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Sample records for phase-ii randomized clinical

  1. Generalized optimal design for two-arm, randomized phase II clinical trials with endpoints from the exponential dispersion family.

    PubMed

    Jiang, Wei; Mahnken, Jonathan D; He, Jianghua; Mayo, Matthew S

    2016-11-01

    For two-arm randomized phase II clinical trials, previous literature proposed an optimal design that minimizes the total sample sizes subject to multiple constraints on the standard errors of the estimated event rates and their difference. The original design is limited to trials with dichotomous endpoints. This paper extends the original approach to be applicable to phase II clinical trials with endpoints from the exponential dispersion family distributions. The proposed optimal design minimizes the total sample sizes needed to provide estimates of population means of both arms and their difference with pre-specified precision. Its applications on data from specific distribution families are discussed under multiple design considerations. Copyright © 2016 John Wiley & Sons, Ltd.

  2. Randomized phase II/III clinical trial of elpamotide for patients with advanced pancreatic cancer: PEGASUS-PC Study.

    PubMed

    Yamaue, Hiroki; Tsunoda, Takuya; Tani, Masaji; Miyazawa, Motoki; Yamao, Kenji; Mizuno, Nobumasa; Okusaka, Takuji; Ueno, Hideki; Boku, Narikazu; Fukutomi, Akira; Ishii, Hiroshi; Ohkawa, Shinichi; Furukawa, Masayuki; Maguchi, Hiroyuki; Ikeda, Masafumi; Togashi, Yosuke; Nishio, Kazuto; Ohashi, Yasuo

    2015-07-01

    Gemcitabine is a key drug for the treatment of pancreatic cancer; however, with its limitation in clinical benefits, the development of another potent therapeutic is necessary. Vascular endothelial growth factor receptor 2 is an essential target for tumor angiogenesis, and we have conducted a phase I clinical trial using gemcitabine and vascular endothelial growth factor receptor 2 peptide (elpamotide). Based on the promising results of this phase I trial, a multicenter, randomized, placebo-controlled, double-blind phase II/III clinical trial has been carried out for pancreatic cancer. The eligibility criteria included locally advanced or metastatic pancreatic cancer. Patients were assigned to either the Active group (elpamotide + gemcitabine) or Placebo group (placebo + gemcitabine) in a 2:1 ratio by the dynamic allocation method. The primary endpoint was overall survival. The Harrington-Fleming test was applied to the statistical analysis in this study to evaluate the time-lagged effect of immunotherapy appropriately. A total of 153 patients (Active group, n = 100; Placebo group, n = 53) were included in the analysis. No statistically significant differences were found between the two groups in the prolongation of overall survival (Harrington-Fleming P-value, 0.918; log-rank P-value, 0.897; hazard ratio, 0.87, 95% confidence interval [CI], 0.486-1.557). Median survival time was 8.36 months (95% CI, 7.46-10.18) for the Active group and 8.54 months (95% CI, 7.33-10.84) for the Placebo group. The toxicity observed in both groups was manageable. Combination therapy of elpamotide with gemcitabine was well tolerated. Despite the lack of benefit in overall survival, subgroup analysis suggested that the patients who experienced severe injection site reaction, such as ulceration and erosion, might have better survival.

  3. A randomized two-stage design for phase II clinical trials based on a Bayesian predictive approach.

    PubMed

    Cellamare, Matteo; Sambucini, Valeria

    2015-03-15

    The rate of failure in phase III oncology trials is surprisingly high, partly owing to inadequate phase II studies. Recently, the use of randomized designs in phase II is being increasingly recommended, to avoid the limits of studies that use a historical control. We propose a two-arm two-stage design based on a Bayesian predictive approach. The idea is to ensure a large probability, expressed in terms of the prior predictive probability of the data, of obtaining a substantial posterior evidence in favour of the experimental treatment, under the assumption that it is actually more effective than the standard agent. This design is a randomized version of the two-stage design that has been proposed for single-arm phase II trials by Sambucini. We examine the main features of our novel design as all the parameters involved vary and compare our approach with Jung's minimax and optimal designs. An illustrative example is also provided online as a supplementary material to this article.

  4. Therapeutic Vaccination with TNF-Kinoid in TNF Antagonist-Resistant Rheumatoid Arthritis: A Phase II Randomized, Controlled Clinical Trial

    PubMed Central

    Durez, Patrick; Vandepapeliere, Pierre; Miranda, Pedro; Toncheva, Antoaneta; Berman, Alberto; Kehler, Tatjana; Mociran, Eugenia; Fautrel, Bruno; Mariette, Xavier; Dhellin, Olivier; Fanget, Bernard; Ouary, Stephane; Grouard-Vogel, Géraldine; Boissier, Marie-Christophe

    2014-01-01

    Objectives Active immunization, or vaccination, with tumor necrosis factor (TNF)-Kinoid (TNF-K) is a novel approach to induce polyclonal anti-TNF antibodies in immune-mediated inflammatory diseases. This study was performed to transfer the proof of concept obtained in mice model of rheumatoid arthritis (RA) into human. We designed a pilot study to demonstrate the feasibility of therapeutic vaccination in RA. Methods This was a phase IIa, placebo-controlled, multicenter study in adults with RA who previously experienced secondary failure of TNF antagonists. Patients were immunized intramuscularly with 2 or 3 doses of placebo (n = 10) or 90 (n = 6), 180 (n = 12), or 360 µg TNF-K (n = 12). The primary objective was to identify the best dose and schedule based on anti-TNF antibody titers. Clinical symptoms and safety were assessed during 12 months and solicited reactions for 7 days after each injection. Results The highest anti-TNF antibody response was detected in patients immunized with 360 µg TNF-K and with 3 injections, although this difference was not significant with all other groups. Similar proportions of patients receiving TNF-K and placebo reported adverse events up to month 12. Serious adverse events were reported by 4 patients treated with TNF-K (13.3%) and 3 treated with placebo (30.0%), all unrelated to treatment. At month 12, DAS28-CRP, tender and swollen joint counts, and HAQ scores decreased significantly more in patients who exhibited anti-TNF antibody response than in patients who did not. Conclusions TNF-K therapeutic vaccination induced dose- and schedule-dependent anti-TNF antibodies in RA patients and was well tolerated. Patients who developed anti-TNF antibodies showed a trend toward clinical improvement. Although the most aggressive dose and schedule, i.e. 360 mg dose administered 3 times, did show a strong trend of higher antibody response, further studies are warranted to examine even higher and more frequent doses in order

  5. Randomized phase II/III trial of post-operative chemoradiotherapy comparing 3-weekly cisplatin with weekly cisplatin in high-risk patients with squamous cell carcinoma of head and neck: Japan Clinical Oncology Group Study (JCOG1008).

    PubMed

    Kunieda, Futoshi; Kiyota, Naomi; Tahara, Makoto; Kodaira, Takeshi; Hayashi, Ryuichi; Ishikura, Satoshi; Mizusawa, Junki; Nakamura, Kenichi; Fukuda, Haruhiko; Fujii, Masato

    2014-08-01

    A randomized Phase II/III study was launched in Japan to evaluate the non-inferiority of concurrent chemoradiotherapy with weekly cisplatin (40 mg/m(2)) compared with concurrent chemoradiotherapy with 3-weekly cisplatin (100 mg/m(2)) for post-operative high-risk patients with locally advanced squamous cell carcinoma of head and neck. This study began in October 2012, and a total of 260 patients will be accrued from 18 institutions within 5 years. The primary endpoint of the Phase II part is proportion of treatment completion and that of the Phase III part is overall survival. The secondary endpoints are relapse-free survival, local relapse-free survival, nutrition-support-free survival, non-hospitalized treatment period during permissible treatment period and adverse events. This trial was registered at the UMIN Clinical Trials Registry as UMIN 000009125 [http://www.umin.ac.jp/ctr/].

  6. 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

  7. A Phase II/III randomized controlled trial comparing perioperative versus postoperative chemotherapy with mFOLFOX6 for lower rectal cancer with suspected lateral pelvic node metastasis: Japan Clinical Oncology Group Study JCOG1310 (PRECIOUS study).

    PubMed

    Ohue, Masayuki; Iwasa, Satoru; Kanemitsu, Yukihide; Hamaguchi, Tetsuya; Shiozawa, Manabu; Ito, Masaaki; Yasui, Masayoshi; Katayama, Hiroshi; Mizusawa, Junki; Shimada, Yasuhiro

    2017-01-01

    A randomized phase II/III trial was started in May 2015 comparing perioperative versus postoperative chemotherapy with modified infusional fluorouracil and folinic acid with oxaliplatin for lower rectal cancer patients with suspected lateral pelvic node metastasis. The standard arm is total mesorectal excision or tumor-specific mesorectal excision with lateral pelvic node dissection (LND) followed by postoperative chemotherapy (modified infusional fluorouracil and folinic acid with oxaliplatin; 12 cycles). The experimental (perioperative chemotherapy) arm is six courses of modified infusional fluorouracil and folinic acid with oxaliplatin before and six courses after total mesorectal excision with lateral pelvic node dissection. The aim of this trial is to confirm the superiority of perioperative chemotherapy. A total of 330 patients will be enrolled over 7 years. The primary endpoint in Phase II part is proportion of R0 resection and that in Phase III part is overall survival. Secondary endpoints are progression-free survival, local progression-free survival, etc. This trial has been registered in the UMIN Clinical Trials Registry as UMIN000017603 [http://www.umin.ac.jp/ctr/index-j.htm].

  8. Phase II, Randomized, Placebo-Controlled Trial of Neoadjuvant Celecoxib in Men With Clinically Localized Prostate Cancer: Evaluation of Drug-Specific Biomarkers

    PubMed Central

    Antonarakis, Emmanuel S.; Heath, Elisabeth I.; Walczak, Janet R.; Nelson, William G.; Fedor, Helen; De Marzo, Angelo M.; Zahurak, Marianna L.; Piantadosi, Steven; Dannenberg, Andrew J.; Gurganus, Robin T.; Baker, Sharyn D.; Parnes, Howard L.; DeWeese, Theodore L.; Partin, Alan W.; Carducci, Michael A.

    2009-01-01

    Purpose Cyclooxygenase-2 (COX-2) is a potential pharmacologic target for the prevention of various malignancies, including prostate cancer. We conducted a randomized, double-blind trial to examine the effect of celecoxib on drug-specific biomarkers from prostate tissue obtained at prostatectomy. Patients and Methods Patients with localized prostate cancer and Gleason sum ≥ 7, prostate-specific antigen (PSA) ≥ 15 ng/mL, clinical stage T2b or greater, or any combination with greater than 45% risk of capsular penetration were randomly assigned to celecoxib 400 mg by mouth twice daily or placebo for 4 to 6 weeks before prostatectomy. The primary end point was the difference in prostatic prostaglandin levels between the two groups. Secondary end points were differences in COX-1 and -2 expressions; oxidized DNA bases; and markers of proliferation, apoptosis and angiogenesis. Tissue celecoxib concentrations also were measured. Tertiary end points were drug safety and compliance. Results Seventy-three patients consented, and 64 were randomly assigned and included in the intention-to-treat analysis. There were no treatment differences in any of the primary or secondary outcomes. Multivariable regression revealed that tumor tissue had significantly lower COX-2 expression than benign prostatic tissue (P = .01) and significantly higher levels of the proliferation marker Ki-67 (P < .0001). Celecoxib was measurable in prostate tissue of patients on treatment, demonstrating that celecoxib reached its target. Celecoxib was safe and resulted in only grade 1 toxicities. Conclusion Treatment with 4 to 6 weeks of celecoxib had no effect on intermediate biomarkers of prostate carcinogenesis, despite the achievement of measurable tissue levels. We caution against using celecoxib 400 mg twice daily as a preventive agent for prostate cancer in additional studies. PMID:19720908

  9. 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

  10. A randomized phase II clinical trial of personalized peptide vaccination with metronomic low-dose cyclophosphamide in patients with metastatic castration-resistant prostate cancer.

    PubMed

    Noguchi, Masanori; Moriya, Fukuko; Koga, Noriko; Matsueda, Satoko; Sasada, Tetsuro; Yamada, Akira; Kakuma, Tatsuyuki; Itoh, Kyogo

    2016-02-01

    This study investigated the effect of metronomic cyclophosphamide (CPA) in combination with personalized peptide vaccination (PPV) on regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC), and whether it could improve the antitumor effect of PPV. Seventy patients with metastatic castration-resistant prostate cancer were randomly assigned (1:1) to receive PPV plus oral low-dose CPA (50 mg/day), or PPV alone. PPV treatment used a maximum of four peptides chosen from 31 pooled peptides according to human leukocyte antigen types and antigen-specific humoral immune responses before PPV, for 8 subcutaneous weekly injections. Peptide-specific cytotoxic T lymphocyte (CTL) and immunoglobulin G responses were measured before and after PPV. The incidence of grade 3 or 4 hematologic adverse events was higher in the PPV plus CPA arm than in the PPV alone arm. Decrease in Treg and increase in MDSC were more pronounced in PPV plus CPA treatment than in PPV alone (p = 0.036 and p = 0.048, respectively). There was no correlation between the changes in Treg or MDSC and CTL response. There was no difference in positive immune responses between the two arms, although overall survival in patients with positive immune responses was longer than in those with negative immune responses (p = 0.001). Significant differences in neither progression-free survival nor overall survival were observed between the two arms. Low-dose CPA showed no change in the antitumor effect of PPV, possibly due to the simultaneous decrease in Treg and increase in MDSC, in patients under PPV.

  11. 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.

  12. Huo-Luo-Xiao-Ling (HLXL)-Dan, a Traditional Chinese Medicine, for Patients with Osteoarthritis of the Knee: A Multi-site, Randomized, Double-blind, Placebo-controlled Phase II Clinical Trial

    PubMed Central

    Lao, Lixing; Hochberg, Marc; Lee, David Y.W.; Gilpin, Adele M.K.; Fong, Harry H.S.; Langenberg, Patrica; Chen, Kevin; Li, Edmund K.; Tam, Lai Shan; Berman, Brian

    2015-01-01

    Objective To examine the efficacy and safety of Huo-Luo-Xiao-Ling (HLXL)-Dan, a traditional Chinese medicine, in patients with knee osteoarthritis (OA). Design A multi-site, randomized, double-blind, placebo-controlled phase II dose-escalation clinical trial was conducted. Eligible patients who fulfilled American College of Rheumatology criteria were randomized to receive either HLXL or placebo. Clinical assessments included measurement of knee pain and function with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), patient global assessment (PGA), and knee pain scores every 2 weeks. A Data and Safety Monitoring Board (DSMB) was established to review the data for ensuring the quality of the trial. Results In the first stage, 28 participants were randomized to receive either low-dose HLXL-Dan (2,400mg/day) or placebo for 6 weeks. The results showed no statistical difference between the two groups. The study was then re-designed following the recommendation of DSMB. Ninety-two patients were enrolled in the second stage and were randomized to receive either high-dose HLXL-Dan (4,000mg/day for week 1–2, and 5,600mg/day for week 3–8) or placebo for 8 weeks. All outcome assessments showed significant improvements for both groups after 8 weeks but no significant between-group differences. The change (mean ± SD) of WOMAC pain and WOMAC function scores of HLXL and placebo group after 8 weeks were −1.2±1.7 VS −1.4±1.5, and −1.1±1.6 VS −1.3±1.5 respectively. No serious adverse events were reported. Conclusion Although safe to use, an 8-week treatment of HLXL-Dan was not superior to placebo for reduction in pain or functional improvement in patients with knee OA. Clinical trial registration number Clinicaltrials.gov (NCT00755326) PMID:26099553

  13. Play the winner for phase II/III clinical trials.

    PubMed

    Yao, Q; Wei, L J

    In comparing two treatments under a typical sequential clinical trial setting, a 50-50 randomization design generates reliable data for making efficient inferences about the treatment difference for the benefit of patients in the general population. However, if the treatment difference is large and the endpoint of the study is potentially fatal, it does not seem appropriate to sacrifice a large number of study patients who are assigned to the inferior arm. An adaptive design is a data-dependent treatment allocation rule that sequentially uses accumulating information about the treatment difference during the trial to modify the allocation rule for new study patients. In this article, we utilize real trials from AIDS and cancer to illustrate the advantage of using adaptive designs. Specifically we show that, with adaptive designs, the loss of power for testing the equality of two treatments is negligible. Moreover, the study patients do not have to pay a handsome price for the benefit of future patients. We also propose multi-stage adaptive rules to relax the administrative burden of implementing the study and to handle continuous response variables, such as the failure time in survival analysis.

  14. Randomized Placebo-Controlled Phase II Trial of Autologous Mesenchymal Stem Cells in Multiple Sclerosis

    PubMed Central

    Blanco, Yolanda; Marín, Pedro; Moreno, Beatriz; Berenguer, Joan; Gabilondo, Iñigo; Martínez-Heras, Eloy; Sola-Valls, Nuria; Arnaiz, Joan-Albert; Andreu, Enrique J.; Fernández, Begoña; Bullich, Santi; Sánchez-Dalmau, Bernardo; Graus, Francesc; Villoslada, Pablo; Saiz, Albert

    2014-01-01

    Objective Uncontrolled studies of mesenchymal stem cells (MSCs) in multiple sclerosis suggested some beneficial effect. In this randomized, double-blind, placebo-controlled, crossover phase II study we investigated their safety and efficacy in relapsing-remitting multiple sclerosis patients. Efficacy was evaluated in terms of cumulative number of gadolinium-enhancing lesions (GEL) on magnetic resonance imaging (MRI) at 6 months and at the end of the study. Methods Patients unresponsive to conventional therapy, defined by at least 1 relapse and/or GEL on MRI scan in past 12 months, disease duration 2 to 10 years and Expanded Disability Status Scale (EDSS) 3.0–6.5 were randomized to receive IV 1–2×106 bone-marrow-derived-MSCs/Kg or placebo. After 6 months, the treatment was reversed and patients were followed-up for another 6 months. Secondary endpoints were clinical outcomes (relapses and disability by EDSS and MS Functional Composite), and several brain MRI and optical coherence tomography measures. Immunological tests were explored to assess the immunomodulatory effects. Results At baseline 9 patients were randomized to receive MSCs (n = 5) or placebo (n = 4). One patient on placebo withdrew after having 3 relapses in the first 5 months. We did not identify any serious adverse events. At 6 months, patients treated with MSCs had a trend to lower mean cumulative number of GEL (3.1, 95% CI = 1.1–8.8 vs 12.3, 95% CI = 4.4–34.5, p = 0.064), and at the end of study to reduced mean GEL (−2.8±5.9 vs 3±5.4, p = 0.075). No significant treatment differences were detected in the secondary endpoints. We observed a non-significant decrease of the frequency of Th1 (CD4+ IFN-γ+) cells in blood of MSCs treated patients. Conclusion Bone-marrow-MSCs are safe and may reduce inflammatory MRI parameters supporting their immunomodulatory properties. ClinicalTrials.gov NCT01228266 PMID:25436769

  15. A phase II randomized clinical trial on cerebral near-infrared spectroscopy plus a treatment guideline versus treatment as usual for extremely preterm infants during the first three days of life (SafeBoosC): study protocol for a randomized controlled trial

    PubMed Central

    2013-01-01

    Background Every year in Europe about 25,000 infants are born extremely preterm. These infants have a 20% mortality rate, and 25% of survivors have severe long-term cerebral impairment. Preventative measures are key to reduce mortality and morbidity in an extremely preterm population. The primary objective of the SafeBoosC phase II trial is to examine if it is possible to stabilize the cerebral oxygenation of extremely preterm infants during the first 72 hours of life through the application of cerebral near-infrared spectroscopy (NIRS) oximetry and implementation of an clinical treatment guideline based on intervention thresholds of cerebral regional tissue saturation rStO2. Methods/Design SafeBoosC is a randomized, blinded, multinational, phase II clinical trial. The inclusion criteria are: neonates born more than 12 weeks preterm; decision to conduct full life support; parental informed consent; and possibility to place the cerebral NIRS oximeter within 3 hours after birth. The infants will be randomized into one of two groups. Both groups will have a cerebral oximeter monitoring device placed within three hours of birth. In the experimental group, the cerebral oxygenation reading will supplement the standard treatment using a predefined treatment guideline. In the control group, the cerebral oxygenation reading will not be visible and the infant will be treated according to the local standards. The primary outcome is the multiplication of the duration and magnitude of rStO2 values outside the target ranges of 55% to 85%, that is, the ‘burden of hypoxia and hyperoxia’ expressed in ‘%hours’. To detect a 50% difference between the experimental and control group in %hours, 166 infants in total must be randomized. Secondary outcomes are mortality at term date, cerebral ultrasound score, and interburst intervals on an amplitude-integrated electroencephalogram at 64 hours of life and explorative outcomes include neurodevelopmental outcome at 2 years corrected

  16. 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

  17. Novel therapies for resistant focal segmental glomerulosclerosis (FONT) phase II clinical trial: study design

    PubMed Central

    2011-01-01

    Background The lack of adequate randomized clinical trials (RCT) has hindered identification of new therapies that are safe and effective for patients with primary focal segmental glomerulosclerosis (FSGS), especially in patients who fail to respond to corticosteroids and immunosuppressive therapies. Recent basic science advances have led to development of alternative treatments that specifically target aberrant pathways of fibrosis which are relevant to disease progression in FSGS. There is a need for a flexible Phase II study design which will test such novel antifibrotic strategies in order to identify agents suitable for phase III testing. Methods/Design The Novel Therapies for Resistant Focal Segmental Glomerulosclerosis (FONT) project is a multicenter Phase I/II RCT designed to investigate the potential efficacy of novel therapies for resistant FSGS. Adalimumab and galactose will be evaluated against conservative therapy consisting of the combination of lisinopril, losartan and atorvastatin. The sample size is defined to assure that if one of the treatments has a superior response rate compared to that of the other treatments, it will be selected with high probability for further evaluation. Comparison of primary and secondary endpoints in each study arm will enable a choice to be made of which treatments are worthy of further study in future Phase III RCT. Discussion This report highlights the key features of the FONT II RCT including the two-step outcome analysis that will expedite achievement of the study objectives. The proposed phase II study design will help to identify promising agents for further testing while excluding ineffective agents. This staged approach can help to prevent large expenditures on unworthy therapeutic agents in the management of serious but rare kidney diseases Trial Registration ClinicalTrials.gov, NCT00814255 PMID:21310077

  18. The design of phase II clinical trials testing cancer therapeutics: consensus recommendations from the clinical trial design task force of the national cancer institute investigational drug steering committee.

    PubMed

    Seymour, Lesley; Ivy, S Percy; Sargent, Daniel; Spriggs, David; Baker, Laurence; Rubinstein, Larry; Ratain, Mark J; Le Blanc, Michael; Stewart, David; Crowley, John; Groshen, Susan; Humphrey, Jeffrey S; West, Pamela; Berry, Donald

    2010-03-15

    The optimal design of phase II studies continues to be the subject of vigorous debate, especially studies of newer molecularly targeted agents. The observations that many new therapeutics "fail" in definitive phase III studies, coupled with the numbers of new agents to be tested as well as the increasing costs and complexity of clinical trials, further emphasize the critical importance of robust and efficient phase II design. The Clinical Trial Design Task Force (CTD-TF) of the National Cancer Institute (NCI) Investigational Drug Steering Committee (IDSC) has published a series of discussion papers on phase II trial design in Clinical Cancer Research. The IDSC has developed formal recommendations about aspects of phase II trial design that are the subject of frequent debate, such as endpoints (response versus progression-free survival), randomization (single-arm designs versus randomization), inclusion of biomarkers, biomarker-based patient enrichment strategies, and statistical design (e.g., two-stage designs versus multiple-group adaptive designs). Although these recommendations in general encourage the use of progression-free survival as the primary endpoint, randomization, inclusion of biomarkers, and incorporation of newer designs, we acknowledge that objective response as an endpoint and single-arm designs remain relevant in certain situations. The design of any clinical trial should always be carefully evaluated and justified based on characteristic specific to the situation.

  19. 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.

  20. Changes in ventricular remodelling and clinical status during the year following a single administration of stromal cell-derived factor-1 non-viral gene therapy in chronic ischaemic heart failure patients: the STOP-HF randomized Phase II trial

    PubMed Central

    Chung, Eugene S.; Miller, Leslie; Patel, Amit N.; Anderson, Russell David; Mendelsohn, Farrell O.; Traverse, Jay; Silver, Kevin H.; Shin, Julia; Ewald, Gregory; Farr, Mary Jane; Anwaruddin, Saif; Plat, Francis; Fisher, Scott J.; AuWerter, Alexander T.; Pastore, Joseph M.; Aras, Rahul; Penn, Marc S.

    2015-01-01

    Background Stromal cell-derived factor-1 (SDF-1) promotes tissue repair through mechanisms of cell survival, endogenous stem cell recruitment, and vasculogenesis. Stromal Cell-Derived Factor-1 Plasmid Treatment for Patients with Heart Failure (STOP-HF) is a Phase II, double-blind, randomized, placebo-controlled trial to evaluate safety and efficacy of a single treatment of plasmid stromal cell-derived factor-1 (pSDF-1) delivered via endomyocardial injection to patients with ischaemic heart failure (IHF). Methods Ninety-three subjects with IHF on stable guideline-based medical therapy and left ventricular ejection fraction (LVEF) ≤40%, completed Minnesota Living with Heart Failure Questionnaire (MLWHFQ) and 6-min walk distance (6 MWD), were randomized 1 : 1 : 1 to receive a single treatment of either a 15 or 30 mg dose of pSDF-1 or placebo via endomyocardial injections. Safety and efficacy parameters were assessed at 4 and 12 months after injection. Left ventricular functional and structural measures were assessed by contrast echocardiography and quantified by a blinded independent core laboratory. Stromal Cell-Derived Factor-1 Plasmid Treatment for Patients with Heart Failure was powered based on change in 6 MWD and MLWHFQ at 4 months. Results Subject profiles at baseline were (mean ± SD): age 65 ± 9 years, LVEF 28 ± 7%, left ventricular end-systolic volume (LVESV) 167 ± 66 mL, N-terminal pro brain natriuretic peptide (BNP) (NTproBNP) 1120 ± 1084 pg/mL, MLWHFQ 50 ± 20 points, and 6 MWD 289 ± 99 m. Patients were 11 ± 9 years post most recent myocardial infarction. Study injections were delivered without serious adverse events in all subjects. Sixty-two patients received drug with no unanticipated serious product-related adverse events. The primary endpoint was a composite of change in 6 MWD and MLWHFQ from baseline to 4 months follow-up. The primary endpoint was not met (P = 0.89). For the patients treated with pSDF-1, there was a trend toward an

  1. Photosensitizer Radachlorin®: Skin cancer PDT phase II clinical trials.

    PubMed

    Kochneva, Elena V; Filonenko, Elena V; Vakulovskaya, Elena G; Scherbakova, Elena G; Seliverstov, Oleg V; Markichev, Nikolay A; Reshetnickov, Andrei V

    2010-12-01

    "Radachlorin"(®), also known in the EU as Bremachlorin, a composition of 3 chlorophyll a derivatives in an aqueous solution, was introduced into the Russian Pharmacopoeia. Its GMP (Good Manufacturing Practice) facility based manufacturing method was patented. Laboratory experiments and clinical phase I were performed. Protocols were designed for PDT of basal cell carcinoma of the skin to result in GCP (Good Clinical Practice)-conformed randomized phase II clinical studies. "Radachlorin"(®) solution for intravenous infusions 0.35% 10mL in the doses of 0.5-0.6 and 1.0-1.2mg/kg and a gel for topical application 0.1% 25g in the dose of 0.1g/cm(2) were photoactivated by 2.5W 662nm semiconductor laser "LAKHTA-MILON(®)" (St. Petersburg, Russia) in light doses of 200, 300 (solution), 400, 600, 800 (gel) J/cm(2). Safety study showed no side effects and a good tolerability of "Radachlorin"(®) by patients. There was no normal skin/subdermal tissue damage after both laser and sun light exposure. The main part (98%) of the drug was excreted or metabolized in the first 48h. Drug administration at a dose of 1.0-1.2mg/kg and irradiation at 3h with 662±3nm light at a dose of 300J/cm(2) (solution) and 4 PDT sessions at an interval of 1 week with 3h gel exposure, followed by 400J/cm(2) light exposure (gel) were found to be the optimal treatment regimes. Having successfully passed clinical trials, "Radachlorin"(®) achieved marketing authorization in Russia in 2009 and a conditional approval in South Korea in 2008. It is a candidate for phase III clinical trials in the EC and may be commercialized as a prospective second-generation photosensitizer.

  2. 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.

  3. 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

  4. Clinical and Biomarker Outcomes of the Phase II Vandetanib Study from the BATTLE Trial

    PubMed Central

    Tsao, Anne S.; Liu, Suyu; Lee, J. Jack; Alden, Christine M.; Blumenschein, George R.; Herbst, Roy; Davis, Suzanne E.; Kim, Edward; Lippman, Scott; Heymach, John; Tran, Hai; Tang, XiMing; Wistuba, Ignacio; Hong, Waun Ki

    2016-01-01

    Background The Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination trial1 prospectively obtained serum and tumor core biopsies and randomized 255 chemorefractory non–small-cell lung cancer (NSCLC) patients into four phase II trials: erlotinib, erlotinib-bexarotene, vandetanib, or sorafenib. Herein, we report the clinical and biomarker results of the phase II vandetanib trial. Results Fifty-four patients received vandetanib. The 8-week disease control rate was 33%, median progression-free survival (PFS) 1.81 months, and median overall survival (OS) 6.5 months. No demographic subgroups had PFS or OS benefit. Eight patients with EGFR mutations had a trend for higher 8-week disease control rate (63% versus 31%; p = 0.12) but worse OS (5.9 months versus 9 months; p = 0.8). Patients with EGFR gene amplification (n = 6) had a worse OS (3.9 months versus 9.5 months; p = 0.04). KRAS mutation patients (3.9 months versus 9.5 months; p = 0.23) also had a worse OS. For the serum biomarker analysis, patients with below the median serum expression of interleukin 9c (p = 0.019) and eotaxin (p = 0.007) had a shorter PFS. A trend toward a shorter PFS was also seen in patients with higher than the median neutrophil gelatinase-associated lipocalin (p = 0.079) and lower than the median TNF-related apoptosis-inducing ligand (p = 0.087). Conclusion Our trial results are largely consistent with the literature in unselected pretreated NSCLC patients. Although vandetanib improved median PFS in EGFR mutation patients with epidermal growth factor receptor tyrosine kinase inhibitor–resistance compared with EGFR wild-type, there was no OS advantage. Although vandetanib is no longer in development in NSCLC, identification of a molecular phenotype that responds to dual epidermal growth factor receptor and vascular endothelial growth factor receptor inhibition would contribute to the field. PMID:23584298

  5. Randomized Phase II Trial of Erlotinib Beyond Progression in Advanced Erlotinib-Responsive Non-Small Cell Lung Cancer

    PubMed Central

    Pennell, Nathan A.; Fu, Pingfu; Saad, Shumaila; Gadgeel, Shirish; Otterson, Gregory A.; Mekhail, Tarek; Snell, Michael; Kuebler, J. Philip; Sharma, Neelesh

    2015-01-01

    Background. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy is clearly beneficial in patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC). However, acquired resistance develops uniformly and the benefit of continuation of EGFR TKI therapy beyond progression remains unclear. Materials and Methods. This was a randomized phase II study of chemotherapy (arm A: pemetrexed or docetaxel) versus chemotherapy plus erlotinib (ERL) (arm B) in patients with progressive NSCLC following clinical benefit from erlotinib. In arm B, chemotherapy was given with erlotinib at an oral daily dose of 150 mg on days 2–19 of each cycle to minimize negative pharmacodynamic interactions. The primary endpoint was that continuation of erlotinib in this patient population could extend progression-free survival (PFS) by 50%. Results. A total of 46 patients were randomized (arm A: 24; arm B: 22). Patient characteristics were well balanced except there were more female patients in arm A (p = .075). The median PFS of patients in arm A was 5.5 months and for those in arm B, 4.4 months (p = .699). The response rates were 13% and 16% in arms A and B, respectively (p = .79). EGFR status data were available for 39 of the 46 patients and no significant difference in PFS was seen for continuing ERL beyond progression in mutation-positive patients. Substantially more toxicity was seen in arm B than arm A. Conclusion. There was added toxicity but no benefit with the continuation of ERL beyond progression along with chemotherapy as compared with chemotherapy alone. Implications for Practice: The benefits of continuing erlotinib upon progression alongside conventional chemotherapy are unclear. This randomized phase II study, initiated prior to the establishment of routine epidermal growth factor receptor (EGFR) mutation testing, addressed this clinically relevant issue through randomizing patients with prior clinical benefit from erlotinib (thereby enriching

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

    PubMed

    Dong, Gaohong

    2014-04-15

    Currently, adaptive phase II/III clinical trials are typically carried out with a strict two-stage design. The first stage is a learning stage called phase II, and the second stage is a confirmatory stage called phase III. Following phase II analysis, inefficacious or harmful dose arms are dropped, then one or two promising dose arms are selected for the second stage. However, there are often situations in which researchers are in dilemma to make 'go or no-go' decision and/or to select 'best' dose arm(s), as data from the first stage may not provide sufficient information for their decision making. In this case, it is challenging to follow a strict two-stage plan. Therefore, we propose a varying-stage adaptive phase II/III clinical trial design, in which we consider whether there is a need to have an intermediate stage to obtain more data, so that a more informative decision could be made. Hence, the number of further investigational stages in our design is determined on the basis of data accumulated to the interim analysis. With respect to adaptations, we consider dropping dose arm(s), switching another plausible endpoint as the primary study endpoint, re-estimating sample size, and early stopping for futility. We use an adaptive combination test to perform final analyses. By applying closed testing procedure, we control family-wise type I error rate at the nominal level of α in the strong sense. We delineate other essential design considerations including the threshold parameters and the proportion of alpha allocated in the two-stage versus three-stage setting.

  7. Tumor and circulating biomarkers in patients with second-line hepatocellular carcinoma from the randomized phase II study with tivantinib

    PubMed Central

    Rimassa, Lorenza; Abbadessa, Giovanni; Personeni, Nicola; Porta, Camillo; Borbath, Ivan; Daniele, Bruno; Salvagni, Stefania; Van Laethem, Jean-Luc; Van Vlierberghe, Hans; Trojan, Jörg; De Toni, Enrico N.; Weiss, Alan; Miles, Steven; Gasbarrini, Antonio; Lencioni, Monica; Lamar, Maria E.; Wang, Yunxia; Shuster, Dale; Schwartz, Brian E.; Santoro, Armando

    2016-01-01

    ARQ 197-215 was a randomized placebo-controlled phase II study testing the MET inhibitor tivantinib in second-line hepatocellular carcinoma (HCC) patients. It identified tumor MET as a key biomarker in HCC. Aim of this research was to study the prognostic and predictive value of tumor (MET, the receptor tyrosine kinase encoded by the homonymous MNNG-HOS transforming gene) and circulating (MET, hepatocyte growth factor [HGF], alpha-fetoprotein [AFP], vascular endothelial growth factor [VEGF]) biomarkers in second-line HCC. Tumor MET-High status was centrally assessed by immunohistochemistry. Circulating biomarkers were centrally analyzed on serum samples collected at baseline and every 4-8 weeks, using medians as cut-off to determine High/Low status. Tumor MET, tested in 77 patients, was more frequently High after (82%) versus before (40%) sorafenib. A significant interaction (p = 0.04) between tivantinib and baseline tumor MET in terms of survival was observed. Baseline circulating MET and HGF (102 patients) High status correlated with shorter survival (HR 0.61, p = 0.03, and HR 0.60, p = 0.02, respectively), while the association between AFP (104 patients) or VEGF (103 patients) status and survival was non-significant. Conclusions: Tumor MET levels were higher in patients treated with sorafenib. Circulating biomarkers such as MET and HGF may be prognostic in second-line HCC. These results need to be confirmed in larger randomized clinical trials. PMID:27579536

  8. A randomized phase II trial of personalized peptide vaccine with low dose cyclophosphamide in biliary tract cancer.

    PubMed

    Shirahama, Takahisa; Muroya, Daisuke; Matsueda, Satoko; Yamada, Akira; Shichijo, Shigeki; Naito, Masayasu; Yamashita, Takuto; Sakamoto, Shinjiro; Okuda, Koji; Itoh, Kyogo; Sasada, Tetsuro; Yutani, Shigeru

    2017-02-11

    Since the prognosis of advanced biliary tract cancer (aBTC) still remains very poor, new therapeutic approaches, including immunotherapies, need to be developed. In the current study, we conducted an open-label randomized phase II study to test whether low dose cyclophosphamide (CPA) could improve antigen-specific immune responses and clinical efficacy of personalized peptide vaccination (PPV) in 49 previously treated aBTC patients. Patients with aBTC refractory to at least one regimen of chemotherapies were randomly assigned to receive PPV with low dose CPA (100 mg/ day for 7 days before vaccination) (PPV/CPA, n=24) or PPV alone (n=25). A maximum of four HLA-matched peptides were selected based on the pre-existing peptide-specific IgG responses, followed by subcutaneous administration. T cell responses to the vaccinated peptides in the PPV/CPA arm tended to be greater than those in the PPV alone arm. The PPV/CPA arm showed significantly better progression-free survival (median time: 6.1 vs 2.9 months; hazard ratio (HR): 0.427; P = 0.008) and overall survival (median time: 12.1 vs 5.9 months; HR: 0.376; P = 0.004), compared to the PPV alone arm. The PPV alone arm, but not the PPV/CPA arm, showed significant increase in plasma IL-6 after vaccinations, which might be associated with inhibition of antigen-specific T cell responses. These results suggested that combined treatment with low dose CPA could provide clinical benefits in aBTC patients under PPV, possibly through prevention of IL-6-mediated immune suppression. Further clinical studies would be recommended to clarify the clinical efficacy of PPV/CPA in aBTC patients. This article is protected by copyright. All rights reserved.

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

    PubMed Central

    Di Maio, Massimo; Bironzo, Paolo

    2016-01-01

    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. PMID:26958498

  10. An evaluation of a Simon 2-Stage phase II clinical trial design incorporating toxicity monitoring.

    PubMed

    Ray, H E; Rai, S N

    2011-05-01

    Phase II clinical trials are usually designed to measure efficacy but patient safety is also a very important aspect. Previous authors suggested a methodology that allows one to monitor the cumulative number of toxic events after each patient is treated, which is also known as continuous toxicity monitoring. In this work we describe how to combine the continuous toxicity monitoring methodology with the Simon 2-Stage design for response. Then we investigate through simulation the combined procedure's type I and type II error rates under various combinations of design parameters. We include the underlying relationship between toxicity and response in our examination of the error rates.

  11. Cerebral near infrared spectroscopy oximetry in extremely preterm infants: phase II randomised clinical trial

    PubMed Central

    Pellicer, Adelina; Alderliesten, Thomas; Austin, Topun; van Bel, Frank; Benders, Manon; Claris, Olivier; Dempsey, Eugene; Franz, Axel R; Fumagalli, Monica; Gluud, Christian; Grevstad, Berit; Hagmann, Cornelia; Lemmers, Petra; van Oeveren, Wim; Pichler, Gerhard; Plomgaard, Anne Mette; Riera, Joan; Sanchez, Laura; Winkel, Per; Wolf, Martin; Greisen, Gorm

    2015-01-01

    Objective To determine if it is possible to stabilise the cerebral oxygenation of extremely preterm infants monitored by cerebral near infrared spectroscopy (NIRS) oximetry. Design Phase II randomised, single blinded, parallel clinical trial. Setting Eight tertiary neonatal intensive care units in eight European countries. Participants 166 extremely preterm infants born before 28 weeks of gestation: 86 were randomised to cerebral NIRS monitoring and 80 to blinded NIRS monitoring. The only exclusion criterion was a decision not to provide life support. Interventions Monitoring of cerebral oxygenation using NIRS in combination with a dedicated treatment guideline during the first 72 hours of life (experimental) compared with blinded NIRS oxygenation monitoring with standard care (control). Main outcome measures The primary outcome measure was the time spent outside the target range of 55-85% for cerebral oxygenation multiplied by the mean absolute deviation, expressed in %hours (burden of hypoxia and hyperoxia). One hour with an oxygenation of 50% gives 5%hours of hypoxia. Secondary outcomes were all cause mortality at term equivalent age and a brain injury score assessed by cerebral ultrasonography. Randomisation Allocation sequence 1:1 with block sizes 4 and 6 in random order concealed for the investigators. The allocation was stratified for gestational age (<26 weeks or ≥26 weeks). Blinding Cerebral oxygenation measurements were blinded in the control group. All outcome assessors were blinded to group allocation. Results The 86 infants randomised to the NIRS group had a median burden of hypoxia and hyperoxia of 36.1%hours (interquartile range 9.2-79.5%hours) compared with 81.3 (38.5-181.3) %hours in the control group, a reduction of 58% (95% confidence interval 35% to 73%, P<0.001). In the experimental group the median burden of hypoxia was 16.6 (interquartile range 5.4-68.1) %hours, compared with 53.6 (17.4-171.3) %hours in the control group (P=0.0012). The

  12. 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.

  13. A randomized phase II trial comparing chemoimmunotherapy with or without bevacizumab in previously untreated patients with chronic lymphocytic leukemia

    PubMed Central

    Kay, Neil E.; Strati, Paolo; LaPlant, Betsy R.; Leis, Jose F.; Nikcevich, Daniel; Call, Timothy G.; Pettinger, Adam M.; Lesnick, Connie E.; Hanson, Curtis A.; Shanafelt, Tait D.

    2016-01-01

    Bevacizumab is a monoclonal antibody targeting vascular endothelial growth factor (VEGF) with in vitro pro-apoptotic and antiangiogenic effects on chronic lymphocytic leukemia (CLL) cells. As monotherapy in patients with CLL, it has no clinical activity. Here we report the results of an open-label, randomized phase II trial comparing the combination of pentostatin, cyclophosphamide and rituximab (PCR) either without or with bevacizumab (PCR-B) in previously untreated CLL patients. A total of 65 evaluable patients were enrolled, 32 receiving PCR and 33 PCR-B. A higher rate of grade 3-4 cardiovascular toxicity was observed with PCR-B (33% vs. 3%, p < 0.003). Patients treated with PCR-B had a trend for a higher complete remission (CR) rate (54.5% vs 31.3%; p = 0.08), longer progression-free survival (PFS)(p = 0.06) and treatment-free survival (TFS)(p = 0.09). No differences in PFS and TFS by IGHV mutational status were observed with the addition of bevacizumab. A significant post-treatment increase in VEGF levels was observed in the PCR-B arm (29.77 to 57.05 pg/mL); in the PCR-B arm, lower baseline CCL-3 levels were significantly associated with achievement of CR (p = 0.01). In conclusion, the addition of bevacizumab to chemoimmunotherapy in CLL is generally well-tolerated and appears to prolong PFS and TFS. PMID:27861157

  14. 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

  15. Cediranib in combination with fulvestrant in hormone-sensitive metastatic breast cancer: a randomized Phase II study.

    PubMed

    Hyams, David M; Chan, Arlene; de Oliveira, Celia; Snyder, Raymond; Vinholes, Jeferson; Audeh, M William; Alencar, Victor M; Lombard, Janine; Mookerjee, Bijoyesh; Xu, John; Brown, Kathryn; Klein, Paula

    2013-10-01

    Hormone receptor-positive breast cancer is treated with estrogen inhibitors. Fulvestrant (FASLODEX™), an estrogen receptor (ER) antagonist with no known agonist effects, competitively binds, blocks and degrades the ER. Vascular endothelial growth factor (VEGF) may mediate resistance to ER antagonists. Cediranib is a highly potent VEGF signaling inhibitor with activity against all three VEGF receptors. This randomized Phase II study evaluated cediranib plus fulvestrant. Postmenopausal women with hormone-sensitive metastatic breast cancer were eligible. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), duration of response, clinical benefit rate (CBR), safety/tolerability and pharmacokinetics (PK). Patients received cediranib 45 mg/day (n=31) or placebo (n=31) both plus fulvestrant. Demographic/baseline characteristics were well balanced. Patients treated with cediranib had a numerical advantage in PFS (hazard ratio=0.867, P=0.669; median 223 vs. 112 days, respectively) and ORR (22 vs. 8 %, respectively) vs. placebo, although not statistically significant. CBR was 42 % in both arms. The most common adverse events (AEs) in the cediranib arm were diarrhea (68 %), fatigue (61 %) and hypertension (55 %). The incidence of grade ≥ 3 AEs (68 % vs. 32 %), serious AEs (48 % vs. 13 %), discontinuation AEs (39 % vs. 10 %), and cediranib dose reductions/interruptions (74 % vs. 32 %) were higher in the cediranib arm. There was no evidence of a clinically relevant effect of cediranib on fulvestrant PK. Cediranib plus fulvestrant may demonstrate clinical activity in this population, but cediranib 45 mg was not sufficiently well tolerated. Investigation of lower doses of cediranib plus hormonal/chemotherapy could be considered.

  16. Randomized Phase II Trial of Adjuvant WT-1 Analog Peptide Vaccine in Patients with Malignant Pleural Mesothelioma after Completion of Multimodality Therapy

    DTIC Science & Technology

    2014-09-01

    Scheinberg DA. Vaccination with Synthetic Analog Peptides Derived from WT1 Oncoprotein Induces T Cell Responses in Patients with Complete Remission ...TITLE:Randomized Phase II Trial of Adjuvant WT-1 Analog Peptide Vaccine in Patients with Malignant Pleural Mesothelioma after Completion of...TITLE:Randomized Phase II Trial of Adjuvant WT-1 Analog Peptide Vaccine in Patients with Malignant Pleural Mesothelioma after Completion of Multimodality

  17. Randomized Phase II Trial of Adjuvant WT-1 Analog Peptide Vaccine in Patients with Malignant Pleural Mesothelioma after Completion of Multimodality Therapy

    DTIC Science & Technology

    2012-09-01

    10-1-0699 TITLE: Randomized Phase II Trial of Adjuvant WT-1 Analog Peptide Vaccine in Patients with Malignant Pleural Mesothelioma after...Prescribed by ANSI Std. Z39.18 W81XWH-10-1-0699 Randomized Phase II Trial of Adjuvant WT-1 Analog Peptide Vaccine in Patients with Malignant... peptides that are given together with Montanide and GM-CSF as immunologic adjuvants. This WT1 vaccine was previously tested in a small pilot trial

  18. 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

  19. Dose-dependent change in biomarkers during neoadjuvant endocrine therapy with fulvestrant: results from NEWEST, a randomized Phase II study.

    PubMed

    Kuter, Irene; Gee, Julia M W; Hegg, Roberto; Singer, Christian F; Badwe, Rajendra A; Lowe, Elizabeth S; Emeribe, Ugochi A; Anderson, Elizabeth; Sapunar, Francisco; Finlay, Pauline; Nicholson, Robert I; Bines, José; Harbeck, Nadia

    2012-05-01

    NEWEST (Neoadjuvant Endocrine Therapy for Women with Estrogen-Sensitive Tumors) is the first study to compare biological and clinical activity of fulvestrant 500 versus 250 mg in the neoadjuvant breast cancer setting. We hypothesized that fulvestrant 500 mg may be superior to 250 mg in blocking estrogen receptor (ER) signaling and growth. A multicenter, randomized, open-label, Phase II study was performed to compare fulvestrant 500 mg (500 mg/month plus 500 mg on day 14 of month 1) versus fulvestrant 250 mg/month for 16 weeks prior to surgery in postmenopausal women with ER+ locally advanced breast cancer. Core biopsies at baseline, week 4, and surgery were assessed for biomarker changes. Primary endpoint: change in Ki67 labeling index (LI) from baseline to week 4 determined by automated computer imaging system (ACIS). Secondary endpoints: ER protein expression and function; progesterone receptor (PgR) expression; tumor response; tolerability. ER and PgR were examined retrospectively using the H score method. A total of 211 patients were randomized (fulvestrant 500 mg: n = 109; 250 mg: n = 102). At week 4, fulvestrant 500 mg resulted in greater reduction of Ki67 LI and ER expression versus 250 mg (-78.8 vs. -47.4% [p < 0.0001] and -25.0 vs. -13.5% [p = 0.0002], respectively [ACIS]); PgR suppression was not significantly different (-22.7 vs. -17.6; p = 0.5677). However, H score detected even greater suppression of ER (-50.3 vs. -13.7%; p < 0.0001) and greater PgR suppression (-80.5 vs. -46.3%; p = 0.0018) for fulvestrant 500 versus 250 mg. At week 16, tumor response rates were 22.9 and 20.6% for fulvestrant 500 and 250 mg, respectively, with considerable decline in all markers by both ACIS and H score. No detrimental effects on endometrial thickness or bone markers and no new safety concerns were identified. This provides the first evidence of greater biological activity for fulvestrant 500 versus 250 mg in depleting ER expression, function, and growth.

