Kang Minhee, Marks Kristen M, Cox Andrea L, Sherman Kenneth E
Center for Biostatistics in AIDS Research in the Department of Biostatistics, Harvard T.H. Chan School of Public Health, 651 Huntington Ave, Boston, MA 02115, USA.
Division of Infectious Diseases, Weill Cornell Medicine, 525 East 68th Street, New York, NY 10065, USA.
Vaccine. 2025 May 10;55:127028. doi: 10.1016/j.vaccine.2025.127028. Epub 2025 Mar 26.
Clinical trial designs that address multiple questions more efficiently are desirable. When we designed a hepatitis B vaccine trial to assess seroprotective outcomes in persons with HIV (PWH), we aimed for an efficient design that addressed three primary objectives in two study populations. The study focused on: PWH who did not respond to prior HBV vaccination, and PWH with no known history of HBV vaccination. Whereas one vaccine regimen was studied in the vaccine-naïve participants, multiple interventions were considered for those with prior nonresponse, with two different vaccines and two dosing schedules. Several features of the trial design required statistical considerations related to multiple testing: (1) assessment of vaccine response in two study populations under one trial, (2) comparisons among multiple treatment arms, and (3) sequential repeated significance tests in interim data monitoring. We describe the features aimed to gain statistical and administrative efficiencies, including reduction in the study sample size of 12 %. We also describe how we controlled type I error and planned interim data monitoring, and highlight the time lag issue due to the laboratory-based immunogenicity endpoint in this international, multi-center trial (NCT04193189).
更高效地解决多个问题的临床试验设计是很有必要的。当我们设计一项乙型肝炎疫苗试验以评估艾滋病毒感染者（PWH）的血清保护结果时，我们旨在设计一种高效的试验，在两个研究人群中实现三个主要目标。该研究聚焦于：对先前乙肝疫苗接种无反应的艾滋病毒感染者，以及无乙肝疫苗接种史的艾滋病毒感染者。在未接种过疫苗的参与者中研究了一种疫苗方案，而对于先前无反应者则考虑了多种干预措施，包括两种不同的疫苗和两种给药方案。试验设计的几个特点需要进行与多重检验相关的统计考量：（1）在一项试验中对两个研究人群的疫苗反应进行评估；（2）多个治疗组之间的比较；（3）在中期数据监测中进行序贯重复显著性检验。我们描述了旨在提高统计和管理效率的特点，包括将研究样本量减少12%。我们还描述了我们如何控制I型错误并计划中期数据监测，并强调了在这项国际多中心试验（NCT04193189）中由于基于实验室的免疫原性终点导致的时间滞后问题。
