| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic obstructive pulmonary disease and asthma |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To investigate whether 12-weeks low dose AZM treatment improves antiviral defence in patients with asthma and COPD. |
|
| E.2.2 | Secondary objectives of the trial |
To investigate whether 12-weeks low dose AZM treatment improves the level of immunoreactivity in patients with asthma and COPD.
To investigate whether 12-weeks low dose AZM treatment reduces markers of neutrophilic and eosinophilic airways inflammation in patients with asthma and COPD.
To investigate if AZM-induced anti-viral and anti-inflammatory changes differ between disease phenotypes (such as eosinophilic and non-eosinophilic).
To investigate whether 12-weeks low dose AZM treatment changes the lung microbiome abundance and profile.
To investigate the effect of low dose AZM on biomarkers of airway inflammation.
To investigate whether 12-weeks low dose AZM treatment changes the gut microbiome abundance and profile, and it’s relation to the respiratory microbiome.
To investigate gene expression in airway epithelium using an unbiased approach before and after treatment.
To investigate gene expression in lung mucosal biopsies using an unbiased approach before and after treatment.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
All subjects
1. Written informed consent.
2. Females of childbearing potential who are sexually active with a nonsterilized male partner must use a highly effective method of contraception from the time informed consent is obtained and must agree to continue using such precautions through Week 14 of the study; cessation of contraception after this point should be discussed with a responsible physician. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. Females of childbearing potential are defined as those who are not surgically sterile (ie, bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or postmenopausal (defined as 12 months with no menses without an alternative medical cause).
Asthma patients (n=40)
1. Diagnosis of asthma according to GINA, with confirmed variable airflow obstruction at screening visit or previously (52).
2. Age ≥18 through 75 years.
3. FEV1 value of ≥ 50% predicted.
4. Maintenance treatment with ICS and ≥ 1 second controller (LABA, LAMA, LTRA or Xanthines) 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 despite maintenance 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 (53).
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) with or without 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. |
|
| E.4 | Principal exclusion criteria |
1.Previous medical history or evidence of an uncontrolled intercurrent illness that in the opinion of the investigator may compromise the safety of the subject in the study or interfere with evaluation of the investigational product or reduce the subject’s ability to participate in the study. Subjects with well-controlled comorbid disease (eg, hypertension, hyperlipidemia, gastroesophageal reflux disease) 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 investigator and/or medical monitor will interfere with the evaluation of the investigational product or interpretation of subject safety or study results (e.g., cystic fibrosis, pulmonary fibrosis, moderate-severe bronchiectasis, allergic bronchopulmonary aspergillosis, Churg-Strauss syndrome, active tuberculosis). In addition for the different groups the following:
a.Patient with asthma: concomitant COPD.
b.Patients with COPD: concomitant asthma (former and current)
c.Healthy subjects: COPD and asthma.
3.Any clinically relevant abnormal findings in hematology or clinical chemistry (laboratory results from Visit 1), physical examination, vital signs during the screening, which in the opinion of the investigator, may put the subject at risk because of his/her participation in the study, or may influence the results of the study, or the subject’s ability to participate in the study.
4.Evidence of active liver disease, including jaundice or aspartate transaminase, alanine transaminase, or alkaline phosphatase >1.5 times the upper limit of normal (laboratory results from Visit 1).
5.GFR <30 ml/min.
6.Acute upper or lower respiratory infections requiring antibiotics or antiviral medications within 2 weeks prior to Visit 1, during the run-in period, or at Visit 2 (randomization).
7.A positive human immunodeficiency virus (HIV) test at screening or subject taking antiretroviral medications, as determined by medical history and/or subject’s verbal report.
8.History of sensitivity to any component of the investigational product formulation or a history of drug or other allergy that, in the opinion of the investigator or medical monitor contraindicates their participation.
9.History of any known primary immunodeficiency disorder excluding asymptomatic selective immunoglobulin A or IgG subclass deficiency.
10.Receipt of any of the following within 30 days prior to Visit 1:
a.Immunoglobulin or blood products, or
b.Receipt of any investigational non-biologic agent within 30 days or 5 half-lives prior Visit 1, whichever is longer.
11.Pregnant, breastfeeding or lactating females
12.History of chronic alcohol or drug abuse within 12 months prior to Visit 1.
13.Planned surgical procedures requiring general anesthesia or in-patient status for > 1 day during the conduct of the study.
14.Unwillingness or inability to follow the procedures outlined in the protocol.
