Morphine Sulfate/Placebo for the Treatment of PulmonAry Fibrosis Cough

NCT04429516 | Completed Phase 3

• 2 other identifiers: RBH2019/0012019-003571-19
• Study Type: interventional
• Target: 44
• Locations: 1 country
• Sites: 1

Brief Summary

Idiopathic pulmonary fibrosis (IPF) is a disease of unknown cause that results in scarring of the lungs. Cough is reported by 85% of patients with IPF and can be a distressing symptom with significant physical, social and psychological consequences particularly anxiety and depression. The cause of cough in IPF is poorly understood and there are currently no proven effective therapies. Morphine has long been advocated for the suppression of chronic cough in other conditions. While morphine is frequently used as a palliative agent for breathlessness in IPF, its effects on cough have never been tested. The aim of this study is therefore to explore and compare the effect of low dose morphine, one of the few therapies shown to be effective in some patients with otherwise refractory chronic cough, in patients with IPF, to an inactive substance known as a placebo. To make a fair comparison, patients will be randomly allocated to receiving either morphine or placebo in a blinded fashion. This means neither the doctor nor the patient will know which drug they are receiving, and the drugs will appear the same. However, the trial is designed so that you will receive both morphine and placebo, but at different times (this is called a cross-over study). More specifically, you will be given either morphine or placebo for 14 days at a time. In this study, it is hypothesised that compared with placebo, low dose (5mg) controlled release Morphine sulfate (MST) will reduce the number of coughs recorded during a 24hr period in patients with IPF.

Conditions

Idiopathic Pulmonary Fibrosis

Outcome Measures

Primary Outcomes (1)

• The percent change in daytime cough frequency (coughs per hour)

  from baseline as assessed by objective digital cough monitoring at Day 14 of treatment

Secondary Outcomes (8)

• Change from baseline in health-related quality of life scores (Living with Idiopathic Pulmonary Fibrosis Questionnaire)

  At Day 0, Day 14, Day 22, Day 36 and Day 50-64

• Change from baseline in health-related quality of life scores (HDAS- Hospital Anxiety and Depression Scale)

  At Day 0, Day 14, Day 22, Day 36 and Day 50-64

• Change from baseline in health-related quality of life scores (K-BILD - King's Brief Interstitial Lung Disease Questionnaire)

  At Day 0, Day 14, Day 22, Day 36 and Day 50-64

• Change from baseline in self-reported cough (Leicester Cough Questionnaire (LCQ)

  At Day 0, Day 14, Day 22, Day 36 and Day 50-64

• Change from baseline in self-reported cough - Visual analogue scale (VAS)

  At Day 0, Day 14, Day 22, Day 36 and Day 50-64

Study Arms (2)

Morphine Sulfate

EXPERIMENTAL

Drug: Morphine Sulfate

Placebo

PLACEBO COMPARATOR

Drug: Placebo oral tablet

Interventions

Morphine Sulfate DRUG

over-encapsulated Morphine Sulfate prolonged release 5mg tablet, twice daily for 14 days. Patients will then crossover after a 7 day wash out period.

Morphine Sulfate

Placebo oral tablet DRUG

capsule containing Microcrystalline Cellulose Ph. Eur, 5 mg twice daily

Placebo

Eligibility Criteria

• Age: 40 Years - 90 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Self-reported cough (\> 8 weeks), with cough VAS ≥ 30/100
• A diagnosis of IPF within 5 years prior to the screening visit, as per applicable ATS/ERS/JRS/ALAT guidelines, in line with hospital records.
• Age 3.1. Male and female participants aged ≥ 40 - 90 years at the time of signing informed consent
• Sex:
• Male participants: A male participant must agree to use contraception as detailed in Appendix 2 of this protocol during the study and for at least 90 days after the follow-up visit, and refrain from donating sperm during this period 4.2 Female participants: A female participant is eligible to participate if she is not pregnant, not breastfeeding, and not a woman of childbearing potential (WOCBP)
• Meeting all of the following criteria during the screening period: FVC ≥ 45% predicted of normal, Forced expiratory volume in 1 second (FEV1)/FVC ≥0.7, DLCO corrected for Hb ≥30% predicted of normal.
• The extent of fibrotic changes is greater than the extent of emphysema on the most recent HRCT scan (investigator determined within 24 months of the study screening visit)
• Written informed consent.

