Oral nicotinamide to reduce actinic cancer: A phase 3 double-blind randomized controlled trial.

9000 Background: Nicotinamide (vitamin B3) enhances DNA repair and prevents cutaneous immune suppression after ultraviolet (UV) radiation exposure. It reduces photocarcinogenesis in mice, and human non-melanoma skin cancers (NMSC) in Phase 2 clinical trials. We report the outcomes of the Phase 3 Oral Nicotinamide to Reduce Actinic Cancer (ONTRAC) Study. Methods: ONTRAC was a double-blind RCT conducted in two tertiary treatment centers in Sydney, Australia from 2012-2014. 386 immune competent participants with ≥ 2 histologically-confirmed NMSC in the past 5 years were randomized (1:1) to oral nicotinamide 500mg bd (NIC) or matched placebo (PBO) for 12 months. The primary endpoint was the number of new NMSCs to 12 months. Secondary endpoints included number of squamous cell carcinomas (SCCs), basal cell carcinomas (BCCs), and actinic keratoses (AKs) to 12 months. Skin reviews by dermatologists were performed 3 monthly. The sample size provided 90% power to detect a 33% difference in NMSC rates. Analysis was by intention-to-treat. Results: The mean age of study population was 66 years, the mean number of NMSC in the past 5 years was 8, and 63% were men. Treatment discontinuation rates were 9% for PBO versus 10% for NIC. 99% of patients underwent at least one post-baseline skin assessment. The average NMSC rate was significantly lower for NIC (1.77) than PBO (2.42). The estimated relative rate reduction (RRR) was 0.23 (95% CI: 0.04 to 0.38, p = 0.02) adjusting for center and NMSC history, and 0.27 (95% CI: 0.05 to 0.44; p = 0.02) with no adjustment. Treatment effects of comparable magnitude were found for both BCCs (RRR = 0.20, 95% CI: -0.06 to 0.39, p = 0.1) and SCCs (RRR = 0.30, 95% CI: 0 to 0.51, p = 0.05). AK counts were reduced for NIC compared to PBO by 11% at 3 months (p = 0.01), 14% at 6 months (p < 0.001), 20% at 9 months (p < 0.0001) and 13% at 12 months (p < 0.005). There were no clinically relevant differences in adverse event rates between the two arms. Conclusions: Nicotinamide reduces NMSC formation in high risk patients and is well tolerated. Furthermore, it is widely accessible as an inexpensive over-the-counter vitamin supplement and presents a new chemopreventive opportunity against NMSCs that is readily translatable into clinical practice. Clinical trial information: ACTRN12612000625875.