| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Obstructive Pulmonary Diseae |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10009033 |
| E.1.2 | Term | Chronic obstructive pulmonary disease |
| E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
|
| 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 determine the effects of the inhaled corticosteroids fluticasone propionate/salmeterol 500/50 mcg vs budesonide/formoterol 400/12 mcg on upper airway bacterial load from throat swabs. |
|
| E.2.2 | Secondary objectives of the trial |
To determine the effects of the inhaled corticosteroids fluticasone propionate/salmeterol 500/50 mcg vs budesonide/formoterol 400/12 mcg on lower airway bacterial load and microbiome from sputum and on upper airway in nasal swab
To compare the effects of fluticasone/salmeterol 250/50mcg vs budesonide/formoterol 400/12 mcg on upper and lower airway microbiome in throat/nasal and sputum samples.
To compare the effects on the upper and lower airway microbiome in throat, nasal swabs and sputum of individual inhaled corticosteroids (ICS) fluticasone propionate and budesonide compared to a dual bronchodilator based regime without ICS
To compare the impact of high and low dose inhaled corticosteroid fluticasone propionate on the upper and lower airway microbiome in throat, nasal swabs and sputum
To determine the combined impact of inhaled corticosteroids on bacterial load in upper and lower airway using throat swabs, nasal swabs and sputum compared to dual bronchodilator regime. In thi |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Male and female patients aged > 40 years
• Current or ex smokers having at least a 10 pack year smoking history
• A clinical diagnosis of COPD made by a physician with a post-bronchodilator FEV1/FVC ratio at screening of <70%
• Severe COPD according to consensus guidelines consisting of a post-bronchodilator FEV1 <50% predicted at screening and/or a history of 2 or more exacerbations in the previous year OR one hospital admission for an exacerbation of COPD in the previous year (equivalent to GOLD 2011 grade C/D)
• Able to perform all study procedures including spirometry and questionnaires with minimal assistance.
|
|
| E.4 | Principal exclusion criteria |
• Inability to give informed consent
• Asthma (defined according to Scottish Intercollegiate Guidelines Network criteria) [29])#
• A primary diagnosis of bronchiectasis confirmed on computed tomography.(it is not necessary to perform a CT scan to exclude this if the patient has not previously had one. Only known bronchiectasis with a previous CT scan should be excluded).
• Antibiotics within the past 28 days, apart from oral macrolides which are permitted if they have been used for at least 3 months prior to randomization
• Oral/ nasal corticosteroids of any kind in the 28 days prior to screening visit
• Current use of the following: roflumilast, ritonavir, itraconazole, telithromycin, or ketoconazole (or other strong CYP3A4 inhibitors).
• Active, or within 28 days of screening visit, oral candidiasis, actively receiving dental treatment for oral infection or poor dentition.
• Immunosuppression including current oral corticosteroids at a dose >5mg for >28 days.
• Glomerular filtration rate (eGFR) below 30ml/min/1.73m2 or requiring dialysis. Last known eGFR result will be used .
• Use of any investigational drugs within five times of the elimination half-life after the last study dose or within 30 days, whichever is longer.
• Known allergy, intolerance or contraindication to any of the study drugs
• Galactose intolerance
• Unstable co-morbidities (cardiovascular disease, active malignancy) which in the opinion of the Investigator would make the patient unsuitable to be enrolled in the study. This includes any abnormality identified on screening bloods or screening ECG which in the opinion of the Investigator would make the patient unsuitable for the study.
• An exacerbation of COPD occurring during the screening to randomisation period. If this occurs the patient should be withdrawn from the study and may be rescreened once they have been free from corticosteroid and antibiotic treatment for 28 days. In these cases patients would receive the current Participant Information Sheet and be consented prior to starting the study from Visit 1.
• Documented that the patient has never received pneumococcal polysaccharide vaccination*
• Receipt of Pneumococcal conjugate vaccine (e.g PCV-13)*
• Pregnancy or breast feeding
• Women of child bearing potential (WOCBP) who are not practicing an acceptable method of contraception (see below)
Acceptable forms of contraception:
• combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, transdermal
• progestogen-only hormonal contraception associated with inhibition of ovulation: oral, injectable, implantable
• intrauterine device (IUD)
• intrauterine hormone-releasing system ( IUS)
• bilateral tubal occlusion
• vasectomised partner
• sexual abstinence
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Bacterial load of total respiratory pathogens determined by quantitative polymerase chain reaction. Continuous variable at 0, 1, 2 and 3 months |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Continuous variable at 0, 1, 2 and 3 months |
|
| E.5.2 | Secondary end point(s) |
To determine the effects of the inhaled corticosteroids fluticasone propionate/salmeterol 500/50 mcg vs budesonide/formoterol 400/12 mcg on lower airway bacterial load and microbiome from sputum and on upper airway in nasal swab
To compare the effects of fluticasone/salmeterol 250/50mcg vs budesonide/formoterol 400/12 mcg on upper and lower airway microbiome in throat/nasal and sputum samples.
To compare the effects on the upper and lower airway microbiome in throat, nasal swabs and sputum of individual inhaled corticosteroids (ICS) fluticasone propionate and budesonide compared to a dual bronchodilator based regime without ICS
To compare the impact of high and low dose inhaled corticosteroid fluticasone propionate on the upper and lower airway microbiome in throat, nasal swabs and sputum
To determine the combined impact of inhaled corticosteroids on bacterial load in upper and lower airway using throat swabs, nasal swabs and sputum compared to dual bronchodilator regime. In this analysis, results from all ICS arms will be pooled.
To evaluate the impact of inhaled corticosteroids on airway and systemic inflammation
To evaluate the safety and tolerability of withdrawal of inhaled corticosteroids in severe COPD
To evaluate if changes in the airway microbiota are associated with AE’s
To determine the impact of ICS withdrawal on airway bacterial load, airway microbiome and airway inflammation. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Continuous variable at 0, 1, 2 and 3 months |
|
| 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 | Yes |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | 6 |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 31 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 31 |
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