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 Aronson, Peter A. Gottlieb, Jens S. Christiansen, Thomas W. Donner, Emanuele Bosi, Bruce W. Bode, Paolo Pozzilli

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

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 (20.20 vs. 20.22 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.

Original languageEnglish
Pages (from-to)2746-2754
Number of pages9
JournalDiabetes Care
Volume37
Issue number10
DOIs
Publication statusPublished - Oct 1 2014

Fingerprint

Type 1 Diabetes Mellitus
Monoclonal Antibodies
C-Peptide
Placebos
Human Herpesvirus 4
Area Under Curve
otelixizumab
Viral Load
Canada
Meals
Blood Cells
Research Design
Randomized Controlled Trials
Insulin
Glucose
Therapeutics

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Advanced and Specialised Nursing

Cite this

Low-dose otelixizumab anti-CD3 monoclonal antibody DEFEND-1 study : Results of the randomized phase III study in recent-onset human type 1 diabetes. / Aronson, Ronnie; Gottlieb, Peter A.; Christiansen, Jens S.; Donner, Thomas W.; Bosi, Emanuele; Bode, Bruce W.; Pozzilli, Paolo.

In: Diabetes Care, Vol. 37, No. 10, 01.10.2014, p. 2746-2754.

Research output: Contribution to journalArticle

Aronson, Ronnie ; Gottlieb, Peter A. ; Christiansen, Jens S. ; Donner, Thomas W. ; Bosi, Emanuele ; Bode, Bruce W. ; Pozzilli, Paolo. / Low-dose otelixizumab anti-CD3 monoclonal antibody DEFEND-1 study : Results of the randomized phase III study in recent-onset human type 1 diabetes. In: Diabetes Care. 2014 ; Vol. 37, No. 10. pp. 2746-2754.
@article{dfefa5683c7c47099f92ed815dc62cbc,
title = "Low-dose otelixizumab anti-CD3 monoclonal antibody DEFEND-1 study: Results of the randomized phase III study in recent-onset human type 1 diabetes",
abstract = "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 (20.20 vs. 20.22 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.",
author = "Ronnie Aronson and Gottlieb, {Peter A.} and Christiansen, {Jens S.} and Donner, {Thomas W.} and Emanuele Bosi and Bode, {Bruce W.} and Paolo Pozzilli",
year = "2014",
month = "10",
day = "1",
doi = "10.2337/dc13-0327",
language = "English",
volume = "37",
pages = "2746--2754",
journal = "Diabetes Care",
issn = "1935-5548",
publisher = "American Diabetes Association Inc.",
number = "10",

}

TY - JOUR

T1 - Low-dose otelixizumab anti-CD3 monoclonal antibody DEFEND-1 study

T2 - Results of the randomized phase III study in recent-onset human type 1 diabetes

AU - Aronson, Ronnie

AU - Gottlieb, Peter A.

AU - Christiansen, Jens S.

AU - Donner, Thomas W.

AU - Bosi, Emanuele

AU - Bode, Bruce W.

AU - Pozzilli, Paolo

PY - 2014/10/1

Y1 - 2014/10/1

N2 - 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 (20.20 vs. 20.22 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.

AB - 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 (20.20 vs. 20.22 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.

UR - http://www.scopus.com/inward/record.url?scp=84908218494&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84908218494&partnerID=8YFLogxK

U2 - 10.2337/dc13-0327

DO - 10.2337/dc13-0327

M3 - Article

C2 - 25011949

AN - SCOPUS:84908218494

VL - 37

SP - 2746

EP - 2754

JO - Diabetes Care

JF - Diabetes Care

SN - 1935-5548

IS - 10

ER -