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Statistical methods for clinical trials of novel PrEP agents

新型 PrEP 药物临床试验的统计方法

基本信息

批准号：
10241934
负责人：
DAVID V. GLIDDEN
金额：
$ 12.11万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-24 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10241934
关键词：
Adherence Adopted Anti-Retroviral Agents Attitude Back Biological Characteristics Clinical Trials Comparison arm Contraceptive methods Controlled Study Data Decision Aid Development Ethics Future HIV HIV Infections HIV Seronegativity HIV risk Implant Incidence Infusion procedures Injectable Injections Lead Methods Modeling Modernization Oral Persons Pharmaceutical Preparations Pharmacology Phase Placebos Population Prevention Randomized Controlled Trials Research Risk Safety Sample Size Specific qualifier value Statistical Methods Subgroup Surveys System Tenofovir Time Weight arm clinical trial analysis cost effectiveness trial emtricitabine flexibility hazard innovation insight microbicide next generation novel pill pre-exposure prophylaxis prevent randomized trial shared decision making software development success tool trial design truvada uptake

项目摘要

PROJECT SUMMARY HIV pre-exposure prophylaxis (PrEP) with co-formulated emtricitabine tenofovir (TDF/FTC) in HIV negative persons is safe and effective for preventing HIV infection. Despite notable successes, PrEP has important limitations as a broad prevention tool. Some people who would benefit from PrEP refuse it or are poorly adherent. Surveys indicate that many of those at risk for HIV believe that daily oral TDF/FTC to be difficult to adhere to or unappealing and would be prefer a non-oral alternative. This has also been shown to be true in contraception. To maximize the benefits of biomedical prevention, we need alternatives to oral TDF/FTC. There is a robust pipeline of novel PrEP methods (NPM) in development. There are antiretrovirals formulated as injectables, infusions, implantables and microbicides. Some of these have entered phase III randomized trials and others could enter trials over the next 2-4 years. Since PrEP has shown effectiveness, the trials must make some provision for it ethically. For injections and implants, TDF/FTC will likely be a comparator arm and the degree of TDF/FTC adherence in these future studies is very uncertain – greatly complicating the comparison of the two arms. Standard methods lead to long expensive studies which will slow PrEP innovation. We believe can significantly increase power and/or lower the cost of future active-controlled randomized trials. By innovatively using post-baseline TDF/FTC pharmacology, which is well-studied in previous trials, to reconstruct a counterfactual placebo arm. This permits comparisons of the novel PrEP method to putative placebo in both intent to treat (ITT) and as-treated (AT) analyses – gaining substantial insight and statistical efficiency. We will also develop models and methods to understand who will sustain engagement with a NPM but not oral PrEP. By leveraging the well-studied TDF/FTC pharmacology and modern causal inference methods, we will to develop analysis methods and non-inferiority frameworks that allow next generation PrEP trials to be smaller, quicker and more informative.

项目总结联合配方恩曲他滨/替诺福韦对HIV阴性患者的暴露前预防(PrEP) 对于预防艾滋病毒感染，人是安全和有效的。尽管取得了显著的成功，PrEP仍具有重要的限制作为一种广泛的预防工具。一些将从PrEP中受益的人拒绝或很穷追随者。调查表明，许多艾滋病毒高危人群认为，每天口服TDF/FTC很难坚持或不吸引人，最好是非口头的。这一点也被证明是正确的避孕。为了最大限度地发挥生物医学预防的益处，我们需要口服TDF/FTC的替代品。有一系列新的PrEP方法(NPM)正在开发中。已经研制出了抗逆转录病毒药物作为注射剂、输液剂、植入物和杀微生物剂。其中一些已经随机进入第三阶段。试验和其他试验可能在未来2-4年内进入试验阶段。由于PrEP已经显示出有效性，试验必须从道德上为它做一些准备。对于注射和植入，TDF/FTC很可能是一个比较臂和在这些未来的研究中，TDF/FTC的遵守程度是非常不确定的--这使得两只手臂的对比。标准方法会导致长期昂贵的研究，这将减缓PrEP的速度创新。我们相信可以显著增加未来主动对照随机试验的功率和/或降低成本。通过创新性地使用基线后TDF/FTC药理学，这在以前的试验中得到了很好的研究，以重建一个反事实的安慰剂手臂。这允许将新的PrEP方法与假设的安慰剂在意向治疗(ITT)和治疗前(AT)分析中-获得实质性的洞察力和统计效率。我们还将开发模型和方法来了解谁将保持与NPM的接触但不是口服PrEP。通过充分利用TDF/FTC药理学和现代因果推理方法，我们将开发分析方法和非劣势框架，允许下一代PrEP 试验规模更小、速度更快、信息量更大。