Randomised, double-blind, placebo controlled study to assess efficacy of topical nicotinamide in the treatment and prevention of actinic keratosis.

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TITLE Randomised, double-blind, placebo controlled study to assess efficacy of topical nicotinamide in the treatment and prevention of actinic keratosis. INTRODUCTION Background: The incidence of skin cancer has reached epidemic proportions. In Australia, despite public health campaigns and widespread sunscreen use, more than 50% of all Caucasian Australians develop non-melanoma skin cancer (NMSC) during their lifetime1, and more than one in 30 will develop melanoma.2 Ultraviolet radiation (UVR) from sunlight is the major cause of NMSC. In humans, both the UVA and UVB wavebands cause immunosuppression and DNA damage and therefore both UVA and UVB are likely to contribute to induction and development of NMSC.3,4 Immunosuppression enhances skin carcinogenesis5, as seen most dramatically in immunosuppressed transplant patients, who have an 82-fold increase in squamous cell carcinoma (SCC) compared with immunologically competent controls.6 Broad-spectrum sunscreens, which filter both UVB and UVA can reduce UV immunosuppression, but sunscreens are generally much better at preventing sunburn than immunosuppression.7,8 Current cosmetically acceptable sunscreens are poorly effective at filtering wavelengths bordering the visible spectrum. As immunosuppression can occur with less than half the amount of UV needed to cause sunburn9, the immune protection afforded by sunscreens “in the field” is likely to be low. Oral nicotinamide (vitamin B3) is available as an over-the-counter vitamin supplement and has been effective for over 50 years in the treatment of autoimmune and inflammatory skin disorders including bullous pemphigoid and rosacea.10 Unlike nicotinic acid, nicotinamide does not cause significant vasodilation or flushing11 and has few or no potential side effects. Although the exact mechanism of action in these settings is unknown, nicotinamide is a known endogenous inhibitor of the nuclear enzyme poly-ADP-ribose polymerase (PARP), which regulates the expression of immunomodulatory proteins such as inducible nitric oxide synthase, ICAM-1, MHC II and NF-kB.12 Nicotinamide is the precursor of NAD and thus a central building block of cellular energy metabolism. In mice, nicotinamide prevents UV-induced carcinogenesis and reduces skin cancer numbers by 60% when applied as a 2.5% lotion.13 Using a delayed type hypersensitivity model our group has demonstrated that nicotinamide lotion completely prevent UV immunosuppression when applied in a double-blinded placebo-controlled manner to the backs of healthy human volunteers. (Submitted for publication). In a subsequent dose-response study, topical nicotinamide was found to be immune protective at concentrations as low as 1%; it could thus be safely and cheaply added to sunscreens or moisturisers to reduce UV immunosuppression and potentially treat or prevent actinic keratosis, premalignant lesions which act as a surrogate marker for squamous cell skin cancers. Aims: This study will compare how effective topical nicotinamide is in the treatment and prevention of actinic keratoses when compared with a placebo lotion over a six month period. Hypothesis: That the twice daily application of topical nicotinamide will reduce the number of new and existing actinic keratoses in a patient population with multiple actinic keratoses when compared with placebo. RESEARCH PLAN AND METHODS Participants Patients to be recruited from general dermatology clinics in RPA. Inclusion Criteria Men and women > 18 years old. Symmetrically distributed non-hyperkeratotic AKs on face / scalp/ upper limbs. Minimum of 4 AKs in one or more treatment areas. Patients have received no other treatments for AKs within the last month. Exclusion criteria Under 18 years old Pregnant or lactating Taking immunosuppressive or photosensitising medications Taking nicotinamide or other vitamin supplements Patients unable to attend for regular follow up Patients with active dermatitis Settings and Location Department of Dermatology, Royal Prince Alfred Hospital, Sydney, NSW. Interventions Volunteers will be randomized to receive either nicotinamide 1% lotion twice daily (bd) or placebo. Blood levels of nicotinamide (NAD) will be measured at baseline and at the completion of the study. Study drug or placebo will be provided to the patients in identical containers and the formulations will be visually indistinguishable. Each patient will be instructed to apply the lotion to the prescribed treatment area twice daily for six months. Containers are returned at each visit and the contents weighed. All patients will be instructed on proper daily use of sunscreens of SPF 30 or greater during the entire study as well as general protective measures. Objectives 1. To compare the efficacy of topical nicotinamide in the prevention of new actinic keratosis with placebo. 2. To compare the efficacy of topical nicotinamide in the treatment of actinic keratosis with placebo. Outcomes The primary endpoint will be the reduction in total A.K. count at 6 months from baseline. A single observer will count and photograph AKs within the fields of treatment. AKs will be graded as II (visible and palpable) or I (palpable only). Patients with thicker hyperkeratotic AKs (III) will be excluded. There will be a secondary endpoint of total A.K. count at 12 weeks to account for appearance of new / subclinical lesions. All adverse events will be reported. The treatment efficacy compared to placebo will be calculated based on intention to treat. Sample size Based on a power of 80% and an average AK count of 10 AKs per patient and a predicted 20% reduction in AK count for nicotinamide treated patients compared to placebo treated patients, a sample size of ~40 patients in each study arm will be required to demonstrate a statistically significant difference using 95% confidence intervals. Should nicotinamide prove more effective at reducing the total AK count at six months, the total sample size required will be reduced. Randomization Sequentially numbered identical containers of nicotinamide and placebo will be randomised at source. Patients and investigators will be blinded to group assignment until the study end. Each patient will be individually randomized so that the code can be broken for a given patient should that need arise ( e.g adverse event) Statistical methods Statistical support is available through Patrick Fitzgerald, senior biostatistician in the University of Sydney. Subgroup analyses will include the effect of age, skin type, and treatment site on efficacy. Adjusted analyses will include the intention to treat population excluding those that withdraw prior to any use of the treatment. Significance of the project: Our preliminary studies have identified an effective topical and oral means of reducing UV immunosuppression in humans, using a compound, which is not limited by toxicity, patent, availability or expense. Changes in numbers of lesions in patients with multiple actinic keratoses can be observed within a period of 6 months.16 We predict that application of topical 1% nicotinamide will result in a 20-40% reduction in actinic keratoses. Confirmatory findings could pave the way for larger scale clinical trials of this agent in high-risk patients to assess subsequent impact on rates of NMSC. In Australia, with more than 374 000 new cases of NMSC each year1, even a modest protective effect of nicotinamide would greatly reduce the morbidity and cost of actinic disease.

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