CORAL Trial: Oral Nalbuphine Reduces Cough in IPF

Key Takeaways

• In the CORAL trial, three nalbuphine ER doses were associated with greater objective cough reduction than placebo at week 6.
• Patient-reported cough frequency improved versus placebo in the 54-mg and 108-mg groups, while the 27-mg group did not separate from placebo on that measure.

The CORAL randomized clinical trial was a randomized, double-blind, placebo-controlled phase 2b study comparing three nalbuphine ER doses with placebo. Cough remains a prominent source of symptom burden in idiopathic pulmonary fibrosis, and effective treatments are still needed. Patient-reported cough frequency also improved in the 54-mg and 108-mg groups.

Of 223 screened patients, 165 were randomized and 160 were included in the primary analysis across 52 sites in 10 countries. Eligible participants had idiopathic pulmonary fibrosis, chronic cough for at least 8 weeks, and a Cough Severity Numerical Rating Scale score of 4 or higher. Participants received nalbuphine ER 27 mg, 54 mg, 108 mg, or placebo twice daily for 6 weeks, with randomization counts of 42, 43, 40, and 40, respectively. Median age was 71 years, 28.5% were female, and mean baseline cough count was 28.3 coughs per hour. The primary endpoint was relative change from baseline in 24-hour cough frequency at week 6, measured with a digital cough monitor.

Week 6 objective cough reductions were 47.9% with 27 mg, 53.4% with 54 mg, and 60.2% with 108 mg, versus 16.9% with placebo. The corresponding P values versus placebo were .008, less than .001, and less than .001 for the three active doses. Absolute cough counts changed from 24.6 to 11.9, 28.0 to 14.9, and 31.5 to 11.9 coughs per hour in the active groups, compared with 29.4 to 28.1 with placebo. Each tested dose separated from placebo on the objective endpoint.

For the key secondary outcome, patient-reported cough frequency was assessed at week 6 on the Evaluating Respiratory Symptoms in IPF cough subscale. Relative changes were -31.4% with 27 mg, -40.6% with 54 mg, and -40.2% with 108 mg, compared with -21.9% with placebo. The corresponding P values were .14, .004, and less than .005, indicating greater improvement than placebo in the 54-mg and 108-mg groups but not in the 27-mg group. Baseline-to-week-6 scores changed from 2.3 to 1.5, 2.6 to 1.4, and 2.4 to 1.4 in the active groups, compared with 2.6 to 1.9 with placebo. Overall, nalbuphine ER was associated with lower cough frequency at 6 weeks, with patient-reported improvement versus placebo in the 54-mg and 108-mg groups.