C103-01 The Effect of Nalbuphine Extended-release Tablets on Breathlessness in Patients With Idiopathic Pulmonary Fibrosis Experiencing Chronic Cough From the Phase 2b CORAL Trial

Rationale Breathlessness, along with cough, greatly impacts daily life in patients with idiopathic pulmonary fibrosis (IPF). Although no pharmacologic therapies effectively relieve dyspnea in these patients, management may include supplemental oxygen, pulmonary rehabilitation, and supportive care. The Evaluating Respiratory Symptoms in IPF (E-RS:IPF)TM is a daily diary used to assess respiratory symptom severity. Its 5-item breathlessness subdomain (higher scores indicate greater severity) serves as an exploratory measure for evaluating treatment effects on breathlessness. Oral nalbuphine extended release (NAL ER) is a kappa receptor agonist and mu receptor antagonist being studied for the treatment of chronic cough. The CORAL trial (NCT05964335) evaluated the efficacy and safety of NAL ER for cough in patients with IPF; an analysis on change in breathlessness using the E-RS:IPF is reported here. Methods CORAL was a randomized, double-blind, placebo (PBO)-controlled study in which patients with IPF and a history of chronic cough (≥8 weeks) were randomly assigned 1:1:1:1 to receive NAL ER (27, 54, or 108 mg twice daily [BID]) or PBO BID for 6 weeks. The primary endpoint was relative change from baseline in 24-hour objective cough frequency at Week 6. A secondary objective was the change from baseline in the E-RS:IPF breathlessness subdomain score at Week 6 for NAL ER vs PBO. Correlation analyses were conducted between change from baseline in scores at Week 6 in E-RS subdomains, Patient Global Impression of Severity (PGI-S) scale, and Leicester Cough Questionnaire (LCQ). Results 165 patients were randomized; the mean age was 70.1 years with 71.5% males. In patients with chronic cough, mean baseline E-RS:IPF breathlessness scores in PBO 27 mg BID, 54 mg BID, and 108 mg BID groups were 8.04, 7.49, 9.20, and 7.56, respectively. Change from baseline in the E-RS:IPF breathlessness scores were statistically significant across Weeks 1-6 with NAL ER 54 mg; PBO-adjusted change at Week 6 was −1.73 (P=.0186). Combining the two highest dose groups, significant correlations were observed in change at Week 6 between the E-RS:IPF breathlessness and cough severity scores measured by the PGI-S (N = 49; r = 0.4656; P=.0007), the E-RS:IPF cough subdomain (cough frequency) (N = 69; r = 0.6289; P<.0001), and quality of life assessed by the LCQ total score (N = 52; r = −0.4877; P=.0002). Conclusion This preliminary analysis shows that NAL ER may reduce breathlessness in IPF patients with chronic cough. Improving breathlessness, in addition to cough, may provide additional improvements in quality of life for patients with IPF and chronic cough.