DIRECT - Innovative Medicines Initiative:
DIabetes REsearCh on patient straTification

Work Package 8 (WP8):
Validation of biomarkers for glycaemic
deterioration in a large clinical trial

The aim of the clinical trial work packages 7&8 will be primarily to validate biomarkers from discovery work packages 2 to 5 as predictors of events in prospective clinical trials. Additionally it may be possible to establish their clinical utility as predictive or response (surrogate) biomarkers for shortening clinical trials.

The clinical trial design will clearly depend upon the biomarkers discovered in part 1 of the project, but will range from a large trial of an intervention to delay progression of diabetes or pre-diabetes to several smaller trials to validate biomarkers of therapeutic response (WP7).

The WP8 trial is envisaged to follow on from outputs of work package 2 (predictive and surrogate biomarkers of glycaemic deterioration) where longer larger trials are needed with hard endpoint. The decision of final study design will depend on the biomarkers available at year four, when we expect to have a range of markers (genomic, proteomic, metabolomic, lipidomic, physiological and imaging) that predict deterioration of glycaemic control in patients with type 2 diabetes.

Possible WP8 clinical trials are:

  • A trial that demonstrates potential surrogate response biomarkers in approx. 2400 patients with established type 2 diabetes currently failing on monotherapy with metformin. Patients would be randomised to usual care addition of a second line agent and would be followed up to establish time to progression to the requirement of a third line agent and that this delay is accompanied by the expected difference in the surrogate biomarker between the treatment arms during follow up.
  • A trial demonstrating the application of biomarkers for predicting progression to diabetes in pre-diabetes patients. Approx. 2400 individuals at high risk of developing diabetes, identified at recruitment on the basis of their risk score and incorporating genomic and physiologic biomarkers arising from the scientific work packages, would be randomised to placebo or medication. The key outcome would be progression to diabetes over 18 months.

  • Sanofi-Aventis Deutschland GmbH
  • University of Dundee
  • University of Bath
  • Helmholtz Zentrum München – Deutsches Forschungszentrum für Gesundheit und Umwelt GmbH
  • Imperial College London
  • University of Lille - CNRS
  • Eli Lilly and Company Ltd.