15.Concurrent enrollment in another clinical study involving an investigational treatment.
16.Receipt of any live or attenuated vaccines within 15 days prior to Visit 1.
17.Long QTc interval on ECG (QTc >480msec).
18.History of the following cardiac comorbidities:
a.Life-threatening arrhythmias
b.Myocardial infarction (NSTEMI or STEMI) less than 6 months before start of the study
c.Unstable angina
d.History of severe heart failure
19.Documented severe hypokalemia (K <3.0 mmol/L) or hypomagnesemia (Mg <0.5 mmol/L).
20.Life expectancy <6 months.
21.Hearing impairment.
22.Oxygen saturation <92% at room air, patients on LTOT, history of chronic respiratory failure (hypercapnia).
Excluded medications
1.Drugs with a risk for long QTc interval and torsade de pointes (see table 2)
2.Drugs that interact with AZM in terms of risk of rhabdomyolosis, such as Simvastatin. Atorvastatin but Fluvastatin or Rosuvastatin may be prescribed instead.
3.Oral corticosteroids (any dose for more than 3 days) or maintenance macrolide treatment 12 weeks prior to Visit 1 or during the run-in period.
4.Use of immunosuppressive medication (e.g, methotrexate, troleandomycin, oral gold, cyclosporine, azathioprine, intramuscular long-acting depot corticosteroid, or any experimental anti-inflammatory therapy) within 3 months prior to Visit 1 and during the study.
5.Receipt of any oral or ophthalmic β-adrenergic antagonists (e.g, propranolol) within 15 days prior to Visit 1. Use of selective beta-blockers for patients with COPD is allowed.
6.Use of anticoagulation treatment (warfarin, clopidogrel) that cannot be withheld prior to bronchoscopy.
7.Receipt of any marketed (including omalizumab) or investigational biologic agent within 4 months or 5 half-lives prior to Visit 1, whichever is longer.
8.Allergen immunotherapy
9.Digoxin and colchicine treatment during the study.
10.Antacida: not excluded, but may reduce plasma levels of AZM, and therefore need to be taken >1 hour before AZM or 2 hours after AZM is taken.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary end point:
Change in HBEC IFN gene and/or protein expression in response to in vitro RV infection and viral mimics.
Supportive primary objective:
Change in viral load (RV16vRNA and/or TCID50 assay) in response to in vitro RV infection.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At baseline (visit 1) and End of treatment (visit4) |
|
| E.5.2 | Secondary end point(s) |
Change in HBEC gene and/or protein expression in response to in vitro stimulation with viral triggers, allergens, scratching of epithelium, and smoke exposure (or a combination of these triggers).
Changes in markers of eosinophilic and neutrophilic inflammation (e.g. number and percentage of eosinophils and neutrophils, cytokines expression) in bronchial biopsies, sputum, BAL and blood. Level of FeNO.
• Change in bronchial epithelial gene and/or protein expression in response to in vitro stimulation with viral triggers, allergens, scratching of epithelium, and smoke exposure, in eosinophilic (blood eosinophils >0.2x109/L) compared to non-eosinophilic patients.
• Changes in BAL, bronchial biopsy and induced sputum inflammatory markers in eosinophilic (blood eosinophils >0.2x109/L) compared to non-eosinophilic patients.
Changes in bronchial brush, BAL and induced sputum microbiome abundance and composition as measured by gene sequencing.
Gene and protein expression in airway mucosa, airway epithelium, sputum and BAL. Including markers such as (but not limited to): TSLP, IL-33, TLRs, RIG-I like receptors, TH1 and TH2 cytokines.
Changes in fecal microbiome abundance and composition as measured by gene sequencing.
RNA seq will be performed and analyzed for (including but not limited to):
• Transcripts most changed by AZM
• Changes in genes known to be involved in epithelial cell dysfunction and/or asthma and COPD
• Differences in epithelial gene expression between clinical phenotypes of asthma and COPD (e.g. eosinophilic vs non-eosinophilic)
RNA seq will be performed and analyzed for (including but not limited to):
• Transcripts most changed by AZM
• Differences in epithelial gene expression between clinical phenotypes of asthma and COPD (e.g. eosinophilic vs non-eosinophilic)
RNA seq will be performed and analyzed for (including but not limited to):
• Transcripts most changed by AZM
• Differences in epithelial gene expression between clinical phenotypes of asthma and COPD (e.g. eosinophilic vs non-eosinophilic)
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| At baseline (visit 1) and End of treatment (visit4) |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
Print
