title: 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.
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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Indiana University and Riley Hospital for Children at Indiana University Health, Indianapolis, Indianapolis, IN, USA. Electronic address: mrigby@iu.edu.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Rigby
authors.affiliation: Indiana University and Riley Hospital for Children at Indiana University Health, Indianapolis, Indianapolis, IN, USA.
authors.forename: Linda A
authors.initials: LA
authors.lastname: DiMeglio
authors.affiliation: Creighton Diabetes Center, Omaha, NE, USA.
authors.forename: Marc S
authors.initials: MS
authors.lastname: Rendell
authors.affiliation: Emory University, Atlanta, GA, USA.
authors.forename: Eric I
authors.initials: EI
authors.lastname: Felner
authors.affiliation: University of North Carolina, Durham, NC, USA.
authors.forename: Jean M
authors.initials: JM
authors.lastname: Dostou
authors.affiliation: University of California San Francisco, San Francisco, CA, USA.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Gitelman
authors.affiliation: University of Arizona, Tucson, AZ, USA.
authors.forename: Chetanbabu M
authors.initials: CM
authors.lastname: Patel
authors.affiliation: University of Arizona, Tucson, AZ, USA.
authors.forename: Kurt J
authors.initials: KJ
authors.lastname: Griffin
authors.affiliation: University of Iowa, Iowa City, Iowa, USA.
authors.forename: Eva
authors.initials: E
authors.lastname: Tsalikian
authors.affiliation: Barbara Davis Center, University of Colorado, Aurora, CO, USA.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Gottlieb
authors.affiliation: Benaroya Research Institute, Seattle, WA, USA.
authors.forename: Carla J
authors.initials: CJ
authors.lastname: Greenbaum
authors.affiliation: Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Sherry
authors.affiliation: Children's Mercy Hospital, Kansas City, MO, USA.
authors.forename: Wayne V
authors.initials: WV
authors.lastname: Moore
authors.affiliation: Children's Hospital Los Angeles, Los Angeles, CA, USA.
authors.forename: Roshanak
authors.initials: R
authors.lastname: Monzavi
authors.affiliation: Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Willi
authors.affiliation: The University of Texas, Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Philip
authors.initials: P
authors.lastname: Raskin
authors.affiliation: University of Minnesota, Minneapolis, MN, USA.
authors.forename: Antoinette
authors.initials: A
authors.lastname: Moran
authors.affiliation: Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: William E
authors.initials: WE
authors.lastname: Russell
authors.affiliation: Rho Federal Systems Division, Chapel Hill, NC, USA.
authors.forename: Ashley
authors.initials: A
authors.lastname: Pinckney
authors.affiliation: Rho Federal Systems Division, Chapel Hill, NC, USA.
authors.forename: Lynette
authors.initials: L
authors.lastname: Keyes-Elstein
authors.affiliation: Immune Tolerance Network, Bethesda, MD, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Howell
authors.affiliation: Immune Tolerance Network, Bethesda, MD, USA.
authors.forename: Sudeepta
authors.initials: S
authors.lastname: Aggarwal
authors.affiliation: Immune Tolerance Network, Bethesda, MD, USA.
authors.forename: Noha
authors.initials: N
authors.lastname: Lim
authors.affiliation: Immune Tolerance Network, Bethesda, MD, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Phippard
authors.affiliation: Benaroya Research Institute, Seattle, WA, USA.
authors.forename: Gerald T
authors.initials: GT
authors.lastname: Nepom
authors.affiliation: National Institutes of Allergy and Infectious Diseases, Bethesda, MD, USA.
authors.forename: James
authors.initials: J
authors.lastname: McNamara
authors.affiliation: Immune Tolerance Network, San Francisco, CA, USA.
authors.forename: Mario R
authors.initials: MR
authors.lastname: Ehlers
mesh_terms: D000293:Adolescent; D000328:Adult; D000077944:Alefacept; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000097:blood* / Q000188:drug therapy* / Q000276:immunology; D004311:Double-Blind Method; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage; D007156:Immunologic Memory / Q000187:drug effects* / Q000276:immunology; D008297:Male; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D055815:Young Adult
chemical_list: D007004:Hypoglycemic Agents; D011993:Recombinant Fusion Proteins; D000077944:Alefacept