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Pivotal Trials (pivotal + trials)
Selected AbstractsLong-Term Migraine Prevention With Topiramate: Open-Label Extension of Pivotal TrialsHEADACHE, Issue 7 2006Alan Rapoport MD Objective.,To demonstrate that topiramate is an effective and generally well-tolerated migraine preventive therapy when used for up to 14 months. Background.,Topiramate 100 and 200 mg/d significantly reduced mean monthly migraine frequency during 2 large, 26-week, randomized, placebo-controlled trials. Only a small number of clinical trials have examined the long-term (,1 year) effectiveness and safety of migraine preventive therapies. Methods.,Five hundred sixty-seven patients with an established history of migraine with or without aura were enrolled in this 8-month, open-label extension of 2 large (49 US and 52 US and Canadian medical centers), randomized, double-blind, placebo-controlled, parallel group, 26-week trials of identical design. To be eligible for the open-label extension, patients were required to have either completed the double-blind phase of the 2 pivotal migraine prevention trials or withdrew after 4 weeks due to lack of efficacy. All eligible patients, regardless of type or dose of study medication (topiramate or placebo) received in the double-blind phase, were titrated to a clinically effective dose of open-label topiramate based on physician judgment of patient response. Efficacy of topiramate was measured as the change in mean monthly migraine frequency. Results.,The mean topiramate dose during the open-label extension phase was 124.7 mg/d and 150.3 mg/d for patients on placebo (n = 159) or topiramate (n = 408), respectively, during the double-blind phase (N = 567, 91% female, mean age 39.4 years). Patients on topiramate for up to 14 months had 2.2 ± 2.4 (mean ± SD) migraines per month after completion of the open-label extension phase (3.4 ± 2.6 at double-blind endpoint). Patients on topiramate during the open-label extension phase only (placebo during the double-blind phase) had 3.0 ± 2.9 migraines per month at open-label extension endpoint (4.9 ± 3.0 migraines per month at double-blind endpoint). Discontinuation rates due to adverse events during the double-blind phase were 22.2% for patients on topiramate and 11.0% for patients on placebo. Discontinuation rates due to adverse events during the open-label extension phase were 8.6% for those patients who had already received topiramate during the double-blind phase and 20.9% for those patients who had previously received placebo. Conclusions.,Patients receiving topiramate experienced a sustained reduction in migraine frequency for up to 14 months. The effectiveness and safety of topiramate was consistent with that observed during 2 26-week pivotal trials. [source] Exenatide effects on glucose metabolism and metabolic disorders common to overweight and obese patients with type 2 diabetesDRUG DEVELOPMENT RESEARCH, Issue 8 2006David M. Webb Abstract The risks of cardiovascular disease (CVD) and type 2 diabetes increase as body mass index increases in overweight (25,30,kg/m2) and obese (>30,kg/m2) individuals. However, these risks can be reduced with even modest weight loss. In patients with established type 2 diabetes, control of both glycemia and body weight are important to minimize the risk of future diabetic complications. Exenatide is a 39-amino-acid peptide incretin mimetic currently approved in the United States for the treatment of type 2 diabetes as an adjunct to sulfonylurea and/or metformin. Phase-3 clinical studies showed exenatide therapy for 30 weeks significantly reduced glycosylated hemoglobin (HbA1c), and fasting and postprandial plasma glucose, while significantly reducing body weight. Open-label extensions from these pivotal trials demonstrated patients treated with exenatide for 2 years had sustained reductions in glycemic control at 30 weeks and a progressive reduction in body weight. Patients treated with exenatide also had improvement in blood pressure, inflammatory markers, and lipid profiles. The glucoregulatory and weight-reducing effects of exenatide are the result of multiple modes of action that mimic several of the glucoregulatory actions of the naturally occurring peptide, glucagon-like peptide-1 (GLP-1). These include restoration of first phase insulin response, enhancement of glucose-dependent insulin secretion, suppression