Antithymocyte globulin therapy for patients with recent-onset type 1 diabetes: 2 year results of a randomised trial.
Antithymocyte globulin therapy for patients with recent-onset type 1 diabetes: 2 year results of a randomised trial.
复制标题
DOI：
10.1007/s00125-016-3917-4
复制
发表时间：
2016-06
期刊：
影响因子：
8.2
通讯作者：
ITN START Study Team
中科院分区：
文献类型：
--
作者：
Gitelman SE;Gottlieb PA;Felner EI;Willi SM;Fisher LK;Moran A;Gottschalk M;Moore WV;Pinckney A;Keyes-Elstein L;Harris KM;Kanaparthi S;Phippard D;Ding L;Bluestone JA;Ehlers MR;ITN START Study Team
1型糖尿病由T细胞介导的β细胞破坏引起。我们在新发1型糖尿病患者中进行了一项抗胸腺细胞球蛋白（ATG）试验（胸腺球蛋白阻止T1 D [START]试验）。我们的目标是评估ATG在2年时保留胰岛功能的长期安全性和有效性。在美国的7所大学医学中心和1所儿童医院进行了一项多中心、随机、双盲、安慰剂对照试验，比较6.5 mg/kg ATG（Thymoglobulin）与安慰剂治疗新发1型糖尿病患者。在数据协调中心使用大小为3或6的排列区组通过计算机生成研究中心分层随机化方案。符合条件的参与者年龄在12至35岁之间，并在诊断后100天内登记。受试者以2：1的比例随机接受6.5 mg/kg ATG（胸腺球蛋白）与安慰剂。参与者是盲态的，研究设计包括两个连续的患者护理团队：一个非盲态研究药物给药团队（前8周）和一个盲态糖尿病管理团队（研究的剩余时间）。在24个月时评估的终点包括膳食刺激的C肽AUC、安全性和免疫应答。58例患者入组; 2年时，35例分配至ATG组，16例分配至安慰剂组完成研究。未达到预先规定的终点。在事后分析中，与安慰剂组患者相比，ATG组的老年患者（年龄22-35岁）在24个月时具有显著更高的C肽AUC。使用24个月时基线C肽的完全保留作为阈值，35名ATG治疗的参与者中有9名（相对于16名安慰剂参与者中的2名）被归类为应答者; 11名应答者中有9名（67%）年龄较大。所有参与者都报告了至少一起不良事件（AE），38名ATG参与者中有1，148起事件，而20名安慰剂参与者中有415起事件;在ATG和安慰剂组中观察到相当数量的感染，两组均无机会性感染或难以清除感染。循环T细胞亚群消耗的ATG部分重建，但调节，幼稚和中央记忆亚群仍然显着耗尽在24个月。β细胞自身抗体在ATG治疗或安慰剂参与者中在24个月内没有变化。在12个月时，ATG治疗的参与者对破伤风和HepA疫苗的体液免疫应答与安慰剂治疗的参与者相似，并且没有增加感染。在大多数新发1型糖尿病患者中，ATG的短暂疗程基本上耗尽了T细胞亚群，包括调节细胞，但在24个月后没有保留胰岛功能。ATG保留了老年参与者的C肽分泌，这可能需要进一步研究。ClinicalTrials.gov NCT 00515099 START数据集可在TrialShare www.itntrialshare.org美国国立卫生研究院（NIH）的国家过敏和传染病研究所（NIAID）中获得。该试验由免疫耐受网络（ITN）进行。本文的在线版本（doi：10.1007/s 00125 -016-3917-4）包含同行评审但未经编辑的补充材料，可供授权用户使用。
Type 1 diabetes results from T cell mediated destruction of beta cells. We conducted a trial of antithymocyte globulin (ATG) in new-onset type 1 diabetes (the Study of Thymoglobulin to ARrest T1D [START] trial). Our goal was to evaluate the longer-term safety and efficacy of ATG in preserving islet function at 2 years. A multicentre, randomised, double-blind, placebo-controlled trial of 6.5 mg/kg ATG (Thymoglobulin) vs placebo in patients with new-onset type 1 diabetes was conducted at seven university medical centres and one Children’s Hospital in the USA. The site-stratified randomisation scheme was computer generated at the data coordinating centre using permuted-blocks of size 3 or 6. Eligible participants were between the ages of 12 and 35, and enrolled within 100 days from diagnosis. Subjects were randomised to 6.5 mg/kg ATG (thymoglobulin) vs placebo in a 2:1 ratio. Participants were blinded, and the study design included two sequential patient-care teams: an unblinded study-drug administration team (for the first 8 weeks), and a blinded diabetes management team (for the remainder of the study). Endpoints assessed at 24 months included meal-stimulated C-peptide AUC, safety and immunological responses. Fifty-eight patients were enrolled; at 2 years, 35 assigned to ATG and 16 to placebo completed the study. The pre-specified endpoints were not met. In post hoc analyses, older patients (age 22–35 years) in the ATG group had significantly greater C-peptide AUCs at 24 months than placebo patients. Using complete preservation of baseline C-peptide at 24 months as threshold, nine of 35 ATG-treated participants (vs 2/16 placebo participants) were classified as responders; nine of 11 responders (67%) were older. All participants reported at least one adverse event (AE), with 1,148 events in the 38 ATG participants vs 415 in the 20 placebo participants; a comparable number of infections were noted in the ATG and placebo groups, with no opportunistic infections nor difficulty clearing infections in either group. Circulating T cell subsets depleted by ATG partially reconstituted, but regulatory, naive and central memory subsets remained significantly depleted at 24 months. Beta cell autoantibodies did not change over the 24 months in the ATG-treated or placebo participants. At 12 months, ATG-treated participants had similar humoral immune responses to tetanus and HepA vaccines as placebo-treated participants, and no increased infections. A brief course of ATG substantially depleted T cell subsets, including regulatory cells, but did not preserve islet function 24 months later in the majority of patients with new-onset type 1 diabetes. ATG preserved C-peptide secretion in older participants, which may warrant further study. ClinicalTrials.gov NCT00515099 START datasets are available in TrialShare www.itntrialshare.org National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH). The trial was conducted by the Immune Tolerance Network (ITN). The online version of this article (doi:10.1007/s00125-016-3917-4) contains peer-reviewed but unedited supplementary material, which is available to authorised users.