Researchers evaluated 3 doses of an oral κ-opioid receptor agonist in patients with idiopathic pulmonary fibrosis and chronic cough using continuous 24-hour digital cough monitoring, according to a recent study.
In a phase 2b randomized clinical trial, researchers reported dose-dependent changes in objectively measured cough frequency among patients with idiopathic pulmonary fibrosis (IPF) and chronic cough treated with oral extended-release nalbuphine. At 6 weeks, mean relative reductions in 24-hour cough frequency were 48% with nalbuphine 27 mg twice daily, 53% with 54 mg twice daily, and 60% with 108 mg twice daily, compared with a 17% reduction with placebo. Improvements in patient-reported cough frequency, cough severity, and cough-related quality of life were observed in the 54-mg and 108-mg groups, while results with the lowest dose were less consistent.
The CORAL trial was a multinational, randomized, double-blind, placebo-controlled, parallel-group phase 2b study conducted at 52 sites in 10 countries. Adults with IPF and chronic cough lasting at least 8 weeks were eligible if they had a cough severity numerical rating scale score of 4 or higher and met prespecified pulmonary function criteria. Patients receiving antifibrotic therapy were permitted to enroll if doses were stable. Between February 2024 and February 2025, 165 patients were randomized in a 1:1:1:1 ratio to nalbuphine extended release at doses of 27 mg, 54 mg, or 108 mg twice daily, or placebo, following a 2-week dose titration period and a 4-week fixed-dose treatment phase.
Among the 160 patients included in the primary analysis, the median age was 71 years, 72% were male, and 77% were receiving antifibrotic therapy. Baseline cough frequency averaged 28 coughs per hour. In the 108-mg group, absolute cough counts declined from 32 to 12 coughs per hour at week 6, compared with a change from 29 to 28 coughs per hour with placebo.
The primary outcome was the relative change from baseline in objectively measured 24-hour cough frequency at week 6, assessed using a validated digital cough monitoring system worn continuously for at least 24 hours. Secondary outcomes included patient-reported cough frequency measured by the Evaluating Respiratory Symptoms in IPF cough subscale, cough severity assessed by the cough severity numerical rating scale, and health-related quality of life measured by the Leicester Cough Questionnaire. Efficacy analyses were conducted using mixed models for repeated measures, with adjustment for baseline cough frequency, sex, and antifibrotic use.
Adverse events, most commonly nausea, vomiting, constipation, dizziness, and somnolence, were generally mild, occurred primarily during dose titration, and infrequently led to treatment discontinuation.
Several limitations were reported. The treatment duration was limited to 6 weeks, precluding assessment of long-term efficacy and safety. As a phase 2b trial, the findings require confirmation in larger, longer phase 3 studies. In addition, the primary statistical analysis assumed that missing data were missing at random, which may introduce bias if treatment discontinuation was related to unobserved factors.
An FDA report on IPF noted that coughing was identified by more than 75% of patients and caregivers as one of the most distressing symptoms, often causing patients to avoid social situations, with patients describing an inability to control their coughing that often led to episodes of shortness of breath, hypoxia, or exhaustion.
Disclosures can be found in the study.
Source: JAMA
