THE DEUTSCHE-NICOTINAMIDE-INTERVENTION-STUDY - AN ATTEMPT TO PREVENT TYPE-1 DIABETES

On the basis of the positive outcome of animal experiments, several la rge placebo-controlled trials are underway and aiming for the first ti me at the prevention of an immune-mediated disease, type 1 diabetes. T he first of these trials, The Deutsche Nicotinamide Intervention Study (DENIS), evaluated the clinical efficacy of high doses of nicotinamid e in children at high risk for lDDM. Nicotinamide has been shown to pr otect beta-cells from inflammatory insults and to improve residual bet a-cell function in patients after onset of IDDM. Individuals at high r isk for developing IDDM within 3 years were identified by screening th e siblings (age 3-12 years) of patients with IDDM for the presence of high titer (greater than or equal to 20 Juvenile Diabetes Foundation [ JDF] U) islet cell antibodies. Probands (n = 55) were randomized into placebo and nicotinamide (slow release, 1.2 g.m(-2).day(-1)) receiving groups and followed prospectively in a controlled clinical trial usin g a sequential design. Rates of diabetes onset were similar in both gr oups throughout the observation period (maximum 3.8 years, median 2.1 years). This sequential design provides a 10% probability of a type II error against a reduction of the cumulative diabetes incidence at 3 y ears from 30 to 6% by nicotinamide. The trial was terminated when the second sequential interim analysis after the eleventh case of diabetes showed that the trial had failed to detect a reduction of the cumulat ive diabetes incidence at 3 years from 30 to 6% (P = 0.97). The group receiving nicotinamide exhibited decreased first-phase insulin secreti on in response to intravenous glucose (P = 0.03). No other side effect s were observed. We conclude that in this subgroup of diabetes-prone i ndividuals at very high risk and with an assumed rapid disease progres sion, nicotinamide treatment did not cause a major decrease or delay o f diabetes development. Hoc-ever, the data do not exclude the possibil ity of a less strong, but potentially meaningful, risk reduction in th is cohort, or a major clinical effect of nicotinamide in individuals w ith less risk of progression to IDDM than studied here.