  20. A wet dressing for male genital surgery: A phase II clinical trial

    PubMed Central

    Vilar, Fábio de Oliveira; Pinto, Flávia Cristina Morone; Albuquerque, Amanda Vasconcelos; Martins, Ana Gabriela Santos; de Araújo, Luiz Alberto Pereira; Aguiar, José Lamartine de Andrade; Lima, Salvador Vilar Correia

    2016-01-01

    ABSTRACT Purpose: This study was to confirm the safety and efficacy of BC dressing when used in surgical male wound healing at the urogenital area. Methods: Open, non-controlled clinical study of phase II. A total of 141 patients, among those children, adolescents and adults with hypospadias (112), epispadias (04), phymosis (13) and Peyronie's disease (12) that had a BC dressing applied over the operated area after surgery. A written informed consent was obtained from all participants. Study exclusion criteria were patients with other alternative treatment indications due to the severity, extent of the injury or the underlying disease. The outcomes evaluated were efficacy, safe and complete healing. The costs were discussed. Results: In 68% patients, the BC dressing fell off spontaneously. The BC was removed without complications in 13% of patients at the outpatient clinic during the follow-up visit and 17% not reported the time of removal. In 3% of the cases, the dressing fell off early. Complete healing was observed between 8th and 10th days after surgery. The BC dressings have shown a good tolerance by all the patients and there were no reports of serious adverse events. Conclusion: The bacterial cellulose dressings have shown efficacy, safety and that can be considered as a satisfactory alternative for postoperative wound healing in urogenital area and with low cost. PMID:27649111

  1. 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

  2. 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

  3. Supplementation of iron in pulmonary hypertension: Rationale and design of a phase II clinical trial in idiopathic pulmonary arterial hypertension.

    PubMed

    Howard, Luke S G E; Watson, Geoffrey M J; Wharton, John; Rhodes, Christopher J; Chan, Kakit; Khengar, Rajeshree; Robbins, Peter A; Kiely, David G; Condliffe, Robin; Elliott, Charlie A; Pepke-Zaba, Joanna; Sheares, Karen; Morrell, Nicholas W; Davies, Rachel; Ashby, Deborah; Gibbs, J Simon R; Wilkins, Martin R

    2013-01-01

    Our aim is to assess the safety and potential clinical benefit of intravenous iron (Ferinject) infusion in iron deficient patients with idiopathic pulmonary arterial hypertension (IPAH). Iron deficiency in the absence of anemia (1) is common in patients with IPAH; (2) is associated with inappropriately raised levels of hepcidin, the key regulator of iron homeostasis; and (3) correlates with disease severity and worse clinical outcomes. Oral iron absorption may be impeded by reduced absorption due to elevated hepcidin levels. The safety and benefits of parenteral iron replacement in IPAH are unknown. Supplementation of Iron in Pulmonary Hypertension (SIPHON) is a Phase II, multicenter, double-blind, randomized, placebo-controlled, crossover clinical trial of iron in IPAH. At least 60 patients will be randomized to intravenous ferric carboxymaltose (Ferinject) or saline placebo with a crossover point after 12 weeks of treatment. The primary outcome will be the change in resting pulmonary vascular resistance from baseline at 12 weeks, measured by cardiac catheterization. Secondary measures include resting and exercise hemodynamics and exercise performance from serial bicycle incremental and endurance cardiopulmonary exercise tests. Other secondary measurements include serum iron indices, 6-Minute Walk Distance, WHO functional class, quality of life score, N-terminal pro-brain natriuretic peptide (NT-proBNP), and cardiac anatomy and function from cardiac magnetic resonance. We propose that intravenous iron replacement will improve hemodynamics and clinical outcomes in IPAH. If the data supports a potentially useful therapeutic effect and suggest this drug is safe, the study will be used to power a Phase III study to address efficacy.

  4. Conservative treatment of retinoblastoma: a prospective phase II randomized trial of neoadjuvant chemotherapy followed by local treatments and chemothermotherapy

    PubMed Central

    Lumbroso-Le Rouic, L; Aerts, I; Hajage, D; Lévy-Gabriel, C; Savignoni, A; Algret, N; Cassoux, N; Bertozzi, A-I; Esteve, M; Doz, F; Desjardins, L

    2016-01-01

    Purpose Intraocular retinoblastoma treatments often combine chemotherapy and focal treatments. A first prospective protocol of conservative treatments in our institution showed the efficacy of the use of two courses of chemoreduction with etoposide and carboplatin, followed by chemothermotherapy using carboplatin as a single agent and diode laser. In order to decrease the possible long-term toxicity of chemotherapy due to etoposide, a randomized neoadjuvant phase II protocol was conducted using vincristine–carboplatin vs etoposide–carboplatin. Patients and methods The study was proposed when initial tumor characteristics did not allow front-line local treatments. Patients included in this phase II noncomparative randomized study of neoadjuvant chemotherapy received vincristin–carboplatin (new arm) vs etoposide–carboplatin (our reference arm). They were subsequently treated by local treatments and chemothermotherapy. Primary end point was the need for secondary enucleation or external beam radiotherapy (EBRT) not exceeding 40% at 2 years. Results A total of 65 eyes in 55 children were included in the study (May 2004 to August 2009). Of these, 32 eyes (27 children) were treated in the arm etoposide–carboplatin and 33 eyes (28 children) in the arm vincristin–carboplatin. At 2 years after treatment, 23/33 (69.7%) eyes were treated and salvaged without EBRT or enucleation in the arm vincristin–carboplatin and 26/32 (81.2%) in the arm etoposide–carboplatin. Conclusion Even if the two treatment arms could be considered as sufficiently active according to the study decision rules, neoadjuvant chemotherapy by two cycles of vincristine–carboplatin followed by chemothermotherapy appear to offer less optimal local control than the etoposide–carboplatin combination. PMID:26427984

  5. 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.

  6. 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.

  7. Recombinant human interleukin-1 receptor antagonist in severe traumatic brain injury: a phase II randomized control trial

    PubMed Central

    Helmy, Adel; Guilfoyle, Mathew R; Carpenter, Keri LH; Pickard, John D; Menon, David K; Hutchinson, Peter J

    2014-01-01

    Traumatic brain injury (TBI) is the commonest cause of death and disability in those aged under 40 years. Interleukin-1 receptor antagonist (IL1ra) is an endogenous competitive antagonist at the interleukin-1 type-1 receptor (IL-1R). Antagonism at the IL-1R confers neuroprotection in several rodent models of neuronal injury (i.e., trauma, stroke and excitotoxicity). We describe a single center, phase II, open label, randomized-control study of recombinant human IL1ra (rhIL1ra, anakinra) in severe TBI, at a dose of 100 mg subcutaneously once a day for 5 days in 20 patients randomized 1:1. We provide safety data (primary outcome) in this pathology, utilize cerebral microdialysis to directly determine brain extracellular concentrations of IL1ra and 41 cytokines and chemokines, and use principal component analysis (PCA) to explore the resultant cerebral cytokine profile. Interleukin-1 receptor antagonist was safe, penetrated into plasma and the brain extracellular fluid. The PCA showed a separation in cytokine profiles after IL1ra administration. A candidate cytokine from this analysis, macrophage-derived chemoattractant, was significantly lower in the rhIL1ra-treated group. Our results provide promising data for rhIL1ra as a therapeutic candidate by showing safety, brain penetration and a modification of the neuroinflammatory response to TBI by a putative neuroprotective agent in humans for the first time. PMID:24569690

  8. Recombinant human interleukin-1 receptor antagonist in severe traumatic brain injury: a phase II randomized control trial.

    PubMed

    Helmy, Adel; Guilfoyle, Mathew R; Carpenter, Keri L H; Pickard, John D; Menon, David K; Hutchinson, Peter J

    2014-05-01

    Traumatic brain injury (TBI) is the commonest cause of death and disability in those aged under 40 years. Interleukin-1 receptor antagonist (IL1ra) is an endogenous competitive antagonist at the interleukin-1 type-1 receptor (IL-1R). Antagonism at the IL-1R confers neuroprotection in several rodent models of neuronal injury (i.e., trauma, stroke and excitotoxicity). We describe a single center, phase II, open label, randomized-control study of recombinant human IL1ra (rhIL1ra, anakinra) in severe TBI, at a dose of 100 mg subcutaneously once a day for 5 days in 20 patients randomized 1:1. We provide safety data (primary outcome) in this pathology, utilize cerebral microdialysis to directly determine brain extracellular concentrations of IL1ra and 41 cytokines and chemokines, and use principal component analysis (PCA) to explore the resultant cerebral cytokine profile. Interleukin-1 receptor antagonist was safe, penetrated into plasma and the brain extracellular fluid. The PCA showed a separation in cytokine profiles after IL1ra administration. A candidate cytokine from this analysis, macrophage-derived chemoattractant, was significantly lower in the rhIL1ra-treated group. Our results provide promising data for rhIL1ra as a therapeutic candidate by showing safety, brain penetration and a modification of the neuroinflammatory response to TBI by a putative neuroprotective agent in humans for the first time.

  9. Phase II Prospective Randomized Trial of a Low-Fat Diet with Fish Oil Supplementation in Men Undergoing Radical Prostatectomy

    PubMed Central

    Aronson, William J.; Kobayashi, Naoko; Barnard, R. James; Henning, Susanne; Jardack, Patricia M.; Liu, Bingrong; Gray, Ashley; Wan, Junxiang; Konijeti, Ramdev; Freedland, Stephen J.; Castor, Brandon; Heber, David; Elashoff, David; Said, Jonathan; Cohen, Pinchas; Galet, Colette

    2011-01-01

    Preclinical studies suggest lowering dietary fat and decreasing the ratio of omega-6 to omega-3 polyunsaturated fatty acids decreases the risk of prostate cancer development and progression. We conducted a phase II randomized trial to test the effect of decreasing dietary fat combined with decreasing the dietary omega-6:omega-3 ratio on biomarkers related to prostate cancer development and progression. Patients undergoing radical prostatectomy were randomly assigned to receive a low-fat diet with 5 grams of fish oil daily (dietary omega-6:omega-3 ratio of 2:1) or a control western diet (omega-6:omega-3 ratio of 15:1) for 4–6 weeks prior to surgery. The primary endpoint was change in serum IGF-1 between arms. Secondary endpoints were serum IGFBP-1, prostate prostaglandin E-2 levels, omega-6:omega-3 fatty acid ratios, COX-2 and markers of proliferation and apoptosis. Fifty-five patients were randomized and 48 completed the trial. There was no treatment difference in the primary outcome. Positive secondary outcomes in the low-fat fish oil vs. western group were reduced benign and malignant prostate tissue omega-6:omega-3 ratios, reduced proliferation (Ki67 index), and reduced proliferation in an ex-vivo bioassay when patient sera was applied to prostate cancer cells in vitro. In summary, 4–6 weeks of a low-fat diet and fish oil capsules to achieve an omega-6:omega-3 fatty acid ratio of 2:1 had no effect on serum IGF-1 levels, though in secondary analyses the intervention resulted in decreased prostate cancer proliferation and decreased prostate tissue omega-6:omega-3 ratios. These results support further studies evaluating reduction of dietary fat with fish oil supplementation on modulating prostate cancer biology. PMID:22027686

  10. 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

  11. Phase II double-blind placebo-controlled randomized study of armodafinil for brain radiation-induced fatigue

    PubMed Central

    Page, Brandi R.; Shaw, Edward G.; Lu, Lingyi; Bryant, David; Grisell, David; Lesser, Glenn J.; Monitto, Drew C.; Naughton, Michelle J.; Rapp, Stephen R.; Savona, Steven R.; Shah, Sunjay; Case, Doug; Chan, Michael D.

    2015-01-01

    Background Common acute-term side effects of brain radiotherapy (RT) include fatigue, drowsiness, decreased physical functioning, and decreased quality of life (QOL). We hypothesized that armodafinil (a wakefulness-promoting drug known to reduce fatigue and increase cognitive function in breast cancer patients receiving chemotherapy) would result in reduced fatigue and sleepiness for patients receiving brain RT. Methods A phase II, multi-institutional, placebo-controlled randomized trial assessed feasibility of armodafinil 150 mg/day in participants receiving brain RT, from whom we obtained estimates of variability for fatigue, sleepiness, QOL, cognitive function, and treatment effect. Results From September 20, 2010, to October 20, 2012, 54 participants enrolled with 80% retention and 94% self-reported compliance. There were no grade 4–5 toxicities, and the incidence of grade 2–3 toxicities was similar between treatment arms, the most common of which were anxiety and nausea (15%), headaches (19%), and insomnia (20%). There were no statistically significant differences in end-RT or 4 week post-RT outcomes between armodafinil and placebo in any outcomes (Functional Assessment of Chronic Illness Therapy [FACIT]-Fatigue, Brief Fatigue Inventory, Epworth Sleepiness Scale, FACT-Brain, and FACIT-cognitive function). However, in participants with more baseline fatigue, those treated with armodafinil did better than those who received the placebo on the end-RT assessments for several outcomes. Conclusion Armodafinil 150 mg/day was well tolerated in primary brain tumor patients undergoing RT with good compliance. While there was no overall significant effect on fatigue, those with greater baseline fatigue experienced improved QOL and reduced fatigue when using armodafinil. These data suggest that a prospective, phase III randomized trial is warranted for patients with greater baseline fatigue. PMID:25972454

  12. One-stage and two-stage designs for phase II clinical trials with survival endpoints.

    PubMed

    Whitehead, John

    2014-09-28

    This work is motivated by trials in rapidly lethal cancers or cancers for which measuring shrinkage of tumours is infeasible. In either case, traditional phase II designs focussing on tumour response are unsuitable. Usually, tumour response is considered as a substitute for the more relevant but longer-term endpoint of death. In rapidly lethal cancers such as pancreatic cancer, there is no need to use a surrogate, as the definitive endpoint is (sadly) available so soon. In uveal cancer, there is no counterpart to tumour response, and so, mortality is the only realistic response available. Cytostatic cancer treatments do not seek to kill tumours, but to mitigate their effects. Trials of such therapy might also be based on survival times to death or progression, rather than on tumour shrinkage. Phase II oncology trials are often conducted with all study patients receiving the experimental therapy, and this approach is considered here. Simple extensions of one-stage and two-stage designs based on binary responses are presented. Outcomes based on survival past a small number of landmark times are considered: here, the case of three such times is explored in examples. This approach allows exact calculations to be made for both design and analysis purposes. Simulations presented here show that calculations based on normal approximations can lead to loss of power when sample sizes are small. Two-stage versions of the procedure are also suggested.

  13. Operating characteristics of a Simon two-stage phase II clinical trial design incorporating continuous toxicity monitoring.

    PubMed

    Ray, H E; Rai, S N

    2012-01-01

    Phase II clinical trials are usually designed to measure efficacy, but safety is also an important end point. Previous authors recommended a method to monitor toxic events after each patient is enrolled, which is also known as continuously monitoring the toxicity. In this work, we investigate combining the usual Simon two-stage design to monitor response with the continuous toxicity monitoring methodology. Theoretical justification is given for the nominal size, probability of early termination, and average sample size under the null hypothesis of the combined testing procedure. A series of simulations are performed to investigate the performance of the combined procedure.

  14. 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

  15. 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.

  16. Randomized Phase II Trial of Gemcitabine Plus TH-302 Versus Gemcitabine in Patients With Advanced Pancreatic Cancer

    PubMed Central

    Borad, Mitesh J.; Reddy, Shantan G.; Bahary, Nathan; Uronis, Hope E.; Sigal, Darren; Cohn, Allen L.; Schelman, William R.; Stephenson, Joe; Chiorean, E. Gabriela; Rosen, Peter J.; Ulrich, Brian; Dragovich, Tomislav; Del Prete, Salvatore A.; Rarick, Mark; Eng, Clarence; Kroll, Stew; Ryan, David P.

    2015-01-01

    Purpose TH-302 is an investigational hypoxia-activated prodrug that releases the DNA alkylator bromo-isophosphoramide mustard in hypoxic settings. This phase II study (NCT01144455) evaluated gemcitabine plus TH-302 in patients with previously untreated, locally advanced or metastatic pancreatic cancer. Patients and Methods Patients were randomly assigned 1:1:1 to gemcitabine (1,000 mg/m2), gemcitabine plus TH-302 240 mg/m2 (G+T240), or gemcitabine plus TH-302 340 mg/m2 (G+T340). Randomized crossover after progression on gemcitabine was allowed. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), tumor response, CA 19-9 response, and safety. Results Two hundred fourteen patients (77% with metastatic disease) were enrolled between June 2010 and July 2011. PFS was significantly longer with gemcitabine plus TH-302 (pooled combination arms) compared with gemcitabine alone (median PFS, 5.6 v 3.6 months, respectively; hazard ratio, 0.61; 95% CI, 0.43 to 0.87; P = .005; median PFS for metastatic disease, 5.1 v 3.4 months, respectively). Median PFS times for G+T240 and G+T340 were 5.6 and 6.0 months, respectively. Tumor response was 12%, 17%, and 26% in the gemcitabine, G+T240, and G+T340 arms, respectively (G+T340 v gemcitabine, P = .04). CA 19-9 decrease was greater with G+T340 versus gemcitabine (−5,398 v −549 U/mL, respectively; P = .008). Median OS times for gemcitabine, G+T240, and G+T340 were 6.9, 8.7, and 9.2 months, respectively (P = not significant). The most common adverse events (AEs) were fatigue, nausea, and peripheral edema (frequencies similar across arms). Skin and mucosal toxicities (2% grade 3) and myelosuppression (55% grade 3 or 4) were the most common TH-302–related AEs but were not associated with treatment discontinuation. Conclusion PFS, tumor response, and CA 19-9 response were significantly improved with G+TH-302. G+T340 is being investigated further in the phase III MAESTRO study

  17. A randomized, phase II study of afatinib versus cetuximab in metastatic or recurrent squamous cell carcinoma of the head and neck†

    PubMed Central

    Seiwert, T. Y.; Fayette, J.; Cupissol, D.; del Campo, J. M.; Clement, P. M.; Hitt, R.; Degardin, M.; Zhang, W.; Blackman, A.; Ehrnrooth, E.; Cohen, E. E. W.

    2014-01-01

    Background Afatinib is an oral, irreversible ErbB family blocker that has shown activity in epidermal growth factor receptor (EGFR)-mutated lung cancer. We hypothesized that the agent would have greater antitumor activity compared with cetuximab in recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients, whose disease has progressed after platinum-containing therapy. Patients and methods An open-label, randomized, phase II trial was conducted in 43 centers; 124 patients were randomized (1 : 1) to either afatinib (50 mg/day) or cetuximab (250 mg/m2/week) until disease progression or intolerable adverse events (AEs) (stage I), with optional crossover (stage II). The primary end point was tumor shrinkage before crossover assessed by investigator (IR) and independent central review (ICR). Results A total of 121 patients were treated (61 afatinib, 60 cetuximab) and 68 crossed over to stage II (32 and 36 respectively). In stage I, mean tumor shrinkage by IR/ICR was 10.4%/16.6% with afatinib and 5.4%/10.1% with cetuximab (P = 0.46/0.30). Objective response rate was 16.1%/8.1% with afatinib and 6.5%/9.7% with cetuximab (IR/ICR). Comparable disease control rates were observed with afatinib (50%) and cetuximab (56.5%) by IR; similar results were seen by ICR. Most common grade ≥3 drug-related AEs (DRAEs) were rash/acne (18% versus 8.3%), diarrhea (14.8% versus 0%), and stomatitis/mucositis (11.5% versus 0%) with afatinib and cetuximab, respectively. Patients with DRAEs leading to treatment discontinuation were 23% with afatinib and 5% with cetuximab. In stage II, disease control rate (IR/ICR) was 38.9%/33.3% with afatinib and 18.8%/18.8% with cetuximab. Conclusion Afatinib showed antitumor activity comparable to cetuximab in R/M HNSCC in this exploratory phase II trial, although more patients on afatinib discontinued treatment due to AEs. Sequential EGFR/ErbB treatment with afatinib and cetuximab provided sustained clinical benefit in patients

  18. Randomized Phase II Trial of Adjuvant WT-1 Analog Peptide Vaccine in Patients with Malignant Pleural Mesothelioma after Completion of Multimodality Therapy

    DTIC Science & Technology

    2015-09-01

    1 Award Number: W81XWH-10-1-0699 TITLE: Randomized Phase II Trial of Adjuvant WT-1 Analog Peptide Vaccine in Patients with Malignant Pleural...WT-1 Analog Peptide Vaccine in Patients with Malignant Pleural Mesothelioma after Completion of Multimodality Therapy 5a. CONTRACT NUMBER 5b...malignant pleural mesothelioma (MPM), and is a rational target for immunotherapy. We have developed a vaccine comprised of four WT1 heteroclitic

  19. Randomized Phase II Trial of Adjuvant WT-1 Analog Peptide Vaccine in Patients with Malignant Pleural Mesothelioma after Completion of Multimodality Therapy

    DTIC Science & Technology

    2013-09-01

    Analog Peptides Derived from WT1 Oncoprotein Induces T Cell Responses in Patients with Complete Remission from Acute Myeloid Leukemia (AML), Blood 2010...10-1-0699 TITLE: Randomized Phase II Trial of Adjuvant WT-1 Analog Peptide Vaccine in Patients with Malignant Pleural Mesothelioma after...vaccine comprised of four WT1 heteroclitic peptides that are given together with Montanide and GM- CSF as immunologic adjuvants. This WT1 vaccine was

  20. Phase II, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Investigate the Immunogenicity and Safety of a West Nile Virus Vaccine in Healthy Adults

    PubMed Central

    Biedenbender, Rex; Bevilacqua, Joan; Gregg, Anne M.; Watson, Mike

    2011-01-01

    Background. ChimeriVax-WN02 is a live, attenuated chimeric vaccine for protection against West Nile virus. This Phase II, randomized, double-blind, placebo–controlled, multicenter study assessed the immunogenicity, viremia, and safety of the ChimeriVax-WN02 vaccine. Methods. The 2-part study included adults in general good health. In part 1, subjects aged 18–40 years were randomized to 1 of 4 treatment groups: ChimeriVax–WN02 3.7- × -105 plaque-forming units (PFU), 3.7 × 104 PFU, 3.7 × 103 PFU, or placebo. In part 2, subjects aged 41–64 and ≥65 years were randomized to receive ChimeriVax-WN02 3.7 × 105 PFU or placebo. Results. In both part 1 and part 2, seroconversion was achieved at day 28 by >96% of subjects in active treatment groups. In part 1, neutralizing antibody titers at day 28 were higher and viremia levels lower with the highest dose, whereas the adverse event profile was similar between the dose groups. In part 2, antibody titers and viremia levels were higher in subjects aged ≥65 years, and more subjects in the 41–64 years cohort experienced adverse events. Conclusions. The ChimeriVax-WN02 vaccine was highly immunogenic in younger adults and the elderly, and it was well tolerated at all dose levels and in all age groups investigated. Clinical Trials.gov identifier: NCT00442169. PMID:21148499

  1. Rationale and design of a Phase II clinical trial of aspirin and simvastatin for the treatment of pulmonary arterial hypertension: ASA-STAT

    PubMed Central

    Kawut, Steven M.; Bagiella, Emilia; Shimbo, Daichi; Lederer, David J.; Al-Naamani, Nadine; Roberts, Kari E.; Barr, R. Graham; Post, Wendy; Horn, Evelyn; Tracy, Russell; Hassoun, Paul; Girgis, Reda

    2011-01-01

    Background Pulmonary arterial hypertension (PAH) is a progressive disease which causes exercise limitation, heart failure, and death. Aspirin and simvastatin are highly effective and safe therapies for other cardiovascular diseases characterized by platelet activation and endothelial dysfunction, but have not been formally studied in PAH. Methods ASA-STAT is a Phase II, randomized, double-blind, placebo-controlled 2 × 2 factorial clinical trial of aspirin and simvastatin in patients with PAH. A total of 92 subjects were to be randomized to aspirin or aspirin placebo and simvastatin or simvastatin placebo. The primary outcome is the distance walked in six minutes at six months after randomization. Secondary measures include brachial artery flow-mediated dilation, circulating biomarkers of platelet and endothelial function, functional class, quality-of-life, and time to clinical end points. The incidence of adverse events will be compared between treatment groups. Screening and Enrollment We screened a total of 712 individuals with PAH. Sixty-five subjects were enrolled when the trial was terminated for futility in reaching the primary end point for simvastatin. Conclusions This study aims to determine whether aspirin or simvastatin have beneficial biologic or clinical effects in patients with PAH. The safety and side effects of these commonly prescribed cardiovascular drugs will also be assessed. PMID:21146637

  2. 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.

  3. 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. PMID:27602225

  4. Phase II clinical trial of peptide cocktail therapy for patients with advanced pancreatic cancer: VENUS-PC study.

    PubMed

    Suzuki, Nobuaki; Hazama, Shoichi; Iguchi, Haruo; Uesugi, Kazuhiro; Tanaka, Hiroaki; Hirakawa, Kosei; Aruga, Atsushi; Hatori, Takashi; Ishizaki, Hidenobu; Umeda, Yuzo; Fujiwara, Toshiyoshi; Ikemoto, Tetsuya; Shimada, Mitsuo; Yoshimatsu, Kazuhiko; Shimizu, Ryoichi; Hayashi, Hiroto; Sakata, Koichiro; Takenouchi, Hiroko; Matsui, Hiroto; Shindo, Yoshitaro; Iida, Michihisa; Koki, Yasunobu; Arima, Hideki; Furukawa, Hiroyuki; Ueno, Tomio; Yoshino, Shigefumi; Nakamura, Yusuke; Oka, Masaaki; Nagano, Hiroaki

    2017-01-01

    We previously conducted a phase I clinical trial combining the HLA-A*2402-restricted KIF20A-derived peptide vaccine with gemcitabine for advanced pancreatic cancer (PC) and confirmed its safety and immunogenicity in cancer patients. In this study, we conducted a multicenter, single-armed, phase II trial using two antiangiogenic cancer vaccines targeting VEGFR1 and VEGFR2 in addition to the KIF20A peptide. We attempted to evaluate the clinical benefit of the cancer vaccination in combination with gemcitabine. Chemotherapy naïve PC patients were enrolled to evaluate primarily the 1-year survival rate, and secondarily overall survival (OS), progression free survival (PFS), response rate (RR), disease control rate (DCR) and the peptide-specific immune responses. All enrolled patients received therapy without the HLA-A information, and the HLA genotypes were used for classification of the patients. Between June 2012 and May 2013, a total of 68 patients were enrolled. No severe systemic adverse effects of Grade 3 or higher related to these three peptides were observed. The 1-year survival rates between the HLA-A*2402-matched and -unmatched groups were not significantly different. In the HLA-A*2402 matched group, patients showing peptide-specific CTL induction for KIF20A or VEGFR1 showed a better prognosis compared to those without such induction (P = 0.023, P = 0.009, respectively). In the HLA-A*2402-matched group, the patients who showed a strong injection site reaction had a better survival rate (P = 0.017) compared to those with a weak or no injection site reaction. This phase II study demonstrated that this therapeutic peptide cocktail might be effective in patients who demonstrate peptide-specific immune reactions although predictive biomarkers are needed for patient selection in its further clinical application.

  5. Phase II cancer clinical trials with a one-sample log-rank test and its corrections based on the Edgeworth expansion.

    PubMed

    Sun, Xiaoqun; Peng, Paul; Tu, Dongsheng

    2011-01-01

    The response rate has been frequently used as the primary endpoint of phase II cancer clinical trials. It may not be an appropriate endpoint when a new treatment is not expected to produce any tumour shrinkage. When a large database for a historical control is available, the direct comparison of survival curves between a new treatment and the historical control may be made in phase II cancer clinical trials. In this paper, a one-sample log-rank test is introduced for the design and analysis of phase II cancer clinical trials with time-to-event endpoints. Corrections to the one-sample log-rank test are also derived based on the Edgeworth expansion. Simulations showed that the original one-sample log-rank test may be preferred if strictly controlling for type I error is important or when the sample size of a phase II trial is as large as 50, and a corrected one-sample log-rank test is used if the sample size of a phase II trial is small. A data set from a clinical trial conducted by the NCIC Clinical Trials Group is used to illustrate the proposed procedures.

  6. Intense Androgen-Deprivation Therapy With Abiraterone Acetate Plus Leuprolide Acetate in Patients With Localized High-Risk Prostate Cancer: Results of a Randomized Phase II Neoadjuvant Study

    PubMed Central

    Taplin, Mary-Ellen; Montgomery, Bruce; Logothetis, Christopher J.; Bubley, Glenn J.; Richie, Jerome P.; Dalkin, Bruce L.; Sanda, Martin G.; Davis, John W.; Loda, Massimo; True, Lawrence D.; Troncoso, Patricia; Ye, Huihui; Lis, Rosina T.; Marck, Brett T.; Matsumoto, Alvin M.; Balk, Steven P.; Mostaghel, Elahe A.; Penning, Trevor M.; Nelson, Peter S.; Xie, Wanling; Jiang, Zhenyang; Haqq, Christopher M.; Tamae, Daniel; Tran, NamPhuong; Peng, Weimin; Kheoh, Thian; Molina, Arturo; Kantoff, Philip W.

    2014-01-01

    Purpose Cure rates for localized high-risk prostate cancers (PCa) and some intermediate-risk PCa are frequently suboptimal with local therapy. Outcomes are improved by concomitant androgen-deprivation therapy (ADT) with radiation therapy, but not by concomitant ADT with surgery. Luteinizing hormone–releasing hormone agonist (LHRHa; leuprolide acetate) does not reduce serum androgens as effectively as abiraterone acetate (AA), a prodrug of abiraterone, a CYP17 inhibitor that lowers serum testosterone (< 1 ng/dL) and improves survival in metastatic PCa. The possibility that greater androgen suppression in patients with localized high-risk PCa will result in improved clinical outcomes makes paramount the reassessment of neoadjuvant ADT with more robust androgen suppression. Patients and Methods A neoadjuvant randomized phase II trial of LHRHa with AA was conducted in patients with localized high-risk PCa (N = 58). For the first 12 weeks, patients were randomly assigned to LHRHa versus LHRHa plus AA. After a research prostate biopsy, all patients received 12 additional weeks of LHRHa plus AA followed by prostatectomy. Results The levels of intraprostatic androgens from 12-week prostate biopsies, including the primary end point (dihydrotestosterone/testosterone), were significantly lower (dehydroepiandrosterone, Δ4-androstene-3,17-dione, dihydrotestosterone, all P < .001; testosterone, P < .05) with LHRHa plus AA compared with LHRHa alone. Prostatectomy pathologic staging demonstrated a low incidence of complete responses and minimal residual disease, with residual T3- or lymph node–positive disease in the majority. Conclusion LHRHa plus AA treatment suppresses tissue androgens more effectively than LHRHa alone. Intensive intratumoral androgen suppression with LHRHa plus AA before prostatectomy for localized high-risk PCa may reduce tumor burden. PMID:25311217

  7. Repurposing Itraconazole as a Treatment for Advanced Prostate Cancer: A Noncomparative Randomized Phase II Trial in Men With Metastatic Castration-Resistant Prostate Cancer

    PubMed Central

    Heath, Elisabeth I.; Smith, David C.; Rathkopf, Dana; Blackford, Amanda L.; Danila, Daniel C.; King, Serina; Frost, Anja; Ajiboye, A. Seun; Zhao, Ming; Mendonca, Janet; Kachhap, Sushant K.; Rudek, Michelle A.; Carducci, Michael A.

    2013-01-01

    Background. The antifungal drug itraconazole inhibits angiogenesis and Hedgehog signaling and delays tumor growth in murine prostate cancer xenograft models. We conducted a noncomparative, randomized, phase II study evaluating the antitumor efficacy of two doses of oral itraconazole in men with metastatic prostate cancer. Patients and Methods. We randomly assigned 46 men with chemotherapy-naïve metastatic castration-resistant prostate cancer (CRPC) to receive low-dose (200 mg/day) or high-dose (600 mg/day) itraconazole until disease progression or unacceptable toxicity. The primary endpoint was the prostate-specific antigen (PSA) progression-free survival (PPFS) rate at 24 weeks; a 45% success rate in either arm was prespecified as constituting clinical significance. Secondary endpoints included the progression-free survival (PFS) rate and PSA response rate (Prostate Cancer Working Group criteria). Exploratory outcomes included circulating tumor cell (CTC) enumeration, serum androgen measurements, as well as pharmacokinetic and pharmacodynamic analyses. Results. The high-dose arm enrolled to completion (n = 29), but the low-dose arm closed early (n = 17) because of a prespecified futility rule. The PPFS rates at 24 weeks were 11.8% in the low-dose arm and 48.0% in the high-dose arm. The median PFS times were 11.9 weeks and 35.9 weeks, respectively. PSA response rates were 0% and 14.3%, respectively. In addition, itraconazole had favorable effects on CTC counts, and it suppressed Hedgehog signaling in skin biopsy samples. Itraconazole did not reduce serum testosterone or dehydroepiandrostenedione sulfate levels. Common toxicities included fatigue, nausea, anorexia, rash, and a syndrome of hypokalemia, hypertension, and edema. Conclusion. High-dose itraconazole (600 mg/day) has modest antitumor activity in men with metastatic CRPC that is not mediated by testosterone suppression. PMID:23340005

  8. A randomized multi-center phase II trial of the angiogenesis inhibitor Cilengitide (EMD 121974) and gemcitabine compared with gemcitabine alone in advanced unresectable pancreatic cancer

    PubMed Central

    Friess, Helmut; Langrehr, Jan M; Oettle, Helmut; Raedle, Jochen; Niedergethmann, Marco; Dittrich, Christian; Hossfeld, Dieter K; Stöger, Herbert; Neyns, Bart; Herzog, Peter; Piedbois, Pascal; Dobrowolski, Frank; Scheithauer, Werner; Hawkins, Robert; Katz, Frieder; Balcke, Peter; Vermorken, Jan; van Belle, Simon; Davidson, Neville; Esteve, Albert Abad; Castellano, Daniel; Kleeff, Jörg; Tempia-Caliera, Adrien A; Kovar, Andreas; Nippgen, Johannes

    2006-01-01

    Background Anti-angiogenic treatment is believed to have at least cystostatic effects in highly vascularized tumours like pancreatic cancer. In this study, the treatment effects of the angiogenesis inhibitor Cilengitide and gemcitabine were compared with gemcitabine alone in patients with advanced unresectable pancreatic cancer. Methods A multi-national, open-label, controlled, randomized, parallel-group, phase II pilot study was conducted in 20 centers in 7 countries. Cilengitide was administered at 600 mg/m2 twice weekly for 4 weeks per cycle and gemcitabine at 1000 mg/m2 for 3 weeks followed by a week of rest per cycle. The planned treatment period was 6 four-week cycles. The primary endpoint of the study was overall survival and the secondary endpoints were progression-free survival (PFS), response rate, quality of life (QoL), effects on biological markers of disease (CA 19.9) and angiogenesis (vascular endothelial growth factor and basic fibroblast growth factor), and safety. An ancillary study investigated the pharmacokinetics of both drugs in a subset of patients. Results Eighty-nine patients were randomized. The median overall survival was 6.7 months for Cilengitide and gemcitabine and 7.7 months for gemcitabine alone. The median PFS times were 3.6 months and 3.8 months, respectively. The overall response rates were 17% and 14%, and the tumor growth control rates were 54% and 56%, respectively. Changes in the levels of CA 19.9 went in line with the clinical course of the disease, but no apparent relationships were seen with the biological markers of angiogenesis. QoL and safety evaluations were comparable between treatment groups. Pharmacokinetic studies showed no influence of gemcitabine on the pharmacokinetic parameters of Cilengitide and vice versa. Conclusion There were no clinically important differences observed regarding efficacy, safety and QoL between the groups. The observations lay in the range of other clinical studies in this setting. The

  9. 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

  10. Gefitinib or Placebo in Combination with Tamoxifen in Patients with Hormone Receptor-Positive Metastatic Breast Cancer: a Randomized Phase II Study

    PubMed Central

    Osborne, C. Kent; Neven, Patrick; Dirix, Luc Y.; Mackey, John R.; Robert, Jean; Underhill, Craig; Schiff, Rachel; Gutierrez, Carolina; Migliaccio, Ilenia; Anagnostou, Valsamo K.; Rimm, David L.; Magill, Patrick; Sellers, Mark

    2011-01-01

    Purpose Increased growth factor signaling may contribute to tamoxifen resistance. This randomized Phase II trial assessed tamoxifen plus placebo or the EGFR inhibitor gefitinib in ER-positive metastatic breast cancer. Experimental Design Patients with newly metastatic disease or recurring after adjuvant tamoxifen (Stratum 1, St1), or recurred during/after adjuvant aromatase inhibitor (AI) or after failed first-line AI (Stratum 2, St2) were eligible. Primary variables were progression-free survival (PFS) (St1) and clinical benefit rate (CBR) (St2). A ≥ 5% improvement in response variables with gefitinib was considered to warrant further investigation. Outcome was correlated with biomarkers measured on the primary tumor. Results In St1 (n=206), the PFS hazard ratios (HR, gefitinib:placebo) were 0.84 (95% CI, 0.59 to 1.18; median PFS 10.9 v 8.8 months). In the St1 endocrine therapy naïve subset (n=158) the HR was 0.78 (95% CI, 0.52 to 1.15), and the prior endocrine-treated subgroup (n=48) 1.47 (95% CI, 0.63 to 3.45). In St1, CBRs were 50.5% with gefitinib and 45.5% with placebo. In St2 (n=84), CBRs were 29.2% with gefitinib and 31.4% with placebo. Biomarker analysis suggested that in St1 there was greater benefit with gefitinib in patients who were ER negative or had lower levels of ER protein. Conclusions In St1, the improved PFS with gefitinib plus tamoxifen met the protocol criteria sufficient to warrant further investigation of this strategy. In St2, there was a numerical disadvantage for gefitinib; additional investigation after AI therapy is not warranted. Studies of predictive biomarkers are needed to subset appropriate patients. PMID:21220480

  11. Phase II, randomized, multicenter, double-blind, placebo-controlled trial of a polyclonal anti-Staphylococcus aureus capsular polysaccharide immune globulin in treatment of Staphylococcus aureus bacteremia.

    PubMed

    Rupp, Mark E; Holley, H Preston; Lutz, Jon; Dicpinigaitis, Peter V; Woods, Christopher W; Levine, Donald P; Veney, Naomi; Fowler, Vance G

    2007-12-01

    New treatment modalities are needed for the treatment of infections due to multidrug-resistant Staphylococcus aureus. S. aureus capsular polysaccharide immune globulin (Altastaph) is a polyclonal immune globulin preparation that is being developed as adjunctive therapy for persons with S. aureus infections complicated by bacteremia. In a phase II, multicenter, randomized, double-blind, placebo-controlled trial, 40 subjects with documented S. aureus bacteremia received standard therapy plus either Altastaph at 200 mg/kg of body weight in each of two infusions 24 h apart or placebo. During the 42-day observation period, antibody pharmacokinetics and safety were the primary characteristics studied. Information regarding the resolution of bacteremia and fever was also analyzed. Anti-type-5 and anti-type-8 capsular antibody levels peaked after the second infusion at 550 mug/ml and 419 mug/ml, respectively, and remained above 100 mug/ml at day 28. A total of 316 adverse events were noted in 39 of 40 subjects. Infusion-related adverse events in Altastaph recipients were infrequent and similar to those among recipients of commercial intravenously administered immunoglobulin G products. Five of 21 (23%) subjects in the Altastaph group died, whereas 2 of 18 (11%) subjects in the placebo group died (P = 0.42). Compared to the control patients, the Altastaph recipients had a shorter median time to the resolution of fever (2 days and 7 days, respectively; P = 0.09) and a shorter length of hospital stay (9 days and 14 days, respectively; P = 0.03). However, these findings are exploratory, and there were few differences in the other variables measured. High levels of opsonizing antibodies were maintained for the initial 4 weeks. Although the study was not powered to show efficacy, these preliminary findings and safety profile suggest that Altastaph may be an effective adjunct to antibiotics and warrants further investigation (ClinicalTrials.gov number NCT00063089).

  12. Phase II, multicenter, open-label, randomized study of YM155 plus docetaxel as first-line treatment in patients with HER2-negative metastatic breast cancer.

    PubMed

    Clemens, Michael R; Gladkov, Oleg A; Gartner, Elaina; Vladimirov, Vladimir; Crown, John; Steinberg, Joyce; Jie, Fei; Keating, Anne

    2015-01-01

    The objective of this study was to assess the efficacy and tolerability of YM155, a survivin suppressor, in combination with docetaxel, compared with docetaxel alone in patients with HER2-negative metastatic breast cancer. This phase II, multicenter, open-label, 2-arm study randomized patients (≥18 years) with histologically or cytologically confirmed stage IV HER2-negative metastatic breast cancer and ≥1 measurable lesion, to receive docetaxel alone or docetaxel plus YM155. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), overall survival (OS), duration of response (DOR), clinical benefit rate (CBR), time to response (TTR), biomarker assessment, and analysis of circulating tumor cells. Patients were women diagnosed with HER2-negative breast cancer; most had received prior drug therapies. The median PFS was 8.4 months with YM155 plus docetaxel (n = 50) and 10.5 months with docetaxel alone (n = 51; HR 1.53; 95 % CI 0.83, 2.83; P = 0.176). No statistically significant differences were observed for secondary endpoints, although slightly greater OS (630 vs 601 days; P = 0.768), CBR (84.3 vs 82.0 %; P = 0.855), DOR, and TTR were observed with docetaxel alone compared with YM155 plus docetaxel, whereas ORR was similar (25.5 vs 26.0). The most common TEAEs observed with YM155 plus docetaxel compared with docetaxel alone were neutropenia (83.3 vs 84.3 %), alopecia (62.5 vs 52.9 %), fatigue (50 vs 41.2 %), and nausea (37.5 vs 41.2 %). Although YM155 is a novel drug that suppresses survivin, YM155 plus docetaxel exhibited no statistically significant differences in endpoints compared with docetaxel alone. The combination regimen was well tolerated.

  13. 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

  14. 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.

  15. Primary analysis of a prospective, randomized, single-blinded phase II trial evaluating the HER2 peptide GP2 vaccine in breast cancer patients to prevent recurrence

    PubMed Central

    Ardavanis, Alexandros; Litton, Jennifer K.; Shumway, Nathan M.; Hale, Diane F.; Murray, James L.; Perez, Sonia A.; Ponniah, Sathibalan; Baxevanis, Constantin N.; Papamichail, Michael

    2016-01-01

    GP2 is a HER2-derived, HLA-A2+ restricted peptide. Phase I studies showed GP2 administered with GM-CSF to be safe and immunogenic. Here we report the primary analysis of a prospective, randomized, multicenter phase II adjuvant trial conducted to determine the vaccine's efficacy. The trial enrolled HLA-A2+, clinically disease-free, node-positive and high-risk node-negative breast cancer patients with tumors expressing HER2 (immunohistochemistry[IHC] 1+-3+). Patients were randomized to GP2+GM-CSF versus GM-CSF alone. Disease-free survival (DFS) was analyzed in intention-to-treat (ITT) and per-treatment cohorts; pre-specified subgroup analyses were performed for patients with IHC 3+ or FISH+ disease. The trial enrolled 180 patients; 89 received GP2+GM-CSF and 91 received GM-CSF alone. The groups were well-matched for clinicopathologic characteristics. Toxicities have been minimal. The Kaplan-Meier estimated 5-year DFS rate in the ITT analyses was 88% (95% CI:78-94%) in vaccinated vs. 81% (95% CI:69-89%) (P = 0.43) in control patients after a 34 month median follow-up. In the per-treatment analysis, the estimated 5-year DFS rates were 94% (95% CI:83-98%) and 85% (73-92%) (P = 0.17). In IHC 3+/FISH+ patients, the estimated 5-year DFS rate was 94% (82-98%) in vaccinated patients (n = 51) vs. 89% (71-96%) in control patients (n = 50), (P = 0.86) in the ITT analyses and 100% vs. 89% (71-96%) in vaccinated vs. control patients in the per-treatment analyses (P = 0.08). While the overall ITT analysis did not demonstrate benefit to vaccination, this trial confirmed that the GP2 vaccine is safe and suggests that vaccination may have clinical activity, particularly in patients with HER2 overexpression who received the full vaccine series (ie per-treatment group). PMID:27589688

  16. 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

  17. Bayesian decision sequential analysis with survival endpoint in phase II clinical trials.

    PubMed

    Zhao, Lili; Woodworth, George

    2009-04-30

    Chen and Chaloner (Statist. Med. 2006; 25:2956-2966. DOI: 10.1002/sim.2429) present a Bayesian stopping rule for a single-arm clinical trial with a binary endpoint. In some cases, earlier stopping may be possible by basing the stopping rule on the time to a binary event. We investigate the feasibility of computing exact, Bayesian, decision-theoretic time-to-event stopping rules for a single-arm group sequential non-inferiority trial relative to an objective performance criterion. For a conjugate prior distribution, exponential failure time distribution, and linear and threshold loss structures, we obtain the optimal Bayes stopping rule by backward induction. We compute frequentist operating characteristics of including Type I error, statistical power, and expected run length. We also briefly address design issues.

  18. The Public Repository of Xenografts (ProXe) enables discovery and randomized phase II-like trials in mice

    PubMed Central

    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.

    2016-01-01

    Summary Over 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, publically available repository of well-characterized leukemia and lymphoma PDXs that undergo orthotopic engraftment called the Public Repository of Xenografts (PRoXe; www.proxe.org). 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-naïve and relapsed/refractory disease. PMID:27070704

  19. 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.

  20. Randomized Phase II Study of 5-Fluorouracil Hepatic Arterial Infusion with or without Antineoplastons as an Adjuvant Therapy after Hepatectomy for Liver Metastases from Colorectal Cancer

    PubMed Central

    Ogata, Yutaka; Matono, Keiko; Tsuda, Hideaki; Ushijima, Masataka; Uchida, Shinji; Akagi, Yoshito; Shirouzu, Kazuo

    2015-01-01

    Background Antineoplastons are naturally occurring peptides and amino acid derivatives found in human blood and urine. Antineoplaston A10 and AS2-1 reportedly control neoplastic growth and do not significantly inhibit normal cell growth. Antineoplastons contain 3-phenylacetylamino-2, 6-piperidinedione (A10), phenylacetylglutamine plus phenylacetylisoglutamine (A10-I), and phenylacetylglutamine plus phenylacetate (AS2-1). This open label, non- blinded randomized phase II study compared the efficacy of hepatic arterial infusion (HAI) with 5-fluorouracil,with or without antineoplastons as a postoperative therapy for colorectal metastasis to the liver. Methods Sixty-five patients with histologically confirmed metastatic colon adenocarcinoma in liver, who had undergone hepatectomy, and/or thermal ablation for liver metastases were enrolled between 1998- 2004 in Kurume University Hospital. Patients were randomly assigned to receive systemic antineoplastons (A10-I infusion followed by per-oral AS2-1) plus HAI (AN arm) or HAI alone (control arm) based on the number of metastases and presence/ absence of extra-hepatic metastasis at the time of surgery. Primary endpoint was cancer-specific survival (CSS); secondary endpoints were relapse-free survival (RFS), status and extent of recurrence, salvage surgery (rate) and toxicity. Findings Overall survival was not statistically improved (p=0.105) in the AN arm (n=32). RFS was not significant (p=0.343). Nevertheless, the CSS rate was significantly higher in the AN arm versus the control arm (n=33) with a median survival time 67 months (95%CI 43-not calculated) versus 39 months (95%CI 28-47) (p=0.037) and 5 year CSS rate 60% versus 32% respectively. Cancer recurred more often in a single organ than in multiple organs in the AN arm versus the control arm. The limited extent of recurrent tumours in the AN arm meant more patients remained eligible for salvage surgery. Major adverse effects of antineoplastons were fullness of the

  1. Sequencing of Sipuleucel-T and Androgen Deprivation Therapy in Men with Hormone-Sensitive Biochemically Recurrent Prostate Cancer: A Phase II Randomized Trial.

