title: Teplizumab treatment may improve C-peptide responses in participants with type 1 diabetes after the new-onset period: a randomised controlled trial.
abstract: OBJECTIVE
  Type 1 diabetes results from a chronic autoimmune process continuing for years after presentation. We tested whether treatment with teplizumab (a Fc receptor non-binding anti-CD3 monoclonal antibody), after the new-onset period, affects the decline in C-peptide production in individuals with type 1 diabetes.
  
  
  METHODS
  In a randomised placebo-controlled trial we treated 58 participants with type 1 diabetes for 4-12 months with teplizumab or placebo at four academic centres in the USA. A central randomisation centre used computer generated tables to allocate treatments. Investigators, patients, and caregivers were blinded to group assignment. The primary outcome was a comparison of C-peptide responses to a mixed meal after 1 year. We explored modification of treatment effects in subgroups of patients.
  
  
  RESULTS
  Thirty-four and 29 subjects were randomized to the drug and placebo treated groups, respectively. Thirty-one and 27, respectively, were analysed. Although the primary outcome analysis showed a 21.7% higher C-peptide response in the teplizumab-treated group (0.45 vs 0.371; difference, 0.059 [95% CI 0.006, 0.115] nmol/l) (p = 0.03), when corrected for baseline imbalances in HbA(1c) levels, the C-peptide levels in the teplizumab-treated group were 17.7% higher (0.44 vs 0.378; difference, 0.049 [95% CI 0, 0.108] nmol/l, p = 0.09). A greater proportion of placebo-treated participants lost detectable C-peptide responses at 12 months (p = 0.03). The teplizumab group required less exogenous insulin (p < 0.001) but treatment differences in HbA(1c) levels were not observed. Teplizumab was well tolerated. A subgroup analysis showed that treatment benefits were larger in younger individuals and those with HbA(1c) <6.5% at entry. Clinical responders to teplizumab had an increase in circulating CD8 central memory cells 2 months after enrolment compared with non-responders.
  
  
  CONCLUSIONS
  This study suggests that deterioration in insulin secretion may be affected by immune therapy with teplizumab after the new-onset period but the magnitude of the effect is less than during the new-onset period. Our studies identify characteristics of patients most likely to respond to this immune therapy.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00378508
  
  
  BACKGROUND
  This work was supported by grants 2007-502, 2007-1059 and 2006-351 from the JDRF and grants R01 DK057846, P30 DK20495, UL1 RR024139, UL1RR025780, UL1 RR024131 and UL1 RR024134 from the NIH.
authors.affiliation: Departments of Immunobiology and Internal Medicine, Yale University, 300 George St, New Haven, CT 06511, USA. Kevan.herold@yale.edu
authors.forename: K C
authors.initials: KC
authors.lastname: Herold
authors.forename: S E
authors.initials: SE
authors.lastname: Gitelman
authors.forename: S M
authors.initials: SM
authors.lastname: Willi
authors.forename: P A
authors.initials: PA
authors.lastname: Gottlieb
authors.forename: F
authors.initials: F
authors.lastname: Waldron-Lynch
authors.forename: L
authors.initials: L
authors.lastname: Devine
authors.forename: J
authors.initials: J
authors.lastname: Sherr
authors.forename: S M
authors.initials: SM
authors.lastname: Rosenthal
authors.forename: S
authors.initials: S
authors.lastname: Adi
authors.forename: M Y
authors.initials: MY
authors.lastname: Jalaludin
authors.forename: A W
authors.initials: AW
authors.lastname: Michels
authors.forename: J
authors.initials: J
authors.lastname: Dziura
authors.forename: J A
authors.initials: JA
authors.lastname: Bluestone
mesh_terms: D000293:Adolescent; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D002096:C-Peptide / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D008297:Male
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D002096:C-Peptide; D006442:Glycated Hemoglobin; D007328:Insulin; C502540:teplizumab