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data safety monitoring board [keywords]
- Challenges of Decision Making Regarding Futility in a Randomized Trial: The Interventional Management of Stroke III Experience. [JOURNAL ARTICLE]
- Stroke 2014 Apr 3.
Interventional Management of Stroke (IMS) III is a randomized, parallel arm trial comparing the approach of intravenous tissue plasminogen activator followed by endovascular treatment with intravenous tissue plasminogen activator alone in patients with acute ischemic stroke presenting <3 hours of symptom onset. The trial intended to enroll 900 subjects to ensure adequate statistical power to detect an absolute 10% difference in the percentage of subjects with good outcome, defined as modified Rankin Scale score of 0 to 2 at 3 months. In April 2012, after 656 subjects were randomized, further enrollment was terminated by the National Institute of Neurological Disorders and Stroke based on the prespecified criterion for futility using conditional power <20%.Conditional power was defined as the likelihood of finding statistical significance at the end of the study, given the accumulated data to date and with the assumption that a minimum hypothesized difference of 10% truly exists between the 2 groups. The evolution of study data leading to futility determination is described, including the interaction between the unblinded study statisticians and the Data and Safety Monitoring Board in the complex deliberation of analysis results.The futility boundary was crossed at the trial's fourth interim analysis. At this point, based on the conditional power criteria, the Data and Safety Monitoring Board recommended termination of the trial.Even in spite of prespecified interim analysis boundaries, interim looks at data pose challenges in interpretation and decision making, underscoring the importance of objective stopping criteria.http://www.clinicaltrials.gov. Unique identifier: NCT00359424.
- The Testosterone Trials: Seven coordinated trials of testosterone treatment in elderly men. [JOURNAL ARTICLE]
- Clin Trials 2014 Mar 31.
The prevalence of low testosterone levels in men increases with age, as does the prevalence of decreased mobility, sexual function, self-perceived vitality, cognitive abilities, bone mineral density, and glucose tolerance, and of increased anemia and coronary artery disease. Similar changes occur in men who have low serum testosterone concentrations due to known pituitary or testicular disease, and testosterone treatment improves the abnormalities. Prior studies of the effect of testosterone treatment in elderly men, however, have produced equivocal results.To describe a coordinated set of clinical trials designed to avoid the pitfalls of prior studies and to determine definitively whether testosterone treatment of elderly men with low testosterone is efficacious in improving symptoms and objective measures of age-associated conditions.We present the scientific and clinical rationale for the decisions made in the design of this set of trials.We designed The Testosterone Trials as a coordinated set of seven trials to determine if testosterone treatment of elderly men with low serum testosterone concentrations and symptoms and objective evidence of impaired mobility and/or diminished libido and/or reduced vitality would be efficacious in improving mobility (Physical Function Trial), sexual function (Sexual Function Trial), fatigue (Vitality Trial), cognitive function (Cognitive Function Trial), hemoglobin (Anemia Trial), bone density (Bone Trial), and coronary artery plaque volume (Cardiovascular Trial). The scientific advantages of this coordination were common eligibility criteria, common approaches to treatment and monitoring, and the ability to pool safety data. The logistical advantages were a single steering committee, data coordinating center and data and safety monitoring board, the same clinical trial sites, and the possibility of men participating in multiple trials. The major consideration in participant selection was setting the eligibility criterion for serum testosterone low enough to ensure that the men were unequivocally testosterone deficient, but not so low as to preclude sufficient enrollment or eventual generalizability of the results. The major considerations in choosing primary outcomes for each trial were identifying those of the highest clinical importance and identifying the minimum clinically important differences between treatment arms for sample size estimation.Potential limitationsSetting the serum testosterone concentration sufficiently low to ensure that most men would be unequivocally testosterone deficient, as well as many other entry criteria, resulted in screening approximately 30 men in person to randomize one participant.Designing The Testosterone Trials as a coordinated set of seven trials afforded many important scientific and logistical advantages but required an intensive recruitment and screening effort.
- Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial. [JOURNAL ARTICLE]
- Lancet Neurol 2014 Mar 27.
Fingolimod has shown reductions in clinical and MRI disease activity in patients with relapsing-remitting multiple sclerosis. We further assessed the efficacy and safety of fingolimod in such patients.We did this placebo-controlled, double-blind phase 3 study predominantly in the USA (101 of 117 centres). Using a computer-generated sequence, we randomly allocated eligible patients-those aged 18-55 years with relapsing-remitting multiple sclerosis-to receive fingolimod 0·5 mg, fingolimod 1·25 mg, or placebo orally once daily (1:1:1; stratified by study centre). On Nov 12, 2009, all patients assigned to fingolimod 1·25 mg were switched to the 0·5 mg dose in a blinded manner after a review of data from other phase 3 trials and recommendation from the data and safety monitoring board, but were analysed as being in the 1·25 mg group in the primary outcome analysis. Our primary endpoint was annualised relapse rate at month 24, analysed by intention to treat. Secondary endpoints included percentage brain volume change (PBVC) from baseline and time-to-disability-progression confirmed at 3 months. This trial is registered with ClinicalTrilals.gov, number NCT00355134.Between June 30, 2006, and March 4, 2009, we enrolled and randomly allocated 1083 patients: 370 to fingolimod 1·25 mg, 358 to fingolimod 0·5 mg, and 355 to placebo. Mean annualised relapse rate was 0·40 (95% CI 0·34-0·48) in patients given placebo and 0·21 (0·17-0·25) in patients given fingolimod 0·5 mg: rate ratio 0·52 (95% CI 0·40-0·66; p<0·0001), corresponding to a reduction of 48% with fingolimod 0·5 mg versus placebo. Mean PBVC was -0·86 (SD 1·22) for fingolimod 0·5 mg versus -1·28 (1·50) for placebo (treatment difference -0·41, 95% CI -0·62 to -0·20; p=0·0002). We recorded no statistically significant between-group difference in confirmed disability progression (hazard rate 0·83 with fingolimod 0·5 mg vs placebo; 95% CI 0·61-1·12; p=0·227). Fingolimod 0·5 mg caused more of the following adverse events versus placebo: lymphopenia (27 [8%] patients vs 0 patients), increased alanine aminotransferase (29 [8%] vs six [2%]), herpes zoster infection (nine [3%] vs three [1%]), hypertension (32 [9%] vs 11 [3%]), first-dose bradycardia (five [1%] vs one [<0·5%]), and first-degree atrioventricular block (17 [5%] vs seven [2%]). 53 (15%) of 358 patients given fingolimod 0·5 mg and 45 (13%) of 355 patients given placebo had serious adverse events over 24 months, which included basal-cell carcinoma (ten [3%] patients vs two [1%] patients), macular oedema (three [1%] vs two [1%]), infections (11 [3%] vs four [1%]), and neoplasms (13 [4%] vs eight [2%]).Our findings expand knowledge of the safety profile of fingolimod and strengthen evidence for its beneficial effects on relapse rates in patients with relapsing-remitting multiple sclerosis. We saw no effect of fingolimod on disability progression. Our findings substantiate the beneficial profile of fingolimod as a disease-modifying agent in the management of patients with relapsing-remitting multiple sclerosis.Novartis Pharma AG.
- Effect of aleglitazar on cardiovascular outcomes after acute coronary syndrome in patients with type 2 diabetes mellitus: the AleCardio randomized clinical trial. [Journal Article, Research Support, Non-U.S. Gov't]
- JAMA 2014 Apr 16; 311(15):1515-25.