    PubMed

    Antonarakis, Emmanuel S; Kibel, Adam S; Yu, Evan Y; Karsh, Lawrence I; Elfiky, Aymen; Shore, Neal D; Vogelzang, Nicholas J; Corman, John M; Millard, Frederick E; Maher, Johnathan C; Chang, Nancy N; DeVries, Todd; Sheikh, Nadeem A; Drake, Charles G

    2016-11-10

    Purpose: STAND, a randomized, phase II, open-label trial (NCT01431391), assessed sequencing of sipuleucel-T (an autologous cellular immunotherapy) with androgen deprivation therapy (ADT) in biochemically recurrent prostate cancer (BRPC) patients at high risk for metastasis.Experimental Design: Men with BRPC following prostatectomy and/or radiotherapy, a PSA doubling time ≤12 months, and no metastasis were enrolled. Patients were randomized (34/arm) to sipuleucel-T followed by ADT (started 2 weeks after sipuleucel-T completion), or ADT followed by sipuleucel-T (started 12 weeks after ADT initiation); ADT continued for 12 months in both arms. The primary endpoint was PA2024-specific T-cell response [enzyme-linked immunospot (ELISPOT)] over time.Results: PA2024-specific ELISPOT responses over time were similar between groups, except at week 6, where responses were higher with sipuleucel-T→ADT versus ADT→sipuleucel-T (P = 0.013). PA2024-specific T-cell proliferation responses, averaged across time points, were approximately 2-fold higher with sipuleucel-T→ADT versus ADT→sipuleucel-T (P = 0.001). PA2024-specific cellular and humoral responses and prostatic acid phosphatase-specific humoral responses increased significantly versus baseline (P < 0.001) and were maintained for 24 months (both arms). Median time-to-PSA recurrence was similar between arms (21.8 vs. 22.6 months, P = 0.357). Development of a PA2024-specific humoral response correlated with prolonged time-to-PSA progression (HR, 0.22; 95% CI, 0.08-0.67; P = 0.007). Sipuleucel-T with ADT was generally well tolerated.Conclusions: Sipuleucel-T→ADT appears to induce greater antitumor immune responses than the reverse sequence. These results warrant further investigation to determine whether this sequence leads to improved clinical outcomes, as well as the independent contribution of ADT alone in terms of immune activation. Clin Cancer Res; 1-9. ©2016 AACR.

  2. 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.

  3. 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

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

    PubMed

    Kwak, Minjung; Jung, Sin-Ho

    2014-05-30

    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.

  5. 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

  6. Immunogenicity and safety of Fluzone(®) intradermal and high-dose influenza vaccines in older adults ≥65 years of age: a randomized, controlled, phase II trial.

    PubMed

    Tsang, Peter; Gorse, Geoffrey J; Strout, Cynthia B; Sperling, Malcolm; Greenberg, David P; Ozol-Godfrey, Ayca; DiazGranados, Carlos; Landolfi, Victoria

    2014-05-01

    We conducted a randomized, controlled, multicenter, phase II study to evaluate the immunogenicity and safety of an investigational intradermal (ID) trivalent influenza vaccine (TIV) and a high-dose (HD) intramuscular (IM) TIV in older adults (≥65 years of age). Older adult subjects were immunized with ID vaccine containing either 15μg hemagglutinin (HA)/strain (n=636) or 21μg HA/strain (n=634), with HD IM vaccine containing 60μg HA/strain (n=320), or with standard-dose (SD) IM vaccine (Fluzone(®); 15μg HA/strain; n=319). For comparison, younger adults (18-49 years of age) were immunized with SD IM vaccine. In older adults, post-vaccination geometric mean titers induced by the ID vaccines were superior to those induced by the SD IM vaccine for the A/H1N1 and A/H3N2 strains and non-inferior for the B strain. Seroconversion rates induced by the ID vaccines were superior to those induced by the SD IM vaccine in older adults for the A/H1N1 and B strains and non-inferior for the A/H3N2 strain. Results did not differ significantly for the two ID vaccine dosages. Post-vaccination geometric mean titers, seroconversion rates, and most seroprotection rates were significantly higher in HD vaccine recipients than in older adult recipients of the SD IM or ID vaccines and, for most measures, were comparable to those of younger adult SD IM vaccine recipients. Injection-site reactions, but not systemic reactions or unsolicited adverse events, were more common with the ID vaccines than with the IM vaccines. No treatment-related serious adverse events were reported. This study demonstrated that: (1) the ID and HD vaccines were well-tolerated and more immunogenic than the SD IM vaccine in older adults; (2) the HD vaccine was more immunogenic than the ID vaccines in older adults; and (3) the HD vaccine in older adults and the SD IM vaccine in younger adults elicited comparable antibody responses (ClinicalTrials.gov identifier no.: NCT00551031).

  7. 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

  8. Multi-Institutional Phase II Clinical Study of Concurrent Chemoradiotherapy for Locally Advanced Cervical Cancer in East and Southeast Asia

    SciTech Connect

    Kato, Shingo; Ohno, Tatsuya; Thephamongkhol, Kullathorn; Chansilpa, Yaowalak

    2010-07-01

    Purpose: To evaluate the toxicity and efficacy of concurrent chemoradiotherapy using weekly cisplatin for patients with locally advanced cervical cancer in East and Southeast Asia, a multi-institutional Phase II clinical study was conducted among eight Asian countries. Methods and Materials: Between April 2003 and March 2006, 120 patients (60 with bulky Stage IIB and 60 with Stage IIIB) with previously untreated squamous cell carcinoma of the cervix were enrolled in the present study. Radiotherapy consisted of pelvic external beam radiotherapy (total dose, 50 Gy) and either high-dose-rate or low-dose-rate intracavitary brachytherapy according to institutional practice. The planned Point A dose was 24-28 Gy in four fractions for high-dose-rate-intracavitary brachytherapy and 40-45 Gy in one to two fractions for low-dose-rate-intracavitary brachytherapy. Five cycles of weekly cisplatin (40 mg/m{sup 2}) were administered during the radiotherapy course. Results: All patients were eligible for the study. The median follow-up was 27.3 months. Of the 120 patients, 100 (83%) received four or five cycles of chemotherapy. Acute Grade 3 leukopenia was observed in 21% of the patients, and Grade 3 gastrointestinal toxicity was observed in 6%. No patient failed to complete the radiotherapy course because of toxicity. The 2-year local control and overall survival rate for all patients was 87.1% and 79.6%, respectively. The 2-year major late rectal and bladder complication rate was 2.5% and 0%, respectively. Conclusion: The results have suggested that concurrent chemoradiotherapy using weekly cisplatin is feasible and effective for patients with locally advanced cervical cancer in East and Southeast Asia.

  9. 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.

  10. 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

  11. Randomized phase II trial of selenomethionine as a modulator of efficacy and toxicity of chemoradiation in squamous cell carcinoma of the head and neck

    PubMed Central

    Mix, Michael; Singh, Anurag K; Tills, Michael; Dibaj, Shiva; Groman, Adrienne; Jaggernauth, Wainwright; Rustum, Youcef; Jameson, Michael B

    2015-01-01

    AIM: To investigate whether selenomethionine (SLM) reduces mucositis incidence in patients with head and neck squamous cell cancer (HNSCC) undergoing concurrent chemoradiation (CRT). METHODS: In this multi-institutional, randomized, double-blind phase II trial, patients with Stage III or IV HNSCC received SLM 3600 μg/m2 or placebo twice daily for 7 d prior to CRT, once daily during CRT, and daily for 3 wk following CRT. CRT consisted of 70 Gy at 2 Gy per fraction with cisplatin 100 mg/m2 IV on days 1, 22, and 43. RESULTS: Eighteen patients were randomized, 10 received SLM, and there were no differences in baseline factors. There was no difference in mucositis or patient-reported side effects between groups. There was no difference in overall or relapse-free survival at 12 mo. CONCLUSION: Addition of SLM to CRT for HNSCC was well-tolerated but did not lower the incidence of severe mucositis or improve quality of life or survival outcomes. PMID:26468453

  12. 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

  13. A phase II clinical trial of a dental health education program delivered by aboriginal health workers to prevent early childhood caries

    PubMed Central

    2012-01-01

    Background Early Childhood Caries (ECC) is a widespread problem in Australian Aboriginal communities causing severe pain and sepsis. In addition dental services are difficult to access for many Aboriginal children and trying to obtain care can be stressful for the parents. The control of dental caries has been identified as a key indictor in the reduction of Indigenous disadvantage. Thus, there is a need for new approaches to prevent ECC, which reflect the cultural norms of Aboriginal communities. Methods/Design This is a Phase II single arm trial designed to gather information on the effectiveness of a dental health education program for Aboriginal children aged 6 months, followed over 2 years. The program will deliver advice from Aboriginal Health Workers on tooth brushing, diet and the use of fluoride toothpaste to Aboriginal families. Six waves of data collection will be conducted to enable estimates of change in parental knowledge and their views on the acceptability of the program. The Aboriginal Health Workers will also be interviewed to record their views on the acceptability and program feasibility. Clinical data on the child participants will be recorded when they are 30 months old and compared with a reference population of similar children when the study began. Latent variable modeling will be used to interpret the intervention effects on disease outcome. Discussion The research project will identify barriers to the implementation of a family centered Aboriginal oral health strategy, as well as the development of evidence to assist in the planning of a Phase III cluster randomized study. Trial registration ACTRN12612000712808 PMID:22909327

  14. 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.

  15. Concurrent or sequential letrozole with adjuvant breast radiotherapy: final results of the CO-HO-RT phase II randomized trial†

    PubMed Central

    Bourgier, C.; Kerns, S.; Gourgou, S.; Lemanski, C.; Gutowski, M.; Fenoglietto, P.; Romieu, G.; Crompton, N.; Lacombe, J.; Pèlegrin, A.; Ozsahin, M.; Rosenstein, B.; Azria, D.

    2016-01-01

    Background We present here final clinical results of the COHORT trial and both translational sub-studies aiming at identifying patients at risk of radiation-induced subcutaneous fibrosis (RISF): (i) radiation-induced lymphocyte apoptosis (RILA) and (ii) candidates of certain single-nucleotide polymorphisms (SNPs). Patients and methods Post-menopausal patients with stage I–II breast cancer (n = 150) were enrolled and assigned to either concurrent (arm A) or sequential radiotherapy (RT)-letrozole (arm B). Among them, 121 were eligible for RILA and SNP assays. Grade ≥2 RISF were the primary end point. Secondary end points were lung and heart events and carcinologic outcome. RILA was performed to predict differences in RISF between individuals. A genome-wide association study was performed to identify SNPs associated with RILA and RISF. Analyses were done by intention to treat. Results After a median follow-up of 74 months, 5 patients developed a grade ≥2 RISF. No significant difference was observed between arms A and B. Neither grade ≥2 lung nor symptomatic cardiac toxicity was observed. Median RILA value of the five patients who had grade ≥2 RISF was significantly lower compared with those who developed grade ≤1 RISF (6.9% versus 13%, P = 0.02). Two SNPs were identified as being significantly associated with RILA: rs1182531 (P = 4.2 × 10−9) and rs1182532 (P = 3.6 × 10−8); both located within the PHACTR3 gene on chromosome 20q13.33. Conclusions With long-term follow-up, letrozole can safely be delivered concomitantly with adjuvant breast RT. Translational sub-studies showed that high RILA values were correlated with patients who did not develop RISF. Registered clinical trial NCT00208273. PMID:26681684

  16. Randomized Phase II Study of Clofarabine-Based Consolidation for Younger Adults With Acute Myeloid Leukemia in First Remission.

    PubMed

    Thomas, Xavier; de Botton, Stéphane; Chevret, Sylvie; Caillot, Denis; Raffoux, Emmanuel; Lemasle, Emilie; Marolleau, Jean-Pierre; Berthon, Céline; Pigneux, Arnaud; Vey, Norbert; Reman, Oumedaly; Simon, Marc; Recher, Christian; Cahn, Jean-Yves; Hermine, Olivier; Castaigne, Sylvie; Celli-Lebras, Karine; Ifrah, Norbert; Preudhomme, Claude; Terré, Christine; Dombret, Hervé

    2017-02-21

    Purpose To evaluate the efficacy and safety of a clofarabine-based combination (CLARA) versus conventional high-dose cytarabine (HDAC) as postremission chemotherapy in younger patients with acute myeloid leukemia (AML). Patients and Methods Patients age 18 to 59 years old with intermediate- or unfavorable-risk AML in first remission and no identified donor for allogeneic stem-cell transplantation (SCT) were eligible. Two hundred twenty-one patients were randomly assigned to receive three CLARA or three HDAC consolidation cycles. The primary end point was relapse-free survival (RFS). To handle the confounding effect of SCT that could occur in patients with late donor identification, hazard ratios (HRs) of events were adjusted on the time-dependent treatment × SCT interaction term. Results At 2 years, RFS was 58.5% (95% CI, 49% to 67%) in the CLARA arm and 46.5% (95% CI, 37% to 55%) in the HDAC arm. Overall, 110 patients (55 in each arm) received SCT in first remission. On the basis of a multivariable Cox-adjusted treatment × SCT interaction, the HR of CLARA over HDAC before or in absence of SCT was 0.65 (95% CI, 0.43 to 0.98; P = .041). In a sensitivity analysis, when patients who received SCT in first remission were censored at SCT time, 2-year RFS was 53.3% (95% CI, 39% to 66%) in the CLARA arm and 31.0% (95% CI, 19% to 43%) in the HDAC arm (HR, 0.63; 95% CI, 0.41 to 0.98; P = .043). Gain in RFS could be related to the lower cumulative incidence of relapse observed in the CLARA arm versus the HDAC arm (33.9% v 46.4% at 2 years, respectively; cause-specific HR, 0.61; 95% CI, 0.40 to 0.94; P = .025). CLARA cycles were associated with higher hematologic and nonhematologic toxicity than HDAC cycles. Conclusion These results suggest that CLARA might be considered as a new chemotherapy option in younger patients with AML in first remission.

  17. A phase II trial of combined treatment of endoscopic mucosal resection and chemoradiotherapy for clinical stage I esophageal carcinoma: Japan Clinical Oncology Group Study JCOG0508.

    PubMed

    Kurokawa, Yukinori; Muto, Manabu; Minashi, Keiko; Boku, Narikazu; Fukuda, Haruhiko

    2009-10-01

    Standard treatment for clinical stage I esophageal cancer with submucosal invasion (T1b) has been surgical resection. We conducted a Phase II trial to evaluate the efficacy and the safety of combined treatment of endoscopic mucosal resection (EMR) and chemoradiotherapy for clinical stage I (T1b) esophageal cancer. Patients diagnosed as having clinical stage I (T1b) esophageal cancer which is considered to be resectable by EMR are eligible. When pathological examination of the EMR specimen confirms T1b tumor with negative or positive resection margin, the patient undergoes chemoradiotherapy. The study continues until 82 patients with T1b tumor with negative resection margin are enrolled from 20 institutions. The primary endpoint is 3-year overall survival (OS) in pT1b cases with negative resection margin. The secondary endpoints are 3-year OS and progression-free survival in all eligible cases, OS in pT1a-MM cases with margin-negative, complications of EMR and adverse events of chemoradiotherapy. The data from this trial will be expected to provide a non-surgical treatment option to the patients with clinical stage I (T1b) esophageal cancer.

  18. Treatment with pentosan polysulphate in patients with MPS I: results from an open label, randomized, monocentric phase II study.

    PubMed

    Hennermann, Julia B; Gökce, Seyfullah; Solyom, Alexander; Mengel, Eugen; Schuchman, Edward H; Simonaro, Calogera M

    2016-11-01

    Current treatment options for MPS I have limited effects on some organs, including the skeletal system. In MPS animal models pentosan polysulphate (PPS) reduces the concentrations of glycosaminoglycans (GAGs) in tissues and body fluids and improves cartilaginous and osseous pathologies. The goals of this study were to investigate primarily the safety and secondary the clinical effects, concerning mobility and pain, of PPS treatment in MPS I patients. Four MPS I-Hurler-Scheie/-Scheie patients aged 35.6 ± 6.4 years with one male were included in the study. All patients were on enzyme replacement therapy since 9.45 ± 3.75 years. PPS was applied subcutaneously in two patients with 1 mg/kg and in two patients with 2 mg/kg, weekly for 12 weeks and then biweekly for 12 weeks. The 24-week treatment with PPS was well tolerated by all patients. Urinary GAG concentrations were reduced from 4.13 ± 1.17 at baseline to 2.69 ± 0.36 mg/mmol creatinine after 24-week treatment with 1 mg/kg PPS, and from 6.71 ± 0.62 to 2.65 ± 0.09 mg/mmol creatinine with 2 mg/kg PPS. An improvement in range of motion was noted in three out of four patients. The pain intensity score was reduced from 4.5 ± 1.77 at baseline to 1.8 ± 0.47 after 24-week treatment with 1 mg/kg PPS; patients with 2 mg/kg PPS already had minimal pain at the start of the study. In conclusion, PPS treatment in a small number of adult MPS I patients was well tolerated and resulted in a significant reduction of urinary GAG excretion and in an improvement of joint mobility and pain.

  19. 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

  20. Phase II, Randomized, Placebo-controlled, 90-day Study of Emixustat HCL in Geographic Atrophy Associated with Dry Age-Related Macular Degeneration

    PubMed Central

    Dugel, Pravin U.; Novack, Roger L.; Csaky, Karl G.; Richmond, Preston P.; Birch, David G.; Kubota, Ryo

    2015-01-01

    Purpose This study assessed the safety, tolerability, and pharmacodynamics of emixustat hydrochloride (ACU-4429), a novel visual cycle modulator, in subjects with geographic atrophy (GA) associated with dry age-related macular degeneration (AMD). Methods Subjects were randomly assigned to oral emixustat (2, 5, 7, or 10 mg once daily) or placebo (3:1 ratio) for 90 days. Recovery of rod photoreceptor sensitivity following a photobleach was measured by electroretinography. Safety evaluations included analysis of adverse events (AEs) and ophthalmic examinations. Results Seventy-two subjects (54 emixustat, 18 placebo) were evaluated. Emixustat suppressed rod photoreceptor sensitivity in a dose-dependent manner. Suppression plateaued by Day 14, and was reversible within 7-14 days after drug cessation. No systemic AEs of concern were noted. Dose-related ocular AEs (chromatopsia, 57% emixustat vs. 17% placebo; and delayed dark adaptation, 48% emixustat vs. 6% placebo) were mild to moderate, and the majority resolved on study or within 7-14 days after study drug cessation. Conclusions In this phase II study, emixustat produced a dose-dependent, reversible effect on rod function, and an ocular AE profile that is consistent with the proposed mechanism of action. These results support further testing of emixustat for the treatment of GA associated with dry AMD. PMID:25932553

  1. 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

  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 Randomized, Phase II, Biomarker-Selected Study Comparing Erlotinib to Erlotinib Intercalated With Chemotherapy in First-Line Therapy for Advanced Non–Small-Cell Lung Cancer

    PubMed Central

    Hirsch, Fred R.; Kabbinavar, Fairooz; Eisen, Tim; Martins, Renato; Schnell, Fredrick M.; Dziadziuszko, Rafal; Richardson, Katherine; Richardson, Frank; Wacker, Bret; Sternberg, David W.; Rusk, Jason; Franklin, Wilbur A.; Varella-Garcia, Marileila; Bunn, Paul A.; Camidge, D. Ross

    2011-01-01

    Purpose Erlotinib prolongs survival in patients with advanced non–small-cell lung cancer (NSCLC). We report the results of a randomized, phase II study of erlotinib alone or intercalated with chemotherapy (CT + erlotinib) in chemotherapy-naïve patients with advanced NSCLC who were positive for epidermal growth factor receptor (EGFR) protein expression and/or with high EGFR gene copy number. Patients and Methods A total of 143 patients were randomly assigned to either erlotinib 150 mg daily orally until disease progression (PD) occurred or to chemotherapy with paclitaxel 200 mg/m2 intravenously (IV) and carboplatin dosed by creatinine clearance (AUC 6) IV on day 1 intercalated with erlotinib 150 mg orally on days 2 through 15 every 3 weeks for four cycles followed by erlotinib 150 mg orally until PD occurred (CT + erlotinib). The primary end point was 6-month progression-free survival (PFS); secondary end points included response rate, PFS, and survival. EGFR, KRAS mutation, EGFR fluorescent in situ hybridization and immunohistochemistry, and E-cadherin and vimentin protein levels were also assessed. Results Six-month PFS rates were 26% and 31% for the two arms (CT + erlotinib and erlotinib alone, respectively). Both were less than the historical control of 45% (P = .001 and P = .011, respectively). Median PFS times were 4.57 and 2.69 months, respectively. Patients with tumors harboring EGFR activating mutations fared better on erlotinib alone (median PFS, 18.2 months v 4.9 months for CT + erlotinib). Conclusion The feasibility of a multicenter biomarker-driven study was demonstrated, but neither treatment arms exceeded historical controls. This study does not support combined chemotherapy and erlotinib in first-line treatment of EGFR-selected advanced NSCLC, and the patients with tumors harboring EGFR mutations had a better outcome on erlotinib alone. PMID:21825259

  4. A Randomized Phase II Trial Investigating the Effect of Platelet Function Inhibition on Circulating Tumor Cells in Patients With Metastatic Breast Cancer

    PubMed Central

    Roop, Ryan P.; Naughton, Michael J.; Van Poznak, Catherine; Schneider, Jochen G.; Lammers, Philip E.; Pluard, Timothy J.; Johnson, Farley; Eby, Charles S.; Weilbaecher, Katherine N.

    2014-01-01

    Background Blockade of platelet activation and aggregation can inhibit metastasis in preclinical models and is associated with cancer prevention. To test whether disruption of platelet function with clopidogrel and aspirin would decrease the number of circulating tumor cells (CTCs) in patients with metastatic breast cancer, a randomized phase II study was performed. Methods Patients with metastatic breast cancer who were not currently receiving cytotoxic chemotherapy were eligible. Patients were randomized to receive either clopidogrel and aspirin or to a control group receiving no treatment. Phlebotomy was performed at baseline, at 2 and 4 weeks, and monthly thereafter to obtain specimens to assess CTC, platelet aggregation, and thrombin activity. The primary end point was the proportion of patients with detectable CTCs at 1 month. Results Forty-eight patients were enrolled and 42 were evaluable at 1 month. Baseline CTC numbers were ≥ 5 in 13% and ≥ 1 in 65% of patients. Despite adequate platelet function inhibition in the treatment group, the proportion of patients with detectable CTCs was similar between the clopidogrel/aspirin and control groups at baseline (P = .21) and 4 weeks (P = .75), showing no treatment effect. Measured endogenous thrombin potential did not correlate with CTC number. No bleeding-related serious adverse events (SAEs) occurred. Conclusion The baseline CTC numbers were lower than expected, decreasing the ability to detect an impact of platelet inhibition on CTCs. Clopidogrel and aspirin were well tolerated. Future studies evaluating the potential therapeutic role of antiplatelet therapy in breast cancer remain of interest, and they may be informed by these results. PMID:24267729

  5. A Randomized Phase II Trial of Short-Course Androgen Deprivation Therapy With or Without Bevacizumab for Patients With Recurrent Prostate Cancer After Definitive Local Therapy

    PubMed Central

    McKay, Rana R.; Zurita, Amado J.; Werner, Lillian; Bruce, Justine Y.; Carducci, Michael A.; Stein, Mark N.; Heath, Elisabeth I.; Hussain, Arif; Tran, Hai T.; Sweeney, Christopher J.; Ross, Robert W.; Kantoff, Philip W.; Slovin, Susan F.

    2016-01-01

    Purpose Patients with recurrent prostate cancer after local treatment make up a heterogeneous population for whom androgen deprivation therapy (ADT) is the usual treatment. The purpose of this randomized phase II trial was to investigate the efficacy and toxicity of short-course ADT with or without bevacizumab in men with hormone-sensitive prostate cancer. Patients and Methods Eligible patients had an increasing prostate-specific antigen (PSA) of ≤ 50 ng/mL and PSA doubling time of less than 18 months. Patients had either no metastases or low burden, asymptomatic metastases (lymph nodes < 3 cm and five or fewer bone metastases). Patients were randomly assigned 2:1 to a luteinizing hormone-releasing hormone agonist, bicalutamide and bevacizumab or ADT alone, for 6 months. The primary end point was PSA relapse-free survival (RFS). Relapse was defined as a PSA of more than 0.2 ng/mL for prostatectomy patients or PSA of more than 2.0 ng/mL for primary radiation therapy patients. Results Sixty-six patients received ADT + bevacizumab and 36 received ADT alone. Patients receiving ADT + bevacizumab had a statistically significant improvement in RFS compared with patients treated with ADT alone (13.3 months for ADT + bevacizumab v 10.2 months for ADT alone; hazard ratio, 0.47; 95% CI, 0.29 to 0.77; log-rank P = .002). Hypertension was the most common adverse event in patients receiving ADT + bevacizumab (36%). Conclusion ADT combined with bevacizumab resulted in an improved RFS for patients with hormone-sensitive prostate cancer. Long-term follow-up is needed to determine whether some patients have a durable PSA response and are able to remain off ADT for prolonged periods. Our data provide rationale for combining vascular endothelial growth factor–targeting therapy with ADT in hormone-sensitive prostate cancer. PMID:27044933

  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.

  7. New film-coated tablet formulation of deferasirox is well tolerated in patients with thalassemia or lower-risk MDS: Results of the randomized, phase II ECLIPSE study.

    PubMed

    Taher, Ali T; Origa, Raffaella; Perrotta, Silverio; Kourakli, Alexandra; Ruffo, Giovan Battista; Kattamis, Antonis; Goh, Ai-Sim; Cortoos, Annelore; Huang, Vicky; Weill, Marine; Merino Herranz, Raquel; Porter, John B

    2017-01-31

    Once-daily deferasirox dispersible tablets (DT) have a well-defined safety and efficacy profile and, compared with parenteral deferoxamine, provide greater patient adherence, satisfaction, and quality of life. However, barriers still exist to optimal adherence, including gastrointestinal tolerability and palatability, leading to development of a new film-coated tablet (FCT) formulation that can be swallowed with a light meal, without the need to disperse into a suspension prior to consumption. The randomized, open-label, phase II ECLIPSE study evaluated the safety of deferasirox DT and FCT formulations over 24 weeks in chelation-naïve or pre-treated patients aged ≥10 years, with transfusion-dependent thalassemia or IPSS-R very-low-, low-, or intermediate-risk myelodysplastic syndromes. One hundred seventy-three patients were randomized 1:1 to DT (n = 86) or FCT (n = 87). Adverse events (overall), consistent with the known deferasirox safety profile, were reported in similar proportions of patients for each formulation (DT 89.5%; FCT 89.7%), with a lower frequency of severe events observed in patients receiving FCT (19.5% vs. 25.6% DT). Laboratory parameters (serum creatinine, creatinine clearance, alanine aminotransferase, aspartate aminotransferase and urine protein/creatinine ratio) generally remained stable throughout the study. Patient-reported outcomes showed greater adherence and satisfaction, better palatability and fewer concerns with FCT than DT. Treatment compliance by pill count was higher with FCT (92.9%) than with DT (85.3%). This analysis suggests deferasirox FCT offers an improved formulation with enhanced patient satisfaction, which may improve adherence, thereby reducing frequency and severity of iron overload-related complications.

  8. Randomized two-stage Phase II clinical trial designs based on Barnard's exact test.

    PubMed

    Shan, Guogen; Ma, Changxing; Hutson, Alan D; Wilding, Gregory E

    2013-01-01

    In areas such as oncology, two-stage designs are often preferred as compared to one-stage designs due to the ability to stop the trial early when faced with evidence of lack of sufficient efficacy and the associated sample size savings. We present exact two-stage designs based on Barnard's exact test for differences in proportions and compare the designs to those proposed by Kepner ( 2010 ) and Jung ( 2010 ). In addition, we present tables of decision rules under a variety of assumed realities for use in trial planning. The procedure is recommended for use due to the substantial sample size savings experienced.

  9. 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

  10. 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

  11. Efficacy of thalidomide for the treatment of amyotrophic lateral sclerosis: A phase II open label clinical trial

    PubMed Central

    STOMMEL, ELIJAH W.; COHEN, JEFFREY A.; FADUL, CAMILO E.; COGBILL, CHRISTOPHER H.; GRABER, DAVID J.; KINGMAN, LINDA; MACKENZIE, TODD; SMITH, JACQUELINE Y. CHANNON; HARRIS, BRENT T.

    2013-01-01

    Neuroinflammation through the cytokine, tumor necrosis factor-alpha (TNF-α) is thought to play an important role in the pathogenesis of amyotrophic lateral sclerosis (ALS). We conducted a preliminary phase II trial of thalidomide, which reduces levels of TNF-α pre-transcriptionally and post-transcriptionally in vivo and has been shown to prolong disease duration and extend the lifespan of transgenic animal models of ALS. Patients who met diagnostic criteria for ALS received thalidomide at escalating doses to a target dose of 400 mg/day. The primary endpoints in the trial were the ALS Functional Rating Scale (ALSFRS) and pulmonary function testing (PFT) curves after nine months of thalidomide treatment that were compared to historical controls. Secondary endpoints were: survival stratified for newly diagnosed and progressive disease, toxicity, quality of life, and serum cytokine measurements. Twenty-three patients were enrolled, but only 18 were evaluable for the primary outcome. There was no improvement in the ALSFRS or PFT compared to historical controls. Thalidomide had several side-effects in our ALS patients. There was no significant shift in cytokine profile after treatment compared to baseline. In conclusion, treatment of ALS with the TNF-α inhibitor, thalidomide, does not appear to effectively modulate disease progression and can cause adverse effects. PMID:19922130

  12. 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

  13. Phase II--clinical trial with biodegradable subdermal contraceptive implant Capronor (4.0-cm single implant). Indian Council of Medical Research Task Force on Hormonal Contraception.

    PubMed

    1991-10-01

    The subdermal biodegradable contraceptive implant Capronor (4.0 cm) was implanted in 41 women to observe the efficacy and side effects. Only one pregnancy was reported at 10 months of use, and the life table continuation rate at 12 months was 82.2 per 100 users. No serious clinical side effects were reported during the study period. The menstrual pattern was disrupted during the first 3 months of implant use in two-thirds of the women which improved by the end of 12 months of use. The results of this Phase II study suggest that Capronor is a safe and effective long-acting contraceptive. These findings need to be confirmed in a Phase III clinical trial on a larger sample size.

  14. Integrated safety profile of single-agent carfilzomib: experience from 526 patients enrolled in 4 phase II clinical studies.

    PubMed

    Siegel, David; Martin, Thomas; Nooka, Ajay; Harvey, R Donald; Vij, Ravi; Niesvizky, Ruben; Badros, Ashraf Z; Jagannath, Sundar; McCulloch, Leanne; Rajangam, Kanya; Lonial, Sagar

    2013-11-01

    Carfilzomib, a selective proteasome inhibitor, was approved in 2012 for the treatment of relapsed and refractory multiple myeloma. Safety data for single-agent carfilzomib have been analyzed for 526 patients with advanced multiple myeloma who took part in one of 4 phase II studies (PX-171-003-A0, PX-171-003-A1, PX-171-004, and PX-171-005). Overall analyses of adverse events and treatment modifications are presented, as well as specific analyses of adverse events by organ system. Overall, the most common adverse events of any grade included fatigue (55.5%), anemia (46.8%), and nausea (44.9%). In the grouped analyses, any grade adverse events were reported in 22.1% for any cardiac (7.2% cardiac failure), 69.0% for any respiratory (42.2% dyspnea), and 33.1% for any grouped renal impairment adverse event (24.1% increased serum creatinine). The most common non-hematologic adverse events were generally Grade 1 or 2 in severity, while Grade 3/4 adverse events were primarily hematologic and mostly reversible. There was no evidence of cumulative bone marrow suppression, either neutropenia or thrombocytopenia, and febrile neutropenia occurred infrequently (1.1%). Notably, the incidence of peripheral neuropathy was low overall (13.9%), including patients with baseline peripheral neuropathy (12.7%). Additionally, the incidence of discontinuations or dose reductions attributable to adverse events was low. These data demonstrate that single-agent carfilzomib has an acceptable safety profile in heavily pre-treated patients with relapsed/refractory multiple myeloma. The tolerable safety profile allows for administration of full-dose carfilzomib, both for extended periods and in a wide spectrum of patients with advanced multiple myeloma, including those with pre-existing comorbidities.

  15. Safety and Efficacy of Autologous CD34+ Hematopoietic Progenitor Cells Transduced with an Anti-Tat Ribozyme in a Multi-Center, Randomized, Placebo-Controlled, Phase II Gene Therapy Trial for the Human Immunodeficiency Virus

    PubMed Central

    Mitsuyasu, Ronald T; Merigan, Thomas C; Carr, Andrew; Zack, Jerome A; Winters, Mark A; Workman, Cassy; Bloch, Mark; Lalezari, Jacob; Becker, Stephen; Thornton, Lorna; Akil, Bisher; Khanlou, Homayoon; Finlayson, Robert; McFarlane, Robert; Smith, Don E; Garsia, Roger; Ma, David; Law, Matthew; Murray, John M.; von Kalle, Christof; Ely, Julie A; Patino, Sharon M; Knop, Alison E; Wong, Philip; Todd, Alison V; Haughton, Margaret; Fuery, Caroline; Macpherson, Janet L; Symonds, Geoff P; Evans, Louise A; Pond, Susan M; Cooper, David A

    2009-01-01

    SUMMARY Gene transfer has potential as a once-only treatment that reduces viral load, preserves the immune system, and avoids lifetime highly active antiretroviral therapy. This study, the first randomized, double-blind, placebo-controlled, phase II cell-delivered gene transfer clinical trial, was conducted in 74 HIV-1 infected adults who received a tat/vpr specific anti-HIV ribozyme (OZ1) or placebo delivered in autologous CD34+ hematopoietic progenitor cells. There were no OZ1-related adverse events. There was no statistical difference in viral load between the OZ1 and placebo group at the primary end-point (average at weeks 47 and 48) but time weighted areas under the curve from weeks 40-48 and 40-100 were significantly lower in the OZ1 group. Throughout the 100 weeks, CD4+ lymphocyte counts were higher in the OZ1 group. This study provides the first indication that cell-delivered gene transfer is safe and biologically active in HIV patients and can be developed as a conventional therapeutic product. PMID:19219022

  16. 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.

  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. Multicenter, double-blind, randomized, phase II trial to assess the safety and efficacy of ceftolozane-tazobactam plus metronidazole compared with meropenem in adult patients with complicated intra-abdominal infections.

    PubMed

    Lucasti, Christopher; Hershberger, Ellie; Miller, Benjamin; Yankelev, Sara; Steenbergen, Judith; Friedland, Ian; Solomkin, Joseph

    2014-09-01

    Ceftolozane-tazobactam (TOL-TAZ) is a novel antibacterial with activity against Pseudomonas aeruginosa and other common Gram-negative pathogens, including extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae, that are associated with complicated intra-abdominal infections (cIAIs). This prospective, double-blind, randomized, multicenter, phase II trial assessed patient clinical and microbiological responses to and the safety of TOL-TAZ plus metronidazole compared with those of meropenem. Hospitalized adults with cIAIs that required surgical intervention were randomized (2:1) to receive intravenous (i.v.) TOL-TAZ (1.5 g [containing 1,000 mg TOL and 500 mg TAZ] every 8 h [q8h]) with or without i.v. metronidazole (500 mg q8h) or i.v. meropenem (1 g q8h) for 4 to 7 days. The primary endpoint was the clinical response at the test-of-cure visit in the microbiologically modified intent-to-treat (mMITT) and microbiologically evaluable (ME) populations. Secondary measures included the patients' microbiological response and safety. In total, 82 patients received TOL-TAZ (90.2% with metronidazole), and 39 received meropenem. For the mMITT population, clinical cure was seen in 83.6% of the patients (51/61; 95% confidence interval [CI], 71.9 to 91.8) who received TOL-TAZ and 96.0% of the patients (24/25; 95% CI, 79.6 to 99.9) who received meropenem (difference, -12.4%; 95% CI, -34.9% to 11.1%); in the ME population, clinical cure was seen in 88.7% and 95.8% of the patients (difference, -7.1%; 95% CI, -30.7% to 16.9%) who received TOL-TAZ and meropenem, respectively. TOL-TAZ demonstrated microbiological success against Escherichia coli (89.5%), Klebsiella pneumoniae (100%), and P. aeruginosa (100%). The adverse event rates were similar in the groups (50.0% with TOL-TAZ and 48.8% with meropenem). TOL-TAZ in combination with metronidazole was well tolerated and resulted in clinical and microbiological success rates supportive of further clinical development in

  19. Pharmacokinetics of tiotropium administered by Respimat(®) in asthma patients: Analysis of pooled data from Phase II and III clinical trials.

    PubMed

    Sharma, Ashish; Kerstjens, Huib A M; Aalbers, René; Moroni-Zentgraf, Petra; Weber, Benjamin; Dahl, Ronald

    2017-02-01

    Tiotropium is a long-acting inhaled antimuscarinic bronchodilator that has recently received marketing authorization for the indication of asthma with dose delivery via the Respimat(®) inhaler, in addition to its widely established role in the management of chronic obstructive pulmonary disease (COPD). This report presents a combined analysis of tiotropium plasma and urine pharmacokinetics at steady state from 8 Phase II/III clinical trials in asthma and delineates the effects of patient characteristics on systemic exposure based on the parameters fe0-24,ss (fraction of dose excreted unchanged in urine over 24 h post-dose at steady-state) and dose-normalized AUCtau,ss and Cmax,ss. Pharmacokinetics were also compared between asthma and COPD, incorporating data from 3 COPD Phase II/III clinical trials. Tiotropium pharmacokinetics in asthma were dose-proportional up to 5 μg dosed once daily. The following factors showed no statistically significant effects on tiotropium systemic exposure in asthma based on analysis of geometric mean ratios and 90% confidence intervals: age, asthma severity, lung function, reversibility testing, allergy status, smoking history, geographical region, and posology (5 μg once daily or 2.5 μg twice daily via Respimat(®)). Asian patients showed a moderately but significantly higher systemic exposure compared to White or Black patients. However, no differences in safety by race were observed. Total systemic exposure (AUCtau,ss) was similar between asthma and COPD, but Cmax,ss was 52% lower in asthma patients compared to COPD. It is concluded that in asthma, patient characteristics have no relevant effect on tiotropium systemic exposure. Since systemic exposure to inhaled drugs is an indicator of safety, the lower Cmax,ss compared to COPD is not considered a concern for tiotropium therapy of asthma.

  20. Comparative effectiveness of combined therapy inhibiting EGFR and VEGF pathways in patients with advanced non-small-cell lung cancer: a meta-analysis of 16 phase II/III randomized trials

    PubMed Central

    Cai, Shangli; Wu, Tongwei; Yan, Guangyue; Cheng, Sijin; Cui, Kang; Xi, Ying; Qi, Xiaolong; Zhang, Jie; Ma, Wang

    2017-01-01

    Background & Aims Combined therapy inhibiting EGFR and VEGF pathways is becoming a promising therapy in the treatment of advanced non-small-cell lung cancer (NSCLC), however, with controversy. The study aims to compare the efficacy of combined inhibition therapy versus control therapy (including placebo, single EGFR inhibition and single VEGF inhibition) in patients with advanced NSCLC. Materials and Methods An adequate literature search in EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), American Society of Clinical Oncology (ASCO) and European Society of Medical Oncology (ESMO) was conducted. Phase II or III randomized controlled trials (RCTs) that compared effectiveness between combined inhibition therapy and control therapy in patients with advanced NSCLC were eligible. The endpoint was overall response rate (ORR), progression free survival (PFS) and overall survival (OS). Results Sixteen phase II or III RCTs involving a total of 7,109 patients were included. The results indicated that the combined inhibition therapy significantly increased the ORR (OR = 1.59, 95% CI = 1.36-1.87, p<0.00001; I2 = 36%) when compared to control therapy. In the subgroup analysis, the combined inhibition therapy clearly increased the ORR (OR = 2.04, 95% CI = 1.60-2.60, p<0.00001; I2 = 0%) and improved the PFS (HR = 0.78, 95% CI = 0.71-0.85, p<0.00001;I2 = 0%) when compared with the placebo, and similar results was detected when compared with the single EGFR inhibition in terms of ORR (OR = 1.39, 95% CI = 1.12-1.74, p = 0.003; I2 = 30%) and PFS (HR = 0.73, 95% CI = 0.67-0.81, p<0.0001; I2 = 50%). No obvious difference was found between the combined inhibition therapy and single VEGF inhibition in term of ORR, however, combined inhibition therapy significantly decreased the PFS when compared to the single VEGF inhibition therapy (HR = 1.70, 95% CI = 1.34-2.17, p<0.0001; I2 = 50%). Besides, no significant difference was observed between the combined inhibition therapy

  1. Randomized, Double-Blind, Placebo-Controlled, Multicenter Phase II Study of Onartuzumab Plus Bevacizumab Versus Placebo Plus Bevacizumab in Patients With Recurrent Glioblastoma: Efficacy, Safety, and Hepatocyte Growth Factor and O(6)-Methylguanine-DNA Methyltransferase Biomarker Analyses.

    PubMed

    Cloughesy, Timothy; Finocchiaro, Gaetano; Belda-Iniesta, Cristóbal; Recht, Lawrence; Brandes, Alba A; Pineda, Estela; Mikkelsen, Tom; Chinot, Olivier L; Balana, Carmen; Macdonald, David R; Westphal, Manfred; Hopkins, Kirsten; Weller, Michael; Bais, Carlos; Sandmann, Thomas; Bruey, Jean-Marie; Koeppen, Hartmut; Liu, Bo; Verret, Wendy; Phan, See-Chun; Shames, David S

    2017-01-20

    Purpose Bevacizumab regimens are approved for the treatment of recurrent glioblastoma in many countries. Aberrant mesenchymal-epithelial transition factor (MET) expression has been reported in glioblastoma and may contribute to bevacizumab resistance. The phase II study GO27819 investigated the monovalent MET inhibitor onartuzumab plus bevacizumab (Ona + Bev) versus placebo plus bevacizumab (Pla + Bev) in recurrent glioblastoma. Methods At first recurrence after chemoradiation, bevacizumab-naïve patients with glioblastoma were randomly assigned 1:1 to receive Ona (15 mg/kg, once every 3 weeks) + Bev (15 mg/kg, once every 3 weeks) or Pla + Bev until disease progression. The primary end point was progression-free survival by response assessment in neuro-oncology criteria. Secondary end points were overall survival, objective response rate, duration of response, and safety. Exploratory biomarker analyses correlated efficacy with expression levels of MET ligand hepatocyte growth factor, O(6)-methylguanine-DNA methyltransferase promoter methylation, and glioblastoma subtype. Results Among 129 patients enrolled (Ona + Bev, n = 64; Pla + Bev, n = 65), baseline characteristics were balanced. The median progression-free survival was 3.9 months for Ona + Bev versus 2.9 months for Pla + Bev (hazard ratio, 1.06; 95% CI, 0.72 to 1.56; P = .7444). The median overall survival was 8.8 months for Ona + Bev and 12.6 months for Pla + Bev (hazard ratio, 1.45; 95% CI, 0.88 to 2.37; P = .1389). Grade ≥ 3 adverse events were reported in 38.5% of patients who received Ona + Bev and 35.9% of patients who received Pla + Bev. Exploratory biomarker analyses suggested that patients with high expression of hepatocyte growth factor or unmethylated O(6)-methylguanine-DNA methyltransferase may benefit from Ona + Bev. Conclusion There was no evidence of further clinical benefit with the addition of onartuzumab to bevacizumab compared with bevacizumab plus placebo in unselected patients with

  2. AT-55FINAL ANALYSIS OF THE BELOB TRIAL (A RANDOMIZED PHASE II STUDY ON BEVACIZUMAB VERSUS BEVACIZUMAB PLUS LOMUSTINE VERSUS LOMUSTINE SINGLE AGENT IN RECURRENT GLIOBLASTOMA) AND FIRST RADIOLOGY REVIEW RESULTS

    PubMed Central

    Taal, Walter; Enting, Roelien; Taphoorn, Martin; Smits, Marion; Dubbink, Hendrikus; Beerepoot, Laurens; Hanse, Monique; Bralten, Linda; Oosterkamp, Hendrika; Walenkamp, Annemiek; Buter, Jan; Honkoop, Aafke; Boerman, Dolf; de Vos, Filip; Bromberg, Jacoline; Vernhout, Rene; van der Holt, Bronno; van den Bent, Martin

    2014-01-01

    INTRODUCTION: Bevacizumab (BEV) is widely used in recurrent glioblastoma, alone or in combination with other agents. There is however no controlled trial to support this use. MATERIAL AND METHODS: In a Dutch multicenter randomized phase II study patients were assigned to BEV 10 mg/kg day 1, 15 and 29 iv, BEV 10 mg/kg day 1, 15 and 29 iv in combination with 110 mg/m2 lomustine orally on day 1, or lomustine 110 mg/m2 orally on day 1, in a 6- weekly schedule . Eligible were patients with histologically proven glioblastoma, first recurrence after chemo-irradiation with temozolomide, having concluded radiotherapy more than 3 months ago, with adequate bone marrow, renal and hepatic function, and WHO performance status (PS) 0-2. Primary endpoint was 9 months overall survival (OS). RESULTS: Between December 2009 and November 2011, 148 eligible patients were enrolled . Median age was 57 years (range, 24-77) and median WHO PS was 1. After a preplanned safety review after the first 8 patients the lomustine dose in the combination arm was reduced to 90 mg/m2, 44 patients were treated at this dose level. 130 patients were evaluable for response. Nine month OS [95% confidence interval] was 43% [29, 57] in the lomustine arm, 38% [25, 51] in the BEV arm, and 59% [43, 72] in the BEV/lomustine 90 arm. Objective response rate (complete or partial response) by local investigator was 5% in the lomustine arm, 38% in the BEV arm and 34% in the BEV/lomustine 90 arm. CONCLUSION: The combination bevacizumab/lomustine warrants further investigation, and is currently investigated in the randomized controlled phase III EORTC trial 26101. At the meeting the analysis based on IDH and MGMT status and the first results on the radiology review, pattern of progression and clinical impact of isolated T2/FLAIR progression will be presented.

