A pragmatic, adaptive clinical trial design for a rare disease: The FOcal Cerebral Arteriopathy Steroid (FOCAS) trial.

BACKGROUND:Pediatric stroke investigators identified as their top research priority a clinical trial of corticosteroids for focal cerebral arteriopathy (FCA). However, FCA is both rare and an acute condition making it infeasible to enroll the large sample sizes needed for standard, confirmatory clinical trials. We present a pragmatic approach to clinical trial design that may inform the approach to other rare disorders. METHODS:We surveyed pediatric stroke experts to determine the level of evidence that would impact their clinical management of FCA. Incorporating survey results, a randomized, group sequential Bayesian adaptive design was proposed based on a quantitative radiologic outcome measure (change from baseline in change in the FCA Severity Score). Using accumulating information, the design determines whether intervention is better than control with high probability. RESULTS:Among 21 (100%) respondents, the probability of corticosteroid efficacy that would lead the experts to treat was 30% (median). The probability of efficacy that would make them unwilling to randomize (because they would feel all children should receive corticosteroids) was 70%. Simulation studies with the proposed design showed that a total of 42 subjects controls the type I error rate at the desired level 0.20 and yields a smaller average sample size and trial duration compared to a conventional design. CONCLUSIONS:Designs in rare diseases require special considerations; this is especially true for this childhood disease, which is both uncommon and acute. This design has incorporated expert consensus to establish the criteria for success, formal monitoring rules for safety, and early stopping rules

Flexible Analytical Methods for Adding a Treatment Arm Mid-Study to an Ongoing Clinical Trial

It is not uncommon to have experimental drugs under different stages of development for a given disease area. Methods are proposed for use when another treatment arm is to be added mid-study to an ongoing clinical trial. Monte Carlo simulation was used to compare potential analytical approaches for pairwise comparisons through a difference in means in independent normal populations including 1.) a linear model adjusting for the design change (stage effect), 2.) pooling data across the stages, or 3.) the use of an adaptive combination test. In the presence of intra-stage correlation (or a non-ignorable fixed stage effect), simply pooling the data will result in a loss of power and will inflate the type I error rate. The linear model approach is more powerful, but the adaptive methods allow for flexibility (re-estimating sample size). The flexibility to add a treatment arm to an ongoing trial may result in cost savings as treatments that become ready for testing can be added to ongoing studies

Platelet‐Oriented Inhibition in New TIA and Minor Ischemic Stroke ( POINT ) Trial: Rationale and design

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/99014/1/ijs12129.pd

Clopidogrel and Aspirin in Acute Ischemic Stroke and High-Risk TIA.

BACKGROUND—Combination antiplatelet therapy with clopidogrel and aspirin may reduce the rate of recurrent stroke during the first 3 months after a minor ischemic stroke or transient ischemic attack (TIA). A trial of combination antiplatelet therapy in a Chinese population has shown a reduction in the risk of recurrent stroke. We tested this combination in an international population. METHODS—In a randomized trial, we assigned patients with minor ischemic stroke or high-risk TIA to receive either clopidogrel at a loading dose of 600 mg on day 1, followed by 75 mg per day, plus aspirin (at a dose of 50 to 325 mg per day) or the same range of doses of aspirin alone. The dose of aspirin in each group was selected by the site investigator. The primary efficacy outcome in a time-to-event analysis was the risk of a composite of major ischemic events, which was defined as ischemic stroke, myocardial infarction, or death from an ischemic vascular event, at 90 days. RESULTS—A total of 4881 patients were enrolled at 269 international sites. The trial was halted after 84% of the anticipated number of patients had been enrolled because the data and safety monitoring board had determined that the combination of clopidogrel and aspirin was associated with both a lower risk of major ischemic events and a higher risk of major hemorrhage than aspirin alone at 90 days. Major ischemic events occurred in 121 of 2432 patients (5.0%) receiving clopidogrel plus aspirin and in 160 of 2449 patients (6.5%) receiving aspirin plus placebo (hazard ratio, 0.75; 95% confidence interval [CI], 0.59 to 0.95; P = 0.02), with most events occurring during the first week after the initial event. Major hemorrhage occurred in 23 patients (0.9%) receiving clopidogrel plus aspirin and in 10 patients (0.4%) receiving aspirin plus placebo (hazard ratio, 2.32; 95% CI, 1.10 to 4.87; P = 0.02). CONCLUSIONS—In patients with minor ischemic stroke or high-risk TIA, those who received a combination of clopidogrel and aspirin had a lower risk of major ischemic events but a higher risk of major hemorrhage at 90 days than those who received aspirin alone. (Funded by the National Institute of Neurological Disorders and Stroke; POINT ClinicalTrials.gov number, NCT00991029.

