title: Antithymocyte globulin treatment for patients with recent-onset type 1 diabetes: 12-month results of a randomised, placebo-controlled, phase 2 trial.
abstract: BACKGROUND
  Type 1 diabetes results from T-cell-mediated destruction of β cells. Findings from preclinical studies and pilot clinical trials suggest that antithymocyte globulin (ATG) might be effective for reducing this autoimmune response. We assessed the safety and efficacy of rabbit ATG in preserving islet function in participants with recent-onset type 1 diabetes, and report here our 12-month results.
  
  
  METHODS
  For this phase 2, randomised, placebo-controlled, clinical trial, we enrolled patients with recent-onset type 1 diabetes, aged 12-35 years, and with a peak C-peptide of 0.4 nM or greater on mixed meal tolerance test from 11 sites in the USA. We used a computer generated randomisation sequence to randomly assign patients (2:1, with permuted-blocks of size three or six and stratified by study site) to receive either 6.5 mg/kg ATG or placebo over a course of four days. All participants were masked and initially managed by an unmasked drug management team, which managed all aspects of the study until month 3. Thereafter, to maintain masking for diabetes management throughout the remainder of the study, participants received diabetes management from an independent, masked study physician and nurse educator. The primary endpoint was the baseline-adjusted change in 2-h area under the curve C-peptide response to mixed meal tolerance test from baseline to 12 months. Analyses were by intention to treat. This is a planned interim analysis of an on-going trial that will run for 24 months of follow-up. This study is registered with ClinicalTrials.gov, number NCT00515099.
  
  
  RESULTS
  Between Sept 10, 2007, and June 1, 2011, we screened 154 individuals, randomly allocating 38 to ATG and 20 to placebo. We recorded no between-group difference in the primary endpoint: participants in the ATG group had a mean change in C-peptide area under the curve of -0.195 pmol/mL (95% CI -0.292 to -0.098) and those in the placebo group had a mean change of -0.239 pmol/mL (-0.361 to -0.118) in the placebo group (p=0.591). All except one participant in the ATG group had both cytokine release syndrome and serum sickness, which was associated with a transient rise in interleukin-6 and acute-phase proteins. Acute T cell depletion occurred in the ATG group, with slow reconstitution over 12 months. However, effector memory T cells were not depleted, and the ratio of regulatory to effector memory T cells declined in the first 6 months and stabilised thereafter. ATG-treated patients had 159 grade 3-4 adverse events, many associated with T-cell depletion, compared with 13 in the placebo group, but we detected no between-group difference in incidence of infectious diseases.
  
  
  CONCLUSIONS
  Our findings suggest that a brief course of ATG does not result in preservation of β-cell function 12 months later in patients with new-onset type 1 diabetes. Generalised T-cell depletion in the absence of specific depletion of effector memory T cells and preservation of regulatory T cells seems to be an ineffective treatment for type 1 diabetes.
authors.affiliation: University of California San Francisco, San Francisco, CA, USA. Electronic address: sgitelma@peds.ucsf.edu.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Gitelman
authors.affiliation: Barbara Davis Center, University of Colorado, Aurora, CO, USA.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Gottlieb
authors.affiliation: Indiana University and Riley Children's Hospital, Indianapolis, Indianapolis, IN, USA.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Rigby
authors.affiliation: Emory University, Atlanta, GA, USA.
authors.forename: Eric I
authors.initials: EI
authors.lastname: Felner
authors.affiliation: Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Willi
authors.affiliation: Children's Hospital of Los Angeles, Los Angeles, CA, USA.
authors.forename: Lynda K
authors.initials: LK
authors.lastname: Fisher
authors.affiliation: University of Minnesota, Minneapolis, MN, USA.
authors.forename: Antoinette
authors.initials: A
authors.lastname: Moran
authors.affiliation: University of California San Diego, San Diego, CA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Gottschalk
authors.affiliation: Children's Mercy Hospital, Kansas City, MO, USA.
authors.forename: Wayne V
authors.initials: WV
authors.lastname: Moore
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: Sudeepta
authors.initials: S
authors.lastname: Aggarwal
authors.affiliation: Immune Tolerance Network, Bethesda, MD, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Phippard
authors.affiliation: Immune Tolerance Network, San Francisco, CA, USA.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Sayre
authors.affiliation: National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.
authors.forename: Linna
authors.initials: L
authors.lastname: Ding
authors.affiliation: University of California San Francisco, San Francisco, CA, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Bluestone
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; D000961:Antilymphocyte Serum / Q000627:therapeutic use*; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000175:diagnosis* / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use*; D008297:Male; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000961:Antilymphocyte Serum; D007155:Immunologic Factors