Download the Free Unbound MEDLINE PubMed App to your smartphone or tablet.
Available for iPhone, iPad, iPod touch, and Android.
data safety monitoring board [keywords]
- Study design considerations for evaluating the efficacy and safety of pancreatic enzyme replacement therapy in patients with cystic fibrosis. [JOURNAL ARTICLE]
- Clin Investig (Lond) 2013 Aug; 3(8):731-741.
In 2006, the US FDA issued a 'Guidance for Industry' regarding submission of New Drug Applications for pancreatic enzyme replacement therapy (PERT) products. Five oral delayed-release PERT products have been approved by the FDA, and several others are under development and/ or evaluation for New Drug Application submission. We present in this paper recommendations of the Cystic Fibrosis Foundation's Cystic Fibrosis (CF) Therapeutics Development Network and Data Safety Monitoring Board regarding study design considerations for evaluating PERT products in patients with CF. Careful attention to study design and accuracy of the outcome measures has confirmed our understanding of the efficacy and safety of PERT for the treatment of exocrine pancreatic insufficiency of CF.
- A systematic review of clozapine induced cardiomyopathy. [REVIEW]
- Int J Cardiol 2014 Aug 1.
Clozapine is a unique anti-psychotic medication that is most effective in the treatment of refractory schizophrenia and reducing suicidality. Cardiomyopathy is among the side effects of this medication that limits its use. There are a number of case reports, case series and expert opinion papers discussing clozapine induced cardiomyopathy, but there is no evidence-based review of the subject to guide clinicians.We undertook a systematic review of the literature on cardiomyopathy associated with clozapine. The primary systemic search was in MEDLINE but EMBASE, PsycINFO, and Cochrane were searched and manufacturers of clozapine were contacted for cases. Articles were then individually reviewed to find additional reports.We identified 17 articles detailing 26 individual cases and 11 additional articles without individual case data. The mean age at time of diagnosis was 33.5years. The mean dose of clozapine on presentation was 360mg. Symptoms developed at an average of 14.4months after initiating clozapine. The clinical presentation was generally consistent with heart failure: including shortness of breath (60%) and palpitations (36%). Echocardiography at presentation showed dilated cardiomyopathy in 39% of cases and was not specified in other cases.There should be a low threshold in performing echocardiography in suspected cases of clozapine induced cardiomyopathy. Clozapine should be withheld in the setting of cardiomyopathy without other explanation. There is limited data on the safety of drug re-challenge in clozapine induced cardiomyopathy. Re-challenge may be considered in carefully selected cases but close monitoring and frequent echocardiography are required.
- Randomized controlled trial of the CGRP receptor antagonist telcagepant for migraine prevention. [JOURNAL ARTICLE]
- Neurology 2014 Aug 8.
To evaluate whether the calcitonin gene-related peptide (CGRP) receptor antagonist telcagepant might be effective for migraine prevention.In this randomized, double-blind, placebo-controlled, multicenter trial (ClinicalTrials.gov NCT00797667), patients experiencing 3-14 migraine days during a 4-week baseline were randomized to telcagepant 140 mg, telcagepant 280 mg, or placebo twice daily for 12 weeks. Efficacy was assessed by mean monthly headache days and migraine/probable migraine days (headache plus ≥1 associated symptom).The trial was terminated following a recommendation from the Safety Monitoring Board due to hepatotoxicity concerns. At termination, the planned 660 patients had been randomized, 656 had been treated with ≥1 dose of study medication, and 14 had completed the trial. The mean treatment duration was 48-50 days. Thirteen patients, all in the telcagepant groups, had an alanine aminotransferase (ALT) elevation ≥3× the upper limit of normal and 7 of these also had an aspartate aminotransferase elevation ≥3× the upper limit of normal. Two patients had very high symptomatic transaminase elevations that occurred within 2-6 weeks of treatment initiation and resolved after treatment discontinuation. The originally planned efficacy analysis over 12 weeks was not performed due to limited data at later time points, but there was evidence that telcagepant resulted in a larger reduction from baseline than placebo for mean monthly headache days (month 1: 140 mg = -2.9, 280 mg = -3.1, placebo = -1.7; p < 0.05) and migraine/probable migraine days (month 1: 140 mg = -2.7, 280 mg = -3.0, placebo = -1.6; p < 0.05).These data suggest a potential role for CGRP receptor antagonism in migraine prophylaxis. However, the observed aminotransferase elevations do not support the use of telcagepant for daily administration.This study provides Class II evidence that in patients with migraine, telcagepant taken daily reduces headache days by 1.4 days per month compared to placebo and causes 2.5% of patients to have elevations of serum ALT levels.