Sex Differences in Clinical Features of Early, Treated Parkinson\u27s Disease

INTRODUCTION: To improve our understanding of sex differences in the clinical characteristics of Parkinson\u27s Disease, we sought to examine differences in the clinical features and disease severity of men and women with early treated Parkinson\u27s Disease (PD) enrolled in a large-scale clinical trial. METHODS: Analysis was performed of baseline data from the National Institutes of Health Exploratory Trials in Parkinson\u27s Disease (NET-PD) Long-term Study-1, a randomized, multi-center, double-blind, placebo-controlled study of 10 grams of oral creatine/day in individuals with early, treated PD. We compared mean age at symptom onset, age at PD diagnosis, and age at randomization between men and women using t-test statistics. Sex differences in clinical features were evaluated, including: symptoms at diagnosis (motor) and symptoms at randomization (motor, non-motor, and daily functioning). RESULTS: 1,741 participants were enrolled (62.5% male). No differences were detected in mean age at PD onset, age at PD diagnosis, age at randomization, motor symptoms, or daily functioning between men and women. Differences in non-motor symptoms were observed, with women demonstrating better performance compared to men on SCOPA-COG (Z = 5.064, p\u3c0.0001) and Symbol Digit Modality measures (Z = 5.221, p\u3c0.0001). CONCLUSIONS: Overall, men and women did not demonstrate differences in clinical motor features early in the course of PD. However, the differences observed in non-motor cognitive symptoms suggests further assessment of the influence of sex on non-motor symptoms in later stages of PD is warranted

Cilostazol for Secondary Stroke Prevention: History, Evidence, Limitations, and Possibilities

Cilostazol is a phosphodiesterase III inhibitor with a long track record of safety that is FDA and EMA approved for the treatment of claudication in patients with peripheral arterial disease. In addition, cilostazol has been approved for secondary stroke prevention in several Asian countries based on trials that have demonstrated a reduction in stroke recurrence among patients with non-cardioembolic stroke. The onset of benefit appears after 60–90 days of treatment, which is consistent with cilostazol’s pleiotropic effects on platelet aggregation, vascular remodeling, blood flow, and plasma lipids. Cilostazol appears safe and does not increase the risk of major bleeding when given alone or in combination with aspirin or clopidogrel. Adverse effects such as headache, gastrointestinal symptoms and palpitations, however, contributed to a 6% increase in drug discontinuation among patients randomized to cilostazol in a large secondary stroke prevention trial (CSPS.com). Due to limitations of prior trials, such as open label design, premature trial termination, large loss to follow-up, lack of functional or cognitive outcome data, and exclusive enrollment in Asia, the existing trials have not led to a change in clinical practice or guidelines in Western countries. These limitations could be addressed by a double-blind placebo-controlled randomized trial conducted in a broader population. If positive, it would increase the evidence in support of long-term treatment with cilostazol for secondary prevention in the millions of patients worldwide who have suffered a non-cardioembolic ischemic stroke

Does a PBL-based medical curriculum predispose training in specific career paths? A systematic review of the literature

Background North American medical schools have used problem-based learning (PBL) structured medical education for more than 60 years. However, it has only recently been introduced in other medical schools outside of North America. Since its inception, there has been the debate on whether the PBL learning process predisposes students to select certain career paths. Objectives To review available evidence to determine the predisposition of specific career paths when undertaking a PBL-based medical curriculum. The career path trajectory was determined as measured by official Matching Programs, self-reported questionnaires and surveys, and formally defined career development milestones. Methods A systematic literature review was performed. PubMed, Medline, Cochrane and ERIC databases were analysed in addition to reference lists for appropriate inclusion. Results Eleven studies fitting the inclusion criteria were identified. The majority of studies showed that PBL did not predispose a student to a career in a specific speciality (n = 7 out of 11 studies, 64%). However, three studies reported a significantly increased number of PBL graduates working in primary care compared to those from a non-PBL curriculum. Conclusions PBL has been shown not to predispose medical students to a career in General Practice or any other speciality. Furthermore, a greater number of similar studies are required before a definitive conclusion can be made in the future