  3. Beating the Odds: Successful Establishment of a Phase II/III Clinical Research Trial in Resource-Poor Liberia during the Largest-Ever Ebola Outbreak

    PubMed Central

    Doe-Anderson, J; Baseler, B; Driscoll, P; Johnson, M; Lysander, J; McNay, L; Njoh, WS; Smolskis, M; Wehrlen, L; Zuckerman, J

    2016-01-01

    It has been argued that a country such as Liberia, not fully recovered from the devastation of decades of civil unrest, lacked the appropriate ethical and regulatory framework, basic human and health care services, and infrastructure to carry out clinical trials according to international standards of quality during a public health emergency. However, as Liberia, Sierra Leone, and Guinea were being ravaged by the largest and most devastating Ebola Virus Disease (EVD) outbreak ever recorded, the topic of conducting clinical trials of experimental vaccine and treatment candidates in these resource-poor countries generated the keen interest and concern of scientists, researchers, physicians, bioethicists, philanthropists, and even politicians. Decisive action on behalf of the Liberian government, and a timely positive and supportive response from the United States (U.S.) government, led to the formation of PREVAIL (Partnership for Research on Ebola Vaccines in Liberia) – a clinical research partnership between the two governments. Within a span of 12 weeks, this partnership accomplished the unimaginable: the successful initiation of a Phase II/III vaccine clinical trial for EVD in Liberia. This paper will discuss the dynamics of the research collaboration, barriers encountered, breakthroughs realized, key elements of success, and lessons learned in the process. PMID:28042619

  4. Effects of Simulated Surface Effect Ship Motions on Crew Habitability. Phase II. Volume 5. Clinical Medical Effects on Volunteers

    DTIC Science & Technology

    1977-05-01

    psychiatrist or a clinical psychologist under his supervision. In addition to a standard clinical psychi- atric interview, the Bender - Gestalt test , the...be- cause of the small sample and because of the many variations of the test conditions, the fol- lowing findings are presented. In all sea state...were excluded by the experimental design. CONCLUSIONS (1) These data indicate that a majority of the subjects tested were able to function for varying

  5. A Phase II, Randomized Study on an Investigational DTPw-HBV/Hib-MenAC Conjugate Vaccine Administered to Infants in Northern Ghana

    PubMed Central

    Hodgson, Abraham; Forgor, Abudulai Adams; Chandramohan, Daniel; Reed, Zarifah; Binka, Fred; Bevilacqua, Cornelia; Boutriau, Dominique; Greenwood, Brian

    2008-01-01

    Background Combining meningococcal vaccination with routine immunization in infancy may reduce the burden of meningococcal meningitis, especially in the meningitis belt of Africa. We have evaluated the immunogenicity, persistence of immune response, immune memory and safety of an investigational DTPw-HBV/Hib-MenAC conjugate vaccine given to infants in Northern Ghana. Methods and Findings In this phase II, double blind, randomized, controlled study, 280 infants were primed with DTPw-HBV/Hib-MenAC or DTPw-HBV/Hib vaccines at 6, 10 and 14 weeks of age. At 12 months of age, children in each group received a challenge dose of serogroup A+C polysaccharides. Antibody responses were assessed pre, and one month-post dose 3 of the priming schedule and pre and 1 month after administration of the challenge dose. One month post-dose 3, 87.8% and 88.2% of subjects in the study group had bactericidal meningococcal serogroup A (SBA-MenA) and meningococcal serogroup C (SBA-MenC) antibody titres ≥1∶8 respectively. Seroprotection/seropositivity rates to the 5 antigens administered in the routine EPI schedule were non-inferior in children in the study group compared to those in the control group. The percentages of subjects in the study group with persisting SBA-MenA titres ≥ 1∶8 or SBA-MenC titres ≥1∶8 at the age of 12 months prior to challenge were significantly higher than in control group (47.7% vs 25.7% and 56.4% vs 5.1% respectively). The administration of 10 μg of serogroup A polysaccharide increased the SBA-MenA GMT by 14.0-fold in the DTPW-HBV/HibMenAC-group compared to a 3.8 fold increase in the control-group. Corresponding fold-increases in SBA-MenC titres following challenge with 10 μg of group C polysaccharide were 18.8 and 1.9 respectively. Reactogenicity following primary vaccination or the administration of the challenge dose was similar in both groups, except for swelling (Grade 3) after primary vaccination which was more frequent in children in the

  6. A Prospective, Multicenter, Randomized Phase II Study to Evaluate the Efficacy and Safety of Eculizumab in Patients with Guillain-Barré Syndrome (GBS): Protocol of Japanese Eculizumab Trial for GBS (JET-GBS)

    PubMed Central

    Yamaguchi, Nobuko; Sato, Yasunori; Nagashima, Kengo; Katayama, Kanako; Sekiguchi, Yukari; Iwai, Yuta; Amino, Hiroshi; Suichi, Tomoki; Yokota, Takanori; Nishida, Yoichiro; Kohara, Nobuo; Hirata, Koichi; Nishiyama, Kazutoshi; Yabe, Ichiro; Kaida, Ken-Ichi; Suzuki, Norihiro; Nodera, Hiroyuki; Tsuji, Shoji; Koike, Haruki; Kira, Jun-Ichi; Hanaoka, Hideki; Kusunoki, Susumu; Kuwabara, Satoshi

    2016-01-01

    Background Guillain-Barré syndrome (GBS) is an immune-mediated neuropathy that causes acute flaccid paralysis. Immunoglobulin and plasma exchange are established treatments for GBS; however, a substantial number of patients, particularly those with severe disease, have poor recovery and residual deficits. Recent studies suggest that complement activation plays a pivotal role in GBS-associated axonal degeneration, and eculizumab is a humanized monoclonal antibody that specifically binds to complement component 5 and potently inhibits complement activation. Objective This clinical trial aims to evaluate the efficacy and safety of eculizumab, a humanized monoclonal antibody directed against complement component 5, for treatment of GBS. Methods The Japanese Eculizumab Trial for GBS (JET-GBS) is a prospective, multicenter, placebo-controlled, double-blind, randomized phase II study conducted at 13 tertiary neurology centers and is funded by the Japan Agency for Medical Research and Development. A total of 33 GBS patients unable to walk independently within 2 weeks from symptom onset (Hughes functional grade 3-5) were randomized at a 2:1 ratio to receive either intravenous eculizumab (900 mg/day) or placebo once weekly for 4 weeks, followed by 20 weeks of follow-up. The primary endpoint for efficacy is the proportion of patients who regain their ability to walk without aid at 4 weeks after the first dose of the study treatment, while primary safety outcomes are the incidence of adverse events and serious adverse events during the trial. Results Enrollment for the trial began in August 2015. This trial is still ongoing. All participants have been enrolled, and follow-up will be completed in October 2016. Conclusions This study is the first to investigate the efficacy and safety of eculizumab for GBS. In case of a positive result, we will plan a phase III trial to investigate this issue in a larger number of patients. ClinicalTrial UMIN Clinical Trials Registry UMIN

  7. 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.

  8. Cisplatin, 5-fluorouracil, and cetuximab (PFE) with or without cilengitide in recurrent/metastatic squamous cell carcinoma of the head and neck: results of the randomized phase I/II ADVANTAGE trial (phase II part)

    PubMed Central

    Vermorken, J. B.; Peyrade, F.; Krauss, J.; Mesía, R.; Remenar, E.; Gauler, T. C.; Keilholz, U.; Delord, J. P.; Schafhausen, P.; Erfán, J.; Brümmendorf, T. H.; Iglesias, L.; Bethe, U.; Hicking, C.; Clement, P. M.

    2014-01-01

    Background Recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M-SCCHN) overexpresses αvβ5 integrin. Cilengitide selectively inhibits αvβ3 and αvβ5 integrins and is investigated as a treatment strategy. Patients and methods The phase I/II study ADVANTAGE evaluated cilengitide combined with cisplatin, 5-fluorouracil, and cetuximab (PFE) in R/M-SCCHN. The phase II part reported here was an open-label, randomized, controlled trial investigating progression-free survival (PFS). Patients received up to six cycles of PFE alone or combined with cilengitide 2000 mg once (CIL1W) or twice (CIL2W) weekly. Thereafter, patients received maintenance therapy (cilengitide arms: cilengitide plus cetuximab; PFE-alone arm: cetuximab only) until disease progression or unacceptable toxicity. Results One hundred and eighty-two patients were treated. Median PFS per investigator read was similar for CIL1W + PFE, CIL2W + PFE, and PFE alone (6.4, 5.6, and 5.7 months, respectively). Accordingly, median overall survival and objective response rates were not improved with cilengitide (12.4 months/47%, 10.6 months/27%, and 11.6 months/36%, respectively). No clinically meaningful safety differences were observed between groups. None of the tested biomarkers (expression of integrins, CD31, Ki-67, vascular endothelial growth factor receptor 2, vascular endothelial-cadherin, type IV collagen, epidermal growth factor receptor, or p16 for human papillomavirus) were predictive of outcome. Conclusion Neither of the cilengitide-containing regimens demonstrated a PFS benefit over PFE alone in R/M-SCCHN patients. PMID:24567516

  9. A phase II study of clinical activity of SCH 717454 (robatumumab) in patients with relapsed osteosarcoma and Ewing sarcoma

    PubMed Central

    Bielack, Stefan S.; Gorlick, Richard G.; Skubitz, Keith; Daw, Najat C.; Herzog, Cynthia E.; Monge, Odd R.; Lassaletta, Alvaro; Boldrini, Erica; Pápai, Zsuzanna; Rubino, Joseph; Pathiraja, Kumudu; Hille, Darcy A.; Ayers, Mark; Yao, Siu‐Long; Nebozhyn, Michael; Lu, Brian; Mauro, David

    2016-01-01

    Abstract Background Robatumumab (19D12; MK‐7454 otherwise known as SCH717454) is a fully human antibody that binds to and inhibits insulin‐like growth factor receptor‐1 (IGF‐1R). This multiinstitutional study (P04720) determined the safety and clinical efficacy of robatumumab in three separate patient groups with resectable osteosarcoma metastases (Group 1), unresectable osteosarcoma metastases (Group 2), and Ewing sarcoma metastases (Group 3). Procedure Robatumumab infusions were administered every 2 weeks and were well tolerated with minimal toxicity. Centrally reviewed response data were available for 144 patients. Results Low disease burden was important for osteosarcoma response: three of 31 patients had complete response or partial response (PR) by Response Evaluation Criteria in Solid Tumors (RECIST) in resectable patients (Group 1) versus zero of 29 in unresectable patients (Group 2); median overall survival was 20 months in Group 1 versus 8.2 months in Group 2. In centrally reviewed patients with Ewing sarcoma with PET‐CT data (N = 84/115), there were six PR, 23 stable disease, and 55 progression of disease by RECIST at 2 months. Patients with Ewing sarcoma had a median overall survival of 6.9 months. However, responding patients with Ewing sarcoma were allowed to continue on treatment after study closure. A minority of patients with metastatic Ewing sarcoma showed clinical responses and have remained healthy after receiving 25–115 doses of robatumumab with remissions of >4 years duration (N = 6). Conclusions These findings show that although the IGF‐1R remains an attractive treatment target, additional research is needed to identify responders and/or means to achieve durable remissions in order to successfully exploit IGF‐1R signal blockade in Ewing sarcoma (clinicaltrials.gov: NCT00617890). PMID:27362300

  10. 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).

  11. 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.

  12. 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

  13. Pharmacodynamic markers and clinical results from the Phase II Study of the SMAC-Mimetic Birinapant in Women with Relapsed Platinum-Resistant or Refractory Epithelial Ovarian Cancer

    PubMed Central

    Chen, Jin-Qiu; Herrmann, Michelle A.; Lee, Jung-min; Kohn, Elise C.; O’Sullivan, Ciara C.; Jordan, Elizabeth; Houston, Nicole; Takebe, Naoko; Kinders, Robert J.; Cao, Liang; Peer, Cody J.; Figg, W. Douglas; Annunziata, Christina M.

    2015-01-01

    Background Inhibitors of Apoptosis Proteins (IAPs) are key regulators of apoptosis, and are frequently dysregulated in ovarian cancer. We hypothesized that blocking IAPs with birinapant would increase tumor cell death resulting in objective response for women with platinum-refractory and resistant ovarian cancer. Methods In this phase II CTEP-sponsored study, patients received birinapant 47mg/m2 on days 1, 8, 15 of 28-day cycles. Pharmacokinetics were obtained in cycle 1. Plasma, peripheral blood mononuclear cells (PBMC) and percutaneous tumor biopsies were collected prior to cycle 1, and after 6 weeks. The primary endpoint was objective response or progression-free survival lasting greater than 6 months in a mini-max design. Results Eleven patients received birinapant, after which accrual was terminated for lack of clinical benefit. Birinapant was well-tolerated, with predominantly grade 2 adverse events (AE) and one grade 3 lymphopenia. Pre-treatment biopsies and PBMCs were collected; paired post-treatment biopsies and PBMC were collected from 7 and 10 patients, respectively. There was consistent downregulation of cIAP1 in tumor (P=0.016) and PBMC (P<0.01). Pro-caspase3 also decreased in tumors (P=0.031) and PBMC (P<0.01); cleaved caspase3 co-localized with gamma-H2AX in tumors after birinapant exposure. Peripheral T- and B-cells decreased significantly post-treatment, but NK-cells did not (P=0.04, P=0.05, P=0.43 respectively). Conclusion Birinapant shows consistent target suppression in vivo, without single agent anti-tumor activity in this small population. Single agent pharmacodynamics were necessary to understand drug mechanism of action and set the stage for rational combination therapy. Preclinical studies are ongoing to identify optimal synergistic combinations for future clinical trials. PMID:26566079

  14. Phase II Clinical Trial of Gefitinib for the Treatment of Chemonaïve Patients with Advanced Non-small Cell Lung Cancer with Poor Performance Status

    PubMed Central

    Karim, Nagla Abdel; Musaad, Salma; Zarzour, Ahmad; Patil, Sadanand; Jazieh, Abdul Rahman

    2014-01-01

    BACKGROUND Patients with advanced non-small cell lung cancer (NSCLC) have no curative treatment options; therefore, improving their quality of life (QOL) is an important goal. Gefitinib, an epidermal growth factor receptor (EGFR) inhibitor, is a safe oral agent that may be of benefit to a specific population of NSCLC. PATIENTS AND METHODS A Phase II clinical trial included chemonaïve patients with advanced NSCLC and poor performance status (PS). Response rate, progression-free survival, overall survival, QOL using the Functional Assessment of Cancer Therapy – Lung (FACT-L) questionnaire, and Trial Outcome Index (TOI) were evaluated. RESULTS Twelve out of 19 enrolled patients were evaluable. The median age for the evaluable patients was 68.8 years (59.7–74.6). Out of all the patients, 7 (58.3%) had adenocarcinoma and 5 (41.7%) had squamous cell carcinoma. The median duration of treatment was 62.5 days (26.5–115.0) in the evaluable patients. Grade 3/4 toxicities included fatigue, rash, diarrhea, and nausea. One patient had partial response, eight patients had stable disease (SD), and three patients progressed. The median overall survival for the evaluable population was 4.9 months (2.3–16). The median progression-free survival was 3.7 months (1.9–6.6). TOI was marginally associated with the overall survival, with a hazard ratio of 0.92 (95% confidence interval: 0.84, 1.0) (P = 0.061). FACT-L score and the TOI were highly correlated (r = 0.96, P < 0.0001). TOI scores were higher in African Americans compared to Caucasians and increased with age. CONCLUSION Our results suggest that gefitinib use in patients with NSCLC and poor PS may improve the QOL of older patients and African American patients. PMID:25520566

  15. 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

  16. Results of Phase II Randomized Study of Low-Dose Decitabine with or without Valproic Acid in Patients with Myelodysplastic Syndrome and Acute Myelogenous Leukemia

    PubMed Central

    Issa, Jean Pierre; Garcia-Manero, Guillermo; Huang, Xuelin; Cortes, Jorge; Ravandi, Farhad; Jabbour, Elias; Borthakur, Gautam; Brandt, Mark; Pierce, Sherry; Kantarjian, Hagop

    2014-01-01

    Background Hypomethylating agents have shown activity in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Pre-clinical and single-arm trials have suggested that adding histone deacetylase (HDAC) inhibitors may synergize the epigenetic modulation of hypomethylating agents and improve treatment results. Study Aim To evaluate the possible benefit of adding valproic acid, an HDAC inhibitor, to decitabine, in the treatment of MDS and AML. Methods Patients with higher risk MDS or with AML and age 60 years or older were eligible. Patients were randomized in a Bayesian response-adaptive design to decitabine 20mg/m2 intravenously (IV) daily for 5 days or to decitabine with valproic acid 50mg/1kg orally daily for 7 days. Courses were repeated every 4 to 6 weeks. A maximum of 150 patients were to be treated. Results A total of 149 patients were treated on study, including 87 patients with MDS and 62 patients with AML. The median age was 69 years (range 20 to 89 years; 42% ≥ 70 years). Overall, 34% of patients achieved CR and 55% had an objective response. The median survival was 11.9 months and the estimated 2-year survival rate was 27%. Outcome was not different with the addition of valproic acid to decitabine versus decitabine alone in relation to CR, overall response, or survival. Subset analyses did not demonstrate a benefit within the MDS or AML categories. Toxicities were higher with the combination, in particular neurotoxicity. Conclusions Adding valproic acid to decitabine was not associated with improved outcome in the treatment of MDS or elderly AML. Future therapies may consider combining hypomethylating agents with better HDAC inhibitors and using different schedules. PMID:25336333

  17. Phase II Study of Temsirolimus in Women With Recurrent or Metastatic Endometrial Cancer: A Trial of the NCIC Clinical Trials Group

    PubMed Central

    Oza, Amit M.; Elit, Laurie; Tsao, Ming-Sound; Kamel-Reid, Suzanne; Biagi, Jim; Provencher, Diane Michele; Gotlieb, Walter H.; Hoskins, Paul J.; Ghatage, Prafull; Tonkin, Katia S.; Mackay, Helen J.; Mazurka, John; Sederias, Joana; Ivy, Percy; Dancey, Janet E.; Eisenhauer, Elizabeth A.

    2011-01-01

    Purpose Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene, and loss of function mutations are common and appear to be important in the pathogenesis of endometrial carcinomas. Loss of PTEN causes deregulated phosphatidylinositol-3 kinase/serine-threonine kinase/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling which may provide neoplastic cells with a selective survival advantage by enhancing angiogenesis, protein translation, and cell cycle progression. Temsirolimus, an ester derivative of rapamycin that inhibits mTOR, was evaluated in this setting. Patients and Methods Sequential phase II studies evaluated single-agent activity of temsirolimus in women with recurrent or metastatic chemotherapy-naive or chemotherapy-treated endometrial cancer. Temsirolimus 25 mg intravenously was administered weekly in 4-week cycles. Results In the chemotherapy-naive group, 33 patients received a median of four cycles (range, one to 23 cycles). Of the 29 patients evaluable for response, four (14%) had an independently confirmed partial response and 20 (69%) had stable disease as best response, with a median duration of 5.1 months (range, 3.7 to 18.4 months) and 9.7 months (range, 2.1 to 14.6 months). Only five patients (18%) had progressive disease. In the chemotherapy-treated group, 27 patients received a median of three cycles (range, one to six cycles). Of the 25 patients evaluable for response, one (4%) had an independently confirmed partial response, and 12 patients (48%) had stable disease, with a median duration of 4.3 months (range, 3.6 to 4.9 months) and 3.7 months (range, 2.4 to 23.2 months). PTEN loss (immunohistochemistry and mutational analysis) and molecular markers of PI3K/Akt/mTOR pathway did not correlate with the clinical outcome. Conclusion mTOR inhibition with temsirolimus has encouraging single-agent activity in endometrial cancer which is higher in chemotherapy-naive patients than in chemotherapy-treated patients and is independent of PTEN

  18. 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

  19. Clonal Evolutionary Analysis during HER2 Blockade in HER2-Positive Inflammatory Breast Cancer: A Phase II Open-Label Clinical Trial of Afatinib +/- Vinorelbine

    PubMed Central

    Schmid, Ramona; Arpornwirat, Wichit; Chitapanarux, Imjai; Ganju, Vinod; Im, Seock-Ah; Kim, Sung-Bae; Dechaphunkul, Arunee; Maneechavakajorn, Jedzada; Spector, Neil; Yau, Thomas; Afrit, Mehdi; Ahmed, Slim Ben; Johnston, Stephen R.; Gibson, Neil; Herrero, Javier; Swanton, Charles

    2016-01-01

    Background Inflammatory breast cancer (IBC) is a rare, aggressive form of breast cancer associated with HER2 amplification, with high risk of metastasis and an estimated median survival of 2.9 y. We performed an open-label, single-arm phase II clinical trial (ClinicalTrials.gov NCT01325428) to investigate the efficacy and safety of afatinib, an irreversible ErbB family inhibitor, alone and in combination with vinorelbine in patients with HER2-positive IBC. This trial included prospectively planned exome analysis before and after afatinib monotherapy. Methods and Findings HER2-positive IBC patients received afatinib 40 mg daily until progression, and thereafter afatinib 40 mg daily and intravenous vinorelbine 25 mg/m2 weekly. The primary endpoint was clinical benefit; secondary endpoints were objective response (OR), duration of OR, and progression-free survival (PFS). Of 26 patients treated with afatinib monotherapy, clinical benefit was achieved in 9 patients (35%), 0 of 7 trastuzumab-treated patients and 9 of 19 trastuzumab-naïve patients. Following disease progression, 10 patients received afatinib plus vinorelbine, and clinical benefit was achieved in 2 of 4 trastuzumab-treated and 0 of 6 trastuzumab-naïve patients. All patients had treatment-related adverse events (AEs). Whole-exome sequencing of tumour biopsies taken before treatment and following disease progression on afatinib monotherapy was performed to assess the mutational landscape of IBC and evolutionary trajectories during therapy. Compared to a cohort of The Cancer Genome Atlas (TCGA) patients with HER2-positive non-IBC, HER2-positive IBC patients had significantly higher mutational and neoantigenic burden, more frequent gain-of-function TP53 mutations and a recurrent 11q13.5 amplification overlapping PAK1. Planned exploratory analysis revealed that trastuzumab-naïve patients with tumours harbouring somatic activation of PI3K/Akt signalling had significantly shorter PFS compared to those without

  20. A randomized Phase II study of veliparib with temozolomide or carboplatin/paclitaxel versus placebo with carboplatin/paclitaxel in BRCA1/2 metastatic breast cancer: design and rationale.

    PubMed

    Isakoff, Steven J; Puhalla, Shannon; Domchek, Susan M; Friedlander, Michael; Kaufman, Bella; Robson, Mark; Telli, Melinda L; Diéras, Véronique; Han, Hyo Sook; Garber, Judy E; Johnson, Eric F; Maag, David; Qin, Qin; Giranda, Vincent L; Shepherd, Stacie P

    2017-02-01

    Veliparib is an orally administered poly(ADP-ribose) polymerase inhibitor that is being studied in Phase I-III clinical trials, including Phase III studies in non-small-cell lung cancer, ovarian cancer and breast cancer. Tumor cells with deleterious BRCA1 or BRCA2 mutations are deficient in homologous recombination DNA repair and are intrinsically sensitive to platinum therapy and poly(ADP-ribose) polymerase inhibitors. We describe herein the design and rationale of a Phase II trial investigating whether the addition of veliparib to temozolomide or carboplatin/paclitaxel provides clinical benefit over carboplatin/paclitaxel with placebo in patients with locally recurrent or metastatic breast cancer harboring a deleterious BRCA1 or BRCA2 germline mutation (Trial registration: EudraCT 2011-002913-12, NCT01506609).

  1. Experimental studies: randomized clinical trials.

    PubMed

    Gjorgov, A N

    1998-01-01

    There are two major approaches to medical investigations: observational studies and experimental trials. The classical application of the experimental design to studies of human populations is the randomized clinical trial of the efficacy of a new drug or treatment. A further application of the experimental studies is to the testing of hypotheses about the etiology of a disease, already tested and corroborated from various forms of observational studies. Ethical considerations and requirements for consent of the experimental subjects are of primary concern in the clinical trials, and those concerns set the first and final limits for implementing a trial. General moral principles in research with human and animal beings, defined by the "Nuremberg Code," deal with strict criteria for approval, endorsement and evaluation of a clinical trial.

  2. PEPCOL: a GERCOR randomized phase II study of nanoliposomal irinotecan PEP02 (MM-398) or irinotecan with leucovorin/5-fluorouracil as second-line therapy in metastatic colorectal cancer.

    PubMed

    Chibaudel, Benoist; Maindrault-Gœbel, Frédérique; Bachet, Jean-Baptiste; Louvet, Christophe; Khalil, Ahmed; Dupuis, Olivier; Hammel, Pascal; Garcia, Marie-Line; Bennamoun, Mostefa; Brusquant, David; Tournigand, Christophe; André, Thierry; Arbaud, Claire; Larsen, Annette K; Wang, Yi-Wen; Yeh, C Grace; Bonnetain, Franck; de Gramont, Aimery

    2016-04-01

    A multicenter, open-label, noncomparative, randomized phase II study (PEPCOL) was conducted to evaluate the efficacy and safety of the irinotecan or PEP02 (MM-398, nanoliposomal irinotecan) with leucovorin (LV)/5-fluorouracil (5-FU) combination as second-line treatment in patients with metastatic colorectal cancer (mCRC). Patients with unresectable mCRC who had failed one prior oxaliplatin-based first-line therapy were randomized toirinotecan with LV/5-FU (FOLFIRI) or PEP02 with LV/5-FU (FUPEP; PEP02 80 mg/m(2) with LV 400 mg/m(2) on day 1 and 5-FU 2400 mg/m(2) on days 1-2). Bevacizumab (5 mg/kg, biweekly) was allowed in both arms. The primary endpoint was 2-month response rate (RR). Fifty-five patients were randomized (FOLFIRI, n = 27; FUPEP, n = 28). In the intent-to-treat population (n = 55), 2-month RR response rate was observed in two (7.4%) and three (10.7%) patients in the FOLFIRI and FUPEP arms, respectively. The most common grade 3-4 adverse events reported in the respective FOLFIRI and FUPEP arms were diarrhea (33% vs. 21%), neutropenia (30% vs. 11%), mucositis (11% vs. 11%), and grade 2 alopecia (26% vs. 25%). FUPEP has activity and acceptable safety profile in oxaliplatin-pretreated mCRC patients.

  3. Randomized Phase II Study of Cabazitaxel Versus Methotrexate in Patients With Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck Previously Treated With Platinum-Based Therapy

    PubMed Central

    Van Maanen, Aline; Vandenbulcke, Jean-Marie; Filleul, Bertrand; Seront, Emmanuel; D’Hondt, Lionel; Lonchay, Christophe; Holbrechts, Stéphane; Boegner, Petra; Brohee, Dany; Dequanter, Didier; Louviaux, Ingrid; Sautois, Brieuc; Whenham, Nicolas; Berchem, Guy; Vanderschueren, Brigitte; Fontaine, Christel; Schmitz, Sandra; Gillain, Aline; Schoonjans, Joelle; Rottey, Sylvie

    2016-01-01

    Lessons Learned Cabazitaxel has activity in squamous cell carcinoma of the head and neck (SCCHN) and taxane-resistant cell lines. For the first time, cabazitaxel was investigated in incurable patients with recurrent SCCHN. Patients were randomly assigned to cabazitaxel every 3 weeks or weekly methotrexate. This phase II study did not meet its primary endpoint. Cabazitaxel has low activity in SCCHN. The toxicity profile in this population also was not favorable owing to the high rate of febrile neutropenia observed (17%). Background. Cabazitaxel is a second-generation taxane that improves the survival of patients with metastatic castrate-resistant prostate cancer following docetaxel therapy. Cabazitaxel has activity in squamous cell carcinoma of the head and neck (SCCHN) and taxane-resistant cell lines. In this randomized phase II trial, we investigated cabazitaxel in patients with recurrent SCCHN. Methods. Patients with incurable SCCHN with progression after platinum-based therapy were randomly assigned to cabazitaxel every 3 weeks (cycle 1, 20 mg/m2, increased to 25 mg/m2 for subsequent cycles in the absence of nonhematological adverse events [AEs] greater than grade 2 and hematological AEs greater than grade 3) or methotrexate (40 mg/m2/week). The patients were stratified according to their performance status and previous platinum-based chemotherapy for palliation versus curative intent. The primary endpoint was the progression-free survival rate (PFSR) at 18 weeks. Results. Of the 101 patients, 53 and 48, with a median age of 58.0 years (range, 41–80), were randomly assigned to cabazitaxel or methotrexate, respectively. The PFSR at 18 weeks was 13.2% (95% confidence interval [CI], 5%–25%) for cabazitaxel and 8.3% (95% CI, 2%–20%) for methotrexate. The median progression-free survival was 1.9 months in both arms. The median overall survival was 5.0 and 3.6 months for cabazitaxel and methotrexate, respectively. More patients experienced serious adverse

  4. Administration of Adult Human Bone Marrow-Derived, Cultured, Pooled, Allogeneic Mesenchymal Stromal Cells in Critical Limb Ischemia Due to Buerger's Disease: Phase II Study Report Suggests Clinical Efficacy.

    PubMed

    Gupta, Pawan K; Krishna, Murali; Chullikana, Anoop; Desai, Sanjay; Murugesan, Rajkumar; Dutta, Santanu; Sarkar, Uday; Raju, Radhakrishnan; Dhar, Anita; Parakh, Rajiv; Jeyaseelan, Lakshmanan; Viswanathan, Pachaiyappan; Vellotare, Prasanth Kulapurathu; Seetharam, Raviraja N; Thej, Charan; Rengasamy, Mathiyazhagan; Balasubramanian, Sudha; Majumdar, Anish S

    2017-03-01

    Critical limb ischemia (CLI) due to Buerger's disease is a major unmet medical need with a high incidence of morbidity. This phase II, prospective, nonrandomized, open-label, multicentric, dose-ranging study was conducted to assess the efficacy and safety of i.m. injection of adult human bone marrow-derived, cultured, pooled, allogeneic mesenchymal stromal cells (BMMSC) in CLI due to Buerger's disease. Patients were allocated to three groups: 1 and 2 million cells/kg body weight (36 patients each) and standard of care (SOC) (18 patients). BMMSCs were administered as 40-60 injections in the calf muscle and locally, around the ulcer. Most patients were young (age range, 38-42 years) and ex-smokers, and all patients had at least one ulcer. Both the primary endpoints-reduction in rest pain (0.3 units per month [SE, 0.13]) and healing of ulcers (11% decrease in size per month [SE, 0.05])-were significantly better in the group receiving 2 million cells/kg body weight than in the SOC arm. Improvement in secondary endpoints, such as ankle brachial pressure index (0.03 [SE, 0.01] unit increase per month) and total walking distance (1.03 [SE, 0.02] times higher per month), were also significant in the group receiving 2 million cells/kg as compared with the SOC arm. Adverse events reported were remotely related or unrelated to BMMSCs. In conclusion, i.m. administration of BMMSC at a dose of 2 million cells/kg showed clinical benefit and may be the best regimen in patients with CLI due to Buerger's disease. However, further randomized controlled trials are required to confirm the most appropriate dose. Stem Cells Translational Medicine 2017;6:689-699.

  5. 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 Central

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

    2015-01-01

    Purpose We conducted a Phase I study of noni in patients with advanced cancer. Quality of life measures were examined as an alternate way to select a Phase II dose of this popular dietary supplement. Patients and Methods Starting at two capsules twice daily (2 grams), the dose suggested for marketed products, dose levels were escalated by 2 grams daily in cohorts of at least five patients until a maximum tolerated dose was found. Patients completed QLQ-C30 Quality of Life, and the Brief Fatigue Inventory (BFI), questionnaires at baseline and at four week intervals. Scopoletin was measured in blood and urine collected at baseline and at approximately four week intervals. Results Fifty-one patients were enrolled at seven dose levels. Seven capsules four times daily (14 grams) was the maximum tolerated dose. No dose limiting toxicity was found but four of eight patients at this level withdrew from the study due to the challenges of ingesting so many capsules. There was a dose response for self reported physical functioning and the control of pain and fatigue. Patients taking four capsules four times daily experienced less fatigue than patients taking lower or higher doses. A relationship between noni dose and blood and urinary scopoletin concentrations was found. Conclusion Measuring quality of life to determine a dose for subsequent Phase II testing is feasible. A noni dose of four capsules four times daily (8 grams) is recommended for Phase II testing where controlling fatigue and maintaining physical function is the efficacy of interest. Scopoletin is a measurable noni ingredient for pharmacokinetic studies in patients with cancer. PMID:22435516

  6. Randomized phase II trial of BCDT [carmustine (BCNU), cisplatin, dacarbazine (DTIC) and tamoxifen] with or without interferon alpha (IFN-alpha) and interleukin (IL-2) in patients with metastatic melanoma.

    PubMed Central

    Johnston, S. R.; Constenla, D. O.; Moore, J.; Atkinson, H.; A'Hern, R. P.; Dadian, G.; Riches, P. G.; Gore, M. E.

    1998-01-01

    The purpose of this study was to evaluate in a randomized phase II trial the efficacy and toxicity of combination biochemotherapy compared with chemotherapy alone in patients with metastatic melanoma. Sixty-five patients with metastatic melanoma (ECOG performance status 0 or 1) were randomized to receive intravenous BCNU 100 mg m(-2) (day 1, alternate courses), cisplatin 25 mg m(-2) (days 1-3), DTIC 220 mg m(-2) (days 1-3) and oral tamoxifen 40 mg (BCDT regimen) with (n = 35) or without (n = 30) subcutaneous interleukin 2 (IL-2) 18 x 10(6) iu t.d.s. (day - 2), 9 x 10(6) iu b.d. (day - 1 and 0) and interferon 2 alpha (IFN-alpha) 9 MU (days 1-3). Evidence for immune activation was determined by flow cytometric analysis of peripheral blood lymphocytes. Treatment was repeated every 4 weeks up to six courses depending on response. The overall response rate of BCDT with IL-2/IFN-alpha was 23% [95% confidence interval (CI) 10-40%] with one complete response (CR) and seven partial responses (PR), and for BCDT alone 27% (95% CI 12-46%) with eight PRs; the median durations of response were 2.8 months and 2.5 months respectively. Sites of response were similar in both groups. There was no difference between the two groups in progression-free survival or overall survival (median survival 5 months for BCDT with IL-2/IFNalpha and 5.5 months for BCDT alone). Although 3 days of subcutaneous IL-2 resulted in significant lymphopenia, evidence of immune activation was indicated by a significant rise in the percentage of CD56- (NK cells) and CD3/HLA-DR-positive (activated T cells) subsets, without any change in the percentage of CD4 or CD4 T-cell subsets. Toxicity assessment revealed a significantly higher incidence of severe thrombocytopenia in patients treated with combination chemotherapy than with chemotherapy alone (37% vs 13%, P = 0.03) and a higher incidence of grade 3/4 flu-like symptoms (20% vs 10%) and fatigue (26% vs 13%). The addition of subcutaneous IL-2 and IFNalpha to

  7. A Phase II Randomized, Controlled Trial of S-Adenosylmethionine in Reducing Serum α-Fetoprotein in Patients with Hepatitis C Cirrhosis and Elevated AFP.

    PubMed

    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

    2015-09-01

    In animal models of hepatocellular carcinoma (HCC), deficiency of S-adenosylmethionine (SAMe) increased the risk of HCC whereas 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 α-fetoprotein (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 g/d, 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. One hundred ten 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.

  8. A Phase II, Randomized, Double-Blind, Placebo-Controlled Study of Siltuximab (Anti-IL-6 mAb) and Bortezomib versus Bortezomib Alone in Patients with Relapsed or Refractory Multiple Myeloma

    PubMed Central

    Orlowski, Robert Z.; Gercheva, Liana; Williams, Cathy; Sutherland, Heather; Robak, Tadeusz; Masszi, Tamás; Goranova-Marinova, Vesselina; Dimopoulos, Meletios A.; Cavenagh, James D.; Špička, Ivan; Maiolino, Angelo; Suvorov, Alexander; Bladé, Joan; Samoylova, Olga; Puchalski, Thomas A.; Reddy, Manjula; Bandekar, Rajesh; van de Velde, Helgi; Xie, Hong; Rossi, Jean-François

    2016-01-01

    We compared the safety and efficacy of siltuximab (S), an anti-interleukin-6 chimeric monoclonal antibody, plus bortezomib (B) with placebo (plc)+B in patients with relapsed/refractory multiple myeloma in a randomized phase II study. Siltuximab was given by 6 mg/kg IV every 2 weeks. On progression, B was discontinued and high-dose dexamethasone could be added to S/plc. Response and progression-free survival (PFS) were analyzed pre-dexamethasone by EBMT criteria. For the 281 randomized patients, median PFS for S+B and plc+B was 8.0 and 7.6 months (HR 0.869, p=0.345), overall response rate was 55% vs. 47% (p=0.213), complete response rate was 11% vs. 7%, and median overall survival (OS) was 30.8 vs. 36.8 months (HR 1.353, p=0.103). Sustained suppression of C-reactive protein, a marker reflective of inhibition of interleukin-6 activity, was seen with S+B. Siltuximab did not affect B pharmacokinetics. S/plc discontinuation (75% vs. 66%), grade ≥3 neutropenia (49% vs. 29%), thrombocytopenia (48% vs. 34%), and all-grade infections (62% vs. 49%) occurred more frequently with S+B. The addition of siltuximab to bortezomib did not appear to improve PFS or OS despite a numerical increase in response rate in patients with relapsed or refractory multiple myeloma. PMID:25294016

  9. A phase II/III randomized study to compare the efficacy and safety of rigosertib plus gemcitabine versus gemcitabine alone in patients with previously untreated metastatic pancreatic cancer†

    PubMed Central

    O'Neil, B. H.; Scott, A. J.; Ma, W. W.; Cohen, S. J.; Aisner, D. L.; Menter, A. R.; Tejani, M. A.; Cho, J. K.; Granfortuna, J.; Coveler, L.; Olowokure, O. O.; Baranda, J. C.; Cusnir, M.; Phillip, P.; Boles, J.; Nazemzadeh, R.; Rarick, M.; Cohen, D. J.; Radford, J.; Fehrenbacher, L.; Bajaj, R.; Bathini, V.; Fanta, P.; Berlin, J.; McRee, A. J.; Maguire, R.; Wilhelm, F.; Maniar, M.; Jimeno, A.; Gomes, C. L.; Messersmith, W. A.

    2015-01-01

    Background Rigosertib (ON 01910.Na), a first-in-class Ras mimetic and small-molecule inhibitor of multiple signaling pathways including polo-like kinase 1 (PLK1) and phosphoinositide 3-kinase (PI3K), has shown efficacy in preclinical pancreatic cancer models. In this study, rigosertib was assessed in combination with gemcitabine in patients with treatment-naïve metastatic pancreatic adenocarcinoma. Materials and methods Patients with metastatic pancreatic adenocarcinoma were randomized in a 2:1 fashion to gemcitabine 1000 mg/m2 weekly for 3 weeks of a 4-week cycle plus rigosertib 1800 mg/m2 via 2-h continuous IV infusions given twice weekly for 3 weeks of a 4-week cycle (RIG + GEM) versus gemcitabine 1000 mg/m2 weekly for 3 weeks in a 4-week cycle (GEM). Results A total of 160 patients were enrolled globally and randomly assigned to RIG + GEM (106 patients) or GEM (54). The most common grade 3 or higher adverse events were neutropenia (8% in the RIG + GEM group versus 6% in the GEM group), hyponatremia (17% versus 4%), and anemia (8% versus 4%). The median overall survival was 6.1 months for RIG + GEM versus 6.4 months for GEM [hazard ratio (HR), 1.24; 95% confidence interval (CI) 0.85–1.81]. The median progression-free survival was 3.4 months for both groups (HR = 0.96; 95% CI 0.68–1.36). The partial response rate was 19% versus 13% for RIG + GEM versus GEM, respectively. Of 64 tumor samples sent for molecular analysis, 47 were adequate for multiplex genetic testing and 41 were positive for mutations. The majority of cases had KRAS gene mutations (40 cases). Other mutations detected included TP53 (13 cases) and PIK3CA (1 case). No correlation between mutational status and efficacy was detected. Conclusions The combination of RIG + GEM failed to demonstrate an improvement in survival or response compared with GEM in patients with metastatic pancreatic adenocarcinoma. Rigosertib showed a similar safety profile to that seen in previous trials using the IV

  10. 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

    2012-09-07

    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.

  11. Efficacy and safety of liraglutide 3.0 mg for weight management are similar across races: subgroup analysis across the SCALE and phase II randomized trials.

    PubMed

    Ard, J; Cannon, A; Lewis, C E; Lofton, H; Vang Skjøth, T; Stevenin, B; Pi-Sunyer, X

    2016-04-01

    The efficacy and safety of liraglutide 3.0 mg versus placebo, as adjunct to diet and exercise, was evaluated in racial subgroups. This post hoc analysis of pooled data from five double-blind randomized, placebo-controlled trials was conducted in 5325 adults with either a body mass index (BMI) ≥27 kg/m(2) plus ≥1 comorbidity or a BMI ≥30 kg/m(2). Statistical interaction tests evaluated possible treatment effect differences between racial subgroups: white (4496, 84.4%), black/African-American (550, 10.3%), Asian (168, 3.2%) and other (111, 2.1%). Effects of liraglutide 3.0 mg on weight loss, associated metabolic effects and safety profile were generally consistent across racial subgroups. All achieved statistically significant mean weight loss at end-of-treatment with liraglutide 3.0 mg versus placebo: white 7.7% versus 2.3%, black/African-American 6.3% versus 1.4%, Asian 6.3% versus 2.5%, other 7.3% versus 0.49%. Treatment effects on weight and cardiovascular risk markers generally showed no dependence on race (interaction test p > 0.05). Adverse events were similar across racial subgroups.

  12. 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.

  13. 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

  14. 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

  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. 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

  17. 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

  18. Combination verteporfin photodynamic therapy ranibizumab-dexamethasone in choroidal neovascularization due to age-related macular degeneration: results of a phase II randomized trial

    PubMed Central

    Gallemore, Ron P; Wallsh, Josh; Hudson, Henry L; Ho, Allen C; Chace, Richard; Pearlman, Joel

    2017-01-01

    Purpose To assess whether combination therapy (CT) reduces retreatments when compared to ranibizumab monotherapy (RM), while safely maintaining similar vision outcomes. Methods In this 24-month trial, patients with age-related macular degeneration (AMD) were randomized to 1) quarter-fluence or 2) half-fluence triple therapy (verteporfin photodynamic therapy [vPDT] + ranibizumab + dexamethasone), 3) half-fluence double therapy (vPDT + ranibizumab), or 4) RM. The primary outcomes were number of retreatment visits and change from baseline in visual acuity (VA) at 12 months. Results One hundred sixty-two subjects enrolled. There were 4.0 (P=0.02), 3.2 (P<0.001), 4.1 (P=0.03), and 5.7 retreatment visits through month 12, and 5.9 (P=0.03), 4.3 (P<0.001), 5.9 (P=0.02) and 8.7 through month 24, in groups 1, 2, 3, and 4, respectively (P-value comparing with RM). Month 12 VA score change from baseline (95% confidence interval) was +3.6 (−0.9 to +8.1), +6.8 (+2.4 to +11.1), +5.0 (+0.6 to +9.3), and +6.5 (+1.7 to +11.4), respectively. Conclusion CT resulted in significantly fewer retreatment visits than a RM regimen at months 12 and 24. VA results appeared similar although wide confidence intervals preclude conclusions regarding vision outcomes. PMID:28182161

  19. A Phase II, Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study of Belimumab in Patients With Active Systemic Lupus Erythematosus

    PubMed Central

    Wallace, Daniel J.; Stohl, William; Furie, Richard A.; Lisse, Jeffrey R.; McKay, James D.; Merrill, Joan T.; Petri, Michelle A.; Ginzler, Ellen M.; Chatham, W. Winn; McCune, W. Joseph; Fernandez, Vivian; Chevrier, Marc R.; Zhong, John; Freimuth, William W.

    2009-01-01

    Objective To assess the safety, tolerability, biological activity, and efficacy of belimumab in combination with standard of care therapy (SOC) in patients with active systemic lupus erythematosus (SLE). Methods Patients with SELENA-SLEDAI score≥4 (N=449) were randomly assigned to belimumab (1, 4, 10 mg/kg) or placebo in a 52-week study. Co-primary endpoints were: 1) percentage change in the SELENA-SLEDAI score at week 24; 2) time to the first SLE flare. Results Significant differences between the treatment and placebo groups were not attained for either primary endpoint and no dose response was observed. Reduction in SELENA-SLEDAI score from baseline was 19.5% in the combined belimumab group versus 17.2% in the placebo group. The median time to first SLE flare was 67 days in the combined belimumab group versus 83 days in the placebo group. However, the median time to first SLE flare during weeks 24–52 was significantly longer with belimumab treatment (154 versus 108 days; P=0.0361). In the subgroup (71.5%) of serologically active patients (ANA ≥1:80 and/or anti-dsDNA ≥30 IU/mL), belimumab treatment resulted in significantly better responses at week 52 than placebo for SELENA-SLEDAI (−28.8% versus −14.2%; P=0.0435); PGA (−32.7% versus −10.7%; P=0.0011); and SF-36 PCS (+3.0 versus +1.2 points; P=0.0410). Treatment with belimumab resulted in 63–71% depletion of naive, activated, and plasmacytoid CD20+ B cells and a 29.4% reduction in anti-dsDNA titers (P ≤0.0017) by week 52. The rates of adverse events (AEs) and serious AEs were similar in the belimumab and placebo groups. Conclusion Belimumab was biologically active and well tolerated. Belimumab effect on the reduction of SLE disease activity or flares was not significant. However, serologically active SLE patients responded significantly better to belimumab therapy plus SOC than SOC alone. PMID:19714604

  20. Paclitaxel, bevacizumab, and everolimus/placebo as first-line treatment for patients with metastatic HER2-negative breast cancer: a randomized placebo-controlled phase II trial of the Sarah Cannon Research Institute.

    PubMed

    Yardley, Denise A; Bosserman, Linda D; O'Shaughnessy, Joyce A; Harwin, William N; Morgan, Susan K; Priego, Victor M; Peacock, Nancy W; Bass, J David; Burris, Howard A; Hainsworth, John D

    2015-11-01

    Amplified PI3K/Akt/mTOR signaling is common in metastatic breast cancer (MBC). The mTOR inhibitor everolimus improves progression-free survival (PFS) when added to steroidal aromatase inhibitor therapy. This randomized phase II trial compares the efficacy of paclitaxel/bevacizumab/everolimus and paclitaxel/bevacizumab/placebo as first-line treatment for MBC. Patients with untreated HER2-negative MBC were randomized (1:1) to receive 28-day cycles of paclitaxel 90 mg/m(2) IV (days 1, 8, and 15) and bevacizumab 10 mg/kg IV (days 1, 15) with either everolimus 10 mg (Arm 1) or placebo (Arm 2) daily. Treatment continued (evaluation every 8 weeks) until progression or unacceptable toxicity. Treatment of 110 patients allowed detection of an improvement in median PFS from 11 to 16 months (70 % power, α = 0.10). Between August 2009 and June 2011, 113 patients (median age 58 years; 88 % ER or PR positive) were randomized (Arm 1, 56; Arm 2, 57). Patients in both arms received a median of six treatment cycles. Median PFS (95 % CI) was 9.1 months (6.8-18.8) for Arm 1, and 7.1 months (5.6-10.8) for Arm 2 (p = 0.89). Comparisons of other efficacy endpoints were also similar in the two treatment arms. Patients receiving everolimus had more anemia, stomatitis, diarrhea, rash, and arthralgia/myalgia, although the overall incidence of severe (grade 3/4) toxicity was similar. The addition of everolimus did not improve the efficacy of weekly paclitaxel/bevacizumab as first-line treatment for patients with HER2-negative MBC. These results contrast with the demonstrated efficacy of adding everolimus to either hormonal or HER2-targeted therapy in previously treated patients.

  1. 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.

  2. Addition of cladribine to the standard induction treatment improves outcomes in a subset of elderly acute myeloid leukemia patients. Results of a randomized Polish Adult Leukemia Group (PALG) phase II trial.

    PubMed

    Pluta, Agnieszka; Robak, Tadeusz; Wrzesien-Kus, Agata; Katarzyna Budziszewska, Bozena; Sulek, Kazimierz; Wawrzyniak, Ewa; Czemerska, Magdalena; Zwolinska, Malgorzata; Golos, Aleksandra; Holowiecka-Goral, Aleksandra; Kyrcz-Krzemien, Slawomira; Piszcz, Jaroslaw; Kloczko, Janusz; Mordak-Domagala, Monika; Lange, Andrzej; Razny, Małgorzata; Madry, Krzysztof; Wiktor-Jedrzejczak, Wieslaw; Grosicki, Sebastian; Butrym, Aleksandra; Kuliczkowski, Kazimierz; Warzocha, Krzysztof; Holowiecki, Jerzy; Giebel, Sebastian; Szydlo, Richard; Wierzbowska, Agnieszka

    2017-04-01

    Intensive induction chemotherapy using anthracycline and cytarabine backbone is considered the most effective upfront therapy in physically fit older patients with acute myeloid leukemia (AML). However, outcomes of the standard induction in elderly AML are inferior to those observed in younger patients, and they are still unsatisfactory. As addition of cladribine to the standard induction therapy is known to improve outcome in younger AML patients. The present randomized phase II study compares efficacy and toxicity of the DAC (daunorubicin plus cytarabine plus cladribine) regimen with the standard DA (daunorubicin plus cytarabine) regimen in the newly diagnosed AML patients over 60 years of age. A total of 171 patients were enrolled in the study (DA, 86; DAC, 85). A trend toward higher complete remission (CR) was observed in the DAC arm compared to the DA arm (44% vs. 34%; P = .19), which did not lead to improved median overall survival, which in the case of the DAC group was 8.6 months compared to in 9.1 months in the DA group (P = .64). However, DAC appeared to be superior in the group of patients aged 60-65 (CR rate: DAC 51% vs. DA 29%; P = .02). What is more, a subgroup of patients, with good and intermediate karyotypes, benefited from addition of cladribine also in terms of overall survival (P = .02). No differences in hematological and nonhematological toxicity between the DA and DAC regimens were observed.

