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“Inhaled medicines can treat cough-related conditions yet provoke cough themselves. Continuous measurement can help sponsors turn that tension into better product decisions.”
The field is acknowledging cough as important problem of IPF patients and moving towards objective and continuous measurement of IPF symptoms in clinical trials.
IPF drug development anchors its endpoints on lung function. Clinical trials measure forced vital capacity, diffusing capacity, and radiographic progression because antifibrotics were approved on these measures, and because of regulatory precedents. However, the patients experience symptoms that are not included in trial endpoints.
Cough was reported by 84% of patients in a prospective IPF cohort, where it also predicted the disease progression [1]. At the FDA’s IPF patient-focused drug development meeting, patients described prolonged, violent coughing fits that caused pain, exhaustion, and the inability to breathe. The patients placed cough among the symptoms that affected their lives most [2].
Cough also carries a prognostic value of its own. In the Pulmonary Fibrosis Foundation Patient Registry, worse cough-specific quality of life was associated with respiratory hospitalization, lung transplantation, and death among 1,447 patients with interstitial lung disease (ILD) [3]. In the Canadian CARE-PF registry, which included 1,061 IPF patients among 3,886 with fibrotic ILD, cough severity worsened over time regardless of ILD targeted therapy and predicted disease progression [4].
Against that weight of evidence, when cough enters an IPF protocol, it is measured in recall- based questionnaires summarizing a patient’s weeks of symptoms, gathered in minutes at a site visit.
FVC is a standardized test with prognostic value, and it is the basis of antifibrotic approvals. It also has three problems as the sole load bearing endpoint. It is effort dependent, it moves slowly, and the better background therapy gets, the less of it there is to measure. An individual participant data meta-analysis of 12 placebo cohorts found a one year FVC decline of 196.5 mL in participants receiving no antifibrotic, against 113.3 mL in those on background antifibrotic therapy [5]. Background treatment roughly halves the decline a trial can detect, which pushes designs toward larger samples and longer follow up to demonstrate the same incremental benefit.
A 2024 symposium report written with direct engagement from patients, investigators, the NIH and the FDA weighed replacing FVC as the primary endpoint, in favor of measures reflecting how patients feel, function and survive [6]. The noise problem is documented at trial scale. A phase 2 trial of pirfenidone in unclassifiable progressive fibrosing ILD was unable to apply its prespecified primary analysis because intraindividual variability in home spirometry values made the planned statistical model unusable [7].
Given how important cough is to patients and how complicated PFDs are, an important endpoint to consider in trials is objective, continuous, passive cough monitoring, run alongside progression markers as a complement to them.
Recall-based instruments and objective monitoring capture different things. Questionnaires record how much the cough bothers the patient, and monitors count how often it happens. The IPF-specific data correlating the two remain thin and inconsistent, so a trial that collects only questionnaires measures one construct and infers the other. Single day recordings raise a separate problem. In a 30 day study of 97 patients with persistent cough, daily cough rates varied widely within individuals,
and the predictability of any single day of monitoring ranged from 95% down to 30% across subjects [8]. Whether a 24 hour recording represents a typical day for an IPF patient is unknown. No IPF-specific consensus exists, and continuous monitoring is the only way to answer the question in either direction.
This is the measurement problem the Hyfe CoughMonitor Suite was built to address. A wrist worn cough monitor processes audio on the device, transmits only cough timestamps, and discards sound after classification, which removes raw audio from the study’s data governance burden entirely. In multicenter validation, the system detected coughs with 90.4% sensitivity and 1.03 false positives per hour across 546 hours of continuous audio [9].
Objective cough frequency is already functioning as a credible primary endpoint in IPF. The phase 2 CANAL trial of nalbuphine ER took objective daytime cough frequency as its primary endpoint and found a 75.1% reduction on drug against 22.6% on placebo [10]. The phase 2b CORAL trial that followed enrolled 165 participants across 10 countries, took relative change in objective 24 hour cough frequency at week 6 as its primary endpoint, and met it at every dose: reductions of 47.9%, 53.4% and 60.2% against 16.9% for placebo, published in JAMA [11]. The next IPF cough protocol can cite two positive trials for this endpoint choice.
The same endpoint has a longer record outside IPF. In refractory chronic cough, the phase 3 COUGH-1 and COUGH-2 trials of gefapixant used objective 24 hour cough frequency as the primary endpoint, and European approval followed on that evidence in 2023 [12]. The program’s later difficulties in the United States turned on effect size, placebo response and the validation of the measurement instrument itself. That history argues for better validated continuous instruments and larger,
more durable effects. The IPF results above deliver both, and objective counting itself remained the accepted approach throughout the US review.
