Journal article
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
The lancet. Diabetes & endocrinology, Vol.1(4), pp.284-294
12/2013
DOI: 10.1016/S2213-8587(13)70111-6
PMCID: PMC3957186
PMID: 24622414
Abstract
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.
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.
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.
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.
Details
- Title: Subtitle
- 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
- Creators
- Eva Tsalikian - University of Iowa, Iowa City, Iowa, USAMark R Rigby - Indiana University and Riley Hospital for Children at Indiana University Health, Indianapolis, Indianapolis, IN, USA. Electronic address: mrigby@iu.eduLinda A DiMeglio - Indiana University and Riley Hospital for Children at Indiana University Health, Indianapolis, Indianapolis, IN, USAJames McNamara - National Institutes of Allergy and Infectious Diseases, Bethesda, MD, USAMarc S Rendell - Creighton Diabetes Center, Omaha, NE, USAEric I Felner - Emory University, Atlanta, GA, USAJean M Dostou - University of North Carolina, Durham, NC, USAChetanbabu M Patel - University of Arizona, Tucson, AZ, USAKurt J Griffin - University of Arizona, Tucson, AZ, USAPeter A Gottlieb - Barbara Davis Center, University of Colorado, Aurora, CO, USACarla J Greenbaum - Benaroya Research Institute, Seattle, WA, USANicole A Sherry - Massachusetts General Hospital, Boston, MA, USAWayne V Moore - Children's Mercy Hospital, Kansas City, MO, USARoshanak Monzavi - Children's Hospital Los Angeles, Los Angeles, CA, USASteven M Willi - Children's Hospital of Philadelphia, Philadelphia, PA, USAPhilip Raskin - The University of Texas, Southwestern Medical Center, Dallas, TX, USAAntoinette Moran - University of Minnesota, Minneapolis, MN, USAWilliam E Russell - Vanderbilt University Medical Center, Nashville, Tennessee, USAAshley Pinckney - Rho Federal Systems Division, Chapel Hill, NC, USALynette Keyes-Elstein - Rho Federal Systems Division, Chapel Hill, NC, USAMichael Howell - Immune Tolerance Network, Bethesda, MD, USASudeepta Aggarwal - Immune Tolerance Network, Bethesda, MD, USANoha Lim - Immune Tolerance Network, Bethesda, MD, USADeborah Phippard - Immune Tolerance Network, Bethesda, MD, USAGerald T Nepom - Benaroya Research Institute, Seattle, WA, USAMario R Ehlers - Immune Tolerance Network, San Francisco, CA, USAType 1 Diabetes With Alefacept (T1DAL) Study Team
- Resource Type
- Journal article
- Publication Details
- The lancet. Diabetes & endocrinology, Vol.1(4), pp.284-294
- DOI
- 10.1016/S2213-8587(13)70111-6
- PMID
- 24622414
- PMCID
- PMC3957186
- ISSN
- 2213-8587
- eISSN
- 2213-8595
- Grant note
- P30 DK017047 / NIDDK NIH HHS U01 AI101984 / NIAID NIH HHS TR000006 / NCATS NIH HHS UL1 TR000442-06 / NCATS NIH HHS UM2 AI117870 / NIAID NIH HHS UL1 RR024131 / NCRR NIH HHS UL1 TR000006 / NCATS NIH HHS UL1TR000003 / NCATS NIH HHS DP3 DK097681 / NIDDK NIH HHS UL1 TR000442 / NCATS NIH HHS UL1 TR000004 / NCATS NIH HHS UL1 TR001108 / NCATS NIH HHS N01 AI015416 / NIAID NIH HHS UL1 RR024134 / NCRR NIH HHS UL1 TR000003 / NCATS NIH HHS UL1RR024134 / NCRR NIH HHS
- Language
- English
- Date published
- 12/2013
- Academic Unit
- Stead Family Department of Pediatrics
- Record Identifier
- 9984093232602771
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