title: Combination therapy with sitagliptin and lansoprazole in patients with recent-onset type 1 diabetes (REPAIR-T1D): 12-month results of a multicentre, randomised, placebo-controlled, phase 2 trial.
abstract: BACKGROUND
  Type 1 diabetes results from autoimmune destruction of pancreatic β cells. Findings from preclinical studies suggest that dipeptidyl peptidase-4 inhibitors and proton-pump inhibitors might enhance β-cell survival and regeneration. We postulated that sitagliptin and lansoprazole would preserve β-cell function in patients with recent-onset type 1 diabetes.
  
  
  METHODS
  We did a double-blind, placebo-controlled, phase 2 trial (REPAIR-T1D). Participants aged 11-36 years, diagnosed with type 1 diabetes within the past 6 months were recruited from Sanford Health Systems (Sioux Falls, SD, USA; Fargo, ND, USA), Children's Hospitals and Clinics of Minnesota (St Paul, MN, USA), and Rady Children's Hospital (San Diego, CA, USA). Participants were randomly assigned (2:1) to receive oral sitagliptin (100 mg for participants ≥18 years, 50 mg for those <18 years) and lansoprazole (60 mg for participants ≥18 years, 30 mg for those <18 years) or matched placebo for 12 months. Randomisation was done by a blocked randomisation process (blocks of three and six), with separate streams for younger (<18 years) and older (≥18 years) participants, and males and females. All participants and personnel remained masked until after the completion of the final 12 month visit, at which time data were unmasked to the analysis team. The primary endpoint was C-peptide response to a mixed meal challenge at 12 months measured as 2 h area under curve. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01155284.
  
  
  RESULTS
  Between Sept 21, 2010, and May 29, 2012, 46 participants were randomly assigned to the treatment group and 22 to the placebo group; of whom 40 participants in the treatment group and 18 in the placebo group completed the 12-month treatment. At 12 months, the mean change in C-peptide area under curve was -229 pmol/L (95% CI -316 to -142) for the treatment group and -253 pmol/L (-383 to -123) for the placebo group; this difference was not significant (p=0·77). No adverse or serious adverse events were probably or definitely related to the study treatment.
  
  
  CONCLUSIONS
  Although the expected change in the primary endpoint was not achieved, not all participants had increases in glucagon-like peptide-1 and gastrin concentrations that were expected with treatment. Although participants did not have adverse events related to study drugs, the study is not powered to address safety definitively. Further trials including these drugs might be warranted, but should be designed to ensure appropriate selection of participants and increases in these intermediary hormones.
  
  
  BACKGROUND
  Sanford Research and JDRF.
authors.affiliation: The Sanford Project, Sanford Research, and Sanford School of Medicine, University of South Dakota, Sioux Falls, SD, USA.
authors.forename: Kurt J
authors.initials: KJ
authors.lastname: Griffin
authors.affiliation: The Sanford Project, Sanford Research, and Sanford School of Medicine, University of South Dakota, Sioux Falls, SD, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Thompson
authors.affiliation: University of California San Diego and Rady Children's Hospital Pediatric Endocrinology, San Diego, CA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Gottschalk
authors.affiliation: Children's Hospitals and Clinics of Minnesota, St Paul, MN, USA.
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Kyllo
authors.affiliation: The Sanford Project, Sanford Research, and Sanford School of Medicine, University of South Dakota, Sioux Falls, SD, USA. Electronic address: alex.rabinovitch@sanfordhealth.org.
authors.forename: Alex
authors.initials: A
authors.lastname: Rabinovitch
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000188:drug therapy* / Q000453:epidemiology; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D064747:Lansoprazole / Q000008:administration & dosage*; D008297:Male; D011719:Pyrazines / Q000008:administration & dosage*; D000068900:Sitagliptin Phosphate; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage*; D014481:United States / Q000453:epidemiology
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D011719:Pyrazines; D014230:Triazoles; D064747:Lansoprazole; D000068900:Sitagliptin Phosphate