Mepolizumab for the Treatment of Chronic Cough With Eosinophilic Airways Diseases (MUCOSA)

Cough is the most common presenting symptom to family physician. Chronic Cough affects approximately 10-12% of the general population and is one of the commonest reasons for referral to secondary care. Unfortunately, there are no licensed treatments for this debilitating condition, which is associated with a poor quality of life, affecting the social, physical and psychological well-being of patients.

The aim of this single-centre proof-of-concept study is to investigate whether mepolizumab reduces objective cough frequency in patients with eosinophilic asthma and non-asthmatic eosinophilic bronchitis presenting with chronic cough. Secondary outcomes including the effects on quality of life, the intensity of irritant sensations, airway hyper-reactivity and inflammatory cells and their progenitors will also be evaluated.

The investigators hypothesize that in patients with asthma and non-asthmatic eosinophilic bronchitis, eosinophils are involved in sensitizing airway nerves and thereby increasing spontaneous objective coughs. The investigators predict that treatment with mepolizumab will reduce airway eosinophilia in patients with chronic cough due to eosinophilic asthma and non-asthmatic eosinophilic bronchitis, thereby causing a reduction in objective cough frequency.

Study Overview

• Status: Recruiting
• Conditions: Asthma; Eosinophilic Bronchitis; Chronic Cough
• Intervention / Treatment: Drug: Mepolizumab; Drug: Normal Saline

Detailed Description

This is a 9-visit randomized, double-blind, placebo-controlled, parallel-group Phase IV study. The purpose of this study is to evaluate the effectiveness of mepolizumab for the treatment of refractory chronic cough in patients with eosinophilic airway disease. Patients will be recruited from secondary care clinics. Patient eligibility will be assessed against the study inclusion/exclusion criteria and patients will undergo informed consent in the research centre. Subjects who provide informed consent and are enrolled in the study will undergo screening procedures.

The study will consist of a Mepolizumab treatment arm and placebo arm (normal saline). Fifteen subjects will be randomly assigned to the treatment arm and fifteen subjects will be randomly assigned to the placebo arm in a 1:1 ratio. Following screening and randomization, subjects will under an 12-week treatment period during which they will receive 4 doses of the study drug at days 0, 28, 56, and 84. The primary study outcomes will be measured at week 14 week, 2 weeks following the treatment period.

At Visit 1 (screening), subjects will undergo screening procedures: complete medical history, physical examination, methacholine challenge, spirometry, sputum induction, and blood sampling. Subjects will complete the Leicester Cough Questionnaire and modified Borg Scale.

At Visit 2, subjects will be fitted with a 24-hour cough monitor.

At Visit 3, 24-hour cough monitors will be removed and subjects will undergo spirometry, blood sampling and sputum induction. Subjects will complete the Leicester Cough Questionnaire, modified Borg Scale, and Cough Severity Visual Analogue Scale. The first dose of the study drug will be administered in the clinical research facility by a study physician.

At Visit 4, subjects will undergo spirometry and blood sampling and complete the Leicester Cough Questionnaire, modified Borg Scale, and Cough Severity Visual Analogue Scale. The second dose of the study drug will be administered in the clinical research facility by a study physician.

At Visit 5, the third dose of the study drug will be administered in the clinical research facility by a study physician. Subjects will be fitted with a 24-hour cough monitor.

At Visit 6, 24-hour cough monitors will be removed and subjects will undergo spirometry, sputum induction and blood sampling and complete the Leicester Cough Questionnaire, modified Borg Scale, and Cough Severity Visual Analogue Scale.

At Visit 7, subjects will undergo spirometry and blood sampling and complete the Leicester Cough Questionnaire, modified Borg Scale, and Cough Severity Visual Analogue Scale. The fourth dose of the study drug will be administered in the clinical research facility by a study physician.

At Visit 8, subjects will be fitted with a 24-hour cough monitor.

At Visit 9, the 24-hour cough monitors will be removed and subjects will undergo spirometry, methacholine challenge, sputum induction, and blood sampling. Subjects will complete the Leicester Cough Questionnaire, modified Borg Scale, and Cough Severity Visual Analogue Scale.

