used treatment for myasthenia gravis (MG) but it has numerous side effects. Methotrexate is a selective inhibitor of dihydrofolate reductase and lymphocyte proliferation and is an effective immuosuppressive medication for autoimmune diseases. Given the negative results of the mycophenolate mofetil study, search for an effective immunosuppressant drug therapy is ongoing. The objective is to determine if oral methotrexate is safe and effective for MG patients who take prednisone. We have initiated a randomized, double-blind, placebo-controlled multicenter trial of methotrexate versus placebo in patients taking at least 10 mg/day of prednisone at enrollment. The methotrexate dose is increased to 20 mg and the prednisone dose is adjusted per protocol during the study. Clinical and laboratory evaluations are performed monthly for 12 months, with the primary efficacy measure being the nine-month prednisone area under the curve (AUC) from months 3 to 12. Secondary outcome measures include MG outcomes, quality of life measures, and a polyglutamation biomarker assay. A total of 18 U.S. sites and 2 Canadian sites are participating, with 48 screened cases, 42 enrolled, with 19 still active in the study. PMID:23278574

  1. A Randomized Controlled Trial of Online versus Clinic-Based CBT for Adolescent Anxiety

    ERIC Educational Resources Information Center

    Spence, Susan H.; Donovan, Caroline L.; March, Sonja; Gamble, Amanda; Anderson, Renee E.; Prosser, Samantha; Kenardy, Justin

    2011-01-01

    Objective: The study examined the relative efficacy of online (NET) versus clinic (CLIN) delivery of cognitive behavior therapy (CBT) in the treatment of anxiety disorders in adolescents. Method: Participants included 115 clinically anxious adolescents aged 12 to 18 years and their parent(s). Adolescents were randomly assigned to NET, CLIN, or…

  2. Acupuncture for Children with Autism Spectrum Disorders: A Systematic Review of Randomized Clinical Trials

    ERIC Educational Resources Information Center

    Lee, Myeong Soo; Choi, Tae-Young; Shin, Byung-Cheul; Ernst, Edzard

    2012-01-01

    This study aimed to assess the effectiveness of acupuncture as a treatment for autism spectrum disorders (ASD). We searched the literature using 15 databases. Eleven randomized clinical trials (RCTs) met our inclusion criteria. Most had significant methodological weaknesses. The studies' statistical and clinical heterogeneity prevented us from…

  3. Citalopram intervention for hostility: results of a randomized clinical trial.

    PubMed

    Kamarck, Thomas W; Haskett, Roger F; Muldoon, Matthew; Flory, Janine D; Anderson, Barbara; Bies, Robert; Pollock, Bruce; Manuck, Stephen B

    2009-02-01

    Hostility is associated with an increased risk for cardiovascular disease (CVD). Because central serotonin may modulate aggression, we might expect selective serotonin reuptake inhibitors (SSRIs) to be effective in reducing hostility. Such effects have never been examined in individuals scoring high on hostility who are otherwise free from major Axis I psychopathology according to criteria in the Diagnostic and Statistical Manual of Mental Disorders (4th ed., Text Revision; American Psychiatric Association, 2000). A total of 159 participants (ages 30?50 years, 50% female) scoring high on 2 measures of hostility and with no current major Axis I diagnosis were randomly assigned to 2 months of citalopram (40 mg, fixed-flexible dose) or placebo. Adherence was assessed by electronic measurement and by drug exposure assessment. Treated participants showed larger reductions in state anger (Condition x Time; p = .01), hostile affect (p = 02), and, among women only, physical and verbal aggression (p = .005) relative to placebo controls. Treatment was also associated with relative increases in perceived social support (p = .04). The findings have implications for understanding the central nervous system correlates of hostility, its associations with other psychosocial risk factors for CVD, and, potentially, the design of effective interventions. PMID:19170463

  4. Anesthetic Efficacy in Irreversible Pulpitis: A Randomized Clinical Trial.

    PubMed

    Allegretti, Carlos E; Sampaio, Roberta M; Horliana, Anna C R T; Armonia, Paschoal L; Rocha, Rodney G; Tortamano, Isabel Peixoto

    2016-01-01

    Inferior alveolar nerve block has a high failure rate in the treatment of mandibular posterior teeth with irreversible pulpitis. The aim of this study was to compare the anesthetic efficacy of 4% articaine, 2% lidocaine and 2% mepivacaine, all in combination with 1:100,000 epinephrine, in patients with irreversible pulpitis of permanent mandibular molars during a pulpectomy procedure. Sixty-six volunteers from the Emergency Center of the School of Dentistry, University of São Paulo, randomly received 3.6 mL of local anesthetic as a conventional inferior alveolar nerve block (IANB). The subjective signal of lip numbness, pulpal anesthesia and absence of pain during the pulpectomy procedure were evaluated respectively, by questioning the patient, stimulation using an electric pulp tester and a verbal analogue scale. All patients reported the subjective signal of lip numbness. Regarding pulpal anesthesia success as measured with the pulp tester, the success rate was respectively 68.2% for mepivacaine, 63.6% for articaine and 63.6% for lidocaine. Regarding patients who reported no pain or mild pain during the pulpectomy, the success rate was, respectively 72.7% for mepivacaine, 63.6% for articaine and 54.5% for lidocaine. These differences were not statistically significant. Neither of the solutions resulted in 100% anesthetic success in patients with irreversible pulpitis of mandibular molars.

  5. Phase II trial of weekly Docetaxel, Zoledronic acid, and Celecoxib for castration-resistant prostate cancer.

    PubMed

    Kattan, Joseph; Bachour, Marwan; Farhat, Fadi; El Rassy, Elie; Assi, Tarek; Ghosn, Marwan

    2016-08-01

    Background Treatment options for patients with metastatic castration-resistance prostate cancer are unsatisfactory. Docetaxel monotherapy offers promising results with a tolerable toxicity profile. However, enhancing the clinical index of Docetaxel-based therapy remains the ultimate goal. Methods We conducted a phase II, open label, multinational prospective trial to evaluate the efficacy of weekly Docetaxel combined with Zoledronic acid and Celecoxib. Eligible patients received 25 mg/m(2) Docetaxel weekly for 3 consecutive weeks every 4 weeks, 4 mg Zoledronic acid every 4 weeks, and 200 mg oral Celecoxib twice daily. Enrollment was terminated prematurely upon the publication of reports of cardiac toxicity associated with cyclooxygenase (COX) 2 inhibitors. Results Our study enrolled 22 patients with a median of 4.7 cycles per patient. The median overall survival (OS) was 9.8 months (range 0.7 to 24.1 months) with 36 % and 4.5 % survival rates at 1 and 2 years, respectively. Our patients had a biologic response in 40.1 % of cases and a palliative response in 72.7 %. Among the eight patients with measurable disease, three had partial responses, two had stable disease, and three had progressive disease, leading to a response rate (RR) of 62.5 %. The observed toxicities were mild and limited to grade 3 events. Nine patients had anemia (40.1 %), 5 had sensory neuropathy (22.7 %) and 2 had stomatitis (9.1 %). Conclusion The combination of Docetaxel, Celecoxib, and Zoledronic acid failed to improve OS or to offer an acceptable biologic response. We do not believe that there is compelling evidence to include either Celecoxib or Zoledronic acid in further phase II/III trials. PMID:27159981

  6. Phase II screening trial of lithium carbonate in amyotrophic lateral sclerosis

    PubMed Central

    Moore, D.H.; Forshew, D.A.; Katz, J.S.; Barohn, R.J.; Valan, M.; Bromberg, M.B.; Goslin, K.L.; Graves, M.C.; McCluskey, L.F.; McVey, A.L.; Mozaffar, T.; Florence, J.M.; Pestronk, A.; Ross, M.; Simpson, E.P.; Appel, S.H.

    2011-01-01

    Objective: To use a historical placebo control design to determine whether lithium carbonate slows progression of amyotrophic lateral sclerosis (ALS). Methods: A phase II trial was conducted at 10 sites in the Western ALS Study Group using similar dosages (300–450 mg/day), target blood levels (0.3–0.8 mEq/L), outcome measures, and trial duration (13 months) as the positive trial. However, taking riluzole was not a requirement for study entry. Placebo outcomes in patients matched for baseline features from a large database of recent clinical trials, showing stable rates of decline over the past 9 years, were used as historical controls. Results: The mean rate of decline of the ALS Functional Rating Scale–Revised was greater in 107 patients taking lithium carbonate (−1.20/month, 95% confidence interval [CI] −1.41 to −0.98) than that in 249 control patients (−1.01/month, 95% CI −1.11 to −0.92, p = 0.04). There were no differences in secondary outcome measures (forced vital capacity, time to failure, and quality of life), but there were more adverse events in the treated group. Conclusions: The lack of therapeutic benefit and safety concerns, taken together with similar results from 2 other recent trials, weighs against the use of lithium carbonate in patients with ALS. The absence of drift over time and the availability of a large database of patients for selecting a matched historical control group suggest that use of historical controls may result in more efficient phase II trials for screening putative ALS therapeutic agents. Classification of evidence: This study provided Class IV evidence that lithium carbonate does not slow the rate of decline of function in patients with ALS over 13 months. Neurology® 2011;77:973–979 PMID:21813790

  7. A phase II study of tamoxifen plus melatonin in metastatic solid tumour patients.

    PubMed

    Lissoni, P; Paolorossi, F; Tancini, G; Ardizzoia, A; Barni, S; Brivio, F; Maestroni, G J; Chilelli, M

    1996-11-01

    Preliminary data would suggest that the pineal hormone, melatonin (MLT), may enhance tamoxifen (TMX) anti-tumour efficacy. Both MLT and TMX have been used as single agents in the palliative treatment of metastatic neoplasms, other than the classical hormone-dependent tumours, without, however, any clear efficacy. On this basis, a phase II study with TMX plus MLT has been performed in untreatable metastatic solid tumour patients. The study included 25 metastatic solid tumour patients other than breast cancer and prostate cancer (six unknown primary tumour; four melanoma; four uterine cervix carcinoma; five pancreatic cancer; three hepatocarcinoma; two ovarian cancer; one non-small-cell lung cancer), for whom no other effective standard therapy was available, because of poor clinical conditions, no response to previous chemotherapies and/or chemotherapy-resistant tumours. Both drugs were given orally every day until disease progression (TMX, 20 mg day-1 at noon; MLT, 20 mg day-1 in the evening). Three patients had a partial response (PR) (12%; 95% confidence limits 2-24%) (one cervix carcinoma; one melanoma; one unknown primary tumour). A stable disease (SD) was achieved in 13 other patients, whereas the remaining nine patients progressed. Performance status (PS) improved in 9/25 patients, whose median score increased from 50% to 70%. Finally, a survival longer than 1 year was observed in 7/25 (28%) patients. This phase II study would suggest that the neuroendocrine combination with TMX plus MLT may have some benefit in untreatable metastatic solid tumour patients, either in controlling cancer cell proliferation or improving the PS.

  8. A phase II study of tamoxifen plus melatonin in metastatic solid tumour patients.

    PubMed Central

    Lissoni, P.; Paolorossi, F.; Tancini, G.; Ardizzoia, A.; Barni, S.; Brivio, F.; Maestroni, G. J.; Chilelli, M.

    1996-01-01

    Preliminary data would suggest that the pineal hormone, melatonin (MLT), may enhance tamoxifen (TMX) anti-tumour efficacy. Both MLT and TMX have been used as single agents in the palliative treatment of metastatic neoplasms, other than the classical hormone-dependent tumours, without, however, any clear efficacy. On this basis, a phase II study with TMX plus MLT has been performed in untreatable metastatic solid tumour patients. The study included 25 metastatic solid tumour patients other than breast cancer and prostate cancer (six unknown primary tumour; four melanoma; four uterine cervix carcinoma; five pancreatic cancer; three hepatocarcinoma; two ovarian cancer; one non-small-cell lung cancer), for whom no other effective standard therapy was available, because of poor clinical conditions, no response to previous chemotherapies and/or chemotherapy-resistant tumours. Both drugs were given orally every day until disease progression (TMX, 20 mg day-1 at noon; MLT, 20 mg day-1 in the evening). Three patients had a partial response (PR) (12%; 95% confidence limits 2-24%) (one cervix carcinoma; one melanoma; one unknown primary tumour). A stable disease (SD) was achieved in 13 other patients, whereas the remaining nine patients progressed. Performance status (PS) improved in 9/25 patients, whose median score increased from 50% to 70%. Finally, a survival longer than 1 year was observed in 7/25 (28%) patients. This phase II study would suggest that the neuroendocrine combination with TMX plus MLT may have some benefit in untreatable metastatic solid tumour patients, either in controlling cancer cell proliferation or improving the PS. PMID:8912546

  9. Suggested response criteria for phase II antitumor drug studies for neurofibromatosis type 2 related vestibular schwannoma

    PubMed Central

    Plotkin, Scott R.; Halpin, Chris; Blakeley, Jaishri O.; Slattery, William H.; Welling, D. Bradley; Chang, Susan M.; Loeffler, Jay S.; Harris, Gordon J.; Sorensen, A. Gregory; McKenna, Michael J.

    2014-01-01

    Neurofibromatosis type 2 (NF2) is a tumor suppressor gene syndrome characterized by multiple schwannomas, especially vestibular schwannomas (VS), and meningiomas. Anticancer drug trials are now being explored, but there are no standardized endpoints in NF2. We review the challenges of NF2 clinical trials and suggest possible response criteria for use in initial phase II studies. We suggest two main response criteria in such trials. Objective radiographic response is defined as a durable 20% or greater reduction in VS volume based on postcontrast T1-weighted MRI images collected with 3 mm or finer cuts through the internal auditory canal. Hearing response is defined as a statistically significant improvement in word recognition scores using 50-word recorded lists in audiology. A possible composite endpoint incorporating both radiographic response and hearing response is outlined. We emphasize pitfalls in response assessment and suggest guidelines to minimize misinterpretations of response. We also identify research goals in NF2 to facilitate future trial conduct, such as identifying the expectations for time to tumor progression and time to measurable hearing loss in untreated NF2-related VS, and the relation of both endpoints to patient prognostic factors (such as age, baseline tumor volume, and measures of disease severity). These data would facilitate future use of endpoints based on stability of tumor size and hearing, which might be more appropriate for testing certain drugs. We encourage adoption of standardized endpoints early in the development of phase II trials for this population to facilitate comparison of results across trials of different agents. PMID:19430883

  10. Analytical strategies for the direct mass spectrometric analysis of steroid and corticosteroid phase II metabolites.

    PubMed

    Antignac, Jean-Philippe; Brosseaud, Aline; Gaudin-Hirret, Isabelle; André, François; Bizec, Bruno Le

    2005-03-01

    The use of steroid hormones as growth promoters remains illegal in Europe. A classical approach used to control their utilization consists to measure the parent drug in target biological matrices. However, this strategy may fail when the parent drug is submitted to extensive metabolism reactions. For urine and tissue samples, chemical or enzymatic hydrolysis is usually applied in order to deconjugate glucuronide and sulfate phase II metabolites. But this treatment lead to the loss of information such as nature and relative proportions of the different conjugated forms, which can be useful, for example, to discriminate an endogenous production from an exogenous administration for natural hormones, or for other clinical or biochemical specific applications. For these purposes, direct measurement of conjugated metabolites using liquid chromatography-tandem mass spectrometry may represent a solution of choice. In this context, the mass spectrometric behavior of 14 steroid and corticosteroid phase II metabolites after electrospray ionization was investigated. Their fragmentation pathways in tandem mass spectrometry revealed some specificities within the different group of conjugates. A specific acquisition program (MRM mode) was developed for the unambiguous identification of the studied reference compounds. A more generic method (Parent Scan mode) was also developed for fishing approaches consisting to monitor several fragment ions typical of each conjugate class. A reverse phase HPLC procedure was also proposed for efficient retention and separation of the studied compounds. Finally, a protocol based on quaternary amine SPE was developed, permitting the separation of free, glucuronide, and sulfate fractions. Preliminary results on biological samples demonstrated the suitability of this analytical strategy for direct measurement of dexamethasone glucuronide and sulfate residues in bovine urine.

  11. What Works in Oklahoma Schools: A Comprehensive Needs Assessment of Oklahoma Schools. Phase II State Report

    ERIC Educational Resources Information Center

    Marzano Research Laboratory, 2010

    2010-01-01

    Phase II provides a more detailed examination of classroom variables important to achievement in Oklahoma schools. Where Phase I addressed all nine of the Oklahoma essential elements using survey data, Phase II focuses on what occurs in Oklahoma classrooms primarily using data from principal interviews, classroom observations (on-site), and video…

  12. Artwork: Johnson Space Center U.S./International Cooperation Phase II -- This is a representation

    NASA Technical Reports Server (NTRS)

    1994-01-01

    Artwork: Johnson Space Center U.S./International Cooperation Phase II -- This is a representation illustrating the United States' international cooperation in space. Phase II of the International Space Station is depicted with elements provided by the United States and Russia comprising the Human Tended Space Station. The scene was produced by John Frassanito and Associates. (JSC ref: S94-30086)

  13. TNX GeoSiphon Cell (TGSC-1) Phase II Single Cell Deployment/Demonstration Final Report

    SciTech Connect

    Phifer, M.A.

    1999-04-15

    This Phase II final report documents the Phase II testing conducted from June 18, 1998 through November 13, 1998, and it focuses on the application of the siphon technology as a sub-component of the overall GeoSiphon Cell technology. [Q-TPL-T-00004

  14. 40 CFR 72.74 - Federal issuance of Phase II permits.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... PROGRAMS (CONTINUED) PERMITS REGULATION Acid Rain Phase II Implementation § 72.74 Federal issuance of Phase II permits. (a)(1) The Administrator will be responsible for administering and enforcing Acid Rain... and enforcing Acid Rain permits for such sources under § 72.73(a). (2) After and to the extent...

  15. 40 CFR 72.74 - Federal issuance of Phase II permits.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... PROGRAMS (CONTINUED) PERMITS REGULATION Acid Rain Phase II Implementation § 72.74 Federal issuance of Phase II permits. (a)(1) The Administrator will be responsible for administering and enforcing Acid Rain... and enforcing Acid Rain permits for such sources under § 72.73(a). (2) After and to the extent...

  16. 40 CFR 72.73 - State issuance of Phase II permits.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... (CONTINUED) PERMITS REGULATION Acid Rain Phase II Implementation § 72.73 State issuance of Phase II permits... permit program under part 70 of this chapter and that has a State Acid Rain program accepted by the Administrator under § 72.71 shall be responsible for administering and enforcing Acid Rain permits effective...

  17. 40 CFR 72.73 - State issuance of Phase II permits.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... (CONTINUED) PERMITS REGULATION Acid Rain Phase II Implementation § 72.73 State issuance of Phase II permits... permit program under part 70 of this chapter and that has a State Acid Rain program accepted by the Administrator under § 72.71 shall be responsible for administering and enforcing Acid Rain permits effective...

  18. 40 CFR 72.74 - Federal issuance of Phase II permits.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... PROGRAMS (CONTINUED) PERMITS REGULATION Acid Rain Phase II Implementation § 72.74 Federal issuance of Phase II permits. (a)(1) The Administrator will be responsible for administering and enforcing Acid Rain... and enforcing Acid Rain permits for such sources under § 72.73(a). (2) After and to the extent...

  19. 40 CFR 72.74 - Federal issuance of Phase II permits.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... PROGRAMS (CONTINUED) PERMITS REGULATION Acid Rain Phase II Implementation § 72.74 Federal issuance of Phase II permits. (a)(1) The Administrator will be responsible for administering and enforcing Acid Rain... and enforcing Acid Rain permits for such sources under § 72.73(a). (2) After and to the extent...

  20. 40 CFR 72.73 - State issuance of Phase II permits.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... (CONTINUED) PERMITS REGULATION Acid Rain Phase II Implementation § 72.73 State issuance of Phase II permits... permit program under part 70 of this chapter and that has a State Acid Rain program accepted by the Administrator under § 72.71 shall be responsible for administering and enforcing Acid Rain permits effective...

  1. 40 CFR 72.73 - State issuance of Phase II permits.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... (CONTINUED) PERMITS REGULATION Acid Rain Phase II Implementation § 72.73 State issuance of Phase II permits... permit program under part 70 of this chapter and that has a State Acid Rain program accepted by the Administrator under § 72.71 shall be responsible for administering and enforcing Acid Rain permits effective...

  2. 40 CFR 72.73 - State issuance of Phase II permits.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... (CONTINUED) PERMITS REGULATION Acid Rain Phase II Implementation § 72.73 State issuance of Phase II permits... permit program under part 70 of this chapter and that has a State Acid Rain program accepted by the Administrator under § 72.71 shall be responsible for administering and enforcing Acid Rain permits effective...

  3. 40 CFR 72.74 - Federal issuance of Phase II permits.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... PROGRAMS (CONTINUED) PERMITS REGULATION Acid Rain Phase II Implementation § 72.74 Federal issuance of Phase II permits. (a)(1) The Administrator will be responsible for administering and enforcing Acid Rain... and enforcing Acid Rain permits for such sources under § 72.73(a). (2) After and to the extent...

  4. 47 CFR 54.310 - Connect America Fund for Price Cap Territories-Phase II

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 47 Telecommunication 3 2014-10-01 2014-10-01 false Connect America Fund for Price Cap Territories... Connect America Fund for Price Cap Territories—Phase II (a) Geographic areas eligible for support. Connect... identified by public notice. (b) Term of support. Connect America Phase II model-based support shall...

  5. 78 FR 8184 - DEEPWATER HORIZON Oil Spill; Final Phase II Early Restoration Plan and Environmental Review

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-02-05

    ... availability of the Phase II DERP/ER was published in the Federal Register on November 6, 2012. (77 FR 66626... DEEPWATER HORIZON Oil Spill; Final Phase II Early Restoration Plan and Environmental Review AGENCY: Interior... (OPA), the National Environmental Policy Act (NEPA), and the Framework Agreement for Early...

  6. Investing in Our Nation's Youth. National Youth Anti-Drug Media Campaign: Phase II (Final Report).

    ERIC Educational Resources Information Center

    Office of National Drug Control Policy, Washington, DC.

    This publication presents the findings from an evaluation of Phase II of the National Youth Anti-Drug Media Campaign. The number one goal of the campaign was to educate youth to reject illegal drugs. This report evaluates Phase II and focuses on the effect of paid television advertising on awareness of anti-drug messages among youth, teens, and…

  7. A steerable/distance enhanced penetrometer delivery system: Phase II. Topical report

    SciTech Connect

    Amini, A.; Shenhar, J.; Lum, K.D.

    1996-05-01

    This report summarizes the phase II work on the Position Location Device (POLO) for penetrometers. Phase II was carried out to generate an integrated design of a full-scale steerable/distance enhanced penetrometer delivery system. Steering provides for the controlled and directional use of the penetrometer, while vibratory thrusting can provide greater penetration ability.

  8. Comprehension of Randomization and Uncertainty in Cancer Clinical Trials Decision Making Among Rural, Appalachian Patients.

    PubMed

    Krieger, Janice L; Palmer-Wackerly, Angela; Dailey, Phokeng M; Krok-Schoen, Jessica L; Schoenberg, Nancy E; Paskett, Electra D

    2015-12-01

    Comprehension of randomization is a vital, but understudied, component of informed consent to participate in cancer randomized clinical trials (RCTs). This study examines patient comprehension of the randomization process as well as sources of ongoing uncertainty that may inhibit a patient's ability to provide informed consent to participate in RCTs. Cancer patients living in rural Appalachia who were offered an opportunity to participate in a cancer treatment RCT completed in-depth interviews and a brief survey. No systematic differences in randomization comprehension between patients who consented and those who declined participation in a cancer RCT were detected. Comprehension is conceptually distinct from uncertainty, with patients who had both high and low comprehension experiencing randomization-related uncertainty. Uncertainty about randomization was found to have cognitive and affective dimensions. Not all patients enrolling in RCTs have a sufficient understanding of the randomization process to provide informed consent. Healthcare providers need to be aware of the different types of randomization-related uncertainty. Efforts to improve informed consent to participate in RCTs should focus on having patients teach back their understanding of randomization. This practice could yield valuable information about the patient's cognitive and affective understanding of randomization as well as opportunities to correct misperceptions. Education about RCTs should reflect patient expectations of individualized care by explaining how all treatments being compared are appropriate to the specifics of a patient's disease.

  9. Robustness of ordinary least squares in randomized clinical trials.

    PubMed

    Judkins, David R; Porter, Kristin E

    2016-05-20

    There has been a series of occasional papers in this journal about semiparametric methods for robust covariate control in the analysis of clinical trials. These methods are fairly easy to apply on currently available computers, but standard software packages do not yet support these methods with easy option selections. Moreover, these methods can be difficult to explain to practitioners who have only a basic statistical education. There is also a somewhat neglected history demonstrating that ordinary least squares (OLS) is very robust to the types of outcome distribution features that have motivated the newer methods for robust covariate control. We review these two strands of literature and report on some new simulations that demonstrate the robustness of OLS to more extreme normality violations than previously explored. The new simulations involve two strongly leptokurtic outcomes: near-zero binary outcomes and zero-inflated gamma outcomes. Potential examples of such outcomes include, respectively, 5-year survival rates for stage IV cancer and healthcare claim amounts for rare conditions. We find that traditional OLS methods work very well down to very small sample sizes for such outcomes. Under some circumstances, OLS with robust standard errors work well with even smaller sample sizes. Given this literature review and our new simulations, we think that most researchers may comfortably continue using standard OLS software, preferably with the robust standard errors.

