Mepolizumab for the Treatment of Chronic Cough With Eosinophilic Airways Diseases

Study Overview
=================
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.

Official Title
-----------------
Mepolizumab for the Treatment of Chronic Cough With Eosinophilic Airways Diseases

Conditions
-----------------
Chronic Cough, Eosinophilic Bronchitis, Asthma

Intervention / Treatment
-----------------
* Drug: Mepolizumab
* Drug: Normal Saline


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Aged ≥18 Subjects with a history of chronic cough (cough lasting for >8 weeks) Evidence of airway eosinophilia (sputum eosinophilia>2%) Forced expiratory volume-1 ≥ 70% of predicted Normal chest x-ray (within the last 6 months) At least one dose of a COVID-19 vaccine a minimum of 2 weeks prior to enrollment Exclusion Criteria: Symptoms of upper respiratory tract infection in the last 1 month which have not resolved. Lower respiratory tract infection or pneumonia in the last 1 month. Subjects with a positive covid-19 test within 2 weeks of screening Subjects with seasonal allergic rhinitis that affects their asthma control Current smoker or ex-smoker with ≥10 pack year smoking history and abstinence of ≤6 months 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. Use of regular maintenance oral corticosteroids or long-acting muscarinic antagonist within 4 weeks prior to enrolment into the study. A previous asthma exacerbation requiring Intensive Care Unit admission. Significant other primary pulmonary disorders in particular; pulmonary embolism, pulmonary hypertension, interstitial lung disease, lung cancer, cystic fibrosis, emphysema or bronchiectasis. Any history or symptoms of cardiovascular disease, particularly coronary artery disease, arrhythmias, hypertension, or congestive heart failure. Any history or symptoms of significant neurologic disease, including transient ischemic attack, stroke, seizure disorder, or behavioural disturbances Uncontrolled diabetes End-stage kidney or liver disease 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. Any history or symptoms of clinically significant autoimmune disease History of anaphylaxis to any biologic therapy or vaccine History of Guillain-Barre Syndrome 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. 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. A history of immunodeficiency disorders including a positive human immunodeficiency virus test Pregnancy or breast-feeding. 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. 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. Use of angiotensin-converting-enzyme inhibitors 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 Use of any other biological within 4 months or 5 half-lives prior to randomization, whichever is longer. 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.) History of psychiatric illness, drug or alcohol abuse which may interfere in the participation of the trial.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Mepolizumab arm<br>Mepolizumab Dosage form: 1ml pre-filled syringe Dosage: 100mg Frequency: 3 doses at days 0, 28, 56 and 84 Duration: 12 weeks | Drug: Mepolizumab<br>* Mepolizumab subcutaneous injection administered 3 times days 0, 28, 56 and 84 during 12 week treatment period.<br>* Other names: Nucala;|
| Placebo Comparator: Placebo arm<br>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<br>* Placebo subcutaneous injection administered 3 times days 0, 28, 56 and 84 during 12 week treatment period.<br>* 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Mepolizumab, Treatment, Anti-interleukin-5, Proof-of-concept study, Randomized, Double-blind, Placebo controlled