- Randomized, double-blind, placebo-controlled clinical trial of a two-day regimen of dihydroartemisinin-piperaquine for malaria prevention halted for concern of prolonged QTc interval. [JOURNAL ARTICLE]
- Antimicrob Agents Chemother 2014 Aug 4.
Dihydroartemisinin-piperaquine, the current first-line drug for uncomplicated P. falciparum and P. vivax in Cambodia, was shown previously to be of benefit as malaria chemoprophylaxis when administered as a monthly 3-day regimen. We sought to evaluate the protective efficacy of a compressed monthly two-day treatment course in the Royal Cambodian Armed Forces.The safety and efficacy of a monthly two-day dosing regimen of dihydroartemisinin-piperaquine were evaluated in a two-arm, randomized, double-blind, placebo-controlled cohort study with 2:1 treatment allocation. Healthy military volunteers in high risk areas along the Thai-Cambodian border were administered two consecutive daily doses of 180 mg dihydroartemisinin and 1440 mg piperaquine within 30 minutes to 3 hours of a meal once per month for four months with periodic electrocardiographic and pharmacokinetic assessment.The study was halted after only 6 weeks (69 of 231 planned volunteers enrolled) when four volunteers met a pre-specified cardiac safety endpoint of QTcF prolongation >500ms. Pharmacodynamic effect on the surface EKG peaked approximately 4 hours after piperaquine dosing and lasted 4-8 hours. Unblinded review by the data safety monitoring board revealed mean QTcF prolongation of 46 ms over placebo at Cmax on day 2.Given that dihydroartemisinin-piperaquine is one of the few remaining effective antimalarials in Cambodia, compressed two-day treatment courses of dihydroartemisinin-piperaquine are best avoided until the clinical significance of these findings are more thoroughly evaluated. Because ECG monitoring is seldom available in endemic areas, repolarization risk could be mitigated by using conventional three-day regimens, fasting, and avoidance of repeated dosing or co-administration with other QT-prolonging medications.ClinicalTrials.gov identifier NCT01624337.
- Independent data monitoring committees: Preparing a path for the future. [Journal Article]
- Am Heart J 2014 Aug; 168(2):135-141.e1.
Independent data monitoring committees (IDMCs) were introduced to monitor patient safety and study conduct in randomized clinical trials (RCTs), but certain challenges regarding the utilization of IDMCs have developed. First, the roles and responsibilities of IDMCs are expanding, perhaps due to increasing trial complexity and heterogeneity regarding medical, ethical, legal, regulatory, and financial issues. Second, no standard for IDMC operating procedures exists, and there is uncertainty about who should determine standards and whether standards should vary with trial size and design. Third, considerable variability in communication pathways exist across IDMC interfaces with regulatory agencies, academic coordinating centers, and sponsors. Finally, there has been a substantial increase in the number of RCTs using IDMCs, yet there is no set of qualifications to help guide the training and development of the next generation of IDMC members. Recently, an expert panel of representatives from government, industry, and academia assembled at the Duke Clinical Research Institute to address these challenges and to develop recommendations for the future utilization of IDMCs in RCTs.
- Safety and effectiveness of the INCRAFT AAA Stent Graft for endovascular repair of abdominal aortic aneurysms. [JOURNAL ARTICLE]
- J Vasc Surg 2014 Jul 19.