No therapy directed against diabetes has been shown to unequivocally reduce the excess risk of cardiovascular complications. Aleglitazar is a dual agonist of peroxisome proliferator-activated receptors with insulin-sensitizing and glucose-lowering actions and favorable effects on lipid profiles.To determine whether the addition of aleglitazar to standard medical therapy reduces cardiovascular morbidity and mortality among patients with type 2 diabetes mellitus and a recent acute coronary syndrome (ACS).AleCardio was a phase 3, multicenter, randomized, double-blind, placebo-controlled trial conducted in 720 hospitals in 26 countries throughout North America, Latin America, Europe, and Asia-Pacific regions. The enrollment of 7226 patients hospitalized for ACS (myocardial infarction or unstable angina) with type 2 diabetes occurred between February 2010 and May 2012; treatment was planned to continue until patients were followed-up for at least 2.5 years and 950 primary end point events were positively adjudicated.Randomized in a 1:1 ratio to receive aleglitazar 150 µg or placebo daily.The primary efficacy end point was time to cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Principal safety end points were hospitalization due to heart failure and changes in renal function.The trial was terminated on July 2, 2013, after a median follow-up of 104 weeks, upon recommendation of the data and safety monitoring board due to futility for efficacy at an unplanned interim analysis and increased rates of safety end points. A total of 3.1% of patients were lost to follow-up and 3.2% of patients withdrew consent. The primary end point occurred in 344 patients (9.5%) in the aleglitazar group and 360 patients (10.0%) in the placebo group (hazard ratio, 0.96 [95% CI, 0.83-1.11]; P = .57). Rates of serious adverse events, including heart failure (3.4% for aleglitazar vs 2.8% for placebo, P = .14), gastrointestinal hemorrhages (2.4% for aleglitazar vs 1.7% for placebo, P = .03), and renal dysfunction (7.4% for aleglitazar vs 2.7% for placebo, P < .001) were increased.Among patients with type 2 diabetes and recent ACS, use of aleglitazar did not reduce the risk of cardiovascular outcomes. These findings do not support the use of aleglitazar in this setting with a goal of reducing cardiovascular risk.clinicaltrials.gov Identifier: NCT01042769.
- Radiofrequency ablation vs endoscopic surveillance for patients with Barrett esophagus and low-grade dysplasia: a randomized clinical trial. [Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't]
- JAMA 2014 Mar 26; 311(12):1209-17.
Barrett esophagus containing low-grade dysplasia is associated with an increased risk of developing esophageal adenocarcinoma, a cancer with a rapidly increasing incidence in the western world.To investigate whether endoscopic radiofrequency ablation could decrease the rate of neoplastic progression.Multicenter randomized clinical trial that enrolled 136 patients with a confirmed diagnosis of Barrett esophagus containing low-grade dysplasia at 9 European sites between June 2007 and June 2011. Patient follow-up ended May 2013.Eligible patients were randomly assigned in a 1:1 ratio to either endoscopic treatment with radiofrequency ablation (ablation) or endoscopic surveillance (control). Ablation was performed with the balloon device for circumferential ablation of the esophagus or the focal device for targeted ablation, with a maximum of 5 sessions allowed.The primary outcome was neoplastic progression to high-grade dysplasia or adenocarcinoma during a 3-year follow-up since randomization. Secondary outcomes were complete eradication of dysplasia and intestinal metaplasia and adverse events.Sixty-eight patients were randomized to receive ablation and 68 to receive control. Ablation reduced the risk of progression to high-grade dysplasia or adenocarcinoma by 25.0% (1.5% for ablation vs 26.5% for control; 95% CI, 14.1%-35.9%; P < .001) and the risk of progression to adenocarcinoma by 7.4% (1.5% for ablation vs 8.8% for control; 95% CI, 0%-14.7%; P = .03). Among patients in the ablation group, complete eradication occurred in 92.6% for dysplasia and 88.2% for intestinal metaplasia compared with 27.9% for dysplasia and 0.0% for intestinal metaplasia among patients in the control group (P < .001). Treatment-related adverse events occurred in 19.1% of patients receiving ablation (P < .001). The most common adverse event was stricture, occurring in 8 patients receiving ablation (11.8%), all resolved by endoscopic dilation (median, 1 session). The data and safety monitoring board recommended early termination of the trial due to superiority of ablation for the primary outcome and the potential for patient safety issues if the trial continued.In this randomized trial of patients with Barrett esophagus and a confirmed diagnosis of low-grade dysplasia, radiofrequency ablation resulted in a reduced risk of neoplastic progression over 3 years of follow-up.trialregister.nl Identifier: NTR1198.