  10. A phase II study of axitinib in advanced neuroendocrine tumors

    PubMed Central

    Strosberg, J R; Cives, M; Hwang, J; Weber, T; Nickerson, M; Atreya, C E; Venook, A; Kelley, R K; Valone, T; Morse, B; Coppola, D; Bergsland, E K

    2016-01-01

    Neuroendocrine tumors (NETs) are highly vascular neoplasms overexpressing vascular endothelial growth factor (VEGF) as well as VEGF receptors (VEGFR). Axitinib is a potent, selective inhibitor of VEGFR-1, -2 and -3, currently approved for the treatment of advanced renal cell carcinoma. We performed an open-label, two-stage design, phase II trial of axitinib 5 mg twice daily in patients with progressive unresectable/metastatic low-to-intermediate grade carcinoid tumors. The primary end points were progression-free survival (PFS) and 12-month PFS rate. The secondary end points included time to treatment failure (TTF), overall survival (OS), overall radiographic response rate (ORR), biochemical response rate and safety. A total of 30 patients were enrolled and assessable for toxicity; 22 patients were assessable for response. After a median follow-up of 29 months, we observed a median PFS of 26.7 months (95% CI, 11.4–35.1), with a 12-month PFS rate of 74.5% (±10.2). The median OS was 45.3 months (95% CI, 24.4–45.3), and the median TTF was 9.6 months (95% CI, 5.5–12). The best radiographic response was partial response (PR) in 1/30 (3%) and stable disease (SD) in 21/30 patients (70%); 8/30 patients (27%) were unevaluable due to early withdrawal due to toxicity. Hypertension was the most common toxicity that developed in 27 patients (90%). Grade 3/4 hypertension was recorded in 19 patients (63%), leading to treatment discontinuation in six patients (20%). Although axitinib appears to have an inhibitory effect on tumor growth in patients with advanced, progressive carcinoid tumors, the high rate of grade 3/4 hypertension may represent a potential impediment to its use in unselected patients. PMID:27080472

  11. A phase II trial of oral gimatecan for recurrent glioblastoma.

    PubMed

    Hu, Jethro; Wen, Patrick Y; Abrey, Lauren E; Fadul, Camilo E; Drappatz, Jan; Salem, Nadia; Supko, Jeffrey G; Hochberg, Fred

    2013-02-01

    Gimatecan is a lipophilic oral camptothecin analogue with preclinical activity in glioma models. We conducted a multicenter phase II trial to evaluate the efficacy of gimatecan in adults with recurrent glioblastoma. Eligibility criteria included ≤1 prior treatment for recurrent disease, age ≥18, Eastern Cooperative Oncology Group performance status 0-1, and normal organ function. Patients taking enzyme-inducing anti-seizure medications were excluded. Gimatecan 1.22 mg/m(2) was given orally once daily for 5 consecutive days during each 28-day cycle. The primary endpoint was progression-free survival at 6 months. A Simon 2-stage optimal design was used in which 19 patients were evaluated in the 1st stage, with an additional 36 patients accrued if >4 patients in stage 1 achieved PFS at 6 months. 29 patients were enrolled in the study, with median age of 58 years (range, 25-77 years); 58.6 % female. All patients received prior surgery, radiation therapy, and at least one chemotherapy regimen. The daily dose was reduced to 1.0 mg/m(2) after four of the first 10 patients experienced grade 4 hematologic toxicity. Treatment-related grade 3/4 toxicities included thrombocytopenia (17.2 %), leukopenia (17.2 %) and neutropenia (10.3 %). None of the 19 patients treated at 1.0 mg/m(2)/day experienced grade 4 hematologic toxicity. One patient had a partial radiographic response by modified Macdonald criteria. Only 3 patients (12 %) were progression-free at 6 months. Median time to progression was 12.0 weeks (7.0, 17.0).Treatment with gimatecan 1.0 mg/m(2)/day for 5 days, repeated every 28-days showed minimal efficacy.

  12. MHD seed recovery and regeneration, Phase II. Final report

    SciTech Connect

    Not Available

    1994-10-01

    This final report summarizes the work performed by the Space and Technology Division of the TRW Space and Electronics Group for the U.S. Department of Energy, Pittsburgh Energy Technology Center for the Econoseed process. This process involves the economical recovery and regeneration of potassium seed used in the MHD channel. The contract period of performance extended from 1987 through 1994 and was divided into two phases. The Phase II test results are the subject of this Final Report. However, the Phase I test results are presented in summary form in Section 2.3 of this Final Report. The Econoseed process involves the treatment of the potassium sulfate in spent MHD seed with an aqueous calcium formate solution in a continuously stirred reactor system to solubilize, as potassium formate, the potassium content of the seed and to precipitate and recover the sulfate as calcium sulfate. The slurry product from this reaction is centrifuged to separate the calcium sulfate and insoluble seed constituents from the potassium formate solution. The dilute solids-free potassium formate solution is then concentrated in an evaporator. The concentrated potassium formate product is a liquid which can be recycled as a spray into the MHD channel. Calcium formate is the seed regenerant used in the Econoseed process. Since calcium formate is produced in the United States in relatively small quantities, a new route to the continuous production of large quantities of calcium formate needed to support an MHD power industry was investigated. This route involves the reaction of carbon monoxide gas with lime solids in an aqueous medium.

  13. NOx control subsystem test plan: LEBS Phase II

    SciTech Connect

    1995-03-16

    It is planned that NO{sub x} control subsystem testing in support of Phase II of the Low-Emissions Boiler Systems (LEBS) Project occur in ABB Power Plant Laboratories` (PPL) pilot scale Boiler Simulation Facility (BSF). This work will be performed to provide necessary design and operational information for inclusion of an optimized NO, control subsystem in the Proof-of-Concept Test Facility (POCTF) and Commercial Generating Unit (CGU) designs. The BSF is a 50 to 90x10{sup 6} BTU/hr (15 to 26 MWt) coal, oil or natural gas fired tangential furnace designed to replicate the residence time/temperature history of a utility scale tangentially fired boiler. All major aspects of a typical utility boiler are duplicated in the BSF including the lower furnace, the ash hopper, multiple burner elevations, the arch section, superheater/reheater panels, and the convective heat transfer surfaces. The furnace walls and heat transfer surfaces are cooled by a surrounding water jacket. Steam generated is vented off at atmospheric pressure so that a constant sink temperature of 100{degrees}C (212{degrees}C) is maintained. The lower furnace water walls are selectively refractory lined to maintain an appropriate furnace gas temperature history. Refractory is required because the sink temperature (100{degrees}C) is cooler than that of a typical, utility boiler, and the surface-to-volume ratio of the BSF is greater than that of a utility boiler due to scale effects. For the subject testing, the BSF will be configured as a coal fired boiler. Design and planning activities associated with the construction of the NO{sub x} control subsystem test unit will continue through June, 1995. Additionally, the schedule for specification of certain low NO{sub x} firing system components was set to allow for precursor, internal and LEBS development activities to occur and subsequently provide necessary design parameters.

  14. When to base clinical policies on observational versus randomized trial data.

    PubMed

    Hornberger, J; Wrone, E

    1997-10-15

    Physicians must decide when the evidence is sufficient to adopt a new clinical policy. Analysis of large clinical and administrative databases is becoming an important source of evidence for changing clinical policies. Because such analysis cannot control for the effects of all potential confounding variables, physicians risk drawing the wrong conclusion about the cause-and-effect relation between a change in clinical policy and outcomes. Randomized studies offer protection against drawing a conclusion that would lead to adoption of an inferior policy. However, a randomized study may be difficult to justify because of the extra costs of collecting data for a randomized study and concerns that a study will not directly benefit the patients enrolled in the study. This article reviews the advantages and disadvantages of basing clinical policy on analysis of large databases compared with conducting a randomized study. A technique is described and illustrated for accessing the potential costs and benefits of conducting such a study. This type of analysis formed the basis for a physician-managed health care organization deciding to sponsor a randomized study among patients with end-stage renal disease as part of a quality-improvement initiative. PMID:9382383

  15. Primary Analysis of a Phase II Randomized Trial Radiation Therapy Oncology Group (RTOG) 0212: Impact of Different Total Doses and Schedules of Prophylactic Cranial Irradiation on Chronic Neurotoxicity and Quality of Life for Patients With Limited-Disease Small-Cell Lung Cancer

    SciTech Connect

    Wolfson, Aaron H.; Bae, Kyounghwa; Komaki, Ritsuko; Meyers, Christina; Movsas, Benjamin; Le Pechoux, Cecile; Werner-Wasik, Maria; Videtic, Gregory M.M.; Garces, Yolanda I.; Choy, Hak

    2011-09-01

    Purpose: To determine the effect of dose and fractionation schedule of prophylactic cranial irradiation (PCI) on the incidence of chronic neurotoxicity (CNt) and changes in quality of life for selected patients with limited-disease small-cell lung cancer (LD SCLC). Methods and Materials: Patients with LD SCLC who achieved a complete response after chemotherapy and thoracic irradiation were eligible for randomization to undergo PCI to a total dose of 25 Gy in 10 daily fractions (Arm 1) vs. the experimental cohort of 36 Gy. Those receiving 36 Gy underwent a secondary randomization between daily 18 fractions (Arm 2) and twice-daily 24 fractions (Arm 3). Enrolled patients participated in baseline and follow-up neuropsychological test batteries along with quality-of-life assessments. Results: A total of 265 patients were accrued, with 131 in Arm 1, 67 in Arm 2, and 66 in Arm 3 being eligible. There are 112 patients (42.2%) alive with 25.3 months of median follow-up. There were no significant baseline differences among groups regarding quality-of-life measures and one of the neuropsychological tests, namely the Hopkins Verbal Learning Test. However, at 12 months after PCI there was a significant increase in the occurrence of CNt in the 36-Gy cohort (p = 0.02). Logistic regression analysis revealed increasing age to be the most significant predictor of CNt (p = 0.005). Conclusions: Because of the increased risk of developing CNt in study patients with 36 Gy, a total PCI dose of 25 Gy remains the standard of care for patients with LD SCLC attaining a complete response to initial chemoradiation.

  16. Combining randomized and non-randomized evidence in clinical research: a review of methods and applications.

    PubMed

    Verde, Pablo E; Ohmann, Christian

    2015-03-01

    Researchers may have multiple motivations for combining disparate pieces of evidence in a meta-analysis, such as generalizing experimental results or increasing the power to detect an effect that a single study is not able to detect. However, while in meta-analysis, the main question may be simple, the structure of evidence available to answer it may be complex. As a consequence, combining disparate pieces of evidence becomes a challenge. In this review, we cover statistical methods that have been used for the evidence-synthesis of different study types with the same outcome and similar interventions. For the methodological review, a literature retrieval in the area of generalized evidence-synthesis was performed, and publications were identified, assessed, grouped and classified. Furthermore real applications of these methods in medicine were identified and described. For these approaches, 39 real clinical applications could be identified. A new classification of methods is provided, which takes into account: the inferential approach, the bias modeling, the hierarchical structure, and the use of graphical modeling. We conclude with a discussion of pros and cons of our approach and give some practical advice. PMID:26035469

  17. Are Randomized Controlled Trials the (G)old Standard? From Clinical Intelligence to Prescriptive Analytics

    PubMed Central

    2016-01-01

    Despite the accelerating pace of scientific discovery, the current clinical research enterprise does not sufficiently address pressing clinical questions. Given the constraints on clinical trials, for a majority of clinical questions, the only relevant data available to aid in decision making are based on observation and experience. Our purpose here is 3-fold. First, we describe the classic context of medical research guided by Poppers’ scientific epistemology of “falsificationism.” Second, we discuss challenges and shortcomings of randomized controlled trials and present the potential of observational studies based on big data. Third, we cover several obstacles related to the use of observational (retrospective) data in clinical studies. We conclude that randomized controlled trials are not at risk for extinction, but innovations in statistics, machine learning, and big data analytics may generate a completely new ecosystem for exploration and validation. PMID:27383622

  18. Are Randomized Controlled Trials the (G)old Standard? From Clinical Intelligence to Prescriptive Analytics.

    PubMed

    Van Poucke, Sven; Thomeer, Michiel; Heath, John; Vukicevic, Milan

    2016-07-06

    Despite the accelerating pace of scientific discovery, the current clinical research enterprise does not sufficiently address pressing clinical questions. Given the constraints on clinical trials, for a majority of clinical questions, the only relevant data available to aid in decision making are based on observation and experience. Our purpose here is 3-fold. First, we describe the classic context of medical research guided by Poppers' scientific epistemology of "falsificationism." Second, we discuss challenges and shortcomings of randomized controlled trials and present the potential of observational studies based on big data. Third, we cover several obstacles related to the use of observational (retrospective) data in clinical studies. We conclude that randomized controlled trials are not at risk for extinction, but innovations in statistics, machine learning, and big data analytics may generate a completely new ecosystem for exploration and validation.

  19. Are Randomized Controlled Trials the (G)old Standard? From Clinical Intelligence to Prescriptive Analytics.

    PubMed

    Van Poucke, Sven; Thomeer, Michiel; Heath, John; Vukicevic, Milan

    2016-01-01

    Despite the accelerating pace of scientific discovery, the current clinical research enterprise does not sufficiently address pressing clinical questions. Given the constraints on clinical trials, for a majority of clinical questions, the only relevant data available to aid in decision making are based on observation and experience. Our purpose here is 3-fold. First, we describe the classic context of medical research guided by Poppers' scientific epistemology of "falsificationism." Second, we discuss challenges and shortcomings of randomized controlled trials and present the potential of observational studies based on big data. Third, we cover several obstacles related to the use of observational (retrospective) data in clinical studies. We conclude that randomized controlled trials are not at risk for extinction, but innovations in statistics, machine learning, and big data analytics may generate a completely new ecosystem for exploration and validation. PMID:27383622

  20. A better alternative to stratified permuted block design for subject randomization in clinical trials.

    PubMed

    Zhao, Wenle

    2014-12-30

    Stratified permuted block randomization has been the dominant covariate-adaptive randomization procedure in clinical trials for several decades. Its high probability of deterministic assignment and low capacity of covariate balancing have been well recognized. The popularity of this sub-optimal method is largely due to its simplicity in implementation and the lack of better alternatives. Proposed in this paper is a two-stage covariate-adaptive randomization procedure that uses the block urn design or the big stick design in stage one to restrict the treatment imbalance within each covariate stratum, and uses the biased-coin minimization method in stage two to control imbalances in the distribution of additional covariates that are not included in the stratification algorithm. Analytical and simulation results show that the new randomization procedure significantly reduces the probability of deterministic assignments, and improve the covariate balancing capacity when compared to the traditional stratified permuted block randomization. PMID:25043719

  1. Effects of unstratified and centre-stratified randomization in multi-centre clinical trials.

    PubMed

    Anisimov, Vladimir V

    2011-01-01

    This paper deals with the analysis of randomization effects in multi-centre clinical trials. The two randomization schemes most often used in clinical trials are considered: unstratified and centre-stratified block-permuted randomization. The prediction of the number of patients randomized to different treatment arms in different regions during the recruitment period accounting for the stochastic nature of the recruitment and effects of multiple centres is investigated. A new analytic approach using a Poisson-gamma patient recruitment model (patients arrive at different centres according to Poisson processes with rates sampled from a gamma distributed population) and its further extensions is proposed. Closed-form expressions for corresponding distributions of the predicted number of the patients randomized in different regions are derived. In the case of two treatments, the properties of the total imbalance in the number of patients on treatment arms caused by using centre-stratified randomization are investigated and for a large number of centres a normal approximation of imbalance is proved. The impact of imbalance on the power of the study is considered. It is shown that the loss of statistical power is practically negligible and can be compensated by a minor increase in sample size. The influence of patient dropout is also investigated. The impact of randomization on predicted drug supply overage is discussed.

  2. BEST: A Randomized Phase II Study of Vascular Endothelial Growth Factor, RAF Kinase, and Mammalian Target of Rapamycin Combination Targeted Therapy With Bevacizumab, Sorafenib, and Temsirolimus in Advanced Renal Cell Carcinoma—A Trial of the ECOG–ACRIN Cancer Research Group (E2804)

    PubMed Central

    Flaherty, Keith T.; Manola, Judith B.; Pins, Michael; McDermott, David F.; Atkins, Michael B.; Dutcher, Janice J.; George, Daniel J.; Margolin, Kim A.; DiPaola, Robert S.

    2015-01-01

    Purpose On the basis of evidence that resistance to vascular endothelial growth factor (VEGF) receptor inhibition is caused by hypoxia-driven residual VEGF and other proangiogenic factors, combinations of agents from these classes were hypothesized to improve treatment outcomes relative to single-agent VEGF pathway blockade. Patients and Methods A total of 361 patients with metastatic clear cell renal cell carcinoma were randomly assigned equally to arm A (bevacizumab monotherapy 10 mg/kg intravenously [IV] every 2 weeks), B (bevacizumab 10 mg/kg IV every 2 weeks and temsirolimus 25 mg IV every week), C (bevacizumab 5 mg/kg IV every 2 weeks and sorafenib 200 mg orally twice daily on days 1 to 5, 8 to 12, 15 to 19, and 22 to 26), or D (sorafenib 200 mg twice daily and temsirolimus 25 mg IV weekly). Progression-free survival was the primary end point. Results Among 331 eligible treated patients, median PFS was 7.5 months for bevacizumab alone (90% CI, 5.8 to 10.8 months), 7.6 months for bevacizumab plus temsirolimus (90% CI, 6.7 to 9.2 months), 9.2 months for bevacizumab plus sorafenib (90% CI, 7.5 to 11.4 months), and 7.4 months for sorafenib plus temsirolimus (90% CI, 5.6 to 7.9 months). Hazard ratios from stratified Cox proportional hazards models were 1.01, 0.89, and 1.07 (with respective P values of .95, .49, and .68) for the three combinations, respectively, compared with bevacizumab alone. Adverse events did not differ significantly among treatment arms. Conclusion The activity of sorafenib, temsirolimus, and bevacizumab administered in doublet combinations did not significantly improve median progression-free survival in comparison with bevacizumab monotherapy. PMID:26077237

  3. Transcranial Direct Current Stimulation Combined with Aerobic Exercise to Optimize Analgesic Responses in Fibromyalgia: A Randomized Placebo-Controlled Clinical Trial

    PubMed Central

    Mendonca, Mariana E.; Simis, Marcel; Grecco, Luanda C.; Battistella, Linamara R.; Baptista, Abrahão F.; Fregni, Felipe

    2016-01-01

    Fibromyalgia is a chronic pain syndrome that is associated with maladaptive plasticity in neural central circuits. One of the neural circuits that are involved in pain in fibromyalgia is the primary motor cortex. We tested a combination intervention that aimed to modulate the motor system: transcranial direct current stimulation (tDCS) of the primary motor cortex (M1) and aerobic exercise (AE). In this phase II, sham-controlled randomized clinical trial, 45 subjects were assigned to 1 of 3 groups: tDCS + AE, AE only, and tDCS only. The following outcomes were assessed: intensity of pain, level of anxiety, quality of life, mood, pressure pain threshold, and cortical plasticity, as indexed by transcranial magnetic stimulation. There was a significant effect for the group-time interaction for intensity of pain, demonstrating that tDCS/AE was superior to AE [F(13, 364) = 2.25, p = 0.007] and tDCS [F(13, 364) = 2.33, p = 0.0056] alone. Post-hoc adjusted analysis showed a difference between tDCS/AE and tDCS group after the first week of stimulation and after 1 month intervention period (p = 0.02 and p = 0.03, respectively). Further, after treatment there was a significant difference between groups in anxiety and mood levels. The combination treatment effected the greatest response. The three groups had no differences regarding responses in motor cortex plasticity, as assessed by TMS. The combination of tDCS with aerobic exercise is superior compared with each individual intervention (cohen's d effect sizes > 0.55). The combination intervention had a significant effect on pain, anxiety and mood. Based on the similar effects on cortical plasticity outcomes, the combination intervention might have affected other neural circuits, such as those that control the affective-emotional aspects of pain. Trial registration: (www.ClinicalTrials.gov), identifier NTC02358902. PMID:27014012

  4. Yakima River Basin Phase II Fish Screen Evaluations, 2001.

    SciTech Connect

    Carter, J.A.; McMichael, Geoffrey A.; Chamness, M.A.

    2002-01-01

    In the summer and fall of 2001 the Pacific Northwest National Laboratory (PNNL) evaluated 23 Phase II fish screen sites in the Yakima River Basin as part of a multi-year study for the Bonneville Power Administration (BPA) on the effectiveness of fish screening devices. Data were collected to determine if velocities in front of the screens and in the bypasses met current National Marine Fisheries Service (NMFS) criteria to promote safe and timely fish passage and whether bypass outfall conditions allowed fish to safely return to the river. Based on our studies in 2001, we concluded that: in general, water velocity conditions at the screen sites met fish passage criteria set forth by the NMFS; most facilities efficiently protected juvenile fish from entrainment, impingement, or migration delay; automated cleaning brushes generally functioned properly; chains and other moving parts were well greased and operative; and removal of sediment build-up and accumulated leafy and woody debris are areas that continue to improve. Continued periodic screen evaluations will increase the effectiveness of screen operation and maintenance practices by confirming the effectiveness (or ineffectiveness) of screen operating procedures at individual sites. Where procedures are being followed and problems still occur, evaluation results can be used to suggest means to better protect fish at screening facilities. There has been a progressive improvement in the maintenance and effectiveness of fish screen facilities in the Yakima River Basin during the last several years, in part, as a result of regular screen evaluations and the rapid feedback of information necessary to improve operations and design of these important fish protection devices. Continued periodic screen evaluations will increase the effectiveness of screen operation and maintenance practices by confirming the effectiveness (or ineffectiveness) of screen operating procedures at individual sites. Where procedures are being

  5. ALTERNATE REDUCTANT COLD CAP EVALUATION FURNACE PHASE II TESTING

    SciTech Connect

    Johnson, F.; Stone, M.; Miller, D.

    2014-09-03

    Savannah River Remediation (SRR) conducted a Systems Engineering Evaluation (SEE) to determine the optimum alternate reductant flowsheet for the Defense Waste Processing Facility (DWPF). Specifically, two proposed flowsheets (nitric–formic–glycolic and nitric–formic–sugar) were evaluated based upon results from preliminary testing. Comparison of the two flowsheets among evaluation criteria indicated a preference towards the nitric–formic–glycolic flowsheet. Further research and development of this flowsheet eliminated the formic acid, and as a result, the nitric–glycolic flowsheet was recommended for further testing. Based on the development of a roadmap for the nitric–glycolic acid flowsheet, Waste Solidification Engineering (WS-E) issued a Technical Task Request (TTR) to address flammability issues that may impact the implementation of this flowsheet. Melter testing was requested in order to define the DWPF flammability envelope for the nitric-glycolic acid flowsheet. The Savannah River National Laboratory (SRNL) Cold Cap Evaluation Furnace (CEF), a 1/12th scale DWPF melter, was selected by the SRR Alternate Reductant project team as the melter platform for this testing. The overall scope was divided into the following sub-tasks as discussed in the Task Technical and Quality Assurance Plan (TTQAP):  Phase I - A nitric–formic acid flowsheet melter test (unbubbled) to baseline the CEF cold cap and vapor space data to the benchmark melter flammability models;  Phase II - A nitric–glycolic acid flowsheet melter test (unbubbled and bubbled) to: o Define new cold cap reactions and global kinetic parameters in support of the melter flammability model development; o Quantify off-gas surging potential of the feed; o Characterize off-gas condensate for complete organic and inorganic carbon species. After charging the CEF with cullet from Phase I CEF testing, the melter was slurry-fed with glycolic flowsheet based SB6-Frit 418 melter feed at 36

  6. Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial.

    PubMed

    Ellis, Ronald J; Toperoff, Will; Vaida, Florin; van den Brande, Geoffrey; Gonzales, James; Gouaux, Ben; Bentley, Heather; Atkinson, J Hampton

    2009-02-01

    Despite management with opioids and other pain modifying therapies, neuropathic pain continues to reduce the quality of life and daily functioning in HIV-infected individuals. Cannabinoid receptors in the central and peripheral nervous systems have been shown to modulate pain perception. We conducted a clinical trial to assess the impact of smoked cannabis on neuropathic pain in HIV. This was a phase II, double-blind, placebo-controlled, crossover trial of analgesia with smoked cannabis in HIV-associated distal sensory predominant polyneuropathy (DSPN). Eligible subjects had neuropathic pain refractory to at least two previous analgesic classes; they continued on their prestudy analgesic regimens throughout the trial. Regulatory considerations dictated that subjects smoke under direct observation in a hospital setting. Treatments were placebo and active cannabis ranging in potency between 1 and 8% Delta-9-tetrahydrocannabinol, four times daily for 5 consecutive days during each of 2 treatment weeks, separated by a 2-week washout. The primary outcome was change in pain intensity as measured by the Descriptor Differential Scale (DDS) from a pretreatment baseline to the end of each treatment week. Secondary measures included assessments of mood and daily functioning. Of 127 volunteers screened, 34 eligible subjects enrolled and 28 completed both cannabis and placebo treatments. Among the completers, pain relief was greater with cannabis than placebo (median difference in DDS pain intensity change, 3.3 points, effect size=0.60; p=0.016). The proportions of subjects achieving at least 30% pain relief with cannabis versus placebo were 0.46 (95%CI 0.28, 0.65) and 0.18 (0.03, 0.32). Mood and daily functioning improved to a similar extent during both treatment periods. Although most side effects were mild and self-limited, two subjects experienced treatment-limiting toxicities. Smoked cannabis was generally well tolerated and effective when added to concomitant analgesic

  7. Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial.