All study procedures will be performed according to local standard operating procedures and be conducted by trained and experienced staff with supervision by medical doctors. Study physicians will administer all study drug injections. Safety will be assessed throughout the study by monitoring for adverse events and serious adverse events.

• Study Type: Interventional
• Enrollment (Anticipated): 30
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Imran Satia, MD, PhD; Phone Number: 76228 905-521-2100; Email: satiai@mcmaster.ca
• Study Contact Backup: Name: Paul O'Byrne, MD; Phone Number: 76373 905-521-2100; Email: obyrnep@mcmaster.ca

Study Locations

• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8S 4L8
      • Recruiting
      • McMaster University
      • Contact: Imran Satia, MD PhD; Email: satiai@mcmaster.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Aged ≥18
2. Subjects with a history of chronic cough (cough lasting for >8 weeks)
3. Evidence of airway eosinophilia (sputum eosinophilia>2%)
4. Forced expiratory volume-1 ≥ 70% of predicted
5. Normal chest x-ray (within the last 6 months)
6. At least one dose of a COVID-19 vaccine a minimum of 2 weeks prior to enrollment

Exclusion Criteria:

1. Symptoms of upper respiratory tract infection in the last 1 month which have not resolved.
2. Lower respiratory tract infection or pneumonia in the last 1 month.
3. Subjects with a positive covid-19 test within 2 weeks of screening
4. Subjects with seasonal allergic rhinitis that affects their asthma control
5. Current smoker or ex-smoker with ≥10 pack year smoking history and abstinence of ≤6 months
6. Symptoms of uncontrolled asthma at screening defined as: Asthma Control Questionnaire-5 >1.5, or use of 3 or more puffs of a short acting beta-2 agonist per week, or an exacerbation in the previous month requiring oral prednisone or antibiotics.
7. Use of regular maintenance oral corticosteroids or long-acting muscarinic antagonist within 4 weeks prior to enrolment into the study.
8. A previous asthma exacerbation requiring Intensive Care Unit admission.
9. Significant other primary pulmonary disorders in particular; pulmonary embolism, pulmonary hypertension, interstitial lung disease, lung cancer, cystic fibrosis, emphysema or bronchiectasis.
10. Any history or symptoms of cardiovascular disease, particularly coronary artery disease, arrhythmias, hypertension, or congestive heart failure.
11. Any history or symptoms of significant neurologic disease, including transient ischemic attack, stroke, seizure disorder, or behavioural disturbances
12. Uncontrolled diabetes
13. End-stage kidney or liver disease
14. Clinically significant abnormalities in laboratory test results during the screening period (including complete blood count, coagulation, electrolytes, liver function tests) unless deemed not significant by the investigator.
15. Any history or symptoms of clinically significant autoimmune disease
16. History of anaphylaxis to any biologic therapy or vaccine
17. History of Guillain-Barre Syndrome
18. A helminth parasitic infection diagnosed within 24 weeks prior to the date of informed consent is obtained that has not been treated with or has failed to respond to standard of care therapy.
19. Positive hepatitis B surface antigen, or hepatitis C virus antibody serology, or a positive medical history for hepatitis B or C. Subjects with a history of hepatitis B vaccination without history of hepatitis B can enroll.
20. A history of immunodeficiency disorders including a positive human immunodeficiency virus test
21. Pregnancy or breast-feeding.

22. Women of childbearing potential must not be actively seeking pregnancy, and must use an effective form of birth control (confirmed by the Investigator). Effective forms of birth control include: true sexual abstinence, a vasectomized sexual partner, Implanon, female sterilization by tubal occlusion, any effective intrauterine device/ intrauterine system levonorgestrel Intrauterine system, Depo-Provera™ injections, oral contraceptive, and Evra Patch™ or Nuvaring™. Women of childbearing potential must agree to use an effective method of birth control, as defined above, from enrolment, throughout the study duration and within the 8 treatment weeks. They must demonstrate a negative serum pregnancy test at screening and demonstrate a negative urine pregnancy test immediately before each dose of study drug or placebo. Women not of childbearing potential are defined as women who are either permanently sterilized (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or who are postmenopausal. Women will be considered postmenopausal if they have been amenorrheic for 12 months prior to the planned date of randomization without an alternative medical cause. The following age-specific requirements apply:

    i. Women <50 years old would be considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatment and follicle stimulating hormone (FSH) levels in the postmenopausal range.

    ii. Women ≥50 years old would be considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatment.

