Highlights
The CORAL Phase 2b randomized clinical trial provides compelling evidence for the efficacy of nalbuphine extended release (ER) in treating idiopathic pulmonary fibrosis (IPF)-associated cough. Key highlights include:
- Dose-Dependent Reduction: All three tested doses of nalbuphine ER (27 mg, 54 mg, and 108 mg twice daily) met the primary endpoint, showing a significant relative reduction in 24-hour cough frequency compared to placebo.
- Objective Measurement: Using digital cough monitors, the study observed reductions in cough frequency ranging from 47.9% to 60.2% across the treatment arms.
- Symptom Improvement: The higher doses (54 mg and 108 mg) also demonstrated statistically significant improvements in patient-reported cough severity and frequency.
- Clinical Significance: These findings suggest nalbuphine ER could be a transformative therapy for a symptom that currently has no approved treatments and severely impacts quality of life.
Introduction: The Burden of Refractory Cough in IPF
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fatal interstitial lung disease characterized by alveolar epithelial cell injury and aberrant fibroproliferative responses. While much focus is placed on lung function decline and mortality, the symptomatic burden of the disease is profound. Chronic cough affects up to 85% of patients with IPF and is often described by patients as one of the most distressing aspects of their condition.
The pathogenesis of IPF-associated cough is multifactorial, involving mechanical distortion of the lung parenchyma, increased sensitivity of the cough reflex (neuroplasticity), and potential comorbidities like gastroesophageal reflux. This cough is typically refractory to conventional antitussives and neuromodulators such as gabapentin or pregabalin, which are often limited by systemic side effects. Until now, the lack of targeted pharmacological interventions has left a significant gap in supportive care for this population.
The CORAL Trial: Study Design and Methodology
The CORAL trial was a double-blind, placebo-controlled Phase 2b study conducted across 52 specialized centers in 10 countries. The study aimed to evaluate the safety and efficacy of nalbuphine ER, a unique opioid modulator that acts as a κ-opioid receptor agonist and a μ-opioid receptor antagonist. This mechanism is hypothesized to provide antitussive effects via the κ-receptor while mitigating the μ-receptor-mediated risks of respiratory depression and addiction.
The trial enrolled 165 patients with a confirmed diagnosis of IPF and chronic cough lasting at least 8 weeks. To ensure a symptomatic population, participants were required to have a Cough Severity Numerical Rating Scale (NRS) score of 4 or higher at baseline. Participants were randomized 1:1:1:1 to receive nalbuphine ER at doses of 27 mg, 54 mg, 108 mg, or a matching placebo, administered twice daily for a 6-week treatment period.
The primary efficacy outcome was the relative change from baseline in 24-hour cough frequency at week 6, measured objectively using a validated digital cough monitor. Secondary outcomes included patient-reported assessments, specifically the Evaluating Respiratory Symptoms in IPF (ERS-IPF) cough subscale.
Key Findings: Objective and Subjective Efficacy
The primary analysis included 160 patients with a median age of 71 years. At baseline, the mean cough frequency was high at 28.3 coughs per hour, highlighting the severity of the disease burden in this cohort.
Objective Cough Frequency (Primary Outcome)
Nalbuphine ER demonstrated a robust, dose-dependent reduction in objective cough frequency at week 6:
- 27 mg Group: 47.9% reduction (p = .008 compared to placebo).
- 54 mg Group: 53.4% reduction (p < .001 compared to placebo).
- 108 mg Group: 60.2% reduction (p < .001 compared to placebo).
- Placebo Group: 16.9% reduction.
The absolute decrease in the 108 mg group was particularly striking, falling from 31.5 coughs/h to 11.9 coughs/h. These results represent some of the most significant reductions in cough frequency observed in any IPF-associated cough trial to date.
Patient-Reported Outcomes (Secondary Outcome)
The subjective experience of the patients aligned with the objective data for the higher doses. For the ERS-IPF cough subscale:
- The 54 mg and 108 mg groups showed significant improvements compared to placebo, with relative changes of -40.6% (p = .004) and -40.2% (p < .005), respectively.
- The 27 mg group showed a -31.4% change, which did not reach statistical significance (p = .14) compared to the placebo group’s -21.9% reduction.
Mechanistic Insights: The Role of κ-Opioid Agonism
The success of nalbuphine ER in this trial underscores the importance of the κ-opioid receptor in modulating the cough reflex. Traditional antitussives like codeine act primarily on μ-opioid receptors, which carry risks of sedation, constipation, and respiratory depression—concerns that are particularly acute in patients with compromised lung function. Nalbuphine’s dual action as a μ-antagonist potentially provides a safer profile for patients with interstitial lung disease while its κ-agonism targets the peripheral and central pathways involved in cough hypersensitivity.
In IPF, the mechanical stress on the lungs may sensitize airway afferents. κ-opioid receptors are expressed on these sensory nerves, and their activation can inhibit the release of tachykinins and other pro-tussive neurotransmitters. By modulating these pathways, nalbuphine ER appears to effectively dampen the exaggerated cough reflex seen in fibrotic lung disease.
Expert Commentary and Clinical Implications
The results of the CORAL trial are highly encouraging for the pulmonary community. Dr. Philip Molyneaux and colleagues have demonstrated that objective cough monitoring is a feasible and sensitive endpoint in clinical trials. The discrepancy between the 27 mg dose’s objective success and its lack of subjective significance suggests that while lower doses reduce the number of coughs, a higher threshold of inhibition may be required for patients to perceive a meaningful change in their symptomatic burden.
However, clinicians must consider the long-term safety and tolerability of nalbuphine ER. While the 6-week results are positive, IPF is a chronic condition, and long-term data on potential side effects such as dizziness, nausea, or fatigue—common with opioid-related medications—will be essential. Furthermore, the interplay between cough suppression and airway clearance needs to be monitored to ensure that reducing cough does not lead to increased mucus retention or secondary infections, although this risk is generally lower in the restrictive lung disease context of IPF than in obstructive diseases like bronchiectasis.
Conclusion
The CORAL trial marks a significant milestone in the symptomatic management of IPF. By achieving a dose-dependent, significant reduction in both objective and subjective cough measures, nalbuphine ER has established itself as a leading candidate for the treatment of IPF-associated chronic cough. Future Phase 3 trials will be necessary to confirm these findings over a longer duration and to further refine the safety profile in this vulnerable patient population. For now, these data offer hope to thousands of patients whose quality of life is currently compromised by an unrelenting and untreatable cough.
Funding and ClinicalTrials.gov
This study was funded by Trevi Therapeutics. Trial registration: ClinicalTrials.gov Identifier: NCT05964335.
References
- Molyneaux PL, Mogulkoc N, Gunen H, et al. Oral Nalbuphine in Idiopathic Pulmonary Fibrosis-Associated Cough: The CORAL Randomized Clinical Trial. JAMA. 2026;2026 Jan 22:e2526179. doi: 10.1001/jama.2025.26179.
- Raghu G, Remy-Jardin M, Richeldi L, et al. Idiopathic Pulmonary Fibrosis (an Update) and Progressive Pulmonary Fibrosis in Adults: An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline. Am J Respir Crit Care Med. 2022;205(9):e18-e47.
- Birring SS, Spinou A. How best to measure cough in clinical trials. J Thorac Dis. 2014;6(Suppl 7):S722-S727.