Guidelines for Intervention Trials in Subjects With Newly Diagnosed Type 1 Diabetes
- 1Benaroya Research Institute at Virginia Mason, Seattle, Washington
- 2Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Victoria, Australia
Type 1, or insulin-dependent diabetes, is an autoimmune disease that culminates in the destruction of insulin-producing β-cells in the islets of the pancreas. Studies in the nonobese diabetic (NOD) mouse model of spontaneous type 1 diabetes provide “proof-of-concept” that the disease is preventable (1). People with type 1 diabetes and their relatives, researchers, government, and industry are eager to move forward and test candidate intervention/prevention therapies in humans. Such therapies may entail risks, including accelerated loss of β-cell function, malignancy, and infection. Scientifically and ethically, investigators are obliged to maximize the information gained from intervention trials and minimize risks. One way of achieving this is by standardizing trial protocols. Standardization of islet autoantibody assays (2–13) and of the intravenous glucose tolerance test for measuring first-phase insulin response (14–18) has been a major advance, allowing stratification for disease risk among relatives. The literature on intervention trials in newly diagnosed type 1 diabetic patients (19–44) reveals that entry criteria, trial design and duration, and outcome measures differ considerably. Adoption of standardized protocols would permit comparative and pooled data analysis and facilitate evaluation of potential therapies.
Our purpose here is to highlight issues pertaining to trial variables and suggest ways of standardizing protocols for phase I and II intervention trials in newly diagnosed patients. These issues will be discussed under three major headings: trial subjects, trial design, and trial outcome measures.
SUBJECTS: INCLUSION CRITERIA
Diagnosis of diabetes
Type 1 diabetes can have different clinical presentations that presumably reflect the nature of the underlying disease pathology, to which we have no direct access. Some patients present acutely with dehydration and ketoacidosis, whereas others have minimal or no symptoms (45,46). Natural history studies have indicated that these differences may correlate with the rate of loss of β-cell function and residual β-cell function, determined …