This study evaluated the 2-year safety and effectiveness of the European First-in-Human INNOVATION trial for the INCRAFT AAA Stent Graft system (Cordis Corp, Bridgewater, NJ), an ultra-low-profile device for the treatment of abdominal aortic aneurysms.From March 2010 to June 2011, the INNOVATION prospective multicenter trial involving six centers in Europe enrolled and treated 60 asymptomatic patients (95% male; mean age, 74.4 ± 6.9 years) with the INCRAFT System. Main inclusion criteria included proximal aortic neck length of 15 mm or more with a diameter up to 27 mm; distal iliac landing zones with a length greater than 10 mm and a diameter between 9 and 18 mm; and aortic bifurcation >18 mm in diameter and access vessels large enough to accept the 14F outer diameter of the delivery system. The primary end point was technical success at 1 month; 2-year safety end points included the absence of device- or procedure-related major adverse events, absence of type I or III endoleaks, and maintenance of device integrity through 2 years of follow-up. Study oversight was provided by a Data Safety Monitoring Board with event adjudication by a Clinical Events Committee and imaging analysis by an independent core laboratory.Of 60 successfully treated patients, two did not come back for their 1-month evaluation but remained enrolled in the study; 56 were evaluated at 1 year and 52 at 2 years. Of the 58 patients, 56 met the 1-month primary safety and effectiveness end point (97%; 95% confidence interval, 88%-100%). All patients were free from aneurysm enlargement through 2 years. There were no type I or III endoleaks at the 2-year time point. All-cause mortality at 2 years was 11.5%, and no death was device or procedure related. In total, three patients required a postprocedure intervention, two to repair a type I endoleak and one for limb occlusion. Core laboratory evaluation of the postoperative imaging studies documented absence of endograft migration and stent fractures in all patients.The INCRAFT AAA Stent Graft System provides a durable solution for patients with abdominal aortic aneurysms, with a low frequency of device-related events through 2 years of follow-up.
- Sildenafil does not improve cardiomyopathy in Duchenne/Becker muscular dystrophy. [JOURNAL ARTICLE]
- Ann Neurol 2014 Jul 4.
Objective: Duchenne and Becker muscular dystrophy (DBMD) are allelic disorders caused by mutations in dystrophin. Adults with DBMD develop life-threatening cardiomyopathy. Inhibition of phosphodiesterase 5 (PDE5) improves cardiac function in mouse models of DBMD. To determine if the PDE5-inhibitor sildenafil benefits human dystrophinopathy, we conducted a randomized, double-blind, placebo-controlled trial (ClinicalTrials.gov, number NCT01168908). Methods: Adults with DBMD and cardiomyopathy (ejection fraction ≤50%) were randomized to receive sildenafil (20mg three times daily) or placebo for 6 months. All subjects received an additional 6 months of open-label sildenafil. The primary endpoint was change in left ventricular end-systolic volume (LVESV) on cardiac MRI. Secondary cardiac endpoints, skeletal muscle function, and quality of life were also assessed. Results: An interim analysis (performed after 15 subjects completed the blinded phase) revealed that 29% (4/14) of subjects had a ≥10% increase in LVESV after 6 months of sildenafil compared to 13% (1/8) of subjects receiving placebo. Subjects with LVESV >120ml at baseline were more likely to worsen at 12 months regardless of treatment assignment (p=0.035). Due to the higher number of subjects worsening on sildenafil, the Data and Safety Monitoring Board recommended early termination of the study. There were no statistically significant differences in outcome measures between treatment arms. Interpretation: Due to the small sample size, comparisons between groups must be interpreted with caution. However, this trial suggests that sildenafil is unlikely to improve cardiac function in adults with DBMD. ANN NEUROL 2014. © 2014 American Neurological Association.
- Blood pressure and LDL-cholesterol targets for prevention of recurrent strokes and cognitive decline in the hypertensive patient: design of the European Society of Hypertension-Chinese Hypertension League Stroke in Hypertension Optimal Treatment randomized trial. [JOURNAL ARTICLE]
- J Hypertens 2014 Jun 27.
