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

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.

Conflict of interest statement

Conflicts of interest

CH, DC, KLK, EB, SJ, KES, SK, and AGD are employees of MacroGenics and potentially own shares or options in the company. NS, JL, SA, BB, JW, and RJF received research and travel support for this study from MacroGenics. JL has received advisory board support from Johnson & Johnson. RJF has received research support within the past 3 years from Tolerx (to study otelixizumab for recent-onset type 1 diabetes); unrelated research support from the US National Institutes of Health (grants R21 HD059292 and T35 DK007405), Gabrielle’s Angel Foundation, Eli Lilly, Diamyd, Pfizer, and Novo Nordisk; and unrestricted research support from Le Bonheur Foundation (Memphis TN, USA). WH chairs the data safety and monitoring board for the BHT-3021-01 insulin plasmid trial (Bayhill Pharmaceuticals). KCH has received research support from MacroGenics, and support from the Juvenile Diabetes Foundation (grant 2008-502) for laboratory studies on patients’ samples from Protégé. RLW is a former employee of MacroGenics and holds restricted stock in the company, and is now an employee of Parexel International, the lead contract research organisation that coordinated the Protégé trial globally. SA has received speaking honoraria from Eli Lilly. SP was formerly employed by MacroGenics and received stock options while employed there. SMJ declares that he has no conflicts of interest.

Copyright © 2011 Elsevier Ltd. All rights reserved.

Figures

Figure 1

Trial profile

Figure 2. Change in AUC of C-peptide from baseline over time and AUC of C-peptide over time

(A) All patients. (B) Children aged 8–11 years. (C) US patients. Statistical testing was not done on absolute AUC values. AUC=area under the curve. *p

Figure 3. Cumulative distribution of change in AUC of C-peptide from baseline at 1 year

(A) All patients (n=298). (B) Children aged 8–11 years. (C) US patients. Because of violations of normality assumptions, inferential comparisons were made with non-parametric methods (Wilcoxon rank-sum test). AUC=area under the curve.

Figure 4. Proportion of patients with HbA1c <7% by daily insulin dose cutoffs

(A) All patients. (B) US Patients. Reported p values are for the 14-day full-dose group versus the placebo group, and were calculated with Fisher’s exact test; p values are not shown when p>0·05. Patients with missing values are counted as not meeting criteria. HbA1c=glycated haemoglobin A1c.

Figure 5. Proportion of patients who met the post-hoc exploratory outcome of HbA1C <7% and insulin use <0·25 U/kg per day at each study visit

HbA1c=glycated haemoglobin A1c.