title: Neurokinin 3 receptor antagonism as a novel treatment for menopausal hot flushes: a phase 2, randomised, double-blind, placebo-controlled trial.
abstract: 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  UK Medical Research Council and National Institute for Health Research.
authors.affiliation: Department of Investigative Medicine, Imperial College London, London, UK.
authors.forename: Julia K
authors.initials: JK
authors.lastname: Prague
authors.affiliation: Department of Investigative Medicine, Imperial College London, London, UK.
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Roberts
authors.affiliation: Department of Investigative Medicine, Imperial College London, London, UK.
authors.forename: Alexander N
authors.initials: AN
authors.lastname: Comninos
authors.affiliation: Department of Investigative Medicine, Imperial College London, London, UK.
authors.forename: Sophie
authors.initials: S
authors.lastname: Clarke
authors.affiliation: Department of Investigative Medicine, Imperial College London, London, UK.
authors.forename: Channa N
authors.initials: CN
authors.lastname: Jayasena
authors.affiliation: Department of Investigative Medicine, Imperial College London, London, UK.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Nash
authors.affiliation: Department of Investigative Medicine, Imperial College London, London, UK.
authors.forename: Chedie
authors.initials: C
authors.lastname: Doyle
authors.affiliation: Department of Investigative Medicine, Imperial College London, London, UK.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Papadopoulou
authors.affiliation: Department of Investigative Medicine, Imperial College London, London, UK.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Bloom
authors.affiliation: Millendo Therapeutics, Inc, Ann Arbor, MI, USA.
authors.forename: Pharis
authors.initials: P
authors.lastname: Mohideen
authors.affiliation: Department of Gynaecology, Queen Charlotte's & Chelsea Hospital and Chelsea and Westminster Hospital, London, UK; Institute of Reproductive and Developmental Biology, Imperial College London, London, UK.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Panay
authors.affiliation: Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: Myra S
authors.initials: MS
authors.lastname: Hunter
authors.affiliation: Mayo Clinic, Rochester, MI, USA.
authors.forename: Johannes D
authors.initials: JD
authors.lastname: Veldhuis
authors.affiliation: Scientific Partnering & Alliances, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Melbourn, UK.
authors.forename: Lorraine C
authors.initials: LC
authors.lastname: Webber
authors.affiliation: Division of Experimental Medicine, Imperial College London, London, UK.
authors.forename: Les
authors.initials: L
authors.lastname: Huson
authors.affiliation: Department of Investigative Medicine, Imperial College London, London, UK. Electronic address: w.dhillo@imperial.ac.uk.
authors.forename: Waljit S
authors.initials: WS
authors.lastname: Dhillo
mesh_terms: D000328:Adult; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D020249:Hormone Replacement Therapy / Q000009:adverse effects / Q000379:methods; D019584:Hot Flashes / Q000188:drug therapy* / Q000209:etiology; D006801:Humans; D008593:Menopause / Q000235:genetics / Q000502:physiology* / Q000523:psychology; D008875:Middle Aged; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D018042:Receptors, Neurokinin-3; C000601381:TACR3 protein, human