You may not qualify if:

• Treatment with immunosuppressive therapy or antibiotics within last 4 weeks. A stable dose of corticosteroids equivalent to prednisolone of 10 mg per day or less, if used for an indication other than pulmonary disease will be permitted
• Current smoker
• History of alcohol and drug(s) addiction
• Regular use of sedative therapies
• Acute IPF exacerbation within 6 months prior to screening and/or during the screening period.
• Concurrent use of pirfenidone or Nintedanib, unless receiving a stable dose for at least 8 weeks prior to screening
• Use of ACE inhibitors
• Patients with co-existent conditions know to be associated with the development of fibrotic lung disease. This includes: connective tissue disease, (plural plaques, mesothelioma), granulomatous disease including sarcoidosis. Patient with auto-immune profile considered diagnostic for a specific connective tissue disease will be excluded, even in the absence of systemic symptoms. Non-specific rises in auto antibodies e.g. rheumatoid factors, anti-nuclear antibody etc. will not be used to exclude individuals from the study.
• Significant other organ co-morbidity including hepatic or renal impairment and pulmonary hypertension (investigator determined).
• Significant coronary artery disease (myocardial infarction within 6 months or ongoing unstable angina within 4 weeks of screening visit) or congestive cardiac failure based on clinical examination
• Patients as significant risk of side effects, intolerance or allergy to morphine
• Pregnant and breastfeeding patients, or women or child-bearing potential, not using a reliable contraceptive method (see Appendix 2). A urine pregnancy test will be performed in females of child-bearing potential at the initial study visit.
• Unable to provide informed written consent
• Predicted life expectancy \< 6 months
• Use of long-term oxygen therapy. Use of ambulatory oxygen will be permitted.

Sponsors & Collaborators

• Royal Brompton & Harefield NHS Foundation Trust: lead

Study Sites (1)

Royal Brompton Hospital

London, SW3 6NP, United Kingdom

Location

Related Publications (6)

• Hope-Gill BD, Hilldrup S, Davies C, Newton RP, Harrison NK. A study of the cough reflex in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2003 Oct 15;168(8):995-1002. doi: 10.1164/rccm.200304-597OC. Epub 2003 Aug 13.

  PMID: 12917229 BACKGROUND

• van Manen MJ, Birring SS, Vancheri C, Cottin V, Renzoni EA, Russell AM, Wijsenbeek MS. Cough in idiopathic pulmonary fibrosis. Eur Respir Rev. 2016 Sep;25(141):278-86. doi: 10.1183/16000617.0090-2015.

  PMID: 27581827 BACKGROUND

• Morice AH, Menon MS, Mulrennan SA, Everett CF, Wright C, Jackson J, Thompson R. Opiate therapy in chronic cough. Am J Respir Crit Care Med. 2007 Feb 15;175(4):312-5. doi: 10.1164/rccm.200607-892OC. Epub 2006 Nov 22.

  PMID: 17122382 BACKGROUND

• Bajwah S, Davies JM, Tanash H, Currow DC, Oluyase AO, Ekstrom M. Safety of benzodiazepines and opioids in interstitial lung disease: a national prospective study. Eur Respir J. 2018 Dec 6;52(6):1801278. doi: 10.1183/13993003.01278-2018. Print 2018 Dec.

  PMID: 30309973 BACKGROUND

• Wu Z, Spencer LG, Banya W, Westoby J, Tudor VA, Rivera-Ortega P, Chaudhuri N, Jakupovic I, Patel B, Thillai M, West A, Wijsenbeek M, Maher TM, Smith JA, Molyneaux PL. Morphine for treatment of cough in idiopathic pulmonary fibrosis (PACIFY COUGH): a prospective, multicentre, randomised, double-blind, placebo-controlled, two-way crossover trial. Lancet Respir Med. 2024 Apr;12(4):273-280. doi: 10.1016/S2213-2600(23)00432-0. Epub 2024 Jan 15.

  PMID: 38237620 DERIVED

• Wu Z, Banya W, Chaudhuri N, Jakupovic I, Maher TM, Patel B, Spencer LG, Thillai M, West A, Westoby J, Wijsenbeek M, Smith J, Molyneaux PL. PAciFy Cough-a multicentre, double-blind, placebo-controlled, crossover trial of morphine sulphate for the treatment of pulmonary Fibrosis Cough. Trials. 2022 Mar 2;23(1):184. doi: 10.1186/s13063-022-06068-4.

  PMID: 35236391 DERIVED

MeSH Terms

Conditions

Idiopathic Pulmonary Fibrosis

Interventions

Morphine

Condition Hierarchy (Ancestors)

Pulmonary Fibrosis; Lung Diseases, Interstitial; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Morphine Derivatives; Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 12, 2020
• First Posted: June 12, 2020
• Study Start: December 17, 2020
• Primary Completion: March 21, 2023
• Study Completion: March 21, 2023
• Last Updated: April 14, 2023

Record last verified: 2023-04

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)