Randomised, double-blind, placebo controlled study to assess efficacy of oral nicotinamide in the treatment and prevention of actinic keratoses

TITLE Randomised, double-blind, placebo controlled study to assess efficacy of oral nicotinamide in the treatment and prevention of actinic keratoses. 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 non-melanoma skin cancer. In humans, both the Ultraviolet A (UVA) and ultraviolet B (UVB) wavebands cause immunosuppression and deoxyribonucleic acid (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 ultraviolet (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. The most commonly used dose in autoimmune blistering disorders is 1500 mg daily10, with these patients often taking nicotinamide for several months. Adverse effects are exceptionally rare at these doses. 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, inter-cellular adhesion molecule 1 (ICAM-1), major histocompatibility II (MHC II) and Nuclear factor kappa-light-chain-enhancer of activated B cell (NF-kB).12 Nicotinamide is the precursor of nicotinamide adenine dinucleotide (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 volunteers14. We subsequently found that oral nicotinamide was also immune protective in healthy, Mantoux-positive volunteers15, without adverse effects, at doses of either 500mg daily or 1500mg daily. Recently, we tested topical 1% nicotinamide on numbers of actinic keratoses, and found a significant reduction in numbers of keratoses at 3 months compared to placebo. We now plan to assess the effects of oral nicotinamide at an intermediate dose (500mg twice daily) on actinic keratoses numbers. We hypothesise that nicotinamide will be well-tolerated, and could be used together with sunscreens 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 oral nicotinamide is in the treatment and prevention of actinic keratoses when compared with a placebo tablet over a four month period. Hypothesis: That the twice daily consumption of 500mg 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 Royal Prince Alfred Hospital. Inclusion Criteria Men and women > 18 years old. Symmetrically distributed non-hyperkeratotic actinic keratoses on face / scalp/ upper limbs. Minimum of 4 actinic keratoses in one or more treatment areas. Patients have received no other treatments for actinic keratoses 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 on face, scalp or arms Liver disease (although hepatic effects of nicotinamide are rare, in contrast to nicotinic acid) Currently taking carbamazepine (case reports of interaction with nicotinamide) Although nicotinamide is unlikely to have significant drug interactions with oral contraceptives, there is currently no available data to show a definite lack of interaction. Women of childbearing potential who are taking the oral contraceptive pill will thus be advised to use additional, barrier contraception during the study. Settings and Location Department of Dermatology, Royal Prince Alfred Hospital, Sydney, NSW. Interventions Volunteers will be randomized to receive either nicotinamide 500mg (Nature’s Own, Virginia, Queensland; widely available in Australian pharmacies and health food stores) twice daily (bd) or placebo (containing 35mg lactose; Australian Custom Pharmaceutical, Sydney) twice daily. Blood levels of nicotinamide (Nicotinamide adenine dinucleotide) as well as electrolytes, creatinine and liver function and full blood count will be measured at baseline and at 2 months; photographs of the actinic keratoses will also be taken at baseline, 2 and 4 months. 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 take the tablets twice daily for four months and to return the containers on study completion. We do not anticipate any adverse effects of daily consumption of this vitamin. All patients will be instructed on proper daily use of Sun Protection Factor (SPF) 30+ sunscreens during the entire study as well as general protective measures. Any lesions suspicious for skin cancer will be biopsied and treated as per usual clinical practice. The development of nonmelanoma skin cancer (which is a common event in this population) does not necessitate interruption of or withdrawal from the protocol. Objective To compare the efficacy of oral nicotinamide in the prevention of new actinic keratosis with placebo. Outcomes The primary endpoint will be the reduction in total actinic keratoses count at 4 months from baseline. A single observer will count, chart on a diagram and photograph actinic keratoses within the fields of treatment. AKs will be graded as II (visible and palpable) or I (palpable only). Patients with thicker hyperkeratotic actinic keratoses (III) will be excluded. There will be a secondary endpoint of total actinic keratoses count at 2 months 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 actinic keratoses count of 20 per patient and a predicted 20% reduction in actinic keratoses count for nicotinamide treated patients compared to placebo treated patients, a sample size of ~18 patients in each study arm will be required to demonstrate a statistically significant difference using 95% confidence intervals. We thus wish to recruit ~ 50 participants, in anticipation of up to 14 drop-outs during the 4 months of the study. 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 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. We predict that use of 1000mg daily of oral 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. 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