Objective
The overall objective is to establish in a prospective, randomized, placebo controlled trial whether daily oral administration of high dose nicotinamide can produce a clinically useful reduction in the rate of progression to IDDM in relatives at increased risk of contracting the disease. Specific aims are:
1.To complete recruitment to the expanded ENDIT trial and perform the 3 year interim statistical review.
2.To extend and strengthen the current multinational programme of screening for risk of IDDM in first degree relatives.
3.To develop and test new strategies for risk assessment within this population, including application of novel miniaturized high-throughput genetic and immune assay systems.
4. To establish an international collaborative network capable of undertaking a programme of prompt, high quality and cost-effective intervention trials in individuals at high risk of progression to IDDM.
Nicotinamide, a soluble B group vitamin, has been known for many years to offer protection to pancreatic beta cells against a variety of toxic agents both in vivo and in vitro. Recent research has established a sound scientific rationale for its use in attempted prevention of human type 1 diabetes, and promising pilot studies have been performed. ENDIT, a five year trial of sustained release nicotinamide versus placebo as a potential means of delaying the onset of type 1 diabetes, is the first multinational diabetes prevention trial to get under way. Non-diabetic high risk first degree relatives have been randomized to treatment in 11 European countries, Canada and the USA, while 11 additional European countries are currently preparing to participate. A total of 201 local centres are involved. The aim over the past 3 years has been to set up the trial and to randomize 320 patients to treatment by the end of 1995; we are on course for this target. The inclusion of additional national groups now enables us to extend recruitment to the trial in order to improve its statistical power. We have therefore increased the target for recruitment to 530 high risk relatives, on the assumption that a minimum of 422 will complete the trial. This will give us 90% power to detect a 40% treatment effect, as against 50% effect with the previous design. Screening and recruitment of the additional numbers needed will be completed by 1997, and the three year interim statistical review, timed from recruitment of the first 211 patients, will be carried out in summer 1998. Further, the network that has been established is now in a position to develop a long term programme of diabetes prevention trials. In preparation for this we are networking the 15 laboratories involved in screening for risk of diabetes more closely, and will extend our training programme. In addition we aim to develop and test novel high throughput screening methods for immune and genetic markers, in concert with the PARADIGM centralized facility, in order to improve the precision and efficiency of risk estimation.