Abstract
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; p1c 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.