Background: Type 1 diabetes results from autoimmune targeting of the pancreatic β cells, likely mediated by effector memory T (Tem) cells. CD2, a T cell surface protein highly expressed on Tem cells, is targeted by the fusion protein alefacept, depleting Tem cells and central memory T (Tcm) cells. We postulated that alefacept would arrest autoimmunity and preserve residual β cells in patients newly diagnosed with type 1 diabetes. Methods: The T1DAL study is a phase 2, double-blind, placebo-controlled trial in patients with type 1 diabetes, aged 12-35 years who, within 100 days of diagnosis, were enrolled at 14 US sites. Patients were randomly assigned (2:1) to receive alefacept (two 12-week courses of 15 mg intramuscularly per week, separated by a 12-week pause) or a placebo. Randomisation was stratified by site, and was computer-generated with permuted blocks of three patients per block. All participants and site personnel were masked to treatment assignment. The primary endpoint was the change from baseline in mean 2 h C-peptide area under the curve (AUC) at 12 months. Secondary endpoints at 12 months were the change from baseline in the 4 h C-peptide AUC, insulin use, major hypoglycaemic events, and HbA1c concentrations. This trial is registered with ClinicalTrials.gov, number NCT00965458. Findings: Of 73 patients assessed for eligibility, 33 were randomly assigned to receive alefacept and 16 to receive placebo. The mean 2 h C-peptide AUC at 12 months increased by 0·015 nmol/L (95% CI -0·080 to 0·110) in the alefacept group and decreased by 0·115 nmol/L (-0·278 to 0·047) in the placebo group, and the difference between groups was not significant (p=0·065). However, key secondary endpoints were met: the mean 4 h C-peptide AUC was significantly higher (mean increase of 0·015 nmol/L [95% CI -0·076 to 0·106] vs decrease of -0·156 nmol/L [-0·305 to -0·006]; p=0·019), and daily insulin use (0·48 units per kg per day for placebo vs 0·36 units per kg per day for alefacept; p=0·02) and the rate of hypoglycaemic events (mean of 10·9 events per person per year for alefacept vs 17·3 events for placebo; p<0·0001) was significantly lower at 12 months in the alefacept group than in the placebo group. Mean HbA1c concentrations at week 52 were not different between treatment groups (p=0·75). So far, no serious adverse events were reported and all patients had at least one adverse event. In the alefacept group, 29 (88%) participants had an adverse event related to study drug versus 15 (94%) participants in the placebo group. In the alefacept group, 14 (42%) participants had grade 3 or 4 adverse events compared with nine (56%) participants in the placebo group; no deaths occurred. Interpretation: Although the primary outcome was not met, at 12 months, alefacept preserved the 4 h C-peptide AUC, lowered insulin use, and reduced hypoglycaemic events, suggesting efficacy. Safety and tolerability were similar in the alefacept and placebo groups. Alefacept could be useful to preserve β-cell function in patients with new-onset type 1 diabetes. Funding: US National Institutes of Health and the Juvenile Diabetes Research Foundation.
Bibliographical noteFunding Information:
The trial was conducted by the Immune Tolerance Network (ITN) and sponsored by the National Institute of Allergy and Infectious Diseases (NIAID). Additional funding was provided by the Juvenile Diabetes Research Foundation (JDRF) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). At Indiana University this project was in part supported by the Indiana Clinical and Translational Sciences Institute , funded in part by grant number TR000006 from the US National Institutes of Health (NIH), National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award ; at UCSF by Grant Numbers UL1 RR024131 and UL1 TR000004 from the National Center for Research Resources and the National Center for Advancing Translational Sciences , US NIH; at CHOP by grants UL1RR024134 and UL1TR000003 from the National Center for Research Resources and the National Center for Advancing Translational Sciences ; at University of Iowa by grant number UL1 TR000442-06 from the National Center for Advancing Translational Sciences, and the NIH; the contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. Astellas Pharma US (Northbrook, IL, USA) provided alefacept (Amevive) and gave input about dosage and safety, but had no direct involvement with study design, conduct, or management; data collection, analysis or interpretation; or manuscript preparation. There are no agreements concerning confidentiality of the data between the sponsor and the authors or the institutions named in the credit lines. The authors provided Astellas a copy of the original manuscript prior to submission. Bayer HealthCare LLC, Diabetes Care (Tarrytown, NY, USA) provided blood glucose monitoring supplies through an Investigator Sponsored Research Grant.
The Immune Tolerance Network, supported partly by the National Institute of Allergy and Infectious Diseases (NIAID) and the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) of the US National Institutes of Health (NIH) and Juvenile Diabetes Research Foundation (JDRF), was responsible for study design, data collection, analysis, and decision to submit the report for publication. Astellas Pharma US (Northbrook, IL, USA) provided drug for this study and was not involved in the development, design or implementation of the trial or the interpretation of the results. The writing team had full access to all of the data in the study and had final responsibility for the decision to submit for publication.
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