Teplizumab for treatment of type 1 diabetes (Protégé study): 1-year results from a randomised, placebo-controlled trial

Lancet. 2011 Aug 6;378(9790):487-97. doi: 10.1016/S0140-6736(11)60931-8. Epub 2011 Jun 28.

Abstract

Background: Findings of small studies have suggested that short treatments with anti-CD3 monoclonal antibodies that are mutated to reduce Fc receptor binding preserve β-cell function and decrease insulin needs in patients with recent-onset type 1 diabetes. In this phase 3 trial, we assessed the safety and efficacy of one such antibody, teplizumab.

Methods: In this 2-year trial, patients aged 8-35 years who had been diagnosed with type 1 diabetes for 12 weeks or fewer were enrolled and treated at 83 clinical centres in North America, Europe, Israel, and India. Participants were allocated (2:1:1:1 ratio) by an interactive telephone system, according to computer-generated block randomisation, to receive one of three regimens of teplizumab infusions (14-day full dose, 14-day low dose, or 6-day full dose) or placebo at baseline and at 26 weeks. The Protégé study is still underway, and patients and study staff remain masked through to study closure. The primary composite outcome was the percentage of patients with insulin use of less than 0·5 U/kg per day and glycated haemoglobin A(1c) (HbA(1C)) of less than 6·5% at 1 year. Analyses included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00385697.

Findings: 763 patients were screened, of whom 516 were randomised to receive 14-day full-dose teplizumab (n=209), 14-day low-dose teplizumab (n=102), 6-day full-dose teplizumab (n=106), or placebo (n=99). Two patients in the 14-day full-dose group and one patient in the placebo group did not start treatment, so 513 patients were eligible for efficacy analyses. The primary outcome did not differ between groups at 1 year: 19·8% (41/207) in the 14-day full-dose group; 13·7% (14/102) in the 14-day low-dose group; 20·8% (22/106) in the 6-day full-dose group; and 20·4% (20/98) in the placebo group. 5% (19/415) of patients in the teplizumab groups were not taking insulin at 1 year, compared with no patients in the placebo group at 1 year (p=0·03). Across the four study groups, similar proportions of patients had adverse events (414/417 [99%] in the teplizumab groups vs 98/99 [99%] in the placebo group) and serious adverse events (42/417 [10%] vs 9/99 [9%]). The most common clinical adverse event in the teplizumab groups was rash (220/417 [53%] vs 20/99 [20%] in the placebo group).

Interpretation: Findings of exploratory analyses suggest that future studies of immunotherapeutic intervention with teplizumab might have increased success in prevention of a decline in β-cell function (measured by C-peptide) and provision of glycaemic control at reduced doses of insulin if they target patients early after diagnosis of diabetes and children.

Funding: MacroGenics, the Juvenile Diabetes Research Foundation, and Eli Lilly.

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Antibodies, Monoclonal, Humanized
  • C-Peptide / blood
  • CD3 Complex / drug effects*
  • CD3 Complex / immunology
  • Canada
  • Child
  • Diabetes Mellitus, Type 1 / blood
  • Diabetes Mellitus, Type 1 / drug therapy*
  • Diabetes Mellitus, Type 1 / immunology*
  • Drug Administration Schedule
  • Drug Eruptions / etiology
  • Europe
  • Female
  • Glycated Hemoglobin A / metabolism
  • Humans
  • Hypoglycemic Agents / administration & dosage
  • Hypoglycemic Agents / adverse effects
  • Hypoglycemic Agents / immunology
  • Hypoglycemic Agents / therapeutic use*
  • India
  • Insulin / administration & dosage
  • Insulin / therapeutic use*
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / immunology
  • Israel
  • Male
  • Mexico
  • Muromonab-CD3 / administration & dosage
  • Muromonab-CD3 / adverse effects
  • Muromonab-CD3 / immunology
  • Muromonab-CD3 / therapeutic use*
  • Treatment Outcome
  • United States
  • Young Adult

Substances

  • Antibodies, Monoclonal, Humanized
  • C-Peptide
  • CD3 Complex
  • Glycated Hemoglobin A
  • Hypoglycemic Agents
  • Insulin
  • Muromonab-CD3
  • teplizumab

Associated data

  • ClinicalTrials.gov/NCT00385697