  3. The interplay of epigenetic therapy and immunity in locally recurrent or metastatic estrogen receptor-positive breast cancer: Correlative analysis of ENCORE 301, a randomized, placebo-controlled phase II trial of exemestane with or without entinostat

    PubMed Central

    Tomita, Yusuke; Lee, Min-Jung; Lee, Sunmin; Tomita, Saori; Chumsri, Saranya; Cruickshank, Scott; Ordentlich, Peter; Trepel, Jane B.

    2016-01-01

    ABSTRACT Entinostat, a class I-selective histone deacetylase inhibitor, has shown promising activity in ENCORE 301, a randomized, placebo-controlled, phase II trial of exemestane with or without entinostat in women with locally recurrent or metastatic estrogen receptor-positive breast cancer progressing on a nonsteroidal aromatase inhibitor. ENCORE 301 showed an 8.3-mo improvement in median overall survival among patients who received entinostat. We investigated the impact of entinostat on immune subsets with CD40, HLA-DR, and immune checkpoint receptor expression analyses in 34 patient blood samples from ENCORE 301. We found that entinostat significantly decreased granulocytic and monocytic MDSCs at cycle 1 day 15. MDSC CD40 was significantly downregulated by entinostat. A significant increase in HLA-DR expression on CD14+ monocytes by entinostat was observed. Entinostat did not impact T-cell subsets or T-cell immune checkpoint receptor expression. Our findings suggest that a significant interplay between this epigenetic regimen and host immune homeostatic mechanisms may impact therapeutic outcome. PMID:27999738

  4. 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

  5. SOLTI NeoPARP: a phase II randomized study of two schedules of iniparib plus paclitaxel versus paclitaxel alone as neoadjuvant therapy in patients with triple-negative breast cancer

    PubMed Central

    Llombart-Cussac, Antonio; Bermejo, Begoña; Villanueva, Cristian; Delaloge, Suzette; Morales, Serafín; Balmaña, Judith; Amillano, Kepa; Bonnefoi, Hervé; Casas, Ana; Manso, Luis; Roché, Henri; Gonzalez-Santiago, Santiago; Gavilá, Joaquín; Sánchez-Rovira, Pedro; Di Cosimo, Serena; Harbeck, Nadia; Charpentier, Eric; Garcia-Ribas, Ignacio; Radosevic-Robin, Nina; Aura, Claudia; Baselga, Jose

    2016-01-01

    Iniparib is an investigational agent with antitumor activity of controversial mechanism of action. Two previous trials in advanced triple-negative breast cancer (TNBC) in combination with gemcitabine and carboplatin showed some evidence of efficacy that was not confirmed. This phase II randomized neoadjuvant study was designed to explore its activity and tolerability with weekly paclitaxel (PTX) as neoadjuvant treatment in TNBC patients. 141 patients with Stage II–IIIA TNBC were randomly assigned to receive PTX (80 mg/m2, d1; n = 47) alone or in combination with iniparib, either once-weekly (PWI) (11.2 mg/kg, d1; n = 46) or twice-weekly (PTI) (5.6 mg/kg, d1, 4; n = 48) for 12 weeks. Primary endpoint was pathologic complete response (pCR) in the breast. pCR rate was similar among the three arms (21, 22, and 19 % for PTX, PWI, and PTI, respectively). Secondary efficacy endpoints were comparable: pCR in breast and axilla (21, 17, and 19 %); best overall response in the breast (60, 61, and 63 %); and breast conservation rate (53, 54, and 50 %). Slightly more patients in the PTI arm presented grade 3/4 neutropenia (4, 0, and 10 %). Grade 1/2 (28, 22, and 29 %), but no grade 3/4 neuropathy, was observed. There were no differences in serious adverse events and treatment-emergent adverse events leading to treatment discontinuation among the three arms. Addition of iniparib to weekly PTX did not add relevant antitumor activity or toxicity. These results do not support further evaluation of the combination of iniparib at these doses plus paclitaxel in early TNBC. PMID:26536871

  6. SOLTI NeoPARP: a phase II randomized study of two schedules of iniparib plus paclitaxel versus paclitaxel alone as neoadjuvant therapy in patients with triple-negative breast cancer.

    PubMed

    Llombart-Cussac, Antonio; Bermejo, Begoña; Villanueva, Cristian; Delaloge, Suzette; Morales, Serafín; Balmaña, Judith; Amillano, Kepa; Bonnefoi, Hervé; Casas, Ana; Manso, Luis; Roché, Henri; Gonzalez-Santiago, Santiago; Gavilá, Joaquín; Sánchez-Rovira, Pedro; Di Cosimo, Serena; Harbeck, Nadia; Charpentier, Eric; Garcia-Ribas, Ignacio; Radosevic-Robin, Nina; Aura, Claudia; Baselga, Jose

    2015-11-01

    Iniparib is an investigational agent with antitumor activity of controversial mechanism of action. Two previous trials in advanced triple-negative breast cancer (TNBC) in combination with gemcitabine and carboplatin showed some evidence of efficacy that was not confirmed. This phase II randomized neoadjuvant study was designed to explore its activity and tolerability with weekly paclitaxel (PTX) as neoadjuvant treatment in TNBC patients. 141 patients with Stage II-IIIA TNBC were randomly assigned to receive PTX (80 mg/m(2), d1; n = 47) alone or in combination with iniparib, either once-weekly (PWI) (11.2 mg/kg, d1; n = 46) or twice-weekly (PTI) (5.6 mg/kg, d1, 4; n = 48) for 12 weeks. Primary endpoint was pathologic complete response (pCR) in the breast. pCR rate was similar among the three arms (21, 22, and 19 % for PTX, PWI, and PTI, respectively). Secondary efficacy endpoints were comparable: pCR in breast and axilla (21, 17, and 19 %); best overall response in the breast (60, 61, and 63 %); and breast conservation rate (53, 54, and 50 %). Slightly more patients in the PTI arm presented grade 3/4 neutropenia (4, 0, and 10 %). Grade 1/2 (28, 22, and 29 %), but no grade 3/4 neuropathy, was observed. There were no differences in serious adverse events and treatment-emergent adverse events leading to treatment discontinuation among the three arms. Addition of iniparib to weekly PTX did not add relevant antitumor activity or toxicity. These results do not support further evaluation of the combination of iniparib at these doses plus paclitaxel in early TNBC.

  7. Analysis of phase II methodologies for single-arm clinical trials with multiple endpoints in rare cancers: An example in Ewing's sarcoma.

    PubMed

    Dutton, P; Love, S B; Billingham, L; Hassan, A B

    2016-09-01

    Trials run in either rare diseases, such as rare cancers, or rare sub-populations of common diseases are challenging in terms of identifying, recruiting and treating sufficient patients in a sensible period. Treatments for rare diseases are often designed for other disease areas and then later proposed as possible treatments for the rare disease after initial phase I testing is complete. To ensure the trial is in the best interests of the patient participants, frequent interim analyses are needed to force the trial to stop promptly if the treatment is futile or toxic. These non-definitive phase II trials should also be stopped for efficacy to accelerate research progress if the treatment proves to be particularly promising. In this paper, we review frequentist and Bayesian methods that have been adapted to incorporate two binary endpoints and frequent interim analyses. The Eurosarc Trial of Linsitinib in advanced Ewing Sarcoma (LINES) is used as a motivating example and provides a suitable platform to compare these approaches. The Bayesian approach provides greater design flexibility, but does not provide additional value over the frequentist approaches in a single trial setting when the prior is non-informative. However, Bayesian designs are able to borrow from any previous experience, using prior information to improve efficiency.

  8. Clinical activity of everolimus in relapsed/refractory marginal zone B-cell lymphomas: results of a phase II study of the International Extranodal Lymphoma Study Group.

    PubMed

    Conconi, Annarita; Raderer, Markus; Franceschetti, Silvia; Devizzi, Liliana; Ferreri, Andrés J M; Magagnoli, Massimo; Arcaini, Luca; Zinzani, Pier Luigi; Martinelli, Giovanni; Vitolo, Umberto; Kiesewetter, Barbara; Porro, Elena; Stathis, Anastasios; Gaidano, Gianluca; Cavalli, Franco; Zucca, Emanuele

    2014-07-01

    The International Extranodal Lymphoma Study Group coordinated a phase II trial to evaluate the activity and safety of everolimus in marginal zone lymphomas (MZLs). Thirty patients with relapsed/refractory MZLs received everolimus for six cycles or until dose-limiting toxicity or progression. Median age was 71 years (range, 51-88 years). Twenty patients had extranodal, six splenic, four nodal MZL. Twenty-four patients had stage III-IV. Median number of prior therapies was two (range 1-5). Seventeen patients had early treatment discontinuation, in most cases due to toxicity. Median number of cycles was 4.5 (range, 1-16). Among the 24 assessable patients, the overall response rate (ORR) was 25% (95% confidence interval: 10-47). Grade 3-4 adverse events were neutropenia and thrombocytopenia (17% of patients, each), infections (17%), mucositis and odontogenic infections (13%) and lung toxicity (3%). The median response duration was 6.8 months (range, 1.4-11.1+). After a median follow-up of 14.5 months, five deaths were reported: four deaths were due to lymphoma, one was due to toxicity. In an intent-to-treat analysis, the projected median progression-free survival was 14 months. The moderate antitumour activity of everolimus in relapsed/refractory MZLs and the observed toxicity limit its therapeutical applicability in these indolent entities. Lower doses of the drug and, perhaps, different strategies including combination with additional agents need to be explored.

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

    PubMed

    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

  10. 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

  11. Safety and acceptability of vaginal disinfection with benzalkonium chloride in HIV infected pregnant women in west Africa: ANRS 049b phase II randomized, double blinded placebo controlled trial. DITRAME Study Group

    PubMed Central

    Msellati, P.; Meda, N.; Leroy, V.; Likikouet, R.; Van de Perre, P.; Cartoux, M.; Bonard, D.; Ouangre, A.; Combe, P.; Gautier-Charpenti..., L.; Sylla-Koko, F.; Lassalle, R.; Dosso, M.; Welffens-Ekra, C.; Dabis, F.; Mandelbrot, L.

    1999-01-01

    OBJECTIVES: To study the tolerance and acceptability in Africa of a perinatal intervention to prevent vertical HIV transmission using benzalkonium chloride disinfection. DESIGN: A randomized, double blinded phase II trial. SETTING: Prenatal care units in Abidjan (Cote d'Ivoire) and Bobo-Dioulasso (Burkina Faso). PATIENTS: Women accepting testing and counselling who were seropositive for HIV-1 and under 37 weeks of pregnancy were eligible. A total of 108 women (54 in each group) enrolled from November 1996 to April 1997, with their informed consent. INTERVENTION: Women self administered daily a vaginal suppository of 1% benzalkonium chloride or matched placebo from 36 weeks of pregnancy, and a single intrapartum dose. The neonate was bathed with 1% benzalkonium chloride solution or placebo within 30 minutes after birth. MAIN OUTCOME MEASURES: Adverse events were recorded weekly, with a questionnaire and speculum examination in women through delivery, and examination of the neonate through day 30. The incidence of genital signs and symptoms in the women and cutaneous or ophthalmological events in newborns were compared between groups on an intent to treat basis. RESULTS: The median duration of prepartum treatment was 21 days (range 0-87 days). Compliance was 87% for prepartum and 69% for intrapartum treatment, and 88% for the neonatal bath, without differences between the two groups. In women, the most frequent event was leucorrhoea; the incidence of adverse events did not differ between treatment groups. In children, the incidence of dermatitis and conjunctivitis did not differ between the benzalkonium chloride and placebo groups (p = 0.16 and p = 0.29, respectively). CONCLUSION: Vaginal disinfection with benzalkonium chloride is a feasible and well tolerated intervention in west Africa. Its efficacy in preventing vertical HIV transmission remains to be demonstrated. 


 PMID:10754950

  12. Flurpiridaz F 18 PET: Phase II Safety and Clinical Comparison with SPECT Myocardial Perfusion Imaging for Detection of Coronary Artery Disease

    PubMed Central

    Berman, Daniel S.; Maddahi, Jamshid; Tamarappoo, B. K.; Czernin, Johannes; Taillefer, Raymond; Udelson, James E.; Gibson, C. Michael; Devine, Marybeth; Lazewatsky, Joel; Bhat, Gajanan; Washburn, Dana

    2015-01-01

    Objectives Phase II trial to assess flurpiridaz F 18 for safety and compare its diagnostic performance for PET myocardial perfusion imaging (MPI) to Tc-99m SPECT-MPI regarding image quality, interpretative certainty, defect magnitude and detection of coronary artery disease (CAD)(≥ 50% stenosis) on invasive coronary angiography (ICA). Background In preclinical and phase I studies, flurpiridaz F 18 has shown characteristics of an essentially ideal MPI tracer. Methods 143 patients from 21 centers underwent rest-stress PET and Tc-99m SPECT-MPI. Eighty-six patients underwent ICA, and 39 had low-likelihood of CAD. Images were scored by 3 independent, blinded readers. Results A higher % of images were rated as excellent/good on PET vs. SPECT on stress (99.2% vs. 88.5%, p<0.01) and rest (96.9% vs. 66.4, p<0.01) images. Diagnostic certainty of interpretation (% cases with definitely abnormal/normal interpretation) was higher for PET vs. SPECT (90.8% vs. 70.9%, p<0.01). In 86 patients who underwent ICA, sensitivity of PET was higher than SPECT [78.8% vs. 61.5%, respectively (p=0.02)]. Specificity was not significantly different (PET:76.5% vs. SPECT:73.5%). Receiver operating characteristic curve area was 0.82±0.05 for PET and 0.70±0.06 for SPECT (p=0.04). Normalcy rate was 89.7% with PET and 97.4% with SPECT (p=NS). In patients with CAD on ICA, the magnitude of reversible defects was greater with PET than SPECT (p=0.008). Extensive safety assessment revealed that flurpiridaz F 18 was safe in this cohort. Conclusions In this Phase 2 trial, PET MPI using flurpiridaz F 18 was safe and superior to SPECT MPI for image quality, interpretative certainty, and overall CAD diagnosis. PMID:23265345

  13. 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.

  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 size planning for phase II trials based on success probabilities for phase III.

    PubMed

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

    2015-01-01

    In recent years, high failure rates in phase III trials were observed. One of the main reasons is overoptimistic assumptions for the planning of phase III resulting from limited phase II information and/or unawareness of realistic success probabilities. We present an approach for planning a phase II trial in a time-to-event setting that considers the whole phase II/III clinical development programme. We derive stopping boundaries after phase II that minimise the number of events under side conditions for the conditional probabilities of correct go/no-go decision after phase II as well as the conditional success probabilities for phase III. In addition, we give general recommendations for the choice of phase II sample size. Our simulations show that unconditional probabilities of go/no-go decision as well as the unconditional success probabilities for phase III are influenced by the number of events observed in phase II. However, choosing more than 150 events in phase II seems not necessary as the impact on these probabilities then becomes quite small. We recommend considering aspects like the number of compounds in phase II and the resources available when determining the sample size. The lower the number of compounds and the lower the resources are for phase III, the higher the investment for phase II should be.

  16. 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.

  17. 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

  18. Concomitant boost IMRT-based neoadjuvant chemoradiotherapy for clinical stage II/III rectal adenocarcinoma: results of a phase II study

    PubMed Central

    2014-01-01

    Aim This study was designed to evaluate the efficacy and toxicities of concomitant boost intensity-modulated radiation therapy (IMRT) along with capecitabine and oxaliplatin, followed by a cycle of Xelox, in neoadjuvant course for locally advanced rectal cancer. Materials and methods Patients with histologically confirmed, newly diagnosed, locally advanced rectal adenocarcinoma (cT3-T4 and/or cN+) located within 12 cm of the anal verge were included in this study. Patients received IMRT to the pelvis of 50 Gy and a concomitant boost of 5 Gy to the primary tumor in 25 fractions, and concurrent with oxaliplatin (50 mg/m2 d1 weekly) and capecitabine (625 mg/m2 bid d1–5 weekly). One cycle of Xelox (oxaliplatin 130 mg/m2 on d1 and capecitabine 1000 mg/m2 twice daily d1–14) was given two weeks after the completion of chemoradiation, and radical surgery was scheduled eight weeks after chemoradiation. Tumor response was evaluated by tumor regression grade (TRG) system and acute toxicities were evaluated by NCI-CTC 3.0 criteria. Survival curves were estimated using the Kaplan-Meier method and compared with Log-rank test. Results A total of 78 patients were included between March 2009 and May 2011 (median age 54 years; 62 male). Seventy-six patients underwent surgical resection. Twenty-eight patients underwent sphincter-sparing lower anterior resection and 18 patients (23.7%) were evaluated as pathological complete response (pCR). The incidences of grade 3 hematologic toxicity, diarrhea, and radiation dermatitis were 3.8%, 10.3%, and 17.9%, respectively. The three-year LR (local recurrence), DFS (disease-free survival) and OS (overall survival) rates were 14.6%, 63.8% and 77.4%, respectively. Initial clinical T stage and tumor regression were independent prognostic factors to DFS. Conclusion An intensified regimen of concomitant boost radiotherapy plus concurrent capecitabine and oxaliplatin, followed by one cycle of Xelox, can be safely administered in patients

  19. Bevacizumab in Combination with Modified FOLFOX6 in Heavily Pretreated Patients with HER2/Neu-Negative Metastatic Breast Cancer: A Phase II Clinical Trial

    PubMed Central

    Wang, Zhonghua; Ragaz, Joseph; Zhang, Jian; Sun, Si; Cao, Jun; Lv, Fangfang; Wang, Leiping; Zhang, Sheng; Ni, Chen; Wu, Zhenhua; Xie, Jie; Hu, Xichun

    2015-01-01

    Background Bevacizumab combined with modified FOLFOX6 is a standard regimen for colorectal cancer. The present study was to determine the efficacy and safety of bevacizumab-modified FOLFOX6 regimen in heavily pretreated patients with human epidermal growth factor receptor 2 (HER2/neu)-negative MBC. Methods Bevacizumab, 5 mg/kg every two weeks or 7.5 mg/kg every three weeks, was administered with modified FOLFOX6 (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, 5-FU 400 mg/m2 on day 1, followed by 5-FU 2400 mg/m2 intravenous infusion over 46 hours every 2 weeks) to patients who failed at least 1 chemotherapy regimen in the metastatic setting. The primary objective was progression free survival (PFS). Secondary objectives included objective response rate (ORR), clinical benefit rate (CBR), overall survival (OS), safety, and the change of tumor size and Eastern Cooperative Oncology Group (ECOG) performance status. Results 69 patients were enrolled. The median PFS was 6.8 months (95% CI, 5.0 to 8.5 months), ORR was 50.0% and median OS was 10.5 months (95% CI, 7.9 to 13.1 months). Patients showing objective responses had a 4.2-month median PFS gain and 5.7-month median OS gain compared with those who did not (P < 0.05). Grade 3 or 4 adverse events occurring in more than one patient were neutropenia (53/69, 76.8%), leukopenia (36/69, 52.2%), thrombocytopenia (13/69, 18.8%), anemia (3/69, 4.3%) and hypertension (3/69, 4.3%). Conclusions Adding bevacizumab to modified FOLFOX6 does have significant anti-tumor activity and good safety profile in heavily pretreated HER2/neu-negative MBC patients. Further trials are required to confirm whether the high ORR can translate into a long-term PFS and even OS benefit. Trial Registration www.clinicaltrials.gov NCT01658033 PMID:26186012

  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. Handling clinical comorbidity in randomized clinical trials in psychiatry.

    PubMed

    O'Hara, Ruth; Beaudreau, Sherry A; Gould, Christine E; Froehlich, Wendy; Kraemer, Helena C

    2017-03-01

    The purpose of this paper is to a) outline the importance of including patients with clinical comorbidities in Randomized Clinical Trials (RCTs) of psychiatric treatments; and b) to propose a specific approach for best handling, analyzing and interpreting the data on clinical comorbidities in terms of their impact on treatment outcomes. To do this we first define and describe clinical comorbidity and differentiate it from other forms of comorbidity. We then describe the methodological and analytical problems associated with excluding patients with clinically comorbid conditions from RCTs, including the impact on the outcomes of RCTs in psychiatry and the impact on evidence-based clinical decision-making. We then address the challenges inherent to including patients with clinical comorbidities in RCTs. Finally, we propose a methodological and analytic approach to deal with these issues in RCTs which aims to significantly improve the information yielded from RCTs in psychiatry, and thus improve clinical decision-making.

  3. A prospective Phase II clinical trial of 5-aminolevulinic acid to assess the correlation of intraoperative fluorescence intensity and degree of histologic cellularity during resection of high-grade gliomas.

    PubMed

    Lau, Darryl; Hervey-Jumper, Shawn L; Chang, Susan; Molinaro, Annette M; McDermott, Michael W; Phillips, Joanna J; Berger, Mitchel S

    2016-05-01

    OBJECT There is evidence that 5-aminolevulinic acid (ALA) facilitates greater extent of resection and improves 6-month progression-free survival in patients with high-grade gliomas. But there remains a paucity of studies that have examined whether the intensity of ALA fluorescence correlates with tumor cellularity. Therefore, a Phase II clinical trial was undertaken to examine the correlation of intensity of ALA fluorescence with the degree of tumor cellularity. METHODS A single-center, prospective, single-arm, open-label Phase II clinical trial of ALA fluorescence-guided resection of high-grade gliomas (Grade III and IV) was held over a 43-month period (August 2010 to February 2014). ALA was administered at a dose of 20 mg/kg body weight. Intraoperative biopsies from resection cavities were collected. The biopsies were graded on a 4-point scale (0 to 3) based on ALA fluorescence intensity by the surgeon and independently based on tumor cellularity by a neuropathologist. The primary outcome of interest was the correlation of ALA fluorescence intensity to tumor cellularity. The secondary outcome of interest was ALA adverse events. Sensitivities, specificities, positive predictive values (PPVs), negative predictive values (NPVs), and Spearman correlation coefficients were calculated. RESULTS A total of 211 biopsies from 59 patients were included. Mean age was 53.3 years and 59.5% were male. The majority of biopsies were glioblastoma (GBM) (79.7%). Slightly more than half (52.5%) of all tumors were recurrent. ALA intensity of 3 correlated with presence of tumor 97.4% (PPV) of the time. However, absence of ALA fluorescence (intensity 0) correlated with the absence of tumor only 37.7% (NPV) of the time. For all tumor types, GBM, Grade III gliomas, and recurrent tumors, ALA intensity 3 correlated strongly with cellularity Grade 3; Spearman correlation coefficients (r) were 0.65, 0.66, 0.65, and 0.62, respectively. The specificity and PPV of ALA intensity 3 correlating

  4. 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.

  5. Phase II study of Cilengitide (EMD 121974, NSC 707544) in patients with non-metastatic castration resistant prostate cancer, NCI-6735. A study by the DOD/PCF Prostate Cancer Clinical Trials Consortium

    PubMed Central

    Alva, Ajjai; Slovin, Susan; Daignault, Stephanie; Carducci, Michael; DiPaola, Robert; Pienta, Ken; Agus, David; Cooney, Kathleen; Chen, Alice; Smith, David C.; Hussain, Maha

    2011-01-01

    Background Integrins mediate invasion and angiogenesis in prostate cancer bone metastases. We conducted a phase II study of Cilengitide, a selective antagonist of αvβ3 and αvβ5 integrins, in non-metastatic castration resistant prostate cancer with rising PSA. Methods Patients were observed for 4 weeks with PSA monitoring, and then treated with 2,000 mg IV of cilengitide twice weekly until toxicity/progression. PSA, circulating tumor cells (CTCs) and circulating endothelial cells (CECs) were monitored each cycle with imaging performed every 3 cycles. Primary end point was PSA decline by ≥ 50%. Secondary endpoints were safety, PSA slope, time to progression (TTP), overall survival (OS), CTCs, CECs and gene expression. Results 16 pts were enrolled; 13 were eligible with median age 65.5 years, baseline PSA 8.4 ng/mL and median Gleason sum 7. Median of 3 cycles was administered. Treatment was well tolerated with 2 grade 3 toxicities and no grade 4 toxicities. There were no PSA responses; 11 patients progressed by PSA after 3 cycles. Median TTP was 1.8 months and median OS has not been reached. Median pre- and on-treatment PSA slopes were 1.1 and 1.8 ng/mL/month. Baseline CTCs were detected in 1/9 patients. CTC increased (0 to 1; 2 pts), remained at 0 (2 pts) or decreased (23 to 0; 1 patient) at progression. Baseline median CEC was 26 (0–61) and at progression, 47 (15–148). Low cell counts precluded gene expression studies. Conclusions Cilengitide was well tolerated but had no detectable clinical activity. CTCs are of questionable utility in non-metastatic prostate cancer. PMID:21049281

  6. A Randomized Phase II Trial of Multi-epitope Vaccination with Melanoma Peptides for Cytotoxic T-Cells and Helper T-Cells for Patients with Metastatic Melanoma (E1602)

    PubMed Central

    Slingluff, Craig L.; Lee, Sandra; Zhao, Fengmin; Chianese-Bullock, Kimberly A.; Olson, Walter; Butterfield, Lisa H.; Whiteside, Theresa; Leming, Philip D.; Kirkwood, John M.

    2013-01-01

    Purpose This multicenter randomized trial was designed to evaluate whether melanoma helper peptides augment cytotoxic T-lymphocyte (CTL) responses to a melanoma vaccine and improve clinical outcome in patients with advanced melanoma. Patients and Methods One hundred seventy-five patients with measurable stage IV melanoma were enrolled into 4 treatment groups, vaccinated with 12 MHC Class I-restricted melanoma peptides (12MP) to stimulate CTL (group A), plus a tetanus peptide (group B) or a mixture of 6 melanoma helper peptides (6MHP, group C) to stimulate helper T lymphocytes (HTL), or with 6MHP alone (group D), in incomplete Freund’s adjuvant (IFA) plus GM-CSF. CTL responses were assessed using an in vitro stimulated IFN-gamma ELIspot assay, and HTL responses using proliferation assay. Results In groups A–D, respectively, CTL response rates to 12MP were 43%, 47%, 28%, and 5%, and HTL response rates to 6MHP were in 3%, 0%, 40% and 41%. Best clinical response was partial response (PR) in 7/148 evaluable patients (4.7%) without significant difference among study arms. Median overall survival (OS) was 11.8 months. Immune response to 6MHP was significantly associated with both clinical response (p=0.036) and OS (p=0.004). Conclusion Each vaccine regimen was immunogenic, but melanoma helper peptides did not augment CTL responses to 12MP. The association of survival and immune response to 6MHP supports further investigation of helper peptide vaccines. For patients with advanced melanoma, multipeptide vaccines should be studied in combination with other potentially synergistic active therapies. PMID:23653149

  7. 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.

  8. 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

  9. Randomized Phase II Study of Dacomitinib (PF-00299804), an Irreversible Pan–Human Epidermal Growth Factor Receptor Inhibitor, Versus Erlotinib in Patients With Advanced Non–Small-Cell Lung Cancer

    PubMed Central

    Ramalingam, Suresh S.; Blackhall, Fiona; Krzakowski, Maciej; Barrios, Carlos H.; Park, Keunchil; Bover, Isabel; Seog Heo, Dae; Rosell, Rafael; Talbot, Denis C.; Frank, Richard; Letrent, Stephen P.; Ruiz-Garcia, Ana; Taylor, Ian; Liang, Jane Q.; Campbell, Alicyn K.; O'Connell, Joseph; Boyer, Michael

    2012-01-01

    Purpose This randomized, open-label trial compared dacomitinib (PF-00299804), an irreversible inhibitor of human epidermal growth factor receptors (EGFR)/HER1, HER2, and HER4, with erlotinib, a reversible EGFR inhibitor, in patients with advanced non–small-cell lung cancer (NSCLC). Patients and Methods Patients with NSCLC, Eastern Cooperative Oncology Group performance status 0 to 2, no prior HER-directed therapy, and one/two prior chemotherapy regimens received dacomitinib 45 mg or erlotinib 150 mg once daily. Results One hundred eighty-eight patients were randomly assigned. Treatment arms were balanced for most clinical and molecular characteristics. Median progression-free survival (PFS; primary end point) was 2.86 months for patients treated with dacomitinib and 1.91 months for patients treated with erlotinib (hazard ratio [HR] = 0.66; 95% CI, 0.47 to 0.91; two-sided P = .012); in patients with KRAS wild-type tumors, median PFS was 3.71 months for patients treated with dacomitinib and 1.91 months for patients treated with erlotinib (HR = 0.55; 95% CI, 0.35 to 0.85; two-sided P = .006); and in patients with KRAS wild-type/EGFR wild-type tumors, median PFS was 2.21 months for patients treated with dacomitinib and 1.84 months for patients treated with erlotinib (HR = 0.61; 95% CI, 0.37 to 0.99; two-sided P = .043). Median overall survival was 9.53 months for patients treated with dacomitinib and 7.44 months for patients treated with erlotinib (HR = 0.80; 95% CI, 0.56 to 1.13; two-sided P = .205). Adverse event-related discontinuations were uncommon in both arms. Common treatment-related adverse events were dermatologic and gastrointestinal, predominantly grade 1 to 2, and more frequent with dacomitinib. Conclusion Dacomitinib demonstrated significantly improved PFS versus erlotinib, with acceptable toxicity. PFS benefit was observed in most clinical and molecular subsets, notably KRAS wild-type/EGFR any status, KRAS wild-type/EGFR wild-type, and EGFR mutants

  10. A randomized, open-label, multicenter, phase II study evaluating the efficacy and safety of BTH1677 (1,3-1,6 beta glucan; Imprime PGG) in combination with cetuximab and chemotherapy in patients with advanced non-small cell lung cancer.

    PubMed

    Thomas, M; Sadjadian, P; Kollmeier, J; Lowe, J; Mattson, P; Trout, J R; Gargano, M; Patchen, M L; Walsh, R; Beliveau, M; Marier, J F; Bose, N; Gorden, K; Schneller, F

    2017-03-16

    Introduction BTH1677, a 1,3-1,6 beta-glucan immunomodulator, stimulates a coordinated anti-cancer immune response in combination with anti-tumor antibody therapies. This phase II study explored the efficacy, pharmacokinetics (PK), and safety of BTH1677 combined with cetuximab/carboplatin/paclitaxel in untreated stage IIIB/IV non-small cell lung cancer (NSCLC) patients. Methods Patients were randomized 2:1 to the BTH1677 arm (N=60; BTH1677, 4 mg/kg, weekly; cetuximab, initial dose 400 mg/m(2) and subsequent doses 250 mg/m(2), weekly; carboplatin, 6 mg/mL/min AUC (area-under-the-curve) by Calvert formula, once each 3-week cycle [Q3W]); and paclitaxel, 200 mg/m(2), Q3W) or Control arm (N=30; cetuximab/carboplatin/paclitaxel as above). Carboplatin/paclitaxel was discontinued after 4-6 cycles; patients who responded or remained stable received maintenance therapy with BTH1677/cetuximab (BTH1677 arm) or cetuximab (Control arm). Investigator and blinded central radiology reviews were conducted. Efficacy assessments included objective response rate (ORR; primary endpoint), disease control rate, duration of objective response, time-to-progression and overall survival (OS); safety was assessed by adverse events (AEs). Potential biomarker analysis for BTH1677 response was also conducted. Results Compared to control treatment, the addition of BTH1677 numerically increased ORR by both investigator (47.8% vs 23.1%; p=0.0468) and central (36.6% vs 23.1%; p=0.2895) reviews. No other endpoints differed between arms. PK was consistent with previous studies. BTH1677 was well tolerated, with AEs expected of the backbone therapy predominating. Biomarker-positive patients displayed better ORR and OS than negative patients. Conclusions BTH1677 combined with cetuximab/carboplatin/paclitaxel was well tolerated and improved ORR as first-line treatment in patients with advanced NSCLC. Future patient selection by biomarker status may further improve efficacy ClinicalTrials.gov Identifier: NCT

  11. Unrelated donor cord blood transplantation for children with severe sickle cell disease: results of one cohort from the phase II study from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN).

    PubMed

    Kamani, Naynesh R; Walters, Mark C; Carter, Shelly; Aquino, Victor; Brochstein, Joel A; Chaudhury, Sonali; Eapen, Mary; Freed, Brian M; Grimley, Michael; Levine, John E; Logan, Brent; Moore, Theodore; Panepinto, Julie; Parikh, Suhag; Pulsipher, Michael A; Sande, Jane; Schultz, Kirk R; Spellman, Stephen; Shenoy, Shalini

    2012-08-01

    The Sickle Cell Unrelated Donor Transplant Trial (SCURT trial) of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) is a phase II study of the toxicity and efficacy of unrelated donor hematopoietic cell transplantation in children with severe sickle cell disease (SCD) using a reduced-intensity conditioning regimen. Here we report the results for the cord blood cohort of this trial. Eight children with severe SCD underwent unrelated donor cord blood transplantation (CBT) following alemtuzumab, fludarabine, and melphalan. Cyclosporine or tacrolimus and mycophenolate mofetil were administered for graft-versus-host disease (GVHD) prophylaxis. Donor/recipient HLA match status was 6 of 6 (n = 1) or 5 of 6 (n = 7), based on low/intermediate-resolution molecular typing at HLA -A, -B, and high-resolution typing at -DRB1. Median recipient age was 13.7 years (range: 7.4-16.2 years), and median weight was 35.0 kg (range: 25.2-90.2 kg). The median pre-cryopreservation total nucleated cell dose was 6.4 × 10(7) /kg (range: 3.1-7.6), and the median postthaw infused CD34 cell dose was 1.5 × 10(5) /kg (range: 0.2-2.3). All patients achieved neutrophil recovery (absolute neutrophil count >500/mm(3)) by day 33 (median: 22 days). Three patients who engrafted had 100% donor cells by day 100, which was sustained, and 5 patients had autologous hematopoietic recovery. Six of 8 patients had a platelet recovery to >50,000/mm(3) by day 100. Two patients developed grade II acute GVHD. Of these, 1 developed extensive chronic GVHD and died of respiratory failure 14 months posttransplantation. With a median follow-up of 1.8 years (range: 1-2.6), 7 patients are alive with a 1-year survival of 100%, and 3 of 8 are alive without graft failure or disease recurrence. Based upon the high incidence of graft rejection after unrelated donor CBT, enrollment onto the cord blood arm of the SCURT trial was suspended. However, because this reduced-intensity regimen has demonstrated a

  12. Clinical effects of prior trastuzumab on combination eribulin mesylate plus trastuzumab as first-line treatment for human epidermal growth factor receptor 2 positive locally recurrent or metastatic breast cancer: results from a Phase II, single-arm, multicenter study

    PubMed Central

    Puhalla, Shannon; Wilks, Sharon; Brufsky, Adam M; O’Shaughnessy, Joyce; Schwartzberg, Lee S; Berrak, Erhan; Song, James; Vahdat, Linda

    2016-01-01

    Eribulin mesylate, a novel nontaxane microtubule dynamics inhibitor in the halichondrin class of antineoplastic drugs, is indicated for the treatment of patients with metastatic breast cancer who previously received ≥2 chemotherapy regimens in the metastatic setting. Primary data from a Phase II trial for the first-line combination of eribulin plus trastuzumab in human epidermal growth factor receptor 2 positive patients showed a 71% objective response rate and tolerability consistent with the known profile of these agents. Here, we present prespecified analyses of efficacy of this combination based on prior trastuzumab use. Patients received eribulin mesylate 1.4 mg/m2 (equivalent to 1.23 mg/m2 eribulin [expressed as free base]) intravenously on days 1 and 8 plus trastuzumab (8 mg/kg intravenously/cycle 1, then 6 mg/kg) on day 1 of each 21-day cycle. Objective response rates, progression-free survival, and tolerability were assessed in patients who had and had not received prior adjuvant or neoadjuvant (neo/adjuvant) trastuzumab treatment. Fifty-two patients (median age: 59.5 years) received eribulin/trastuzumab for a median treatment duration of ~31 weeks; 40.4% (n=21) had been previously treated with neo/adjuvant trastuzumab prior to treatment with eribulin plus trastuzumab for metastatic disease (median time between neo/adjuvant and study treatment: 23 months). In trastuzumab-naïve patients (n=31) compared with those who had received prior trastuzumab, objective response rate was 77.4% versus 61.9%, respectively; duration of response was 11.8 versus 9.5 months, respectively; clinical benefit rate was 87.1% versus 81.0%, respectively; and median progression-free survival was 12.2 versus 11.5 months, respectively. The most common grade 3/4 treatment-emergent adverse events (occuring in ≥5% of patients) in patients who received prior trastuzumab versus trastuzumab naïve patients, respectively, were neutropenia (47.6% vs 32.3%), peripheral neuropathy (14

  13. Decreased organ failure in patients with severe SIRS and septic shock treated with the platelet-activating factor antagonist TCV-309: a prospective, multicenter, double-blind, randomized phase II trial. TCV-309 Septic Shock Study Group.

    PubMed

    Poeze, M; Froon, A H; Ramsay, G; Buurman, W A; Greve, J W

    2000-10-01

    Sepsis and organ failure remain the main cause of death on the ICU. Sepsis is characterized by a severe inflammatory response, in which platelet-activating factor (PAF) is considered to play an important role. This study investigated whether treatment with the PAF-antagonist TCV-309 reduces morbidity and mortality in patients with septic shock. The study was conducted as a double-blind, randomized, placebo controlled multicenter study. The included patients had to fulfill the SIRS criteria with a clinical suspicion of infection, an admission APACHE II score greater than 15, and shock, defined as a mean arterial pressure <70 mmHg and/or a decrease > or =40 mmHg despite adequate fluid resuscitation. Patients received 1.0 mg/kg TCV-309 or placebo, twice daily, intravenously during 14 days. The prospectively set goals were MOF score, recovery from shock, mortality, and assessment of the safety of the medication. A total of 98 patients were included of which 97 were analyzed on an intention-to-treat basis. The overall survival at day 56 of TCV-309 treated patients was similar compared to placebo treated patients (51.0% vs. 41.7%, P = 0.47). In contrast, the mean percentage of failed organs per patient present after 14 days in the TCV-309 treated patients was significantly lower compared to the placebo treated patients (11.9% vs. 25.1%, P = 0.04), leading to a reduced need for vasopressors, dialysis, and ventilatory support. Furthermore, the mean APACHE-II score during treatment with TCV-309 was significantly lower and the number of patients recovered from shock after day 14 was significantly higher in the TCV-309 treated patient group (2/32 vs. 9/29, P = 0.01). The number of adverse events was not significantly different between the TCV-309 and placebo treated patients. TCV-309 did not change overall mortality of septic shock, however a substantial reduction in organ dysfunction and morbidity, frequently associated with septic shock was achieved, without significant

  14. 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

  15. 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

  16. Preliminary CALS Phase II Architecture. Volume 19

    DTIC Science & Technology

    1989-07-03

    IDEF ICAM Definition Languages 5 IDEFO ICAM Definition Language: Activity Modeling IDEFIX ICAM Definition Language: Data Modeling 3 IDS Integrated Design...level. At the Conceptual Description level, data are defined by an integrated semantic data model, such as those produced using the IDEFIX modeling...Architecture with the dominate focus on the data dictionary for the IWSDB, represented by an IDEFIX semantic data model. It is at this level that CALS Phase II

  17. 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

  18. A randomized Phase II trial of the tumor vascular disrupting agent CA4P (fosbretabulin tromethamine) with carboplatin, paclitaxel, and bevacizumab in advanced nonsquamous non-small-cell lung cancer

    PubMed Central

    Garon, Edward B; Neidhart, Jeffrey D; Gabrail, Nashat Y; de Oliveira, Moacyr R; Balkissoon, Jai; Kabbinavar, Fairooz

    2016-01-01

    Introduction Combretastatin A4-phosphate, fosbretabulin tromethamine (CA4P) is a vascular disrupting agent that targets tumor vasculature. This study evaluated the safety of CA4P when combined with carboplatin, paclitaxel, and bevacizumab in chemotherapy-naïve subjects with advanced nonsquamous, non-small-cell lung cancer. Methods Adult subjects with confirmed American Joint Committee on Cancer six stage IIIB/IV non-small-cell lung cancer and an Eastern Cooperative Oncology Group performance score of 0 or 1 were randomized to receive six cycles (treatment phase) of paclitaxel (200 mg/m2), carboplatin (area under the concentration versus time curve 6), and bevacizumab (15 mg/kg) on day 1 and repeated every 21 days, or this regimen plus CA4P (60 mg/m2) on days 7, 14, and 21 of each cycle. Subjects could then receive additional maintenance treatment (excluding carboplatin and paclitaxel) for up to 1 year. Results Sixty-three subjects were randomized, 31 to control and 32 to CA4P, and 19 (61.3%) and 17 (53.1%), respectively, completed the treatment phase. Exposure to study treatment and dose modifications were comparable between the randomized groups. The overall incidence of treatment-emergent adverse events was similar between groups, with increased neutropenia, leukopenia, and hypertension in the CA4P group. Deaths, serious adverse events, and early discontinuations from treatment were comparable between the randomized treatment groups. The overall tumor response rate with CA4P was 50% versus 32% in controls. Overall and progression-free survival rates were comparable between the groups. Conclusion CA4P plus carboplatin, paclitaxel, and bevacizumab appears to be a tolerable regimen with an acceptable toxicity profile in subjects with advanced non-small-cell lung cancer. PMID:27942221

  19. Laparoscopic Radiofrequency Fibroid Ablation: Phase II and Phase III Results

    PubMed Central

    Pemueller, Rodolfo Robles; Garza Leal, José Gerardo; Abbott, Karen R.; Falls, Janice L.; Macer, James

    2014-01-01

    Background and Objectives: To review phase II and phase III treatments of symptomatic uterine fibroids (myomas) using laparoscopic radiofrequency volumetric thermal ablation (RFVTA). Methods: We performed a retrospective, multicenter clinical analysis of 206 consecutive cases of ultrasound-guided laparoscopic RFVTA of symptomatic myomas conducted on an outpatient basis under two phase II studies at 2 sites (n = 69) and one phase III study at 11 sites (n = 137). Descriptive and exploratory, general trend, and matched-pair analyses were applied. Results: From baseline to 12 months in the phase II study, the mean transformed symptom severity scores improved from 53.9 to 8.8 (P < .001) (n = 57), health-related quality-of-life scores improved from 48.5 to 92.0 (P < .001) (n = 57), and mean uterine volume decreased from 204.4 cm3 to 151.4 cm3 (P = .008) (n = 58). Patients missed a median of 4 days of work (range, 2–10 days). The rate of possible device-related adverse events was 1.4% (1 of 69). In the phase III study, approximately 98% of patients were assessed at 12 months, and their transformed symptom severity scores, health-related quality-of-life scores, mean decrease in uterine volume, and mean menstrual bleeding reduction were also significant. Patients in phase III missed a median of 5 days of work (range, 1–29 days). The rate of periprocedural device-related adverse events was 3.5% (5 of 137). Despite the enrollment requirement for patients in both phases to have completed childbearing, 4 pregnancies occurred within the first year after treatment. Conclusions: RFVTA does not require any uterine incisions and provides a uterine-sparing procedure with rapid recovery, significant reduction in uterine size, significant reduction or elimination of myoma symptoms, and significant improvement in quality of life. PMID:24960480

  20. Twelve-week, multicenter, placebo-controlled, randomized, double-blind, parallel-group, comparative phase II/III study of benzoyl peroxide gel in patients with acne vulgaris: A secondary publication.

    PubMed

    Kawashima, Makoto; Sato, Shinichi; Furukawa, Fukumi; Matsunaga, Kayoko; Akamatsu, Hirohiko; Igarashi, Atsuyuki; Tsunemi, Yuichiro; Hayashi, Nobukazu; Yamamoto, Yuki; Nagare, Toshitaka; Katsuramaki, Tsuneo

    2017-03-11

    A placebo-controlled, randomized, double-blind, parallel-group, comparative, multicenter study was conducted to investigate the efficacy and safety of benzoyl peroxide (BPO) gel, administrated once daily for 12 weeks to Japanese patients with acne vulgaris. Efficacy was evaluated by counting all inflammatory and non-inflammatory lesions. Safety was evaluated based on adverse events, local skin tolerability scores and laboratory test values. All 609 subjects were randomly assigned to receive the study products (2.5% and 5% BPO and placebo), and 607 subjects were included in the full analysis set, 544 in the per protocol set and 609 in the safety analyses. The median rates of reduction from baseline to the last evaluation of the inflammatory lesion counts, the primary end-point, in the 2.5% and 5% BPO groups were 72.7% and 75.0%, respectively, and were significantly higher than that in the placebo group (41.7%). No deaths or other serious adverse events were observed. The incidences of adverse events in the 2.5% and 5% BPO groups were 56.4% and 58.8%, respectively; a higher incidence than in the placebo group, but there was no obvious difference between the 2.5% and 5% BPO groups. All adverse events were mild or moderate in severity. Most adverse events did not lead to study product discontinuation. The results suggested that both 2.5% and 5% BPO are useful for the treatment of acne vulgaris.

  1. A randomized, double-blind, phase II, exploratory trial evaluating the palliative benefit of either continuing pamidronate or switching to zoledronic acid in patients with high-risk bone metastases from breast cancer.

    PubMed

    Jacobs, C; Kuchuk, I; Bouganim, N; Smith, S; Mazzarello, S; Vandermeer, L; Dranitsaris, G; Dent, S; Gertler, S; Verma, S; Song, X; Simos, S; Cella, D; Clemons, M

    2016-01-01

    Previous studies suggest switching from pamidronate to a more potent bone-targeted agent is associated with biomarker and palliative response in breast cancer patients with bone metastases. Until now, this has not been addressed in a double-blind, randomized trial. Breast cancer patients with high-risk bone metastases, despite >3 months of pamidronate, were randomized to either continue pamidronate or switch to zoledronic acid every 4 weeks for 12 weeks. Primary outcome was the proportion of patients achieving a fall in serum C-telopeptide (sCTx) at 12 weeks. Secondary outcomes included difference in mean sCTx, pain scores, quality of life, toxicity, and skeletal-related events (SREs). Seventy-three patients entered the study; median age 61 years (range 37-87). Proportion of patients achieving a fall in sCTx over the 12-week evaluation period was 26/32 (81 %) with zoledronic acid and 18/29 (62 %) with pamidronate (p = 0.095). Mean decrease in sCTx (mean difference between groups = 50 ng/L, 95 % CI 18-84; p = 0.003) was significantly greater in patients who received zoledronic acid. Quality of life, pain scores, toxicity, and frequency of new SREs were comparable between the two arms. While a switch from pamidronate to zoledronic acid resulted in reduction in mean sCTx, there were no significant differences between the arms for proportion of patients achieving a reduction in sCTx, quality of life, pain scores, toxicity or SREs. Given the lack of palliative improvement, the current data do not support a switching strategy.

  2. Laparoscopy Assisted versus Open Distal Gastrectomy with D2 Lymph Node Dissection for Advanced Gastric Cancer: Design and Rationale of a Phase II Randomized Controlled Multicenter Trial (COACT 1001)

    PubMed Central

    Nam, Byung Ho; Reim, Daniel; Eom, Bang Wool; Yu, Wan Sik; Park, Young Kyu; Ryu, Keun Won; Lee, Young Joon; Yoon, Hong Man; Lee, Jun Ho; Jeong, Oh; Jeong, Sang Ho; Lee, Sang Eok; Lee, Sang Ho; Yoon, Ki Young; Seo, Kyung Won; Chung, Ho Young; Kwon, Oh Kyoung; Kim, Tae Bong; Lee, Woon Ki; Park, Seong Heum; Sul, Ji-Young; Yang, Dae Hyun; Lee, Jong Seok

    2013-01-01

    Purpose Laparoscopy-assisted distal gastrectomy for early gastric cancer has gained acceptance and popularity worldwide. However, laparoscopy-assisted distal gastrectomy for advanced gastric cancer is still controversial. Therefore, we propose this prospective randomized controlled multi-center trial in order to evaluate the safety and feasibility of laparoscopy assisted D2-gastrectomy for advanced stage gastric cancer. Materials and Methods Patients undergoing distal gastrectomy for advanced gastric cancer staged cT2/3/4 cN0/1/2/3a cM0 by endoscopy and computed tomography are eligible for enrollment after giving their informed consent. Patients will be randomized either to laparoscopy-assisted distal gastrectomy or open distal gastrectomy. Sample size calculation revealed that 102 patients are to be included per treatment arm. The primary endpoint is the non-compliance rate of D2 dissection; relevant secondary endpoints are three-year disease free survival, surgical and postoperative complications, hospital stay and unanimity rate of D2 dissection evaluated by reviewing the intraoperative video documentation. Discussion Oncologic safety is the major concern regarding laparoscopy-assisted distal gastrectomy for advanced gastric cancer. Therefore, the non-compliance rate of clearing the N2 area was chosen as the most important parameter for the technical feasibility of the laparoscopic procedure. Furthermore, surgical quality will be carefully reviewed, that is, three independent experts will review the video records and score with a check list. For a long-term result, disease free survival is considered a secondary endpoint for this trial. This study will offer promising evidence of the feasibility and safety of Laparoscopy-assisted distal gastrectomy for advanced gastric cancer.Trial Registration: NCT01088204 (international), NCCCTS-09-448 (Korea). PMID:24156036

  3. 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

  4. 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.

