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

<b><i>Introduction:</i></b> 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. <b><i>Methods:</i></b> 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 <i>Pneumocystis jirovecii</i> pneumonia during the first 12 weeks of treatment. <b><i>Results:</i></b> 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. <b><i>Conclusions:</i></b> 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：尽管目前已采用最优临床诊疗方案，仍有高达30%的免疫球蛋白A肾病（immunoglobulin A nephropathy, IgAN）患者会进展为需接受透析或肾移植的肾衰竭。IgA肾病全球糖皮质激素治疗评估（TESTING）研究旨在评估糖皮质激素用于IgAN患者的获益与风险。本研究现将该试验的设计方案及研究受试者的基线特征进行报道。
方法：本研究为研究者发起的多中心、双盲、安慰剂对照随机试验，纳入经肾活检确诊的IgAN患者，且满足每日蛋白尿≥1 g、估算肾小球滤过率（estimated glomerular filtration rate, eGFR）为20~120 mL/min/1.73 m²，同时受试者已接受至少3个月的标准治疗，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治疗。原始研究方案将受试者按1:1比例随机分配至口服甲泼尼龙组（0.6~0.8 mg/kg/日，最大剂量48 mg/日），治疗2个月后以每月8 mg的幅度减量，总减量周期为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，试验方案进行调整：改为低剂量甲泼尼龙组（0.4 mg/kg/日，最大剂量32 mg/日）治疗2个月后，以每月4 mg的幅度减量，总减量周期为6~9个月，或匹配安慰剂组。2016年后入组的受试者还需在治疗前12周接受耶氏肺孢子菌肺炎（Pneumocystis jirovecii pneumonia）的预防性治疗。
结果：本研究的招募周期为2012年5月至2019年11月。在发现严重感染发生率过高时，已有262名受试者被随机分配至原始全剂量治疗方案组，并于2016年完成中期分析（interim analysis）。此后，另有241名受试者被随机分配至调整后的低剂量方案组，最终共纳入来自中国（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。随机入组受试者的平均年龄为38岁，女性占比39%，随机入组时的平均eGFR为62.7 mL/min/1.73 m²，24小时尿蛋白平均水平为2.54 g。本研究的主要终点为复合终点，包括较基线eGFR下降40%或肾衰竭（透析、肾移植或肾病相关死亡）；受试者将被随访至至少160名随机入组受试者出现主要终点事件。同时将按照预设亚组进行分析，并整体评估糖皮质激素给药方案对eGFR变化斜率与白蛋白尿的影响。
结论：TESTING研究（整合全剂量与低剂量方案数据）将明确糖皮质激素治疗对高危IgAN患者主要肾脏结局的获益与治疗风险，并提供不同给药剂量的相对疗效数据。