of inappropriate glucagon secretion, slowing of gastric emptying, and affects on satiety leading to reduced food intake. Further research is required to fully understand the role for exenatide to potentially alleviate metabolic disorders associated with type 2 diabetes, including CVD and obesity. Drug Dev. Res. 67:666,676, 2006. © 2006 Wiley-Liss, Inc. [source] Long-Term Migraine Prevention With Topiramate: Open-Label Extension of Pivotal TrialsHEADACHE, Issue 7 2006Alan Rapoport MD Objective.,To demonstrate that topiramate is an effective and generally well-tolerated migraine preventive therapy when used for up to 14 months. Background.,Topiramate 100 and 200 mg/d significantly reduced mean monthly migraine frequency during 2 large, 26-week, randomized, placebo-controlled trials. Only a small number of clinical trials have examined the long-term (,1 year) effectiveness and safety of migraine preventive therapies. Methods.,Five hundred sixty-seven patients with an established history of migraine with or without aura were enrolled in this 8-month, open-label extension of 2 large (49 US and 52 US and Canadian medical centers), randomized, double-blind, placebo-controlled, parallel group, 26-week trials of identical design. To be eligible for the open-label extension, patients were required to have either completed the double-blind phase of the 2 pivotal migraine prevention trials or withdrew after 4 weeks due to lack of efficacy. All eligible patients, regardless of type or dose of study medication (topiramate or placebo) received in the double-blind phase, were titrated to a clinically effective dose of open-label topiramate based on physician judgment of patient response. Efficacy of topiramate was measured as the change in mean monthly migraine frequency. Results.,The mean topiramate dose during the open-label extension phase was 124.7 mg/d and 150.3 mg/d for patients on placebo (n = 159) or topiramate (n = 408), respectively, during the double-blind phase (N = 567, 91% female, mean age 39.4 years). Patients on topiramate for up to 14 months had 2.2 ± 2.4 (mean ± SD) migraines per month after completion of the open-label extension phase (3.4 ± 2.6 at double-blind endpoint). Patients on topiramate during the open-label extension phase only (placebo during the double-blind phase) had 3.0 ± 2.9 migraines per month at open-label extension endpoint (4.9 ± 3.0 migraines per month at double-blind endpoint). Discontinuation rates due to adverse events during the double-blind phase were 22.2% for patients on topiramate and 11.0% for patients on placebo. Discontinuation rates due to adverse events during the open-label extension phase were 8.6% for those patients who had already received topiramate during the double-blind phase and 20.9% for those patients who had previously received placebo. Conclusions.,Patients receiving topiramate experienced a sustained reduction in migraine frequency for up to 14 months. The effectiveness and safety of topiramate was consistent with that observed during 2 26-week pivotal trials. [source] Assessment of hepatitis C virus-RNA clearance under combination therapy for hepatitis C virus genotype 1: performance of the transcription-mediated amplification assayJOURNAL OF VIRAL HEPATITIS, Issue 1 2008D. Ferraro Summary., Monitoring of HCV-RNA in blood during antiviral therapy is performed mostly by commercially available reverse transcription polymerase chain reaction-based (RT-PCR) assays, with a lower detection limit of 30,50 IU/mL of HCV-RNA. Use of different tests in the pivotal trials of combination therapy has generated some discordance, in terms of predictive value of the early virological response (EVR). To evaluate whether the use of a more sensitive test, as a qualitative assay based on transcription mediated amplification (TMA) with a lower detection limit of 5,10 IU/mL of HCV-RNA, may obtain a better prediction of EVR and of the ultimate virological outcome, we retrospectively evaluated serial samples from 108 naïve patients with HCV genotype 1 chronic hepatitis, treated with pegylated ,2b interferon plus ribavirin for 48 weeks and with a 24 weeks stopping rule. Serum samples of patients, obtained during treatment at weeks 4, 12, 24 and 48 and after treatment at week 24, were evaluated by TMA. Comparison of the RT-PCR and TMA assays for the qualitative detection of HCV-RNA showed no significant differences in performance