Mathieu Chantal, Wych Julie, Hendriks A Emile J, Van Ryckeghem Lisa, Tree Timothy, Chmura Piotr, Möller Christopher, Casteels Kristina, Danne Thomas, Reschke Felix, Šmigoc Schweiger Darja, Battelino Tadej, Johannesen Jesper, Rami-Merhar Birgit, Pieber Thomas, De Block Christophe, Evans Mark, Hilbrands Robert, Bosi Emanuele, Willemsen Ruben H, Basu Supriyo, Pulkkinen Mari-Anne, Knip Mikael, Cnop Miriam, Nitsche Almut, Schulte Anke M, Niemöller Elisabeth, Peakman Mark, Wilhelm-Benartzi Charlotte, Gillespie David, Overbergh Lut, Mander Adrian P, Marcovecchio M Loredana
Department of Endocrinology, UZ Gasthuisberg, UZ Leuven, Leuven, Belgium; Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium.
Centre for Trials Research College of Biomedical and Life Sciences, Cardiff University, Cardiff, UK.
Lancet. 2025 Sep 27;406(10510):1375-1388. doi: 10.1016/S0140-6736(25)01674-5. Epub 2025 Sep 18.
Type 1 diabetes remains an important health-care problem, with no disease-modifying therapies available in people with recent-onset, clinical type 1 diabetes. Adaptive trial designs, allowing faster evaluation of treatment modalities, remain underexplored in this stage of the disease. We aimed to identify the minimum effective dose of antithymocyte globulin (ATG) in people aged 5-25 years with recent-onset, clinical type 1 diabetes.
MELD-ATG was a phase 2, double-blind, randomised, placebo-controlled, multi-arm, adaptive dose-ranging, parallel-cohort trial done in 14 accredited trial centres in eight countries (the UK, Denmark, Germany, Finland, Italy, Belgium, Austria, and Slovenia). Participants aged 5-25 years, diagnosed with clinical, stage 3 type 1 diabetes 3-9 weeks before treatment, with random C-peptide concentrations 0·2 nmol/L or more and at least one diabetes-related autoantibody (GADA, IA-2A, or ZnT8) were randomly assigned by a web-based randomisation system into seven consecutive cohorts receiving placebo, 2·5 mg/kg ATG, 1·5 mg/kg ATG, 0·5 mg/kg ATG, or 0·1 mg/kg ATG. Participants in cohort 1 were randomly assigned 1:1:1:1:1, participants in cohorts 2 and 3 were randomly assigned 1:1:1:1, and participants in cohorts 4-7 were randomly assigned 1:1:1. All cohorts included one placebo group and one 2·5 mg/kg ATG group. The other groups were assigned to ATG doses that were determined based on accruing data and the decision of the dose determining committee. The trial cohorts were stratified by age group (5-9 years, 10-17 years, and 18-25 years) with block sizes varying by cohort. Concealment lists, outlining the treatment allocation, were only available for the pharmacists; participants and study teams were masked to treatment allocation. ATG was administered by an intravenous infusion over 2 consecutive days. The primary outcome was the area under the curve (AUC) of the stimulated C-peptide concentration during a 2-h mixed-meal tolerance test at 12 months measured as ln(AUC C-peptide + 1). Conditional on finding a statistically significant difference at p<0·05 for 2·5 mg/kg ATG versus placebo, the minimum effective dose of ATG was determined. All randomly assigned participants were included in the primary analysis. All participants who received the study drug were included in the safety analysis. The trial was registered at ClinicalTrials.gov (NCT04509791) and is completed.
Between Nov 24, 2020, and Dec 13, 2023, 152 people were recruited and screened, 117 of whom were randomly assigned (placebo n=31, 0·1 mg/kg ATG n=6, 0·5 mg/kg ATG n=35, 1·5 mg/kg ATG n=12, and 2·5 mg/kg n=33). 54 (46%) of 117 participants were male and 63 (54%) were female. Participants were mainly European. The 0·1 mg/kg dose and the 1·5 mg/kg dose were progressively dropped from the study. At 12 months, the mean ln(AUC C-peptide + 1) was 0·411 nmol/L per min (SD 0·032) in the placebo group and 0·535 nmol/L per min (0·032) in the 2·5 mg/kg ATG group. The mean difference in the ln(AUC C-peptide + 1) between 2·5 mg/kg ATG and placebo was 0·124 nmol/L per min (95% CI 0·043-0·205; p=0·0028). At 12 months, the mean ln(AUC C-peptide + 1) in the 0·5 mg/kg ATG group, the remaining middle dose, was 0·513 nmol/L per min (SD 0·032), with a mean baseline-adjusted difference from placebo of 0·102 nmol/L per min (95% CI 0·021-0·183; p=0·014). Cytokine release syndrome occurred in 11 (33%) of 33 participants in the 2·5 mg/kg ATG group, eight (24%) of 34 in the 0·5mg/kg ATG group, and no participants in the placebo group. Serum sickness occurred in 27 (82%) participants in the 2·5 mg/kg ATG group, 11 (32%) in the 0·5 mg/kg ATG group, and no participants in the placebo group. There were no deaths related to adverse events.
