Challenges in developing endpoints for type 1 diabetes intervention studies

Abstract

Development of efficient and safe intervention strategies for preserving and/or restoring endogenous insulin production in type 1 diabetes has encountered a wide range of challenges, including lack of standardized trial protocols and of consensus on appropriate efficacy endpoints. For the greatest part, difficulties resided in choosing the most suitable assay(s) and parameter(s) to assess the beta-cell function. It is now an accepted approach to evaluate endogenous insulin secretion by measuring C-peptide levels (with highly sensitive and normalized measurement methods) in response to a physiologic stimulus (liquid mixed-meal) under standardized conditions. Preventive interventions mandate the identification of well-defined, reliable and validated mechanistic or immunological markers of efficacy that would correlate with (and predict) the clinical outcome. This has not been consistently achieved to date. However, it has been generally agreed that for preventive studies performed very early in the disease course (in subjects without signs of autoimmunity against beta-cells) development of two or more islet related autoantibodies could be employed as biomarkers of disease and thereafter, diagnostic criteria of diabetes serve as suitable endpoints.This report summarizes the conclusions of the D-Cure workshop of international experts held in Barcelona in April 2007 and the current recommendations and updates in the field.

Evaluation of Long-Term Treatment Effect in a Type 1 Diabetes Intervention Trial: Differences After Stimulation With Glucagon or a Mixed Meal

“…Since insulin and C-peptide are cosecreted by b-cells on an equimolar basis, stimulated secretion of C-peptide is widely accepted as a measure of b-cell function (1)(2)(3)(4). Moreover, the Diabetes Control and Complications Trial demonstrated that levels of stimulated C-peptide as low as 0.2 nmol/L are clinically meaningful and could prevent or delay long-term diabetes complications (5,6).…”

Regulatory and policy issues for T1DM immunotherapy

“…15,16 The key unresolved question is what would be regarded by the regulatory authorities as the minimally acceptable treatment effect size at the end of the treatment period-and various points beyond. Given the lack of availability of an approved therapy, it is conceivable that FDA would accept on the order of a 20-30% placebo-adjusted difference in C-peptide secretion.…”

Understanding Pancreatic Secretion in Type 1 Diabetes

“…This test shows the typical postprandial response of the cell and its interaction with the various hormones secreted during oral feeding. It is the most physiological test among the above cited (76,83). Oral glucose tolerance test (OGTT) is the determination of glucose, insulin and CP after 10 hours of fasting and 30, 60, 90, 120 minutes after ingestion of 75g anhydrous glucose orally administered.…”