Study Design and Oversight

The ONTRAC study was conducted at the Royal Prince Alfred and Westmead Hospitals in Sydney. The protocol of the study was approved by the human ethics committees of the University of Sydney and of each participating center, and all the study participants provided written informed consent. All the authors participated in the design of the study, collected the data, and contributed to the analysis or interpretation of the data (or both). All the authors vouch for the completeness and accuracy of the data and analyses and for the fidelity of the study to the protocol, which is available with the full text of this article at NEJM.org. The first author wrote the first draft of the manuscript; no one who was not an author contributed to the writing of the manuscript. The decision to submit the manuscript for publication was made by all the authors. There were no agreements regarding data confidentiality between the sponsor (University of Sydney) and the authors. The nicotinamide and placebo tablets used in the study were donated by the manufacturer (Blackmores), which had no role in the design of the study, in the accrual or analysis of data, in reviewing the manuscript, or in the decision to submit the manuscript for publication.

Study Participants

Eligible participants were 18 years of age or older and had had at least two histologically confirmed nonmelanoma skin cancers in the previous 5 years. Participants were ineligible if they were immunosuppressed; were pregnant or breast-feeding; had notably impaired liver or kidney function; had active peptic ulcer disease, a recent myocardial infarction, hypotension, a genetic skin-cancer syndrome, or large areas of confluent skin cancer (i.e., individual lesions that could not be counted); or had used nicotinamide supplements, oral retinoids, or field treatments for actinic keratosis, such as topical fluorouracil, in the previous 4 weeks. Participants were also excluded if they had had metastatic cancer, invasive melanoma, or an internal malignant condition in the previous 5 years.

Study Procedures

We randomly assigned participants in a 1:1 ratio to receive either 500 mg of nicotinamide (Insolar, Blackmores) twice daily or matched placebo. Randomization was performed centrally with stratification according to 5-year history of nonmelanoma skin cancer (<6 vs ≥6 nonmelanoma skin cancers), sex, and study site. Nicotinamide and placebo were administered in identical coated tablets. Participants received either nicotinamide or placebo for 12 months, and adherence was monitored by two of the authors who counted the remaining tablets at each visit through 12 months. Skin-cancer checks were performed by dermatologists, who were unaware of the study-group assignments, at baseline and at visits at 3-month intervals (hereafter referred to as 3-month visits) for 18 months. Detected lesions that did not immediately warrant biopsy were monitored at subsequent visits, and if they were later found to be malignant on biopsy, the date of their initial detection was assigned as the date of detection for analyses. Actinic keratoses on the face, scalp, forearms, and hands were counted by means of palpation and observation at baseline and at the 3-month visits through 12 months by a single author at each site, who was unaware of the study-group assignments.

The histologic diagnosis of skin cancer was made by histopathologists at each site according to routine clinical practice. All new squamous lesions, including invasive squamous-cell carcinoma, keratoacanthomas, Bowen’s disease (squamous-cell carcinoma in situ [full-thickness epidermal dysplasia]), and actinic keratoses (partial-thickness epidermal dysplasia),20 and new high-risk subtypes of basal-cell carcinoma (morpheic, infiltrating, and micronodular)20 were additionally reviewed by a single histopathologist, who was unaware of the study-group assignments, to ensure consistent classification of the types of squamous-cell carcinoma and subtypes of basal-cell carcinoma. New melanomas and severely dysplastic nevi were reviewed by a single histopathologist with subspecialty expertise in melanocytic neoplasms, who was unaware of the study-group assignments. Assessments for adverse events were performed over the course of the entire 12-month intervention period and for 30 days thereafter. Blood samples were obtained at baseline and at 12 months for full blood counts and for assessment of electrolyte levels and renal and liver function.

Study End Points

The primary end point was the number of new, histologically confirmed nonmelanoma skin cancers (i.e., basal-cell carcinomas plus squamous-cell carcinomas, including invasive and in situ squamous-cell carcinoma) through the end of the 12-month intervention period. Secondary end points included the number of new basal-cell carcinomas, new squamous-cell carcinomas, and actinic keratoses during the 12-month intervention period, the number of new nonmelanoma skin cancers in the 6-month postintervention period, and the safety of nicotinamide as assessed by the numbers and types of adverse events. Because previous studies have suggested a benefit from nicotinamide21,22 with respect to cognitive function and transepidermal water loss, these variables were also prespecified as secondary end points, but the results are not presented here.

Statistical Analysis

We estimated that with a sample size of 386, the study would have 90% power to detect a 33% lower rate of new nonmelanoma skin cancers with nicotinamide than with placebo at 12 months at a 5% level of significance, assuming that nonmelanoma skin cancer counts would follow a Poisson distribution and that a mean of 1.0 new nonmelanoma skin cancers per person would be detected in the placebo group, and allowing for an average rate of nonadherence of up to 10%. Analyses were prespecified in a statistical analysis plan (see the protocol) and were performed according to the intention-to-treat principle. In accordance with the provision specified in the statistical analysis plan, a negative binomial model was used for the analysis of data on nonmelanoma skin cancer because of overdispersion that rendered the Poisson model inappropriate. Models included an offset term to account for variation in the duration of follow-up. The primary analysis of nonmelanoma skin cancers included center and 5-year nonmelanoma skin cancer history as covariates; these covariates were omitted in a secondary sensitivity analysis. The same approach was used for the analysis of basal-cell carcinomas and squamous-cell carcinomas.

The consistency of the treatment effect with respect to the primary end point was investigated by means of a series of prespecified subgroup analyses that tested for an interaction between study-group assignment and age, sex, 5-year nonmelanoma skin cancer history, actinic keratosis count at baseline, smoking, nonsteroidal antiinflammatory drug use at baseline,23 and statin use at baseline.24 With an assumption of independence among the seven tests of interaction, there was a 30% probability that at least one P value would be less than 0.05 by chance alone. We explored the consistency of the treatment effect on the rate of nonmelanoma skin cancer over time by using generalized estimating equations to fit a negative binomial model for repeated measures to the data on nonmelanoma skin cancer collected at the 3-month visits. The data on actinic keratosis counts collected at the 3-month visits were analyzed with the use of a mixed-effects model for repeated measures. Models for repeated measures included study group, center, baseline value, time point, and the interaction between time and study group as covariates. No formal adjustment for multiple comparisons was made to P values from secondary analyses.