Low-dose otelixizumab anti-CD3 monoclonal antibody DEFEND-1 study: Results of the randomized phase III study in recent-onset human type 1 diabetes

Diabetes Care

Volumn 37, Issue 10, 2014, Pages 2746-2754

  Aronson, Ronnie ^a   Gottlieb, Peter A ^b   Christiansen, Jens S ^c   Donner, Thomas W ^d   Bosi, Emanuele ^e   Bode, Bruce W ^f   Pozzilli, Paolo ^g,h  

^a LMC DIABETES AND ENDOCRINOLOGY   (Canada)

^b UNIVERSITY OF COLORADO   (United States)

^c AARHUS UNIVERSITY   (Denmark)

^d JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

^e SAN RAFFAELE HOSPITAL   (Italy)

^f EMORY UNIVERSITY   (United States)

^g UNIVERSITY CAMPUS BIO MEDICO   (Italy)

^h QUEEN MARY UNIVERSITY OF LONDON   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

C PEPTIDE; GLUCOSE; HEMOGLOBIN A1C; INSULIN; OTELIXIZUMAB; PLACEBO; T LYMPHOCYTE RECEPTOR; ANTIDIABETIC AGENT; CD3 ANTIGEN; MONOCLONAL ANTIBODY;

ADOLESCENT; ADULT; AREA UNDER THE CURVE; ARTICLE; CHILD; CONTROLLED STUDY; DOUBLE BLIND PROCEDURE; DRUG EFFICACY; DRUG SAFETY; DRUG TOLERABILITY; EPSTEIN BARR VIRUS; EPSTEIN BARR VIRUS INFECTION; FEMALE; FEVER; GLUCOSE BLOOD LEVEL; GLYCEMIC CONTROL; HEADACHE; HEMOGLOBIN BLOOD LEVEL; HUMAN; INCIDENCE; INSULIN DEPENDENT DIABETES MELLITUS; LOW DRUG DOSE; LYMPHOCYTE SUBPOPULATION; MACULOPAPULAR RASH; MAJOR CLINICAL STUDY; MALE; MULTICENTER STUDY; NAUSEA; OROPHARYNX PAIN; PAPULAR RASH; PHARYNGITIS; PHASE 3 CLINICAL TRIAL; PREVALENCE; PROTEIN BLOOD LEVEL; PROTEIN SECRETION; RANDOMIZED CONTROLLED TRIAL; SCHOOL CHILD; TREATMENT OUTCOME; VIRUS LOAD; VIRUS REACTIVATION; BLOOD; CANADA; CLINICAL TRIAL; DIABETES MELLITUS, TYPE 1; DOSE RESPONSE; EPIDEMIOLOGY; EUROPE; IMMUNOLOGY; MIDDLE AGED; ONSET AGE; UNITED STATES; YOUNG ADULT;

ADOLESCENT; ADULT; AGE OF ONSET; ANTIBODIES, MONOCLONAL, HUMANIZED; ANTIGENS, CD3; C-PEPTIDE; CANADA; CHILD; DIABETES MELLITUS, TYPE 1; DOSE-RESPONSE RELATIONSHIP, DRUG; EUROPE; FEMALE; HUMANS; HYPOGLYCEMIC AGENTS; INSULIN; MALE; MIDDLE AGED; UNITED STATES; YOUNG ADULT;

EID: 84908218494     PISSN: 01495992     EISSN: 19355548     Source Type: Journal    
DOI: 10.2337/dc13-0327     Document Type: Article

References (30)