- Atacicept in multiple sclerosis (ATAMS): a randomised, placebo-controlled, double-blind, phase 2 trial. [Journal Article]
- Lancet Neurol 2014 Apr; 13(4):353-63.
Depletion of B lymphocytes is associated with suppression of inflammatory activity in multiple sclerosis. We aimed to assess the safety and efficacy of atacicept, a recombinant fusion protein that suppresses B-cell function and antibody production.In this placebo-controlled, double-blind, 36-week, phase 2 trial (ATAMS) in Australia, Canada, Europe, and the USA, patients aged 18-60 years with relapsing multiple sclerosis were randomly assigned via an interactive voice response system in a 1:1:1:1 ratio, stratified by geographical region, to receive weekly subcutaneous injections with atacicept (25, 75, or 150 mg) or placebo. Both patients and study personnel were masked to treatment assignment. The primary endpoint was the change in mean number of gadolinium-enhancing lesions on T1-weighted MRI per patient per scan between weeks 12 and 36. Efficacy endpoints were analysed in the intention-to-treat population. Patients who completed week 36 were eligible to participate in a long-term extension study (ATAMS EXT), consisting of a double-blind phase followed by an open-label phase, for a total study time of up to 5 years. The study was terminated early after the independent data and safety monitoring board noted an increased annualised relapse rate with atacicept. The protocol was subsequently amended to include a 60-week safety follow-up, to allow treatment with approved multiple sclerosis drugs, and to change the primary endpoint to gadolinium-enhancing T1 lesions per scan during the entire double-blind period of ATAMS. Both the trial and the extension are registered with ClinicalTrials.gov, numbers NCT00642902 (ATAMS) and NCT00853762 (ATAMS EXT).Between April 23, 2008, and early study termination on Sept 11, 2009, 255 patients were randomly assigned: 63 to placebo, 63 to atacicept 25 mg, 64 to 75 mg, and 65 to 150 mg. 90 (35%) patients completed the week 36 treatment visit, 26 (10%) discontinued before study termination (including one who dropped out before receiving study treatment), and 139 (55%) discontinued because of study termination. During the double-blind period of ATAMS, annualised relapse rates were higher in the atacicept groups than in the placebo group (atacicept 25 mg, 0·86, 95% CI 0·43-1·74; 75 mg, 0·79, 0·40-1·58; 150 mg, 0·98, 0·52-1·81; placebo, 0·38, 0·17-0·87). Mean numbers of gadolinium-enhancing T1 lesions per scan were similar in all groups (25 mg, 2·26, 0·97-5·27; 75 mg, 2·30, 1·08-4·92; 150 mg, 2·49, 1·18-5·27; placebo, 3·07, 1·40-6·77). Seven patients (one taking placebo and six atacicept) discontinued treatment because of adverse events. One death occurred in the placebo group. During the safety follow-up, immunoglobulin concentrations and B-cell counts returned towards predose values and annualised relapse rates in the atacicept groups decreased until they were similar to that of the placebo groupIncreased clinical disease activity associated with atacicept suggests that the role of B cells and humoral immunity in multiple sclerosis is complex. For studies that explore therapeutic immunomodulation in multiple sclerosis, rigorous monitoring for negative effects on clinical and MRI outcomes is warranted.Merck Serono (Merck KGaA) and EMD Serono (Merck KGaA).
- Predicting clinical trial results based on announcements of interim analyses. [Journal Article]
- Trials 2014.:73.
