Center for Drug Clinical Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Front Immunol. 2021 Nov 16;12:783246. doi: 10.3389/fimmu.2021.783246. eCollection 2021.
This study aimed to develop a placebo response model for pharmaceutical clinical trials of primary Sjogren's syndrome,and to quantitatively analyze the distribution and related factors influencing the placebo response to further optimize the design of clinical trials and evaluate the results of single-arm clinical trials. Public databases, including PubMed, Embase, and Cochrane Library were searched for reports on randomized placebo-controlled trials for Sjögren's syndrome which used the change from baseline in ESSDAI score as the primary outcome. The model-based meta-analysis method was used to evaluate the time course and the related influencing factors of the placebo response for ESSDAI in such clinical trials. A virtual placebo control group was constructed based on the final placebo response model to determine the treatment efficacy of belimumab and cyclosporine A for primary Sjögren's syndrome in a single-arm study. A total of 12 studies involving 450 subjects were included in the analysis. The established model described the time-course characteristics of the changes in ESSDAI score from the baseline in the 48 weeks placebo group. We found that the onset time of placebo response was approximately 12 weeks, and its efficacy plateaued at 48 weeks. The baseline ESSDAI score had a significant effect on the maximum value of the placebo response; the maximum value of the placebo response decreased by 0.552 for every 1 score rise in the baseline ESSDAI score. The efficacy of belimumab and cyclosporine A in the single-arm trial was comparable to that of the placebo response at the same baseline; no significant therapeutic advantage was observed. The placebo response model established in this study could provide a basis for designing clinical trials for primary Sjogren's syndrome in the future. It may also provide a reliable external efficacy control standard for single-arm clinical trials.
本研究旨在为原发性干燥综合征的药物临床试验建立安慰剂反应模型，并定量分析影响安慰剂反应的分布和相关因素，以进一步优化临床试验设计并评估单臂临床试验的结果。检索了 PubMed、Embase 和 Cochrane Library 等公共数据库中报告的使用 ESSDAI 评分从基线变化作为主要结局的原发性干燥综合征随机安慰剂对照试验。使用基于模型的荟萃分析方法评估了此类临床试验中 ESSDAI 的安慰剂反应的时间过程和相关影响因素。基于最终的安慰剂反应模型构建了虚拟安慰剂对照组，以确定贝鲁单抗和环孢素 A 治疗原发性干燥综合征的单臂研究中的治疗效果。共有 12 项研究涉及 450 名受试者被纳入分析。所建立的模型描述了 48 周安慰剂组中 ESSDAI 评分从基线变化的时间过程特征。我们发现安慰剂反应的起始时间约为 12 周，其疗效在 48 周时达到平台期。基线 ESSDAI 评分对安慰剂反应的最大值有显著影响；基线 ESSDAI 评分每升高 1 分，安慰剂反应的最大值下降 0.552。在单臂试验中，贝鲁单抗和环孢素 A 的疗效与相同基线时的安慰剂反应相当；未观察到明显的治疗优势。本研究建立的安慰剂反应模型可为未来原发性干燥综合征的临床试验设计提供依据，也可为单臂临床试验提供可靠的外部疗效对照标准。