    PubMed

    Ellis, Ronald J; Toperoff, Will; Vaida, Florin; van den Brande, Geoffrey; Gonzales, James; Gouaux, Ben; Bentley, Heather; Atkinson, J Hampton

    2009-02-01

    Despite management with opioids and other pain modifying therapies, neuropathic pain continues to reduce the quality of life and daily functioning in HIV-infected individuals. Cannabinoid receptors in the central and peripheral nervous systems have been shown to modulate pain perception. We conducted a clinical trial to assess the impact of smoked cannabis on neuropathic pain in HIV. This was a phase II, double-blind, placebo-controlled, crossover trial of analgesia with smoked cannabis in HIV-associated distal sensory predominant polyneuropathy (DSPN). Eligible subjects had neuropathic pain refractory to at least two previous analgesic classes; they continued on their prestudy analgesic regimens throughout the trial. Regulatory considerations dictated that subjects smoke under direct observation in a hospital setting. Treatments were placebo and active cannabis ranging in potency between 1 and 8% Delta-9-tetrahydrocannabinol, four times daily for 5 consecutive days during each of 2 treatment weeks, separated by a 2-week washout. The primary outcome was change in pain intensity as measured by the Descriptor Differential Scale (DDS) from a pretreatment baseline to the end of each treatment week. Secondary measures included assessments of mood and daily functioning. Of 127 volunteers screened, 34 eligible subjects enrolled and 28 completed both cannabis and placebo treatments. Among the completers, pain relief was greater with cannabis than placebo (median difference in DDS pain intensity change, 3.3 points, effect size=0.60; p=0.016). The proportions of subjects achieving at least 30% pain relief with cannabis versus placebo were 0.46 (95%CI 0.28, 0.65) and 0.18 (0.03, 0.32). Mood and daily functioning improved to a similar extent during both treatment periods. Although most side effects were mild and self-limited, two subjects experienced treatment-limiting toxicities. Smoked cannabis was generally well tolerated and effective when added to concomitant analgesic

  8. Using imprecise probabilities to address the questions of inference and decision in randomized clinical trials.

    PubMed

    Gurrin, Lyle C; Sly, Peter D; Burton, Paul R

    2002-05-01

    Randomized controlled clinical trials play an important role in the development of new medical therapies. There is, however, an ethical issue surrounding the use of randomized treatment allocation when the patient is suffering from a life threatening condition and requires immediate treatment. Such patients can only benefit from the treatment they actually receive and not from the alternative therapy, even if it ultimately proves to be superior. We discuss a novel new way to analyse data from such clinical trials based on the use of the recently developed theory of imprecise probabilities. This work draws an explicit distinction between the related but nevertheless distinct questions of inference and decision in clinical trials. The traditional question of scientific interest asks 'Which treatment offers the greater chance of success?' and is the primary reason for conducting the clinical trial. The question of decision concerns the welfare of the patients in the clinical trial, asking whether the accumulated evidence favours one treatment over the other to such an extent that the next patient should decline randomization and instead express a preference for one treatment. Consideration of the decision question within the framework of imprecise probabilities leads to a mathematical definition of equipoise and a method for governing the randomization protocol of a clinical trial. This paper describes in detail the protocol for the conduct of clinical trials based on this new method of analysis, which is illustrated in a retrospective analysis of data from a clinical trial comparing the anti-emetic drugs ondansetron and droperidol in the treatment of postoperative nausea and vomiting. The proposed methodology is compared quantitatively using computer simulation studies with conventional clinical trial designs and is shown to maintain high statistical power with reduced sample sizes, at the expense of a high type I error rate that we argue is irrelevant in some

  9. Riposte to Guest Commentaries on 'Problems associated with randomized controlled clinical trials in breast cancer.

    PubMed

    Johnson, A E

    1998-08-01

    This paper addresses the objections of Professor M. Baum and Mr W. J. Cunliffe to my thesis that the randomized controlled clinical trial is a poor tool for the investigation of the treatment of breast cancer, argued in a discussion paper entitled 'Problems associated with randomized controlled clinical trials in breast cancer' (A.E. Johnson, 1998, Journal of Evaluation in Clinical Practice 4, 119-126). The objections range from those that have a philosophical basis, through those founded on differing concepts of the classification of primary tumours and the nature of the metastatic tumour, to those that question the reliability and usefulness of the clinical evaluation of response to treatment in terms of histological grade and rate of tumour shrinkage. An alternative approach to research through primary systemic therapy with selection of treatment according to predicted tumour behaviour was severely criticized, both on the preceding grounds and because it was assumed that the alternative to randomization is management by anecdote. These objections are examined and evidence in support of reliable and useful clinical measurement of response is presented in some detail. The problems associated with randomization as a technique for the evaluation of treatments, when the intrinsic variability of tumours is very large without the intervention of treatment, remain unsolved.

  10. A phase II trial of the BCL-2 homolog domain 3 mimetic AT-101 in combination with docetaxel for recurrent, locally advanced, or metastatic head and neck cancer

    PubMed Central

    Swiecicki, Paul L.; Bellile, Emily; Sacco, Assuntina G.; Pearson, Alexander T.; Taylor, Jeremy M. G.; Jackson, Trachette L.; Chepeha, Douglas B.; Spector, Matthew E.; Shuman, Andrew; Malloy, Kelly; Moyer, Jeffrey; McKean, Erin; McLean, Scott; Sukari, Ammar; Wolf, Gregory T.; Eisbruch, Avraham; Prince, Mark; Bradford, Carol; Carey, Thomas E.; Wang, Shaomeng; Nör, Jacques E.; Worden, Francis P.

    2016-01-01

    Background AT-101 is a BCL-2 Homolog domain 3 mimetic previously demonstrated to have tumoricidal effects in advanced solid organ malignancies. Given the evidence of activity in xenograft models, treatment with AT-101 in combination with docetaxel is a therapeutic doublet of interest in metastatic head and neck squamous cell carcinoma. Patients and Methods Patients included in this trial had unresectable, recurrent, or distantly metastatic head and neck squamous cell carcinoma (R/M HNSCC) not amenable to curative radiation or surgery. This was an open label randomized, phase II trial in which patients were administered AT-101 in addition to docetaxel. The three treatment arms were docetaxel, docetaxel plus pulse dose AT-101, and docetaxel plus metronomic dose AT-101. The primary endpoint of this trial was overall response rate. Results Thirty-five patients were registered and 32 were evaluable for treatment response. Doublet therapy with AT-101 and docetaxel was well tolerated with only 2 patients discontinuing therapy due to treatment related toxicities. The overall response rate was 11% (4 partial responses) with a clinical benefit rate of 74%. Median progression free survival was 4.3 months (range: 0.7–13.7) and overall survival was 5.5 months (range: 0.4–24). No significant differences were noted between dosing strategies. Conclusion Although met with a favorable toxicity profile, the addition of AT-101 to docetaxel in R/M HNSCC does not appear to demonstrate evidence of efficacy. PMID:27225873

  11. Lenalidomide treatment and prognostic markers in relapsed or refractory chronic lymphocytic leukemia: data from the prospective, multicenter phase-II CLL-009 trial

    PubMed Central

    Bühler, A; Wendtner, C-M; Kipps, T J; Rassenti, L; Fraser, G A M; Michallet, A-S; Hillmen, P; Dürig, J; Gregory, S A; Kalaycio, M; Aurran-Schleinitz, T; Trentin, L; Gribben, J G; Chanan-Khan, A; Purse, B; Zhang, J; De Bedout, S; Mei, J; Hallek, M; Stilgenbauer, S

    2016-01-01

    Efficacy of lenalidomide was investigated in 103 patients with relapsed/refractory chronic lymphocytic leukemia (CLL) treated on the prospective, multicenter randomized phase-II CLL-009 trial. Interphase cytogenetic and mutational analyses identified TP53 mutations, unmutated IGHV, or del(17p) in 36/96 (37.5%), 68/88 (77.3%) or 22/92 (23.9%) patients. The overall response rate (ORR) was 40.4% (42/104). ORRs were similar irrespective of TP53 mutation (36.1% (13/36) vs 43.3% (26/60) for patients with vs without mutation) or IGHV mutation status (45.0% (9/20) vs 39.1% (27/68)); however, patients with del(17p) had lower ORRs than those without del(17p) (21.7% (5/22) vs 47.1% (33/70); P=0.049). No significant differences in progression-free survival and overall survival (OS) were observed when comparing subgroups defined by the presence or absence of high-risk genetic characteristics. In multivariate analyses, only multiple prior therapies (⩾3 lines) significantly impacted outcomes (median OS: 21.2 months vs not reached; P=0.019). This analysis indicates that lenalidomide is active in patients with relapsed/refractory CLL with unfavorable genetic profiles, including TP53 inactivation or unmutated IGHV. (ClinicalTrials.gov identifier: NCT00963105). PMID:26967821

  12. Defining a Clinically Meaningful Effect for the Design and Interpretation of Randomized Controlled Trials

    PubMed Central

    Kraemer, Helena C.; Epstein, Robert S.; Frank, Ellen; Haynes, Ginger; Laughren, Thomas P.; Mcnulty, James; Reed, Shelby D.; Sanchez, Juan; Leon, Andrew C.

    2013-01-01

    Objective: This article captures the proceedings of a meeting aimed at defining clinically meaningful effects for use in randomized controlled trials for psychopharmacological agents. Design: Experts from a variety of disciplines defined clinically meaningful effects from their perspectives along with viewpoints about how to design and interpret randomized controlled trials. Setting: The article offers relevant, practical, and sometimes anecdotal information about clinically meaningful effects and how to interpret them. Participants: The concept for this session was the work of co-chairs Richard Keefe and the late Andy Leon. Faculty included Richard Keefe, PhD; James McNulty, AbScB; Robert S. Epstein, MD, MS; Shelby D. Reed, PhD; Juan Sanchez, MD; Ginger Haynes, PhD; Andrew C. Leon, PhD; Helena Chmura Kraemer, PhD; Ellen Frank, PhD, and Kenneth L. Davis, MD. Results: The term clinically meaningful effect is an important aspect of designing and interpreting randomized controlled trials but can be particularly difficult in the setting of psychopharmacology where effect size may be modest, particularly over the short term, because of a strong response to placebo. Payers, regulators, patients, and clinicians have different concerns about clinically meaningful effects and may describe these terms differently. The use of moderators in success rate differences may help better delineate clinically meaningful effects. Conclusion: There is no clear consensus on a single definition for clinically meaningful differences in randomized controlled trials, and investigators must be sensitive to specific concerns of stakeholders in psychopharmacology in order to design and execute appropriate clinical trials. PMID:23882433

  13. Phase II randomised trial of chemoradiotherapy with FOLFOX4 or cisplatin plus fluorouracil in oesophageal cancer

    PubMed Central

    Conroy, T; Yataghène, Y; Etienne, P L; Michel, P; Senellart, H; Raoul, J L; Mineur, L; Rives, M; Mirabel, X; Lamezec, B; Rio, E; Le Prisé, E; Peiffert, D; Adenis, A

    2010-01-01

    Background: Concurrent chemoradiotherapy is a valuable treatment option for localised oesophageal cancer (EC), but improvement is still needed. A randomised phase II trial was initiated to assess the feasibility and efficacy in terms of the endoscopic complete response rate (ECRR) of radiotherapy with oxaliplatin, leucovorin and fluorouracil (FOLFOX4) or cisplatin/fluorouracil. Methods: Patients with unresectable EC (any T, any N, M0 or M1a), or medically unfit for surgery, were randomly assigned to receive either six cycles (three concomitant and three post-radiotherapy) of FOLFOX4 (arm A) or four cycles (two concomitant and two post-radiotherapy) of cisplatin/fluorouracil (arm B) along with radiotherapy 50 Gy in both arms. Responses were reviewed by independent experts. Results: A total of 97 patients were randomised (arm A/B, 53/44) and 95 were assessable. The majority had squamous cell carcinoma (82% arm A/B, 42/38). Chemoradiotherapy was completed in 74 and 66%. The ECRR was 45 and 29% in arms A and B, respectively. Median times to progression were 15.2 and 9.2 months and the median overall survival was 22.7 and 15.1 months in arms A and B, respectively. Conclusion: Chemoradiotherapy with FOLFOX4, a well-tolerated and convenient combination with promising efficacy, is now being tested in a phase III trial. PMID:20940718

  14. Piotron. II. Methods and initial results of dynamic pion therapy in phase II studies

    SciTech Connect

    von Essen, C.F.; Blattmann, H.; Bodendoerfer, G.; Mizoe, J.; Pedroni, E.; Walder, E.; Zimmermann, A.

    1985-02-01

    Negative pi-meson (pion) therapy employing dynamic scanning with a focused spot of convergent beams has been in use since 1981 at SIN. Three-dimensional conformation of the treatment volume to the target volume can thus be achieved. Following previously reported Phase I and Ib clinical trials, a Phase II trial was initiated with the goal of treating primary deep-seated tumors in a dose optimization schedule which included stepwise increase of total pion dose and of target volume. Patients with multicentric superficial bladder tumors who were cystectomy candidates were initially selected. Since then, more invasive cases have been treated. Treatment reactions ranged from a faint erythema and increase of bladder frequency to dry desquamation, mild nausea, moderate dysuria, and moderate proctitis or diarrhea with mucus. These reactions were closely related to treatment volume and site. One severe late cystitis has occurred in a patient treated with 2 courses of pions (4475 rad). Mild to moderate late proctitis has been seen in 4 patients. Ten of 13 bladder cancer patients had local control of disease while all 3 pancreas or biliary tract cancer patients had microscopic residual disease locally at time of death from metastasis. A total of 11 of 17 patients are thus clinically or pathologically free of local tumor to time of last observation.

  15. A phase II trial of bryostatin 1 in patients with non-Hodgkin's lymphoma

    PubMed Central

    Blackhall, F H; Ranson, M; Radford, J A; Hancock, B W; Soukop, M; McGown, A T; Robbins, A; Halbert, G

    2001-01-01

    Bryostatin 1 is a naturally occurring macrocyclic lactone with promising antitumour and immunomodulatory function in preclinical and phase I clinical investigations. In this phase II study, 17 patients with progressive non-Hodgkin's lymphoma of indolent type (NHL), previously treated with chemotherapy, received a median of 6 (range 1–9) intravenous infusions of 25 μg/m2bryostatin 1 given once weekly over 24 hours. In 14 evaluable patients no responses were seen. Stable disease was attained in one patient for 9 months. The principal toxicities were myalgia and phlebitis. Treatment was discontinued early because of toxicity alone (phlebitis) in 2 patients, toxicity in addition to progressive disease in 3 patients (myalgia and phlebitis n = 2; thrombocytopenia n = 1) and progressive disease in 5 patients. The results fail to demonstrate efficacy of this regimen of bryostatin 1 in the treatment of NHL. In light of preclinical data that demonstrate synergy between bryostatin 1 and several cytotoxic agents and cytokines, clinical studies to investigate bryostatin 1 in combination are warranted. We also present data to demonstrate that central venous lines may be used in future studies to avoid phlebitis. © 2001 Cancer Research Campaign http://www.bjcancer.com PMID:11263437

  16. Understanding pharmacology in humans: Phase I and Phase II (data generation).

    PubMed

    Merlo Pich, Emilio

    2011-10-01

    The discovery of novel drugs is a complex and highly regulated process organized around a critical moment, that is, when the novel compound is tested in humans. This process encompasses a series of clinical studies, identified as Phase I and Phase II, whose composite outcome should deliver the data needed for an informed decision about progressing or not the compound in full development (Phase III). Over the last 10 years the global delivery of novel treatments from the pharmaceutical industry has plunged to the level of the '70ies in spite of a 10-fold larger investment, the differential mostly due to failures in Phase III. There is the need to improve the decision making at the early clinical stage by using innovation and the high-profile achievements of basic science generated in academic and biomedical labs. A specific attention should be paid to applied biotechnologies, in particular nanotechnology and biomedical devices not only for drug deliver but also for biomarker detection. This path, also supported by regulatory agencies, is calling for an important change of perspective about how drug discovery is made, which we believe should start from the full implementation of the paradigm of Translational Medicine. PMID:21783419

  17. The Effect of Applying Direct Observation of Procedural Skills (DOPS) on Nursing Students’ Clinical Skills: A Randomized Clinical Trial

    PubMed Central

    Hengameh, Habibi; Afsaneh, Raiesifar; Morteza, Khaghanizade; Hosein, Mahmudi; Marjan, Seyed Mazhari; Ebadi, Abbas

    2015-01-01

    Background: Remarkable advances in educational measurement have proved need to the implementation of modern and appropriate methods of clinical evaluation. This study was carried out to compare the effect of applying direct observation procedural skills and routine evaluation method on clinical skills of nursing students. Methods: This randomized clinical trial was conducted on students of Nursing Army College, Tehran, Iran. After obtaining approval from the Ethics Committee of the Baqiyatallah University of Medical Sciences Research Deputy, all nursing students and instructors who agreed to participate in this study sign the informed consent. The participants were randomly assigned into intervention and control groups. After the teachers were trained and an inter-raters reliability test was conducted, evaluation was performed through DOPS in the intervention group while the control groups were evaluated through the routine method. Assessment checklists for two procedures (Intra venous catheterization and change dressing) were valid and reliable. Finally data were analyzed through descriptive and analytical statistics (Chi-square, t-test, Repeated Measure ANOVA) using SPSS version 16. Results: No significant difference was observed between the two groups in terms of demographic variables (P>0.05), but a significant difference was observed between intervention and control scores (P=0.000). In other words, application of DOPS has improved clinical skills of the students significantly. Conclusion: Using this new method improved the students’ scores in clinical procedures implementation; therefore, we suggest that nursing colleges apply this evaluation method for clinical education. PMID:26153199

  18. Mindfulness-Based Stress Reduction for the Treatment of Adolescent Psychiatric Outpatients: A Randomized Clinical Trial

    ERIC Educational Resources Information Center

    Biegel, Gina M.; Brown, Kirk Warren; Shapiro, Shauna L.; Schubert, Christine M.

    2009-01-01

    Research has shown that mindfulness-based treatment interventions may be effective for a range of mental and physical health disorders in adult populations, but little is known about the effectiveness of such interventions for treating adolescent conditions. The present randomized clinical trial was designed to assess the effect of the…

  19. Competitive Employment for Youth with Autism Spectrum Disorders: Early Results from a Randomized Clinical Trial

    ERIC Educational Resources Information Center

    Wehman, Paul H.; Schall, Carol M.; McDonough, Jennifer; Kregel, John; Brooke, Valerie; Molinelli, Alissa; Ham, Whitney; Graham, Carolyn W.; Riehle, J. Erin; Collins, Holly T.; Thiss, Weston

    2014-01-01

    For most youth with autism spectrum disorders (ASD), employment upon graduation from high school or college is elusive. Employment rates are reported in many studies to be very low despite many years of intensive special education services. This paper presented the preliminary results of a randomized clinical trial of Project SEARCH plus ASD…

  20. Positive Family Intervention for Severe Challenging Behavior I: A Multisite Randomized Clinical Trial

    ERIC Educational Resources Information Center

    Durand, V. Mark; Hieneman, Meme; Clarke, Shelley; Wang, Mo; Rinaldi, Melissa L.

    2013-01-01

    The present study was a multisite randomized clinical trial assessing the effects of adding a cognitive-behavioral intervention to positive behavior support (PBS). Fifty-four families who met the criteria of (a) having a child with a developmental disability, (b) whose child displayed serious challenging behavior (e.g., aggression, self-injury,…

  1. Monthly high dose vitamin D treatment for the prevention of functional decline: a randomized clinical trial

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Importance: Vitamin D deficiency has been associated with poor physical performance. Objective: To determine the effectiveness of high dose vitamin D in lowering the risk of functional decline. Design, Setting, and Participants: One-year double-blind, randomized clinical trial conducted in Zurich,...

  2. Prediction of Response to Treatment in a Randomized Clinical Trial of Marital Therapy

    ERIC Educational Resources Information Center

    Atkins, David C.; Berns, Sara B.; George, William H.; Doss, Brian D.; Gattis, Krista; Christensen, Andrew

    2005-01-01

    This study investigated demographic, intrapersonal, and interpersonal predictors of treatment response in a randomized clinical trial of 134 distressed married couples, which examined traditional (N. S. Jacobson & G. Margolin, 1979) and integrative (N. S. Jacobson & A. Christensen, 1996) behavioral couple therapy. Results based on hierarchical…

  3. Enhancing Attachment Organization among Maltreated Children: Results of a Randomized Clinical Trial

    ERIC Educational Resources Information Center

    Bernard, Kristin; Dozier, Mary; Bick, Johanna; Lewis-Morrarty, Erin; Lindhiem, Oliver; Carlson, Elizabeth

    2012-01-01

    Young children who have experienced early adversity are at risk for developing disorganized attachments. The efficacy of Attachment and Biobehavioral Catch-up (ABC), an intervention targeting nurturing care among parents identified as being at risk for neglecting their young children, was evaluated through a randomized clinical trial. Attachment…

  4. Cognitive-Behavioral Therapy for Intermittent Explosive Disorder: A Pilot Randomized Clinical Trial

    ERIC Educational Resources Information Center

    McCloskey, Michael S.; Noblett, Kurtis L.; Deffenbacher, Jerry L.; Gollan, Jackie K.; Coccaro, Emil F.

    2008-01-01

    No randomized clinical trials have evaluated the efficacy of psychotherapy for intermittent explosive disorder (IED). In the present study, the authors tested the efficacy of 12-week group and individual cognitive-behavioral therapies (adapted from J. L. Deffenbacher & M. McKay, 2000) by comparing them with a wait-list control in a randomized…

  5. A Randomized Clinical Trial of Alternative Stress Management Interventions in Persons with HIV Infection

    ERIC Educational Resources Information Center

    McCain, Nancy L.; Gray, D. Patricia; Elswick, R. K., Jr.; Robins, Jolynne W.; Tuck, Inez; Walter, Jeanne M.; Rausch, Sarah M.; Ketchum, Jessica McKinney

    2008-01-01

    Research in psychoneuroimmunology suggests that immunosuppression associated with perceived stress may contribute to disease progression in persons with HIV infection. While stress management interventions may enhance immune function, few alternative approaches have yet been tested. This randomized clinical trial was conducted to test effects of…

  6. Moving from Efficacy to Effectiveness in Cognitive Behavioral Therapy for Psychosis: A Randomized Clinical Practice Trial

    ERIC Educational Resources Information Center

    Lincoln, Tania M.; Ziegler, Michael; Mehl, Stephanie; Kesting, Marie-Luise; Lullmann, Eva; Westermann, Stefan; Rief, Winfried

    2012-01-01

    Objective: Randomized controlled trials have attested the efficacy of cognitive behavioral therapy (CBT) in reducing psychotic symptoms. Now, studies are needed to investigate its effectiveness in routine clinical practice settings. Method: Eighty patients with schizophrenia spectrum disorders who were seeking outpatient treatment were randomized…

  7. Using Minitel Network and New Software Engineering Techniques for Randomized Clinical Trials Management

    PubMed Central

    Lepage, E.; Tavernier, H.; Bouhaddou, O.; Jais, JP.; Gisselbrecht, C.; Aurengo, A.; Boiron, M.

    1989-01-01

    The usual Randomized Clinical Trials (RCT) management using an anachronic procedure involving a flowsheet exchange between the remote centers and the coordinating center presents a number of inadequacies. Eligibility criteria are not always verified by the coordinating center before inclusion in the trial and randomization. Laboratory tests and therapeutic adjustments are frequently decided from memory by the clinician which often leads to data oversight and variability of therapeutic decisions. This results in protocol deviations and alteration of the efficiency of the RCT. HICREN is a medical consultation system designed to take into account the different difficulties encountered during RCT driving. The system integrates a clinical database with artificial intelligence technics to manage clinical trial data on non-expensive and widely available Minitel® terminals. Randomization is then possible, after eligibility criteria are satisfied, anytime and anywhere in France through the national telematic network. HICREN also includes an intuitive graphic interface to increase physician's compliance: a user friendly dialogue manager supports on line data entry with multi-windowing facilities and pull down menus. Interactive data validation is achieved through an interface to dedicated C programs. Patient follow up is achieved by an expert system that proposes appropriate dose of treatment according to the rules defined in the trial. At present, HICREN is implemented on the CISARC system for conducting three randomized clinical trials and one epidemiologic study.

  8. Creation and implementation of a historical controls database from randomized clinical trials

    PubMed Central

    Desai, Jigar R; Bowen, Edward A; Danielson, Mark M; Allam, Rajasekhar R; Cantor, Michael N

    2013-01-01

    Background Ethical concerns about randomly assigning patients to suboptimal or placebo arms and the paucity of willing participants for randomization into control and experimental groups have renewed focus on the use of historical controls in clinical trials. Although databases of historical controls have been advocated, no published reports have described the technical and informatics issues involved in their creation. Objective To create a historical controls database by leveraging internal clinical trial data at Pfizer, focusing on patients who received only placebo in randomized controlled trials. Methods We transformed disparate clinical data sources by indexing, developing, and integrating clinical data within internal databases and archives. We focused primarily on trials mapped into a consistent standard and trials in the pain therapeutic area as a pilot. Results Of the more than 20 000 internal Pfizer clinical trials, 2404 completed placebo controlled studies with a parallel design were identified. Due to challenges with informed consent and data standards used in older clinical trials, studies completed before 2000 were excluded, yielding 1134 studies from which placebo subjects and associated clinical data were extracted. Conclusions It is technically feasible to pool portions of placebo populations through a stratification and segmentation approach for a historical placebo group database. A sufficiently large placebo controls database would enable previous distribution calculations on representative populations to supplement, not eliminate, the placebo arm of future clinical trials. Creation of an industry-wide placebo controls database, utilizing a universal standard, beyond the borders of Pfizer would add significant efficiencies to the clinical trial and drug development process. PMID:23449762

  9. Modular microfluidic system for emulation of human phase I/phase II metabolism.

    PubMed

    Kampe, Thomas; König, Anna; Schroeder, Hendrik; Hengstler, Jan G; Niemeyer, Christof M

    2014-03-18

    We present a microfluidic device for coupled phase I/phase II metabolic reactions in vitro. The chip consists of microchannels, which are used as packed bed reactor compartments, filled with superparamagnetic microparticles bearing recombinant microsomal phase I cytochrome P450 or phase II conjugating enzymes (UDP-glucuronosyltransferase). Online coupling of the microfluidic device with LC/MS enabled the quantitative assessment of coupled phase I/phase II transformations, as demonstrated for two different substrates, 7-benzyloxy-4-trifluoromethylcoumarin (BFC) and dextromethorphan (DEX). In contrast, conventional sequential one-pot incubations did not generate measurable amounts of phase II metabolites. Because the microfluidic device is readily assembled from standard parts and can be equipped with a variety of recombinant enzymes, it provides a modular platform to emulate and investigate hepatic metabolism processes, with particular potential for targeted small-scale synthesis and identification of metabolites formed by sequential action of specific enzymes. PMID:24597510

  10. 7 CFR 3403.8 - Proposal format for phase II applications.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ...) Commercialization Plan. A succinct commercialization plan must be included in each SBIR Phase II proposal moving toward commercialization. Elements of a commercialization plan may include the following: (i) Company... commercialization. (ii) Customer and competition. Clear description of key technology objectives,...

