DIABETES/METABOLISM RESEARCH AND REVIEWS REVIEW ARTICLE Diabetes Metab Res Rev 2009; 25: 694–704. Published online 21 September 2009 in Wiley InterScience (www.interscience.wiley.com) DOI: 10.1002/dmrr.1002 Challenges in developing endpoints for type 1 diabetes intervention studies † Simona Cernea 1 Itamar Raz 2 Kevan C. Herold 3 Boaz Hirshberg 4 Bart O. Roep 5 Desmond A. Schatz 6 G. Alexander Fleming 7 Paolo Pozzilli 1 Randie Little 8 Nanette C. Schloot 9 R. David G. Leslie 10 Jay S. Skyler 11 Jerry P. Palmer 12 * 1 Department of Endocrinology and Diabetes, University Campus Bio-Medico, Rome, Italy 2 Diabetes Center, Hadassah-Hebrew University Medical School, Jerusalem, Israel 3 Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA 4 Clinical Research, AstraZeneca LLP, Wilmington, DE, USA 5 Department of Immunohaematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands 6 Department of Pediatrics, University of Florida, Gainesville, FL, USA 7 Kinexum LLC, Harpers Ferry, WV, USA 8 Department of Pathology and Anatomical Sciences, University of Missouri School of Medicine, Columbia, MO, USA 9 German Diabetes Center, Institute for Clinical Diabetology, Leibniz-Center for Diabetes Research at the Heinrich-Heine-University, Duesseldorf, Germany 10 Centre for Diabetes and Metabolic Medicine, Institute of Cell and Molecular Science, London, UK 11 Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA 12 Department of Medicine, University of Washington, Seattle, WA, USA † Updated Report of a D-Cure Workshop, Barcelona, 24–25 April 2007. *Correspondence to: Jerry P. Palmer, Department of Medicine, University of Washington, Seattle, WA, USA. E-mail: jpp@u.washington.edu Received: 3 March 2009 Revised: 7 June 2009 Accepted: 3 July 2009 Summary 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 β -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 β -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. Copyright  2009 John Wiley & Sons, Ltd. Keywords type 1 diabetes; C-peptide; intervention studies The ultimate goal of therapies aiming to reverse type 1 diabetes mellitus (T1DM) is to restore or preserve β -cell mass and function while altering the autoimmune process directed against the pancreatic islet β cells. With emergence of new therapies evaluated in clinical research there is an obvious need for establishment of consensus regarding appropriate outcome measures. In this review article we outline the minutes of a D-Cure workshop which convened a panel of international experts to facilitate this aim (Barcelona, April 2007), with an update of previously published recommendations and an assessment of the current status of endpoints in immune therapy in T1DM. Summary of previous recommendations in T1DM clinical trials 1. Primary outcome for T1DM clinical trials to preserve β -cell function. In 2001 an American Diabetes Association (ADA) workshop evaluated several potential efficacy outcome measures and concluded that the mea- surement of stimulated C-peptide under standardized conditions (which provides a direct estimate of the endogenous insulin secretion) is the Copyright  2009 John Wiley & Sons, Ltd.