Route and duration of antibiotic therapy in acute cellulitis: a systematic review and meta-analysis of the effectiveness and harms of antibiotic treatment

Objectives Compared with guideline recommendations, antibiotic overuse is common in treating cellulitis. We conducted a systematic review and meta-analyses on antibiotic route and duration of treatment for cellulitis in adults and children. Methods We searched MEDLINE, EMBASE and trial registries from inception to Dec 11, 2019 for interventional and observational studies of antibiotic treatment for cellulitis. Exclusions included case series/reports, pre-septal/orbital cellulitis and non-English language articles. Random-effects meta-analyses were used to produce summary relative risk (RR) estimates for our primary outcome of clinical response. PROSPERO CRD42018100602. Results We included 47/8423 articles, incorporating data from eleven trials (1855 patients) in two meta-analyses. The overall risk of bias was moderate. Only two trials compared the same antibiotic agent in each group. We found no evidence of difference in clinical response rates for antibiotic route or duration (RR(oral:IV)=1.12, 95%CI 0.98–1.27, I 2=32% and RR(shorter:longer)=0.99, 95%CI 0•96–1.03, I 2 = 0%, respectively). Findings were consistent in observational studies. Follow-up data beyond 30 days were sparse. Conclusions The evidence base for antibiotic treatment decisions in cellulitis is flawed by biased comparisons, short follow-up and lack of data around harms of antibiotic overuse. Future research should focus on developing patient-tailored antibiotic prescribing for cellulitis to reduce unnecessary antibiotic use

Design innovations and baseline findings in a long-term Parkinson's trial: the National Institute of Neurological Disorders and Stroke Exploratory Trials in Parkinson's Disease Long-Term Study-1

Based on the preclinical data and the results of a phase II futility study, creatine was selected for an efficacy trial in Parkinson's disease (PD). We present the design rationale and a description of the study cohort at baseline. A randomized, multicenter, double-blind, parallel-group, placebo-controlled phase III study of creatine (10 g daily) in participants with early, treated PD, the Long-term Study-1 (LS-1), is being conducted by the National Institute of Neurological Disorders and Stroke Exploratory Trials in Parkinson's Disease network. The study utilizes a global statistical test (GST) encompassing five clinical rating scales to provide a multidimensional assessment of disease progression. A total of 1,741 PD participants from 45 sites in the United States and Canada were randomized 1:1 to either 10 g of creatine/day or matching placebo. Participants are being evaluated for a minimum of 5 years. The LS-1 baseline cohort includes participants treated with dopaminergic therapy and generally mild PD. LS-1 represents the largest cohort of patients with early treated PD ever enrolled in a clinical trial. The GST approach should provide high power to test the hypothesis that daily administration of creatine (10 g/day) is more effective than placebo in slowing clinical decline in PD between baseline and the 5-year follow-up visit against the background of dopaminergic therapy and best PD care

A pragmatic, adaptive clinical trial design for a rare disease: The FOcal Cerebral Arteriopathy Steroid (FOCAS) trial.

BACKGROUND:Pediatric stroke investigators identified as their top research priority a clinical trial of corticosteroids for focal cerebral arteriopathy (FCA). However, FCA is both rare and an acute condition making it infeasible to enroll the large sample sizes needed for standard, confirmatory clinical trials. We present a pragmatic approach to clinical trial design that may inform the approach to other rare disorders. METHODS:We surveyed pediatric stroke experts to determine the level of evidence that would impact their clinical management of FCA. Incorporating survey results, a randomized, group sequential Bayesian adaptive design was proposed based on a quantitative radiologic outcome measure (change from baseline in change in the FCA Severity Score). Using accumulating information, the design determines whether intervention is better than control with high probability. RESULTS:Among 21 (100%) respondents, the probability of corticosteroid efficacy that would lead the experts to treat was 30% (median). The probability of efficacy that would make them unwilling to randomize (because they would feel all children should receive corticosteroids) was 70%. Simulation studies with the proposed design showed that a total of 42 subjects controls the type I error rate at the desired level 0.20 and yields a smaller average sample size and trial duration compared to a conventional design. CONCLUSIONS:Designs in rare diseases require special considerations; this is especially true for this childhood disease, which is both uncommon and acute. This design has incorporated expert consensus to establish the criteria for success, formal monitoring rules for safety, and early stopping rules