  11. 40 CFR 300.305 - Phase II-Preliminary assessment and initiation of action.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... SUBSTANCES POLLUTION CONTINGENCY PLAN Operational Response Phases for Oil Removal § 300.305 Phase II... effective and immediate removal of the discharge or mitigation or prevention of a substantial threat of...

  12. 40 CFR 300.305 - Phase II-Preliminary assessment and initiation of action.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... SUBSTANCES POLLUTION CONTINGENCY PLAN Operational Response Phases for Oil Removal § 300.305 Phase II... effective and immediate removal of the discharge or mitigation or prevention of a substantial threat of...

  13. 40 CFR 300.305 - Phase II-Preliminary assessment and initiation of action.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... SUBSTANCES POLLUTION CONTINGENCY PLAN Operational Response Phases for Oil Removal § 300.305 Phase II... effective and immediate removal of the discharge or mitigation or prevention of a substantial threat of...

  14. 40 CFR 300.305 - Phase II-Preliminary assessment and initiation of action.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... SUBSTANCES POLLUTION CONTINGENCY PLAN Operational Response Phases for Oil Removal § 300.305 Phase II... effective and immediate removal of the discharge or mitigation or prevention of a substantial threat of...

  15. 40 CFR 300.305 - Phase II-Preliminary assessment and initiation of action.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... SUBSTANCES POLLUTION CONTINGENCY PLAN Operational Response Phases for Oil Removal § 300.305 Phase II... effective and immediate removal of the discharge or mitigation or prevention of a substantial threat of...

  16. Feasibility study of a clinically-integrated randomized trial of modifications to radical prostatectomy

    PubMed Central

    2012-01-01

    Abstract Background Numerous technical modifications to radical prostatectomy have been proposed. Such modifications are likely to lead to only slight improvements in outcomes. Although small differences would be worthwhile, an appropriately powered randomized trial would need to be very large, and thus of doubtful feasibility given the expense, complexity and regulatory burden of contemporary clinical trials. We have proposed a novel methodology, the clinically-integrated randomized trial, which dramatically streamlines trial procedures in order to reduce the marginal cost of an additional patient towards zero. We aimed to determine the feasibility of implementing such a trial for radical prostatectomy. Methods Patients undergoing radical prostatectomy as initial treatment for prostate cancer were randomized in a factorial design to involvement of the fascia during placement of the anastomotic sutures, urethral irrigation, both or neither. Endpoint data were obtained from routine clinical documentation. Accrual and compliance rates were monitored to determine the feasibility of the trial. Results From a total of 260 eligible patients, 154 (59%) consented; 56 patients declined to participate, 20 were not approached on recommendation of the treating surgeon, and 30 were not approached for logistical reasons. Although recording by surgeons of the procedure used was incomplete (~80%), compliance with randomization was excellent when it was recorded, with only 6% of procedures inconsistent with allocation. Outcomes data was received from 71% of patients at one year. This improved to 83% as the trial progressed. Conclusions A clinically-integrated randomized trial was conducted at low cost, with excellent accrual, and acceptable compliance with treatment allocation and outcomes reporting. This demonstrates the feasibility of the methodology. Improved methods to ensure documentation of surgical procedures would be required before wider implementation. Trial registration

  17. "Geographical randomization" and "social exploitation" in clinical research: world trials in Santiago, Chile.

    PubMed

    Bicudo, Edison

    2011-05-01

    In the discussion of global clinical trials, two ideas are frequently advanced. Firstly, it is sometimes articulated that companies can displace clinical protocols between countries quite easily (what I propose to call "geographical randomization"). The second idea conveys that global trials lead to the exploitation of poor regions and poor people ("social exploitation"). By analyzing the context of Santiago, the capital city of Chile, I argue that, although these ideas are not myths, they cannot capture the whole complexity of global trials. On the one hand, geographical factors restrain the mobility of the clinical trials industry. On the other, studies tend to be concentrated in wealthier areas with more affluent people.

  18. Functional design criteria for project W-252, phase II liquid effluent treatment and disposal. Revision 2

    SciTech Connect

    Hatch, C.E.

    1995-05-01

    This document is the Functional Design Criteria for Project W-252. Project W-252 provides the scope to provide BAT/AKART (best available technology...) to 200 Liquid Effluent Phase II streams (B-Plant). This revision (Rev. 2) incorporates a major descoping of the project. The descoping was done to reflect a combination of budget cutting measures allowed by a less stringent regulatory posture toward the Phase II streams

  19. Phase II experiment test plan: solar photovoltaic/thermal residential experiment

    SciTech Connect

    Sheldon, D. B.

    1980-01-23

    The Solar Photovoltaic/Thermal Energy Project being carried out by the Massachusetts Institute of Technology Lincoln Laboratory under US Department of Energy funding requires a Phase II test plan for its Solar Energy Research Facility (SERF) located at the University of Texas at Arlington. This Phase II test plan is provided. The purpose of the research being conducted at the SERF is reviewed, and references describing Phase I work are listed.

  20. Designing a series of decision-theoretic phase II trials in a small population.

    PubMed

    Hee, Siew Wan; Stallard, Nigel

    2012-12-30

    This paper introduces a decision-theoretic design for a series of phase II trials. Instead of designing phase II trials individually, we proposed a development plan that consists of a series of phase II trials and one phase III trial such that the long-term expected utility on the whole is optimized. The phase II trials are conducted sequentially, and patients are recruited sequentially to each phase II trial. At each interim stage, a decision is made to continue recruiting patients to the current trial, to stop and recommend the treatment proceeds to a phase III trial, to stop and initiate a new phase II trial or to stop and cease the development plan. The methodology uses a hybrid approach in which it is assumed that the data from the final phase III trial will be analysed using a classical frequentist hypothesis test. The expected power of this test based on some specified prior distribution for the effect of the experimental treatment is then used in a utility function, which is used to obtain the optimal design for the whole series of trials. PMID:22927289

  1. The Serum Changes of Neuron-Specific Enolase and Intercellular Adhesion Molecule-1 in Patients With Diffuse Axonal Injury Following Progesterone Administration: A Randomized Clinical Trial

    PubMed Central

    Shahrokhi, Nader; Soltani, Zahra; Khaksari, Mohammad; Karamouzian, Saeid; Mofid, Behshad; Asadikaram, Gholamreza

    2016-01-01

    Background Improvement of neurologic outcome in progesterone-administered patients with diffuse axonal injury (DAI) has been found in a recent study. Also, there has been interest in the importance of serum parameters as predictors of outcome in traumatic brain injury. Objectives The aim of this study was to examine the effect of progesterone administration on serum levels of neuron-specific enolase (NSE), and intercellular adhesion molecule-1 (ICAM-1) in clinical DAI. Patients and Methods In this study, the serum levels of ICAM-1 and NSE of 32 male DAI patients (18 - 60 years of age, a Glasgow coma scale of 12 or less, and admitted within 4 hours after injury) who were randomized for a controlled phase II trial of progesterone were analyzed. The analysis was performed between the control and progesterone groups at admission time, and 24 hours and six days after DAI, respectively. Results A reduction in the serum level of ICAM-1 was noticed in the progesterone group 24 hours after the injury (P < 0.05). There was no significant difference in the serum level of NSE between the study groups during evaluation. At 24 hours after the injury, the level of ICAM-1 in the control group was higher than that at admission time (P < 0.05). The lowest level of NSE in the two groups was seen six days after DAI (P < 0.01). Conclusions In summary, progesterone administration reduced serum ICAM-1, and whereby may attenuate blood brain barrier disruption, the latter needs further investigation for confirmation. PMID:27800469

  2. Double-blind, placebo-controlled, randomized, pilot clinical trial of ImmunoGuard--a standardized fixed combination of Andrographis paniculata Nees, with Eleutherococcus senticosus Maxim, Schizandra chinensis Bail. and Glycyrrhiza glabra L. extracts in patients with Familial Mediterranean Fever.

    PubMed

    Amaryan, G; Astvatsatryan, V; Gabrielyan, E; Panossian, A; Panosyan, V; Wikman, G

    2003-05-01

    Double blind, randomized, placebo controlled pilot study of ImmunoGuard--a standardized fixed combination of Andrographis paniculata Nees., Eleutherococcus senticosus Maxim., Schizandra chinensis Bail., and Glycyrrhiza glabra L. special extracts standardized for the content of Andrographolide (4 mg/tablet), Eleuteroside E, Schisandrins and Glycyrrhizin, was carried out in two parallel groups of patients. The study was conducted in 24 (3-15 years of both genders) patients with Familial Mediterranean Fever (FMF), 14 were treated with tablets of series A (verum) and 10 patients received series B product (placebo). The study medication was taken three times of four tablets daily for 1 month. Daily dose of the andrographolide--48 mg. The primary outcome measures in physician's evaluation were related to duration, frequency and severity of attacks in FMF patients (attacks characteristics score). The patient's self-evaluation was based mainly on symptoms--abdominal, chest pains, temperature, arthritis, myalgia, erysipelas-like erythema. All of 3 features (duration, frequency, severity of attacks) showed significant improvement in the verum group as compared with the placebo. In both clinical and self evaluation the severity of attacks was found to show the most significant improvement in the verum group. Both the clinical and laboratory results of the present phase II (pilot) clinical study suggest that ImmunoGuard is a safe and efficacious herbal drug for the management of patients with FMF. PMID:12809357

  3. Pharmacokinetic Profile of Subcutaneous Testosterone Enanthate Delivered via a Novel, Prefilled Single‐Use Autoinjector: A Phase II Study

    PubMed Central

    Kaminetsky, Jed; Swerdloff, Ronald S.

    2015-01-01

    Abstract Introduction Hypogonadism is one of the most common male endocrine problems. Although many treatments are currently available, unmet need exists for new testosterone (T) replacement therapies that are simple to administer and use, are safe, and mimic physiologic T levels. Aim The study aim was to determine the pharmacokinetics (PK), safety, and tolerability of T enanthate (TE) administered via a novel single‐use autoinjector system, which was designed to eject high‐viscosity solutions from a prefilled syringe fitted with a five‐eighths‐inch 27‐gauge needle. Methods Thirty‐nine men with hypogonadism entered this dose‐finding, open‐label, parallel‐group study. Patients were washed out of their topical T regimens and randomized to receive 50 or 100 mg of subcutaneous (SC) TE weekly. The reference group were patients with hypogonadism who were maintained on standard 200‐mg intramuscular (IM) TE. Main Outcome Measure The primary outcome measure was the PK profile of SC TE, analyzed in reference to T levels used by the Food and Drug Administration to approve T products. Secondary outcome measures were safety and tolerability assessments. Results Both doses of SC TE achieved normal average concentrations of serum T within a 168‐h dosing interval after injection. Concentration ranges were similar at all time points following 50‐mg SC TE injections and following the third injection in the 100‐mg arm. Mean steady‐state T concentration at week 6 was 422.4 and 895.5 ng/dL for the 50‐ and 100‐mg SC TE arms, respectively. SC TE demonstrated PK dose proportionality. SC TE restored normal serum T with low variation relative to 200‐mg IM without clinically significant adverse events. Conclusions Administration of TE via this novel injection system restored T levels to normal range in men with hypogonadism. SC TE dosed weekly demonstrated steady, dose‐proportional measures of exposure and was well‐tolerated. Kaminetsky J, Jaffe JS

  4. A phase II study of ixabepilone and trastuzumab for metastatic HER2-positive breast cancer

    PubMed Central

    Tolaney, S. M.; Najita, J.; Sperinde, J.; Huang, W.; Chen, W. Y.; Savoie, J.; Fornier, M.; Winer, E. P.; Bunnell, C.; Krop, I. E.

    2013-01-01

    Background A multicenter NCI-sponsored phase II study was conducted to analyze the safety and efficacy of the combination of ixabepilone with trastuzumab in patients with metastatic HER2-positive breast cancer. Patients and methods Two cohorts were enrolled: cohort 1 had received no prior chemotherapy or trastuzumab for metastatic disease and cohort 2 had received 1–2 prior trastuzumab-containing regimens for metastatic disease. Patients in both cohorts received ixabepilone 40 mg/m2 as a 3-h infusion and trastuzumab on day 1 of a 21-day cycle. Tumor biomarkers that may predict response to trastuzumab were explored. Results Thirty-nine women entered the study with 15 patients in cohort 1 and 24 patients in cohort 2. Across both cohorts, the overall RR was 44%, with a clinical benefit rate (CR + PR + SD for at least 24 weeks) of 56%. Treatment-related toxic effects included neuropathy (grade ≥2, 56%), leukopenia (grade ≥2, 26%), myalgias (grade ≥2, 21%), neutropenia (grade ≥2, 23%), and anemia (grade ≥2, 18%). Conclusions This represents the first study of the combination of ixabepilone with trastuzumab for the treatment of metastatic HER2-positive breast cancer. These results suggest that the combination has encouraging activity as first and subsequent line therapy for metastatic breast cancer. PMID:23559151

  5. NRF2 and the Phase II Response in Acute Stress Resistance Induced by Dietary Restriction

    PubMed Central

    Hine, Christopher M.; Mitchell, James R.

    2013-01-01

    Dietary restriction (DR) as a means to increase longevity is well-established in a number of model organisms from yeast to primates. DR also improves metabolic fitness and increases resistance to acute oxidative, carcinogenic and toxicological stressors - benefits with more immediate potential for clinical translation than increased lifespan. While the detailed mechanism of DR action remains unclear, a conceptual framework involving an adaptive, or hormetic response to the stress of nutrient/energy deprivation has been proposed. A key prediction of the hormesis hypothesis of DR is that beneficial adaptations occur in response to an increase in reactive oxygen/nitrogen species (ROS). These ROS may be derived either from increased mitochondrial respiration or increased xenobiotic metabolism in the case of some DR mimetics. This review will focus on the potential role of the redox-sensing transcription factor NF-E2-related factor 2 (NRF2) and its control of the evolutionarily conserved antioxidant/redox cycling and detoxification systems, collectively known as the Phase II response, in the adaptive response to DR. PMID:23505614

  6. Phase II Trial of Talampanel, a Glutamate Receptor Inhibitor, for Adults with Recurrent Malignant Gliomas

    PubMed Central

    Iwamoto, Fabio M.; Kreisl, Teri N.; Kim, Lyndon; Duic, J. Paul; Butman, John A.; Albert, Paul S.; Fine, Howard A.

    2010-01-01

    Background: Glioma cells secrete glutamate and also express AMPA glutamate receptors, which contribute to proliferation, migration and neurotoxicity of malignant gliomas. Talampanel is an oral AMPA receptor inhibitor with excellent CNS penetration and good tolerability in clinical trials for epilepsy and other neurological disorders. Methods: We conducted a phase II trial to evaluate the efficacy of talampanel in patients with recurrent malignant glioma as measured by 6-month progression free survival (PFS6). Results: Thirty patients (22 glioblastomas [GBM], 8 anaplastic gliomas [AG]; 63% men) with median age of 51 years (range, 20 to 67) and median KPS of 80 were included. Patients tolerated treatment well and most adverse events were mild and reversible; the most common toxicities were fatigue (27%), dizziness (23%) and ataxia (17%). There was only one partial response (5%) in the GBM stratum and none among AG patients. With a median follow-up of 13 months, 28 patients (93%) had died. The PFS6 was 4.6% for the initial 22 GBM patients and the study was terminated early due to treatment futility; PFS6 was 0% for 8 AG patients. Median PFS was 5.9 weeks for GBM and 8.9 weeks for AG patients. Median overall survival was 13 weeks for GBM and 14 months for AG patients. Conclusion: Talampanel was well tolerated but had no significant activity as a single agent in unselected recurrent malignant gliomas. PMID:20143438

  7. Non-thermal Plasma Activates Human Keratinocytes by Stimulation of Antioxidant and Phase II Pathways

    PubMed Central

    Schmidt, Anke; Dietrich, Stephan; Steuer, Anna; Weltmann, Klaus-Dieter; von Woedtke, Thomas; Masur, Kai; Wende, Kristian

    2015-01-01

    Non-thermal atmospheric pressure plasma provides a novel therapeutic opportunity to control redox-based processes, e.g. wound healing, cancer, and inflammatory diseases. By spatial and time-resolved delivery of reactive oxygen and nitrogen species, it allows stimulation or inhibition of cellular processes in biological systems. Our data show that both gene and protein expression is highly affected by non-thermal plasma. Nuclear factor erythroid-related factor 2 (NRF2) and phase II enzyme pathway components were found to act as key controllers orchestrating the cellular response in keratinocytes. Additionally, glutathione metabolism, which is a marker for NRF2-related signaling events, was affected. Among the most robustly increased genes and proteins, heme oxygenase 1, NADPH-quinone oxidoreductase 1, and growth factors were found. The roles of NRF2 targets, investigated by siRNA silencing, revealed that NRF2 acts as an important switch for sensing oxidative stress events. Moreover, the influence of non-thermal plasma on the NRF2 pathway prepares cells against exogenic noxae and increases their resilience against oxidative species. Via paracrine mechanisms, distant cells benefit from cell-cell communication. The finding that non-thermal plasma triggers hormesis-like processes in keratinocytes facilitates the understanding of plasma-tissue interaction and its clinical application. PMID:25589789

  8. Non-thermal plasma activates human keratinocytes by stimulation of antioxidant and phase II pathways.

    PubMed

    Schmidt, Anke; Dietrich, Stephan; Steuer, Anna; Weltmann, Klaus-Dieter; von Woedtke, Thomas; Masur, Kai; Wende, Kristian

    2015-03-13

    Non-thermal atmospheric pressure plasma provides a novel therapeutic opportunity to control redox-based processes, e.g. wound healing, cancer, and inflammatory diseases. By spatial and time-resolved delivery of reactive oxygen and nitrogen species, it allows stimulation or inhibition of cellular processes in biological systems. Our data show that both gene and protein expression is highly affected by non-thermal plasma. Nuclear factor erythroid-related factor 2 (NRF2) and phase II enzyme pathway components were found to act as key controllers orchestrating the cellular response in keratinocytes. Additionally, glutathione metabolism, which is a marker for NRF2-related signaling events, was affected. Among the most robustly increased genes and proteins, heme oxygenase 1, NADPH-quinone oxidoreductase 1, and growth factors were found. The roles of NRF2 targets, investigated by siRNA silencing, revealed that NRF2 acts as an important switch for sensing oxidative stress events. Moreover, the influence of non-thermal plasma on the NRF2 pathway prepares cells against exogenic noxae and increases their resilience against oxidative species. Via paracrine mechanisms, distant cells benefit from cell-cell communication. The finding that non-thermal plasma triggers hormesis-like processes in keratinocytes facilitates the understanding of plasma-tissue interaction and its clinical application.

  9. Phase II Randomized Trial of the Combination of Cetuximab and Sorafenib or Single Agent Cetuximab

    ClinicalTrials.gov

    2015-08-03

    Metastatic Squamous Neck Cancer With Occult Primary Squamous Cell Carcinoma; Recurrent Metastatic Squamous Neck Cancer With Occult Primary; Recurrent Salivary Gland Cancer; Recurrent Squamous Cell Carcinoma of the Hypopharynx; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Nasopharynx; Recurrent Squamous Cell Carcinoma of the Oropharynx; Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Recurrent Verrucous Carcinoma of the Larynx; Recurrent Verrucous Carcinoma of the Oral Cavity; Salivary Gland Squamous Cell Carcinoma; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IVA Salivary Gland Cancer; Stage IVA Squamous Cell Carcinoma of the Larynx; Stage IVA Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVA Squamous Cell Carcinoma of the Oropharynx; Stage IVA Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IVA Verrucous Carcinoma of the Larynx; Stage IVA Verrucous Carcinoma of the Oral Cavity; Stage IVB Salivary Gland Cancer; Stage IVB Squamous Cell Carcinoma of the Larynx; Stage IVB Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVB Squamous Cell Carcinoma of the Oropharynx; Stage IVB Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IVB Verrucous Carcinoma of the Larynx; Stage IVB Verrucous Carcinoma of the Oral Cavity; Stage IVC Salivary Gland Cancer; Stage IVC Squamous Cell Carcinoma of the Larynx; Stage IVC Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVC Squamous Cell Carcinoma of the Oropharynx; Stage IVC Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IVC Verrucous Carcinoma of the Larynx; Stage IVC Verrucous Carcinoma of the Oral Cavity; Tongue Cancer; Untreated Metastatic Squamous Neck Cancer With Occult Primary

  10. Antibiotic Selection Pressure and Macrolide Resistance in Nasopharyngeal Streptococcus pneumoniae: A Cluster-Randomized Clinical Trial

    PubMed Central

    Skalet, Alison H.; Cevallos, Vicky; Ayele, Berhan; Gebre, Teshome; Zhou, Zhaoxia; Jorgensen, James H.; Zerihun, Mulat; Habte, Dereje; Assefa, Yared; Emerson, Paul M.; Gaynor, Bruce D.; Porco, Travis C.; Lietman, Thomas M.; Keenan, Jeremy D.

    2010-01-01

    Background It is widely thought that widespread antibiotic use selects for community antibiotic resistance, though this has been difficult to prove in the setting of a community-randomized clinical trial. In this study, we used a randomized clinical trial design to assess whether macrolide resistance was higher in communities treated with mass azithromycin for trachoma, compared to untreated control communities. Methods and Findings In a cluster-randomized trial for trachoma control in Ethiopia, 12 communities were randomized to receive mass azithromycin treatment of children aged 1–10 years at months 0, 3, 6, and 9. Twelve control communities were randomized to receive no antibiotic treatments until the conclusion of the study. Nasopharyngeal swabs were collected from randomly selected children in the treated group at baseline and month 12, and in the control group at month 12. Antibiotic susceptibility testing was performed on Streptococcus pneumoniae isolated from the swabs using Etest strips. In the treated group, the mean prevalence of azithromycin resistance among all monitored children increased from 3.6% (95% confidence interval [CI] 0.8%–8.9%) at baseline, to 46.9% (37.5%–57.5%) at month 12 (p = 0.003). In control communities, azithromycin resistance was 9.2% (95% CI 6.7%–13.3%) at month 12, significantly lower than the treated group (p<0.0001). Penicillin resistance was identified in 0.8% (95% CI 0%–4.2%) of isolates in the control group at 1 year, and in no isolates in the children-treated group at baseline or 1 year. Conclusions This cluster-randomized clinical trial demonstrated that compared to untreated control communities, nasopharyngeal pneumococcal resistance to macrolides was significantly higher in communities randomized to intensive azithromycin treatment. Mass azithromycin distributions were given more frequently than currently recommended by the World Health Organization's trachoma program. Azithromycin use in this setting did

  11. Potential barriers to randomized clinical trials in infants with brachial plexus birth palsy

    PubMed Central

    Figoni, Andrew; Bauer, Andrea; James, Michelle

    2016-01-01

    Randomized clinical trials (RCTs) are the gold standard for comparing medical treatments. However, pediatric surgical RCTs are uncommon. We sought the opinions of parents whose children had undergone reconstructive nerve surgery regarding participating in research studies. Twenty-nine of 30 parents indicated they would enroll their child in a research study, and 24 of these would enroll in a surgical RCT. However, the most common reason for willingness to participate was a desire to help their child, demonstrating a fundamental misunderstanding of RCTs. The burden is on the researcher to ascertain the subject’s level of understanding before consenting to randomization. PMID:25856278

  12. Phase II Audit Report - Energy & Water Audits of LLNL Facilities

    SciTech Connect

    Horst, B I; Jacobs, P C; Pierce, S M

    2005-08-03

    This report describes Phase II of a project conducted for the Mechanical Utilities Division (UTel), Energy Management Program at Lawrence Livermore National Laboratory (LLNL) by Architectural Energy Corporation (AEC). The overall project covers energy efficiency and water conservation auditing services for 215 modular and prefabricated buildings at LLNL. The primary goal of this project is to demonstrate compliance with DOE Order 430.2A, Contractor Requirements Document section 2.d (2) Document, to demonstrate annual progress of at least 10 percent toward completing energy and water audits of all facilities. Although this project covers numerous buildings, they are all similar in design and use. The approach employed for completing audits for these facilities involves a ''model-similar building'' approach. In the model-similar building approach, similarities between groups of buildings are established and quantified. A model (or test case) building is selected and analyzed for each model-similar group using a detailed DOE-2 simulation. The results are extended to the group of similar buildings based on careful application of quantified similarities, or ''extension measures''. This approach leverages the relatively minor effort required to evaluate one building in some detail to a much larger population of similar buildings. The facility wide energy savings potential was calculated for a select set of measures that have reasonable payback based on the detailed building analysis and are otherwise desirable to the LLNL facilities staff. The selected measures are: (1) HVAC Tune-up. This is considered to be a ''core measure'', based on the energy savings opportunity and the impact on thermal comfort. All HVAC units in the study are assumed to be tuned up under this measure. See the Appendix for a detailed calculation by building and HVAC unit. (2) HVAC system scheduling. This is also considered to be a ''core measure'', based on the energy savings opportunity and

  13. Liraglutide efficacy and action in non-alcoholic steatohepatitis (LEAN): study protocol for a phase II multicentre, double-blinded, randomised, controlled trial

    PubMed Central

    Armstrong, Matthew J; Barton, Darren; Gaunt, Piers; Hull, Diana; Guo, Kathy; Stocken, Deborah; Gough, Stephen C L; Tomlinson, Jeremy W; Brown, Rachel M; Hübscher, Stefan G; Newsome, Philip N

