Clinical trials : journal of the Society for Clinical Trials
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The COVID-19 pandemic has highlighted the challenges of evidence-based health policymaking, as critical precautionary decisions, such as school closures, had to be made urgently on the basis of little evidence. As primary and secondary schools once again close in the face of surging infections, there is an opportunity to rigorously study their reopening. ⋯ But when and how can they be reopened safely? We argue that a cluster randomized trial is a rigorous and ethical way to resolve these uncertainties. We discuss key scientific, ethical, and resource considerations both to inform trial design of school reopenings and to prompt discussion of the merits and feasibility of conducting such a trial.
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Given the extent of osteoporosis in people with Duchenne muscular dystrophy treated with glucocorticoids and the limited evidence of bone-protective therapies, clinical trials are needed. We conducted surveys to obtain the opinion of young people with Duchenne muscular dystrophy, parents/guardians and neuromuscular clinicians on the feasibility of osteoporosis clinical trials in this population. ⋯ There is great awareness of bone health and the need for bone-protective trials among people with Duchenne muscular dystrophy and their carers. However, a proportion of people with Duchenne muscular dystrophy and parents are reluctant to participate in a placebo-controlled osteoporosis trial that included a parenteral therapy. A larger proportion of health care experts are unwilling to enrol their patients in such a trial. Our finding is relevant for the design of bone-protective studies in Duchenne muscular dystrophy.
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Endpoint choice for randomized controlled trials of treatments for novel coronavirus-induced disease (COVID-19) is complex. Trials must start rapidly to identify treatments that can be used as part of the outbreak response, in the midst of considerable uncertainty and limited information. COVID-19 presentation is heterogeneous, ranging from mild disease that improves within days to critical disease that can last weeks to over a month and can end in death. While improvement in mortality would provide unquestionable evidence about the clinical significance of a treatment, sample sizes for a study evaluating mortality are large and may be impractical, particularly given a multitude of putative therapies to evaluate. Furthermore, patient states in between "cure" and "death" represent meaningful distinctions. Clinical severity scores have been proposed as an alternative. However, the appropriate summary measure for severity scores has been the subject of debate, particularly given the variable time course of COVID-19. Outcomes measured at fixed time points, such as a comparison of severity scores between treatment and control at day 14, may risk missing the time of clinical benefit. An endpoint such as time to improvement (or recovery) avoids the timing problem. However, some have argued that power losses will result from reducing the ordinal scale to a binary state of "recovered" versus "not recovered." ⋯ Time-to-event analysis methods have advantages in the COVID-19 setting, unless the optimal time for evaluating treatment effect is known in advance. Even when the optimal time is known, a time-to-event approach may increase power for interim analyses.
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In oncology, new combined treatments make it difficult to order dose levels according to monotonically increasing toxicity. New flexible dose-finding designs that take into account uncertainty in dose levels ordering were compared with classical designs through simulations in the setting of the monotonicity assumption violation. We give recommendations for the choice of dose-finding design. ⋯ Innovative oncology treatments may no longer follow monotonic dose levels ordering which makes standard phase I methods fail. In such a setting, appropriate designs, as the No Monotonicity Assumption or Partial Ordering Continual Reassessment Method designs, should be used to safely determine recommended for phase II dose.
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Randomized Controlled Trial Multicenter Study
Anti-Thrombotic Therapy to Ameliorate Complications of COVID-19 (ATTACC): Study design and methodology for an international, adaptive Bayesian randomized controlled trial.
Mortality from COVID-19 is high among hospitalized patients and effective therapeutics are lacking. Hypercoagulability, thrombosis and hyperinflammation occur in COVID-19 and may contribute to severe complications. Therapeutic anticoagulation may improve clinical outcomes through anti-thrombotic, anti-inflammatory and anti-viral mechanisms. Our primary objective is to evaluate whether therapeutic-dose anticoagulation with low-molecular-weight heparin or unfractionated heparin prevents mechanical ventilation and/or death in patients hospitalized with COVID-19 compared to usual care. ⋯ Using an adaptive trial design, the Anti-Thrombotic Therapy To Ameliorate Complications of COVID-19 trial will establish whether therapeutic anticoagulation can reduce mortality and/or avoid the need for mechanical ventilation in patients hospitalized with COVID-19. Leveraging existing networks to recruit sites will increase enrollment and mitigate enrollment risk in sites with declining COVID-19 cases.