Teplizumab for treatment of type 1 diabetes (Protégé study): 1-year results from a randomised, placebo-controlled trial.
Teplizumab for treatment of type 1 diabetes (Protégé study): 1-year results from a randomised, placebo-controlled trial.
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DOI：
10.1016/s0140-6736(11)60931-8
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发表时间：
2011-08-06
期刊：
影响因子：
168.9
通讯作者：
Daifotis, Anastasia G.
中科院分区：
文献类型：
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作者：
Sherry, Nicole;Hagopian, William;Ludvigsson, Johnny;Jain, Sunil M.;Wahlen, Jack;Ferry, Robert J., Jr.;Bode, Bruce;Aronoff, Stephen;Holland, Christopher;Carlin, David;King, Karen L.;Wilder, Ronald L.;Pillemer, Stanley;Bonvini, Ezio;Johnson, Syd;Stein, Kathryn E.;Koenig, Scott;Herold, Kevan C.;Daifotis, Anastasia G.
小型研究的结果表明，抗CD 3单克隆抗体（经突变以减少Fc受体结合）的短期治疗可保护β细胞功能，并减少近期发作的1型糖尿病患者的胰岛素需求。在这项3期试验中，我们评估了一种这样的抗体teplizumab的安全性和有效性。在这项为期2年的试验中，年龄在8-35岁之间，被诊断患有1型糖尿病12周或更短时间的患者在北美，欧洲，以色列和印度的83个临床中心招募和治疗。根据计算机生成的区组随机化，通过交互式电话系统将参与者分配（2：1：1：1比例），在基线和26周时接受三种方案之一的teplizumab输注（14天全剂量，14天低剂量或6天全剂量）或安慰剂。Protégé研究仍在进行中，患者和研究工作人员保持盲态直至研究结束。主要复合终点是1年时胰岛素使用量低于0.5 U/kg/天且糖化血红蛋白A1 c（HbA 1C）低于6.5%的患者百分比。分析包括至少接受一剂研究药物的所有患者。本试验在ClinicalTrials.gov注册，编号NCT 00385697。筛选了763名患者，其中516名患者随机接受14天全剂量teplizumab（n=209），14天低剂量teplizumab（n=102），6天全剂量teplizumab（n=106）或安慰剂（n=99）。14天全剂量组的2例患者和安慰剂组的1例患者未开始治疗，因此513例患者有资格进行疗效分析。1年时，各组之间的主要结局无差异：14天全剂量组为19.8%（41/207）; 14天低剂量组为13.7%（14/102）; 6天全剂量组为20.8%（22/106）;安慰剂组为20.4%（20/98）。teplizumab组中有5%（19/415）的患者在1年时未服用胰岛素，而安慰剂组中没有患者在1年时服用胰岛素（p= 0.03）。在四个研究组中，发生不良事件的患者比例相似（teplizumab组414/417 [99%] vs安慰剂组98/99 [99%]）和严重不良事件（42/417 [10%] vs 9/99 [9%]）。teplizumab组最常见的临床不良事件是皮疹（220/417 [53%] vs安慰剂组20/99 [20%]）。探索性分析的结果表明，如果teplizumab免疫干预的未来研究针对糖尿病诊断后的早期患者和儿童，则可能在预防β细胞功能下降（通过C肽测量）和减少胰岛素剂量时提供血糖控制方面取得更大成功。
Findings of small studies have suggested that short treatments with anti-CD3 monoclonal antibodies that are mutated to reduce Fc receptor binding preserve β-cell function and decrease insulin needs in patients with recent-onset type 1 diabetes. In this phase 3 trial, we assessed the safety and efficacy of one such antibody, teplizumab. In this 2-year trial, patients aged 8–35 years who had been diagnosed with type 1 diabetes for 12 weeks or fewer were enrolled and treated at 83 clinical centres in North America, Europe, Israel, and India. Participants were allocated (2:1:1:1 ratio) by an interactive telephone system, according to computer-generated block randomisation, to receive one of three regimens of teplizumab infusions (14-day full dose, 14-day low dose, or 6-day full dose) or placebo at baseline and at 26 weeks. The Protégé study is still underway, and patients and study staff remain masked through to study closure. The primary composite outcome was the percentage of patients with insulin use of less than 0.5 U/kg per day and glycated haemoglobin A1c (HbA1C) of less than 6.5% at 1 year. Analyses included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00385697. 763 patients were screened, of whom 516 were randomised to receive 14-day full-dose teplizumab (n=209), 14-day low-dose teplizumab (n=102), 6-day full-dose teplizumab (n=106), or placebo (n=99). Two patients in the 14-day full-dose group and one patient in the placebo group did not start treatment, so 513 patients were eligible for efficacy analyses. The primary outcome did not differ between groups at 1 year: 19·8% (41/207) in the 14-day full-dose group; 13·7% (14/102) in the 14-day low-dose group; 20·8% (22/106) in the 6-day full-dose group; and 20·4% (20/98) in the placebo group. 5% (19/415) of patients in the teplizumab groups were not taking insulin at 1 year, compared with no patients in the placebo group at 1 year (p=0·03). Across the four study groups, similar proportions of patients had adverse events (414/417 [99%] in the teplizumab groups vs 98/99 [99%] in the placebo group) and serious adverse events (42/417 [10%] vs 9/99 [9%]). The most common clinical adverse event in the teplizumab groups was rash (220/417 [53%] vs 20/99 [20%] in the placebo group). Findings of exploratory analyses suggest that future studies of immunotherapeutic intervention with teplizumab might have increased success in prevention of a decline in β-cell function (measured by C-peptide) and provision of glycaemic control at reduced doses of insulin if they target patients early after diagnosis of diabetes and children.