    2013-01-01

    Introduction Non-alcoholic steatohepatitis (NASH) is now the commonest cause of chronic liver disease. Despite this, there are no universally accepted pharmacological therapies for NASH. Liraglutide (Victoza), a human glucagon-like peptide-1 (GLP-1) analogue, has been shown to improve weight loss, glycaemic control and liver enzymes in type 2 diabetes. There is currently a lack of prospective-controlled studies investigating the efficacy of GLP-1 analogues in patients with NASH. Methods and analysis Liraglutide efficacy and action in NASH (LEAN) is a phase II, multicentre, double-blinded, placebo-controlled, randomised clinical trial designed to investigate whether a 48-week treatment with 1.8 mg liraglutide will result in improvements in liver histology in patients with NASH. Adult, overweight (body mass index ≥25 kg/m2) patients with biopsy-confirmed NASH were assessed for eligibility at five recruitment centres in the UK. Patients who satisfied the eligibility criteria were randomly assigned (1:1) to receive once-daily subcutaneous injections of either 1.8 mg liraglutide or liraglutide-placebo (control). Using A'Hern's single stage phase II methodology (significance level 0.05; power 0.90) and accounting for an estimated 20% withdrawal rate, a minimum of 25 patients were randomised to each treatment group. The primary outcome measure will be centrally assessed using an intention-to-treat analysis of the proportion of evaluable patients achieving an improvement in liver histology between liver biopsies at baseline and after 48 weeks of treatment. Histological improvement will be defined as a combination of the disappearance of active NASH and no worsening in fibrosis. Ethics and dissemination The protocol was approved by the National Research Ethics Service (East Midlands—Northampton committee; 10/H0402/32) and the Medicines and Healthcare products Regulatory Agency. Recruitment into the LEAN started in August 2010 and ended in May 2013, with 52

  14. Clinical and radiographic comparison of various medicaments used for pulpotomy in primary molars: A randomized clinical trial

    PubMed Central

    Goyal, Prachi; Pandit, I. K.; Gugnani, Neeraj; Gupta, Monica; Goel, Richa; Gambhir, Ramandeep Singh

    2016-01-01

    Objective: To evaluate and compare the efficacy of ferric sulfate, glutaraldehyde, and mineral trioxide aggregate (MTA) as pulpotomy medicaments in primary molars. Materials and Methods: This was a perspective randomized clinical trial. A total of 90 molars from 42 children aged 4–8 years were selected for pulpotomy procedure. Teeth were randomly divided into three equal groups of 30 teeth each. Teeth in Group I were intended to be treated with ferric sulfate, Group II were intended to be treated with buffered glutaraldehyde and Group III with MTA. All the molars were evaluated clinically at 24 h and both clinically and radio graphically at 1, 3, and 6 months. The observations were statistically analyzed using Chi-square test and Fisher's exact test. Results: After 1 month, there was no clinical finding observed in all the three groups. At 3 months postoperative evaluation, 13.3% of teeth in Group I and 12.5% of teeth in Group II had mobility. At 6 months interval, pain and sinus formation each was noted in 9.1% of primary teeth in Group I while periodontal ligament widening was reported in 66.7% of teeth in Group I and 85.7% of teeth in Group II. Conclusion: MTA exhibited overall best results as pulpotomy agent for primary molars followed by 15.5% ferric sulfate, whereas 2% buffered glutaraldehyde was found to be least effective as a pulpotomy agent. PMID:27403046

  15. Is fresh frozen plasma clinically effective? A systematic review of randomized controlled trials.

    PubMed

    Stanworth, S J; Brunskill, S J; Hyde, C J; McClelland, D B L; Murphy, M F

    2004-07-01

    Summary Randomized controlled trials of good quality are a recognized means to robustly assess the efficacy of interventions in clinical practice. A systematic identification and appraisal of all randomized trials involving fresh frozen plasma (FFP) has been undertaken in parallel to the drafting of the updated British Committee for Standards in Haematology guidelines on the use of FFP. A total of 57 trials met the criteria for inclusion in the review. Most clinical uses of FFP, currently recommended by practice guidelines, are not supported by evidence from randomized trials. In particular, there is little evidence for the effectiveness of the prophylactic use of FFP. Many published trials on the use of FFP have enrolled small numbers of patients, and provided inadequate information on the ability of the trial to detect meaningful differences in outcomes between the two patient groups. Other concerns about the design of the trials include the dose of FFP used, and the potential for bias. No studies have taken adequate account of the extent to which adverse effects might negate the clinical benefits of treatment with FFP. There is a need to consider how best to develop new trials to determine the efficacy of FFP in different clinical scenarios to provide the evidence base to support national guidelines for transfusion practice. Trials of modified FFP (e.g. pathogen inactivated) are of questionable value when there is little evidence that the standard product is an effective treatment. PMID:15198745

  16. Differentiation therapy in poor risk myeloid malignancies: Results of companion phase II studies.

    PubMed

    Norsworthy, Kelly J; Cho, Eunpi; Arora, Jyoti; Kowalski, Jeanne; Tsai, Hua-Ling; Warlick, Erica; Showel, Margaret; Pratz, Keith W; Sutherland, Lesley A; Gore, Steven D; Ferguson, Anna; Sakoian, Sarah; Greer, Jackie; Espinoza-Delgado, Igor; Jones, Richard J; Matsui, William H; Smith, B Douglas

    2016-10-01

    Pre-clinical data in non-M3 AML supports the use of differentiation therapy, but clinical activity has been limited. Myeloid growth factors can enhance anti-leukemic activity of differentiating agents in vitro. We conducted companion phase II trials investigating sargramostim (GM-CSF) 125μg/m(2)/day plus 1) bexarotene (BEX) 300mg/m(2)/day or 2) entinostat (ENT) 4-8mg/m(2)/week in patients with MDS or relapsed/refractory AML. Primary endpoints were response after at least two treatment cycles and toxicity. 26 patients enrolled on the BEX trial had a median of 2 prior treatments and 24 enrolled on the ENT trial had a median of 1. Of 13 response-evaluable patients treated with BEX, the best response noted was hematologic improvement in neutrophils (HI-N) seen in 4 (31%) patients; none achieved complete (CR) or partial remission (PR). Of 10 treated with ENT, there was 1 (10%) partial remission (PR) and 2 (20%) with HI-N. The secondary endpoint responses of HI-N with each combination were accompanied by a numerical increase in ANC (BEX: 524 to 931 cells/mm(3), p=0.096; ENT: 578 to 1 137 cells/mm(3), p=0.15) without increasing marrow blasts. Shared grade 3-4 non-hematologic toxicities included febrile neutropenia, bone pain, fatigue, and dyspnea. GM-CSF plus either BEX or ENT are well tolerated in resistant and refractory MDS and AML and showed modest clinical and biologic activity, most commonly HI-N.

  17. 78 FR 63479 - Meta-Analyses of Randomized Controlled Clinical Trials (RCTs) for the Evaluation of Risk To...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-10-24

    ... HUMAN SERVICES Food and Drug Administration Meta-Analyses of Randomized Controlled Clinical Trials (RCTs... constructive discussion and information-sharing about best practices in meta-analyses of clinical trial data... scientific approaches for the conduct and assessment of meta-analyses of randomized controlled...

  18. Divalproex Sodium for the Treatment of PTSD and Conduct Disordered Youth: A Pilot Randomized Controlled Clinical Trial

    ERIC Educational Resources Information Center

    Steiner, Hans; Saxena, Kirti S.; Carrion, Victor; Khanzode, Leena A.; Silverman, Melissa; Chang, Kiki

    2007-01-01

    We examined the efficacy of divalproex sodium (DVP) for the treatment of PTSD in conduct disorder, utilizing a previous study in which 71 youth were enrolled in a randomized controlled clinical trial. Twelve had PTSD. Subjects (all males, mean age 16, SD 1.0) were randomized into high and low dose conditions. Clinical Global Impression (CGI)…

  19. Diabetic foot infection: a critical review of recent randomized clinical trials on antibiotic therapy.

    PubMed

    Crouzet, J; Lavigne, J P; Richard, J L; Sotto, A

    2011-09-01

    Controlled clinical trials are essential tools for evaluating the efficacy of antibiotic treatment against infection, but the results of such trials critically depend on sensitive, reproducible, and feasible outcome measures. We reviewed randomized controlled trials on the antibiotic treatment of diabetic foot infection published between 1999 and 2009 in terms of quality and endpoints. Discrepancies in study design, inclusion criteria, statistical methodology, and the varying definitions of both clinical and microbiological endpoints between the published studies, make it difficult to compare them, as well as to determine which regimen may be the most appropriate for patients with diabetic foot infection.

  20. Randomized Clinical Trial of a Sustained-Exposure Ciprofloxacin for Intratympanic Injection During Tympanostomy Tube Surgery

    PubMed Central

    Mair, Eric A.; Moss, Jonathan R.; Dohar, Joseph E.; Antonelli, Patrick J.; Bear, Moraye; LeBel, Carl

    2016-01-01

    Objective: This exploratory clinical trial evaluated the safety and clinical activity of a novel, sustained-exposure formulation of ciprofloxacin microparticulates in poloxamer (OTO-201) administered during tympanostomy tube placement in children. Methods: Double-blind, randomized, prospective, placebo- and sham-controlled, multicenter Phase 1b trial in children (6 months to 12 years) with bilateral middle ear effusion requiring tympanostomy tube placement. Patients were randomized to intraoperative OTO-201 (4 mg or 12 mg), placebo, or sham (2:1:1 ratio). Results: Eighty-three patients (52 male/31 female; mean age, 2.80 years) were followed for safety (otoscopic exams, cultures, audiometry, and tympanometry) and clinical activity, defined as treatment failure (physician-documented otorrhea and/or otic or systemic antibiotic use ≥3 days post surgery). At baseline, 14.3% to 36.8% of children showed positive cultures of middle ear effusion samples in at least 1 ear. Through day 15, treatment failures accounted for 14.3%, 15.8%, 45.5%, and 42.9% of patients (OTO-201 4 mg, OTO-201 12 mg, placebo, and sham, respectively); treatment failure reductions for OTO-201 doses were significant compared to pooled control (P values = .023 and .043, respectively). Observed OTO-201 safety profile was indistinguishable from placebo or sham. Conclusions: Results of this first clinical trial suggest that OTO-201 was well tolerated and shows preliminary clinical activity in treating tympanostomy tube otorrhea. PMID:26296929

  1. Phase II Trial of Dolastatin-10, a Novel Anti-Tubulin Agent, in Metastatic Soft Tissue Sarcomas

    PubMed Central

    Balcerzak, S. P.; Kraft, A. S.; Edmonson, J. H.; Okuno, S. H.; Davey, M.; Mclaughlin, S.; Beard, M. T.; Rogatko, A.

    2004-01-01

    Patients:Soft tissue sarcomas are uncommon malignancies with few therapeutic options for recurrent or metastatic disease. Dolastatin-10 (Dol-10) is a pentapeptide anti-microtubule agent that binds to tubulin sites distinct from vinca alkaloids. Based on the novel mechanism of action, limited activity of other anti-microtubular agents, and anti-neoplastic activity in pre-clinical screening of Dol-10, this multi-institutional phase II study was conducted to determine the objective response rate of Dol-10 in recurrent or metastatic soft tissue sarcomas that had not been treated with chemotherapy outside of the adjuvant setting. Methods: Dol-10 was given intravenously at a dose of 400 μg/m2 and repeated every 21 days. Toxicities were assessed using the Common Toxicity Criteria (version 2.0). Radiographic studies and tumor measurements were repeated every two cycles to assess response [Miller AB, et al. Cancer 1981; 47(1): 207]. Results: Dol-10 was associated with hematological toxicity and with some vascular toxicities. There was no significant gastrointestinal, hepatic or renal toxicity. There was one death on study due to respiratory failure. There were no objective responses in 12 patients treated with Dol-10. Discussion: Based on this phase II trial, further study of Dol-10 on this schedule is not recommended in advanced or metastatic soft tissue sarcomas. PMID:18521404

  2. Clinical performance of a light-cured denture base material compared to polymethylmethacrylate--a randomized clinical study.

    PubMed

    Gohlke-Wehrße, Hanna-Lena; Giese-Kraft, Katja; Wöstmann, Bernd

    2012-06-01

    The aim of this study was to evaluate the clinical long-term performance of a visible light-cured resin (VLCR) denture base material and to compare it to a well-established polymethylmethacrylate (PMMA)-based denture acrylic in a randomized split-mouth clinical long-term study. One hundred removable partial dentures in 90 patients, with at least two saddles each, were investigated. One saddle was made of VLCR, while the other was made of PMMA at random. Plaque adhesion, tissue reaction, and technical parameters of the dentures were assessed 6, 12, and 18 months after treatment. Statistical analysis was performed using the Wilcoxon rank-sum test. Though VLCR showed higher plaque adhesion than PMMA after 6, 12, and 18 months (p < 0.001), there were no important differences with regard to tissue reaction. Concerning plaque adhesion, surface quality with regard to the lower side, interfaces between denture acrylic and metal and the boundary between denture acrylic and denture tooth PMMA was rated higher than VLCR. The surface quality of the upper side of the denture saddles showed no significant differences (p > 0.05). Neither VLCR nor PMMA showed discoloration at any point in time (p > 0.05). It can be concluded that VLCR is a viable alternative for the production of removable dentures. Especially in patients with hypersensitivities to PMMA, VLCR is particularly suitable for clinical use.

  3. Non-participation in a randomized controlled trial: the effect on clinical and non-clinical variables.

    PubMed

    Vermaire, J H; van Loveren, C; Poorterman, J H G; Hoogstraten, J

    2011-01-01

    Studies reporting clinical and non-clinical parameters of participants and non-participants of clinical trials are scarce. In the available studies non-participants were likely to show less favourable outcomes than participants on both socioeconomic parameters as well as on caries experience. However, the impact of non-participation on the total sample of the research population is not established. In the present study, as part of baseline data collection for a randomized controlled trial on caries-preventive strategies, 346 parents of children 6.0 years (± 3 months) of age were approached to let their child participate. Sixty parents refused, but 56 of them were willing to fill out the same set of questionnaires and to allow their child to be clinically examined once. Parents from participating children had higher socioeconomic status, were more often of autochthonous origin and scored better on knowledge questions than parents of non-participating children. Furthermore, parents of participating children reported a higher willingness to invest, were more likely to hold on to regular meals and their child had lower levels of plaque compared to non-participating children. Surprisingly, the participating children had higher dmfs scores than the non-participating children. Their care index (fs/ds + fs) was higher than that of non-participating children. Based on the findings of this study, the presumption that non-participating children will show less favourable clinical outcomes cannot be supported. Although participants differed from non-participants, they did not differ from the total population. It is suggested that the external validity of a randomized controlled trial on caries-preventive strategies is not necessarily affected by non-participation bias. PMID:21576959

  4. Intracerebral administration of CpG oligonucleotide for patients with recurrent glioblastoma: a phase II study.

    PubMed

    Carpentier, Alexandre; Metellus, Philippe; Ursu, Renata; Zohar, Sarah; Lafitte, Francois; Barrié, Maryline; Meng, Yuxia; Richard, Margaretha; Parizot, Christophe; Laigle-Donadey, Florence; Gorochov, Guy; Psimaras, Dimitri; Sanson, Marc; Tibi, Annick; Chinot, Olivier; Carpentier, Antoine F

    2010-04-01

    Immunostimulating oligodeoxynucleotides containing CpG motifs (CpG-ODN) have shown promising efficacy in cancer models when injected locally. In a phase I clinical trial, intratumoral infusions of CpG-ODN in glioblastoma (GBM) patients were well tolerated at doses up to 20 mg. This phase II trial was designed to study the efficacy of a local treatment by CpG-ODN in patients with recurrent GBMs. Patients with recurrent GBM occurring at least 3 months after radiotherapy, and previously treated with 1 or 2 regimens of chemotherapy received 20 mg of CpG-ODN (CpG-28) by convection-enhanced delivery. The primary endpoint was the percentage of patients without tumor progression 6 months after inclusion. Secondary endpoints were tolerance, survival, and radiological response. Thirty-four patients were enrolled in two centers between November 2004 and March 2006. Thirty-one patients received CpG-ODN treatment. The progression-free survival (PFS) at 6 months was 19%. One partial response and 3 minor responses were observed. The median overall survival was 28 weeks. Eight patients (24%) were alive 1 year after inclusion and 5 patients (15%) were alive after 2 years. Treatment was usually well tolerated. As reported previously, the most common toxicities were lymphopenia, mild fever, seizures, and transient neurological worsening. Despite a few cases showing a radiological response, CpG-28 showed modest activity on the 6-month PFS in this patient population. The molecular or clinical characteristics of a subgroup of patients that could potentially benefit from such an approach remain to be defined. PMID:20308317

  5. A phase II trial of ISIS 3521 in patients with metastatic colorectal cancer.

    PubMed

    Marshall, John L; Eisenberg, Steven G; Johnson, Michael D; Hanfelt, John; Dorr, F Andrew; El-Ashry, Dorraya; Oberst, Michael; Fuxman, Yair; Holmlund, Jon; Malik, Shakun

    2004-11-01

    This phase II study was designed to characterize the clinical activity of ISIS 3521 in patients with metastatic colorectal cancer (CRC). Sixteen patients with pretreated or refractory CRC were treated with ISIS 3521. Eleven patients were given a dose of 2.0 mg/kg per day, and 5 patients received 3.0 mg/kg per day given over 21 days followed by a 7-day rest period. Patients continued with study until evidence of disease progression or unacceptable toxicity was detected. Patients underwent baseline tumor biopsies followed by a second biopsy during the last week of the first 21-day infusion. All 16 patients underwent baseline tumor biopsies, and 12 of the 16 patients underwent on-study tumor biopsies. No evidence of tumor response was observed. One patient had stable disease after 2 cycles and remained on for 1 additional cycle only to demonstrate progression of disease at that time. No dose-limiting or other significant toxicities were observed at both dosages, which could not be explained by progression of disease. Fatigue was common in all patients treated but was not dose limiting, and there was no evidence of coagulopathy. Analysis of the tumor biopsies obtained from the 11 evaluable samples showed marked uptake of ISIS 3521 in the normal liver parenchyma. However, there was minimal uptake within the tumor cells. In addition, no evidence of any alteration in protein kinase C-a within the tumors or any downstream effects leading to apoptosis were observed. ISIS 3521 demonstrated no clinical activity or target modulation in refractory metastatic CRC.

  6. Systemic corticosteroid monotherapy for clinically diagnosed acute rhinosinusitis: a randomized controlled trial

    PubMed Central

    Venekamp, Roderick P.; Bonten, Marc J.M.; Rovers, Maroeska M.; Verheij, Theo J.M.; Sachs, Alfred P.E.

    2012-01-01

    Background: Patients with acute rhinosinusitis are frequently encountered in primary care. Although corticosteroids are being increasingly used for symptom control, evidence supporting their use is inconclusive. We conducted a randomized controlled trial to examine the effectiveness of systemic corticosteroid monotherapy for clinically diagnosed, uncomplicated acute rhinosinusitis. Methods: We conducted a block-randomized, double-blind, placebo-controlled clinical trial at 54 primary care practices (68 family physicians) in the Netherlands between Dec. 30, 2008, and Apr. 28, 2011. Adult patients with clinically diagnosed acute rhinosinusitis were randomly assigned to receive either prednisolone 30 mg/d or placebo for 7 days and asked to complete a symptom diary for 14 days. The primary outcome measure was the proportion of patients with resolution of facial pain or pressure on day 7. Results: Of the 185 patients included in the trial (93 in the treatment group, 92 in the placebo group), 2 withdrew from the study and 9 were excluded from the primary analysis because of incomplete symptom reporting. The remaining 174 patients (88 in the treatment group, 86 in the placebo group) were included in the intention-to-treat analysis. The proportions of patients with resolution of facial pain or pressure on day 7 were 62.5% (55/88) in the prednisolone group and 55.8% (48/86) in the placebo group (absolute risk difference 6.7%, 95% confidence interval −7.9% to 21.2%). The groups were similar with regard to the decrease over time in the proportion of patients with total symptoms (combined symptoms of runny nose, postnasal discharge, nasal congestion, cough and facial pain) and health-related quality of life. Adverse events were mild and did not differ significantly between the groups. Interpretation: Systemic corticosteroid monotherapy had no clinically relevant beneficial effects among patients with clinically diagnosed acute rhinosinusitis. Netherlands Trial Register

  7. Analysis of the O-antigen biosynthesis regions of phase II isolates of Coxiella burnetii.

    PubMed

    Denison, Amy M; Massung, Robert F; Thompson, Herbert A

    2007-02-01

    The O-antigen-encoding region in the genomes of 14 isolates of Coxiella burnetii was examined by PCR. Five phase I isolates (Nine Mile clone 7, KAV, Ohio, Henzerling RSA 343, Q173) were analyzed and no deletions were detected. Two other isolates of unknown phase (Scottish, WAV) were examined, but no deletions were detected. In contrast, RSA 514 and three phase II isolates (Nine Mile phase II clone 4, Nine Mile phase II clone 1, Nine Mile Baca) contained large deletions, and the latter two were further characterized by DNA sequencing. Three other phase II isolates (Henzerling RSA 331, M44, Australian QD) contained no apparent deletions. Reactivity to phase I- and phase II-specific antibodies by immunofluorescence assay was used to further characterize isolates. Selected ORFs in Australian QD and M44 DNA were sequenced to detect mutations, and no significant changes were found. Australian QD RNA was examined by reverse transcriptase-PCR specific to the four ORFs hypothesized to encode the O-antigen sugar virenose, which this isolate has been shown to lack, as well as one that is predicted to encode part of the O-antigen ABC transporter. Each of these five genes was found to be expressed.

  8. Quality Randomized Clinical Trials of Topical Diabetic Foot Ulcer Healing Agents

    PubMed Central

    Bolton, Laura L.

    2016-01-01

    Significance: Diabetic foot ulcers (DFU) significantly add to global economic, social, and clinical burdens. Healing a DFU fast and well limits complications that can lead to lower extremity amputation, morbidity, and mortality. Recent Advances: Many promising topical DFU healing agents have been studied in randomized clinical trials (RCT), but only one, becaplermin, has been cleared for this use by the United States Food and Drug Administration (FDA). Critical Issues: This critical review of DFU topical healing RCTs summarizes issues identified in their design and conduct, highlighting ways to improve study quality so researchers can increase the likelihood of RCT success in propelling effective topical DFU healing agents toward clinical use. Key issues include (1) inadequate sample size, (2) risk of bias, (3) irrelevant or unreported inclusion criteria, (4) substandard outcome measures, (5) unmatched group characteristics that predict nonhealing at baseline, (6) unequal or uncontrolled concurrent interventions or standard of care, (7) heterogeneous subject or DFU samples (8) unblinded allocation, treatment, or outcome measures, or (9) inadequate follow-up for clinical relevance. These can add bias or unexplained variability to RCT outcomes, limiting clinical or statistical significance and accuracy of results. Future Directions: This critical review summarizes ways to overcome these deficiencies to optimize DFU clinical trial design and conduct. It provides a blueprint for future excellence in RCTs testing safety and efficacy of topical DFU healing agents and smoothing the path to their clinical use. PMID:26989579

  9. Seismic fragility of nuclear power plant components (Phase II)

    SciTech Connect

    Bandyopadhyay, K.K.; Hofmayer, C.H.; Kassir, M.K.; Pepper, S.E. )

    1990-02-01

    As part of the Component Fragility Program which was initiated in FY 1985, three additional equipment classes have been evaluated. This report contains the fragility results and discussions on these equipment classes which are switchgear, I and C panels and relays. Both low and medium voltage switchgear assemblies have been considered and a separate fragility estimate for each type is provided. Test data on cabinets from the nuclear instrumentation/neutron monitoring system, plant/process protection system, solid state protective system and engineered safeguards test system comprise the BNL data base for I and C panels (NSSS). Fragility levels have been determined for various failure modes of switchgear and I C panels, and the deterministic results are presented in terms of test response spectra. In addition, the test data have been evaluated for estimating the respective probabilistic fragility levels which are expressed in terms of a median value, an uncertainty coefficient, a randomness coefficient and an HCLPF value. Due to a wide variation of relay design and the fragility level, a generic fragility level cannot be established for relays. 7 refs., 13 figs., 12 tabs.

  10. Randomized clinical trials as reflexive-interpretative process in patients with rheumatoid arthritis: a qualitative study.

    PubMed

    de Jorge, Mercedes; Parra, Sonia; de la Torre-Aboki, Jenny; Herrero-Beaumont, Gabriel

    2015-08-01

    Patients in randomized clinical trials have to adapt themselves to a restricted language to capture the necessary information to determine the safety and efficacy of a new treatment. The aim of this study was to explore the experience of patients with rheumatoid arthritis after completing their participation in a biologic therapy randomized clinical trial for a period of 3 years. A qualitative approach was used. The information was collected using 15 semi-structured interviews of patients with rheumatoid arthritis. Data collection was guided by the emergent analysis until no more relevant variations in the categories were found. The data were analysed using the grounded theory method. The objective of the patients when entering the study was to improve their quality of life by initiating the treatment. However, the experience changed the significance of the illness as they acquired skills and practical knowledge related to the management of their disease. The category "Interactional Empowerment" emerged as core category, as it represented the participative experience in a clinical trial. The process integrates the follow categories: "weight of systematisation", "working together", and the significance of the experience: "the duties". Simultaneously these categories evolved. The clinical trial monitoring activities enabled patients to engage in a reflexive-interpretative mechanism that transformed the emotional and symbolic significance of their disease and improved the empowerment of the patient. A better communicative strategy with the health professionals, the relatives of the patients, and the community was also achieved. PMID:25636236

  11. [Medicinal glaucoma therapy. What can we learn from large randomized clinical trials?].

