N Engl J Med 2019 08 9;381(7):603-613. Epub 2019 Jun 9.
From the Departments of Immunobiology and Internal Medicine, Yale University, New Haven, CT (K.C.H.); the Departments of Epidemiology and Pediatrics, University of South Florida, Tampa (B.N.B., J.P.K., H.R.), the Department of Medicine, University of Miami, Miami (J.B.M., J.S.S.), and the Department of Pediatrics, University of Florida, Gainesville (D.S.) - all in Florida; Benaroya Research Institute, Seattle (S.A.L., M.J.D., P.S.L., C.J.G.); the Diabetes Center, University of California at San Francisco, San Francisco (J.A.B., S.E.G.); the Department of Pediatrics, Indiana University, Indianapolis (L.A.D.); the Barbara Davis Diabetes Center, University of Colorado, Anschultz (P.A.G.); Children's Mercy Hospital, Kansas City, MO (W.M.); the Department of Pediatrics, University of Minnesota, Minneapolis (A.M.); the Department of Pediatrics and Cell and Developmental Biology, Vanderbilt University, Nashville (W.E.R.); the Department of Pediatrics, University of Iowa, Iowa City (E.T.); the Hospital for Sick Children, University of Toronto, Toronto (D.K.W.); and Forschergruppe Diabetes, Technical University Munich, at Klinikum rechts der Isar, Munich, Germany (A.-G.Z.).
Background: Type 1 diabetes is a chronic autoimmune disease that leads to destruction of insulin-producing beta cells and dependence on exogenous insulin for survival. Some interventions have delayed the loss of insulin production in patients with type 1 diabetes, but interventions that might affect clinical progression before diagnosis are needed.
Methods: We conducted a phase 2, randomized, placebo-controlled, double-blind trial of teplizumab (an Fc receptor-nonbinding anti-CD3 monoclonal antibody) involving relatives of patients with type 1 diabetes who did not have diabetes but were at high risk for development of clinical disease. Patients were randomly assigned to a single 14-day course of teplizumab or placebo, and follow-up for progression to clinical type 1 diabetes was performed with the use of oral glucose-tolerance tests at 6-month intervals.
Results: A total of 76 participants (55 [72%] of whom were ≤18 years of age) underwent randomization - 44 to the teplizumab group and 32 to the placebo group. The median time to the diagnosis of type 1 diabetes was 48.4 months in the teplizumab group and 24.4 months in the placebo group; the disease was diagnosed in 19 (43%) of the participants who received teplizumab and in 23 (72%) of those who received placebo. The hazard ratio for the diagnosis of type 1 diabetes (teplizumab vs. placebo) was 0.41 (95% confidence interval, 0.22 to 0.78; P = 0.006 by adjusted Cox proportional-hazards model). The annualized rates of diagnosis of diabetes were 14.9% per year in the teplizumab group and 35.9% per year in the placebo group. There were expected adverse events of rash and transient lymphopenia. KLRG1+TIGIT+CD8+ T cells were more common in the teplizumab group than in the placebo group. Among the participants who were HLA-DR3-negative, HLA-DR4-positive, or anti-zinc transporter 8 antibody-negative, fewer participants in the teplizumab group than in the placebo group had diabetes diagnosed.
Conclusions: Teplizumab delayed progression to clinical type 1 diabetes in high-risk participants. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01030861.).