23. Male patients not using an acceptable method of contraception. All male patients who are sexually active must agree to use an acceptable method of contraception (condom with or without spermicide, vasectomy) from the first dose of study drug until their last dose.
24. Use of angiotensin-converting-enzyme inhibitors
25. Use of immunosuppressive medication (including but not limited to: methotrexate, cyclosporine, azathioprine, intramuscular long-acting depot corticosteroid, oral corticosteroid, or any experimental anti-inflammatory therapy) within 3 months prior to the date informed consent is obtained
26. Use of any other biological within 4 months or 5 half-lives prior to randomization, whichever is longer.
27. Any centrally acting medication within the last 2 weeks which in the view of the investigator could influence the coughing (Any participant who is taking amitriptyline, dextromethorphan, pregabalin, gabapentin or opioids will not be eligible to take part in this study unless they are willing and medically able to withdraw from such medication for the duration of the study. The reason for this is that centrally acting medications may influence coughing rates.)
28. History of psychiatric illness, drug or alcohol abuse which may interfere in the participation of the trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Mepolizumab arm; Mepolizumab Dosage form: 1ml pre-filled syringe Dosage: 100mg Frequency: 3 doses at days 0, 28, 56 and 84 Duration: 12 weeks	Drug: Mepolizumab; Mepolizumab subcutaneous injection administered 3 times days 0, 28, 56 and 84 during 12 week treatment period.; Other Names: Nucala
Placebo Comparator: Placebo arm; Normal Saline (0.09% normal saline) Dosage form: 1ml pre-filled syringe Dosage: n/a Frequency: 3 doses at days 0, 28, 56 and 84 Duration: 12 weeks	Drug: Normal Saline; Placebo subcutaneous injection administered 3 times days 0, 28, 56 and 84 during 12 week treatment period.; Other Names: 0.09% normal saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cough frequency	Change in 24 hour cough frequency (coughs/hour) from baseline to visit 8 of treatment with Mepolizumab compared with placebo.	14 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Awake cough frequency at 8 weeks	Change in awake cough frequency (coughs/hour) from baseline to visit 5 of treatment with Mepolizumab compared with placebo among all participants and by disease group (participants with asthma and participants with non-asthmatic eosinophilic bronchitis).	8 weeks
Awake cough frequency at 14 weeks	Change in awake cough frequency (coughs/hour) from baseline to visit 8 of treatment with Mepolizumab compared with placebo among all participants and by disease group (participants with asthma and participants with non-asthmatic eosinophilic bronchitis).	14 weeks
Night-time cough frequency at 8 weeks	Change in night-time cough frequency (coughs/hour) from baseline to visit 5 of treatment with Mepolizumab compared with placebo among all participants and by disease group (participants with asthma and participants with non-asthmatic eosinophilic bronchitis).	8 weeks
Night-time cough frequency at 14 weeks	Change in night-time cough frequency (coughs/hour) from baseline to visit 8 of treatment with Mepolizumab compared with placebo among all participants and by disease group (participants with asthma and participants with non-asthmatic eosinophilic bronchitis).	14 weeks
Percent reduction in 24 hour cough frequency at 8 weeks	Percentage of participants with a reduction in 24-hour cough frequency of ≥30% from baseline to visit 5 of treatment with Mepolizumab compared with placebo among all participants and by disease group (participants with asthma and participants with non-asthmatic eosinophilic bronchitis).	8 weeks
Percent reduction in 24 hour cough frequency at 14 weeks	Percentage of participants with a reduction in 24-hour cough frequency of ≥30% from baseline to visit 8 of treatment with Mepolizumab compared with placebo among all participants and by disease group (participants with asthma and participants with non-asthmatic eosinophilic bronchitis).	14 weeks
Cough severity and intensity of sensations at 8 weeks	Change in the cough severity and intensity of sensations (itch, tickle, irritation, urge to cough on a modified Borg Scale (mBorg Scale)) from baseline to visit 5 of treatment with Mepolizumab compared with placebo among all participants and by disease group (participants with asthma and participants with non-asthmatic eosinophilic bronchitis). The mBorg scale minimum value is 0 for no cough sensations and the maximum value is 10 for most severe cough sensations.	8 weeks
