Abstract
<title>Abstract</title> <p>Background: Refractory chronic cough (RCC) persists despite systematic evaluation showing no clear cause, or despite adequate treatment of an identified or strongly suspected cause. RCC remains difficult to treat. Although gabapentinoids can reduce cough and improve quality of life, their benefits may be limited by slow onset, central nervous system adverse effects, and relapse after discontinuation. Crisugabalin is a third-generation alpha2delta ligand that has shown favorable efficacy and tolerability in chronic pain studies, and may therefore represent a potential treatment option for RCC. Methods: This single-centre, randomized, double-blind, placebo-controlled trial will enroll 70 adults with RCC and allocate them 1:1 to oral crisugabalin 20 mg twice daily or matching placebo for 8 weeks, followed by 4 weeks of follow-up. The primary outcome is the change from baseline to week 4 in objectively measured 24-hour cough frequency. Secondary outcomes include patient-reported cough severity and quality of life, cough sensitivity, psychological measures, and safety outcomes. Discussion: This trial will provide preliminary randomised evidence on the efficacy and safety of crisugabalin for RCC and inform the design of future larger multicentre studies. However, as a single-centre exploratory trial with a modest sample size and short follow-up, it may have limited generalisability and may not fully assess sustained symptom improvement after discontinuation, recurrence, rare adverse events, or comparative effectiveness versus existing neuromodulators. Trial registration: Chinese Clinical Trial Registry, ChiCTR2500113498. Registered 28 November 2025.</p>