Clinical trial NCT04765722: Mepolizumab for the Treatment of Chronic Cough With Eosinophilic Airways Diseases
Official title: Mepolizumab for the Treatment of Chronic Cough With Eosinophilic Airways Diseases
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Chronic Cough
Eosinophilic Bronchitis
Asthma
Keywords: Mepolizumab
Treatment
Anti-interleukin-5
Proof-of-concept study
Randomized
Double-blind
Placebo controlled
Lead sponsor: McMaster University
Sponsor class: OTHER
Collaborators: name: University of Manchester
First posted: 2021-02-21
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Single-centre, randomized, double-blind, placebo-controlled, parallel-group proof-of-concept study to evaluate the effectiveness of 4 doses of mepolizumab for the treatment of refractory chronic cough in patients with asthma and non-asthmatic eosinophilic bronchitis. The study will have 2 arms, each with 15 participants, and a total of 9 visits per subject. Subjects will be screened and within 2 weeks randomized to the intervention (mepolizumab) or placebo arm. Subjects will receive the intervention over a 12 week period at visits 3, 4, 5, and 7. The primary outcome will be measured at visit 14 which will occur 2 weeks after the final intervention dose.
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Cough frequency
timeFrame: 14 weeks
Secondary outcomes:
measure: Awake cough frequency at 8 weeks
timeFrame: 8 weeks
measure: Awake cough frequency at 14 weeks
timeFrame: 14 weeks
measure: Night-time cough frequency at 8 weeks
timeFrame: 8 weeks
measure: Night-time cough frequency at 14 weeks
timeFrame: 14 weeks
measure: Percent reduction in 24 hour cough frequency at 8 weeks
timeFrame: 8 weeks
measure: Percent reduction in 24 hour cough frequency at 14 weeks
timeFrame: 14 weeks
measure: Cough severity and intensity of sensations at 8 weeks
timeFrame: 8 weeks
measure: Cough severity and intensity of sensations at 14 weeks
timeFrame: 14 weeks
measure: Cough severity at 8 weeks
timeFrame: 8 weeks
measure: Cough severity at 14 weeks
timeFrame: 14 weeks
measure: Leicester Cough Questionnaire at 8 weeks
timeFrame: 8 weeks
measure: Leicester Cough Questionnaire at 14 weeks
timeFrame: 14 weeks
measure: Blood eosinophils at 8 weeks
timeFrame: 8 weeks
measure: Blood eosinophils at 14 weeks
timeFrame: 14 weeks
measure: Sputum eosinophils at 8 weeks
timeFrame: 8 weeks
measure: Sputum eosinophils at 14 weeks
timeFrame: 14 weeks
Other outcomes:
measure: Methacholine provocative concentration20 at 14 weeks
timeFrame: 14 weeks
measure: Total and activated mature eosinophils at 14 weeks
timeFrame: 14 weeks
Locations:
city: Hamilton
country: Canada
facility: McMaster University
state: Ontario
Study officials:
affiliation: McMaster University
name: Imran Satia, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.