Cough severity and intensity of sensations at 14 weeks	Change in the cough severity and intensity of sensations (itch, tickle, irritation, urge to cough on a modified Borg Scale (mBorg Scale)) from baseline to visit 8 of treatment with Mepolizumab compared with placebo among all participants and by disease group (participants with asthma and participants with non-asthmatic eosinophilic bronchitis). The mBorg scale minimum value is 0 for no cough sensations and the maximum value is 10 for most severe cough sensations.	14 weeks
Cough severity at 8 weeks	Change in the cough severity measured using the Cough Severity Visual Analogue Scale (0-100mm) from baseline to visit 5 of treatment with Mepolizumab compared with placebo among all participants and by disease group (participants with asthma and participants with non-asthmatic eosinophilic bronchitis). Participants will rate their severity of cough on the scale which has a minimum value of 0 equalling "no cough" and a maximum value of 100 equalling "worst cough". A higher score indicates greater cough severity.	8 weeks
Cough severity at 14 weeks	Change in the cough severity measured using the Cough Severity Visual Analogue Scale (0-100mm) from baseline to visit 8 of treatment with Mepolizumab compared with placebo among all participants and by disease group (participants with asthma and participants with non-asthmatic eosinophilic bronchitis). Participants will rate their severity of cough on the scale which has a minimum value of 0 equalling "no cough" and a maximum value of 100 equalling "worst cough". A higher score indicates greater cough severity.	14 weeks
Leicester Cough Questionnaire at 8 weeks	Change in Leicester Cough Questionnaire (LCQ) score from baseline to visit 5 of treatment with Mepolizumab compared with placebo among all participants and by disease group (participants with asthma and participants with non-asthmatic eosinophilic bronchitis). The LCQ is a 7 point Likert scale where the minimum value is 1 indicating chronic cough impacts the participants all the time and a maximum value of 7 indicating chronic cough impacts the participants none of the time.	8 weeks
Leicester Cough Questionnaire at 14 weeks	Change in Leicester Cough Questionnaire (LCQ) score from baseline to visit 8 of treatment with Mepolizumab compared with placebo among all participants and by disease group (participants with asthma and participants with non-asthmatic eosinophilic bronchitis). The LCQ is a 7 point Likert scale where the minimum value is 1 indicating chronic cough impacts the participants all the time and a maximum value of 7 indicating chronic cough impacts the participants none of the time.	14 weeks
Blood eosinophils at 8 weeks	Change in blood eosinophils from baseline to visit 5 of treatment with Mepolizumab compared with placebo among all participants and by disease group (participants with asthma and participants with non-asthmatic eosinophilic bronchitis).	8 weeks
Blood eosinophils at 14 weeks	Change in blood eosinophils from baseline to visit 8 of treatment with Mepolizumab compared with placebo among all participants and by disease group (participants with asthma and participants with non-asthmatic eosinophilic bronchitis).	14 weeks
Sputum eosinophils at 8 weeks	Change in sputum eosinophils from baseline to visit 5 of treatment with Mepolizumab compared with placebo among all participants and by disease group (participants with asthma and participants with non-asthmatic eosinophilic bronchitis).	8 weeks
Sputum eosinophils at 14 weeks	Change in sputum eosinophils from baseline to visit 8 of treatment with Mepolizumab compared with placebo among all participants and by disease group (participants with asthma and participants with non-asthmatic eosinophilic bronchitis).	14 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Methacholine provocative concentration20 at 14 weeks	Change in methacholine provocative concentration20 from baseline to visit 8 of treatment with Mepolizumab compared with placebo among all participants and by disease group (participants with asthma and participants with non-asthmatic eosinophilic bronchitis).	14 weeks
Total and activated mature eosinophils at 14 weeks	Change in total and activated mature eosinophils in blood and sputum from baseline to visit 8 of treatment with Mepolizumab compared with placebo among all participants and by disease group (participants with asthma and participants with non-asthmatic eosinophilic bronchitis).	14 weeks

