On the basis of the positive outcome of animal experiments, several large placebo-controlled trials are underway and aiming for the first time at the prevention of an immune-mediated disease,
type 1 diabetes. The first of these trials, The Deutsche
Nicotinamide Intervention Study (DENIS), evaluated the clinical efficacy of high doses of
nicotinamide in children at high risk for
IDDM.
Nicotinamide has been shown to protect beta-cells from inflammatory insults and to improve residual beta-cell function in patients after onset of
IDDM. Individuals at high risk for developing
IDDM within 3 years were identified by screening the siblings (age 3-12 years) of patients with
IDDM for the presence of high titer (> or =20 Juvenile Diabetes Foundation [JDF] U) islet cell
antibodies. Probands (n = 55) were randomized into placebo and
nicotinamide (slow release, 1.2 g x m(-2) x day(-1)) receiving groups and followed prospectively in a controlled clinical trial using a sequential design. Rates of diabetes onset were similar in both groups 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 years 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 cumulative diabetes incidence at 3 years from 30 to 6% (P = 0.97). The group receiving
nicotinamide exhibited decreased first-phase insulin secretion in response to intravenous
glucose (P = 0.03). No other side effects were observed. We conclude that in this subgroup of diabetes-prone individuals at very high risk and with an assumed rapid
disease progression,
nicotinamide treatment did not cause a major decrease or delay of diabetes development. However, the data do not exclude the possibility of a less strong, but potentially meaningful, risk reduction in this cohort, or a major clinical effect of
nicotinamide in individuals with less risk of progression to
IDDM than studied here.