Mepolizumab for the Treatment of Chronic Cough With Eosinophilic Airways Diseases
Mepolizumab for the Treatment of Chronic Cough With Eosinophilic Airways Diseases
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 pilot 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.
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.
Inclusion Criteria:

 1. Aged ≥18-75

 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)

 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. 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.

 13. Any history or symptoms of clinically significant autoimmune disease

 14. History of anaphylaxis to any biologic therapy or vaccine

 15. History of Guillain-Barre Syndrome

 16. 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.

 17. 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.

 18. A history of immunodeficiency disorders including a positive human immunodeficiency
 virus test

 19. Pregnancy or breast-feeding.

 20. 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.

 21. 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.

 22. Use of angiotensin-converting-enzyme inhibitors

 23. 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

 24. Use of any other biological within 4 months or 5 half-lives prior to randomization,
 whichever is longer.

 25. 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.)

 26. History of psychiatric illness, drug or alcohol abuse which may interfere in the
 participation of the trial.