  5. 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.

  6. Pretest Predictions for Phase II Ventilation Tests

    SciTech Connect

    Yiming Sun

    2001-09-19

    The objective of this calculation is to predict the temperatures of the ventilating air, waste package surface, and concrete pipe walls that will be developed during the Phase II ventilation tests involving various test conditions. The results will be used as inputs to validating numerical approach for modeling continuous ventilation, and be used to support the repository subsurface design. The scope of the calculation is to identify the physical mechanisms and parameters related to thermal response in the Phase II ventilation tests, and describe numerical methods that are used to calculate the effects of continuous ventilation. The calculation is limited to thermal effect only. This engineering work activity is conducted in accordance with the ''Technical Work Plan for: Subsurface Performance Testing for License Application (LA) for Fiscal Year 2001'' (CRWMS M&O 2000d). This technical work plan (TWP) includes an AP-2.21Q, ''Quality Determinations and Planning for Scientific, Engineering, and Regulatory Compliance Activities'', activity evaluation (CRWMS M&O 2000d, Addendum A) that has determined this activity is subject to the YMP quality assurance (QA) program. The calculation is developed in accordance with the AP-3.12Q procedure, ''Calculations''. Additional background information regarding this activity is contained in the ''Development Plan for Ventilation Pretest Predictive Calculation'' (DP) (CRWMS M&O 2000a).

  7. Status of the GERDA Phase II upgrade

    NASA Astrophysics Data System (ADS)

    Wagner, Victoria

    2016-06-01

    The GERDA experiment is designed to search for neutrinoless double beta (0νββ) decay of 76Ge. In Phase I of the experiment a background index of 10-2 cts/(keV.kg.yr) was reached. A lower limit on the half-life of the 0νββ decay of 76Ge was set to 2.1.1025 yr (at 90% C.L.). The aim of Phase II is to reach a sensitivity of the half-life of about 1026 yr. To increase the exposure thirty new Broad Energy Germanium (BEGe) detectors have been produced. These detectors are distinct for their improved energy resolution and enhanced pulse shape discrimination of signal from background events. Further background reduction will be reached by a light instrumentation to read out argon scintillation light. In April 2015 the light instrumentation together with eight BEGe detectors has been successfully deployed in the GERDA cryostat. In a commissioning run it was shown that two of the major background components, external γ-rays from 214Bi and 208Tl decays, were suppressed up to two orders of magnitude. We are confident to reach a background index of 10-3 cts/(keV.kg.yr) which is the design goal for GERDA Phase II.

  8. A Randomized Phase II Study to Assess the Efficacy of Pemetrexed or Sunitinib or Pemetrexed Plus Sunitinib in the Second-Line Treatment of Advanced Non–Small-Cell Lung Cancer

    PubMed Central

    Heist, Rebecca S.; Wang, Xiaofei; Hodgson, Lydia; Otterson, Gregory A.; Stinchcombe, Thomas E.; Gandhi, Leena; Villalona-Calero, Miguel A.; Watson, Peter; Vokes, Everett E.; Socinski, Mark A.

    2014-01-01

    Background Second-line chemotherapy for advanced non-small cell lung cancer (NSCLC) improves survival modestly but new strategies are needed. This trial was designed to evaluate an antivascular endothelial growth factor strategy with or without standard chemotherapy in previously treated NSCLC. Methods Patients with stage IIIB/IV NSCLC with performance status 0 to 1 progressive after first-line chemotherapy were eligible for randomization to pemetrexed, sunitinib, or the combination. Patients were stratified by performance status, stage, and sex. Primary objective was 18-week progression-free survival (PFS) rate; secondary objectives included response, overall survival (OS), and toxicity. Target accrual was 225. The study was terminated early because of decreasing accrual rates. Results Between April 2008 and September 2011, 130 patients were registered and randomized; of this, 125 patients were treated. Baseline characteristics in the three arms were well balanced. Toxicity was higher in the sunitinib-containing arms. The 18-week PFS rate in the pemetrexed, sunitinib, and combination arms was 54% (95% confidence interval [CI], 40–71), 37% (95% CI, 25–54), and 48% (95% CI, 35–66), respectively (p= 0.25). Median PFS in the pemetrexed, sunitinib, and combination arms in months was 4.9 (2.1–8.8), 3.3 (2.3–4.2), and 3.7 (2.5–5.8), respectively (p= 0.18). There was an overall statistically significant difference in OS between the three arms: median OS in months was 10.5 (8.3–20.2) for pemetrexed, 8.0 (6.8–13.5) for sunitinib, and 6.7 (4.1–10.1) for the combination (p= 0.03). Conclusion Pemetrexed had a superior toxicity profile to either sunitinib or the combination of pemetrexed and sunitinib. The 18-week PFS rate was not significantly different between the arms. OS was significantly better with pemetrexed alone compared with the two sunitinib-containing arms, with the doublet performing worst for OS. PMID:24419419

  9. A phase II randomized trial evaluating gefitinib intercalated with pemetrexed/platinum chemotherapy or pemetrexed/platinum chemotherapy alone in unselected patients with advanced non-squamous non-small cell lung cancer

    PubMed Central

    Yu, Hui; Zhang, Jian; Wu, Xianghua; Luo, Zhiguo; Wang, Huijie; Sun, Si; Peng, Wei; Qiao, Jie; Feng, Yu; Wang, Jialei; Chang, Jianhua

    2014-01-01

    Current pemetrexed/platinum chemotherapy does not produce a satisfactory therapeutic response in advanced lung cancer patients. The aim of this study was to determine whether the administration of gefitinib, a tyrosine kinase inhibitor (TKI), intercalated with pemetrexed/platinum could improve the efficacy in chemotherapy-naïve patients with advanced non-squamous NSCLC without subsequent gefitinib maintenance therapy. Treatment-naïve patients with stage IIIB or IV NSCLC were randomly assigned to receive pemetrexed (500 mg/m2 d1) and either cisplatin (75 mg/m2 d1) or carboplatin (AUC = 5 d1) plus gefitinib (250 mg/d on days 3 to 16 of a 3-week cycle) (PC-G) or pemetrexed–platinum (PC) alone. Randomization was stratified according to the tobacco smoking status and EGFR mutational status of the patients. The primary endpoint was the non-progression rate (NPR) at 12 weeks. Secondary endpoints included progression-free survival (PFS), overall response rate (ORR), overall survival (OS), and biosafety. The NPR at 12 weeks was 84.5% for the PC-G treatment arm and 83.1% for the PC treatment arm (P = 0.87). Median PFS was 7.9 months for the PC-G arm and 7.0 months for the PC arm (P = 0.57). The ORR was 50.0% for the PC-G arm and 47.4% for the PC arm (P = 0.78). Median survival was 25.4 mo for the PC-G arm and 20.8 mo for the PC arm (P = 0.54). The incidence of adverse events was similar between the two treatment arms, except for a higher incidence of skin rash with PC-G. Predefined subgroup analyses demonstrated that PC-G significantly increased the PFS compared with the PC regimen in patients with EGFR mutations (P = 0.017). Although gefitinib intercalated with pemetrexed/platinum chemotherapy did not improve the NPR at 12 weeks compared with chemotherapy, an improvement in the PFS for the intercalated treatment arm was seen in the subgroup of patients with EGFR mutations. PMID:24755888

  10. Phase II, open label, randomized comparative trial of ondansetron alone versus the combination of ondansetron and aprepitant for the prevention of nausea and vomiting in patients with hematologic malignancies receiving regimens containing high-dose cytarabine.

    PubMed

    Badar, Talha; Cortes, Jorge; Borthakur, Gautam; O'Brien, Susan; Wierda, William; Garcia-Manero, Guillermo; Ferrajoli, Alessandra; Kadia, Tapan; Poku, Rebeca; Kantarjian, Hagop; Mattiuzzi, Gloria

    2015-01-01

    Background. Aprepitant is a P/neurokinin-1 receptor antagonist approved for the prevention of CINV in moderate emetic risk chemotherapy. We explored its effectiveness in patients with leukemia receiving cytarabine-based chemotherapy. Methods. Patients were randomized to ondansetron (OND) 8 mg IV 30 minutes before cytarabine followed by 24 mg IV continuous infusion daily until 6-12 hours after the last dose of chemotherapy alone or with aprepitant (APREP) oral 125 mg 6-12 hrs before chemotherapy and 80 mg daily until 1 day after the last dose of chemotherapy. Results. Forty-nine patients were enrolled in each arm; 42 in OND and 41 in OND + APREP arm were evaluable for efficacy. The ORR with OND + APREP was 80% compared to 67% with OND alone (P = 0.11). On days 6 and 7, higher proportion of patients treated with OND + APREP were free from nausea (74%, 74% versus 68%, 67%; P = 0.27 and 0.18, resp.). Requirement of rescue medications on days 2 and 3 was fewer in OND + APREP arm 7% and 5% compared to 21% and 16% in the OND arm, respectively (P = 0.06 and P = 0.07). Conclusions. There was a trend for overall improvement in emesis with ondansetron plus aprepitant. The potential benefit of this approach with specific chemotherapy combinations remains to be determined.

  11. Safety and efficacy of different lenalidomide starting doses in patients with relapsed or refractory chronic lymphocytic leukemia: results of an international multicenter double-blinded randomized phase II trial.

    PubMed

    Wendtner, Clemens M; Hallek, Michael; Fraser, Graeme A M; Michallet, Anne-Sophie; Hillmen, Peter; Dürig, Jan; Kalaycio, Matt; Gribben, John G; Stilgenbauer, Stephan; Buhler, Andreas; Kipps, Thomas J; Purse, Brendan; Zhang, Jennie; De Bedout, Sabine; Mei, Jay; Chanan-Khan, Asher

    2016-01-01

    The objective of this study was to evaluate the safety and efficacy of different lenalidomide starting doses in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). CLL patients were randomized to receive lenalidomide at initial doses of 5, 10, or 15 mg/d (N = 103). Doses were escalated by 5 mg every 28-d up to a maximum of 25 mg/d; dose reductions in up to 5 mg decrements were permitted. The most common grade ≥3 adverse events (AEs) were neutropenia and thrombocytopenia. Ten patients died during therapy (four deaths considered as related to lenalidomide); 12 patients experienced second primary malignancies. The most common cause for treatment discontinuation was AEs. Overall response rates were similar across arms. Progression-free survival and overall survival rates were longer in patients who escalated treatment (to 15 or 20 mg/d) versus those who did not. Lower starting doses allowed subsequent dose escalation of lenalidomide while maintaining an acceptable tolerability profile in patients with relapsed/refractory CLL.

  12. Phase II, Open Label, Randomized Comparative Trial of Ondansetron Alone versus the Combination of Ondansetron and Aprepitant for the Prevention of Nausea and Vomiting in Patients with Hematologic Malignancies Receiving Regimens Containing High-Dose Cytarabine

    PubMed Central

    Badar, Talha; Cortes, Jorge; Borthakur, Gautam; O'Brien, Susan; Wierda, William; Garcia-Manero, Guillermo; Ferrajoli, Alessandra; Kadia, Tapan; Poku, Rebeca; Kantarjian, Hagop; Mattiuzzi, Gloria

    2015-01-01

    Background. Aprepitant is a P/neurokinin-1 receptor antagonist approved for the prevention of CINV in moderate emetic risk chemotherapy. We explored its effectiveness in patients with leukemia receiving cytarabine-based chemotherapy. Methods. Patients were randomized to ondansetron (OND) 8 mg IV 30 minutes before cytarabine followed by 24 mg IV continuous infusion daily until 6–12 hours after the last dose of chemotherapy alone or with aprepitant (APREP) oral 125 mg 6–12 hrs before chemotherapy and 80 mg daily until 1 day after the last dose of chemotherapy. Results. Forty-nine patients were enrolled in each arm; 42 in OND and 41 in OND + APREP arm were evaluable for efficacy. The ORR with OND + APREP was 80% compared to 67% with OND alone (P = 0.11). On days 6 and 7, higher proportion of patients treated with OND + APREP were free from nausea (74%, 74% versus 68%, 67%; P = 0.27 and 0.18, resp.). Requirement of rescue medications on days 2 and 3 was fewer in OND + APREP arm 7% and 5% compared to 21% and 16% in the OND arm, respectively (P = 0.06 and P = 0.07). Conclusions. There was a trend for overall improvement in emesis with ondansetron plus aprepitant. The potential benefit of this approach with specific chemotherapy combinations remains to be determined. PMID:25654108

  13. B-IGEV (bortezomib plus IGEV) versus IGEV before high-dose chemotherapy followed by autologous stem cell transplantation in relapsed or refractory Hodgkin lymphoma: a randomized, phase II trial of the Fondazione Italiana Linfomi (FIL).

    PubMed

    Balzarotti, Monica; Brusamolino, Ercole; Angelucci, Emanuele; Carella, Angelo Michele; Vitolo, Umberto; Russo, Eleonora; Congiu, Angelagiovanna; Gotti, Manuel; Massidda, Stefania; Botto, Barbara; Annechini, Giorgia; Spina, Michele; Re, Alessandro; Zilioli, Vittorio Ruggero; Merli, Francesco; Salvi, Flavia; Stelitano, Caterina; Bonfichi, Maurizio; Rodari, Marcello; Murru, Roberta; Magagnoli, Massimo; Anastasia, Antonella; Mazza, Rita; Giordano, Laura; Santoro, Armando

    2016-10-01

    This randomized, multicenter study evaluates the addition of bortezomib (13 mg/m(2)) to IGEV (B-IGEV) in patients with relapsed/refractory Hodgkin Lymphoma (HL). Patients received either four courses of IGEV alone (n = 40) or B-IGEV (n = 40). The primary endpoint was the complete response (CR) proportion, evaluated by FDG-PET, after induction chemotherapy. CR proportion was 39% with B-IGEV and 53% with IGEV. PFS and OS were similar between the two groups (two-year PFS: 58% vs 56%; two-year OS: 93% vs 81%). The PET-negative status after treatment was the only variable favorably influencing both PFS (two-year PFS: 77% vs 40%; p = 0.002) and OS (two-year OS: 100% vs 76%; p < 0.001). Toxicity was overall similar with the two regimens. The addition of bortezomib to IGEV does not improve response in relapsed/refractory HL patients. However, its favorable therapeutic and safety profile, and the prognostic role of pre-transplant PET negativity in patients receiving IGEV-based regimens are confirmed.

  14. 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,…

  15. Randomized Phase II Study of Erlotinib in Combination With Placebo or R1507, a Monoclonal Antibody to Insulin-Like Growth Factor-1 Receptor, for Advanced-Stage Non–Small-Cell Lung Cancer

    PubMed Central

    Ramalingam, Suresh S.; Spigel, David R.; Chen, David; Steins, Martin B.; Engelman, Jeffrey A.; Schneider, Claus-Peter; Novello, Silvia; Eberhardt, Wilfried E.E.; Crino, Lucio; Habben, Kai; Liu, Lian; Jänne, Pasi A.; Brownstein, Carrie M.; Reck, Martin

    2011-01-01

    Purpose R1507 is a selective, fully human, recombinant monoclonal antibody (immunoglobulin G1 subclass) against insulin-like growth factor-1 receptor (IGF-1R). The strong preclinical evidence supporting coinhibition of IGF-1R and epidermal growth factor receptor (EGFR) as anticancer therapy prompted this study. Patients and Methods Patients with advanced-stage non–small-cell lung cancer (NSCLC) with progression following one or two prior regimens, Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2, and measurable disease were eligible. Patients were randomly assigned to receive erlotinib (150 mg orally once a day) in combination with either placebo, R1507 9 mg/kg weekly, or R1507 16 mg/kg intravenously once every 3 weeks. Treatment cycles were repeated every 3 weeks. The primary end point was comparison of the 12-week progression-free survival (PFS) rate. Results In all, 172 patients were enrolled: median age, 61 years; female, 33%; never-smokers, 12%; and performance status 0 or 1, 88%. The median number of R1507 doses was six for the weekly arm and 3.5 for the every-3-weeks arm. Grades 3 to 4 adverse events occurred in 37%, 44%, and 48% of patients with placebo, R1507 weekly, and R1507 every 3 weeks, respectively. The 12-week PFS rates were 39%, 37%, and 44%, and the median overall survival was 8.1, 8.1, and 12.1 months for the three groups, respectively, with statistically nonsignificant hazard ratios. The 12-week PFS rate in patients with KRAS mutation was 36% with R1507 compared with 0% with placebo. Conclusion The combination of R1507 with erlotinib did not provide PFS or survival advantage over erlotinib alone in an unselected group of patients with advanced NSCLC. Predictive biomarkers are essential for further development of combined inhibition of IGF-1R and EGFR. PMID:22025157

  16. 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.

  17. 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.

  18. 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.

  19. 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

  20. Propensity score matching in randomized clinical trials.

    PubMed

    Xu, Zhenzhen; Kalbfleisch, John D

    2010-09-01

    Cluster randomization trials with relatively few clusters have been widely used in recent years for evaluation of health-care strategies. On average, randomized treatment assignment achieves balance in both known and unknown confounding factors between treatment groups, however, in practice investigators can only introduce a small amount of stratification and cannot balance on all the important variables simultaneously. The limitation arises especially when there are many confounding variables in small studies. Such is the case in the INSTINCT trial designed to investigate the effectiveness of an education program in enhancing the tPA use in stroke patients. In this article, we introduce a new randomization design, the balance match weighted (BMW) design, which applies the optimal matching with constraints technique to a prospective randomized design and aims to minimize the mean squared error (MSE) of the treatment effect estimator. A simulation study shows that, under various confounding scenarios, the BMW design can yield substantial reductions in the MSE for the treatment effect estimator compared to a completely randomized or matched-pair design. The BMW design is also compared with a model-based approach adjusting for the estimated propensity score and Robins-Mark-Newey E-estimation procedure in terms of efficiency and robustness of the treatment effect estimator. These investigations suggest that the BMW design is more robust and usually, although not always, more efficient than either of the approaches. The design is also seen to be robust against heterogeneous error. We illustrate these methods in proposing a design for the INSTINCT trial.

  1. 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…

  2. 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.

  3. 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

    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

    2015-04-01

    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.

  4. 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

  5. Stochastic inequality probabilities for adaptively randomized clinical trials.

    PubMed

    Cook, John D; Nadarajah, Saralees

    2006-06-01

    We examine stochastic inequality probabilities of the form P (X > Y) and P (X > max (Y, Z)) where X, Y, and Z are random variables with beta, gamma, or inverse gamma distributions. We discuss the applications of such inequality probabilities to adaptively randomized clinical trials as well as methods for calculating their values.

  6. Power Analysis of Cutoff-Based Randomized Clinical Trials.

    ERIC Educational Resources Information Center

    Cappelleri, Joseph C.; And Others

    1994-01-01

    A statistical power algorithm based on the Fisher Z method is developed for cutoff-based random clinical trials and the single cutoff-point (regression-discontinuity) design that has no randomization. This article quantifies power and sample size estimates for various levels of power and cutoff-based assignment. (Author/SLD)

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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

  12. 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...

  13. 40 CFR 72.44 - Phase II repowering extensions.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... (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...

  14. 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...

  15. 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...

  16. 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...

  17. Final Report on Phase II; Study of Academic Library Consortia.

    ERIC Educational Resources Information Center

    Cuadra, Carlos A.; And Others

    Phase II involves a case-study analysis of 15 selected consortia to help determine the usefulness and effectiveness of academic library consortia. The two major products resulting from the project are the "Directory of Academic Library Consortia" and the "Guidelines for the Development of Academic Library Consortia." The Phase II report presents…

  18. The SIMPLE Phase II dark matter search

    NASA Astrophysics Data System (ADS)

    Felizardo, M.; Girard, T. A.; Morlat, T.; Fernandes, A. C.; Ramos, A. R.; Marques, J. G.; Kling, A.; Puibasset, J.; Auguste, M.; Boyer, D.; Cavaillou, A.; Poupeney, J.; Sudre, C.; Carvalho, F. P.; Prudêncio, M. I.; Marques, R.; Simple Collaboration

    2014-04-01

    Phase II of SIMPLE (Superheated Instrument for Massive ParticLe Experiments) searched for astroparticle dark matter using superheated liquid C2ClF5 droplet detectors. Each droplet generally requires an energy deposition with linear energy transfer (LET) ≳150 keV/μm for a liquid-to-gas phase transition, providing an intrinsic rejection against minimum ionizing particles of order 10-10, and reducing the backgrounds to primarily α and neutron-induced recoil events. The droplet phase transition generates a millimetric-sized gas bubble that is recorded by acoustic means. We describe the SIMPLE detectors, their acoustic instrumentation, and the characterizations, signal analysis and data selection, which yield a particle-induced, "true nucleation" event detection efficiency of better than 97% at a 95% C.L. The recoil-α event discrimination, determined using detectors first irradiated with neutrons and then doped with alpha emitters, provides a recoil identification of better than 99%; it differs from those of COUPP and PICASSO primarily as a result of their different liquids with lower critical LETs. The science measurements, comprising two shielded arrays of fifteen detectors each and a total exposure of 27.77 kgd, are detailed. Removal of the 1.94 kgd Stage 1 installation period data, which had previously been mistakenly included in the data, reduces the science exposure from 20.18 to 18.24 kgd and provides new contour minima of σp=4.3×10-3 pb at 35 GeV /c2 in the spin-dependent sector of astroparticle dark matter-proton interactions and σN=3.6×10-6 pb at 35 GeV /c2 in the spin-independent sector. These results are examined with respect to the fluorine spin and halo parameters used in the previous data analysis.

  19. 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.

  20. Proposal for a "phase II" multicenter trial model for preclinical new antiepilepsy therapy development.

    PubMed

    O'Brien, Terence J; Ben-Menachem, Elinor; Bertram, Edward H; Collins, Stephen D; Kokaia, Merab; Lerche, Holger; Klitgaard, Henrik; Staley, Kevin J; Vaudano, Elisabetta; Walker, Matthew C; Simonato, Michele

    2013-08-01

    There is a pressing need to address the current major gaps in epilepsy treatment, in particular drug-resistant epilepsy, antiepileptogenic therapies, and comorbidities. A major concern in the development of new therapies is that current preclinical testing is not sufficiently predictive for clinical efficacy. Methodologic limitations of current preclinical paradigms may partly account for this discrepancy. Here we propose and discuss a strategy for implementing a "phase II" multicenter preclinical drug trial model based on clinical phase II/III studies designed to generate more rigorous preclinical data for efficacy. The goal is to improve the evidence resulting from preclinical studies for investigational new drugs that have shown strong promise in initial preclinical "phase I" studies. This should reduce the risk for expensive clinical studies in epilepsy and therefore increase the appeal for funders (industry and government) to invest in their clinical development.

  1. The Changing Landscape of Randomized Clinical Trials in Cardiovascular Disease.

    PubMed

    Jones, W Schuyler; Roe, Matthew T; Antman, Elliott M; Pletcher, Mark J; Harrington, Robert A; Rothman, Russell L; Oetgen, William J; Rao, Sunil V; Krucoff, Mitchell W; Curtis, Lesley H; Hernandez, Adrian F; Masoudi, Frederick A

    2016-10-25

    Large randomized clinical trials in cardiovascular disease have proliferated over the past 3 decades, with results that have influenced every aspect of cardiology practice. Despite these advances, there remains a substantial need for more high-quality evidence to inform cardiovascular clinical practice, given the increasing prevalence of cardiovascular disease around the world. Traditional clinical trials are increasingly challenging due to rising costs, increasing complexity and length, and burdensome institutional and regulatory requirements. This review will examine the current landscape of cardiovascular clinical trials in the United States, highlight recently conducted registry-based clinical trials, and discuss the potential attributes of the recently launched pragmatic clinical trial by the Patient-Centered Outcomes Research Institute's National Patient-Centered Clinical Research Network, called the ADAPTABLE (Aspirin Dosing: A Patient-centric Trial Assessing the Benefits and Long-term Effectiveness) trial.

  2. Sears Point Tidal Marsh Restoration Project: Phase II

    EPA Pesticide Factsheets

    Information about the SFBWQP Sears Point Tidal Marsh Restoration Project: Phase II, part of an EPA competitive grant program to improve SF Bay water quality focused on restoring impaired waters and enhancing aquatic resources.

  3. Planning Targets for Phase II Watershed Implementation Plans

    EPA Pesticide Factsheets

    On August 1, 2011, EPA provided planning targets for nitrogen, phosphorus and sediment for the Phase II Watershed Implementation Plans (WIPs) of the Chesapeake Bay TMDL. This page provides the letters containing those planning targets.

  4. South Bay Salt Pond Tidal Wetland Restoration Phase II Planning

    EPA Pesticide Factsheets

    Information about the SFBWQP South Bay Salt Pond Tidal Wetland Restoration Phase II Planning project, part of an EPA competitive grant program to improve SF Bay water quality focused on restoring impaired waters and enhancing aquatic re

  5. South Bay Salt Pond Restoration, Phase II at Ravenswood

    EPA Pesticide Factsheets

    Information about the South Bay Salt Pond Restoration Project: Phase II Construction at Ravenswood, part of an EPA competitive grant program to improve SF Bay water quality focused on restoring impaired waters and enhancing aquatic resources.

  6. Demonstration of Spray Booth Recirculation and Partitioning - Phase II

    DTIC Science & Technology

    1996-01-01

    electrostatic paint spray enclosures, such as the high volume, low pressure ( HVLP ) systems employed at Barstow MCLB, a minimum linear velocity of 100 fpm must be...SUBTITLE 5. FUNDING NUMBERS Demonstration of Spray Booth Recirculation and Partitioning - Phase II N/A 6. AUTHOR(S) D. Proffitt, R.K. Clayton, & J...ANSI Std. Z39-18 298-102 * , 85-1996 Demonstration of Spray Booth Recirculation and Partitioning - Phase II David Proffitt and Russell K. Clayton

  7. The Systems Approach to Functional Job Analysis. Task Analysis of the Physician's Assistant: Volume II--Curriculum and Phase I Basic Core Courses and Volume III--Phases II and III--Clinical Clerkships and Assignments.

    ERIC Educational Resources Information Center

    Wake Forest Univ., Winston Salem, NC. Bowman Gray School of Medicine.

    This publication contains a curriculum developed through functional job analyses for a 24-month physician's assistant training program. Phase 1 of the 3-phase program is a 6-month basic course program in clinical and bioscience principles and is required of all students regardless of their specialty interest. Phase 2 is a 6 to 10 month period of…

  8. 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.

  9. 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

  10. Results of a phase II study of thalidomide and azacitidine in patients with clinically advanced myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML) and low blast count acute myeloid leukemia (AML).

    PubMed

    Kenealy, Melita; Patton, Nigel; Filshie, Robin; Nicol, Andrew; Ho, Shir-Jing; Hertzberg, Mark; Mills, Tony; Prosser, Ian; Link, Emma; Cowan, Linda; Zannino, Diana; Seymour, John F

    2017-02-01

    Single agent azacitidine or immunomodulatory drugs are effective in myelodysplastic syndrome (MDS), with differing target mechanisms and toxicities. Objectives of this ALLG MDS3 study in clinically advanced MDS, AMML and low blast AML were to establish safety, response and quality of life of azacitidine and thalidomide. Patients received azacitidine (75mg/m(2)/d sc 7days every 28 days), and oral thalidomide up to 100mg/d for maximum 12months. Eighty patients registered; median age 68 years (range 42-82), 49% IPSS int2-high. With 36.5 months follow up, patients received median 9 cycles azacitidine, 6.1mths thalidomide. Nonhematologic toxicity grade 3+ in 85%, commonly infections. Overall response rate was 63%; 26% CR were unaffected by IPSS. Median response duration 26.3months; overall survival was 28.1months. This combination azacitidine and thalidomide in clinically advanced MDS, CMML and low-blast AML was tolerable without unexpected toxicity and encouraging responses support further investigation of combination approaches with hypomethylating agent and immunomodulatory drug.

  11. 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.

  12. 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

  13. Bayesian population finding with biomarkers in a randomized clinical trial.

    PubMed

    Morita, Satoshi; Müller, Peter

    2017-03-03

    The identification of good predictive biomarkers allows investigators to optimize the target population for a new treatment. We propose a novel utility-based Bayesian population finding (BaPoFi) method to analyze data from a randomized clinical trial with the aim of finding a sensitive patient population. Our approach is based on casting the population finding process as a formal decision problem together with a flexible probability model, Bayesian additive regression trees (BART), to summarize observed data. The proposed method evaluates enhanced treatment effects in patient subpopulations based on counter-factual modeling of responses to new treatment and control for each patient. In extensive simulation studies, we examine the operating characteristics of the proposed method. We compare with a Bayesian regression-based method that implements shrinkage estimates of subgroup-specific treatment effects. For illustration, we apply the proposed method to data from a randomized clinical trial.

  14. Reintegration the Role of Spouse Telephone Battlemind Randomized Clinical Trial

    DTIC Science & Technology

    2010-10-01

    Award Number: W81XWH-09-1-0242 TITLE: Reintegration The Role Of Spouse Telephone Battlemind Randomized Clinical Trial PRINCIPAL INVESTIGATOR...Iraq and Afghanistan service members. The goal is to build spouses’ resilience to cope with reintegration challenges, help them serve as a support...and family may have changed during deployment; negotiation; strategies to reduce or eliminate reintegration difficulties; strategies to support the

  15. Safety and efficacy of stereotactic body radiation therapy combined with S-1 simultaneously followed by sequential S-1 as an initial treatment for locally advanced pancreatic cancer (SILAPANC) trial: study design and rationale of a phase II clinical trial

    PubMed Central

    Zhu, Xiaofei; Ju, Xiaoping; Cao, Fei; Fang, Fang; Qing, Shuiwang; Shen, Yuxin; Jia, Zhen; Cao, Yangsen; Zhang, Huojun

    2016-01-01

    Introduction Upfront surgeries are not beneficial to most patients with pancreatic cancer. Therefore, more emphasis has been placed chemoradiotherapy in locally advanced pancreatic cancer recently. Gemcitabine-based regimens or FOLFIRINOX (a chemotherapy regimen including leucovorin, 5-FU, irinotecan, oxaliplatin) has been proven as a standard chemotherapy in pancreatic cancer. However, severe toxicities may prevent the completion of chemotherapy. S-1 has showed better objective response rates, similar overall survival rates and progression-free survival rates compared with gemcitabine, revealing that S-1 may be a potential candidate in treating pancreatic cancer, especially for patients refractory to gemcitabine. Additionally, stereotactic body radiation therapy with Cyberknife could provide better efficacy than conventional radiotherapy in pancreatic cancer. Therefore, Cyberknife with S-1 simultaneously followed by sequential S-1 as an initial treatment may bring about favourable outcomes but needs further studies. Methods and analysis The S-1 as an initial treatment for locally advanced pancreatic cancer (SILAPANC) trial is a prospective, single-centre, one armed ongoing study. 190 eligible patients are required to initially receive Cyberknife with 1 cycle of S-1 simultaneously. After the concurrent chemoradiotherapy, 2 or 3 cycles of S-1 are sequentially given. Doses and fractions depend on the locations and volumes of tumours and the adjacent organs at risk. S-1 is taken orally, 2 times a day, at a dose of 80 mg/m2 for 28 days, followed by a 14-day interval. The primary objectives are overall survival and 1-year, 2-year, 3-year, 4-year and 5-year overall survival rates. The secondary objectives are cancer-specific survival, progression-free survival, time to progression, local control rates, clinical benefit rates, radiation-induced acute and late toxicities, adverse effects of chemotherapy and quality of life of patients. Besides, variables most

  16. 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

  17. 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.

  18. Effect of a misspecification of response rates on type I and type II errors, in a phase II Simon design.

    PubMed

    Baey, Charlotte; Le Deley, Marie-Cécile

    2011-07-01

    Phase-II trials are a key stage in the clinical development of a new treatment. Their main objective is to provide the required information for a go/no-go decision regarding a subsequent phase-III trial. In single arm phase-II trials, widely used in oncology, this decision relies on the comparison of efficacy outcomes observed in the trial to historical controls. The false positive rate generally accepted in phase-II trials, around 10%, contrasts with the very high attrition rate of new compounds tested in phase-III trials, estimated at about 60%. We assumed that this gap could partly be explained by the misspecification of the response rate expected with standard treatment, leading to erroneous hypotheses tested in the phase-II trial. We computed the false positive probability of a defined design under various hypotheses of expected efficacy probability. Similarly we calculated the power of the trial to detect the efficacy of a new compound for different expected efficacy rates. Calculations were done considering a binary outcome, such as the response rate, with a decision rule based on a Simon two-stage design. When analysing a single-arm phase-II trial, based on a design with a pre-specified null hypothesis, a 5% absolute error in the expected response rate leads to a false positive rate of about 30% when it is supposed to be 10%. This inflation of type-I error varies only slightly according to the hypotheses of the initial design. Single-arm phase-II trials poorly control for the false positive rate. Randomised phase-II trials should, therefore, be more often considered.

  19. Lifestyle Modification for Resistant Hypertension: The TRIUMPH Randomized Clinical Trial

    PubMed Central

    Blumenthal, James A.; Sherwood, Andrew; Smith, Patrick J.; Mabe, Stephanie; Watkins, Lana; Lin, Pao-Hwa; Craighead, Linda W.; Babyak, Michael; Tyson, Crystal; Young, Kenlyn; Ashworth, Megan; Kraus, William; Liao, Lawrence; Hinderliter, Alan

    2015-01-01

    Background Resistant hypertension (RH) is a growing health burden in this country affecting as many as one in five adults being treated for hypertension. RH is associated with increased risk of adverse cardiovascular disease (CVD) events and all-cause mortality. Strategies to reduce blood pressure in this high risk population are a national priority. Methods TRIUMPH is a single site, prospective, randomized clinical trial (RCT) to evaluate the efficacy of a center-based lifestyle intervention consisting of exercise training, reduced sodium and calorie DASH eating plan, and weight management compared to standardized education and physician advice in treating patients with RH. Patients (N=150) will be randomized in a 2:1 ratio to receive either a 4-month supervised lifestyle intervention delivered in the setting of a cardiac rehabilitation center or to a standardized behavioral counseling session to simulate real-world medical practice. The primary end point is clinic blood pressure; secondary endpoints include ambulatory blood pressure and an array of CVD biomarkers including left ventricular hypertrophy, arterial stiffness, baroreceptor reflex sensitivity, insulin resistance, lipids, sympathetic nervous system activity, and inflammatory markers. Lifestyle habits, blood pressure and CVD risk factors also will be measured at one year follow-up. Conclusions The TRIUMPH randomized clinical trial (ClinicalTrials.gov NCT02342808) is designed to test the efficacy of an intensive, center-based lifestyle intervention compared to a standardized education and physician advice counseling session on blood presssure and CVD biomarkers in patients with RH after 4 months of treatment, and will determine whether lifestyle changes can be maintained for a year. PMID:26542509

  20. Project Management of Randomized Clinical Trials: A Narrative Review

    PubMed Central

    Goodarzynejad, Hamidreza; Babamahmoodi, Abdolreza

    2015-01-01

    Context: A well-structured protocol for a clinical trial may be able to answer clinical questions, but it cannot be deemed enough to ensure success in the face of incompetent management of time as well as human and economic resources. To address this problem, in this article, we present our literature review on evidence as to how a good knowledge of proper management among researchers can enhance the likelihood of the success of clinical trial projects. Evidence Acquisition: Using multiple search strategies, we conducted a literature review on published studies in the English language from 2002 to 2012 by searching the Cochrane Database of Systematic Reviews, MEDLINE, Google Scholar, and EMBASE. Results: Our review suggests that a successful trial requires a work plan or work scope as well as a timeline. The trial manager should subsequently manage the study in accordance with the plan and the timeline. Many research units have called for a clinical project manager with scientific background and regulatory skills to effect coordination among various aspects of a clinical trial. Conclusions: Project management may benefit both the managerial and scientific aspects of medical projects and reduce fund waste. However, little has been written to date on project management in the context of clinical research. The suggestions represent the views of the individual authors. To provide a high level of evidence in this regard, we recommend that a randomized controlled trial be performed to compare trial projects progressed with and without the use of project management. PMID:26430517

  1. Dietary chemoprevention strategies for induction of phase II xenobiotic-metabolizing enzymes in lung carcinogenesis: A review

    PubMed Central

    Tan, Xiang-Lin; Spivack, Simon D.

    2013-01-01

    Lung cancer is the leading cause of cancer mortality for men and women in the United States and is a growing worldwide problem. Protection against lung cancer is associated with higher dietary intake of fruits and vegetables, according to recent large epidemiologic studies. One strategy for lung cancer chemoprevention focuses on the use of agents to modulate the metabolism and disposition of tobacco, environmental and endogenous carcinogens through upregulation of detoxifying phase II enzymes. We summarize the substantial evidence that suggests that induction of phase II enzymes, particularly the glutathione S-transferases, plays a direct role in chemoprotection against lung carcinogenesis. The engagement of the Keap1–Nrf2 complex regulating the antioxidant response element (ARE) signaling pathway has been identified as a key molecular target of chemopreventive phase II inducers in several systems. Monitoring of phase II enzyme induction has led to identification of novel chemopreventive agents such as the isothiocyanate sulforaphane, and the 1,2-dithiole-3-thiones. However, no agents have yet demonstrated clear benefit in human cell systems, or in clinical trials. Alternative strategies include: (a) using intermediate cancer biomarkers for the endpoint in human trials; (b) high-throughput small molecule discovery approaches for induced expression of human phase II genes; and (c) integrative approaches that consider pharmacogenetics, along with pharmacokinetics and pharmacodynamics in target lung tissue. These approaches may lead to a more effective strategy of tailored chemoprevention efforts using compounds with proven human activity. PMID:19185948

  2. Dietary chemoprevention strategies for induction of phase II xenobiotic-metabolizing enzymes in lung carcinogenesis: A review.

    PubMed

    Tan, Xiang-Lin; Spivack, Simon D

    2009-08-01

    Lung cancer is the leading cause of cancer mortality for men and women in the United States and is a growing worldwide problem. Protection against lung cancer is associated with higher dietary intake of fruits and vegetables, according to recent large epidemiologic studies. One strategy for lung cancer chemoprevention focuses on the use of agents to modulate the metabolism and disposition of tobacco, environmental and endogenous carcinogens through upregulation of detoxifying phase II enzymes. We summarize the substantial evidence that suggests that induction of phase II enzymes, particularly the glutathione S-transferases, plays a direct role in chemoprotection against lung carcinogenesis. The engagement of the Keap1-Nrf2 complex regulating the antioxidant response element (ARE) signaling pathway has been identified as a key molecular target of chemopreventive phase II inducers in several systems. Monitoring of phase II enzyme induction has led to identification of novel chemopreventive agents such as the isothiocyanate sulforaphane, and the 1,2-dithiole-3-thiones. However, no agents have yet demonstrated clear benefit in human cell systems, or in clinical trials. Alternative strategies include: (a) using intermediate cancer biomarkers for the endpoint in human trials; (b) high-throughput small molecule discovery approaches for induced expression of human phase II genes; and (c) integrative approaches that consider pharmacogenetics, along with pharmacokinetics and pharmacodynamics in target lung tissue. These approaches may lead to a more effective strategy of tailored chemoprevention efforts using compounds with proven human activity.

  3. Mutual interactions between flavonoids and enzymatic and transporter elements responsible for flavonoid disposition via phase II metabolic pathways.

    PubMed

    Jiang, Wen; Hu, Ming

    2012-09-21

    Flavonoids, existing mainly as glycosides in nature, have multiple "claimed" beneficial effects in humans. Flavonoids are extensively metabolized in enterocytes and hepatocytes by phase II enzymes such as UGTs and SULTs to form glucuronides and sulfates, respectively. These glucuronides and sulfates are subsequently excreted via ABC transporters (e.g., MRP2 or BCRP). Therefore, it is the interplay between phase II enzymes and efflux transporters that affects the disposition of flavonoids and leads to the low bioavailability of flavonoid aglycones. Flavonoids can also serve as chemical regulators that affect the activity or expression levels of phase II enzymes including UGTs, SULTs and GSTs, and transporters including P-gp, MRP2, BCRP, OATP and OAT. In general, flavonoids may exert the inhibitory or inductive effects on the phase II enzymes and transporters via multiple mechanisms that may involve different nuclear receptors. Since flavonoids may affect the metabolic pathways shared by many important clinical drugs, drug-flavonoid interaction is becoming an increasingly important concern. This review article focused on the disposition of flavonoids and effects of flavonoids on relevant enzymes (e.g. UGTs and SULTs) and transporters (e.g. MRP2 and BCRP) involved in the interplay between phase II enzymes and efflux transporters. The effects of flavonoids on other metabolic enzymes (e.g. GSTs) or transporters (e.g. P-gp, OATP and OAT) are also addressed but that is not the emphasis of this review.

  4. Mutual interactions between flavonoids and enzymatic and transporter elements responsible for flavonoid disposition via phase II metabolic pathways

    PubMed Central

    Jiang, Wen; Hu, Ming

    2014-01-01

    Flavonoids, existing mainly as glycosides in nature, have multiple “claimed” beneficial effects in humans. Flavonoids are extensively metabolized in enterocytes and hepatocytes by phase II enzymes such as UGTs and SULTs to form glucuronides and sulfates, respectively. These glucuronides and sulfates are subsequently excreted via ABC transporters (e.g., MRP2 or BCRP). Therefore, it is the interplay between phase II enzymes and efflux transporters that affects the disposition of flavonoids and leads to the low bioavailability of flavonoid aglycones. Flavonoids can also serve as chemical regulators that affect the activity or expression levels of phase II enzymes including UGTs, SULTs and GSTs, and transporters including P-gp, MRP2, BCRP, OATP and OAT. In general, flavonoids may exert the inhibitory or inductive effects on the phase II enzymes and transporters via multiple mechanisms that may involve different nuclear receptors. Since flavonoids may affect the metabolic pathways shared by many important clinical drugs, drug-flavonoid interaction is becoming an increasingly important concern. This review article focused on the disposition of flavonoids and effects of flavonoids on relevant enzymes (e.g. UGTs and SULTs) and transporters (e.g. MRP2 and BCRP) involved in the interplay between phase II enzymes and efflux transporters. The effects of flavonoids on other metabolic enzymes (e.g. GSTs) or transporters (e.g. P-gp, OATP and OAT) are also addressed but that is not the emphasis of this review. PMID:25400909

  5. 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…

  6. Effect of denosumab on Japanese patients with rheumatoid arthritis: a dose–response study of AMG 162 (Denosumab) in patients with RheumatoId arthritis on methotrexate to Validate inhibitory effect on bone Erosion (DRIVE)—a 12-month, multicentre, randomised, double-blind, placebo-controlled, phase II clinical trial

    PubMed Central

    Takeuchi, Tsutomu; Tanaka, Yoshiya; Ishiguro, Naoki; Yamanaka, Hisashi; Yoneda, Toshiyuki; Ohira, Takeshi; Okubo, Naoki; Genant, Harry K

    2016-01-01

    Objectives To evaluate efficacy and safety of three different regimens of denosumab, a fully human monoclonal antibody to receptor activator of nuclear factor kappa B (RANK) ligand (RANKL), for Japanese patients with rheumatoid arthritis (RA). Methods In this multicentre, randomised, placebo-controlled phase II study, 350 Japanese patients with RA between 6 months and <5 years, stratified by glucocorticoid use and rheumatoid factor status, were randomly assigned to subcutaneous injections of placebo or denosumab 60 mg every 6 months (Q6M), every 3 months (Q3M) or every 2 months (Q2M). All patients basically continued methotrexate treatment and had a supplement of calcium and vitamin D throughout the study. The primary endpoint was change in the modified Sharp erosion score from baseline to 12 months. Results Denosumab significantly inhibited the progression of bone erosion at 12 months compared with the placebo, and the mean changes of the modified Sharp erosion score at 12 months from baseline were 0.99, 0.27 (compared with placebo, p=0.0082), 0.14 (p=0.0036) and 0.09 (p<0.0001) in the placebo, Q6M, Q3M and Q2M, respectively. Secondary endpoint analysis revealed that denosumab also significantly inhibited the increase of the modified total Sharp score compared with the placebo, with no obvious evidence of an effect on joint space narrowing for denosumab. As shown in previous studies, denosumab increased bone mineral density. No apparent difference was observed in the safety profiles of denosumab and placebo. Conclusions Addition of denosumab to methotrexate has potential as a new therapeutic option for patients with RA with risk factors of joint destruction. Trial registration number JapicCTI-101263. PMID:26585988

  7. The pursuit of balance: An overview of covariate-adaptive randomization techniques in clinical trials.

    PubMed

    Lin, Yunzhi; Zhu, Ming; Su, Zheng

    2015-11-01

    Randomization is fundamental to the design and conduct of clinical trials. Simple randomization ensures independence among subject treatment assignments and prevents potential selection biases, yet it does not guarantee balance in covariate distributions across treatment groups. Ensuring balance in important prognostic covariates across treatment groups is desirable for many reasons. A broad class of randomization methods for achieving balance are reviewed in this paper; these include block randomization, stratified randomization, minimization, and dynamic hierarchical randomization. Practical considerations arising from experience with using the techniques are described. A review of randomization methods used in practice in recent randomized clinical trials is also provided.

  8. 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.

  9. 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.

  10. 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.

  11. Fluoride concentration from dental sealants: a randomized clinical trial.

    PubMed

    Campus, G; Carta, G; Cagetti, M G; Bossù, M; Sale, S; Cocco, F; Conti, G; Nardone, M; Sanna, G; Strohmenger, L; Lingström, P

    2013-07-01

    A randomized clinical trial was performed in schoolchildren (6-7 yrs) to evaluate fluoride concentration in interproximal fluid after the placement of 3 different sealants. The sample consisted of 2,776 children randomly divided: 926 in the high-viscosity Glass-ionomer Cement group (GIC group), 923 in the fluoride Resin-based group (fluoride-RB group), and 927 in the no-fluoride Resin-based group (RB group). In total, 2,640 children completed the trial. Sealants were applied following manufacturer's instructions. Interproximal fluid samples were collected at baseline and 2, 7, and 21 days after application of sealants, by insertion of a standardized paperpoint into the interproximal mesial space of the sealed tooth for 15 seconds. Fluoride concentration was evaluated by means of a fluoride ion-selective electrode. At 2 days after sealant application, fluoride concentration was significantly higher in GIC and fluoride-RB groups compared with that in the RB group (p < .01). Mean fluoride concentrations after 7 days were 2.54 (SE 0.68) ppm, 0.85 (SE 0.26) ppm, and 0.53 (SE 0.11) ppm for the three groups, respectively. After 21 days, fluoride concentration in the GIC group remained higher than that in the other two groups. High-viscosity GIC sealants increased the fluoride concentrations in interproximal fluid more than did a Resin-based sealant containing fluoride.

  12. 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

  13. Dressing Wear Time after Breast Reconstruction: A Randomized Clinical Trial

    PubMed Central

    Paiva, Luiz Francisley; Fonseca, Fernando Elias Martins; Cabral, Isaías Vieira; Pinto, Natália Lana Larcher; Juliano, Yara

    2016-01-01

    Background The evidence to support dressing standards for breast surgery wounds is empiric and scarce. Objective This two-arm randomized clinical trial was designed to assess the effect of dressing wear time on surgical site infection (SSI) rates, skin colonization and patient perceptions. Methods A total of 200 breast cancer patients undergoing breast reconstruction were prospectively enrolled. Patients were randomly allocated to group I (dressing removed on the first postoperative day, n = 100) or group II (dressing removed on the sixth postoperative day, n = 100). SSIs were defined and classified according to criteria from the Centers for Disease Control and Prevention. Samples collected before placing the dressing and after 1 day (group I) and 6 days (both groups) were cultured for skin colonization assessments. Patients preferences and perceptions with regard to safety, comfort and convenience were recorded and analyzed. Results A total of 186 patients completed the follow-up. The global SSI rate was 4.5%. Six patients in group I and three in group II had SSI (p = 0.497). Before dressing, the groups were similar with regard to skin colonization. At the sixth day, there was a higher colonization by coagulase-negative staphylococci in group I (p<0.0001). Patients preferred to keep dressing for six days (p<0.0001), and considered this a safer choice (p<0.05). Conclusions Despite group I had a higher skin colonization by coagulase-negative staphylococci on the sixth postoperative day, there was no difference in SSI rates. Patients preferred keeping dressing for six days and considered it a safer choice. Trial Registration ClinicalTrials.gov NCT01148823 PMID:27911904

  14. BEATRIX-II, phase II: Data summary report

    SciTech Connect

    Slagle, O.D.; Hollenberg, G.W.