In young people with recent-onset, clinical type 1 diabetes, 2·5 mg/kg and 0·5 mg/kg ATG reduced loss of β-cell function, showing the potential of an affordable, repurposed agent, ATG, in a low and safe dose, as a disease-modifying agent in this population.
The European Union's Innovative Medicines Initiative 2 Joint Undertaking INNODIA.
1型糖尿病仍然是一个重要的医疗保健问题，对于近期发病的临床1型糖尿病患者，尚无改善病情的疗法。适应性试验设计能够更快地评估治疗方式，但在该疾病的这一阶段仍未得到充分探索。我们旨在确定5至25岁近期发病的临床1型糖尿病患者中抗胸腺细胞球蛋白（ATG）的最低有效剂量。
MELD-ATG是一项2期、双盲、随机、安慰剂对照、多臂、适应性剂量范围、平行队列试验，在八个国家（英国、丹麦、德国、芬兰、意大利、比利时、奥地利和斯洛文尼亚）的14个认可试验中心进行。年龄在5至25岁之间、在治疗前3至9周被诊断为临床3期1型糖尿病、随机C肽浓度为0.2 nmol/L或更高且至少有一种糖尿病相关自身抗体（GADA、IA-2A或ZnT8）的参与者，通过基于网络的随机系统被随机分配到七个连续队列中，分别接受安慰剂、2.5 mg/kg ATG、1.5 mg/kg ATG、0.5 mg/kg ATG或0.1 mg/kg ATG。队列1的参与者按1:1:1:1:1随机分配，队列2和队列3的参与者按1:1:1:1随机分配，队列4至7的参与者按1:1:1随机分配。所有队列均包括一个安慰剂组和一个2.5 mg/kg ATG组。其他组被分配到根据累积数据和剂量决定委员会的决定确定的ATG剂量。试验队列按年龄组（5至9岁、10至17岁和18至25岁）分层，每组的区组大小不同。仅药剂师可获取概述治疗分配的隐藏列表；参与者和研究团队对治疗分配不知情。ATG通过连续2天的静脉输注给药。主要结局是在12个月时2小时混合餐耐量试验中刺激C肽浓度的曲线下面积（AUC），以ln（AUC C肽 + 1）测量。若2.5 mg/kg ATG与安慰剂相比在p<0.05时存在统计学显著差异，则确定ATG的最低有效剂量。所有随机分配的参与者均纳入主要分析。所有接受研究药物的参与者均纳入安全性分析。该试验已在ClinicalTrials.gov注册（NCT04509791）且已完成。
2020年11月24日至2023年12月13日期间，共招募并筛选了152人，其中117人被随机分配（安慰剂组n = 31，0.1 mg/kg ATG组n = 6，0.5 mg/kg ATG组n = 35，1.5 mg/kg ATG组n = 12，2.5 mg/kg组n = 33）。117名参与者中54名（46%）为男性，63名（54%）为女性。参与者主要为欧洲人。0.1 mg/kg剂量组和1.5 mg/kg剂量组逐渐退出研究。12个月时，安慰剂组的平均ln（AUC C肽 + 1）为0.411 nmol/L每分钟（标准差0.032），2.5 mg/kg ATG组为0.535 nmol/L每分钟（0.032）。2.5 mg/kg ATG组与安慰剂组的ln（AUC C肽 + 1）平均差值为0.124 nmol/L每分钟（95%置信区间0.043 - 0.205；p = 0.0028）。12个月时，剩余中间剂量的0.5 mg/kg ATG组的平均ln（AUC C肽 + 1）为0.513 nmol/L每分钟（标准差0.032），与安慰剂相比的平均基线调整差值为0.102 nmol/L每分钟（95%置信区间0.021 - 0.183；p = 0.014）。2.5 mg/kg ATG组的33名参与者中有11名（33%）发生细胞因子释放综合征，0.5 mg/kg ATG组的34名参与者中有8名（24%）发生，安慰剂组无参与者发生。2.5 mg/kg ATG组的27名（82%）参与者发生血清病，0.5 mg/kg ATG组的11名（32%）参与者发生，安慰剂组无参与者发生。无与不良事件相关的死亡。
在近期发病的临床1型糖尿病年轻人中，2.5 mg/kg和0.5 mg/kg的ATG可减少β细胞功能丧失，显示出一种价格合理、重新利用的药物ATG以低且安全的剂量作为该人群改善病情药物的潜力。
欧盟创新药物倡议2联合事业INNODIA。