Announcements of interim analyses of a clinical trial convey information about the results beyond the trial's Data Safety Monitoring Board (DSMB). The amount of information conveyed may be minimal, but the fact that none of the trial's stopping boundaries has been crossed implies that the experimental therapy is neither extremely effective nor hopeless. Predicting success of the ongoing trial is of interest to the trial's sponsor, the medical community, pharmaceutical companies, and investors. We determine the probability of trial success by quantifying only the publicly available information from interim analyses of an ongoing trial. We illustrate our method in the context of the National Surgical Adjuvant Breast and Bowel (NSABP) trial, C-08.We simulated trials based on the specifics of the NSABP C-08 protocol that were publicly available. We quantified the uncertainty around the treatment effect using prior weights for the various possibilities in light of other colon cancer studies and other studies of the investigational agent, bevacizumab. We considered alternative prior distributions.Subsequent to the trial's third interim analysis, our predictive probabilities were: that the trial would eventually be successful, 48.0%; would stop for futility, 7.4%; and would continue to completion without statistical significance, 44.5%. The actual trial continued to completion without statistical significance.Announcements of interim analyses provide information outside the DSMB's sphere of confidentiality. This information is potentially helpful to clinical trial prognosticators. 'Information leakage' from standard interim analyses such as in NSABP C-08 is conventionally viewed as acceptable even though it may be quite revealing. Whether leakage from more aggressive types of adaptations is acceptable should be assessed at the design stage.
- Effects of galantamine in a 2-year, randomized, placebo-controlled study in Alzheimer's disease. [Journal Article]
- Neuropsychiatr Dis Treat 2014.:391-401.
Currently available treatments for Alzheimer's disease (AD) can produce mild improvements in cognitive function, behavior, and activities of daily living in patients, but their influence on long-term survival is not well established. This study was designed to assess patient survival and drug efficacy following a 2-year galantamine treatment in patients with mild to moderately severe AD.In this multicenter, double-blind study, patients were randomized 1:1 to receive galantamine or placebo. One primary end point was safety; mortality was assessed. An independent Data Safety Monitoring Board monitored mortality for the total deaths reaching prespecified numbers, using a time-to-event method and a Cox-regression model. The primary efficacy end point was cognitive change from baseline to month 24, as measured by the Mini-Mental State Examination (MMSE) score, analyzed using intent-to-treat analysis with the 'last observation carried forward' approach, in an analysis of covariance model.In all, 1,024 galantamine- and 1,021 placebo-treated patients received study drug, with mean age ~73 years, and mean (standard deviation [SD]) baseline MMSE score of 19 (4.08). A total of 32% of patients (661/2,045) completed the study, 27% (554/2,045) withdrew, and 41% (830/2,045) did not complete the study and were discontinued due to a Data Safety Monitoring Board-recommended early study termination. The mortality rate was significantly lower in the galantamine group versus placebo (hazard ratio [HR] =0.58; 95% confidence interval [CI]: 0.37; 0.89) (P=0.011). Cognitive impairment, based on the mean (SD) change in MMSE scores from baseline to month 24, significantly worsened in the placebo (-2.14 [4.34]) compared with the galantamine group (-1.41 [4.05]) (P<0.001). Functional impairment, based on mean (SD) change in the Disability Assessment in Dementia score (secondary end point), at month 24 significantly worsened in the placebo (-10.81 [18.27]) versus the galantamine group (-8.16 [17.25]) (P=0.002). Incidences of treatment-emergent adverse events were 54.0% for the galantamine and 48.6% for the placebo group.Long-term treatment with galantamine significantly reduced mortality and the decline in cognition and daily living activities, in mild to moderate AD patients.This study is registered at ClinicalTrials.gov (NCT00679627).
- IN.PACT Amphirion paclitaxel eluting balloon versus standard percutaneous transluminal angioplasty for infrapopliteal revascularization of critical limb ischemia: rationale and protocol for an ongoing randomized controlled trial. [Journal Article, Research Support, Non-U.S. Gov't]
- Trials 2014.:63.