The SBP values to be achieved by antihypertensive therapy in order to maximize reduction of cardiovascular outcomes are unknown; neither is it clear whether in patients with a previous cardiovascular event, the optimal values are lower than in the low-to-moderate risk hypertensive patients, or a more cautious blood pressure (BP) reduction should be obtained. Because of the uncertainty whether 'the lower the better' or the 'J-curve' hypothesis is correct, the European Society of Hypertension and the Chinese Hypertension League have promoted a randomized trial comparing antihypertensive treatment strategies aiming at three different SBP targets in hypertensive patients with a recent stroke or transient ischaemic attack. As the optimal level of low-density lipoprotein cholesterol (LDL-C) level is also unknown in these patients, LDL-C-lowering has been included in the design.The European Society of Hypertension-Chinese Hypertension League Stroke in Hypertension Optimal Treatment trial is a prospective multinational, randomized trial with a 3 × 2 factorial design comparing: three different SBP targets (1, <145-135; 2, <135-125; 3, <125 mmHg); two different LDL-C targets (target A, 2.8-1.8; target B, <1.8 mmol/l). The trial is to be conducted on 7500 patients aged at least 65 years (2500 in Europe, 5000 in China) with hypertension and a stroke or transient ischaemic attack 1-6 months before randomization. Antihypertensive and statin treatments will be initiated or modified using suitable registered agents chosen by the investigators, in order to maintain patients within the randomized SBP and LDL-C windows. All patients will be followed up every 3 months for BP and every 6 months for LDL-C. Ambulatory BP will be measured yearly.Primary outcome is time to stroke (fatal and non-fatal). Important secondary outcomes are: time to first major cardiovascular event; cognitive decline (Montreal Cognitive Assessment) and dementia. All major outcomes will be adjudicated by committees blind to randomized allocation. A Data and Safety Monitoring Board has open access to data and can recommend trial interruption for safety.It has been calculated that 925 patients would reach the primary outcome after a mean 4-year follow-up, and this should provide at least 80% power to detect a 25% stroke difference between SBP targets and a 20% difference between LDL-C targets.
- Analysis of warning letters issued by the US Food and Drug Administration to clinical investigators, institutional review boards and sponsors: a retrospective study. [JOURNAL ARTICLE]
- J Med Ethics 2014 Jun 25.
The US Food and Drug Administration (FDA) issues warning letters to all research stakeholders if unacceptable deficiencies are found during site visits. Warning letters issued by the FDA between January 2011 and December 2012 to clinical investigators and institutional review boards (IRBs) were reviewed for various violation themes and compared to similar studies in the past. Warning letters issued to sponsors between January 2005 and December 2012 were analysed for the first time for a specific set of violations using descriptive statistics. Failure to protect subject safety and to report adverse events to IRBs was found to be significant compared to prior studies for clinical investigators, while failure to follow standard operating procedures and maintain documentation was noted as significant in warning letters to IRBs. Failure to maintain minutes of meeting and to follow written procedures for continuing review were new substantial violations in warning letters issued to IRBs. Forty-six warning letters were issued to sponsors, the most common violations being failure to follow a monitoring schedule (58.69%), failure to obtain investigator agreement (34.78%), failure to secure investigators' compliance (30.43%), and failure to maintain data records and ship documents to investigators (30.43%). Appropriate methods for handling clinical trial procedural violations should be developed and implemented worldwide.
- FluMum: a prospective cohort study of mother-infant pairs assessing the effectiveness of maternal influenza vaccination in prevention of influenza in early infancy. [Journal Article]
- BMJ Open 2014; 4(6):e005676.
Influenza vaccination in pregnancy is recommended for all women in Australia, particularly those who will be in their second or third trimester during the influenza season. However, there has been no systematic monitoring of influenza vaccine uptake among pregnant women in Australia. Evidence is emerging of benefit to the infant with respect to preventing influenza infection in the first 6 months of life. The FluMum study aims to systematically monitor influenza vaccine uptake during pregnancy in Australia and determine the effectiveness of maternal vaccination in preventing laboratory-confirmed influenza in their offspring up to 6 months of age.A prospective cohort study of 10 106 mother-infant pairs recruited between 38 weeks gestation and 55 days postdelivery in six Australian capital cities. Detailed maternal and infant information is collected at enrolment, including influenza illness and vaccination history with a follow-up data collection time point at infant age 6 months. The primary outcome is laboratory-confirmed influenza in the infant. Case ascertainment occurs through searches of Australian notifiable diseases data sets once the infant turns 6 months of age (with parental consent). The primary analysis involves calculating vaccine effectiveness against laboratory-confirmed influenza by comparing the incidence of influenza in infants of vaccinated mothers to the incidence in infants of unvaccinated mothers. Secondary analyses include annual and pooled estimates of the proportion of mothers vaccinated during pregnancy, the effectiveness of maternal vaccination in preventing hospitalisation for acute respiratory illness and modelling to assess the determinants of vaccination.The study was approved by all institutional Human Research Ethics Committees responsible for participating sites. Study findings will be published in peer review journals and presented at national and international conferences.The study is registered with the Australia and New Zealand Clinical Trials Registry (ANZCTR) number: 12612000175875.