Low-Dose Otelixizumab Anti-CD3 Monoclonal Antibody DEFEND-1 Study: Results of the Randomized Phase III Study in Recent-Onset Human Type 1 Diabetes
- Ronnie Aronson1⇑,
- Peter A. Gottlieb2,
- Jens S. Christiansen3,
- Thomas W. Donner4,
- Emanuele Bosi5,
- Bruce W. Bode6,
- Paolo Pozzilli7,8,
- for the DEFEND Investigator Group*
- 1LMC Diabetes & Endocrinology, Toronto, Ontario, Canada
- 2University of Colorado, Denver, CO
- 3University of Aarhus, Aarhus University Hospital, Aarhus, Denmark
- 4Johns Hopkins University School of Medicine, Baltimore, MD
- 5San Raffaele Hospital Scientific Institute, Vita Salute San Raffaele University, Milan, Italy
- 6Emory University, Atlanta Diabetes Associates, Atlanta, GA
- 7Università Campus Bio-Medico di Roma, Rome, Italy
- 8Barts and the London School of Medicine and Dentistry, Queen Mary, University of London, London, U.K.
- Corresponding author: Ronnie Aronson, .
OBJECTIVE Previous studies demonstrated that the anti-CD3 monoclonal antibody otelixizumab, administered at a total dose of 48–64 mg, can slow the loss of C-peptide in recent-onset type 1 diabetes patients, with frequent reactivation of Epstein Barr virus (EBV). The DEFEND-1 (Durable Response Therapy Evaluation for Early or New-Onset Type 1 Diabetes) trial was designed to test whether a lower dose of otelixizumab could preserve C-peptide secretion in new-onset type 1 diabetes patients.
RESEARCH DESIGN AND METHODS A multicenter, randomized, placebo-controlled trial was performed in sites in the U.S., Canada, and Europe. Two hundred eighty-one patients were randomized to treatment with 3.1 mg otelixizumab administered over 8 days or placebo. The primary end point of the study was the change in C-peptide area under the curve (AUC) from a 2-h mixed-meal tolerance test at month 12.
RESULTS The change in 2-h C-peptide AUC was not different between placebo-treated patients and otelixizumab-treated patients (−0.20 vs. −0.22 nmol/L, P = 0.81). Secondary end points, including HbA1c, glucose variability, and insulin dose, were also not statistically different between the two groups. More patients in the otelixizumab group than in the placebo group experienced adverse events, mostly grade 1 or grade 2. There was no EBV reactivation (viral load >10,000 copies/106 peripheral blood mononuclear cells) in the otelixizumab group, in contrast with previously published studies at higher doses of otelixizumab.
CONCLUSIONS Otelixizumab was well tolerated in patients with recent-onset type 1 diabetes at a total dose of 3.1 mg, but did not achieve preservation of levels of C-peptide or other markers of metabolic control.
↵* A complete list of investigators can be found in the online Appendix.
- Received February 7, 2013.
- Accepted June 6, 2014.
- © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.