Teplizumab for treatment of type 1 diabetes (Protege study): 1-year results from a randomised, placebo-controlled trial

被引:369
作者
Sherry, Nicole [1 ]
Hagopian, William [2 ]
Ludvigsson, Johnny [3 ]
Jain, Sunil M. [4 ]
Wahlen, Jack [5 ]
Ferry, Robert J., Jr. [6 ,7 ]
Bode, Bruce [8 ]
Aronoff, Stephen [9 ]
Holland, Christopher [10 ]
Carlin, David [10 ]
King, Karen L. [10 ]
Wilder, Ronald L. [11 ]
Pillemer, Stanley [12 ]
Bonvini, Ezio [10 ]
Johnson, Syd [10 ]
Stein, Kathryn E. [10 ]
Koenig, Scott [10 ]
Herold, Kevan C. [13 ]
Daifotis, Anastasia G. [10 ]
机构
[1] Massachusetts Gen Hosp, Boston, MA 02114 USA
[2] NW Diabet Res Inst, Seattle, WA USA
[3] Linkoping Univ, Fac Hlth Sci, Dept Clin & Expt Med, Div Pediat, Linkoping, Sweden
[4] TOTALL Diabet Hormone Res Inst, Indore, Madhya Pradesh, India
[5] Endocrine Res Specialists, Ogden, UT USA
[6] Le Bonheur Childrens Hosp, Div Pediat Endocrinol & Metab, Memphis, TN USA
[7] Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA
[8] Atlanta Diabet Associates, Atlanta, GA USA
[9] Res Inst Dallas, Dallas, TX USA
[10] MacroGenics, Rockville, MD USA
[11] PAREXEL Int, Durham, NC USA
[12] Amer Biopharma Corp, Gaithersburg, MD USA
[13] Yale Univ, New Haven, CT USA
基金
美国国家卫生研究院;
关键词
MONOCLONAL-ANTIBODY; INSULIN-SECRETION; IMMUNE THERAPY;
D O I
10.1016/S0140-6736(11)60931-8
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background Findings of small studies have suggested that short treatments with anti-CD3 monoclonal antibodies that are mutated to reduce Fc receptor binding preserve beta-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. Methods 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 Protege 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 A(1c) (HbA(1c)) 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. Findings 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). Interpretation Findings of exploratory analyses suggest that future studies of immunotherapeutic intervention with teplizumab might have increased success in prevention of a decline in beta-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.
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收藏
页码:487 / 497
页数:11
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