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A novel formulation of inhaled sodium cromoglicate (PA101) in idiopathic pulmonary fibrosis and chronic cough: a randomised, double-blind, proof-of-concept, phase 2 trial

Birring, Surinder S.; Wijsenbeek, Marlies S.; Agrawal, Sanjay; van den Berg, Jan W.K.; Stone, Helen; Morice, Alyn H.; van den Berg, Jan W. K.; Maher, Toby M.; Berg, Jan van den; Tutuncu, Ahmet; Morice, Alyn; Wijsenbeek, Marlies; Birring, Surinder; Maher, Toby

Authors

Surinder S. Birring

Marlies S. Wijsenbeek

Sanjay Agrawal

Jan W.K. van den Berg

Helen Stone

Alyn H. Morice

Jan W. K. van den Berg

Toby M. Maher

Jan van den Berg

Ahmet Tutuncu

Alyn Morice

Marlies Wijsenbeek

Surinder Birring

Toby Maher

Abstract

Background Cough can be a debilitating symptom of idiopathic pulmonary fibrosis (IPF) and is difficult to treat. PA101 is a novel formulation of sodium cromoglicate delivered via a high-efficiency eFlow nebuliser that achieves significantly higher drug deposition in the lung compared with the existing formulations. We aimed to test the efficacy and safety of inhaled PA101 in patients with IPF and chronic cough and, to explore the antitussive mechanism of PA101, patients with chronic idiopathic cough (CIC) were also studied. Methods This pilot, proof-of-concept study consisted of a randomised, double-blind, placebo-controlled trial in patients with IPF and chronic cough and a parallel study of similar design in patients with CIC. Participants with IPF and chronic cough recruited from seven centres in the UK and the Netherlands were randomly assigned (1:1, using a computer-generated randomisation schedule) by site staff to receive PA101 (40 mg) or matching placebo three times a day via oral inhalation for 2 weeks, followed by a 2 week washout, and then crossed over to the other arm. Study participants, investigators, study staff, and the sponsor were masked to group assignment until all participants had completed the study. The primary efficacy endpoint was change from baseline in objective daytime cough frequency (from 24 h acoustic recording, Leicester Cough Monitor). The primary efficacy analysis included all participants who received at least one dose of study drug and had at least one post-baseline efficacy measurement. Safety analysis included all those who took at least one dose of study drug. In the second cohort, participants with CIC were randomly assigned in a study across four centres with similar design and endpoints. The study was registered with ClinicalTrials.gov (NCT02412020) and the EU Clinical Trials Register (EudraCT Number 2014-004025-40) and both cohorts are closed to new participants. Findings Between Feb 13, 2015, and Feb 2, 2016, 24 participants with IPF were randomly assigned to treatment groups. 28 participants with CIC were enrolled during the same period and 27 received study treatment. In patients with IPF, PA101 reduced daytime cough frequency by 31·1% at day 14 compared with placebo; daytime cough frequency decreased from a mean 55 (SD 55) coughs per h at baseline to 39 (29) coughs per h at day 14 following treatment with PA101, versus 51 (37) coughs per h at baseline to 52 (40) cough per h following placebo treatment (ratio of least-squares [LS] means 0·67, 95% CI 0·48–0·94, p=0·0241). By contrast, no treatment benefit for PA101 was observed in the CIC cohort; mean reduction of daytime cough frequency at day 14 for PA101 adjusted for placebo was 6·2% (ratio of LS means 1·27, 0·78–2·06, p=0·31). PA101 was well tolerated in both cohorts. The incidence of adverse events was similar between PA101 and placebo treatments, most adverse events were mild in severity, and no severe adverse events or serious adverse events were reported. Interpretation This study suggests that the mechanism of cough in IPF might be disease specific. Inhaled PA101 could be a treatment option for chronic cough in patients with IPF and warrants further investigation.

Journal Article Type Article
Publication Date Oct 1, 2017
Journal The lancet respiratory medicine
Print ISSN 2213-2600
Electronic ISSN 2213-2619
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 5
Issue 10
Pages 806-815
Institution Citation Birring, S. S., Wijsenbeek, M. S., Agrawal, S., van den Berg, J. W., Stone, H., Maher, T. M., …Morice, A. (2017). A novel formulation of inhaled sodium cromoglicate (PA101) in idiopathic pulmonary fibrosis and chronic cough: a randomised, double-blind, proof-of-concept, phase 2 trial. The lancet. Respiratory medicine, 5(10), 806-815. https://doi.org/10.1016/S2213-2600%2817%2930310-7
DOI https://doi.org/10.1016/S2213-2600%2817%2930310-7
Keywords Idiopathic pulmonary fibrosis; Cough; Chronic cough; Idiopathic cough; Chronic idiopathic cough; Cough frequency; Cromolyn sodium; Disodium cromoglycate; Quality of life
Publisher URL http://www.sciencedirect.com/science/article/pii/S2213260017303107

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©2017, Elsevier. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/


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Copyright Statement
©2017, Elsevier. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/




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