    PubMed

    Jünemann, A G M; Huchzermeyer, C; Rejdak, R

    2013-12-01

    The prospective multicenter randomized controlled clinical trials (RCTs) Ocular Hypertension Glaucoma Treatment Study (OHTS), Early Manifest Glaucoma Trial (EMGT), Advanced Glaucoma Intervention Study (AGIS), Collaborative Initial Glaucoma Treatment Study (CITGS) and Collaborative Normal Tension Glaucoma Study (CNGTS) are often named as landmarks for glaucoma management as the results of these studies provided the evidence for numerous therapeutic decisions in clinical practice. The studies confirmed the consensus that reduction of intraocular pressure reduces the risk of glaucoma progression covering the whole spectrum of glaucoma from ocular hypertension to advanced glaucoma. Furthermore, the identification of new risk factors allows a higher precision of assessment of the risk of progression. The RCTs achieved the main goal of high level of evidence, thus making progress in the understanding of glaucoma and its treatment and bridging consensus-based and evidence-based decisions. However, the implementation of the results into clinical practice needs adequate and accurate interpretation of the results.

  12. A 2-stage phase II design with direct assignment option in stage II for initial marker validation.

    PubMed

    An, Ming-Wen; Mandrekar, Sumithra J; Sargent, Daniel J

    2012-08-15

    Biomarkers are critical to targeted therapies, as they may identify patients more likely to benefit from a treatment. Several prospective designs for biomarker-directed therapy have been previously proposed, differing primarily in the study population, randomization scheme, or both. Recognizing the need for randomization, yet acknowledging the possibility of promising but inconclusive results after a stage I cohort of randomized patients, we propose a 2-stage phase II design on marker-positive patients that allows for direct assignment in a stage II cohort. In stage I, marker-positive patients are equally randomized to receive experimental treatment or control. Stage II has the option to adopt "direct assignment" whereby all patients receive experimental treatment. Through simulation, we studied the power and type I error rate of our design compared with a balanced randomized two-stage design, and conducted sensitivity analyses to study the effect of timing of stage I analysis, population shift effects, and unbalanced randomization. Our proposed design has minimal loss in power (<1.8%) and increased type I error rate (<2.1%) compared with a balanced randomized design. The maximum increase in type I error rate in the presence of a population shift was between 3.1% and 5%, and the loss in power across possible timings of stage I analysis was less than 1.2%. Our proposed design has desirable statistical properties with potential appeal in practice. The direct assignment option, if adopted, provides for an "extended confirmation phase" as an alternative to stopping the trial early for evidence of efficacy in stage I.

  13. Efficacy of extended intramammary ceftiofur therapy against mild to moderate clinical mastitis in Holstein dairy cows: A randomized clinical trial

    PubMed Central

    Truchetti, Geoffrey; Bouchard, Émile; DesCôteaux, Luc; Scholl, Daniel; Roy, Jean-Philippe

    2014-01-01

    Few studies have investigated the efficacy of extended ceftiofur therapy and none have focused on extended therapy for naturally occurring clinical mastitis. The objective of this study was to compare the efficacy of extended intramammary ceftiofur therapy of 8 d duration with a standard 2-day regimen for the treatment of naturally occurring mild to moderate clinical mastitis in lactating dairy cows. Holstein cows from 22 dairy herds (n = 241) were randomly allocated to the 2 treatment groups. For each case of mastitis, 125 mg of ceftiofur hydrochloride was administered intramammary once a day for 2 or 8 d. Clinical cure, 21 d after the last treatment, was 89% (98/110) in each group. Bacteriological cure 21 d after the last treatment for the 2- and 8-day regimens were 32% (15/47) and 61% (25/41), respectively, for all bacteria (P = 0.007), 64% (9/14) and 82% (9/11), respectively, for streptococci (P = 0.50), and 0% (0/20) and 47% (9/19), respectively, for Staphylococcus aureus (P = 0.0004). There were no statistical differences between groups for new intramammary infections. Overall, ceftiofur extended therapy increased cure when compared to a 2-day regimen for the treatment of naturally occurring mild to moderate clinical mastitis in lactating dairy cows. PMID:24396178

  14. Recognition and Evaluation of Clinical Section Headings in Clinical Documents Using Token-Based Formulation with Conditional Random Fields.

    PubMed

    Dai, Hong-Jie; Syed-Abdul, Shabbir; Chen, Chih-Wei; Wu, Chieh-Chen

    2015-01-01

    Electronic health record (EHR) is a digital data format that collects electronic health information about an individual patient or population. To enhance the meaningful use of EHRs, information extraction techniques have been developed to recognize clinical concepts mentioned in EHRs. Nevertheless, the clinical judgment of an EHR cannot be known solely based on the recognized concepts without considering its contextual information. In order to improve the readability and accessibility of EHRs, this work developed a section heading recognition system for clinical documents. In contrast to formulating the section heading recognition task as a sentence classification problem, this work proposed a token-based formulation with the conditional random field (CRF) model. A standard section heading recognition corpus was compiled by annotators with clinical experience to evaluate the performance and compare it with sentence classification and dictionary-based approaches. The results of the experiments showed that the proposed method achieved a satisfactory F-score of 0.942, which outperformed the sentence-based approach and the best dictionary-based system by 0.087 and 0.096, respectively. One important advantage of our formulation over the sentence-based approach is that it presented an integrated solution without the need to develop additional heuristics rules for isolating the headings from the surrounding section contents. PMID:26380302

  15. Effects of Vitamin D Intake on FEV1 and COPD Exacerbation: A Randomized Clinical Trial Study

    PubMed Central

    Zendedel, Abolfazl; Gholami, Mohammadreza; Anbari, Khatereh; Ghanadi, Kourosh; Bachari, Elham Ceneicel; Azargon, Alireza

    2015-01-01

    Aim: This study aimed to evaluate the effects of vitamin D intake on COPD exacerbation and FEV1 in the patients with severe and very severe COPD. Methods: This double blind placebo control randomized clinical trial study was done in the Ashayer university hospital in Khorramabad in 2012. Eighty eight patients with severe and very severe COPD were randomly selected from those who recoursed to the internal medicine clinic of Ashayer hospital. They were randomly allocated to case and placebo group. The patients received routine treatment for COPD. Along with the routine treatment, placebo group received 100,000 IU of oral vitamin D per month, for 6 months. Data was analyzed using SPSS computer software, paired t-test, independent t-test, non parametric t-test and Pearson correlation coefficients. Results: In each group, there were 44 patients. After the intervention, there were significant differences in FEV1 and the number of COPD exacerbation between the case and control group patients. Also, after the study, in the case group, FEV1 was increased and the number of COPD exacerbation was decreased significantly. Conclusion: Vitamin D intake decreased COPD exacerbation and improved FEV1 in the patients with severe and very severe COPD. It is suggested that baseline serum vitamin D levels will recorded in similar studies and the effect of vitamin D intake will evaluated regarding the baseline serum vitamin D levels. PMID:25946929

  16. On the use of the Positive and Negative Syndrome Scale in randomized clinical trials.

    PubMed

    Nicotra, Eraldo; Casu, Gianluca; Piras, Sara; Marchese, Giorgio

    2015-07-01

    In the last 25 years, the Positive and Negative Syndrome Scale (PANSS) has been largely used to assess schizophrenia symptom intensity, but little information is available on how this scale was generally applied when evaluating the efficacy of schizophrenia therapies in randomized clinical trials. In the attempt to address this topic, a systematic PubMed Search was carried out using the keywords "PANSS" and "Randomized Clinical Trials". The analysis of retrieved articles highlighted that PANSS has constituted a suitable psychometric instrument to investigate the efficacy of pharmacological and non-pharmacological therapies. However, the information potentially provided by this scale was only partially reported in research articles, when characterizing the symptomatic features of patients at baseline. Furthermore, a consensus is needed to identify methodological strategies that may properly adapt PANSS-subscale structure with the symptomatic profiles of individuals enrolled in randomized controlled trials. The possibility that PANSS interview procedures and enrollment eligibility criteria may influence the symptomatic composition of patients involved in these studies is also discussed. PMID:25937460

  17. Rotary instruments in the treatment of chronic periodontitis: A randomized clinical trial

    PubMed Central

    Dahiya, Parveen; Kamal, Reet

    2013-01-01

    Background: The study aimed at comparing the effectiveness of rotary instruments with hand instruments in non-surgical treatment of chronic periodontitis. Materials and Methods: Thirty-eight patients with chronic periodontitis, enrolled to this randomized, controlled clinical trial, were divided into two groups. Patients in the control group received scaling and root planing with hand instruments, whereas patients in the test group received treatment with rotary instruments. Clinical assessment by plaque index, bleeding on probing, probing depth, gingival recession, and clinical attachment level was made prior to and at 6 months after treatment. Differences in the clinical parameters were analyzed using the Wilcoxon signed rank test and Mann–Whitney U test. Results: Both treatments resulted in a significant improvement in all clinical recordings, but no differences in any of the investigated parameters were observed at baseline between the two groups. Conclusion: Non-surgical periodontal therapy with the tested rotary instruments may lead to clinical improvements comparable to those obtained with conventional hand instruments. PMID:24554884

  18. Two-year clinical evaluation of resin composite in posterior teeth: A randomized controlled study

    PubMed Central

    Gianordoli-Neto, Ranulfo; Padovani, Gislaine Cristina; Mondelli, José; de Lima Navarro, Maria Fidela; Mendonça, Juliano Sartori; Santiago, Sérgio Lima

    2016-01-01

    Background: Clinical evaluations as fundamental method to prove the efficiency of restorative materials. Aim: This study evaluated the clinical performance of restorative systems during 2 years of clinical service. Materials and Methods: This study assessed the clinical performance of restorative systems (Filtek Z250 and P60), during 2 years of clinical service, using the US Public Health Service system. The randomized and double-blind study comprising thirty volunteers. The restorations were evaluated at baseline, 6, 12, and 24 months. It was used the following criteria: marginal discoloration (MD), marginal integrity (MI), superficial texture (ST), wear (W), postoperative sensitivity (PS) and recurrent caries (RC). Results: Statistic analysis was performed using Fisher's and McNemar's exact tests and Pearsons's Chi-square in a significance level of 5%. The results at baseline and 24 months for Group I were: MD – 100, 100%; MI – 100, 88.6%; ST – 100, 94.3%; W – 100, 94.3%; PS – 100, 100%; RC – 100, 100%, of alpha scores; Group II: MD – 100, 97.1%; MI – 100, 91.4%; ST – 100, 94.3%; W – 100, 91.4%; PS – 100, 100%; RC – 100, 100%, of alpha scores. It was observed no statistical difference in the evaluated criteria and period. Conclusions: After 24 months of evaluation, both restorative systems exhibited acceptable clinical performance. PMID:27563176

  19. Uncomplicated Pregnancies and Ultrasounds for Fetal Growth Restriction: A Pilot Randomized Clinical Trial.

    PubMed

    Hammad, Ibrahim A; Chauhan, Suneet P; Mlynarczyk, Malgorzata; Rabie, Nader; Goodie, Chris; Chang, Eugene; Magann, Everett F; Abuhamad, Alfred Z

    2016-03-01

    Objective The purpose of this multicenter pilot study was to determine the feasibility of randomizing uncomplicated pregnancies (UPs) to have third trimester ultrasonographic exams (USE) versus routine prenatal care (RPNC) to improve the detection of small for gestational age (SGA; birth weight < 10% for GA). Material and Methods At three referral centers, 50 UPs were randomized after gestational diabetes was ruled out. Women needed to screen, consenting, and loss to follow-up was ascertained, as was the detection rate of SGA in the two groups. Results During the study period at the three centers, there were 7,680 births, of which 64% were uncomplicated. Of the 234 women approached for randomization, 36% declined. We recruited 149 women and had follow-up delivery data on 97%. The antenatal detection rate of SGA in the intervention group was 67% (95% confidence intervals 31-91%) and 9% (0.5-43%) in control. Conclusion The pilot study provides feasibility data for a multicenter randomized clinical trial to determine if third trimester USE, compared with RPNC, improves the detection of SGA and composite neonatal morbidity. PMID:26929878

  20. Glutamine randomized studies in early life: the unsolved riddle of experimental and clinical studies.

    PubMed

    Briassouli, Efrossini; Briassoulis, George

    2012-01-01

    Glutamine may have benefits during immaturity or critical illness in early life but its effects on outcome end hardpoints are controversial. Our aim was to review randomized studies on glutamine supplementation in pups, infants, and children examining whether glutamine affects outcome. Experimental work has proposed various mechanisms of glutamine action but none of the randomized studies in early life showed any effect on mortality and only a few showed some effect on inflammatory response, organ function, and a trend for infection control. Although apparently safe in animal models (pups), premature infants, and critically ill children, glutamine supplementation does not reduce mortality or late onset sepsis, and its routine use cannot be recommended in these sensitive populations. Large prospectively stratified trials are needed to better define the crucial interrelations of "glutamine-heat shock proteins-stress response" in critical illness and to identify the specific subgroups of premature neonates and critically ill infants or children who may have a greater need for glutamine and who may eventually benefit from its supplementation. The methodological problems noted in the reviewed randomized experimental and clinical trials should be seriously considered in any future well-designed large blinded randomized controlled trial involving glutamine supplementation in critical illness.

  1. Glutamine Randomized Studies in Early Life: The Unsolved Riddle of Experimental and Clinical Studies

    PubMed Central

    Briassouli, Efrossini; Briassoulis, George

    2012-01-01

    Glutamine may have benefits during immaturity or critical illness in early life but its effects on outcome end hardpoints are controversial. Our aim was to review randomized studies on glutamine supplementation in pups, infants, and children examining whether glutamine affects outcome. Experimental work has proposed various mechanisms of glutamine action but none of the randomized studies in early life showed any effect on mortality and only a few showed some effect on inflammatory response, organ function, and a trend for infection control. Although apparently safe in animal models (pups), premature infants, and critically ill children, glutamine supplementation does not reduce mortality or late onset sepsis, and its routine use cannot be recommended in these sensitive populations. Large prospectively stratified trials are needed to better define the crucial interrelations of “glutamine-heat shock proteins-stress response” in critical illness and to identify the specific subgroups of premature neonates and critically ill infants or children who may have a greater need for glutamine and who may eventually benefit from its supplementation. The methodological problems noted in the reviewed randomized experimental and clinical trials should be seriously considered in any future well-designed large blinded randomized controlled trial involving glutamine supplementation in critical illness. PMID:23019424

  2. A phase II study of laquinimod in Crohn's disease

    PubMed Central

    D'Haens, Geert; Sandborn, William J; Colombel, Jean Frederic; Rutgeerts, Paul; Brown, Kurt; Barkay, Hadas; Sakov, Anat; Haviv, Asi; Feagan, Brian G

    2015-01-01

    Objective Laquinimod is an oral therapeutic agent under investigation for the treatment of Crohn's disease (CD), Huntington's disease, lupus nephritis and multiple sclerosis. This dose escalation study evaluated the safety and efficacy of laquinimod as induction therapy in patients with active moderate–severe CD. Design Multicentre, double-blind, sequential-cohort, randomised controlled trial with laquinimod doses of 0.5, 1, 1.5 or 2 mg/day or placebo (n=45 per cohort randomised in a 2:1 ratio) for 8 weeks with 4-week follow-up. Stable concomittant therapies and prior use of anti-tumour necrosis factor agents were permitted. Comprehensive safety assessments were performed and efficacy analyses included the proportions of patients in clinical remission (CD Activity Index (CDAI) <150 and no treatment failure (TF)), and with a clinical response (70 or 100 point CDAI reduction from baseline or remission and no TF). Results 117 patients received laquinimod and 63 patients received placebo. The overall incidence of adverse events (AEs) in the laquinimod group was similar to the pooled placebo group (86.2%–96.7% vs 82.5%) and most AEs were mild to moderate in severity. Treatment with laquinimod 0.5 mg showed consistent effects on remission (48.3% (CI 31% to 66%) vs 15.9% (CI 9% to 27%)), response 100 (55.2% (CI 37% to 71%) vs 31.7% (CI 22% to 44%)) and response 70 (62.1% (CI 44% to 77%) vs 34.9% (CI 24% to 47%)) versus placebo. Laquinimod 1.0 mg showed less benefit (26.7% remission (CI 14% to 44%) and 53.3% response 70 (CI 36% to 70%)), and no effect was noted on remission/response at higher doses. Conclusions Laquinimod was safe and well tolerated, and the effects on remission and response of the 0.5 mg dose suggest a treatment benefit in patients with CD. Trial registration number NCT00737932. PMID:25281416

  3. Clinical Hypnosis in the Treatment of Post-Menopausal Hot Flashes: A Randomized Controlled Trial

    PubMed Central

    Elkins, Gary R.; Fisher, William I.; Johnson, Aimee K.; Carpenter, Janet S.; Keith, Timothy Z.

    2012-01-01

    Objective The use of estrogen and progesterone to manage vasomotor symptoms (i.e., hot flashes, night sweats) has declined due to concerns over their risks and there is an increased interest in alternate, effective, and low-risk treatments. This study reports the results of a randomized, controlled trial of clinical hypnosis in treating vasomotor symptoms among post-menopausal women. Methods Randomized, single-blind, controlled, clinical trial involving 187 post-menopausal women reporting a minimum of seven hot flashes per day, or at least 50 hot flashes a week at baseline between December 2008 and April 2012. Eligible participants received five weekly sessions of either clinical hypnosis or structured-attention control. Primary outcomes were hot flash frequency (subjectively and physiologically recorded) and hot flash score assessed by daily diaries at weeks 2–6, and 12. Secondary outcomes included measures of hot flash related daily interference, sleep quality and treatment satisfaction. Results In a modified intent-to-treat analysis that included all randomized participants that provided data, reported subjective hot flash frequency from baseline to week 12 showed a mean reduction of 55.82 hot flashes for the clinical hypnosis intervention (74.16%), versus a 12.89 hot flash reduction (17.13%) for the control (p<.001, 95% CI, 36.15–49.67). Mean reduction in hot flash score was 18.83 (80.32%) for the clinical hypnosis intervention as compared to 3.53 (15.38%) for the control (p<.001, 95% CI, 12.60–17.54). At 12 week follow-up, the mean reduction in physiologically monitored hot flashes was 5.92 (56.86%) for clinical hypnosis and .88 (9.94%) for the control (p<.001, 95% CI, 2.00–5.46). Secondary outcomes were significantly improved compared to control at 12 week follow-up in hot flash related interference (p<.001, 95% CI, 2.74–4.02), sleep quality (p<.001, 95% CI, 3.65–5.84), and treatment satisfaction (p<.001, 95% CI, 7.79–8.59). Conclusion Compared

  4. RadSTraM: Radiological Source Tracking and Monitoring, Phase II Final Report

    SciTech Connect

    Warren, Tracy A; Walker, Randy M; Hill, David E; Gross, Ian G; Smith, Cyrus M; Abercrombie, Robert K

    2008-12-01

    This report focuses on the technical information gained from the Radiological Source Tracking and Monitoring (RadSTraM) Phase II investigation and its implications. The intent of the RadSTraM project was to determine the feasibility of tracking radioactive materials in commerce, particularly International Atomic Energy Agency (IAEA) Category 3 and 4 materials. Specifically, Phase II of the project addressed tracking radiological medical isotopes in commerce. These categories of materials are susceptible to loss or theft but the problem is not being addressed by other agencies.

  5. OCCIDENTAL VERTICAL MODIFIED IN SITU PROCESS FOR THE RECOVERY OF OIL FROM OIL SHALE. PHASE II

    SciTech Connect

    Nelson, Reid M.

    1980-09-01

    The progress presented in this report covers the period June 1, 1980 through August 31, 1980 under the work scope for.Phase II of the DOE/Occidental Oil Shale, Inc. (OOSI) Cooperative Agreement. The major activities at OOSI 1s Logan Wash site during the quarter were: mining the voids at all levels for Retorts 7, 8 and 8x; completing Mini-Retort (MR) construction; continuing surface facility construction; tracer testing the MR 1 s; conducting Retorts 7 & 8 related Rock Fragmentation tests; setting up and debugging the Sandia B-61 trailer; and preparing the Phase II instrumentation plan.

  6. THE CHEMICAL AND ANTIVIRAL PROPERTIES OF THE SOMATIC ANTIGEN OF PHASE II SHIGELLA SONNEI

    PubMed Central

    Jesaitis, Margeris A.; Goebel, Walther F.

    1952-01-01

    1. The somatic antigen of Phase II Shigella sonnei can be isolated by extracting phenol-killed microorganisms with water. This substance inactivates all T phages to which this bacillus is susceptible. 2. The Phase II antigen is constituted from a protein and a phosphorylated lipocarbohydrate. The major portion of the protein component can be removed by digestion with pancreatin. The enzymatically degraded antigen thus obtained can be further dissociated into its protein and lipocarbohydrate components by treatment with 90 per cent phenol. Glucose, galactose, glucosamine, and an aldoheptose have been identified as the monosaccharide constituents of the lipocarbohydrate. PMID:13000053

  7. Thiazolidinediones for nonalcoholic steatohepatitis: A meta-analysis of randomized clinical trials

    PubMed Central

    He, Lingling; Liu, Xiaoli; Wang, Lijia; Yang, Zhiyun

    2016-01-01

    Abstract The findings regarding the effects of thiazolidinediones (TZDs) in nonalcoholic steatohepatitis (NASH) patients have been inconsistent, and the assessment of different clinical variables for evaluating the effects of TZDs confound a direct comparison of the results of different randomized clinical trials (RCTs), especially with regard to lifestyle changes. In this paper, we performed a meta-analysis of randomized controlled trials to clarify the effects of TZD treatment with and without lifestyle changes on histological markers of NASH and clinical variables related to insulin resistance (IR), hyperlipidemia, and obesity. We searched the literature using the following MeSH terms: “nonalcoholic steatohepatitis,” “non-alcoholic steatohepatitis,” “thiazolidinedione,” “pioglitazone,” “rosiglitazone,” “randomized,” and “clinical trial.” Five eligible RCTs were selected, in which patients were treated with either pioglitazone or rosiglitazone, with or without lifestyle changes. We compared the effects of TZD treatment on hepatic fibrosis, lobular inflammation, IR improvement, fasting serum insulin, adiposity, and dyslipidemia between the various studies using fixed and random effects models, and heterogeneity in clinical outcomes was assessed. Significant improvement in hepatic fibrosis did not occur among the patients treated with TZDs alone or in those who underwent both lifestyle changes and TZD therapy. Lobular inflammation decreased in NASH patients who received TZD treatment and in those who underwent both TZD therapy and lifestyle changes. Although TZD treatment resulted in no significant improvement in IR, NASH patients who underwent both lifestyle changes and TZD therapy experienced a significantly greater reduction in their fasting insulin level than that observed in the control patients, whereas patients treated with TZDs alone did not. Although TZD-treated patients experienced significantly greater weight gain than the

  8. A Phase II Study of Cixutumumab (IMC-A12, NSC742460) in Advanced Hepatocellular Carcinoma

    PubMed Central

    Abou-Alfa, Ghassan K.; Capanu, Marinela; O’Reilly, Eileen M.; Ma, Jennifer; Chou, Joanne F.; Gansukh, Bolorsukh; Shia, Jinru; Kalin, Marcia; Katz, Seth; Abad, Leslie; Reidy-Lagunes, Diane L.; Kelsen, David P.; Chen, Helen X.; Saltz, Leonard B.

    2014-01-01

    Background and Aims IGF-IR is implicated in hepatic carcinogenesis. This and preliminary evidence of biological activity of anti-IGF-1R monoclonal antibody cixutumumab in phase I trials prompted this phase II study. Methods Patients with advanced HCC, Child-Pugh A-B8, received cixutumumab 6 mg/kg weekly, in a Simon two-stage design study, with the primary endpoints being 4-month PFS and RECIST-defined response rate. Tissue and circulating markers plus different HCC scoring systems were evaluated for correlation with PFS and OS. Results As a result of pre-specified futility criteria, only stage 1 was accrued: N= 24: median age 67.5 years (range 49–83), KPS 80% (70–90%), 20 males (83%), 9 stage III (37%)/15 stage IV (63%), 18 Child-Pugh A (75%), 11 HBV (46%) /10 HCV (42%)/11 alcoholic cirrhosis (46%)/2 NASH (8%), 11 (46%) diabetic. Median number of doses: 7 (range 1–140). Grade 3/4 toxicities > 10% included: diabetes, elevated liver function tests, hyponatremia, and lymphopenia. Four-month PFS was 30% (95% CI 13–48), and there were no objective responses. Median overall survival was 8 months (95%CI 5.8– 14). IGF-R1 staining did not correlate with outcome. Elevated IGFBP-1 correlated with improved PFS (1.2 [95%CI 1–1.4]; p 0.009) and OS (1.2 [95%CI 1.1–1.4]; p 0.003). Conclusions Cixutumumab monotherapy did not have clinically meaningful activity in this unselected HCC population. Grade 3–4 hyperglycemia occurred in 46% of patients. Elevated IGFBP-1 correlated with improved PFS and OS. PMID:24045151

  9. Phase II Trial of Imatinib in AIDS-Associated Kaposi's Sarcoma: AIDS Malignancy Consortium Protocol 042

    PubMed Central

    Koon, Henry B.; Krown, Susan E.; Lee, Jeannette Y.; Honda, Kord; Rapisuwon, Suthee; Wang, Zhenghe; Aboulafia, David; Reid, Erin G.; Rudek, Michelle A.; Dezube, Bruce J.; Noy, Ariela

    2014-01-01

    Purpose Kaposi's sarcoma (KS) is a disease of multifocal vascular proliferation that requires infection with KS herpes virus (KSHV/HHV-8). Activation of the c-kit and platelet-derived growth factor (PDGF) receptors by autocrine/paracrine mechanisms follows endothelial cell KSHV infection. In a pilot study, imatinib, a c-kit/PDGF-receptor inhibitor, induced partial regression of AIDS-associated KS (AIDS-KS) in five of 10 patients. Patients and Methods This multicenter phase II study was designed to estimate the response rate to imatinib in AIDS-KS. Secondary objectives included investigation of predictors of response and imatinib pharmacokinetics in patients on antiretrovirals. Patients received imatinib 400 mg/day by mouth for up to 12 months with dose escalation up to 600 mg/day at 3 months if their disease was stable. Results Thirty patients were treated at 12 AIDS Malignancy Consortium sites. Ten patients (33.3%) achieved partial response, six (20%) had stable disease, and seven (23.3%) exhibited KS progression. Nine patients completed 52 weeks of imatinib therapy. The median treatment duration was 22.5 weeks. Only five patients (16.7%) discontinued therapy owing to adverse events. Antiretroviral regimens did not significantly alter imatinib metabolism. Activating mutations in PDGF-R and c-kit were not found at baseline or at disease progression. We found no correlation with response with changes in any of the candidate cytokines. Conclusion Imatinib has activity in AIDS-KS. Pharmacokinetic interactions with antiretroviral drugs did not correlate with toxicity. Thirty percent of patients showed long-term clinical benefit and remained on imatinib for the entire year. These results suggest imatinib is well tolerated and may be an alternative therapy for some patients with AIDS-KS. PMID:24378417

  10. Phase II Trial of Neoadjuvant Bevacizumab, Capecitabine, and Radiotherapy for Locally Advanced Rectal Cancer

    SciTech Connect

    Crane, Christopher H.; Eng, Cathy; Feig, Barry W.; Das, Prajnan; Skibber, John M.; Chang, George J.; Wolff, Robert A.; Krishnan, Sunil; Hamilton, Stanley; Janjan, Nora A.; Maru, Dipen M.; Ellis, Lee M.; Rodriguez-Bigas, Miguel A.

