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Objective: To evaluate the efficacy of orvepitant (10 or 30 mg given once daily, orally for 4 weeks), a neurokinin-1 receptor antagonist, compared with placebo in reducing the intensity of epidermal growth factor receptor inhibitor (EGFRI)-induced intense pruritus., Design: Randomised, double-blind, placebo-controlled clinical trial., Setting: 15 hospitals in Italy and five hospitals in the UK., Participants: 44 patients aged ≥18 years receiving an EGFRI for a histologically confirmed malignant solid tumour and experiencing moderate or intense pruritus after EGFRI treatment., Intervention: 30 or 10 mg orvepitant or placebo tablets once daily for 4 weeks (randomised 1:1:1)., Primary and Secondary Outcome Measures: The primary endpoint was change from baseline in mean patient-recorded numerical rating scale (NRS) score (over the last three recordings) at week 4. Secondary outcome measures were NRS score, verbal rating scale score, Skindex-16 and Leeds Sleep Evaluation Questionnaire at each study visit (baseline, weeks 1, 4, 8); rescue medication use; EGFRI dose reduction; and study withdrawal because of intense uncontrolled pruritus., Results: The trial was terminated early because of recruitment challenges; only 44 of the planned 90 patients were randomised. All patients were analysed for efficacy and safety. Mean NRS score change from baseline to week 4 was -2.78 (SD: 2.64) points in the 30 mg group, -3.04 (SD: 3.06) points in the 10 mg group and -3.21 (SD: 1.77) points in the placebo group; the difference between orvepitant and placebo was not statistically significant. No safety signal was detected. Adverse events related to orvepitant (asthenia, dizziness, dry mouth, hyperhidrosis) were all of mild or moderate severity., Conclusions: Orvepitant was safe and well tolerated. No difference in NRS score between the orvepitant and placebo groups was observed at the week 4 primary endpoint. A number of explanations for this outcome are possible., Trial Registration Number: EudraCT2013-002763-25., Competing Interests: Competing interests: MT is a current employee and ER is a past employee of NeRRe Therapeutics, and both are inventors on a granted patent on novel uses of orvepitant. BV and PG received payment from NeRRe as investigators in this study. AD received payment from NeRRe for service as the chief medical officer for this study. DJ is an employee of Cromsource, who received payment from NeRRe for statistical analysis of this study. PH has received payment from NeRRe as a consultant. MEL reports receiving personal fees from Legacy Healthcare Services, AdgeroBio Pharmaceuticals, Amryt Pharma, Celldex Therapeutics, Debiopharm, Galderma Research and Development, Johnson & Johnson, Novocure, Lindi Skin, Merck Sharp and Dohme, Helsinn Healthcare, Janssen Research & Development, Menlo Therapeutics, Novartis Pharmaceuticals, F Hoffmann-La Roche, AbbVie, Boehringer Ingelheim Pharma, Allergan, Amgen, ER Squibb & Sons, EMD Serono, AstraZeneca Pharmaceuticals, Genentech, Leo Pharma, Seattle Genetics, Bayer, Männer SAS, Lutris Pharma, Pierre Fabre, Paxman Cooler, Adjucare, Dignitana, Biotechspert, Teva Pharmaceuticals Mexico, Parexel, OnQuality Pharmaceuticals, Novartis, Our Brain Bank, Millennium Pharmaceuticals, and research funding from Berg Health, Bristol-Myers Squibb, Lutris Pharma, Novocure, Paxman, Biotest and Veloce BioPharma. GT reports no conflicts of interest. AW reports receiving payment from NeRRe as chair of the advisory board and from Advent Life Sciences for consultancy, Canbex Therapeutics as a non-executive director (past position), Calcico Therapeutics as chairman (past position) and a non-executive director (past position), and the Wellcome Trust as a member of grant committees. SS reports receiving payment from NeRRe as a member of the advisory board and from Almirall, Astellas Pharma, Beiersdorf, Celgene, Chugai Pharma, Creabilis, Daiichi Sankyo, Galderma, Helsinn, Kiniska Pharmaceuticals, Kneipp, Maruho, Merz Pharma, Novartis, Pierre Fabre Laboratories, Sienna Biopharmaceuticals and Ziarco as a member of their advisory boards and from Menlo Therapeutics as an investigator and participation as an investigator in trials sponsored by Dermascence, Trevi Therapeutics and Vanda Pharmaceuticals., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)