The effectiveness and durability of endovascular revascularization therapies for chronic critical limb ischemia (CLI) are challenged by the extensive burden of infrapopliteal arterial disease and lesion-related characteristics (e.g., severe calcification, chronic total occlusions), which frequently result in poor clinical outcomes. While infrapopliteal vessel patency directly affects pain relief and wound healing, sustained patency and extravascular care both contribute to the ultimate "patient-centric" outcomes of functional limb preservation, mobility and quality of life (QoL).IN.PACT DEEP is a 2:1 randomized controlled trial designed to assess the efficacy and safety of infrapopliteal arterial revascularization between the IN.PACT Amphirion™ paclitaxel drug-eluting balloon (IA-DEB) and standard balloon angioplasty (PTA) in patients with Rutherford Class 4-5-6 CLI.This multicenter trial has enrolled 358 patients at 13 European centers with independent angiographic core lab adjudication of the primary efficacy endpoint of target lesion late luminal loss (LLL) and clinically driven target lesion revascularization (TLR) in major amputation-free surviving patients through 12-months. An independent wound core lab will evaluate all ischemic wounds to assess the extent of healing and time to healing at 1, 6, and 12 months. A QoL questionnaire including a pain scale will assess changes from baseline scores through 12 months. A Clinical Events Committee and Data Safety Monitoring Board will adjudicate the composite primary safety endpoints of all-cause death, major amputation, and clinically driven TLR at 6 months and other trial endpoints and supervise patient safety throughout the study. All patients will be followed for 5 years. A literature review is presented of the current status of endovascular treatment of CLI with drug-eluting balloon and standard PTA. The rationale and design of the IN.PACT DEEP Trial are discussed. IN.PACT DEEP is a milestone, prospective, randomized, robust, independent core lab-adjudicated CLI trial that will evaluate the role of a new infrapopliteal revascularization technology, the IA-DEB, compared to PTA. It will assess the overall impact on infrapopliteal artery patency, limb salvage, wound healing, pain control, QoL, and patient mobility. The 1-year results of the adjudicated co-primary and secondary endpoints will be available in 2014.NCT00941733.
- Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. [Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't]
- N Engl J Med 2014 Mar 13; 370(11):997-1007.
Patients with relapsed chronic lymphocytic leukemia (CLL) who have clinically significant coexisting medical conditions are less able to undergo standard chemotherapy. Effective therapies with acceptable side-effect profiles are needed for this patient population.In this multicenter, randomized, double-blind, placebo-controlled, phase 3 study, we assessed the efficacy and safety of idelalisib, an oral inhibitor of the delta isoform of phosphatidylinositol 3-kinase, in combination with rituximab versus rituximab plus placebo. We randomly assigned 220 patients with decreased renal function, previous therapy-induced myelosuppression, or major coexisting illnesses to receive rituximab and either idelalisib (at a dose of 150 mg) or placebo twice daily. The primary end point was progression-free survival. At the first prespecified interim analysis, the study was stopped early on the recommendation of the data and safety monitoring board owing to overwhelming efficacy.The median progression-free survival was 5.5 months in the placebo group and was not reached in the idelalisib group (hazard ratio for progression or death in the idelalisib group, 0.15; P<0.001). Patients receiving idelalisib versus those receiving placebo had improved rates of overall response (81% vs. 13%; odds ratio, 29.92; P<0.001) and overall survival at 12 months (92% vs. 80%; hazard ratio for death, 0.28; P=0.02). Serious adverse events occurred in 40% of the patients receiving idelalisib and rituximab and in 35% of those receiving placebo and rituximab.The combination of idelalisib and rituximab, as compared with placebo and rituximab, significantly improved progression-free survival, response rate, and overall survival among patients with relapsed CLL who were less able to undergo chemotherapy. (Funded by Gilead; ClinicalTrials.gov number, NCT01539512.).