1. Brink SJ. Complications of pediatric and adolescent type 1 diabetes mellitus. Curr Diab Rep 2001;1:47-55.
2. The Diabetes Control and Complications Trial Research Group. Effect of intensive therapy on residual beta-cell function in patients with type 1 diabetes in the diabetes control and complications trial. A randomized, controlled trial. Ann Intern Med 1998;128:517-523.
3. Gillespie KM. Type 1 diabetes: pathogenesis and prevention. CMAJ 2006;175:165-170.
4. Roep BO. The role of T-cells in the pathogenesis of Type 1 diabetes: from cause to cure. Diabetologia 2003;46:305-321.
5. Mallone R, van Endert P. T cells in the pathogenesis of type 1 diabetes. Curr Diab Rep 2008; 8:101-106.
6. Mehta SN, Wolfsdorf JI. Contemporary management of patients with type 1 diabetes. Endocrinol Metab Clin North Am 2010;39:573-593.
7. Edelman SV, Weyer C. Unresolved challenges with insulin therapy in type 1 and type 2 diabetes: potential benefit of replacing amylin, a second beta-cell hormone. Diabetes Technol Ther 2002;4:175-189.
8. Hale G, Rebello P, Al Bakir I, et al. Pharmacokinetics and antibody responses to the CD3 antibody otelixizumab used in the treatment of type 1 diabetes. J Clin Pharmacol 2010;50:1238-1248.
9. Chatenoud L. CD3-specific antibody-induced active tolerance: from bench to bedside. Nat Rev Immunol 2003;3:123-132.
10. Mehta DS, Christmas RA, Waldmann H, Rosenzweig M. Partial and transient modulation of the CD3-T-cell receptor complex, elicited by low-dose regimens of monoclonal anti-CD3, is sufficient to induce disease remission in non-obese diabetic mice. Immunology 2010;130:103-113.
11. Keymeulen B, Walter M, Mathieu C, et al. Four-year metabolic outcome of a randomised controlled CD3-antibody trial in recent-onset type 1 diabetic patients depends on their age and baseline residual beta cell mass. Diabetologia 2010;53:614-623.
12. Keymeulen B, Vandemeulebroucke E, Ziegler AG, et al. Insulin needs after CD3- Antibody therapy in new-onset type 1 diabetes. N Engl J Med 2005;352:2598-2608.
13. Palmer JP, Fleming GA, Greenbaum CJ, et al. C-peptide is the appropriate outcome measure for type 1 diabetes clinical trials to preserve beta-cell function: report of an ADA workshop, 21-22 October 2001. Diabetes 2004;53: 250-264.
14. Food and Drug Administration. Considerations for allogeneic pancreatic islet cell products [article online], 2009. Available fromhttp://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/UCM182441.pdf. Accessed 11 June 2014.
15. Centers for Disease Control and Prevention. Body mass index [article online], 2011. Available from http://www.cdc.gov/healthyweight/assessing/bmi/index.html. Accessed 11 June 2014.
16. Greenbaum CJ, Mandrup-Poulsen T, McGee PF, et al.; Type 1 Diabetes Trial Net Research Group; European C-Peptide Trial Study Group. Mixed-meal tolerance test versus glucagon stimulation test for the assessment of betacell function in therapeutic trials in type 1 diabetes. Diabetes Care 2008;31:1966-1971.
17. Kovatchev BP, Otto E, Cox D, Gonder- Frederick L, Clarke W. Evaluation of a new measure of blood glucose variability in diabetes. Diabetes Care 2006;29:2433-2438.
18. Service FJ, Molnar GD, Rosevear JW, Ackerman E, Gatewood LC, Taylor WF. Mean amplitude of glycemic excursions, a measure of diabetic instability. Diabetes 1970;19:644- 655.
19. Workgroup on Hypoglycemia, American Diabetes Association. Defining and reporting hypoglycemia in diabetes: a report from the American Diabetes Association Workgroup on Hypoglycemia. Diabetes Care 2005;28:1245- 1249.
20. Food and Drug Administration. Diabetes mellitus: developing drugs and therapeutic biologics from treatment and prevention [article online], 2008. Available from http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071624.pdf. Accessed 11 June 2014.
21. Herold KC, Gitelman S, Greenbaum C, et al.; Immune Tolerance Network ITN007AI Study Group. Treatment of patients with new onset Type 1 diabetes with a single course of anti- CD3 mAb Teplizumab preserves insulin production for up to 5 years. Clin Immunol 2009;132: 166-173.
22. Chatenoud L. The use of CD3-specific antibodies in autoimmune diabetes: a step toward the induction of immune tolerance in the clinic. Handb Exp Pharmacol 2008;221-236.
23. Herold KC, Hagopian W, Auger JA, et al. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med 2002; 346:1692-1698.
24. Sherry N, Hagopian W, Ludvigsson J, et al.; Prot ég é Trial Investigators. Teplizumab for treatment of type 1 diabetes (Prot égé study): 1-year results from a randomised, placebocontrolled trial. Lancet 2011;378:487-497.
25. Ambery P, Donner TW, Biswas N, Donaldson J, Dayan CM. Efficacy and safety of low-dose otelixizumab anti-CD3 monoclonal antibody in preserving C-peptide secretion in adolescent type 1 diabetes: DEFEND-2, a randomized, placebo-controlled, double-blind, multi-centre study. Diabet Med 2014;31:399- 402.
26. Waldron-Lynch F, Henegariu O, Deng S, et al. Teplizumab induces human gut-tropic regulatory cells in humanized mice and patients. Sci Transl Med 2012;4:118ra12.
27. Loechelt BJ, BoulwareD, GreenM, et al.; Type 1 Diabetes TrialNet Daclizumab/Mycophenolic Acid Study Group. Epstein-Barr and other herpesvirus infections in patients with early onset type 1 diabetes treated with daclizumab and mycophenolate mofetil. Clin Infect Dis 2013;56: 248-254.
28. Pescovitz MD, Greenbaum CJ, Krause- Steinrauf H, et al.; Type 1 Diabetes TrialNet Anti-CD20 Study Group. Rituximab, B-lymphocyte depletion, and preservation of beta-cell function. N Engl J Med 2009;361:2143-2152.
29. Pescovitz MD, Torgerson TR, Ochs HD, et al.; Type 1 Diabetes TrialNet Study Group. Effect of rituximab on human in vivo antibody immune responses. J Allergy Clin Immunol 2011;128:1295-1302, e5.
30. Pozzilli P. Type 1 diabetes mellitus in 2011: heterogeneity of T1DM raises questions for therapy. Nat Rev Endocrinol 2012; 8:78-80.