Anti-viral Effects of Azithromycin in Patients With Asthma and COPD

Inclusion Criteria:

• Asthma patients (n=40)

1. Diagnosis of asthma according to GINA, with confirmed variable airflowobstruction at screening visit or previously.
2. Age ≥ 18 through 75 years.
3. A postbronchodilator FEV1 ≥ 50% predicted
4. Maintenance treatment with ICS and ≥ 1 second controller (LABA, LAMA, LTRA orXanthines) for at least three months prior to Visit 1.
5. Non-smokers (<10 packyears, quit >6 months).
6. ≥ 1 Systemic steroid treated exacerbation in the past one year despitemaintenance treatment with inhaled corticosteroids.
7. Eosinophilic (n=20, blood eosinophils ≥ 0.200x109/L) and non-eosinophilic (n=20,blood eosinophils <0.200x109/L) phenotypes.

• COPD patients (n=40)

1. Diagnosis of COPD according to GOLD
2. Age ≥ 45 through 75 years.
3. ≥ 10 packyears smoking history (current or ex-smokers).
4. A postbronchodilator FEV1 ≥ 30% predicted.
5. Maintenance treatment with long-acting bronchodilators (LABA and/or LAMA) ≥ ICS.
6. ≥ 1 Systemic steroid and/or antibiotic treated exacerbation in the past one year.
7. Eosinophilic (n=20, blood eosinophils ≥0.200x109/L) and non-eosinophilic (n=20,blood eosinophils <0.200x109/L) phenotypes.

• Healthy controls (n=20)

1. Asymptomatic
2. Non-smoking (<10 packyears, quit >6 months)
3. Normal spirometry (FEV1, FVC, FEV1/FVC ratio: all >LLN)
4. FeNO < 25 ppb
5. Non-atopic based on skin-prick test
6. Negative mannitol provocation test
7. Younger (n=10, 18-45 years) and older (n=10, >45-75 years) subjects.

Exclusion Criteria:

• Any of the following would exclude the subject from participation in the study:

1. Previous medical history or evidence of an uncontrolled intercurrent illness thatin the opinion of the investigator may compromise the safety of the subject inthe study or interfere with evaluation of the investigational product or reducethe subject's ability to participate in the study. Subjects with well-controlledcomorbid disease (e.g., hypertension, hyperlipidemia, gastroesophageal refluxdisease) on a stable treatment regimen for 15 days prior to Visit 1 are eligible.
2. Any concomitant respiratory disease that in the opinion of the investigatorand/or medical monitor will interfere with the evaluation of the investigationalproduct or interpretation of subject safety or study results (e.g., cysticfibrosis, pulmonary fibrosis, moderate-severe bronchiectasis, allergicbronchopulmonary aspergillosis, Churg-Strauss syndrome, active tuberculosis). Inaddition for the different groups the following:
3. Patient with asthma: concomitant COPD.
4. Patients with COPD: concomitant asthma (former and current)
5. Healthy subjects: COPD and asthma.
6. Any clinically relevant abnormal findings in hematology or clinical chemistry (laboratory results from Visit 1), physical examination, vital signs during thescreening, which in the opinion of the investigator, may put the subject at riskbecause of his/her participation in the study, or may influence the results ofthe study, or the subject's ability to participate in the study.
7. Evidence of active liver disease, including jaundice or aspartate transaminase,alanine transaminase, or alkaline phosphatase >1.5 times the upper limit ofnormal (laboratory results from Visit 1).
8. GFR <30 ml/min.
9. Acute upper or lower respiratory infections requiring antibiotics or antiviralmedications within 2 weeks prior to Visit 1, during the run-in period, or atVisit 2 (randomization).
10. A positive human immunodeficiency virus (HIV) test at screening or subject takingantiretroviral medications, as determined by medical history and/or subject'sverbal report.
11. History of sensitivity to any component of the investigational productformulation or a history of drug or other allergy that, in the opinion of theinvestigator or medical monitor contraindicates their participation.
12. History of any known primary immunodeficiency disorder excluding asymptomaticselective immunoglobulin A or IgG subclass deficiency.
13. Receipt of any of the following within 30 days prior to Visit 1:
14. Immunoglobulin or blood products, or
15. Receipt of any investigational non-biologic agent within 30 days or 5half-lives prior Visit 1, whichever is longer.
16. Pregnant, breastfeeding or lactating females
17. History of chronic alcohol or drug abuse within 12 months prior to Visit 1.
18. Planned surgical procedures requiring general anesthesia or in-patient status for > 1 day during the conduct of the study.
19. Unwillingness or inability to follow the procedures outlined in the protocol.
20. Concurrent enrollment in another clinical study involving an investigationaltreatment.
21. Receipt of any live or attenuated vaccines within 15 days prior to Visit 1.
22. Long QTc interval on ECG (QTc >480msec).
23. History of the following cardiac comorbidities:
24. Life-threatening arrhythmias
25. Myocardial infarction (NSTEMI or STEMI) less than 6 months before start ofthe study
26. Unstable angina
27. History of severe heart failure
28. Documented severe hypokalemia (K <3.0 mmol/L) or hypomagnesemia (Mg <0.5 mmol/L).
29. Life expectancy <6 months.
30. Hearing impairment.
31. Oxygen saturation <92% at room air, patients on LTOT, history of chronicrespiratory failure (hypercapnia).