    1996-05-01

    The BEATRIX-II experimental program was an International Energy Agency sponsored collaborative effort between Japan, Canada, and the United States to evaluate the performance of ceramic solid breeder materials in a fast-neutron environment at high burnup levels. This report addresses the Phase II activities, which included two in situ tritium-recovery canisters: temperature-change and temperature-gradient. The temperature-change canister contained a Li{sub 2}O ring specimen that had a nearly uniform temperature profile and was capable of temperature changes between 530 and 640{degrees}C. The temperature-gradient canister contained a Li{sub 2}ZrO{sub 3} pebble bed operating under a thermal gradient of 440 to 1100{degrees}C. Postirradiation examination was carried out to characterize the Phase II in situ specimens and a series of nonvented capsules designed to address the compatibility of beryllium with lithium-ceramic solid-breeder materials. The results of the BEATRIX-II, Phase II, irradiation experiment provided an extensive data base on the in situ tritium-release characteristics of Li{sub 2}O and Li{sub 2}ZrO{sub 3} for lithium burnups near 5%. The composition of the sweep gas was found to be a critical parameter in the recovery of tritium from both Li{sub 2}O and Li{sub 2}ZrO{sub 3}. Tritium inventories measured confirmed that Li{sub 2}O and Li{sub 2}ZrO{sub 3} exhibited very low tritium retention during the Phase II irradiation. Tritium inventories in Li{sub 2}ZrO{sub 3} after Phase II tended to be larger than those found for Li{sub 2}ZrO{sub 3} in other in situ experiments, but the larger values may reflect the larger generation rates in BEATRIX-II. A series of 20 capsules was irradiated to determine the compatibility of lithium ceramics and beryllium under conditions similar to a fusion blanket. It is concluded that Li{sub 2}O and Li{sub 2}ZrO{sub 3} should remain leading candidates for use in a solid-breeder fusion-blanket application.

  15. 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

  16. Design of Phase II cancer trials for evaluation of cytostatic/cytotoxic agents.

    PubMed

    Kocherginsky, Masha; Cohen, Ezra E W; Karrison, Theodore

    2009-01-01

    For experimental anticancer agents that may have both cytostatic and cytotoxic effects, assessment of response rates alone may not capture the full impact of the treatment. Oncologists are therefore interested in assessing both response and stable disease rates in early phase clinical trials of such therapies. We describe the design of a single-arm, Phase II clinical trial for the simultaneous evaluation of objective response and stable disease (lack of early tumor progression) rates using standard RECIST criteria. Demonstration of a sufficiently high rate for either of these endpoints will lead to rejection of the null hypothesis and a conclusion that the treatment warrants further study. A design is chosen that satisfies the desired type I error constraint and has sufficient statistical power at several selected points within the alternative hypothesis space using a restricted search algorithm. An early stopping rule for lack of efficacy is incorporated. The method is illustrated by the design of a Phase II clinical trial in head and neck cancer.

  17. 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

  18. 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.

  19. 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 Central

    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

    2011-01-01

    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. PMID:21292895

  20. 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

  1. 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).

  2. 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.

  3. 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.

  4. The PICASSO Dark Matter Experiment - Getting Ready for Phase II

    NASA Astrophysics Data System (ADS)

    Krauss, Carsten B.; Picasso Collaboration

    2011-12-01

    PICASSO is a dark matter search experiment that uses the superheated droplet technique to find spin-dependently interacting WIMPs. A set of 1 l detectors with a total active mass of 19.4 g was used to prove the validity of the technique. The data from this run disfavors WIMP-proton cross sections larger than 1.3 pb for a WIMP mass of 29 GeV. Currently phase II of PICASSO is getting started. It will consist of 32 4.5 l detectors with a projected active mass of 2.5 kg and improved detectors.

  5. Reservoir modeling of the Phase II Hot Dry Rock System

    SciTech Connect

    Zyvoloski, G.

    1984-01-01

    The Phase II system has been created with a series of hydraulic fracturing experiments at the Fenton Hill Hot Dry Rock site. Experiment 2032, the largest of the fracturing operations, involved injecting 5.6 million gallons (21,200m/sup 3/) of water into wellbore EE-2 over the period December 6-9, 1983. The experiment has been modeled using geothermal simulator FEHM developed at Los Alamos National Laboratory. The modeling effort has produced strong evidence of a large highly fractured reservoir. Two long term heat extraction schemes for the reservoir are studied with the model.

  6. Randomized clinical trial of peganum oil for knee osteoarthritis.

    PubMed

    Abolhassanzadeh, Zohreh; Aflaki, Elham; Yousefi, Gholamhossein; Mohagheghzadeh, Abdolali

    2015-04-01

    Osteoarthritis affects about 50% of people aged older than 65 years. Pain is the most important symptom in this disease. Today public interest in the use of complementary medicine, especially traditional herbal medicines has increased. The present study was designed to investigate the efficacy of traditional preparation of Peganum harmala L oil on patients with knee osteoarthritis. The product has been analyzed and standardized by high-performance liquid chromatography. A double blind controlled randomized clinical trial consisting of 54 patients were performed. Patients rubbed the drug or control (olive oil) on the knee 4 drops 3 times a day for 4 weeks. The patients were asked to fill out the Western Ontario and McMaster Universities Arthritis Index and Visual Analogue Scale questionnaires at week 0 and 4. The adapted results from the questionnaires showed that pain and difficulty in function were significantly decreased in Peganum oil group after 4 weeks. There was no significant difference in stiffness change between 2 groups.

  7. Emtonjeni-A Structural Intervention to Integrate Sexual and Reproductive Health into Public Sector HIV Care in Cape Town, South Africa: Results of a Phase II Study.

    PubMed

    Mantell, J E; Cooper, D; Exner, T M; Moodley, J; Hoffman, S; Myer, L; Leu, C-S; Bai, D; Kelvin, E A; Jennings, K; Stein, Z A; Constant, D; Zweigenthal, V; Cishe, N; Nywagi, N

    2017-03-01

    Integration of sexual and reproductive health within HIV care services is a promising strategy for increasing access to family planning and STI services and reducing unwanted pregnancies, perinatal HIV transmission and maternal and infant mortality among people living with HIV and their partners. We conducted a Phase II randomized futility trial of a multi-level intervention to increase adherence to safer sex guidelines among those wishing to avoid pregnancy and adherence to safer conception guidelines among those seeking conception in newly-diagnosed HIV-positive persons in four public-sector HIV clinics in Cape Town. Clinics were pair-matched and the two clinics within each pair were randomized to either a three-session provider-delivered enhanced intervention (EI) (onsite contraceptive services and brief milieu intervention for staff) or standard-of-care (SOC) provider-delivered intervention. The futility analysis showed that we cannot rule out the possibility that the EI intervention has a 10 % point or greater success rate in improving adherence to safer sex/safer conception guidelines than does SOC (p = 0.573), indicating that the intervention holds merit, and a larger-scale confirmatory study showing whether the EI is superior to SOC has merit.

  8. Gender differences in clinical outcomes for cocaine dependence: Randomized clinical trials of behavioral therapy and disulfiram✩

    PubMed Central

    DeVito, Elise E.; Babuscio, Theresa A.; Nich, Charla; Ball, Samuel A.; Carroll, Kathleen M.

    2014-01-01

    Background Despite extensive research on gender differences in addiction, there are relatively few published reports comparing treatment outcomes for women versus men based on evidence-based treatments evaluated in randomized clinical trials. Methods An aggregate sample comprised of data from five randomized clinical trials of treatment for cocaine dependence (N = 434) was evaluated for gender differences in clinical outcomes. Secondary analyses compared gender differences in outcome by medication condition (disulfiram versus no medication) and across multiple behavioral treatment conditions. Results Women, compared with men, had poorer treatment outcomes on multiple measures of cocaine use during treatment and at post-treatment follow-up. These results appear to be primarily accounted for by disulfiram being less effective in women compared with men. There was no evidence of meaningful gender differences in outcome as a function of the behavioral therapies evaluated. Conclusions These findings suggest that women and men may benefit to similar degrees from some empirically validated behavioral treatments for addiction. Conversely, some addiction pharmacotherapies, such as disulfiram, may be associated with poorer outcomes among women relative to men and point to the need for careful assessment of pharmacological treatments in both sexes prior to widespread clinical implementation. PMID:25457739

  9. Challenges and Potential Solutions to Meeting Accrual Goals in a Phase II Chemoprevention Trial for Prostate Cancer

    PubMed Central

    Kumar, Nagi; Crocker, Theresa; Smith, Tiffany; Pow-Sang, Julio; Spiess, Philippe E.; Egan, Kathleen; Quinn, Gwen; Schell, Michael; Sebti, Said; Kazi, Aslam; Chuang, Tian; Salup, Raoul; Helal, Mohamed; Zagaja, Gregory; Trabulsi, Edouard; McLarty, Jerry; Fazili, Tajammul; Williams, Christopher R.; Schreiber, Fred; Slaton, Joel; Anderson, J Kyle

    2011-01-01

    Objective The goal of this report is to describe the on going strategies, successes, challenges and solutions for recruitment in this multi-center, phase II chemoprevention trial targeting men at high risk for prostate cancer. Methods We developed and implemented a multi-center clinical trial in institutions with supportive infrastructure, lead by a recruitment team of experienced and committed physicians and clinical trial staff, implementing multi-media and community outreach strategies to meet recruitment goals. Screening logs were reviewed to identify trends as well as patient, protocol and infrastructure -related barriers impacting accrual and revisions to protocol implemented. Results Between January 2008 and February 2011 a total of 3547 individuals were prescreened with 94% (n=3092) determined to be ineligible based on diagnosis of cancer or benign biopsy results. Of these, 216 were considered eligible for further screening with 52% (n=113) declining to participate due to patient related factors and 14% (n=29) eliminated due to protocol-related criteria for exclusion. Ninety four (94) subjects consented to participate with 34% of these subjects (n=74) meeting all eligibility criteria to be randomized to receive study agent or placebo. Across all sites, 99% of the recruitment of subjects in this clinical trial is via physician recruitment and referral with less than 1% responding to other recruitment strategies. Conclusion A contemporary approach to subject recruitment and frequent evaluation is needed to assure responsiveness to emerging challenges to accrual and the evolving scientific literature. A focus on investing on improving systems for physician recruitment may be key to meeting recruitment target in chemoprevention trials. PMID:22101219

  10. Balancing Contamination and Referral Bias in a Randomized Clinical Trial: An Application of Pseudo-Cluster Randomization

    PubMed Central

    Pence, Brian W.; Gaynes, Bradley N.; Thielman, Nathan M.; Heine, Amy; Mugavero, Michael J.; Turner, Elizabeth L.; Quinlivan, Evelyn B.

    2015-01-01

    In randomized trials of provider-focused clinical interventions, treatment allocation often cannot be blinded to participants, study staff, or providers. The choice of unit of randomization (patient, provider, or clinic) entails tradeoffs in cost, power, and bias. Provider- or clinic-level randomization can minimize contamination, but it incurs the equally problematic potential for referral bias; that is, because arm assignment of future participants generally cannot be concealed, differences between arms may arise in the types of patients enrolled. Pseudo-cluster randomization is a novel study design that balances these competing validity threats. Providers are randomly assigned to an imbalanced proportion of intervention-arm participants (e.g., 80% or 20%). Providers can be masked to the imbalance, avoiding referral bias. Contamination is reduced because only a minority of control-arm participants are treated by majority-intervention providers. Pseudo-cluster randomization was implemented in a randomized trial of a decision support intervention to manage depression among patients receiving human immunodeficiency virus care in the southern United States in 2010–2014. The design appears successful in avoiding referral bias (participants were comparable between arms on important characteristics) and contamination (key depression treatment indicators were comparable between usual care participants managed by majority-intervention and majority-usual care providers and were markedly different compared with intervention participants). PMID:26628511

  11. 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.

  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. {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.

  14. Repurposing Diflunisal for Familial Amyloid Polyneuropathy: A Randomized Clinical Trial

    PubMed Central

    Berk, John L.; Suhr, Ole B.; Obici, Laura; Sekijima, Yoshiki; Zeldenrust, Steven R.; Yamashita, Taro; Heneghan, Michael A.; Gorevic, Peter D.; Litchy, William J.; Wiesman, Janice F.; Nordh, Erik; Corato, Manuel; Lozza, Alessandro; Cortese, Andrea; Robinson-Papp, Jessica; Colton, Theodore; Rybin, Denis V.; Bisbee, Alice B.; Ando, Yukio; Ikeda, Shu-ichi; Seldin, David C.; Merlini, Giampaolo; Skinner, Martha; Kelly, Jeffery W.; Dyck, Peter J.

    2014-01-01

    Importance Familial amyloid polyneuropathy (ATTR-FAP), a lethal genetic disease caused by aggregation of variant transthyretin, induces progressive peripheral nerve deficits and disability. Diflunisal, a non-steroidal anti-inflammatory agent, stabilizes transthyretin tetramers and prevents amyloid fibril formation in vitro. Objective To determine the effect of diflunisal on polyneuropathy progression in patients with ATTR-FAP. Design, Setting, and Patients We conducted an investigator-initiated international, randomized, double-blind, placebo-controlled study at amyloid centers in Sweden (Umea), Italy (Pavia), Japan (Matsumoto and Kumamoto), England (London), and the United States (Boston, New York, Rochester, MN) from 2006 through 2012. 130 ATTRFAP patients with clinically detectable peripheral or autonomic neuropathy were randomly assigned to diflunisal 250 mg or placebo twice daily for 2 years. Main Outcome Measures The primary endpoint, the difference in polyneuropathy progression between treatments, was measured by the Neuropathy Impairment Score plus 7 nerve tests (NIS+7) which ranges from 0 (no neurologic deficits) to 270 points (no detectable peripheral nerve function). Secondary outcomes included a quality of life questionnaire (Short Form-36 (SF-36)) and modified body mass index (mBMI). Results One hundred thirty randomized patients (66 placebo, 64 diflunisal) underwent serial NIS+7 evaluations over 2 years. Due to attrition, we employed likelihood based modeling and multiple imputation (MI) analysis of baseline to 2 year data. By MI, NIS+7 increased 25.0 points (95% CI, 18.4 to 31.6) among placebo and 8.7 points (95% CI, 3.3 to 14.1) in the diflunisal group, a difference of 16.3 points (95% CI, 8.1 to 24.5, p=0.001). Mean SF-36 physical scores fell 4.9 points (95% CI, −7.6 to −2.2) among placebo and rose 1.5 points (95% CI, −0.8 to 3.7) in the diflunisal group (p=0.003). SF-36 mental scores declined 1.1 (95% CI, −4.3 to 2.0) among placebo while

  15. Guidelines for randomized clinical trial protocol content: a systematic review

    PubMed Central

    2012-01-01

    Background All randomized clinical trials (RCTs) require a protocol; however, numerous studies have highlighted protocol deficiencies. Reporting guidelines may improve the content of research reports and, if developed using robust methods, may increase the utility of reports to stakeholders. The objective of this study was to systematically identify and review RCT protocol guidelines, to assess their characteristics and methods of development, and to compare recommendations. Methods We conducted a systematic review of indexed literature (MEDLINE, EMBASE and the Cochrane Methodology Register from inception to September 2010; reference lists; related article features; forward citation searching) and a targeted search of supplementary sources, including a survey of major trial funding agencies in six countries. Records were eligible if they described a content guideline in English or French relevant to RCT protocols. Guidelines were excluded if they specified content for protocols for trials of specific procedures or conditions or were intended to assess trial quality. We extracted guideline characteristics and methods. Content was mapped for a subset of guidelines that described development methods or had institutional endorsement. Results Forty guidelines published in journals, books and institutional reports were included in the review; seven were specific to RCT protocols. Only eight (20%) described development methods which included informal consensus methods, pilot testing and formal validation; no guideline described all of these methods. No guideline described formal consensus methods or a systematic retrieval of empirical evidence to inform its development. The guidelines included a median of 23 concepts per guideline (interquartile range (IQR) = 14 to 34; range = 7 to 109). Among the subset of guidelines (n = 23) for which content was mapped, approximately 380 concepts were explicitly addressed (median concepts per guideline IQR = 31 (24

  16. Randomized clinical trials of constitutional acupuncture: a systematic review.

    PubMed

    Lee, Myeong Soo; Shin, Byung-Cheul; Choi, Sun-Mi; Kim, Jong Yeol

    2009-09-01

    The aim of this systematic review is to compile and critically evaluate the evidence from randomized clinical trials (RCTs) for the effectiveness of acupuncture using constitutional medicine compared to standard acupuncture. Ten databases were searched through to December 2008 without language restrictions. We also hand-searched nine Korean journals of oriental medicine. We included prospective RCTs of any form of acupuncture with or without electrical stimulation. The included trials had to investigate constitutional medicine. There were no restrictions on population characteristics. Forty-one relevant studies were identified, and three RCTs were included. The methodological quality of the trials was variable. One RCT found Sasang constitutional acupuncture to be superior to standard acupuncture in terms of the Unified PD Rating Scale and freezing gate in Parkinson's disease (PD). Another two RCTs reported favorable effects of eight constitutional acupuncture on pain reduction in patients with herniated nucleus pulposi and knee osteoarthritis. Meta-analysis demonstrated positive results for eight constitutional acupuncture compared to standard acupuncture on pain reduction (weighted mean difference: 10 cm VAS, 1.69, 95% CI 0.85-2.54, P < 0.0001; heterogeneity: tau(2) = 0.00, chi(2) = 0.00, P = 0.96, I(2) = 0%). Our results provide suggestive evidence for the effectiveness of constitutional acupuncture in treating pain conditions compared to standard acupuncture. However, the total number of RCTs and the total sample size included in our analysis were too small to draw definite conclusions. Future RCTs should assess larger patient samples with longer treatment periods and appropriate controls.

  17. Randomized clinical trial: effect of the 5-HT4 receptor agonist revexepride on reflux parameters in patients with persistent reflux symptoms despite PPI treatment

    PubMed Central

    Tack, J; Zerbib, F; Blondeau, K; des Varannes, S B; Piessevaux, H; Borovicka, J; Mion, F; Fox, M; Bredenoord, A J; Louis, H; Dedrie, S; Hoppenbrouwers, M; Meulemans, A; Rykx, A; Thielemans, L; Ruth, M

    2015-01-01

    Background Approximately, 20–30% of patients with gastro-esophageal reflux disease (GERD) experience persistent symptoms despite treatment with proton pump inhibitors (PPIs). These patients may have underlying dysmotility; therefore, targeting gastric motor dysfunction in addition to acid inhibition may represent a new therapeutic avenue. The aim of this study was to assess the pharmacodynamic effect of the prokinetic agent revexepride (a 5-HT4 receptor agonist) in patients with GERD who have persistent symptoms despite treatment with a PPI. Methods This was a phase II, exploratory, multicenter, randomized, placebo-controlled, double-blind, parallel-group study in patients with GERD who experienced persistent symptoms while taking a stable dose of PPIs (http://ClinicalTrials.gov identifier: NCT01370863). Patients were randomized to either revexepride (0.5 mg, three times daily) or matching placebo for 4 weeks. Reflux events and associated characteristics were assessed by pH/impedance monitoring and disease symptoms were assessed using electronic diaries and questionnaires. Key Results In total, 67 patients were enrolled in the study. There were no significant differences between study arms in the number, the mean proximal extent or the bolus clearance times of liquid-containing reflux events. Changes from baseline in the number of heartburn, regurgitation, and other symptom events were minimal for each treatment group and no clear trends were observed. Conclusions & Inferences No clear differences were seen in reflux parameters between the placebo and revexepride groups. PMID:25530111

  18. 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

  19. 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.

  20. 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.

  1. First Results of the Phase II SIMPLE Dark Matter Search

    NASA Astrophysics Data System (ADS)

    Felizardo, M.; Morlat, T.; Fernandes, A. C.; Girard, T. A.; Marques, J. G.; Ramos, A. R.; Auguste, M.; Boyer, D.; Cavaillou, A.; Sudre, C.; Poupeney, J.; Payne, R. F.; Miley, H. S.; Puibasset, J.

    2010-11-01

    We report results of a 14.1kgd measurement with 15 superheated droplet detectors of total active mass 0.208 kg, comprising the first stage of a 30kgd Phase II experiment. In combination with the results of the neutron-spin sensitive XENON10 experiment, these results yield a limit of |ap|<0.32 for MW=50GeV/c2 on the spin-dependent sector of weakly interacting massive particle-nucleus interactions with a 50% reduction in the previously allowed region of the phase space, formerly defined by XENON, KIMS, and PICASSO. In the spin-independent sector, a limit of 2.3×10-5pb at MW=45GeV/c2 is obtained.

  2. 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.

  3. Steam generator tube integrity program: Phase II, Final report

    SciTech Connect

    Kurtz, R.J.; Bickford, R.L.; Clark, R.A.; Morris, C.J.; Simonen, F.A.; Wheeler, K.R.

    1988-08-01

    The Steam Generator Tube Integrity Program (SGTIP) was a three phase program conducted for the US Nuclear Regulatory Commission (NRC) by Pacific Northwest Laboratory (PNL). The first phase involved burst and collapse testing of typical steam generator tubing with machined defects. The second phase of the SGTIP continued the integrity testing work of Phase I, but tube specimens were degraded by chemical means rather than machining methods. The third phase of the program used a removed-from-service steam generator as a test bed for investigating the reliability and effectiveness of in-service nondestructive eddy-current inspection methods and as a source of service degraded tubes for validating the Phase I and Phase II data on tube integrity. This report describes the results of Phase II of the SGTIP. The object of this effort included burst and collapse testing of chemically defected pressurized water reactor (PWR) steam generator tubing to validate empirical equations of remaining tube integrity developed during Phase I. Three types of defect geometries were investigated: stress corrosion cracking (SCC), uniform thinning and elliptical wastage. In addition, a review of the publicly available leak rate data for steam generator tubes with axial and circumferential SCC and a comparison with an analytical leak rate model is presented. Lastly, nondestructive eddy-current (EC) measurements to determine accuracy of defect depth sizing using conventional and alternate standards is described. To supplement the laboratory EC data and obtain an estimate of EC capability to detect and size SCC, a mini-round robin test utilizing several firms that routinely perform in-service inspections was conducted.

  4. Review of the randomized clinical stroke rehabilitation trials in 2009

    PubMed Central

    Rabadi, Meheroz H.

    2011-01-01

    Summary Background Recent review of the available evidence on interventions for motor recovery after stroke, showed that improvements in recovery of arm function were seen for constraint-induced movement therapy, electromyographic biofeedback, mental practice with motor imagery, and robotics. Similar improvement in transfer ability or balance were seen with repetitive task training, biofeedback, and training with a moving platform. Walking speed was improved by physical fitness training, high-intensity physiotherapy and repetitive task training. However, most of these trials were small and had design limitations. Material/Methods In this article, randomized control trials (RCT’s) published in 2009 of rehabilitation therapies for acute (≤2 weeks), sub-acute (2 to 12 weeks) and chronic (≥12 weeks) stroke was reviewed. A Medline search was performed to identify all RCT’s in stroke rehabilitation in the year 2009. The search strategy that was used for PubMed is presented in the Appendix 1. The objective was to examine the effectiveness of these treatment modalities in stroke rehabilitation. Results This generated 35 RCT’s under 5 categories which were found and analyzed. The methodological quality was assessed by using the PEDro scale for external and internal validity. Conclusions These trials were primarily efficacy studies. Most of these studies enrolled small numbers of patient which precluded their clinical applicability (limited external validity). However, the constraint induced movement therapy (CIT), regularly used in chronic stroke patients did not improve affected arm-hand function when used in acute stroke patients at ≤4 weeks. Intensive CIT did not lead to motor improvement in arm-hand function. Robotic arm treatment helped decrease motor impairment and improved function in chronic stroke patients only. Therapist provided exercise programs (when self-administered by patients during their off-therapy time in a rehabilitation setting) did improve

  5. Isac Sc-Linac Phase-II Helium Refrigerator Commissioning and First Operational Experience at Triumf

    NASA Astrophysics Data System (ADS)

    Sekachev, I.; Kishi, D.; Laxdal, R. E.

    2010-04-01

    ISAC Phase-II is an upgrade of the radioactive isotope superconducting linear accelerator, SC-linac, at TRIUMF. The Phase-I section of the accelerator, medium-beta, is operational and is cooled with a 600 W helium refrigerator, commissioned in March 2005. An identical refrigerator is being used with the Phase-II segment of the accelerator; which is now under construction. The second refrigerator has been commissioned and tested with the Phase-I section of the linac and is used for Phase-II linac development, including new SC-cavity performance tests. The commissioning of the Phase-II refrigeration system and recent operational experience is presented.

  6. Doxycycline in early CJD: a double-blinded randomised phase II and observational study

    PubMed Central

    Varges, Daniela; Manthey, Henrike; Heinemann, Uta; Ponto, Claudia; Schmitz, Matthias; Schulz-Schaeffer, Walter J; Krasnianski, Anna; Breithaupt, Maren; Fincke, Fabian; Kramer, Katharina; Friede, Tim; Zerr, Inga

    2017-01-01

    Objectives The main objective of the present study is to study the therapeutic efficiency of doxycycline in a double-blinded randomised phase II study in a cohort of patients with sporadic Creutzfeldt-Jakob disease (sCJD). Methods From the National Reference Center of TSE Surveillance in Germany, patients with probable or definite sCJD were recruited for a double-blinded randomised study with oral doxycycline (EudraCT 2006-003934-14). In addition, we analysed the data from patients with CJD who received compassionate treatment with doxycycline in a separate group. Potential factors which influence survival such as age at onset, gender, codon 129 polymorphism and cognitive functions were evaluated. The primary outcome measure was survival. Results Group 1: in the double-blinded randomised phase II study, 7 patients in the treatment group were compared with 5 controls. Group 2: 55 patients with sCJD treated with oral doxycycline were analysed and compared with 33 controls by a stratified propensity score applied to a Cox proportional hazard analysis. The results of both studies were combined by means of a random-effects meta-analysis. A slight increase in survival time in the doxycycline treatment group was observed (p=0.049, HR=0.63 (95% CI 0.402 to 0.999)). Conclusions On the basis of our studies, a larger trial of doxycycline should be performed in persons in the earliest stages of CJD. Trial registration number EudraCT 2006-003934-14; Results. PMID:27807198

  7. 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

  8. 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

  9. 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.

  10. In utero Repair of Myelomeningocele: Rationale, Initial Clinical Experience and a Randomized Controlled Prospective Clinical Trial

    PubMed Central

    Danzer, Enrico; Flake, Alan W.

    2008-01-01

    Myelomeningocele (MMC), one of the most common congenital malformations, can result in severe lifelong disabilities, including paraplegia, hydrocephalus, Arnold-Chiari II malformation, incontinence, sexual dysfunction, skeletal deformations, and mental impairment. MMC was the first nonlethal anomaly to be treated by fetal surgery. Studies in animals provide compelling evidence that the primary cause of the neurological deficit associated with MMC is not simply incomplete neurulation but rather chronic mechanical injury and amniotic-fluid-induced chemical trauma that progressively damage the exposed neural tissue during gestation. Initial results suggest that the surgical repair of MMC before 25 weeks of gestation may preserve neurological function, reverse the hindbrain herniation of the Arnold-Chiari II malformation, and obviate the need for postnatal placement of a ventriculoperitoneal shunt. As it is currently unknown whether fetal surgery for MMC is truly beneficial compared to standard postnatal care, a randomized, controlled clinical trial has been initiated within the United States. PMID:22479081

  11. 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.

  12. 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.

  13. Characterization of ToxCast Phase II compounds disruption of ...

    EPA Pesticide Factsheets

    The development of multi-well microelectrode array (mwMEA) systems has increased in vitro screening throughput making them an effective method to screen and prioritize large sets of compounds for potential neurotoxicity. In the present experiments, a multiplexed approach was used to determine compound effects on both neural function and cell health in primary cortical networks grown on mwMEA plates following exposure to ~1100 compounds from EPA’s Phase II ToxCast libraries. On DIV 13, baseline activity (40 min) was recorded prior to exposure to each compound at 40 µM. DMSO and the GABAA antagonist bicuculline (BIC) were included as controls on each mwMEA plate. Changes in spontaneous network activity (mean firing rate; MFR) and cell viability (lactate dehydrogenase; LDH and CellTiter Blue; CTB) were assessed within the same well following compound exposure. Activity calls (“hits”) were established using the 90th and 20th percentiles of the compound-induced change in MFR (medians of triplicates) across all tested compounds; compounds above (top 10% of compounds increasing MFR), and below (bottom 20% of compounds decreasing MFR) these thresholds, respectively were considered hits. MFR was altered beyond one of these thresholds by 322 compounds. Four compound categories accounted for 66% of the hits, including: insecticides (e.g. abamectin, lindane, prallethrin), pharmaceuticals (e.g. haloperidol, reserpine), fungicides (e.g. hexaconazole, fenamidone), and h

  14. 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.

  15. The phase II ATLAS Pixel upgrade: the Inner Tracker (ITk)

    NASA Astrophysics Data System (ADS)

    Flick, T.

    2017-01-01

    The entire tracking system of the ATLAS experiment will be replaced during the LHC Phase II shutdown (foreseen to take place around 2025) by an all-silicon detector called the ITk (Inner Tracker). The pixel detector will comprise the five innermost layers, and will be instrumented with new sensor and readout electronics technologies to improve the tracking performance and cope with the HL-LHC environment, which will be severe in terms of occupancy and radiation. Several layout options are being investigated. All of these include a barrel part and ring-shaped supports in the endcap regions. All structures will be based on low mass, highly stable and highly thermally conductive carbon-based materials cooled by evaporative carbon dioxide. Different designs of planar, 3D, and CMOS sensors are being investigated to identify the optimal technology for the different pixel layers. While the RD53 Collaboration is developing the new readout chip, the pixel off-detector readout electronics will be implemented in the framework of the general ATLAS trigger and DAQ system. A readout speed of up to 5 Gbit/s per data link (FE-chip) will be needed in the innermost layers going down to 640 Mbit/s for the outermost. This paper presents an overview of the different components of the ITk and the current status of the developments.

  16. 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.

  17. 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).

  18. Background rejection of n+ surface events in GERDA Phase II

    NASA Astrophysics Data System (ADS)

    Lehnert, Björn

    2016-05-01

    The GERDA experiment searches for neutrinoless double beta (0vββ) decay in 76Ge using an array of high purity germanium (HPGe) detectors immersed in liquid argon (LAr). Phase II of the experiment uses 30 new broad energy germanium (BEGe) detectors with superior pulse shape discrimination capabilities compared to the previously used semi-coaxial detector design. By far the largest background component for BEGe detectors in GERDA are n+-surface events from 42K β decays which are intrinsic in LAr. The β particles with up to 3.5 MeV can traverse the 0.5 to 0.9 mm thick electrode and deposit energy within the region of interest for the 0vββ decay. However, those events have particular pulse shape features allowing for a strong discrimination. The understanding and simulation of this background, showing a reduction by up to a factor 145 with pulse shape discrimination alone, is presented in this work.

  19. 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

  20. Comparative Effectiveness of Goal Setting in Diabetes Mellitus Group Clinics:Randomized Clinical Trial

    PubMed Central

    Naik, Aanand D.; Palmer, Nynikka; Petersen, Nancy J.; Street, Richard L.; Rao, Radha; Suarez-Almazor, Maria; Haidet, Paul

    2011-01-01

    Background Diabetes group clinics can effectively control hypertension, but data to support glycemic control is equivocal. This study evaluated the comparative effectiveness of two diabetes group clinic interventions on glycosolated hemoglobin (HbA1c) levels in primary care. Methods Participants (n = 87) were recruited from a diabetes registry of a single regional VA medical center to participate in an open, randomized comparative effectiveness study. Two primary care based diabetes group interventions of three months duration were compared. Empowering Patients in Care (EPIC) was a clinician-led, patient-centered group clinic consisting of four sessions on setting self-management action plans (diet, exercise, home monitoring, medications, etc.) and communicating about progress with action plans. The comparison intervention consisted of group education sessions with a diabetes educator and dietician followed by an additional visit with one’s primary care provider. HbA1c levels were compared post-intervention and at one-year follow-up. Results Participants in the EPIC intervention had significantly greater improvements in HbA1c levels immediately following the active intervention (8.86 to 8.04 vs. 8.74 to 8.70, mean [SD] between-group difference 0.67±1.3, P=.03) and these differences persisted at 1 year follow-up (.59±1.4, P=.05). A repeated measures analysis using all study time points found a significant time-by-treatment interaction effect on HbA1c levels favoring the EPIC intervention (F(2,85) =3.55, P= .03). The effect of the time-by-treatment interaction appears to be partially mediated by diabetes self-efficacy (F(1,85) =10.39, P= .002). Conclusions Primary care based diabetes group clinics that include structured goal-setting approaches to self-management can significantly improve HbA1c levels post-intervention and maintain improvements for 1-year. Trial registration ClinicalTrials.gov Identifier: NCT00481286 PMID:21403042

  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 72.74 - 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...

  3. 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...

  4. 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...

  5. 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...

  6. 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...

  7. 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...

  8. 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...

  9. 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...

  10. 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...

  11. Emerging Roles of Nrf2 and Phase II Antioxidant Enzymes in Neuroprotection

    PubMed Central

    Zhang, Meijuan; An, Chengrui; Gao, Yanqin; Leak, Rehana K.; Chen, Jun; Zhang, Feng

    2013-01-01

    Phase II metabolic enzymes are a battery of critical proteins that detoxify xenobiotics by increasing their hydrophilicity and enhancing their disposal. These enzymes have long been studied for their preventative and protective effects against mutagens and carcinogens and for their regulation via the Keap1 (Kelch-like ECH associated protein 1) / Nrf2 (Nuclear factor erythroid 2 related factor 2) / ARE (antioxidant response elements) pathway. Recently, a series of studies have reported the altered expression of phase II genes in postmortem tissue of patients with various neurological diseases. These observations hint at a role for phase II enzymes in the evolution of such conditions. Furthermore, promising findings reveal that overexpression of phase II genes, either by genetic or chemical approaches, confers neuroprotection in vitro and in vivo. Therefore, there is a need to summarize the current literature on phase II genes in the central nervous system (CNS). This should help guide future studies on phase II genes as therapeutic targets in neurological diseases. In this review, we first briefly introduce the concept of phase I, II and III enzymes, with a special focus on phase II enzymes. We then discuss their expression regulation, their inducers and executors. Following this background, we expand our discussion to the neuroprotective effects of phase II enzymes and the potential application of Nrf2 inducers to the treatment of neurological diseases. PMID:23025925

  12. 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

  13. 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)

  14. 7 CFR 3403.8 - Proposal format for phase II applications.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... Collection. Each Phase II applicant will be required to provide information to the Tech-Net Database System... applicants into Tech-Net: (i) Any business concern or subsidiary established for the commercial application... conducted under each Phase II award; and (iv) Updates to information in the Tech-Net database for any...

  15. 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.

  16. The Development of New Measures of Cognitive Variables in Elementary School Children (Phase II). Final Report.

    ERIC Educational Resources Information Center

    Asher, J. William; And Others

    This report covers Phase II of a two-phase project concerned with the development of new measures of cognitive variables in elementary school children. The four tasks undertaken in Phase II were: (1) prepare, revise and describe instruments designed to measure the cognitive variables categorized as concept formation, language development, logical…

  17. 78 FR 30951 - SBIR/STTR Phase I to Phase II Transition Benchmarks

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-05-23

    ... From the Federal Register Online via the Government Publishing Office SMALL BUSINESS ADMINISTRATION SBIR/STTR Phase I to Phase II Transition Benchmarks AGENCY: U.S. Small Business Administration. ACTION: Notice for Small Business Innovation Research Program Phase I to Phase II Transition...

  18. 7 CFR 3403.8 - Proposal format for phase II applications.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... Collection. Each Phase II applicant will be required to provide information to the Tech-Net Database System... applicants into Tech-Net: (i) Any business concern or subsidiary established for the commercial application... conducted under each Phase II award; and (iv) Updates to information in the Tech-Net database for any...

  19. 7 CFR 3403.8 - Proposal format for phase II applications.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... Collection. Each Phase II applicant will be required to provide information to the Tech-Net Database System... applicants into Tech-Net: (i) Any business concern or subsidiary established for the commercial application... conducted under each Phase II award; and (iv) Updates to information in the Tech-Net database for any...

  20. 7 CFR 3403.8 - Proposal format for phase II applications.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... Collection. Each Phase II applicant will be required to provide information to the Tech-Net Database System... applicants into Tech-Net: (i) Any business concern or subsidiary established for the commercial application... conducted under each Phase II award; and (iv) Updates to information in the Tech-Net database for any...

  1. A Phase II Study of RO4929097 Gamma-Secretase Inhibitor in Metastatic Melanoma: SWOG 0933

    PubMed Central

    Lee, Sylvia M.; Moon, James; Redman, Bruce G.; Chidiac, Tarek; Flaherty, Lawrence E.; Zha, Yuanyuan; Othus, Megan; Ribas, Antoni; Sondak, Vernon K.

    2014-01-01

    Background Aberrant Notch activation confers a proliferative advantage onto many human tumors, including melanoma. This phase II trial assessed the antitumor activity of RO4929097, a gamma-secretase inhibitor of Notch signaling, on the progression-free and overall survival of patients with advanced melanoma. Methods Chemotherapy-naïve patients with metastatic melanoma of cutaneous or unknown origin were treated with RO4929097 at a dose of 20 mg orally daily, 3 consecutive days per week. A two-step accrual design was used, with an interim analysis on the first 32 patients, and continuation of enrollment if ≥4/32 patients responded. Results Thirty-six patients from 23 institutions were enrolled; 32 patients were evaluable. RO4929097 was well-tolerated, and most toxicities were grade 1 or 2. The most common toxicities were nausea (53%), fatigue (41%), and anemia (22%). There was 1 confirmed partial response lasting 7 months, and 8 patients with stable disease lasting at least through week 12, with one of these continuing for 31 months. The 6-month PFS was 9% (95% CI: 2–22%), and 1-year OS was 50% (95% CI: 32–66%). Peripheral blood T cell assays showed no significant inhibition of IL-2 production, a surrogate pharmacodynamic marker of Notch inhibition, suggesting that the drug levels were insufficient to achieve Notch target inhibition. Conclusions RO4929097 showed minimal clinical activity against metastatic melanoma in this phase II trial, possibly due to inadequate exposure to therapeutic drug levels. While Notch inhibition remains a compelling target in melanoma, our results do not support further investigation of RO4929097 at this dose and schedule. PMID:25250858

  2. 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

  3. 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.

  4. Ultrafiltration of Kraft Black Liquor: Phase II, Final report

    SciTech Connect

    Hill, M.K.

    1987-09-01

    The major justification for examining ultrafiltration was to lower the viscosity of the Kraft Black Liquor by recovering it as an ultrafiltration permeate from which the highest MW lignin had been removed. The liquor could then be concentrated to a higher percentage solids before firing into the recovery boiler. Consequent energy savings for the 1000 ton/day pulp mill would be 2.05 x 10 Btu/y for each percentage increase in TDS (total dissolved solids) to the recovery boiler. This Phase II report gives data on viscosity with percentage solids of KBL permeates. Another favorable effect of ultrafiltration on the permeate properties is disproportionate removal of multivalent ions including the major scaling ion CaS . If this high-viscosity high-Ca retentate could be treated to lower its viscosity and to release the Ca in a non-scaling form, this would enhance the possibility that ultrafiltration might be useful in a mill situation. Included in this report are data on the results of treating the retentate fraction. Other justifications for this program included further information in KBL properties: lignin MW in the KBL at high pH; elemental and sugar analyses; and differential properties of lignins in the retentate and the permeate fractions. A preliminary economic analysis of ultrafiltration is contained in this report. These analyses indicate that with flux rates now attainable, ultrafiltration would not be economically justified at this time if the only justification is to lower KBL viscosity. For certain situations where high Ca liquors present a scaling problem, especially in an evaporator-limited mill, the economics are more favorable. There are also unsolved problems relating to the use of the high viscosity retentate.

  5. A Phase II Study of Sorafenib in Advanced Uterine Carcinoma / Carcinosarcoma: A Trial of the Chicago, PMH, and California Phase II Consortia

    PubMed Central

    Nimeiri, Halla S.; Oza, Amit M.; Morgan, Robert J.; Huo, Dezheng; Elit, Laurie; Knost, James A.; Wade, James L.; Agamah, Edem; Vokes, Everett E.; Fleming, Gini F.

    2010-01-01

    Objectives To determine the efficacy and safety of single agent sorafenib, an oral multi-targeted tyrosine kinase inhibitor, in patients with advanced uterine carcinoma and carcinosarcoma. Methods This multi-institutional non-randomized phase II trial enrolled two cohorts: patients with uterine carcinoma (cohort A) and uterine carcinosarcoma (cohort B). Eligibility criteria included measurable disease, 0–1 prior chemotherapy regimens, and ECOG performance status ≤ 2. Sorafenib at a dose of 400 mg was administered orally twice daily. A cycle was defined as 28 days. Objective tumor response was the primary endpoint and was assessed following every two cycles. Results Fifty–six patients (40 with carcinoma, 16 with carcinosarcoma) were enrolled between March 2005 and August 2007. Two (5%) patients with uterine carcinoma had a partial response (PR) and 17 (42.5%) achieved stable disease (SD). Five had SD lasting at least 4 months. The 6-month progression free survival rate for patients with carcinoma was 29%, and the median overall survival was 11.4 months. No patients with carcinosarcoma had an objective response. Four (25%) had SD, and one had SD lasting 18 months. The 6-month progression free survival rate was 13%, and the median overall survival was 5.0 months. Grade 3/4 drug related toxicities included: hypertension (13%), hand-foot syndrome (13%), hypophosphatemia (7%), anemia (5%), rash (5%), diarrhea (5%), thrombosis (5%), fatigue (5%) and bleeding (5%). Conclusion Sorafenib had minimal activity in patients with uterine carcinoma. Predictive factors for potential benefit are needed. PMID:20117828

  6. Randomized clinical trial of topical tranexamic acid after reduction mammoplasty

    PubMed Central

    Ausen, K; Fossmark, R; Spigset, O; Pleym, H

    2015-01-01

    Background The antifibrinolytic drug tranexamic acid is currently being rediscovered for both trauma and major surgery. Intravenous administration reduces the need for blood transfusion and blood loss by about one-third, but routine administration in surgery is not yet advocated owing to concerns regarding thromboembolic events. The aim of this study was to investigate whether topical application of tranexamic acid to a wound surface reduces postoperative bleeding. Methods This was a randomized double-blind placebo-controlled trial on 30 consecutive women undergoing bilateral reduction mammoplasty. On one side the wound surfaces were moistened with 25 mg/ml tranexamic acid before closure, and placebo (saline) was used on the other side. Drain fluid production was measured for 24 h after surgery, and pain was measured after 3 and 24 h. Postoperative complications including infection, seroma, rebleeding and suture reactions were recorded. Results Topical application of tranexamic acid to the wound surface after reduction mammoplasty reduced drain fluid production by 39 per cent (median 12·5 (range 0–44) versus 20·5 (0–100) ml; P = 0·038). Adverse effects were not observed. There were no significant differences in postoperative pain scores or complications. Conclusion Topical application of dilute tranexamic acid reduced bleeding in this model. The study adds to the evidence that this simple procedure may reduce wound bleeding after surgery. Registration number: NCT01964781 (http://www.clinicaltrials.gov). PMID:26349843

  7. Citalopram Intervention for Hostility: Results of a Randomized Clinical Trial

    PubMed Central

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

    2009-01-01

    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 DSM-IV Axis I psychopathology. 159 participants (ages 30–50, 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 subjects showed larger reductions in state anger (condition-by-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). Findings have implications for understanding the CNS correlates of hostility, its associations with other psychosocial risk factors for CVD, and, potentially, for the design of effective interventions. PMID:19170463

  8. 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.

  9. 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…

  10. 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…

  11. Thymostimulin in advanced hepatocellular carcinoma: A phase II trial

    PubMed Central

    Dollinger, Matthias M; Behrens, Christa M; Lesske, Joachim; Behl, Susanne; Behrmann, Curd; Fleig, Wolfgang E

    2008-01-01

    Background Thymostimulin is a thymic peptide fraction with immune-mediated cytotoxicity against hepatocellular carcinoma in vitro. In a phase II trial, we investigated safety and efficacy including selection criteria for best response in advanced or metastasised hepatocellular carcinoma. Methods 44 patients (84 % male, median age 69 years) not suitable or refractory to conventional therapy received thymostimulin 75 mg subcutaneously five times per week for a median of 8.2 months until progression or complete response. 3/44 patients were secondarily accessible to local ablation or chemoembolisation. Primary endpoint was overall survival, secondary endpoint tumor response or progression-free survival. A multivariate Cox's regression model was used to identify variables affecting survival. Results Median survival was 11.5 months (95% CI 7.9–15.0) with a 1-, 2- and 3-year survival of 50%, 23% and 9%. In the univariate analysis, a low Child-Pugh-score (p = 0.01), a low score in the Okuda- and CLIP-classification (p < 0.001) or a low AFP-level (p < 0.001) were associated with better survival, but not therapy modalities other than thymostimulin (p = 0.1) or signs of an invasive HCC phenotype such as vascular invasion (p = 0.3) and metastases (p = 0.1). The only variables independently related to survival in the Cox's regression model were Okuda stage and presence of liver cirrhosis (p < 0.01) as well as response to thymostimulin (p < 0.05). Of 39/44 patients evaluable for response, two obtained complete responses (one after concomitant radiofrequency ablation), five partial responses (objective response 18%), twenty-four stable disease (tumor control rate 79%) and eight progressed. Median progression-free survival was 6.4 months (95% CI 0.8–12). Grade 1 local reactions following injection were the only side effects. Conclusion Outcome in our study rather depended on liver function and intrahepatic tumor growth (presence of liver cirrhosis and Okuda stage) in addition

  12. Alternate Reductant Cold Cap Evaluation Furnace Phase II Testing

    SciTech Connect

    Johnson, F. C.; Stone, M. E.; Miller, D. H.

    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: Define new cold cap reactions and global kinetic parameters in support of the melter flammability model development; Quantify off-gas surging potential of the feed; 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% waste

  13. 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

  14. Mercury Phase II Study - Mercury Behavior in Salt Processing Flowsheet

    SciTech Connect

    Jain, V.; Shah, H.; Bannochie, C. J.; Wilmarth, W. R.