when these tests were used at the end of the treatment period for assessing patients without an on-treatment virological response and those who eventually obtain a sustained virological response. Our results show instead that the use of TMA assay to detect HCV-RNA at 12 and 24 weeks of the combination therapy is more effective than RT-PCR in identifying patients with the highest probability of sustained HCV-RNA clearance. [source] Critical role of ribavirin for the achievement of early virological response to HCV therapy in HCV/HIV-coinfected patientsJOURNAL OF VIRAL HEPATITIS, Issue 6 2007B. Ramos Summary., The response to hepatitis C virus (HCV) therapy seems to be lower in HCV/HIV-coinfected patients than in HCV-monoinfected individuals. Given that most pivotal trials conducted in coinfected patients have used the combination of pegylated interferon (pegIFN) along with fixed low doses (800 mg/day) of ribavirin (RBV), it is unclear whether HIV itself and/or suboptimal RBV exposure could explain this poorer outcome. Two well-defined end points of early virological response were evaluated in Peginterferon Ribavirina España Coinfección (PRESCO), a multicentre trial in which the combination of pegIFN plus RBV (1000 mg if body weight <75 kg and 1200 mg if >75 kg) was prescribed to coinfected patients. For comparisons, we used unpublished data from early kinetics in two other large trials, one performed in HIV-negative patients [Pegasys International Study Group (PISG)] in which RBV 1000,1200 mg/day was used and another [AIDS Pegasys Ribavirin Coinfection Trial (APRICOT)] in which HIV-positive patients received fixed low RBV doses (800 mg/day). A total of 348 HCV/HIV-coinfected patients from the PRESCO trial were analysed as well as all patients treated with pegIFN plus RBV, who completed 12 weeks of therapy in the comparative studies (435 in PISG and 268 in APRICOT). Negative serum HCV-RNA at week 4 (which has the highest positive predictive value of sustained virological response, SVR) was attained in 33.3%, 31.2% and 13% of treated patients with HCV genotype 1, respectively, in PRESCO, PISG and APRICOT. For HCV genotypes 2/3, responses were 83.7%, 84.2% and 37%, respectively. A decline lower than 2 log10 at week 12 (which has the highest negative predictive value of SVR) was seen in 25.5%, 19.5% and 37% of HCV genotype-1-infected patients, and in 2.1%, 2.9% and 12% of genotypes-2/3-infected patients, respectively. Prescription of high RBV doses enhances the early virological response to HCV therapy in HCV/HIV-coinfected patients, with results approaching those seen in HCV-monoinfected patients. [source] Pivotal studies of orphan drugs approved for neurological diseases,ANNALS OF NEUROLOGY, Issue 2 2009Jun Mitsumoto MPH Objective To identify design elements of clinical trials leading to US Food and Drug Administration approval of drugs for neurological diseases with and without orphan indications. Methods We used publicly available information to identify approvals for drugs for neurological diseases with an orphan indication (n = 19) and compared them with recent approvals for drugs for neurological diseases without an orphan indication (n = 20). We identified "pivotal trials" from drug labels and drug approval packages, and assessed them on four elements of clinical trial design: control, blinding, randomization, and size. Results All drugs for neurological diseases (100%) approved without an orphan indication included at least two randomized, double-blind, placebo-controlled trials. In comparison, 32% of drugs with an orphan indication had at least two such trials (p < 0.001) and 74% had at least one (p = 0.02). Thirty-three pivotal trials were conducted for the 19 drugs approved with an orphan indication. Of the 33 trials, 11 (33%) did not use a placebo control, 9 (27%) were not double blind, and 4 (12%) were not randomized. Drugs approved without an orphan indication had more pivotal trials per drug (3.8 vs 1.7 trials; p < 0.001) and a larger mean trial size (506 vs 164 trial participants; p < 0.001). Interpretation The US Food and Drug Administration has approved orphan drugs for neurological diseases without randomized, doubled-blind, placebo-controlled pivotal trials. As orphan drug development grows, demand will likely increase for alternative designs for conducting adequate and well-controlled studies to demonstrate drug efficacy. Ann Neurol 