Supplementary Material for: Statistical Analysis Plan for the INTEnsive Care Bundle with Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial: A Stepped-Wedge Cluster Randomized Controlled Trial

The third INTEnsive care bundle with blood pressure Reduction in Acute Cerebral hemorrhage Trial (INTERACT3) is an international, multicenter, stepped-wedge (4 phases/3 steps) cluster randomized trial involving 110 hospitals in mainly low- and middle-income countries during 2017–2022. The aim is to determine the effectiveness of a goal-directed care bundle of intensive blood pressure (BP) lowering, glycemic control, antipyrexia, and anticoagulation reversal treatment versus usual standard of care, in patients with acute intracerebral hemorrhage (ICH). After a “usual care” period, hospitals were randomly allocated to implementing care-bundle protocols for control targets (systolic BP <140 mm Hg; glucose 6.1–7.8/7.8–10.0 mmol/L according to diabetes mellitus status; temperature ≤37.5°C; normalization of anticoagulation). A sample size of 8,360 patients (mean 19 per phase per site) provides 90% power (α = 0.05) for a 5.6% absolute improvement in the primary outcome of scores on the modified Rankin scale at 6 months, analyzed by ordinal logistic regression. A detailed statistical analysis plan (SAP) was developed to prespecify the method of analysis for all outcomes and key variables collected in the trial. The primary analysis will use ordinal logistic regression adjusted for the stepped-wedge design. The SAP also includes planned sensitivity analyses, including covariate adjustments, missing data imputations, and subgroup analysis. This SAP allows transparent, verifiable, and prespecified analyses in consideration of the challenges in conducting the study during the COVID pandemic. It also avoids analysis bias arising from prior knowledge of the findings in determining the benefits and harms of a care bundle in acute ICH.

急性脑出血强化降压集束化干预第三阶段临床试验（INTERACT3）是一项国际多中心、阶梯式楔形设计（stepped-wedge design）整群随机试验（cluster randomized trial），于2017-2022年在以中低收入国家为主的110家医院开展。本研究旨在明确针对急性脑出血（intracerebral hemorrhage, ICH）患者，以目标为导向的强化血压（blood pressure, BP）降低、血糖控制、退热及抗凝逆转治疗集束化干预方案，相较于常规标准照护的有效性。在“常规照护”阶段结束后，各医院被随机分配至实施针对以下控制目标的集束化干预方案流程：收缩压<140mmHg；血糖水平根据糖尿病患病状态分为6.1~7.8/7.8~10.0mmol/L；体温≤37.5℃；抗凝治疗状态恢复正常。本研究共纳入8360例患者（每个研究阶段每家医院平均19例），当以有序logistic回归（ordinal logistic regression）分析6个月时改良Rankin量表（modified Rankin scale）评分这一主要结局指标时，该样本量可达到90%的检验效能（α=0.05），能够检测出5.6%的绝对改善率。研究团队已制定详细的统计分析计划（statistical analysis plan, SAP），预先明确本试验所有结局指标及采集的关键变量的分析方法。主要分析将采用针对阶梯式楔形设计（stepped-wedge design）进行校正的有序logistic回归（ordinal logistic regression）模型。该统计分析计划还包含预设的敏感性分析，包括协变量校正、缺失数据插补及亚组分析。鉴于新冠疫情期间开展本研究面临的诸多挑战，该统计分析计划可确保分析过程透明、可验证且预先设定。同时，该计划可避免因预先知晓研究结果而产生的分析偏倚，从而客观评估急性脑出血集束化干预方案的获益与风险。