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Lancet Diabetes Endocrinol. 2013 Dec;1(4):284-94. doi: 10.1016/S2213-8587(13)70111-6. Epub 2013 Sep 23.

Targeting of memory T cells with alefacept in new-onset type 1 diabetes (T1DAL study): 12 month results of a randomised, double-blind, placebo-controlled phase 2 trial.

Author information

1
Indiana University and Riley Hospital for Children at Indiana University Health, Indianapolis, Indianapolis, IN, USA. Electronic address: mrigby@iu.edu.
2
Indiana University and Riley Hospital for Children at Indiana University Health, Indianapolis, Indianapolis, IN, USA.
3
Creighton Diabetes Center, Omaha, NE, USA.
4
Emory University, Atlanta, GA, USA.
5
University of North Carolina, Durham, NC, USA.
6
University of California San Francisco, San Francisco, CA, USA.
7
University of Arizona, Tucson, AZ, USA.
8
University of Iowa, Iowa City, Iowa, USA.
9
Barbara Davis Center, University of Colorado, Aurora, CO, USA.
10
Benaroya Research Institute, Seattle, WA, USA.
11
Massachusetts General Hospital, Boston, MA, USA.
12
Children's Mercy Hospital, Kansas City, MO, USA.
13
Children's Hospital Los Angeles, Los Angeles, CA, USA.
14
Children's Hospital of Philadelphia, Philadelphia, PA, USA.
15
The University of Texas, Southwestern Medical Center, Dallas, TX, USA.
16
University of Minnesota, Minneapolis, MN, USA.
17
Vanderbilt University Medical Center, Nashville, Tennessee, USA.
18
Rho Federal Systems Division, Chapel Hill, NC, USA.
19
Immune Tolerance Network, Bethesda, MD, USA.
20
National Institutes of Allergy and Infectious Diseases, Bethesda, MD, USA.
21
Immune Tolerance Network, San Francisco, CA, USA.

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; 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.

Comment in

PMID:
24622414
PMCID:
PMC3957186
DOI:
10.1016/S2213-8587(13)70111-6
[Indexed for MEDLINE]
Free PMC Article

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