2009;66:184,190 [source] An Adaptive Two-stage Design with Treatment Selection Using the Conditional Error Function ApproachBIOMETRICAL JOURNAL, Issue 4 2006Jixian Wang Abstract As an approach to combining the phase II dose finding trial and phase III pivotal trials, we propose a two-stage adaptive design that selects the best among several treatments in the first stage and tests significance of the selected treatment in the second stage. The approach controls the type I error defined as the probability of selecting a treatment and claiming its significance when the selected treatment is indifferent from placebo, as considered in Bischoff and Miller (2005). Our approach uses the conditional error function and allows determining the conditional type I error function for the second stage based on information observed at the first stage in a similar way to that for an ordinary adaptive design without treatment selection. We examine properties such as expected sample size and stage-2 power of this design with a given type I error and a maximum stage-2 sample size under different hypothesis configurations. We also propose a method to find the optimal conditional error function of a simple parametric form to improve the performance of the design and have derived optimal designs under some hypothesis configurations. Application of this approach is illustrated by a hypothetical example. (© 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim) [source] Interferon beta-1b treatment in patients with relapsing,remitting multiple sclerosis under a standardized protocol in SpainACTA NEUROLOGICA SCANDINAVICA, Issue 4 2000T. Arbizu Objective, A protocol system is being used in Spain for the prescription of innovative drugs including interferon beta-1b (IFN,-1b). Petitions for dispensing and reimbursement are based on the inclusion and exclusion criteria of pivotal trials, and are reviewed individually for approval by specialist committees. To estimate the performance of IFN,-1b in the clinical setting, data collected by the INSALUD and regional health services of Andalusia and Catalonia, together responsible for the healthcare of nearly 30 million individuals, were compiled in a common database for analysis. Methods, Data comprise demographic and disease characteristics at the time of petition and at follow-up 3 months after treatment initiation and every 6 months thereafter. Efficacy was estimated by mean number of relapses per year, proportion of relapse-free patients, and disease progression as measured by the Expanded Disability Status Scale (EDSS). Safety parameters included adverse events and laboratory analyses. Results, Between September 1995 and database cutoff in mid-1998, petitions of 1419 patients were approved for IFN,-1b treatment. Patients were homogenous across the three databases and in the subgroups of patients completing 1 year (n=940) and 2 years (n=302) of treatment. There was a marked decrease in the mean number of relapses in the first 12 months of IFN,-1b treatment for the 938 patients documented for 12 months, with a mean of 0.4 (±0.7 SD) relapses per patient and year, and a 2-year mean of 0.9 (±1.20 SD) in the 302 patients documented for 24 months. Of the 938 patients followed for ,12 months, 505 (53.8%) were documented as being relapse-free during 12 months of treatment, and 146 (48.3%) of the 302 patients followed for ,24 months, were relapse-free during 24 months of treatment. There were no differences in mean or median EDSS scores between baseline and months 12 and 24. Skin disorders were the most frequent adverse events, reported in over one-third of all patients; there were 159 injection site events, most frequently erythema (115 events). Systemic AEs pointing towards flu-like symptoms were reported in 288 of 1419 patients (20.3%). Leukopenia was the most frequently reported laboratory event. Elevations in liver transaminases were noted for 12 patients (0.8%) with SGOT increase and 7 (0.5%) with SGPT increase. Conclusion, The protocol system has helped make IFN, treatment available to 8,10% of the estimated 15,000,18,000 MS patients in the regions studied. In terms of efficacy, IFN,-1b performed in line with the pivotal study results. The safety profile of IFN,-1b was consistent with the published findings and the drug labelling, and no new side effects or increased incidence of known side effects was observed. [source] | ||||||||||