Journal article
Alefacept provides sustained clinical and immunological effects in new-onset type 1 diabetes patients
The Journal of clinical investigation, Vol.125(8), pp.3285-3296
08/03/2015
DOI: 10.1172/JCI81722
PMCID: PMC4623571
PMID: 26193635
Abstract
BACKGROUND.
Type 1 diabetes (T1D) results from destruction of pancreatic β cells by autoreactive effector T cells. We hypothesized that the immunomodulatory drug alefacept would result in targeted quantitative and qualitative changes in effector T cells and prolonged preservation of endogenous insulin secretion by the remaining β cells in patients with newly diagnosed T1D.
METHODS.
In a multicenter, randomized, double-blind, placebo-controlled trial, we compared alefacept (two 12-week courses of 15 mg/wk i.m., separated by a 12-week pause) with placebo in patients with recent onset of T1D. Endpoints were assessed at 24 months and included meal-stimulated C-peptide AUC, insulin use, hypoglycemic events, and immunologic responses.
RESULTS.
A total of 49 patients were enrolled. At 24 months, or 15 months after the last dose of alefacept, both the 4-hour and the 2-hour C-peptide AUCs were significantly greater in the treatment group than in the control group (
P
= 0.002 and 0.015, respectively). Exogenous insulin requirements were lower (
P
= 0.002) and rates of major hypoglycemic events were about 50% reduced (
P
< 0.001) in the alefacept group compared with placebo at 24 months. There was no apparent between-group difference in glycemic control or adverse events. Alefacept treatment depleted CD4
+
and CD8
+
central memory T cells (Tcm) and effector memory T cells (Tem) (
P
< 0.01), preserved Tregs, increased the ratios of Treg to Tem and Tcm (
P
< 0.01), and increased the percentage of PD-1
+
CD4
+
Tem and Tcm (
P
< 0.01).
CONCLUSIONS.
In patients with newly diagnosed T1D, two 12-week courses of alefacept preserved C-peptide secretion, reduced insulin use and hypoglycemic events, and induced favorable immunologic profiles at 24 months, well over 1 year after cessation of therapy.
TRIAL REGISTRATION.
https://clinicaltrials.gov/ NCT00965458
.
FUNDING.
NIH and Astellas.
Details
- Title: Subtitle
- Alefacept provides sustained clinical and immunological effects in new-onset type 1 diabetes patients
- Creators
- Mark R Rigby - Section of Pediatric Endocrinology and Diabetology, Department of Pediatrics, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, Indiana, USAKristina M Harris - Biomarker Discovery Research, ITN, Bethesda, Maryland, USAAshley Pinckney - Biostatistics, Rho Inc., Federal Systems Division, Chapel Hill, North Carolina, USALinda A DiMeglio - Section of Pediatric Endocrinology and Diabetology, Department of Pediatrics, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, Indiana, USAMarc S Rendell - Creighton Diabetes Center, Omaha, Nebraska, USAEric I Felner - Department of Pediatrics, Division of Pediatric Endocrinology, Emory University School of Medicine, Atlanta, Georgia, USAJean M Dostou - Division of Endocrinology, Department of Medicine, University of North Carolina School of Medicine at Chapel Hill, Durham, North Carolina, USAStephen E Gitelman - Department of Pediatrics, Division of Endocrinology, UCSF, San Francisco, California, USAKurt J Griffin - Department of Pediatric Endocrinology, University of Arizona, Tucson, Arizona, USAEva Tsalikian - Department of Pediatrics, Division of Pediatric Endocrinology and Diabetes, University of Iowa, Iowa City, Iowa, USAPeter A Gottlieb - Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, Colorado, USACarla J Greenbaum - Benaroya Research Institute at Virginia Mason, Seattle, Washington, USANicole A Sherry - Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts, USAWayne V Moore - Pediatric Endocrinology, Children’s Mercy Hospital, University of Missouri, Kansas City, Missouri, USARoshanak Monzavi - Center for Endocrinology, Diabetes, and Metabolism, Children’s Hospital Los Angeles, Department of Pediatrics, USC Keck School of Medicine, Los Angeles, California, USASteven M Willi - Department of Endocrinology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USAPhilip Raskin - Department of Internal Medicine, Division of Endocrinology, The University of Texas Southwestern Medical Center, Dallas, Texas, USALynette Keyes-Elstein - Biostatistics, Rho Inc., Federal Systems Division, Chapel Hill, North Carolina, USAS. Alice Long - Benaroya Research Institute at Virginia Mason, Seattle, Washington, USASai Kanaparthi - Biomarker Discovery Research, ITN, Bethesda, Maryland, USANoha Lim - Biomarker Discovery Research, ITN, Bethesda, Maryland, USADeborah Phippard - Biomarker Discovery Research, ITN, Bethesda, Maryland, USACarol L Soppe - Clinical Trials Group, ITN, San Francisco, California, USAMargret L Fitzgibbon - Division of Allergy, Immunology, and Transplantation, National Institutes of Allergy and Infectious Diseases, Rockville, Maryland, USAJames McNamara - Division of Allergy, Immunology, and Transplantation, National Institutes of Allergy and Infectious Diseases, Rockville, Maryland, USAGerald T Nepom - Benaroya Research Institute at Virginia Mason, Seattle, Washington, USAMario R Ehlers - Clinical Trials Group, ITN, San Francisco, California, USAImmune Tolerance Network ITN TIDAL
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.125(8), pp.3285-3296
- DOI
- 10.1172/JCI81722
- PMID
- 26193635
- PMCID
- PMC4623571
- NLM abbreviation
- J Clin Invest
- ISSN
- 0021-9738
- eISSN
- 1558-8238
- Publisher
- American Society for Clinical Investigation
- Language
- English
- Date published
- 08/03/2015
- Academic Unit
- Stead Family Department of Pediatrics; Fraternal Order of Eagles Diabetes Research Center
- Record Identifier
- 9984093495802771
Metrics
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