Multicentre, 2×2 factorial, randomised, open-label trial of neuromodulators and cough control therapy for refractory or unexplained chronic cough: the FORTITUDE trial protocol.

Abstract

While clinicians commonly prescribe neuromodulators for the treatment of refractory or unexplained chronic cough, no trials have directly compared these treatments. Furthermore, although guidelines recommend non-pharmacological management involving physiotherapy and speech-language therapy, few trials have evaluated its effectiveness. FORTITUDE (<i>F</i>act<i>O</i>rial <i>R</i>andomized <i>T</i>r<i>I</i>al <i>T</i>o eval<i>U</i>ate neuromo<i>D</i>ulators and cough control th<i>E</i>rapy) is a 6-week, 2×2 factorial, randomised, open-label trial with an observational extension up to 1 year. The trial will include Canadian hospital sites enrolling 124 patients. Patients ≥18 years old with either refractory or unexplained chronic cough will undergo independent 1:1 randomisation to pharmacotherapy-either low-dose morphine (up to 5 mg two times per day) or pregabalin (up to 150 mg two times per day)-and concurrent cough control therapy (CCT) or no CCT. The CCT will consist of five virtual sessions delivered over 6 weeks by a trained physiotherapist or speech-language pathologist. Change from baseline in 24-hour cough frequency at 6 weeks represents the primary outcome. Secondary outcomes include change from baseline in awake, sleep and cough bout frequencies; cough severity on the McMaster Cough Severity Questionnaire and the 100-mm Visual Analogue Scale; and cough quality of life on the Leicester Cough Questionnaire at 6 weeks. We will analyse safety and tolerability at 6 weeks and explore potential interactions between neuromodulators and CCT. Follow-up in an observational extension of up to 12 months post-randomisation will assess long-term treatment patterns, adherence and safety in a real-world setting. Health Canada's Pharmaceutical Drugs Directorate has provided approval to conduct this study. We have approval from the Hamilton Integrated Research Ethics Board of the Main Coordinating Site, with ethics pending at other participating sites. Results of the main trial and the observational extension will be published as manuscripts in peer-reviewed journals. NCT07288528.