Antithymocyte globulin treatment for patients with recent-onset type 1 diabetes: 12-month results of a randomised, placebo controlled, phase 2 trial

DIABETES TECHNOLOGY & THERAPEUTICS Volume 16, Supplement 1, 2014 a Mary Ann Liebert, Inc. DOI: 10.1089/dia.2014.1510 ORIGINAL ARTICLE Immune Intervention for Type 1 Diabetes, 2012–2013 Jay S. Skyler Introduction Results T Teplizumab (14-day full dose) reduced the loss of C-peptide mean area under curve (AUC; a prespecified secondary end- point) at 2 years versus placebo. In analyses of subsets at entry, U.S. residents, patients with C-peptide mean AUC > 0.2 nmol/L, those randomized < 6 weeks after diagnosis, HbA1c < 7.5% (58 mmol/mol), insulin use < 0.4 U/kg/day, and ages 8–17, each had greater teplizumab-associated C-peptide preservation than their counterparts. Exogenous insulin needs tended to be re- duced versus placebo. Antidrug antibodies developed in some patients without apparent change in drug efficacy. No new safety or tolerability issues were observed during year 2. his chapter of the ATTD 2013 Yearbook reviews the key articles that have appeared between July 2012 and August 2013 in the area of immune intervention in type 1 diabetes. Also included are two studies dealing with beta-cell regen- eration or replacement. The first three studies discussed deal with anti-CD3 monoclonal antibody therapy. Teplizumab preserves C-peptide in recent-onset type 1 diabetes: 2-year results from the randomized, placebo-controlled Protege trial Hagopian W 1 , Ferry RJ Jr 2 , Sherry N 3 , Carlin D 4 , Bonvini E 4 , Johnson S 4 , Stein KE 4 , Koenig S 4 , Daifotis AG 4 , Herold KC 5 , Ludvigsson J 6 ; for the Prote´ge´ Trial Investigators Pacific Northwest Diabetes Research Institute, Seattle, WA; 2 Divi- sion of Pediatric Endocrinology and Metabolism, Le Bonheur Chil- dren’s Hospital and University of Tennessee Health Science Center, Memphis, TN; 3 Massachusetts General Hospital, Boston, MA; MacroGenics, Rockville, MD; 5 Departments of Immunobiology and Internal Medicine, Yale University, New Haven, CT; and 6 Division of Pediatrics, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linko¨ping University, Linko¨ping, Sweden Conclusion Anti-CD3 therapy reduced C-peptide loss and thus pre- served b-cell function for 2 years. Diabetes 2013 Jun 25: [Epub ahead of print]; DOI: 10/2337/db13-0236 Background Two years ago we discussed the 1-year results of the Prote´ge´ phase 3 study using teplizumab. The primary outcome measure—a composite of the percentage of patients with in- sulin use of < 0.5 U/kg per day and HbA1c of < 6.5% at 1 year— was not met. However, exploratory analyses suggested that teplizumab could help preserve b-cell function—as measured by C-peptide—at 1 year, particularly in subgroups such as children. This report describes the 2-year results from this study. Methods Of the 516 subjects randomized, 462 completed 2 years of follow-up. Treatment was given both at study entry and 6 months later. Comment Previous reports have shown that a short course of hu- manized anti-CD3 monoclonal antibody—either with teplizumab or otelixizumab—preserved b-cell function as measured by C-peptide. The Prote´ge´ study selected a different primary outcome measure—a composite of the percentage of patients with insulin use of < 0.5 U/kg/ day plus HbA1c of < 6.5% at 1 year. That outcome was not met, and thus many have labeled the Prote´ge´ study a failure. Yet, in the original report, teplizumab was found to preserve b-cell function at 1 year. The current article demonstrates that this effect was maintained at 2 years. As noted in our earlier discussion of the 1-year results, there was no prior basis for the outcome measure se- lected. Moreover, taking two continuous variables (in- sulin use and HbA1c) and converting them to a single combined dichotomous variable reduces the statistical power of assessment of continuous variables. The C- peptide results, both at 1 year and at 2 years, highlight the problem. Thus, although the original primary outcome was not met, we are still learning from the Prote´ge´ study. Division of Endocrinology, Diabetes, & Metabolism, and Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL. S-85