Background: Hot flushes (HF) affect 70% of menopausal women and can be debilitating. Oestrogen administration is effective but not without risk. Neurokinin B signalling is increased in menopausal women, and is likely critical in the aetiology of their HF. We therefore hypothesised that a neurokinin 3 receptor (NK3R) antagonist could attenuate menopausal flushing.
Design: This single-centre, phase 2, randomised, double-blind, placebo-controlled, crossover trial assessed the efficacy of an oral NK3R antagonist (MLE4901) on menopausal HF (Clinicaltrials.gov NCT02668185; funding MRC, NIHR). Of 68 women screened, 37 were randomised and included in an ITT analysis (aged 4962 years, with >7 HF/24 h some of which were bothersome or severe). Participants received 4 weeks of MLE4901 and four weeks of placebo in random order separated by a 2 week washout period. Primary outcome was total number of HF during the fourth week of both treatment periods. Post-hoc time course analysis was conducted in a modified ITT population (minimum n=34) to ascertain the therapeutic profile of MLE4901.
Results: Primary outcome: MLE4901 significantly reduced the total weekly number of HF by 45% points compared to placebo (adjusted means: placebo 49.01 (CI: 40.8158.56), MLE4901 19.35 (CI: 15.9923.42), P<0.0001), and by 73% compared to baseline. By day 3 of treatment, MLE4901 reduced the frequency of HF by 72% compared to baseline (CI: −81.3 to −63.3, P<0.0001; 51% point decrease compared to placebo (CI: −63.5 to −38.4)), and this effect persisted throughout dosing. HF severity was also reduced by 38% compared to baseline by day 3 (CI: −46.1 to −29.1, P<0.001), as was HF bother by 39% (CI: −47.5 to −30.1, P<0.0001), and HF interference by 61% (CI: −79.1 to −43, P=0.0006); all continued to improve throughout dosing and were positively correlated (r=0.760.93, P<0.001). Treatment was well tolerated.
Conclusion: NK3R antagonist therapy (MLE4901) could be practice changing as it is well tolerated, and HF symptoms are rapidly relieved without oestrogen exposure. Larger scale studies of longer duration are imminent.