    2010-03-01

    Purpose: We designed this Phase II trial to assess the efficacy and safety of the addition of bevacizumab to concurrent neoadjuvant capecitabine-based chemoradiation in locally advanced rectal cancer. Methods: Between April 2004 and December 2007, 25 patients with clinically staged T3N1 (n = 20) or T3N0 (n = 5) rectal cancer received neoadjuvant therapy with radiotherapy (50.4 Gy in 28 fractions over 5.5 weeks), bevacizumab every 2 weeks (3 doses of 5 mg/kg), and capecitabine (900 mg/m{sup 2} orally twice daily only on days of radiation), followed by surgical resection a median of 7.3 weeks later. Results: Procedures included abdominoperineal resection (APR; 6 patients), proctectomy with coloanal anastamosis (8 patients), low anterior resection (10 patients), and local excision (1 patient). Eight (32%) of 25 patients had a pathologic complete response, and 6 (24%) of 25 had <10% viable tumor cells in the specimen. No patient had Grade 3 hand-foot syndrome, gastrointestinal toxicity, or significant hematologic toxicity. Three wound complications required surgical intervention (one coloanal anastamostic dehiscence requiring completion APR and two perineal wound dehiscences after initial APR). Five minor complications occurred that resolved without operative intervention. With a median follow-up of 22.7 months (range, 4.5-32.4 months), all patients were alive; one patient has had a recurrence in the pelvis (2-year actuarial rate, 6.2%) and 3 had distant recurrences. Conclusions: The addition of bevacizumab to neoadjuvant chemoradiation resulted in encouraging pathologic complete response without an increase in acute toxicity. The impact of bevacizumab on perineal wound and anastamotic healing due to concurrent bevacizumab requires further study.

  11. Phase II Results of RTOG 0537: A Phase II/III Study Comparing Acupuncture-like Transcutaneous Electrical Nerve Stimulation Versus Pilocarpine in Treating Early Radiation-Induced Xerostomia

    PubMed Central

    Wong, Raimond K. W.; James, Jennifer L.; Sagar, Stephen; Wyatt, Gwen; Nguyen-Tân, Phuc Felix; Singh, Anurag K.; Lukaszczyk, Barbara; Cardinale, Francis; Yeh, Alexander M.; Berk, Lawrence

    2011-01-01

    Purpose This phase II component of a multi-institutional phase II/III randomized trial assessed the feasibility and preliminary efficacy of acupuncture-like transcutaneous electrical nerve stimulation (ALTENS) in reducing radiation-induced xerostomia. Methods Head and neck cancer patients who were 3–24 months from completing radiotherapy ± chemotherapy (RT±C) and experiencing xerostomia symptoms with basal whole saliva production ≥0.1 ml/min and without recurrence were eligible. Patients received twice weekly ALTENS sessions (24 over 12 weeks) using a Codetron™ unit. The primary objective assessed the feasibility of ALTENS treatment. A patient was considered compliant if 19/24 ALTENS were delivered, with a targeted 85% compliance rate. Secondary objectives measured treatment-related toxicities and ALTENS effect on overall radiation-induced xerostomia burden using the University of Michigan Xerostomia-Related Quality of Life Scale (XeQOLS). Results Of 48 accrued patients, 47 were evaluable. Median age was 60 years; 84% were male, 70% completed RT±C for > 12 months and 21% had received prior pilocarpine. All ALTENS sessions were completed in 34 patients, but 9 and 1 completed 20–23 and 19 sessions respectively, representing a 94% total compliance rate. 6-month XeQOLS scores were available for 35 patients; 30 (86%) achieved a positive treatment response with a mean reduction of 35.9% (SD 36.1). Five patients developed grade 1–2 gastrointestinal toxicity and one had grade 1 pain event. Conclusions ALTENS treatment for radiation-induced xerostomia can be uniformly delivered in a cooperative multicenter setting and has possible beneficial treatment response. Given these results, the phase III component of this study was initiated. PMID:22252927

  12. The case for randomized controlled trials to assess the impact of clinical information systems

    PubMed Central

    Wyatt, Jeremy C

    2011-01-01

    There is a persistent view of a significant minority in the medical informatics community that the randomized controlled trial (RCT) has a limited role to play in evaluating clinical information systems. A common reason voiced by skeptics is that these systems are fundamentally different from drug interventions, so the RCT is irrelevant. There is an urgent need to promote the use of RCTs, given the shift to evidence-based policy and the need to demonstrate cost-effectiveness of these systems. The authors suggest returning to first principles and argue that what is required is clarity about how to match methods to evaluation questions. The authors address common concerns about RCTs, and the extent to which they are fallacious, and also discuss the challenges of conducting RCTs in informatics and alternative study designs when randomized trials are infeasible. While neither a perfect nor universal evaluation method, RCTs form an important part of an evaluator's toolkit. PMID:21270132

  13. Efficient and robust method for comparing the immunogenicity of candidate vaccines in randomized clinical trials.

    PubMed

    Gilbert, Peter B; Sato, Alicia; Sun, Xiao; Mehrotra, Devan V

    2009-01-14

    In randomized clinical trials designed to compare the magnitude of vaccine-induced immune responses between vaccination regimens, the statistical method used for the analysis typically does not account for baseline participant characteristics. This article shows that incorporating baseline variables predictive of the immunogenicity study endpoint can provide large gains in precision and power for estimation and testing of the group mean difference (requiring fewer subjects for the same scientific output) compared to conventional methods, and recommends the "semiparametric efficient" method described in Tsiatis et al. [Tsiatis AA, Davidian M, Zhang M, Lu X. Covariate adjustment for two-sample treatment comparisons in randomized clinical trials: a principled yet flexible approach. Stat Med 2007. doi:10.1002/sim.3113] for practical use. As such, vaccine clinical trial programs can be improved (1) by investigating baseline predictors (e.g., readouts from laboratory assays) of vaccine-induced immune responses, and (2) by implementing the proposed semiparametric efficient method in trials where baseline predictors are available. PMID:19022314

  14. AIDS Clinical Trials Group Longitudinal Linked Randomized Trials (ALLRT): Rationale, Design, and Baseline Characteristics

    PubMed Central

    Smurzynski, Marlene; Collier, Ann C.; Koletar, Susan L.; Bosch, Ronald J.; Wu, Kunling; Bastow, Barbara; Benson, Constance A.

    2009-01-01

    Purpose ALLRT is a longitudinal cohort study of HIV-infected subjects prospectively randomized into selected clinical trials for antiretroviral (ARV) treatment-naïve and ARV treatment-experienced individuals conducted by the AIDS Clinical Trials Group (ACTG). We describe the rationale, design, and baseline characteristics of the ALLRT cohort and its potential to address important research questions related to ARV therapy. Method Standardized visits occur every 16 weeks to evaluate long-term clinical, virologic, and immunologic outcomes associated with ARV treatment. Results A total of 4,371 subjects enrolled in ALLRT from January 2000 through June 2007. Of these, 3,146 (72%) were ARV naïve at parent study entry (18% female, 44% white, 32% black, 21% Hispanic; median age 37 years, CD4 count 218 cells/μL, follow-up 3.6 years; 343 [11%] followed ≥8 years) and 1,225 (28%) were treatment experienced (13% female, 59% white, 20% black, 17% Hispanic; median age 42 years, CD4 count 325 cells/μL, follow-up 5.7 years). Conclusions ALLRT provides the opportunity to understand long-term ramifications of therapeutic ARV choices and determine whether these vary by treatment regimen, timing of treatment initiation, or treatment changes over long-term follow-up. Investigations based on uniform data and specimen collection in the context of randomized ARV treatments will be critical to developing more successful long-term therapeutic strategies for HIV treatment. PMID:18753121

  15. A 3-year randomized clinical trial evaluating two different bonded posterior restorations: Amalgam versus resin composite

    PubMed Central

    Kemaloglu, Hande; Pamir, Tijen; Tezel, Huseyin

    2016-01-01

    Objective: To compare the performance and postoperative sensitivity of a posterior resin composite with that of bonded amalgam in 40 (n = 20) large sized cavities and to evaluate whether resin composite could be an alternative for bonded amalgam. Materials and Methods: This was a randomized clinical trial. Twenty patients in need of at least two posterior restorations were recruited. Authors randomly assigned one half of the restorations to receive bonded amalgam and the other half to composite restorations. Forty bonded amalgams (n = 20) and composites (n = 20) were evaluated for their performance on modified-US Public Health Service criteria and postoperative sensitivity using visual analogue scale (VAS) for 36-months. Results: Success rate of this study was 100%. First clinical alterations were rated as Bravo after 1 year in marginal discoloration, marginal adaptation, anatomical form, and surface roughness for both amalgam and composite. At the 3rd year, overall “Bravo” rated restorations were 12 for bonded amalgam and 13 for resin composites. There were no significant differences among the VAS scores of composites and bonded amalgams for all periods (P > 0.05) except for the comparisons at the 3rd year evaluation (P < 0.05). Conclusions: Within the limitation of this study, both resin composite and bonded amalgam were clinically acceptable. Postoperative sensitivity results tend to decrease more in composite restorations rather than amalgams. Therefore, it was concluded that posterior resin composite can be used even in large sized cavities. PMID:27011734

  16. A commentary on randomized clinical trials: How to produce them with a good level of evidence

    PubMed Central

    Flecha, Olga Dumont; Douglas de Oliveira, Dhelfeson Willya; Marques, Leandro Silva; Gonçalves, Patricia Furtado

    2016-01-01

    Randomized clinical trial (RCT) is the gold standard study for the evaluation of health interventions and is considered the second level of evidence for clinical decision making. However, the quality of the evidence produced by these studies is dependent on the methodological rigor employed at every stage of their execution. The purpose of randomization is to create groups that are comparable independent of any known or unknown potential confounding factor. A critical evaluation of the literature reveals that, for many years, RCTs have been developed based on inaccurate methodological criteria, and empirical evidence began to accumulate. Thus, guidelines were developed to assist authors, reviewers, and editors in the task of developing and assessing the methodological consistency of this type of study. The objective of this article is to review key aspects to design a good-quality RCT, supporting the scientific community in the production of reliable evidence and favoring clinical decision making to allow the patient to receive the best health care. PMID:27141473

  17. Clinical and Morphological Changes Following 2 Rehabilitation Programs for Acute Hamstring Strain Injuries: A Randomized Clinical Trial

    PubMed Central

    SILDER, AMY; SHERRY, MARC A.; SANFILIPPO, JENNIFER; TUITE, MICHAEL J.; HETZEL, SCOTT J.; HEIDERSCHEIT, BRYAN C.

    2013-01-01

    STUDY DESIGN Randomized, double-blind, parallel-group clinical trial. OBJECTIVES To assess differences between a progressive agility and trunk stabilization rehabilitation program and a progressive running and eccentric strengthening rehabilitation program in recovery characteristics following an acute hamstring injury, as measured via physical examination and magnetic resonance imaging (MRI). BACKGROUND Determining the type of rehabilitation program that most effectively promotes muscle and functional recovery is essential to minimize reinjury risk and to optimize athlete performance. METHODS Individuals who sustained a recent hamstring strain injury were randomly assigned to 1 of 2 rehabilitation programs: (1) progressive agility and trunk stabilization or (2) progressive running and eccentric strengthening. MRI and physical examinations were conducted before and after completion of rehabilitation. RESULTS Thirty-one subjects were enrolled, 29 began rehabilitation, and 25 completed rehabilitation. There were few differences in clinical or morphological outcome measures between rehabilitation groups across time, and reinjury rates were low for both rehabilitation groups after return to sport (4 of 29 subjects had reinjuries). Greater craniocaudal length of injury, as measured on MRI before the start of rehabilitation, was positively correlated with longer return-to-sport time. At the time of return to sport, although all subjects showed a near-complete resolution of pain and return of muscle strength, no subject showed complete resolution of injury as assessed on MRI. CONCLUSION The 2 rehabilitation programs employed in this study yielded similar results with respect to hamstring muscle recovery and function at the time of return to sport. Evidence of continuing muscular healing is present after completion of rehabilitation, despite the appearance of normal physical strength and function on clinical examination. LEVEL OF EVIDENCE Therapy, level 1b–. J Orthop

  18. The role of gender in a smoking cessation intervention: a cluster randomized clinical trial

    PubMed Central

    2011-01-01

    Background The prevalence of smoking in Spain is high in both men and women. The aim of our study was to evaluate the role of gender in the effectiveness of a specific smoking cessation intervention conducted in Spain. Methods This study was a secondary analysis of a cluster randomized clinical trial in which the randomization unit was the Basic Care Unit (family physician and nurse who care for the same group of patients). The intervention consisted of a six-month period of implementing the recommendations of a Clinical Practice Guideline. A total of 2,937 current smokers at 82 Primary Care Centers in 13 different regions of Spain were included (2003-2005). The success rate was measured by a six-month continued abstinence rate at the one-year follow-up. A logistic mixed-effects regression model, taking Basic Care Units as random-effect parameter, was performed in order to analyze gender as a predictor of smoking cessation. Results At the one-year follow-up, the six-month continuous abstinence quit rate was 9.4% in men and 8.5% in women (p = 0.400). The logistic mixed-effects regression model showed that women did not have a higher odds of being an ex-smoker than men after the analysis was adjusted for confounders (OR adjusted = 0.9, 95% CI = 0.7-1.2). Conclusions Gender does not appear to be a predictor of smoking cessation at the one-year follow-up in individuals presenting at Primary Care Centers. ClinicalTrials.gov Identifier NCT00125905. PMID:21605389

  19. Immune Function Effects of Dental Amalgam in Children: A Randomized Clinical Trial

    PubMed Central

    Shenker, Bruce J.; Maserejian, Nancy N.; Zhang, Annie; McKinlay, Sonja

    2010-01-01

    Background Dental amalgam is a widely used restorative material containing 50% elemental mercury that emits mercury vapor. No randomized clinical trials have determined whether there are adverse immunologic effects associated with this low-level mercury exposure in children. The objective of this study was to evaluate a sub-population of the New England Children’s Amalgam Trial (NECAT) for in vitro manifestations of immunotoxic effects of dental amalgam. Methods A randomized clinical trial in which children requiring dental restorative treatment were randomized to either amalgam for posterior restorations or resin composite. A total of 66 children, aged 6–10 years, were assessed for total white cell numbers, T-cell, B-cell, neutrophil and monocyte responsiveness over a five-year period. Owing to the small number of participants, the study is exploratory in nature with limited statistical power. Results The mean number of tooth surfaces restored during the five-year period was 7.8 for the amalgam group and 10.1 for composite group. In the amalgam group there was a slight, but not statistically significant, decline in responsiveness of T-cells and monocytes at 5–7 days post treatment; no differences were consistently observed at 6, 12 or 60 months. Conclusions This study confirms that treatment of children with dental amalgams leads to increased, albeit low level, exposure to mercury. In this exploratory analysis of immune function, amalgam exposure did not cause overt immune deficits, although small transient effects were observed 5–7 days post restoration. Clinical implications These findings suggest that immunotoxic effects of amalgam restorations in children need not be a concern when choosing this restorative dental material. PMID:18978388

  20. A Hybrid Process Fidelity Assessment in a Home-based Randomized Clinical Trial

    PubMed Central

    WILDE, MARY H.; LIEBEL, DIANNE; FAIRBANKS, EILEEN; WILSON, PAULA; LASH, MARGARET; SHAH, SHIVANI; McDONALD, MARGARET V.; BRASCH, JUDITH; ZHANG, FENG; SCHEID, EILEEN; McMAHON, JAMES M.

    2016-01-01

    A process fidelity assessment was conducted as a nested study within a home-based randomized clinical trial teaching self-management to 101 long-term indwelling urinary catheter users in the treatment group. Our hybrid model combined external assessments (outside observations and tape recordings) with internal evaluation methods (through study nurse forms and notes) for a comprehensive process fidelity assessment. Barriers, patient-related issues, and nurse perspectives were identified demonstrating the complexity in home care intervention research. The complementary and synergistic approaches provided in depth information about the context of the delivery and the impact of the intervention on study outcomes. PMID:25894688

  1. Marital Status and Satisfaction Five Years Following a Randomized Clinical Trial Comparing Traditional versus Integrative Behavioral Couple Therapy

    ERIC Educational Resources Information Center

    Christensen, Andrew; Atkins, David C.; Baucom, Brian; Yi, Jean

    2010-01-01

    Objective: To follow distressed married couples for 5 years after their participation in a randomized clinical trial. Method: A total of 134 chronically and seriously distressed married couples were randomly assigned to approximately 8 months of either traditional behavioral couple therapy (TBCT; Jacobson & Margolin, 1979) or integrative…

  2. Randomized Clinical Trial Replication of a Psychosocial Treatment for Children with High-Functioning Autism Spectrum Disorders

    ERIC Educational Resources Information Center

    Thomeer, Marcus L.; Lopata, Christopher; Volker, Martin A.; Toomey, Jennifer A.; Lee, Gloria K.; Smerbeck, Audrey M.; Rodgers, Jonathan D.; McDonald, Christin A.; Smith, Rachael A.

    2012-01-01

    This replication randomized clinical trial examined the efficacy of a comprehensive psychosocial intervention for children aged 7 to 12 years with high-functioning autism spectrum disorders (HFASDs). Participants were randomly assigned to treatment or wait-list conditions. Treatment included instruction and therapeutic activities targeting social…

  3. 78 FR 30951 - SBIR/STTR Phase I to Phase II Transition Benchmarks

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-05-23

    ... INFORMATION: Section 4(a)(3)(iii) of the SBIR Policy Directive (77 FR 46806) and the STTR Policy Directive (77 FR 46855) require each agency to establish an SBA-approved Phase I-Phase II Transition Rate benchmark... benchmarks can take effect. As a result, on October 16, 2012, at 77 FR 63410, SBA published the...

  4. Iowa High School Industrial Arts Curriculum Project. Report on Year One of Phase II.

    ERIC Educational Resources Information Center

    Des Moines Public Schools, IA.

    Phase II of the Iowa High School Industrial Arts project sought to revise industrial arts content to include the infusion of new technologies, structured mathematics and science content, and a less project-oriented approach to teaching. The project identified a philosophical basis and a content structure; set priorities for development and…

  5. Emotional Intelligence and Implications for Counseling Self-Efficacy: Phase II

    ERIC Educational Resources Information Center

    Easton, Crystal; Martin, William E.; Wilson, Sheilah

    2008-01-01

    The authors present Phase II of a 9-month study of the relationship between emotional intelligence and counseling self-efficacy. One-hundred eighteen counselors-in-training and professional counselors completed the Counseling Self-Estimate Inventory (COSE) and Emotional Judgment Inventory (EJI). There was a significant correlation between 2 of the…

  6. SH-2F LAMPS Instructional Systems Development: Phase II. Final Report.

    ERIC Educational Resources Information Center

    Gibbons, Andrew S.; Hymes, Jonah P.

    This project was one of four aircrew training development projects in a continuing study of the methodology, effectiveness, and resource requirements of the Instructional Systems Development (ISD) process. This report covers the Phase II activities of a two-phase project for the development of aircrew training for SH-2F anti-submarine warfare…

  7. 40 CFR 125.91 - What is a “Phase II Existing Facility”?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... Applicable to Cooling Water Intake Structures for Phase II Existing Facilities Under Section 316(b) of the...: (1) It is a point source. (2) It uses or proposes to use cooling water intake structures with a total design intake flow of 50 million gallons per day (MGD) or more to withdraw cooling water from waters...

  8. 40 CFR 76.7 - Revised NOX emission limitations for Group 1, Phase II boilers.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 17 2012-07-01 2012-07-01 false Revised NOX emission limitations for Group 1, Phase II boilers. 76.7 Section 76.7 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) ACID RAIN NITROGEN OXIDES EMISSION REDUCTION PROGRAM § 76.7 Revised...

  9. 40 CFR 76.7 - Revised NOX emission limitations for Group 1, Phase II boilers.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 16 2010-07-01 2010-07-01 false Revised NOX emission limitations for Group 1, Phase II boilers. 76.7 Section 76.7 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) ACID RAIN NITROGEN OXIDES EMISSION REDUCTION PROGRAM § 76.7 Revised...

  10. 40 CFR 76.7 - Revised NOX emission limitations for Group 1, Phase II boilers.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 16 2011-07-01 2011-07-01 false Revised NOX emission limitations for Group 1, Phase II boilers. 76.7 Section 76.7 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) ACID RAIN NITROGEN OXIDES EMISSION REDUCTION PROGRAM § 76.7 Revised...

  11. 40 CFR 76.7 - Revised NOX emission limitations for Group 1, Phase II boilers.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 17 2014-07-01 2014-07-01 false Revised NOX emission limitations for Group 1, Phase II boilers. 76.7 Section 76.7 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) ACID RAIN NITROGEN OXIDES EMISSION REDUCTION PROGRAM § 76.7 Revised...

  12. 40 CFR 76.7 - Revised NOX emission limitations for Group 1, Phase II boilers.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 17 2013-07-01 2013-07-01 false Revised NOX emission limitations for Group 1, Phase II boilers. 76.7 Section 76.7 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) ACID RAIN NITROGEN OXIDES EMISSION REDUCTION PROGRAM § 76.7 Revised...

  13. NATO/CCMS PILOT STUDY CLEAN PRODUCTS AND PROCESSES (PHASE II) 2003 ANNUAL REPORT

    EPA Science Inventory

    The 6th annual meeting of the NATO CCMS Pilot Study, Clean Products and Processes, was held in Cetraro, Italy, from May 11 to 15, 2003. This was also the first meeting of its Phase II study. 24 country representatives attended this meeting. This meeting was very ably run by th...

  14. 40 CFR 125.91 - What is a “Phase II Existing Facility”?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... Applicable to Cooling Water Intake Structures for Phase II Existing Facilities Under Section 316(b) of the...: (1) It is a point source. (2) It uses or proposes to use cooling water intake structures with a total design intake flow of 50 million gallons per day (MGD) or more to withdraw cooling water from waters...

  15. Washington Phase II Fish Diversion Screen Evaluations in the Yakima River Basin, 1998.

    SciTech Connect

    Blanton, S.L.; McMichael, Geoffrey A.; Neitzel, D.A.

    1999-12-01

    Pacific Northwest National Laboratory (PNNL) evaluated 19 Phase II screen sites in the Yakima River Basin as part of a multi-year study for the Bonneville Power Administration (BPA) on the effectiveness of fish screening devices. The sites were examined to determine if they were being effectively operated and maintained to provide fish a safe, efficient return to the Yakima River.

  16. Income Verification Pilot Project (Phase II): Results of Quality Assurance Evaluation, 1982-83 School Year.

    ERIC Educational Resources Information Center

    Applied Management Sciences, Inc., Silver Spring, MD.

    Presented in this report are selected findings of the Income Verification Pilot Project (IVPP), an investigation examining misreporting of applicant income and family size on applications for government-sponsored school meal benefits. As reported here, Phase II of the project provided for a comprehensive assessment of specific quality assurance…

  17. Analysis of thermophilic fungal populations during phase II of composting for the cultivation of Agaricus subrufescens.

    PubMed

    Souza, Thiago Pereira; Marques, Simone Cristina; da Silveira e Santos, Débora Marques; Dias, Eustáquio Souza

    2014-09-01

    The composition and genetic diversity of fungal populations during phase II of compost production for the cultivation of Agaricus subrufescens was determined using culture-dependent and -independent methods on days 3, 6, 10, 12, and 14 of phase II composting. The isolates were morphologically characterized and subsequently analyzed using repetitive extragenic palindromic sequences (rep-PCR), and the intergenic region was sequenced to genetically identify the isolates. Changes on in the filamentous fungi population were analyzed using denaturing gradient gel electrophoresis (DGGE), and the resulting bands were sequenced. The population did not significantly change from day 3 to 10 (2.55 x 10(5) -6 x 10(5) CFU g(-1)), and maximum counts on day 14 of phase II composting (6.92 log CFU g(-1)). In the morphological characterization, Scytalidium thermophilum, Thermomyces lanuginosus, and Thermomyces ibadanensis were the most abundant identified species. The 26 most abundant isolates identified by morphological analysis were characterized using rep-PCR. A significant amount of genetic diversity was detected among the isolates of all three studied species. Based on the DGGE analysis, the diversity of the fungi was reduced during phase II composting, and S. thermophilum was the predominant species identified throughout the entire process. Thus, this study presents the first report of the involvement of T. ibadanensis in the production of compost for Agaricus mushroom cultivation.

