• DOI:10.1111/bjd.14648
• Corpus ID: 36847268

Oral nicotinamide reduces transepidermal water loss: a randomized controlled trial

@article{Chen2016OralNR,
  title={Oral nicotinamide reduces transepidermal water loss: a randomized controlled trial},
  author={Andrew C Chen and A.J. Martin and R.A. Dalziell and Gary M. Halliday and Diona L Damian},
  journal={British Journal of Dermatology},
  year={2016},
  volume={175}
}

• A. C. Chen, A. Martin, +2 authors D. Damian
• Published 1 December 2016
• Medicine
• British Journal of Dermatology

DEAR EDITOR, Transepidermal water loss (TEWL) is a measure of barrier function which correlates with stratum corneum disruption and clinical severity in atopic dermatitis. Emollients may increase or decrease TEWL, but may not fully restore barrier function. Nicotinamide (an amide form of vitamin B3) has central roles in energy metabolism and DNA repair. We recently found that nicotinamide reduced new nonmelanoma skin cancers and actinic keratoses in patients at high risk. Nicotinamide also increases biosynthesis of stratum corneum lipids such as ceramides. Aquaporin-3, which encodes water-permeable channels, is associated with increased TEWL and is upregulated in atopic dermatitis. Nicotinamide attenuates aquaporin-3 upregulation in vitro and topical nicotinamide may reduce TEWL. In 20 healthy participants 5% nicotinamide cream was associated with increased stratum corneum thickness and decreased TEWL compared with vehicle after 28 days. The effect of oral nicotinamide on TEWL in humans is unknown. We measured TEWL 3-monthly for 12 months in participants at one study site within the ONTRAC (Oral Nicotinamide To Reduce Actinic Cancer) randomized trial to evaluate the effect of oral nicotinamide on TEWL. Eligible adults with two or more nonmelanoma skin cancers in the past 5 years were recruited to the phase 3 double-blind ONTRAC study (Australian New Zealand Clinical Trials Registry number ACTRN12612000625875), conducted at two sites in Sydney, Australia. Participants at the Royal Prince Alfred Hospital site (n = 292) also took part in the TEWL study; the skin cancer data have been reported previously. Exclusion criteria included immunosuppression, pregnancy/breastfeeding, significant hepatic or renal impairment, recent oral retinoid use, actinic keratosis field treatments or nicotinamide supplements in the past 4 weeks. The study was approved by the relevant human ethics committees and conducted in accordance with Declaration of Helsinki principles. All participants provided written informed consent. Participants were enrolled (A.C.C., D.L.D.) and randomized 1 : 1 (NHMRC Clinical Trials Centre) to receive nicotinamide 500 mg twice daily or placebo for 12 months, with stratification by 5-year nonmelanoma skin cancer history (< 6; ≥ 6), sex and study site. Identically coated tablets [nicotinamide 500 mg (Insolar) or placebo] were manufactured and supplied by Blackmores Ltd (Warriewood, NSW, Australia). Two averaged TEWL measurements were taken 3-monthly for 12 months, with a VapoMeter (Delfin Technologies Ltd, Kuopio, Finland) at three body sites (midline forehead, left volar forearm and left medial lower leg) by a single investigator blinded to allocation. Compliance was measured by tablet counts at each visit. Participants were asked to avoid make-up, sunscreens or moisturizers on TEWL measurement days, and were rested for at least 5 min before each measurement. The primary endpoint of ONTRAC, upon which the sample size was based, was new skin cancers to 12 months. TEWL was a secondary endpoint. Analyses were by intention-to-treat and pre-specified in a statistical analysis plan. The 3-monthly post-baseline TEWL data were analysed using a mixed model for repeated measures that included treatment group, centre, baseline value, time point, and a time-by-treatment group interaction as covariates. The right-skewed distribution of the TEWL data was rectified by applying a loge transformation (with results back-transformed for reporting). From July 2012 to June 2013, 292 participants at the Royal Prince Alfred Hospital were randomized to receive placebo (n = 147) or nicotinamide (n = 145; Fig. S1). Median compliance was 96% and 94%, respectively, and the groups were clinically similar (Table 1). Mean ambient temperature and mean relative humidity during TEWL measurements were 22 6 °C (SD 1 2) and 53 2% (SD 8 7), respectively. TEWL was increased in winter and reduced by nicotinamide. Baseline TEWL measurements were higher on the forehead (mean, 23 g m 2 h ) compared with the limbs (baseline forearm and lower leg TEWL 9 8 and 9 7 g m 2 h , respectively). In participants taking placebo, there was a 15% relative increase in TEWL on the forehead in winter (June–August) compared with summer (December– February; P < 0 0001). Seasonal differences in limb TEWL were not significant. TEWL on the face and limbs tended to be lower with nicotinamide (Fig. 1). For the forehead, the estimated reduction in mean TEWL with nicotinamide compared with placebo was 5% at 3 months [95% confidence interval (CI) –1% to 10%; P = 0 13], 5% at 6 months (95% CI 1% to 10%; P = 0 13), 6% at 9 months (95% CI 1–12%; P = 0 033) and 6% at 12 months (95% CI 0–12%; P = 0 039). The estimated reduction in mean limb TEWL (arm + leg) with nicotinamide was 2% at 3 months (95% CI 5% to 9%; P = 0 53), 4% at 6 months (95% CI 4% to 11%; P = 0 30), 1% at 9 months (95% CI 6% to 9%; P = 0 72) and 8% at 12 months (95%