    2016-07-25

    Mercury (Hg) in the Savannah River Site Liquid Waste System (LWS) originated from decades of canyon processing where it was used as a catalyst for dissolving the aluminum cladding of reactor fuel. Approximately 60 metric tons of mercury is currently present throughout the LWS. Mercury has long been a consideration in the LWS, from both hazard and processing perspectives. In February 2015, a Mercury Program Team was established at the request of the Department of Energy to develop a comprehensive action plan for long-term management and removal of mercury. Evaluation was focused in two Phases. Phase I activities assessed the Liquid Waste inventory and chemical processing behavior using a system-by-system review methodology, and determined the speciation of the different mercury forms (Hg+, Hg++, elemental Hg, organomercury, and soluble versus insoluble mercury) within the LWS. Phase II activities are building on the Phase I activities, and results of the LWS flowsheet evaluations will be summarized in three reports: Mercury Behavior in the Salt Processing Flowsheet (i.e. this report); Mercury Behavior in the Defense Waste Processing Facility (DWPF) Flowsheet; and Mercury behavior in the Tank Farm Flowsheet (Evaporator Operations). The evaluation of the mercury behavior in the salt processing flowsheet indicates, inter alia, the following: (1) In the assembled Salt Batches 7, 8 and 9 in Tank 21, the total mercury is mostly soluble with methylmercury (MHg) contributing over 50% of the total mercury. Based on the analyses of samples from 2H Evaporator feed and drop tanks (Tanks 38/43), the source of MHg in Salt Batches 7, 8 and 9 can be attributed to the 2H evaporator concentrate used in assembling the salt batches. The 2H Evaporator is used to evaporate DWPF recycle water. (2) Comparison of data between Tank 21/49, Salt Solution Feed Tank (SSFT), Decontaminated Salt Solution Hold Tank (DSSHT), and Tank 50 samples suggests that the total mercury as well as speciated

  15. Dietary fiber supplementation for fecal incontinence: a randomized clinical trial.

    PubMed

    Bliss, Donna Z; Savik, Kay; Jung, Hans-Joachim G; Whitebird, Robin; Lowry, Ann; Sheng, Xiaoyan

    2014-10-01

    Dietary fiber supplements are used to manage fecal incontinence (FI), but little is known about the fiber type to recommend or the level of effectiveness of such supplements, which appears related to the fermentability of the fiber. The aim of this single-blind, randomized controlled trial was to compare the effects of three dietary fiber supplements (carboxymethylcellulose [CMC], gum arabic [GA], or psyllium) with differing levels of fermentability to a placebo in community-living individuals incontinent of loose/liquid feces. The primary outcome was FI frequency; secondary outcomes included FI amount and consistency, supplement intolerance, and quality of life (QoL). Possible mechanisms underlying supplement effects were also examined. After a 14-day baseline, 189 subjects consumed a placebo or 16 g total fiber/day of one of the fiber supplements for 32 days. FI frequency significantly decreased after psyllium supplementation versus placebo, in both intent-to-treat and per-protocol mixed model analyses. CMC increased FI frequency. In intent-to-treat analysis, the number of FI episodes/week after supplementation was estimated to be 5.5 for Placebo, 2.5 for Psyllium, 4.3 for GA, and 6.2 for CMC. Only psyllium consumption resulted in a gel in feces. Supplement intolerance was low. QoL scores did not differ among groups. Patients with FI may experience a reduction in FI frequency after psyllium supplementation, and decreased FI frequency has been shown to be an important personal goal of treatment for patients with FI. Formation of a gel in feces appears to be a mechanism by which residual psyllium improved FI.

  16. Vitamin D and Serum Cytokines in a Randomized Clinical Trial

    PubMed Central

    Yusupov, Eleanor; Li-Ng, Melissa; Pollack, Simcha; Yeh, James K.; Mikhail, Mageda; Aloia, John F.

    2010-01-01

    Background. The role of vitamin D in the body's ability to fight influenza and URI's may be dependent on regulation of specific cytokines that participate in the host inflammatory response. The aim of this study was to test the hypothesis that vitamin D can influence intracellular signaling to regulate the production of cytokines. Subjects and Methods. This study was a 3-month prospective placebo-controlled trial of vitamin D3 supplementation in ambulatory adults [Li-Ng et al., 2009]. 162 volunteers were randomized to receive either 50 μg/d (2000 IU) of vitamin D3 or matching placebo. 25(OH)D and the levels of 10 different cytokines (IL-2, 4, 5, 6, 8, 10, 13, GM-CSF, IFN-γ, TNF-α) were measured in the serum of participants at baseline and the final visit. There were 6 drop-outs from the active vitamin D group and 8 from the placebo group. Results. In the active vitamin D group, we found a significant median percent decline in levels of GM-CSF (−62.9%, P < .0001), IFN-γ (−38.9%, P < .0001), IL-4 (−50.8%, P = .001), IL-8 (−48.4%, P < .0001), and IL-10 (−70.4%, P < .0001). In the placebo group, there were significant declines for GM-CSF (−53.2%, P = .0007) and IFN-γ (−34.4%, P = .0011). For each cytokine, there was no significant difference in the rate of decline between the two groups. 25(OH)D levels increased in the active vitamin D group from a mean of 64.3 ± 25.4 nmol/L to 88.5 ± 23.2 nmol/L. Conclusions. The present study did not show that vitamin D3 supplementation changed circulating cytokine levels among healthy adults. PMID:20871847

  17. 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

  18. Rationale and design of a randomized controlled, clinical trial investigating a comprehensive exercise stimulus for improving mobility disability outcomes in persons with multiple sclerosis.

    PubMed

    Motl, Robert W; Pilutti, Lara A; Sandroff, Brian M; Klaren, Rachel; Balantrapu, Swathi; McAuley, Edward; Sosnoff, Jacob J; Fernhall, Bo

    2013-05-01

    This randomized controlled trial (RCT) examines the effect of a comprehensive exercise training stimulus on physiological function and mobility disability (i.e., problems walking) in individuals with multiple sclerosis (MS) who have walking impairment. This trial will recruit 30 persons with MS across central Illinois who have an Expanded Disability Status Scale score between 4.0 and 6.0, and those persons will be randomized into either the intervention or control arm of the study; the participants will not be blinded regarding group assignment. The intervention will incorporate equal amounts of aerobic, resistance, and balance modes of training delivered 3 times/week with a gradual progression of duration and intensity across a 6-month period. The control will involve stretching along with minimal muscle strengthening stimuli and will be delivered on the same frequency and duration. The primary outcomes will be clinical, kinematic, patient-rated, and physiological measures of mobility disability. The secondary outcomes will be measures of physiological function including aerobic capacity, muscle strength, and balance. This study will lay the foundation for the design of a subsequent Phase II or Phase III RCT by (a) providing effect sizes that can be included in a power analysis for sample size estimation and (b) investigating whether aerobic capacity, muscle strength, and balance are possible factors associated with the beneficial effect of exercise training on walking outcomes. Taken as a whole, the proposed study and our subsequent research agenda has the potential for advancing the management of mobility disability using exercise training in the 2nd stage of MS.

  19. 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.

  20. Comprehension of Randomization and Uncertainty in Cancer Clinical Trials Decision-Making among Rural, Appalachian Patients

    PubMed Central

    Krieger, Janice L.; Palmer-Wackerly, Angela; Dailey, Phokeng M.; Krok-Schoen, Jessica L.; Schoenberg, Nancy E.; Paskett, Electra D.

    2015-01-01

    Objective 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. Methods Cancer patients living in rural Appalachia who were offered an opportunity to participate in cancer treatment RCT completed in-depth interviews and a brief survey. Results 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. Conclusion Not all patients enrolling in RCTs have 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. PMID:25608719

  1. Mechanical and Thermal Prototype Testing for a Rotatable Collimator for the LHC Phase II Collimation Upgrade

    SciTech Connect

    Smith, Jeffrey Claiborne; Doyle, Eric; Keller, Lewis; Lundgren, Steven; Markiewicz, Thomas Walter; /SLAC

    2010-08-26

    The Phase II upgrade to the LHC collimation system calls for complementing the robust Phase I graphite collimators with high Z, low impedance Phase II collimators. The design for the collimation upgrade has not been finalized. One option is to use metallic rotatable collimators and testing of this design will be discussed here. The Phase II collimators must be robust in various operating conditions and accident scenarios. A prototype collimator jaw has been tested for both mechanical and thermal compliance with the design goals. Thermal expansion bench-top tests are compared to ANSYS simulation results.

  2. Phase II randomised discontinuation trial of the MET/VEGF receptor inhibitor cabozantinib in metastatic melanoma

    PubMed Central

    Daud, Adil; Kluger, Harriet M; Kurzrock, Razelle; Schimmoller, Frauke; Weitzman, Aaron L; Samuel, Thomas A; Moussa, Ali H; Gordon, Michael S; Shapiro, Geoffrey I

    2017-01-01

    Background: A phase II randomised discontinuation trial assessed cabozantinib (XL184), an orally bioavailable inhibitor of tyrosine kinases including VEGF receptors, MET, and AXL, in a cohort of patients with metastatic melanoma. Methods: Patients received cabozantinib 100 mg daily during a 12-week lead-in. Patients with stable disease (SD) per Response Evaluation Criteria in Solid Tumours (RECIST) at week 12 were randomised to cabozantinib or placebo. Primary endpoints were objective response rate (ORR) at week 12 and postrandomisation progression-free survival (PFS). Results: Seventy-seven patients were enroled (62% cutaneous, 30% uveal, and 8% mucosal). At week 12, the ORR was 5% 39% of patients had SD. During the lead-in phase, reduction in target lesions from baseline was seen in 55% of evaluable patients overall and in 59% of evaluable patients with uveal melanoma. Median PFS after randomisation was 4.1 months with cabozantinib and 2.8 months with placebo (hazard ratio of 0.59; P=0.284). Median PFS from study day 1 was 3.8 months, 6-month PFS was 33%, and median overall survival was 9.4 months. The most common grade 3/4 adverse events were fatigue (14%), hypertension (10%), and abdominal pain (8%). One treatment-related death was reported from peritonitis due to diverticular perforation. Conclusions: Cabozantinib has clinical activity in patients with metastatic melanoma, including uveal melanoma. Further clinical investigation is warranted. PMID:28103611

  3. 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.

  4. 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.

  5. 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

  6. 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

  7. Comparing community and specialty provider-based recruitment in a randomized clinical trial: clinical trial in fecal incontinence

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Recruitment of participants to clinical trials remains a significant challenge, especially for research addressing topics of a sensitive nature such as fecal incontinence (FI). The Fiber Study, a randomized controlled trial on symptom management for FI, successfully enrolled 189 community-living adu...

  8. 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

  9. 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

  10. 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

  11. 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

  12. Yakima Fish Passage : Phase II : Fish Screen Construction.

    SciTech Connect

    United States. Bureau of Reclamation. Pacific Northwest Region.

    2003-03-01

    Accomplishments in 2001--2002 were spotty and limited due primarily to right-of-way problems at several sites and unanticipated changes in scope at some sites. Changes in BPA funding procedures have also impacted our ability to accomplish previously scheduled work. The following is a brief summary of work accomplished and scheduled at the remaining Phase II sites. (1) Selah-Moxee Fish Screen--Construction at this site was started in October 2001 and was completed in March 2002. We have settled the contractor claims and have closed out the construction contract. The O&M Agreement with the irrigation district was also completed in 2002. Work remains to complete the Designer's Operating Criteria. (2) Scott Fish Screen--Considerable effort was spent in 2001 and 2002 to try to resolve right-of-way issues at this site. However, these problems proved to be insurmountable, and this site has been dropped from the Phase n Program. The only thing remaining on Scott (as far as the Phase n program is concerned) is to prepare a brief wrap-up report to send to all interested parties to summarize what has been done and to explain the status of the diversion from a fish passage standpoint. (3) Packwood Fish Screen--Designs and specifications for the civil works were completed for this screen in 2002. The screen, screen cleaner, and other metal work have already been fabricated by WDFW Screen Shop. Award of a construction contract was scheduled for September 2002. The BP A lands staff has experienced significant delays in obtaining an easement from the state of Washington for a piece of the John Wayne Trail right-of-way currently occupied by the existing screen. As a result, the construction contract has been rescheduled for award in the fall of 2003. We are ready to proceed with construction if BP A can obtain the necessary easements by May 2003. (4) Fogarty Fish Screen--We opened bids on this site in August, 2002. There was only one responsive bidder and the bid was nearly double

  13. 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

  14. 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

  15. 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…

  16. A Strategy to Use Soft Data Effectively in Randomized Controlled Clinical Trials.

    ERIC Educational Resources Information Center

    Kraemer, Helena Chmura; Thiemann, Sue

    1989-01-01

    Sees soft data, measures having substantial intrasubject variability due to errors of measurement or response inconsistency, as important measures of response in randomized clinical trials. Shows that using intensive design and slope of response on time as outcome measure maximizes sample retention and decreases within-group variability, thus…

  17. 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,…

  18. 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…

  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. 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…

  1. 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…

  2. 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,...

  3. 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…

  4. 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…

  5. Randomized Trial of a Web-Based Intervention to Address Barriers to Clinical Trials

    PubMed Central

    Wong, Yu-Ning; Albrecht, Terrance; Manne, Sharon; Miller, Suzanne M.; Flamm, Anne Lederman; Benson, Al Bowen; Buzaglo, Joanne; Collins, Michael; Egleston, Brian; Fleisher, Linda; Katz, Michael; Kinzy, Tyler G.; Liu, Tasnuva M.; Margevicius, Seunghee; Miller, Dawn M.; Poole, David; Roach, Nancy; Ross, Eric; Schluchter, Mark D.

    2016-01-01

    Purpose Lack of knowledge and negative attitudes have been identified as barriers to participation in clinical trials by patients with cancer. We developed Preparatory Education About Clinical Trials (PRE-ACT), a theory-guided, Web-based, interactive computer program, to deliver tailored video educational content to patients in an effort to overcome barriers to considering clinical trials as a treatment option. Patients and Methods A prospective, randomized clinical trial compared PRE-ACT with a control condition that provided general clinical trials information produced by the National Cancer Institute (NCI) in text format. One thousand two hundred fifty-five patients with cancer were randomly allocated before their initial visit with an oncologist to PRE-ACT (n = 623) or control (n = 632). PRE-ACT had three main components: assessment of clinical trials knowledge and attitudinal barriers, values assessment with clarification back to patients, and provision of a video library tailored to address each patient’s barriers. Outcomes included knowledge and attitudes and preparation for decision making about clinical trials. Results Both PRE-ACT and control interventions improved knowledge and attitudes (all P < .001) compared with baseline. Patients randomly allocated to PRE-ACT showed a significantly greater increase in knowledge (P < .001) and a significantly greater decrease in attitudinal barriers (P < .001) than did their control (text-only) counterparts. Participants in both arms significantly increased their preparedness to consider clinical trials (P < .001), and there was a trend favoring the PRE-ACT group (P < .09). PRE-ACT was also associated with greater patient satisfaction than was NCI text alone. Conclusion These data show that patient education before the first oncologist visit improves knowledge, attitudes, and preparation for decision making about clinical trials. Both text and tailored video were effective. The PRE-ACT interactive video program was

  6. 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

  7. 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.

  8. "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.

  9. Attitudes Toward Participation in Breast Cancer Randomized Clinical Trials in the African American Community

    PubMed Central

    Linden, Hannah M.; Reisch, Lisa M.; Hart, Alton; Harrington, Margaret A.; Nakano, Connie; Jackson, J. Carey; Elmore, Joann G.

    2013-01-01

    Participation of African Americans in research trials is low. Understanding the perspectives of African American patients toward participation in clinical trials is essential to understanding the disparities in participation rates compared with whites. A qualitative study was conducted to discover attitudes of the African American community regarding willingness to participate in breast cancer screening and randomized clinical trials. Six focus groups consisting of 8 to 11 African American women (N = 58), aged 30 to 65, were recruited from local churches. Focus group sessions involved a 2-hour audiotaped discussion facilitated by 2 moderators. A breast cancer randomized clinical trial involving an experimental breast cancer treatment was discussed to identify the issues related to willingness to participate in such research studies. Six themes surrounding willingness to participate in randomized clinical trials were identified: (1) Significance of the research topic to the individual and/or community; (2) level of trust in the system; (3) understanding of the elements of the trial; (4) preference for “natural treatments” or “religious intervention” over medical care; (5) cost-benefit analysis of incentives and barriers; and (6) openness to risk versus a preference for proven treatments. The majority (80%) expressed willingness or open-mindedness to the idea of participating in the hypothetical trial. Lessons learned from this study support the selection of a culturally diverse research staff and can guide the development of research protocols, recruitment efforts, and clinical procedures that are culturally sensitive and relevant. PMID:17666974

  10. 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.

  11. Probability of success for phase III after exploratory biomarker analysis in phase II.

    PubMed

    Götte, Heiko; Kirchner, Marietta; Sailer, Martin Oliver

    2017-02-23

    The probability of success or average power describes the potential of a future trial by weighting the power with a probability distribution of the treatment effect. The treatment effect estimate from a previous trial can be used to define such a distribution. During the development of targeted therapies, it is common practice to look for predictive biomarkers. The consequence is that the trial population for phase III is often selected on the basis of the most extreme result from phase II biomarker subgroup analyses. In such a case, there is a tendency to overestimate the treatment effect. We investigate whether the overestimation of the treatment effect estimate from phase II is transformed into a positive bias for the probability of success for phase III. We simulate a phase II/III development program for targeted therapies. This simulation allows to investigate selection probabilities and allows to compare the estimated with the true probability of success. We consider the estimated probability of success with and without subgroup selection. Depending on the true treatment effects, there is a negative bias without selection because of the weighting by the phase II distribution. In comparison, selection increases the estimated probability of success. Thus, selection does not lead to a bias in probability of success if underestimation due to the phase II distribution and overestimation due to selection cancel each other out. We recommend to perform similar simulations in practice to get the necessary information about the risk and chances associated with such subgroup selection designs.

  12. Phase II trial of sequential gefitinib after minor response or partial response to chemotherapy in Chinese patients with advanced non-small-cell lung cancer

    PubMed Central

    Xu, Jian Ming; Han, Yu; Li, Yue Min; Zhao, Chuan Hua; Wang, Yan; Paradiso, Angelo

    2006-01-01

    Background Basic research of gefitinib (Iressa, ZD1839) has demonstrated the combination effects of gefitinib and chemotherapy were sequence-dependent. To evaluate the efficacy of sequential administration of gefitinib following a minor response or partial response to two to three cycles of chemotherapy, a phase II clinical trial was done in Chinese patients with advanced non-small-cell lung cancer (NSCLC). Methods Thirty-three consecutive patients with advanced NSCLC that had been pretreated with at least one chemotherapeutic regimen and were responding to chemotherapy following 2 to 3 cycles of treatment, entered the trial from May 2004 to February 2006. Patients received gefitinib at an oral dose of 250 mg once daily for 4 weeks. Results Thirty-three patients were evaluable for response and toxicity. The objective response rate was 24.2% (8 of 33)(95% CI, 11% to 42%). The symptom improvement rate was 54.5% (18 of 33) (95% CI, 41% to 69%). The median duration of response was 7 months (95%CI, 4.0 to 13.2 months). The median time to disease progression (TTP) was 6.5 months (95%CI, 0.7 to 16.6 months). The median overall survival time (OS) was 9.8 months (range, 2.1 to 18.0 months), and the actuarial 1-year survival was 36.4%. Toxicity was relatively mild and included only one patient (3.0%) with grade 4 diarrhea, 1 (3.0%) with grade 3 rash, 1 (3.0%) with grade 3 nausea, and 1 with grade 3 vomiting (3.0%). Conclusion Preliminary results suggest that sequential administration of gefitinib following a response to chemotherapy may be beneficial for Chinese patients with advanced NSCLC. Further randomized clinical trials are needed. PMID:17173694

  13. Final results of a phase II study of nab-paclitaxel, bevacizumab, and gemcitabine as first-line therapy for patients with HER2-negative metastatic breast cancer.

    PubMed

    Lobo, Christopher; Lopes, Gilberto; Baez, Odalys; Castrellon, Aurelio; Ferrell, Annapoorna; Higgins, Connie; Hurley, Erin; Hurley, Judith; Reis, Isildinha; Richman, Stephen; Seo, Pearl; Silva, Orlando; Slingerland, Joyce; Tukia, Keleni; Welsh, Catherine; Glück, Stefan

    2010-09-01

    In order to examine the efficacy and safety of nanoparticle albumin-bound paclitaxel (nab-P) in combination with bevacizumab (B) and gemcitabine (G) for the first-line treatment of patients with HER2-negative metastatic breast cancer (MBC). In this single-center, open-label phase II trial, patients with HER2-negative MBC received gemcitabine 1500 mg/m(2), nab-paclitaxel 150 mg/m(2), and bevacizumab 10 mg/kg (each administered intravenously) on days 1 and 15 of a 28-day cycle. The primary end point was progression free survival (PFS); secondary end points were overall response rate (ORR), complete (CR) and partial (PR) response rates, clinical benefit (ORR + stable disease), overall survival (OS), and safety. Thirty patients were enrolled. One patient was ineligible and was not included in analysis. Median PFS was 10.4 months (95% CI: 5.6-15.2 months). ORR was 75.9%, comprising eight (27.6%) CRs and 14 (48.3%) PRs; five patients had stable disease (SD) and two patients (6.9%) had progressive disease (PD) as their best response. The clinical benefit rate was 93.1% (27/29) in the overall group and 84.6% in the triple-negative cohort (11/13). The 18-month survival rate was 77.2% (95% CI: 51.1-90.5%). Eight (27.6%) patients experienced grade 3 or 4 toxicity: grade 4 neutropenic fever (n = 1) and grade 3 infection (n = 6), leukopenia, thrombocytopenia, peripheral neuropathy, seizure, shortness of breath, hematuria, and cardiac tamponade (one each). First-line therapy with nab-P, B, and G demonstrated a median PFS of 10.4 months and a 75.9% ORR with acceptable toxicity; this novel combination warrants investigation in a randomized study.

  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. Design of a Rotatable Copper Collimator for the LHC Phase II Collimation Upgrade

    SciTech Connect

    Smith, Jeffrey Claiborne; Doyle, Eric; Keller, Lewis; Lundgren, Steven; Markiewicz, Thomas Walter; Lari, Luisella; /LPHE, Lausanne

    2010-02-15

    The Phase II upgrade to the LHC collimation system calls for complementing the robust Phase I graphite collimators with high Z, low impedance Phase II collimators. The design for the collimation upgrade has not been finalized. One option is to use metallic rotatable collimators and this design will be discussed here. The Phase II collimators must be robust in various operating conditions and accident scenarios. Design issues include: (1) Collimator jaw deflection and sagitta due to heating must be small when operated in the steady state condition, (2) Collimator jaws must withstand transitory periods of high beam impaction with no permanent damage, (3) Jaws must recover from accident scenario where up to 8 full intensity beam pulses impact on the jaw surface and (4) The beam impedance contribution due to the collimators must be small to minimize coherent beam instabilities.

  16. 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)…

  17. 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.

  18. Phase II Trial of Combination Thalidomide plus Temozolomide in Patients with Metastatic Malignant Melanoma: Southwest Oncology Group S0508

    PubMed Central

    Clark, Joseph I.; Moon, James; Hutchins, Laura F.; Sosman, Jeffrey A.; Kast, W. Martin; Da Silva, Diane M.; Liu, P.Y.; Thompson, John A.; Flaherty, Lawrence E.; Sondak, Vernon K.

    2009-01-01

    Purpose In limited institution Phase II studies, thalidomide and temozolomide has yielded response rates (RR) up to 32% for advanced melanoma, leading to the use of this combination as “standard” by some. We conducted a multi-center Phase II trial to better define the clinical efficacy of thalidomide and temozolomide and the immune modulatory effects of thalidomide, when combined with temozolomide, in patients with metastatic melanoma. Patients and Methods Patients must have had stage IV cutaneous melanoma, no active brain metastases, Zubrod PS 0–1, up to 1 prior systemic therapy excluding thalidomide, temozolomide or dacarbazine, adequate organ function, and given informed consent. The primary endpoint was 6-month progression-free survival (PFS). Secondary endpoints included survival (OS), RR, toxicities, and assessment of relationships between biomarkers and clinical outcomes. Patients received thalidomide (200mg/d escalated to 400mg/d for patients <70, or 100mg/d escalated to 250mg/d for patients ≥70) plus temozolomide (75mg/m2/d × 6 weeks then 2 weeks rest). Results Sixty-four patients were enrolled; 2 refused treatment. The 6-month PFS was 15% (95% CI, 6%–23%); 1-year OS was 35% (95% CI, 24%–47%); RR was 13% (95% CI, 5%–25%), all partial. One treatment-related death occurred from myocardial infarction; 3 other Grade 4 events occurred including pulmonary embolism, neutropenia and CNS ischemia. There was no significant correlation between biomarkers and PFS or OS. Conclusion This combination of thalidomide and temozolomide does not appear to have a clinical benefit that exceeds dacarbazine alone. We would not recommend it further for phase III trials or for standard community use. PMID:19918923

  19. LYSIS OF T4 PHAGE BY THE SPECIFIC LIPOCARBOHYDRATE OF PHASE II SHIGELLA SONNEI

    PubMed Central

    Jesaitis, Margeris A.; Goebel, Walther F.

    1955-01-01

    When the specific lipocarbohydrate of Phase II Sh. sonnei and T4 phage react in vitro, the virus is rapidly inactivated and the content of the viral membrane is released into the surrounding medium. The reaction between phage and lipocarbohydrate proceeds only in the presence of a lipide constituent which can be extracted from the polysaccharide, rendering the latter inactive, and which can be replaced by certain fatty acids. It has been suggested that the lipocarbohydrate is the receptor substance of the Phase II bacillus which specifically combines with and brings about disintegration of the virus when the latter infects the host cell. PMID:13271686

  20. 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.

  1. 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.

  2. Randomized clinical trials of self-management with Asian/Pacific Islanders.

    PubMed

    Inouye, Jillian; Braginsky, Nafanua; Kataoka-Yahiro, Merle

    2011-11-01

    Little has been reported in the literature about self-management strategies of chronic conditions in Asian and Pacific Islanders (APIs). The purpose of this systematic review was to investigate randomized clinical trials (RCTs) of self-management strategies of chronic conditions in APIs. Twenty-one studies were included in the final review, published between 1997 and 2010. Initially, the Jadad Scoring of Quality of Reports of Randomized Clinical Trials (JSQRRC) was used to determine the quality of RCT studies. The researchers then did a systematic review of each of the RCTs based on the JSQRRC criteria. JSQRRC scores ranged from 8 to 12, M = 9.6. Descriptive analysis indicated cognitive behavioral interventions as an effective treatment methodology for APIs. The results underscore the importance of clarifying the methodological components and reporting of RCTs. Interventions appropriate for APIs using disaggregated ethnic groups are essential to determine specific cultural responses to treatments and outcomes.

  3. Yoga for low back pain: a systematic review of randomized clinical trials.

    PubMed

    Posadzki, Paul; Ernst, Edzard

    2011-09-01

    It has been suggested that yoga has a positive effect on low back pain and function. The objective of this systematic review was to assess the effectiveness of yoga as a treatment option for low back pain. Seven databases were searched from their inception to March 2011. Randomized clinical trials were considered if they investigated yoga in patients with low back pain and if they assessed pain as an outcome measure. The selection of studies, data extraction and validation were performed independently by two reviewers. Seven randomized controlled clinical trials (RCTs) met the inclusion criteria. Their methodological quality ranged between 2 and 4 on the Jadad scale. Five RCTs suggested that yoga leads to a significantly greater reduction in low back pain than usual care, education or conventional therapeutic exercises. Two RCTs showed no between-group differences. It is concluded that yoga has the potential to alleviate low back pain. However, any definitive claims should be treated with caution.

  4. Extracting temporal constraints from clinical research eligibility criteria using conditional random fields.

    PubMed

    Luo, Zhihui; Johnson, Stephen B; Lai, Albert M; Weng, Chunhua

    2011-01-01

    Temporal constraints are present in 38% of clinical research eligibility criteria and are crucial for screening patients. However, eligibility criteria are often written as free text, which is not amenable for computer processing. In this paper, we present an ontology-based approach to extracting temporal information from clinical research eligibility criteria. We generated temporal labels using a frame-based temporal ontology. We manually annotated 150 free-text eligibility criteria using the temporal labels and trained a parser using Conditional Random Fields (CRFs) to automatically extract temporal expressions from eligibility criteria. An evaluation of an additional 60 randomly selected eligibility criteria using manual review achieved an overall precision of 83%, a recall of 79%, and an F-score of 80%. We illustrate the application of temporal extraction with the use cases of question answering and free-text criteria querying.

  5. 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

  6. Short-term inspiratory muscle training potentiates the benefits of aerobic and resistance training in patients undergoing CABG in phase II cardiac rehabilitation program

    PubMed Central

    Hermes, Bárbara Maria; Cardoso, Dannuey Machado; Gomes, Tiago José Nardi; dos Santos, Tamires Daros; Vicente, Marília Severo; Pereira, Sérgio Nunes; Barbosa, Viviane Acunha; de Albuquerque, Isabella Martins

    2015-01-01

    Objective To investigate the efficiency of short-term inspiratory muscle training program associated with combined aerobic and resistance exercise on respiratory muscle strength, functional capacity and quality of life in patients who underwent coronary artery bypass and are in the phase II cardiac rehabilitation program. Methods A prospective, quasi-experimental study with 24 patients who underwent coronary artery bypass and were randomly assigned to two groups in the Phase II cardiac rehabilitation program: inspiratory muscle training program associated with combined training (aerobic and resistance) group (GCR + IMT, n=12) and combined training with respiratory exercises group (GCR, n=12), over a period of 12 weeks, with two sessions per week. Before and after intervention, the following measurements were obtained: maximal inspiratory and expiratory pressures (PImax and PEmax), peak oxygen consumption (peak VO2) and quality of life scores. Data were compared between pre- and post-intervention at baseline and the variation between the pre- and post-phase II cardiac rehabilitation program using the Student's t-test, except the categorical variables, which were compared using the Chi-square test. Values of P<0.05 were considered statistically significant. Results Compared to GCR, the GCR + IMT group showed larger increments in PImax (P<0.001), PEmax (P<0.001), peak VO2 (P<0.001) and quality of life scores (P<0.001). Conclusion The present study demonstrated that the addition of inspiratory muscle training, even when applied for a short period, may potentiate the effects of combined aerobic and resistance training, becoming a simple and inexpensive strategy for patients who underwent coronary artery bypass and are in phase II cardiac rehabilitation. PMID:27163422

  7. A Value-Theoretic Expert System for Evaluating Randomized Clinical Trials

    PubMed Central

    Klein, David A.; Lehmann, Harold P.; Shortliffe, Edward H.

    1990-01-01

    Multiattribute Value Theory (MVT) provides a formal approach to evaluating populations of similar alternatives. In this paper, we illustrate the employment of MVT in the context of medical expert systems by describing RCTE, a prototype application for performing comparative analyses of randomized clinical trials (RCTs). RCTE employs MVT to evaluate RCTs and implements techniques from Interpretive Value Analysis to explain such evaluations automatically. Although experimental, our approach suggests that MVT provides a basis for evaluating similar alternatives in selected medical expert systems.

  8. Rapid Extremity Pain Relief by Battlefield Acupuncture after Orthopedic Surgery: A Randomized Clinical Trial

    DTIC Science & Technology

    2017-03-21

    FINAL REPORT Project Title: Rapid Extremity Pain Relief by Battlefield Acupuncture after Orthopedic Surgery: A Randomized Clinical Trial...surgeries. These invasive procedures result in swelling and pain . The side effects of the pain medications are well known and a decrease in their use could...relieving acute extremity pain , reducing medication use, decreasing time to full ambulation and improving quality of life than placebo acupuncture or

  9. 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

  10. 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

  11. Model based design and analysis of phase II HIV-1 trials.

    PubMed

    Rekić, Dinko; Röshammar, Daniel; Simonsson, Ulrika S H

    2013-08-01

    This work explores the advantages of a model based drug development (MBDD) approach for the design and analysis of antiretroviral phase II trials. Two different study settings were investigated: (1) a 5-arm placebo-controlled parallel group dose-finding/proof of concept (POC) study and (2) a comparison of investigational drug and competitor. Studies were simulated using a HIV-1 dynamics model in NONMEM. The Monte-Carlo Mapped Power method determined the sample size required for detecting a dose-response relationship and a significant difference in effect compared to the competitor using a MBDD approach. Stochastic simulation and re-estimation were used for evaluation of model parameter precision and bias given different sample sizes. Results were compared to those from an unpaired, two-sided t test and ANOVA (p ≤ 0.05). In all scenarios, the MBDD approach resulted in smaller study sizes and more precisely estimated treatment effect than conventional statistical analysis. Using a MBDD approach, a sample size of 15 patients could be used to show POC and estimate ED50 with a good precision (relative standard error, 25.7 %). A sample size of 10 patients per arm was needed using the MBDD approach for detecting a difference in treatment effect of ≥20 % at 80 % power, a 3.4-fold reduction in sample size compared to a t test. The MBDD approach can be used to achieve more precise dose-response characterization facilitating decision making and dose selection. If necessitated, the sample size needed to reach a desired power can potentially be reduced compared to traditional statistical analyses. This may allow for comparison against competitors already in early clinical studies.

  12. Phase II Study of Temozolomide (TMZ) and Everolimus (RAD001) Therapy for Metastatic Melanoma

    PubMed Central

    Dronca, Roxana S.; Allred, Jacob B.; Perez, Domingo G.; Nevala, Wendy K.; Lieser, Elizabeth A.T.; Thompson, Michael; Maples, William J.; Creagan, Edward T.; Pockaj, Barbara A.; Kaur, Judith S.; Moore, Timothy D.; Marchello, Benjamin T.; Markovic, Svetomir N.

    2014-01-01

    Objective Mammalian target of rapamycin (mTOR) pathway is activated in malignant melanoma and in situ lesions as opposed to benign nevi. Inhibition of PI3K-Akt-mTOR signaling is implicated in sensitization of melanoma cells to alkylating agents [temozolomide (TMZ)] and inhibition of tumor angiogenesis. Methods We conducted a single-arm phase II multi-institution cooperative group study to assess the antitumor activity and safety profile of the combination of TMZ and the rapamycin derivative everolimus in patients with metastatic unresectable malignant melanoma. Patients received 10 mg/d of RAD001 for 5 of 7 days (ie, 50 mg/ wk) and 200 mg/m2/d of TMZ for 5 days each cycle. Results Of the first 39 eligible patients, 17 were PFS-9 successes, for a predetermined threshold of 18/39 patients for a positive trial. Overall, 21 of 48 patients were progression free at 9 weeks, for an event-free survival rate of 44% (95% confidence interval, 29%–59%). The median progression-free survival was 2.4 months and the median overall survival was 8.6 months. Four patients achieved a partial response; the median duration of response was 15.1 months. No complete remissions were observed. Treatment was in general well tolerated with only 1 patient discontinuing therapy due to toxicity (hyperlipidemia). Conclusions The combination of TMZ and RAD001 was well tolerated but failed to meet/exceed our study threshold for promising clinical activity in patients with metastatic melanoma. PMID:23357973

  13. Phase II Study of Everolimus and Letrozole in Patients With Recurrent Endometrial Carcinoma

    PubMed Central

    Slomovitz, Brian M.; Jiang, Yunyun; Yates, Melinda S.; Soliman, Pamela T.; Johnston, Taren; Nowakowski, Maureen; Levenback, Charles; Zhang, Qian; Ring, Kari; Munsell, Mark F.; Gershenson, David M.; Lu, Karen H.; Coleman, Robert L.

    2015-01-01

    Purpose The phosphoinositol-3 kinase (PI3K) pathway is frequently dysregulated in endometrial cancer (EC). Hormonal manipulation leads to response in some patients with EC, but resistance derived from PI3K pathway activation has been documented. Targeting mammalian target of rapamycin (mTOR) may overcome endocrine resistance. We conducted a two-institution phase II trial of everolimus and letrozole in women with recurrent EC. Patients and Methods Patients were considered incurable, had measurable disease, and were treated with up to two prior cytotoxic regimens. Everolimus was administered orally at 10 mg daily and letrozole was administered orally at 2.5 mg daily. Each cycle consisted of 4 weeks of therapy. Patients were treated until progression, toxicity, or complete response (CR). The primary end point was the clinical benefit rate (CBR), which was defined as CR, partial response, or stable disease (≥ 16 weeks) by RECIST 1.0 criteria. Translational studies were performed to correlate biomarkers with response. Results Thirty-eight patients were enrolled (median age, 62 years; range, 24 to 82 years). Thirty-five patients were evaluable for response. The CBR was 40% (14 of 35 patients); the median number of cycles among responders was 15 (range, seven to 29 cycles). The confirmed objective response rate (RR) was 32% (11 of 35 patients; nine CRs and two partial responses; median, 15 cycles; range, eight to 29 cycles). Twenty percent of patients (seven of 35 patients) were taken off treatment after a prolonged CR and at the discretion of the treating clinician. None of the patients discontinued treatment as a result of toxicity. Serous histology was the best predictor of lack of response. Patients with endometrioid histology and CTNNB1 mutations responded well to everolimus and letrozole. Conclusion Everolimus plus letrozole results in a high CBR and RR in patients with recurrent EC. Further development of this combination in recurrent endometrioid EC is under way

  14. 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.

  15. 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.

  16. Point estimation and p-values in phase II adaptive two-stage designs with a binary endpoint.

    PubMed

    Kunzmann, K; Kieser, M

    2017-03-15

    Clinical trials in phase II of drug development are frequently conducted as single-arm two-stage studies with a binary endpoint. Recently, adaptive designs have been proposed for this setting that enable a midcourse modification of the sample size. While these designs are elaborated with respect to hypothesis testing by assuring control of the type I error rate, the topic of point estimation has up to now not been addressed. For adaptive designs with a prespecified sample size recalculation rule, we propose a new point estimator that both assures compatibility of estimation and test decision and minimizes average mean squared error. This estimator can be interpreted as a constrained posterior mean estimate based on the non-informative Jeffreys prior. A comparative investigation of the operating characteristics demonstrates the favorable properties of the proposed approach. Copyright © 2016 John Wiley & Sons, Ltd.

  17. Phase II dose-response trials: A simulation study to compare analysis method performance under design considerations.

    PubMed

    Rekowski, Jan; Köllmann, Claudia; Bornkamp, Björn; Ickstadt, Katja; Scherag, André

    2017-02-21

    Phase II trials are intended to provide information about the dose-response relationship and to support the choice of doses for a pivotal phase III trial. Recently, new analysis methods have been proposed to address these objectives, and guidance is needed to select the most appropriate analysis method in specific situations. We set up a simulation study to evaluate multiple performance measures of one traditional and three more recent dose-finding approaches under four design options and illustrate the investigated analysis methods with an example from clinical practice. Our results reveal no general recommendation for a particular analysis method across all design options and performance measures. However, we also demonstrate that the new analysis methods are worth the effort compared to the traditional ANOVA-based approach.

  18. Effects of Clinical Pilates Exercises on Patients Developing Lymphedema after Breast Cancer Treatment: A Randomized Clinical Trial

    PubMed Central

    Şener, Hülya Özlem; Malkoç, Mehtap; Ergin, Gülbin; Karadibak, Didem; Yavuzşen, Tuğba

    2017-01-01

    Objective The aim of the present study was to compare the effects of clinical Pilates exercises with those of the standard lymphedema exercises on lymphedema developing after breast cancer treatment. Materials and Methods The study comprised 60 female patients with a mean age of 53.2±7.7 years who developed lymphedema after having breast cancer treatment. The patients were randomized into two groups: the clinical Pilates exercise group (n=30), and the control group (n=30). Before, and at the 8th week of treatment, the following parameters were measured: the severity of lymphedema, limb circumferences, body image using the Social Appearance Anxiety Scale, quality of life with the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ-BR23), and upper extremity function using the Disabilities of the Arm, Shoulder and Hand (DASH) outcome measure. Both groups performed one-hour exercises three days a week for 8 weeks. Results After treatment, the symptoms recovered significantly in both groups. Reductions in the severity of lymphedema, improvements in the social appearance anxiety scale scores, quality of life scores, and upper extremity functions scores in the clinical Pilates exercise group were greater than those in the control group. Clinical Pilates exercises were determined to be more effective on the symptoms of patients with lymphedema than were standard lymphedema exercises. Conclusions Clinical Pilates exercises could be considered a safe model and would contribute to treatment programs. PMID:28331763

  19. Improving PTSD Outcomes in OIF/OEF Returnees: A Randomized Clinical Trial of Hydrocortisone Augmentation of Prolonged Exposure Therapy

    DTIC Science & Technology

    2012-08-01

    Award Number: W81XWH-10-2-0072 TITLE: Improving PTSD Outcomes in OIF/OEF Returnees: A Randomized Clinical Trial of Hydrocortisone...SUBTITLE 5a. CONTRACT NUMBER Improving PTSD Outcomes in OIF/OEF Returnees: A Randomized Clinical Trial of Hydrocortisone Augmentation of Prolonged... clinical trial of Prolonged Exposure (PE) with glucocorticoid augmentation (with 30 mg Cortef) or placebo. (0 to 4 months)  Train new study personnel in

  20. 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

  1. Early hormonal data from a multicentre phase II trial using transdermal oestrogen patches as first-line hormonal therapy in patients with locally advanced or metastatic prostate cancer

    PubMed Central

    Langley, Ruth E.; Godsland, Ian F.; Kynaston, Howard; Clarke, Noel W.; Rosen, Stuart D.; Morgan, Rachel C.; Pollock, Philip; Kockelbergh, Roger; Lalani, El-Nasir; Dearnaley, David; Parmar, Mahesh; Abel, Paul D.

    2008-01-01

    OBJECTIVE To assess the hormonal effects of Fem7® (Merck, KGaA, Darmstadt, Germany) 100 μg transdermal oestrogen patches on men undergoing first-line androgen-deprivation therapy for prostate cancer. PATIENTS AND METHODS PATCH is a multicentre, randomized, phase II trial for men with locally advanced or metastatic prostate cancer, comparing luteinizing hormone-releasing hormone agonist therapy with oestrogen patches. To assess the dosing schedule for the patches, as this was the first time that this brand of patch had been used in men, and to reassure patients and participating clinicians, the Independent Data Monitoring Committee agreed to early release of hormonal data from this study. RESULTS Oestradiol, testosterone and prostate-specific antigen (PSA) levels are presented for the first group of 14 patients who received the patches (with 1 withdrawal) and for whom there were ≥12 weeks of follow-up by March 2007. After 12 weeks, testosterone levels (nmol/L) in eight of the 13 patients were <1.7, two were 1.7–2 and three were >2. The median (range) serum oestradiol levels was 442 (52.1–1542) pmol/L and all patients had a PSA response, with eight having a PSA level of <4 ng/mL. CONCLUSION These results confirm that oestrogen patches produce castrate levels of testosterone and concomitant PSA responses. They also highlighted the potential differences between different brands of oestrogen patches, and the need to monitor hormonal response, toxicity and efficacy until more experience with oestrogen patches for this clinical indication is obtained. The number of patches recommended in the PATCH study has now been increased. PMID:18422771

  2. Phase II multi-institutional prospective randomised trial comparing S-1+paclitaxel with S-1+cisplatin in patients with unresectable and/or recurrent advanced gastric cancer

    PubMed Central

    Mochiki, E; Ogata, K; Ohno, T; Toyomasu, Y; Haga, N; Fukai, Y; Aihara, R; Ando, H; Uchida, N; Asao, T; Kuwano, H

    2012-01-01

    Background: A combination of S-1 and cisplatin has been shown to be effective with acceptable safety for the first-line treatment of far-advanced gastric cancer in Japan. This is the first randomised phase II trial to compare S-1+paclitaxel with S-1+cisplatin in this setting. Methods: Patients with unresectable and/or recurrent advanced gastric cancer were randomly assigned to receive one of the two regimens: S-1 (40 mg m−2 twice daily) on days 1–14 plus paclitaxel (60 mg m−2) on days 1, 8, and 15 of a 4-week cycle (S-1+paclitaxel) or S-1 (40 mg m−2 twice daily) on days 1–21 plus cisplatin (60 mg m−2) on day 8 of a 5-week cycle (S-1+cisplatin). The primary end point was the response rate (RR). Secondary end points included progression-free survival (PFS), overall survival (OS), and safety. Results: A total of 83 patients were eligible for safety and efficacy analyses. In the S-1+paclitaxel and S-1+cisplatin groups, RRs (52.3% vs 48.7% P=0.74) and median PFS (9 vs 6 months; P=0.50) were similar. The median OS was similar in the S-1+paclitaxel and S-1+cisplatin groups (16 vs 17 months; P=0.84). The incidence of grade 3 or higher haematological toxicity was 19.0% with S-1+paclitaxel and 19.5% with S-1+cisplatin. The incidence of grade 3 or higher non-haematological toxicity was 14.2% with S-1+paclitaxel and 17.1% with S-1+cisplatin. Conclusion: S-1+paclitaxel was suggested to be a feasible and effective non-platinum-based regimen for chemotherapy in patients with advanced gastric cancer. Our results should be confirmed in multicenter, phase III-controlled clinical trials. PMID:22617130

  3. Oral high dose ascorbic acid treatment for one year in young CMT1A patients: a randomised, double-blind, placebo-controlled phase II trial

    PubMed Central

    2009-01-01

    Background High dose oral ascorbic acid substantially improved myelination and locomotor function in a Charcot-Marie-Tooth type 1A mouse model. A phase II study was warranted to investigate whether high dose ascorbic acid also has such a substantial effect on myelination in Charcot-Marie-Tooth type 1A patients and whether this treatment is safe. Methods Patients below age 25 years were randomly assigned to receive placebo or ascorbic acid (one gram twice daily) in a double-blind fashion during one year. The primary outcome measure was the change over time in motor nerve conduction velocity of the median nerve. Secondary outcome measures included changes in minimal F response latencies, compound muscle action potential amplitude, muscle strength, sensory function, Charcot-Marie-Tooth neuropathy score, and disability. Results There were no significant differences between the six placebo-treated (median age 16 years, range 13 to 24) and the five ascorbic acid-treated (19, 14 to 24) patients in change in motor nerve conduction velocity of the median nerve (mean difference ascorbic acid as opposed to placebo treatment of 1.3 m/s, confidence interval -0.3 to 3.0 m/s, P = 0.11) or in change of any of the secondary outcome measures over time. One patient in the ascorbic acid group developed a skin rash, which led to discontinuation of the study medication. Conclusion Oral high dose ascorbic acid for one year did not improve myelination of the median nerve in young Charcot-Marie-Tooth type 1A patients. Treatment was relatively safe. Trial registration Current Controlled Trials ISRCTN56968278, ClinicalTrials.gov NCT00271635. PMID:19909499

  4. A randomized clinical trial evaluating the success rate of ethanol wet bonding technique and two adhesives

    PubMed Central

    Mortazavi, Vajihesadat; Samimi, Pouran; Rafizadeh, Mojgan; Kazemi, Shantia

    2012-01-01

    Background: Composite resin restorations may have a short lifespan due to the degradation of resin–dentin interface. Ethanol wet bonding technique may extend the longevity of resin–dentin bond. The purpose of this one year randomized clinical trial was to compare clinical performance of two adhesives with ethanol wet bonding technique. Materials and Methods: This randomized clinical trial was performed on 36 non-carious cervical lesions in 12 patients restored with composite resin using one of the following approaches: 1. OptiBond FL (Kerr, USA); 2. Clearfil SE Bond (Kuraray, Japan) with enamel etching and 3. Ethanol wet bonding technique with the part of adhesive of OptiBond FL. The clinical success rate was assessed after 24 h, 6, 9 and 12 months according to the United States Public Health Service (USPHS) criteria: Marginal discoloration, marginal defect, retention rate, caries occurrence, and postoperative sensitivity. The tooth vitality was also assessed. Results: The retention rate was 100% at baseline and at 6 months follow up for all types of bonding protocols and was 91.67% at 9 and 12 months follow up for ethanol wet bonding group. None of the restorations in three groups showed marginal defects, marginal discoloration or caries occurrence and were vital after 12 months. There was no statistically significant difference between three groups after 12 months follow up (p value = 0.358). Conclusions: Composite restorations placed using ethanol wet bonding technique presented equal performance to the other groups. PMID:23559924

  5. 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…

  6. 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

    ... Department of Environmental Protection and Fish and Wildlife Conservation Commission; and For the State of... 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...

  7. Implementation of a Proficiency-Based Diploma System in Maine: Phase II--District Level Analysis

    ERIC Educational Resources Information Center

    Silvernail, David L.; Stump, Erika K.; McCafferty, Anita Stewart; Hawes, Kathryn M.

    2014-01-01

    This report describes the findings from Phase II of a study of Maine's implementation of a proficiency-based diploma system. At the request of the Joint Standing Committee on Education and Cultural Affairs of the Maine Legislature, the Maine Policy Research Institute (MEPRI) has conducted a two-phased study of the implementation of Maine law…

  8. 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...

  9. 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...

  10. 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...

  11. 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...

  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. 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.

  14. 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…

  15. 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.

  16. 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...

  17. 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…

  18. 76 FR 55947 - Industrial Relations Promotion Project, Phase II in Vietnam

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-09

    ... of the Secretary Industrial Relations Promotion Project, Phase II in Vietnam AGENCY: Bureau of... funded.. DAI, through its Industrial Relations Promotion Project (IRRP), is the only organization that...: white.brenda.j@dol.gov . All inquiries should make reference to the USDOL Industrial Relations...

  19. 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...

  20. Project Care Phase II: A Case Study in the Evaluation of Communication and Learning Materials.

    ERI