Collaborators and Investigators

• Sponsor: McMaster University
• Collaborators: GlaxoSmithKline; University of Manchester
• Investigators: Principal Investigator: Imran Satia, MD, PhD, McMaster University

Publications and helpful links

General Publications

• Song WJ, Chang YS, Faruqi S, Kim JY, Kang MG, Kim S, Jo EJ, Kim MH, Plevkova J, Park HW, Cho SH, Morice AH. The global epidemiology of chronic cough in adults: a systematic review and meta-analysis. Eur Respir J. 2015 May;45(5):1479-81. doi: 10.1183/09031936.00218714. Epub 2015 Feb 5. No abstract available.
• Irwin RS, Baumann MH, Bolser DC, Boulet LP, Braman SS, Brightling CE, Brown KK, Canning BJ, Chang AB, Dicpinigaitis PV, Eccles R, Glomb WB, Goldstein LB, Graham LM, Hargreave FE, Kvale PA, Lewis SZ, McCool FD, McCrory DC, Prakash UBS, Pratter MR, Rosen MJ, Schulman E, Shannon JJ, Hammond CS, Tarlo SM. Diagnosis and management of cough executive summary: ACCP evidence-based clinical practice guidelines. Chest. 2006 Jan;129(1 Suppl):1S-23S. doi: 10.1378/chest.129.1_suppl.1S. No abstract available.
• Schappert SM, Burt CW. Ambulatory care visits to physician offices, hospital outpatient departments, and emergency departments: United States, 2001-02. Vital Health Stat 13. 2006 Feb;(159):1-66.
• French CL, Irwin RS, Curley FJ, Krikorian CJ. Impact of chronic cough on quality of life. Arch Intern Med. 1998 Aug 10-24;158(15):1657-61. doi: 10.1001/archinte.158.15.1657.
• Brightling CE, Ward R, Goh KL, Wardlaw AJ, Pavord ID. Eosinophilic bronchitis is an important cause of chronic cough. Am J Respir Crit Care Med. 1999 Aug;160(2):406-10. doi: 10.1164/ajrccm.160.2.9810100.
• Gibson PG, Dolovich J, Denburg J, Ramsdale EH, Hargreave FE. Chronic cough: eosinophilic bronchitis without asthma. Lancet. 1989 Jun 17;1(8651):1346-8. doi: 10.1016/s0140-6736(89)92801-8.
• Carney IK, Gibson PG, Murree-Allen K, Saltos N, Olson LG, Hensley MJ. A systematic evaluation of mechanisms in chronic cough. Am J Respir Crit Care Med. 1997 Jul;156(1):211-6. doi: 10.1164/ajrccm.156.1.9605044.
• Satia I, Watson R, Scime T, Dockry RJ, Sen S, Ford JW, Mitchell PD, Fowler SJ, Gauvreau GM, O'Byrne PM, Smith JA. Allergen challenge increases capsaicin-evoked cough responses in patients with allergic asthma. J Allergy Clin Immunol. 2019 Sep;144(3):788-795.e1. doi: 10.1016/j.jaci.2018.11.050. Epub 2019 Jan 17.
• Drake MG, Scott GD, Blum ED, Lebold KM, Nie Z, Lee JJ, Fryer AD, Costello RW, Jacoby DB. Eosinophils increase airway sensory nerve density in mice and in human asthma. Sci Transl Med. 2018 Sep 5;10(457):eaar8477. doi: 10.1126/scitranslmed.aar8477.

Study record dates

Study Major Dates

• Study Start (Actual): December 14, 2021
• Primary Completion (Anticipated): December 31, 2023
• Study Completion (Anticipated): April 30, 2024

Study Registration Dates

• First Submitted: February 5, 2021
• First Submitted That Met QC Criteria: February 19, 2021
• First Posted (Actual): February 21, 2021

Study Record Updates

• Last Update Posted (Actual): March 15, 2023
• Last Update Submitted That Met QC Criteria: March 13, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: Treatment; Mepolizumab; Randomized; Double-blind; Placebo controlled; Anti-interleukin-5; Proof-of-concept study
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; Bronchial Diseases; Signs and Symptoms, Respiratory; Lung Diseases, Obstructive; Cough; Bronchitis
• Other Study ID Numbers: ISS-21-4463

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No