Nicotinamide for Skin Cancer Prevention: Phase 3 Trial Timeline
When assessing methods to protect skin tissue from ultraviolet damage, randomized clinical trials provide the necessary evidence to separate physiological theory from verified outcomes. In 2015, The New England Journal of Medicine published a phase 3 study investigating whether oral nicotinamide, a specific form of vitamin B3, could reduce the development of new skin cancers in individuals with severe existing sun damage. This timeline and background explainer details the structural design of that clinical evaluation, the data collected across 18 months, and the defined boundaries of its findings.
Scientific Background: Ultraviolet Damage and Cellular Defense
Ultraviolet (UV) radiation is the principal driver of nonmelanoma skin cancers, primarily basal-cell carcinoma and squamous-cell carcinoma. Sunlight exposure induces direct damage to cellular DNA and suppresses local cutaneous immune surveillance. Prior laboratory and clinical research demonstrated that nicotinamide helps counter these effects by protecting against UV-induced damage and decreasing the formation of premalignant actinic keratoses. To understand the primary skin lesions examined in these trials, review our guide to types of skin cancer.
The ONTRAC Trial Design: Tracking 386 Participants
To rigorously test whether oral supplementation could translate biological protection into fewer actual tumors, researchers conducted the ONTRAC study (Australian New Zealand Clinical Trials Registry number ACTRN12612000625875), supported by the National Health and Medical Research Council. The trial followed a phase 3, multicenter, double-blind, randomized, controlled design structured around specific criteria:
- Target Population: Investigators recruited 386 participants who had a confirmed history of at least two nonmelanoma skin cancers within the previous 5 years.
- Allocation: Participants were randomly assigned in a 1:1 ratio to receive either oral nicotinamide twice daily or an identical placebo twice daily.
- Intervention Period: The assigned regimen lasted for 12 months.
- Surveillance Schedule: Certified dermatologists evaluated every participant at 3-month intervals for a total of 18 months, extending 6 months beyond the active treatment window.
Month 0 to Month 12: Primary Endpoints and Tumor Counts
The primary endpoint of the trial was the total number of new nonmelanoma skin cancers—combining basal-cell carcinomas and squamous-cell carcinomas—diagnosed during the 12-month intervention period. Secondary endpoints included separate counts for each cancer type and safety assessments.
As documented in the New England Journal of Medicine trial publication, the active intervention group experienced a measurable reduction in tumor development at 12 months:
- The overall rate of new nonmelanoma skin cancers was 23% lower in the nicotinamide group compared to the placebo group (95% confidence interval [CI], 4 to 38; P=0.02).
- New squamous-cell carcinomas showed a 30% lower rate in participants receiving nicotinamide (95% CI, 0 to 51; P=0.05).
- New basal-cell carcinomas showed a 20% lower rate in the nicotinamide group (95% CI, -6 to 39; P=0.12).
Researchers reported no noteworthy differences between the study groups regarding the number or types of adverse events during the 12-month intervention period, demonstrating that the oral regimen was well tolerated by participants.
Tracking Actinic Keratoses Across 3-Month Checkpoints
In addition to invasive tumors, the ONTRAC investigators systematically tallied premalignant lesions known as actinic keratoses at every 3-month clinical assessment. These scaly sun spots frequently develop on chronically sun-exposed tissue; readers can learn more about identifying them in our explainer on actinic keratosis.
Relative to the placebo group, participants taking nicotinamide exhibited persistent reductions in actinic keratoses counts throughout the entire 12-month treatment timeline:
- Month 3: 11% lower count (P=0.01)
- Month 6: 14% lower count (P<0.001)
- Month 9: 20% lower count (P<0.001)
- Month 12: 13% lower count (P=0.001)
The Post-Intervention Phase: Cessation at Month 12
The final phase of the protocol, running from month 12 to month 18, evaluated whether the protective effects persisted after participants stopped taking the intervention. During this 6-month postintervention monitoring period, participants attended regular 3-month evaluations without receiving either agent.
The clinical data revealed that once nicotinamide was discontinued, there was no evidence of ongoing protective benefit. The rate of new nonmelanoma skin cancers rebounded toward control levels once active supplementation ceased. This outcome indicated that the chemopreventive effect depended on continued administration rather than inducing permanent cellular alterations.
Trial Boundaries and Practical Context
Interpreting this clinical trial requires recognizing several crucial limits. The phase 3 randomized trial of nicotinamide assessed a very specific population: high-risk adults with multiple prior nonmelanoma skin cancers. The data cannot be generalized to suggest identical percentage reductions in low-risk individuals without a history of skin cancer.
Furthermore, the trial strictly evaluated nonmelanoma skin cancers (basal-cell and squamous-cell carcinomas) and did not measure protection against melanoma. While oral nicotinamide proved safe and effective in this controlled cohort, chemoprevention supplements do not replace fundamental sun-safety measures or regular examinations by a qualified medical professional.
Sources
A Phase 3 Randomized Trial of Nicotinamide for Skin-Cancer Chemoprevention. - PubMed (National Library of Medicine / The New England Journal of Medicine, 2015)
Published October 31, 2026. Sources are linked in the text. See our Medical Disclaimer.