Late Breaking Abstract - Efficacy and safety of nalbuphine extended-release in refractory chronic cough: results from the phase 2a RIVER trial

<bold>Background:</bold> Nalbuphine extended-release (NAL ER) acts on the cough reflex arc centrally and peripherally as a kappa agonist and mu antagonist (KAMA), targeting opioid receptors involved in controlling chronic cough. <bold>Aims and Objectives:</bold> The RIVER trial (<ext-link>NCT05962151</ext-link>) evaluated NAL ER in patients with refractory chronic cough (RCC). <bold>Methods:</bold> This double-blind, placebo (PBO)-controlled, crossover study enrolled patients with RCC stratified by 24-h cough frequency at screening (10-19 coughs/h [moderate] and ≥20 coughs/h [severe]) measured by a cough monitor. Patients were randomly assigned to 1 of 2 21-day treatment sequences: NAL ER to PBO or PBO to NAL ER, with a 21-d washout between treatments. NAL ER was titrated every 7 d (27 mg, 54 mg, and 108 mg, all BID). The primary endpoint was relative change from baseline in 24-h objective cough frequency at day 21 in all patients. <bold>Results:</bold> Sixty-six patients were randomized (mean age, 60.2 y; mean cough frequency, 34.7 coughs/h). NAL ER 108 mg and PBO reduced 24-h cough frequency 65% and 9% at day 21, respectively (PBO-adjusted improvement of 57%; P<.0001). Moderate and severe cough frequency subgroups achieved PBO-adjusted improvements of 76% and 50%, respectively (both P<.0001). At day 7, mean (SD) 24-hour cough frequency significantly decreased with 27 mg NAL ER BID (–15.67 [13.61]; P<.0001). No serious treatment-emergent adverse events (TEAEs) were reported; 10 patients discontinued treatment due to TEAEs. The most common (≥5%) TEAEs were constipation, nausea, somnolence, headache, dizziness, and fatigue. <bold>Conclusions:</bold> The significant reduction in 24-h cough frequency supports further investigation of NAL ER for RCC.