Supplementary Material for: The Therapeutic Evaluation of Steroids in IgA Nephropathy Global (TESTING) Study: Trial Design and Baseline Characteristics

Introduction: Despite optimal current care, up to 30% of individuals suffering from immunoglobulin A nephropathy (IgAN) will develop kidney failure requiring dialysis or kidney transplantation. The Therapeutic Evaluation of STeroids in IgA Nephropathy Global (TESTING) study was designed to assess the benefits and risks of steroids in people with IgAN. We report the trial design as well as the baseline characteristics of study participants. Methods: It is an investigator-initiated, multicenter, double-blind, placebo-controlled, randomized trial of individuals with kidney biopsy-confirmed IgAN, proteinuria ≥1 g/day, and an estimated GFR of 20–120 mL/min/1.73 m2, following at least 3 months of standard of care including maximum labelled (or tolerated) dose of renin-angiotensin system blockade. The original study design randomized participants 1:1 to oral methylprednisolone (0.6–0.8 mg/kg/day, maximum 48 mg/day) for 2 months, with subsequent weaning by 8 mg/day/month over 6–8 months, or matching placebo. The intervention was modified in 2016 (due to an excess of serious infection) to low-dose methylprednisolone (0.4 mg/kg/day, maximum 32 mg/day) for 2 months, followed by weaning by 4 mg/day/month over 6–9 months, or matching placebo. Participants recruited after 2016 also received prophylaxis against Pneumocystis jirovecii pneumonia during the first 12 weeks of treatment. Results: The study recruitment period extended from May 2012 to November 2019. By the time the excess of serious infections was observed, 262 participants had been randomized to the original full-dose treatment algorithm, and an interim analysis was reported in 2016. Subsequently, 241 additional participants were randomized to a revised low-dose protocol, for a total of 503 participants from China (373), India (78), Canada (24), Australia (18), and Malaysia (10). The mean age of randomized participants was 38, 39% were female, mean eGFR at randomization was 62.7 mL/min/1.73 m2, and mean 24-h urine protein 2.54 g. The primary endpoint is a composite of 40% eGFR decline from baseline or kidney failure (dialysis, transplantation, or death due to kidney disease), and participants will be followed until the primary outcome has been observed in at least 160 randomized participants. Analyses will also be made across predefined subgroups. Effects on eGFR slope and albuminuria will also be assessed overall, as well as by the steroid dosing regimen. Conclusions: The TESTING study (combined full and low dose) will define the benefits of corticosteroid use on major kidney outcomes, as well as the risks of therapy, and provide data on the relative effects of different doses, in individuals with high-risk IgAN.## 引言 尽管目前已采取最优诊疗方案，仍有高达30%的免疫球蛋白A肾病（immunoglobulin A nephropathy, IgAN）患者会进展为需要透析或肾移植的肾衰竭。IgAN全球糖皮质激素治疗评估（Therapeutic Evaluation of STeroids in IgA Nephropathy Global, TESTING）研究旨在评估糖皮质激素用于IgAN患者的获益与风险。本文报告该试验的设计方案及研究受试者的基线特征。 ## 方法 本研究为研究者发起的多中心、双盲、安慰剂对照、随机对照试验，纳入经肾活检确诊的IgAN患者，且满足尿蛋白≥1 g/天、估算肾小球滤过率（estimated glomerular filtration rate, eGFR）为20~120 mL/min/1.73 m²，受试者需先接受至少3个月的标准诊疗方案，包括最大获批剂量（或可耐受剂量）的肾素-血管紧张素系统阻断剂（renin-angiotensin system blockade, RAS阻断剂）。 原始研究方案按1:1比例将受试者随机分为两组：口服甲泼尼龙组（0.6~0.8 mg/kg/天，最大剂量48 mg/天，疗程2个月，随后以8 mg/天/月的速率减量，总减量周期6~8个月）或匹配安慰剂组。2016年，因观察到严重感染发生率过高，研究方案进行了调整：改为低剂量甲泼尼龙组（0.4 mg/kg/天，最大剂量32 mg/天，疗程2个月，随后以4 mg/天/月的速率减量，总减量周期6~9个月）或匹配安慰剂组。2016年后入组的受试者在治疗前12周还需接受耶氏肺孢子菌肺炎（Pneumocystis jirovecii pneumonia）的预防治疗。 ## 结果 本研究的入组周期为2012年5月至2019年11月。在观察到严重感染发生率过高时，已有262名受试者按原始全剂量治疗方案完成随机分组，研究团队于2016年报告了中期分析结果。随后，又有241名受试者按调整后的低剂量方案完成随机分组，最终本研究共纳入来自中国（373例）、印度（78例）、加拿大（24例）、澳大利亚（18例）及马来西亚（10例）的503名受试者。 随机分组受试者的平均年龄为38岁，女性占比39%；随机分组时的平均eGFR为62.7 mL/min/1.73 m²，平均24小时尿蛋白定量为2.54 g。本研究的主要终点为复合终点：较基线eGFR下降≥40%，或进展为肾衰竭（需透析、肾移植，或因肾病死亡）；受试者将被随访至至少160名随机分组受试者出现主要终点事件。研究还将针对预设亚组进行分析，并整体评估糖皮质激素给药方案对eGFR变化率及白蛋白尿的影响。 ## 结论 TESTING研究（整合全剂量与低剂量方案数据）将明确高风险IgAN患者使用糖皮质激素对主要肾脏结局的获益及治疗风险，并提供不同给药剂量的相对效应数据。