  18. New York State Educational Information System (NYSEIS) Systems Design. Volume I, Phase II. Final Report.

    ERIC Educational Resources Information Center

    Price Waterhouse and Co., New York, NY.

    This volume on Phase II of the New York State Educational Information System (NYSEIS) describes the Gross Systems Analysis and Design, which includes the general flow diagram and processing chart for each of the student, personnel, and financial subsystems. Volume II, Functional Specifications, includes input/output requirements and file…

  19. Generation of phase II in vitro metabolites using homogenized horse liver.

    PubMed

    Wong, Jenny K Y; Chan, George H M; Leung, David K K; Tang, Francis P W; Wan, Terence S M

    2016-02-01

    The successful use of homogenized horse liver for the generation of phase I in vitro metabolites has been previously reported by the authors' laboratory. Prior to the use of homogenized liver, the authors' laboratory had been using mainly horse liver microsomes for carrying out equine in vitro metabolism studies. Homogenized horse liver has shown significant advantages over liver microsomes for in vitro metabolism studies as the procedures are much quicker and have higher capability for generating more in vitro metabolites. In this study, the use of homogenized liver has been extended to the generation of phase II in vitro metabolites (glucuronide and/or sulfate conjugates) using 17β-estradiol, morphine, and boldenone undecylenate as model substrates. It was observed that phase II metabolites could also be generated even without the addition of cofactors. To the authors' knowledge, this is the first report of the successful use of homogenized horse liver for the generation of phase II metabolites. It also demonstrates the ease with which both phase I and phase II metabolites can now be generated in vitro simply by using homogenized liver without the need for ultracentrifuges or tedious preparation steps.

  20. Definition of the Semisubmersible Floating System for Phase II of OC4

    SciTech Connect

    Robertson, A.; Jonkman, J.; Masciola, M.; Song, H.; Goupee, A.; Coulling, A.; Luan, C.

    2014-09-01

    Phase II of the Offshore Code Comparison Collaboration Continuation (OC4) project involved modeling of a semisubmersible floating offshore wind system as shown below. This report documents the specifications of the floating system, which were needed by the OC4 participants for building aero-hydro-servo-elastic models.

  1. Upregulation of phase II enzymes through phytochemical activation of Nrf2 protects cardiomyocytes against oxidant stress.

    PubMed

    Reuland, Danielle J; Khademi, Shadi; Castle, Christopher J; Irwin, David C; McCord, Joe M; Miller, Benjamin F; Hamilton, Karyn L

    2013-03-01

    Increased production of reactive oxygen species has been implicated in the pathogenesis of cardiovascular disease (CVD), and enhanced endogenous antioxidants have been proposed as a mechanism for regulating redox balance. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a transcriptional regulator of phase II antioxidant enzymes, and activation of Nrf2 has been suggested to be an important step in attenuating oxidative stress associated with CVD. A well-defined combination of five widely studied medicinal plants derived from botanical sources (Bacopa monniera, Silybum marianum (milk thistle), Withania somnifera (Ashwagandha), Camellia sinensis (green tea), and Curcuma longa (turmeric)) has been shown to activate Nrf2 and induce phase II enzymes through the antioxidant response element. The purpose of these experiments was to determine if treatment of cardiomyocytes with this phytochemical composition, marketed as Protandim, activates Nrf2, induces phase II detoxification enzymes, and protects cardiomyocytes from oxidant-induced apoptosis in a Nrf2-dependent manner. In cultured HL-1 cardiomyocytes, phytochemical treatment was associated with nuclear accumulation of Nrf2, significant induction of phase II enzymes, and concomitant protection against hydrogen peroxide-induced apoptosis. The protection against oxidant stress was abolished when Nrf2 was silenced by shRNA, suggesting that our phytochemical treatment worked through the Nrf2 pathway. Interestingly, phytochemical treatment was found to be a more robust activator of Nrf2 than oxidant treatment, supporting the use of the phytochemicals as a potential treatment to increase antioxidant defenses and protect heart cells against an oxidative challenge.

  2. Community Based Model for Training Ex-Offenders in Entrepreneurial Competencies, Phase II. Final Report.

    ERIC Educational Resources Information Center

    Springfield Urban League, Inc., IL.

    An Urban League project in Springfield, Illinois, provided instruction in small business management to persons who had been convicted of a crime. Phase II of the project required designing a self-instructional workbook and tape to be used when classes were not available. A resource guide listing agencies providing assistance to business persons…

  3. 40 CFR 125.91 - What is a “Phase II Existing Facility”?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... Applicable to Cooling Water Intake Structures for Phase II Existing Facilities Under Section 316(b) of the...: (1) It is a point source. (2) It uses or proposes to use cooling water intake structures with a total design intake flow of 50 million gallons per day (MGD) or more to withdraw cooling water from waters...

  4. 40 CFR 125.91 - What is a “Phase II Existing Facility”?

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... Applicable to Cooling Water Intake Structures for Phase II Existing Facilities Under Section 316(b) of the...: (1) It is a point source. (2) It uses or proposes to use cooling water intake structures with a total design intake flow of 50 million gallons per day (MGD) or more to withdraw cooling water from waters...

  5. 40 CFR 125.91 - What is a “Phase II Existing Facility”?

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... Applicable to Cooling Water Intake Structures for Phase II Existing Facilities Under Section 316(b) of the...: (1) It is a point source. (2) It uses or proposes to use cooling water intake structures with a total design intake flow of 50 million gallons per day (MGD) or more to withdraw cooling water from waters...

  6. 48 CFR 1852.219-81 - Limitation on subcontracting-SBIR Phase II program.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 48 Federal Acquisition Regulations System 6 2012-10-01 2012-10-01 false Limitation on subcontracting-SBIR Phase II program. 1852.219-81 Section 1852.219-81 Federal Acquisition Regulations System... (OCT 2006) The Contractor shall perform a minimum of one-half of the research and/or analytical...

  7. 48 CFR 1852.219-81 - Limitation on subcontracting-SBIR Phase II program.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 48 Federal Acquisition Regulations System 6 2014-10-01 2014-10-01 false Limitation on subcontracting-SBIR Phase II program. 1852.219-81 Section 1852.219-81 Federal Acquisition Regulations System... (OCT 2006) The Contractor shall perform a minimum of one-half of the research and/or analytical...

  8. 78 FR 5765 - Wireline Competition Bureau Releases Connect America Phase II Cost Model Virtual Workshop...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-01-28

    ...] Wireline Competition Bureau Releases Connect America Phase II Cost Model Virtual Workshop Discussion Topics... Competition Bureau releases for discussion a number of virtual workshop topics related to the development and... comments. Virtual Workshop: In addition to the usual methods for filing electronic comments, the...

  9. Career Options Research and Development. Materials From Phase II Final Report.

    ERIC Educational Resources Information Center

    YMCA of Metropolitan Chicago, IL. Career Options Research and Development (CORD).

    The Social Service Aide Project for the training and education of paraprofessionals is a part of the Career Options Research and Development project of the Young Men's Christian Association of Chicago. These materials from the Phase II Final Report include: (1) Fourth Quarterly Progress Report (July-September 1970)," (2) "Systems Approach to Job…

  10. Phase II: Resource and Referral Service, Research and Development Exchange. Final Report.

    ERIC Educational Resources Information Center

    Hull, William L.

    Activities of the Resource and Referral Service (RRS), a central service contractor to the Research and Development Exchange (RDx), are documented for the period between March 1, 1977, when Phase II was funded, to November 30, 1977. Product outputs from RRS are described and related to project objectives. The objectives, which correspond to…

  11. DEMONSTRATION OF FUEL CELLS TO RECOVER ENERGY FROM LANDFILL GAS: PHASE II. PRETREATMENT SYSTEM PERFORMANCE MEASUREMENT

    EPA Science Inventory

    The report describes Phase II of a demonstration of the utilization of commercial phosphoric acid fuel cells to recover energy from landfill gas. This phase consisted primarily of the construction and testing of a Gas Pretreatment Unit (GPU) whose function is to remove those impu...

  12. An Experimental Evaluation of Hyperactivity and Food Additives. 1977-Phase II.

    ERIC Educational Resources Information Center

    Harley, J. Preston; And Others

    Phase II of a study on the effectiveness of B. Feingold's recommended diet for hyperactive children involved the nine children (mean age 9 years) who had shown the "best" response to diet manipulation in Phase I. Each child served as his own control and was challenged with specified amounts of placebo and artificial color containing food items…

  13. A Collaborative Paradigm for Improving Management of Sleep Disorders in Primary Care: A Randomized Clinical Trial

    PubMed Central

    Edinger, Jack D.; Grubber, Janet; Ulmer, Christi; Zervakis, Jennifer; Olsen, Maren

    2016-01-01

    Objectives: To test a collaborative care model for interfacing sleep specialists with primary care providers to enhance patients' sleep disorders management. Methods: This study used a randomized, parallel group, clinical intervention trial design. A total of 137 adult (29 women) VA outpatients with sleep complaints were enrolled and randomly assigned to (1) an intervention (INT) consisting of a one-time consultation with a sleep specialist who provided diagnostic feedback and treatment recommendations to the patient and the patient's primary care provider; or (2) a control condition consisting of their usual primary care (UPC). Provider-focused outcomes included rates of adherence to recommended diagnostic procedures and sleep-focused interventions. Patient-focused outcomes included measures taken from sleep diaries and actigraphy; Pittsburgh Sleep Quality Index (PSQI) scores; and self-report measures of sleepiness, fatigue, mood, quality of life, and satisfaction with health care. Results: The proportions of provider-initiated sleep-focused interventions were significantly higher in the INT group than in the UPC group for polysomnography referrals (49% versus 6%; P < 0.001) and mental health clinic referrals (19% versus 6%; P = 0.02). At the 10-mo follow up, INT recipients showed greater estimated mean reductions in diary total wake time (−17.0 min; 95% confidence interval [CI]: −30.9, −3.1; P = 0.02) and greater increases in sleep efficiency (+3.7%; 95% CI: 0.8, 6.5; P = 0.01) than did UPC participants. A greater proportion of the INT group showed ≥ 1 standard deviation decline on the PSQI from baseline to the 10-mo follow-up (41% versus 21%; P = 0.02). Moreover, 69% of the INT group had normal (≤ 10) Epworth Sleepiness Scale scores at the 10-mo follow-up, whereas only 50% of the UPC group fell below this clinical cutoff (P = 0.03). Conclusions: A one-time sleep consultation significantly increased healthcare providers' attention to sleep problems and

  14. Cluster-Randomized Trial of Clinical Pharmacist Tobacco Cessation Counseling Among Patients with Cardiovascular Disease.

    PubMed

    Adams, Jody; Cymbala, Alicia A; Delate, Thomas; Kurz, Deanna; Olson, Kari L; Youngblood, Morgan; Zadvorny, Emily

    2015-08-01

    Optimal management of patients with cardiovascular disease (CVD) includes evaluation of risk factors using a team-based approach. Tobacco use often receives less attention than other CVD risk factors; therefore, utilization of nonphysician health care providers may be valuable in addressing tobacco use. The purpose of this trial was to assess the impact of brief, structured, telephone tobacco cessation counseling (BST) delivered by clinical pharmacists on tobacco cessation attempts compared to usual care. The BST consisted of 1 to 5 minutes discussing 3 key counseling points, including a recommendation to quit and education about cessation aids. This was a cluster-randomized trial of tobacco-using patients with CVD who were enrolled in a clinical pharmacist-managed, physician-directed, CVD disease state management service. Clinical pharmacists were randomized to provide usual care (control) or BST (intervention) to their tobacco-using patients during a 4-month period. Patients were surveyed 3 months later to assess their tobacco cessation attempts, use of tobacco cessation aids, and self-reported cessation. One hundred twenty patients were enrolled. Subjects were predominately white males, aged ≥65 years, with a history of myocardial infarction. One hundred and four subjects completed the follow-up survey. No differences were detected between the 36.2% and 38.6% of control and intervention subjects, respectively, reporting a tobacco cessation attempt (P=0.804) or in the other outcomes (all P>0.05). A BST delivered by clinical pharmacists may not adequately affect patient motivation enough to increase tobacco cessation attempts in tobacco-dependent patients with CVD. Future research is needed to evaluate other team-based strategies that can decrease tobacco use in patients with CVD. PMID:25647441

  15. Phase II Study of Lapatinib in Combination With Trastuzumab in Patients With Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer: Clinical Outcomes and Predictive Value of Early [18F]Fluorodeoxyglucose Positron Emission Tomography Imaging (TBCRC 003)

    PubMed Central

    Lin, Nancy U.; Guo, Hao; Yap, Jeffrey T.; Mayer, Ingrid A.; Falkson, Carla I.; Hobday, Timothy J.; Dees, E. Claire; Richardson, Andrea L.; Nanda, Rita; Rimawi, Mothaffar F.; Ryabin, Nicole; Najita, Julie S.; Barry, William T.; Arteaga, Carlos L.; Wolff, Antonio C.; Krop, Ian E.; Winer, Eric P.; Van den Abbeele, Annick D.

    2015-01-01

    Purpose Lapatinib plus trastuzumab improves outcomes relative to lapatinib alone in heavily pretreated, human epidermal growth factor receptor 2–positive metastatic breast cancer (MBC). We tested the combination in the earlier-line setting and explored the predictive value of [18F]fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) for clinical outcomes. Patients and Methods Two cohorts were enrolled (cohort 1: no prior trastuzumab for MBC and ≥ 1 year from adjuvant trastuzumab, if given; cohort 2: one to two lines of chemotherapy including trastuzumab for MBC and/or recurrence < 1 year from adjuvant trastuzumab). The primary end point was objective response rate by RECIST v1.0; secondary end points included clinical benefit rate (complete response plus partial response plus stable disease ≥ 24 weeks) and progression-free survival. [18F]FDG-PET scans were acquired at baseline, week 1, and week 8. Associations between metabolic response and clinical outcomes were explored. Results Eighty-seven patients were registered (85 were evaluable for efficacy). The confirmed objective response rate was 50.0% (95% CI, 33.8% to 66.2%) in cohort 1 and 22.2% (95% CI, 11.3% to 37.3%) in cohort 2. Clinical benefit rate was 57.5% (95% CI, 40.9% to 73.0%) in cohort 1 and 40.0% (95% CI, 25.7% to 55.7%) in cohort 2. Median progression-free survival was 7.4 and 5.3 months, respectively. Lack of week-1 [18F]FDG-PET/computed tomography ([18F]FDG-PET/CT) response was associated with failure to achieve an objective response by RECIST (negative predictive value, 91% [95% CI, 74% to 100%] for cohort 1 and 91% [95% CI, 79% to 100%] for cohort 2). Conclusion Early use of lapatinib and trastuzumab is active in human epidermal growth factor receptor 2–positive MBC. Week-1 [18F]FDG-PET/CT may allow selection of patients who can be treated with targeted regimens and spared the toxicity of chemotherapy. PMID:26169615

  16. Cognitive behavioral stress management effects on injury and illness among competitive athletes: a randomized clinical trial.

    PubMed

    Perna, Frank M; Antoni, Michael H; Baum, Andrew; Gordon, Paul; Schneiderman, Neil

    2003-01-01

    Cognitive behavioral stress management (CBSM) has previously been found to reduce fatigue, depression, and cortisol response to heavy exercise training among competitive collegiate athletes and to speed physical and psychological recovery from surgery. Our study assessed the efficacy of a CBSM program to reduce the frequency of injury and illness among collegiate athletes in a randomized, single-blind, controlled clinical trial. Following assessment of baseline medical history, mood state, stress, cortisol, sleep, alcohol use, and exercise training, collegiate rowers were stratified by gender and competitive level and randomly assigned to either a control group or a CBSM group. Exercise training information and psychosocial assessments were repeated immediately following the intervention period, and health care providers who were blinded to participant assignment recorded the frequency of medical visits and the number of days injured or ill until the end of the season. Athletes randomly assigned to a CBSM group experienced significant reductions in the number of illness and injury days as compared to control group athletes. CBSM participants also had half the number of health service visits as did controls. The data suggest that a time-limited CBSM intervention designed specifically for an athlete population may be an effective prophylactic treatment to reduce the incidence of injury and illness among competitive collegiate athletes.

  17. Randomized clinical trial of LigaSure versus conventional suture ligation in thyroid surgery

    PubMed Central

    2012-01-01

    Background In thyroid surgery vessel division and haemostasis make up an important and time consuming part of the operation. While the presence of the recurrent laryngeal nerve limits the liberal use of diathermia, the many arterial and venous branches to and from the thyroid gland necessitates the use of numerous conventional suture ligatures.This study evaluates the effect of using a vessel sealing system on operation time during thyroid surgery. Methods A randomized clinical trial was performed between September 2005 and October 2008 in a teaching hospital. Forty patients undergoing total hemithyroidectomy participated in the trial. Twenty were randomized to the intraoperative use of the LigaSure Precise™ vessel sealing system, and twenty to the use of conventional suture ligatures. Results The total median operation time was 10 minutes shorter in the LigaSure group (56 versus 66 minutes, P = 0.001). No significant differences in complications were noticed. Conclusion Using an electrothermal vessel sealing system during thyroid surgery is time saving. Trial registration This trial was registered in the international standard randomized controlled trials number register (ISRCTNR) under number ISRCTNR82389535. PMID:22257756

  18. The Effects of Inhalation Aromatherapy on Anxiety in Patients With Myocardial Infarction: A Randomized Clinical Trial

    PubMed Central

    Najafi, Zahra; Taghadosi, Mohsen; Sharifi, Khadijeh; Farrokhian, Alireza; Tagharrobi, Zahra

    2014-01-01

    Background: Anxiety is an important mental health problem in patients with cardiac disease. Anxiety reduces patients’ quality of life and increases the risk of different cardiac complications. Objectives: The aim of this study was to investigate the effects of inhalation aromatherapy on anxiety in patients with myocardial infarction. Patients and Methods: This was a randomized clinical trial conduced on 68 patients with myocardial infarction hospitalized in coronary care units of a large-scale teaching hospital affiliated to Kashan University of Medical Sciences, Kashan, Iran in 2013. By using the block randomization technique, patients were randomly assigned to experimental (33 patients receiving inhalation aromatherapy with lavender aroma twice a day for two subsequent days) and control (35 patients receiving routine care of study setting including no aromatherapy) groups. At the beginning of study and twenty minutes after each aromatherapy session, anxiety state of patients was assessed using the Spielberger’s State Anxiety Inventory. Data was analyzed using SPSS v. 16.0. We used Chi-square, Fisher’s exact, independent-samples T-test and repeated measures analysis of variance to analyze the study data. Results: The study groups did not differ significantly regarding baseline anxiety mean and demographic characteristics. However, after the administration of aromatherapy, anxiety mean in the experimental group was significantly lower than the control group. Conclusions: Inhalation aromatherapy with lavender aroma can reduce anxiety in patients with myocardial infarction. Consequently, healthcare providers, particularly nurses, can use this strategy to improve postmyocardial infarction anxiety management. PMID:25389481

  19. Impact of educational strategies in low-risk prenatal care: systematic review of randomized clinical trials.

    PubMed

    Silva, Esther Pereira da; Lima, Roberto Teixeira de; Osório, Mônica Maria

    2016-09-01

    This study aimed to analyze the impact of educational strategies developed in low-risk prenatal care on obstetric outcomes from a systematic literature review. This review consulted databases PubMed, Medline, SciELO and Lilacs, analyzing randomized clinical trials with the following birth outcomes: birth weight, prematurity and breastfeeding, using the following combination of keywords: pre-natal, antenatal visits, education, health education, pregnancy outcomes, birth weight, prematurity, breastfeeding and randomized clinical trial. Nine studies were included following quality evaluation. Actions prove to be more effective when extended to the postpartum period. Most of them occurred during home visits and had a positive impact on breastfeeding and birth weight. The establishment of groups of pregnant women contributed to lower prevalence of prematurity. Breastfeeding was found to be the outcome most sensitive to educational strategies. Educational practices during the prenatal period contributed to favorable obstetric outcomes as they minimized pregnant women concerns and anxiety during the pregnancy process, preparing them for childbirth and postpartum, and should be incorporated into health services' work process. PMID:27653079

  20. Dipeptidyl peptidase-4 inhibitors and fracture risk: an updated meta-analysis of randomized clinical trials.

    PubMed

    Fu, Jianying; Zhu, Jianhong; Hao, Yehua; Guo, Chongchong; Zhou, Zhikun

    2016-01-01

    Data on the effects of dipeptidyl peptidase-4 (DPP-4) inhibitors on fracture risk are conflicting. Here, we performed a systematic review and meta-analysis of randomized controlled trials (RCTs) assessing the effects of DPP-4 inhibitors. Electronic databases were searched for relevant published articles, and unpublished studies presented at ClinicalTrials.gov were searched for relevant clinical data. Eligible studies included prospective randomized trials evaluating DPP-4 inhibitors versus placebo or other anti-diabetic medications in patients with type 2 diabetes. Study quality was determined using Jadad scores. Statistical analyses were performed to calculate the risk ratios (RRs) and 95% confidence intervals (CIs) using fixed-effects models. There were 62 eligible RCTs with 62,206 participants, including 33,452 patients treated with DPP-4 inhibitors. The number of fractures was 364 in the exposed group and 358 in the control group. The overall risk of fracture did not differ between patients exposed to DPP-4 inhibitors and controls (RR, 0.95; 95% CI, 0.83-1.10; P = 0.50). The results were consistent across subgroups defined by type of DPP-4 inhibitor, type of control, and length of follow-up. The study showed that DPP-4 inhibitor use does not modify the risk of bone fracture compared with placebo or other anti-diabetic medications in patients with type 2 diabetes. PMID:27384445

  1. Improving efficiency of inferences in randomized clinical trials using auxiliary covariates.

    PubMed

    Zhang, Min; Tsiatis, Anastasios A; Davidian, Marie

    2008-09-01

    The primary goal of a randomized clinical trial is to make comparisons among two or more treatments. For example, in a two-arm trial with continuous response, the focus may be on the difference in treatment means; with more than two treatments, the comparison may be based on pairwise differences. With binary outcomes, pairwise odds ratios or log odds ratios may be used. In general, comparisons may be based on meaningful parameters in a relevant statistical model. Standard analyses for estimation and testing in this context typically are based on the data collected on response and treatment assignment only. In many trials, auxiliary baseline covariate information may also be available, and it is of interest to exploit these data to improve the efficiency of inferences. Taking a semiparametric theory perspective, we propose a broadly applicable approach to adjustment for auxiliary covariates to achieve more efficient estimators and tests for treatment parameters in the analysis of randomized clinical trials. Simulations and applications demonstrate the performance of the methods. PMID:18190618

  2. Effectiveness of dry needling for chronic nonspecific neck pain: a randomized, single-blinded, clinical trial.

    PubMed

    Cerezo-Téllez, Ester; Torres-Lacomba, María; Fuentes-Gallardo, Isabel; Perez-Muñoz, Milagros; Mayoral-Del-Moral, Orlando; Lluch-Girbés, Enrique; Prieto-Valiente, Luis; Falla, Deborah

    2016-09-01

    Chronic neck pain attributed to a myofascial pain syndrome is characterized by the presence of muscle contractures referred to as myofascial trigger points. In this randomized, parallel-group, blinded, controlled clinical trial, we examined the effectiveness of deep dry needling (DDN) of myofascial trigger points in people with chronic nonspecific neck pain. The study was conducted at a public Primary Health Care Centre in Madrid, Spain, from January 2010 to December 2014. A total of 130 participants with nonspecific neck pain presenting with active myofascial trigger points in their cervical muscles were included. These participants were randomly allocated to receive: DDN plus stretching (n = 65) or stretching only (control group [n = 65]). Four sessions of treatment were applied over 2 weeks with a 6-month follow-up after treatment. Pain intensity, mechanical hyperalgesia, neck active range of motion, neck muscle strength, and perceived neck disability were measured at baseline, after 2 sessions of intervention, after the intervention period, and 15, 30, 90, and 180 days after the intervention. Significant and clinically relevant differences were found in favour of dry needling in all the outcomes (all P < 0.001) at both short and long follow-ups. Deep dry needling and passive stretching is more effective than passive stretching alone in people with nonspecific neck pain. The results support the use of DDN in the management of myofascial pain syndrome in people with chronic nonspecific neck pain. PMID:27537209

  3. Impact of educational strategies in low-risk prenatal care: systematic review of randomized clinical trials.

    PubMed

    Silva, Esther Pereira da; Lima, Roberto Teixeira de; Osório, Mônica Maria

    2016-09-01

    This study aimed to analyze the impact of educational strategies developed in low-risk prenatal care on obstetric outcomes from a systematic literature review. This review consulted databases PubMed, Medline, SciELO and Lilacs, analyzing randomized clinical trials with the following birth outcomes: birth weight, prematurity and breastfeeding, using the following combination of keywords: pre-natal, antenatal visits, education, health education, pregnancy outcomes, birth weight, prematurity, breastfeeding and randomized clinical trial. Nine studies were included following quality evaluation. Actions prove to be more effective when extended to the postpartum period. Most of them occurred during home visits and had a positive impact on breastfeeding and birth weight. The establishment of groups of pregnant women contributed to lower prevalence of prematurity. Breastfeeding was found to be the outcome most sensitive to educational strategies. Educational practices during the prenatal period contributed to favorable obstetric outcomes as they minimized pregnant women concerns and anxiety during the pregnancy process, preparing them for childbirth and postpartum, and should be incorporated into health services' work process.

  4. Dipeptidyl peptidase-4 inhibitors and fracture risk: an updated meta-analysis of randomized clinical trials

    PubMed Central

    Fu, Jianying; Zhu, Jianhong; Hao, Yehua; Guo, Chongchong; Zhou, Zhikun

    2016-01-01

    Data on the effects of dipeptidyl peptidase-4 (DPP-4) inhibitors on fracture risk are conflicting. Here, we performed a systematic review and meta-analysis of randomized controlled trials (RCTs) assessing the effects of DPP-4 inhibitors. Electronic databases were searched for relevant published articles, and unpublished studies presented at