B29-19 Nalbuphine Extended Release Reduces Cough Bouts in Patients With Refractory Chronic Cough in the Phase 2a RIVER Trial

Rationale Refractory chronic cough (RCC) carries a high burden of disease and impact on patients’ quality of life, and no therapies have been approved in the United States. Oral nalbuphine extended release (NAL ER) is a kappa receptor agonist and mu receptor antagonist that acts on the cough reflex arc centrally and peripherally by targeting opioid receptors involved in cough. NAL ER treatment demonstrated a significant reduction in 24-hour objective cough frequency vs placebo (PBO) in patients with RCC in the RIVER trial (NCT05962151). While the primary endpoint of the RIVER trial was 24-hour cough frequency (coughs/hour) at Day 21 from a digital cough monitor (VitaloJAK), cough events often occur in clusters, or bouts, which may be more meaningful to patients. This post hoc analysis evaluated the effect of NAL ER on cough bouts (ie, clusters of sequential coughs). Methods This was a double-blind, PBO-controlled, two-period crossover study that stratified patients with RCC into 2 subgroups based on 24-hour cough frequency at screening (10-19 coughs/hour and ≥20 coughs/hour). Patients were randomly assigned to one of two 21-day treatment sequences: NAL ER to PBO or PBO to NAL ER, with a 21-day washout period in between. NAL ER was titrated every 7 days (27 mg, 54 mg, and 108 mg, all twice daily [BID]). Cough bouts were analyzed from 24-hour cough frequency data at baseline and Day 21. Cough bouts (≥2 coughs) were generated by combing consecutive cough sounds within 2 seconds of one another and analyzed with a mixed model repeated measures analysis. Results Cough data were analyzed in 59 patients who received PBO and 63 patients who received NAL ER. Mean baseline 24-hour cough bout counts were 173.0 with PBO and 193.7 with NAL ER. At Day 21, mean 24-hour cough bout counts were 144.4 with PBO and 108.4 with NAL ER (108 mg BID). Treatment with NAL ER resulted in a significant reduction in the number of cough bouts from baseline compared with PBO at Day 21; the relative change from baseline in cough bout count was 5.7% with PBO (N = 56) and −60.7% with NAL ER (N = 58; P<.0001). Similar improvements compared with PBO were seen at Day 7 (27 mg BID) and Day 14 (54 mg BID). Conclusions Consistent with results observed for cough frequency, NAL ER significantly reduced the number of cough bouts compared with PBO in patients with RCC.