Timing favors IPF for three reasons. First, the endpoint has trial precedent inside IPF itself, which spares any sponsor the burden of being first. Second, the commercial logic of the indication is shifting. As background antifibrotics improve, new entrants increasingly need to differentiate on how patients feel, and a progression endpoint structurally cannot reward an antitussive or symptom-focused benefit. Objective cough frequency is the credible instrument for proving that kind of benefit. Third, an unresolved scientific question is waiting on this kind of data. Investigators have speculated that the pressures generated by repeated coughing might themselves enhance activation of profibrotic mechanisms and worsen disease [13]. That hypothesis is unproven and should be treated strictly as an open question. If it holds, cough reduction becomes a disease-relevant target and continuous cough data becomes disease relevant evidence. Either way, the question cannot be answered with questionnaires.
Cough is the symptom IPF patients report as ruining their days, it predicts outcomes in its own right, and today’s approved drugs do nothing for it. A continuous objective cough endpoint complements FVC and DLCO without competing with them, supports a differentiated label, and rewards exactly the mechanisms that progression endpoints cannot. The field’s remaining open questions, day to day stability and the relationship between counts and patient report, can only be resolved by the data continuous monitoring produces. The first drug proven both to slow decline and to relieve cough will hold a real labeling and commercial advantage, and continuous objective monitoring is how a sponsor proves it.
References
[1] Ryerson CJ, Abbritti M, Ley B, Elicker BM, Jones KD, Collard HR. Cough predicts prognosis in idiopathic pulmonary fibrosis. Respirology. 2011;16(6):969-975. doi:10.1111/j.1440-1843.2011.01996.x
[2] U.S. Food and Drug Administration, Center for Drug Evaluation and Research. The Voice of the Patient: Idiopathic Pulmonary Fibrosis. Report from the Patient-Focused Drug Development meeting of September 26, 2014. Silver Spring, MD: FDA; 2015.
[3] Lee J, White E, Freiheit E, et al. Cough-specific quality of life predicts disease progression among patients with interstitial lung disease: data from the Pulmonary Fibrosis Foundation Patient Registry. Chest. 2022;162(3):603-613. doi:10.1016/j.chest.2022.03.025
[4] Khor YH, Johannson KA, Marcoux V, et al.; CARE-PF Investigators. Epidemiology and prognostic significance of cough in fibrotic interstitial lung disease. Am J Respir Crit Care Med. 2024;210(8):1035-1044. doi:10.1164/rccm.202311-2101OC
[5] Khan FA, Stewart I, Moss S, Fabbri L, Robinson KA, Johnson SR, Jenkins RG. Three-month FVC change: a trial endpoint for idiopathic pulmonary fibrosis based on individual participant data meta-analysis. Am J Respir Crit Care Med. 2022;205(8):936-948. doi:10.1164/rccm.202109-2091OC
[6] Raghu G, et al. Meaningful endpoints for idiopathic pulmonary fibrosis (IPF) clinical trials: emphasis on ‘feels, functions, survives’. Am J Respir Crit Care Med. 2024;209(6):647-669. doi:10.1164/rccm.202312-2213SO
[7] Maher TM, Corte TJ, Fischer A, et al. Pirfenidone in patients with unclassifiable progressive fibrosing interstitial lung disease: a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet Respir Med. 2020;8(2):147-157. doi:10.1016/S2213-2600(19)30341-8
[8] Chung KF, Chaccour C, Jover L, Galvosas M, Song WJ, Rudd M, Small P. Longitudinal cough frequency monitoring in persistent coughers: daily variability and predictability. Lung. 2024;202(5):561-568. doi:10.1007/s00408-024-00734-x
[9] Chaccour C, Sánchez-Olivieri I, Siegel S, et al. Validation and accuracy of the Hyfe cough monitoring system: a multicenter clinical study. Sci Rep. 2025;15:880. doi:10.1038/s41598-025-85341-3
[10] Maher TM, et al. Nalbuphine tablets for cough in patients with idiopathic pulmonary fibrosis (CANAL). NEJM Evid. 2023;2(8):EVIDoa2300083. doi:10.1056/EVIDoa2300083
[11] Molyneaux PL, et al. Oral nalbuphine in idiopathic pulmonary fibrosis-associated cough: the CORAL randomized clinical trial. JAMA. 2026;335(12):1050-1059. doi:10.1001/jama.2025.26179
[12] McGarvey LP, Birring SS, Morice AH, et al. Efficacy and safety of gefapixant, a P2X3 receptor antagonist, in refractory chronic cough and unexplained chronic cough (COUGH-1 and COUGH-2): results from two double-blind, randomised, parallel-group, placebo-controlled, phase 3 trials. Lancet. 2022;399(10328):909-923. doi:10.1016/S0140-6736(21)02348-5
[13] van Manen MJG, Birring SS, Vancheri C, Cottin V, Renzoni EA, Russell AM, Wijsenbeek MS. Cough in idiopathic pulmonary fibrosis. Eur Respir Rev. 2016;25(141):278-286. doi:10.1183/16000617.0090-2015
