BACKGROUND: Hot flushes affect 70% of menopausal women and often severely impact 
physical, psychosocial, sexual, and overall wellbeing. Hormone replacement 
therapy is effective but is not without risk. Neurokinin B signalling is 
increased in menopausal women, and has been implicated as an important mediator 
of hot flushes.
METHODS: This phase 2, randomised, double-blind, placebo-controlled, 
single-centre, crossover trial assessed the effectiveness of an oral neurokinin 
3 receptor antagonist (MLE4901) on menopausal hot flushes. Eligible participants 
were healthy women aged 40-62 years, having seven or more hot flushes in every 
24 h of which some were reported as being severe or bothersome, who had not had 
a menstrual period for at least 12 months, and who had not been taking any 
medication shown to improve menopausal flushes in the preceding 8 weeks. 
Participants received 4 weeks of MLE4901 (40 mg, orally, twice daily) and 
placebo (orally, twice daily) in random order separated by a 2 week washout 
period. Randomisation was completed by a central computer, and participants were 
allocated to treatment number in numerical order. The primary outcome was the 
total number of hot flushes during the final week of both treatment periods. 
Analyses were by intention to treat and per protocol using generalised linear 
mixed models and standard crossover analysis. All analyses were prespecified in 
the study protocol. The trial is registered at ClinicalTrials.gov, number 
NCT02668185.
FINDINGS: 68 women were screened between Feb 3 and Oct 10, 2016, of which 37 
were randomly assigned and included in an intention-to-treat analysis. 28 
participants completed the trial and were included in a per-protocol analysis. 
MLE4901 significantly reduced the total weekly number of hot flushes by 45 
percentage points (95% CI 22-67) compared with the placebo (intention-to-treat 
adjusted means: placebo 49·01 [95% CI 40·81-58·56] vs MLE4901 19·35 
[15·99-23·42]; adjusted estimate of difference 29·66 [17·39-42·87], p<0·0001). 
Treatment was well tolerated. Three participants developed a transaminase rise 
(alanine aminotransferase 4·5-5·9 times the upper limit of normal) with a normal 
bilirubin 28 days after starting MLE4901, which normalised within 90 days.
INTERPRETATION: Treatment with a neurokinin 3 receptor antagonist (MLE4901) 
could be practice changing as it safely and effectively relieves hot flush 
symptoms without the need for oestrogen exposure. Larger scale studies of longer 
duration are now indicated.
FUNDING: UK Medical Research Council and National Institute for Health Research.