title: The use of intermediate endpoints in the design of type 1 diabetes prevention trials.
abstract: OBJECTIVE
  This paper presents a rationale for the selection of intermediate endpoints to be used in the design of type 1 diabetes prevention clinical trials.
  
  
  METHODS
  Relatives of individuals diagnosed with type 1 diabetes were enrolled on the TrialNet Natural History Study and screened for diabetes-related autoantibodies. Those with two or more such autoantibodies were analysed with respect to increased HbA1c, decreased C-peptide following an OGTT, or abnormal OGTT values as intermediate markers of disease progression.
  
  
  RESULTS
  Over 2 years, a 10% increase in HbA1c, and a 20% or 30% decrease in C-peptide from baseline, or progression to abnormal OGTT, occurred with a frequency between 20% and 41%. The 3- to 5-year risk of type 1 diabetes following each intermediate endpoint was high, namely 47% to 84%. The lower the incidence of the endpoint being reached, the higher the risk of diabetes. A diabetes prevention trial using these intermediate endpoints would require a 30% to 50% smaller sample size than one using type 1 diabetes as the endpoint.
  
  
  CONCLUSIONS
  The use of an intermediate endpoint in diabetes prevention is based on the generally held view of disease progression from initial occurrence of autoantibodies through successive immunological and metabolic changes to manifest type 1 diabetes. Thus, these markers are suitable for randomised phase 2 trials, which can more rapidly screen promising new therapies, allowing them to be subsequently confirmed in definitive phase 3 trials.
authors.affiliation: Division of Informatics and Biostatistics, Department of Pediatrics, University of South Florida, Tampa, FL 33612, USA. jpkrischer@epi.usf.edu
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Krischer
mesh_terms: D000293:Adolescent; D000328:Adult; D001323:Autoantibodies / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D002096:C-Peptide / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000378:metabolism / Q000517:prevention & control*; D005260:Female; D005951:Glucose Tolerance Test; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D001786:Blood Glucose; D002096:C-Peptide; D006442:Glycated Hemoglobin