| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic obstructive pulmonary disease (COPD) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic obstructive pulmonary disease (COPD) |
|
| 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 | 18.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10010953 |
| E.1.2 | Term | COPD exacerbation |
| E.1.2 | System Organ Class | 100000004855 |
|
| 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 |
| Show superiority in the efficacy of flutiform 250/10 μg (2 puffs bid) compared with formoterol 12 μg (1 puff bid) based on the annual rate of moderate and severe COPD exacerbations during the 52-week treatment period. |
|
| E.2.2 | Secondary objectives of the trial |
• Show superiority in the efficacy of flutiform 125/5 μg (2 puffs bid) compared with formoterol 12 μg (1 puff bid) based on the annual rate of moderate and severe COPD exacerbations during the 52-week treatment period
• Compare flutiform (at each dose) with formoterol 12 μg (1 puff bid) for the secondary efficacy and safety endpoints. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
For subjects who agree to be included in any of the five sub-sets additional testing will be carried out at the relevant visits.
- Sub-set 1 - serial laboratory and ECG assessments (approximately 125 subjects / treatment group)
- Sub-set 2 – biomarkers (approximately 100 subjects / treatment group)
- Sub-set 3 – holter monitoring (approximately 100 subjects / treatment group)
- Sub-set 4 - urinary cortisol (approximately 50 subjects / treatment group not receiving ICS prior to run-in)
- Sub-set 5 – pharmacogenomic samples (available to all subjects who sign additional consent)
Pharmacogenomic samples will be stored at the clinical laboratory to provide a resource for future studies which will examine why subjects may respond differently to certain drugs by analyzing specific genetic markers. |
|
| E.3 | Principal inclusion criteria |
1. Male or Female subjects aged ≥ 40 years at screening visit
a. Female subjects of child bearing potential (less than 1 year post-menopausal) must have a negative urine pregnancy test prior to first dose of study medication, be non-lactating, and willing to use adequate and highly effective methods of birth control throughout the study such as sterilisation, implants, injectables, combined oral contraceptives, some intra-uterine devices, sexual abstinence or vasectomised partner.
b. Male subjects with a partner of child bearing potential must be willing to use adequate and highly effective methods of birth control throughout the study.
2. Smoking history of ≥ 10 pack years (equivalent to, for example, 20 cigarettes/day for 10 yrs or 10 cigarettes/day for 20 yrs ) (pack year = (number of cigarettes per day ÷ 20) x number of years of smoking)
3. Diagnosis of COPD as evidenced by:
a. Clinical symptoms of COPD (e.g. chronic cough, sputum production, dyspnoea) and
b. Post-bronchodilator FEV1 / FVC ratio < 0.7 measured at screening and
c. ≤ 50 % FEV1 predicted normal measured at screening
4. Documented history of ≥ 1 moderate or severe COPD exacerbation in previous year (requiring treatment with systemic corticosteroids and/or antibiotics and/or hospitalisation)
5. Willing and able to replace current COPD therapy with study medication
6. Able to demonstrate correct use of a pMDI without a spacer
7. Willing and able to attend all study visits and complete study assessments
8. Able to provide signed informed consent. |
|
| E.4 | Principal exclusion criteria |
1. Ongoing moderate or severe exacerbation of COPD (see section 10 of protocol)
2. Current diagnosis of asthma
3. Documented evidence of α1-antitrypsin deficiency as the underlying cause of COPD
4. Other active respiratory disease such as active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension, interstitial lung disease, cystic fibrosis, bronchiolitis obliterans
5. Previous lung resection
6. Use of long-term oxygen therapy (LTOT) at least 12 hours daily or mechanical ventilation
7. Chest X-ray or CT scan that reveals evidence of clinically significant abnormalities reflective of active disease not believed to be due to COPD
8. Evidence of uncontrolled cardiovascular disease
9. Evidence of clinically significant renal, hepatic, gastrointestinal, or psychiatric disease
10. Current malignancy or a previous history of cancer which has been in remission for < 5 years (basal cell or squamous cell carcinoma of the skin which has been resected is not excluded)
11. Clinically significant sleep apnoea requiring use of continuous positive airway pressure (CPAP) device or non-invasive positive pressure ventilation (NIPPV) device
12. Participation in the acute phase of a pulmonary rehabilitation programme within 4 weeks prior to screening or during the study
13. Known or suspected history of drug or alcohol abuse in the last 2 years
14. Requiring treatment with any of the prohibited concomitant medications
15. Known or suspected hypersensitivity or contraindication to any of the study drugs or excipients
16. Received an investigational drug within 30 days of the screening visit (12 weeks if an oral or injectable steroid). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary efficacy endpoint:
• Annualised rate of moderate and severe COPD exacerbations during the 52-week treatment period (based on medical intervention).
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Secondary Endpoints for high and medium dose of flutiform®
• The pre-morning dose FEV1 values at each post-baseline time-point
• Annualised Rate of COPD Exacerbations (EXACT)
• Time to First Moderate or Severe COPD Exacerbation (Medical Intervention)
• Saint George’s Respiratory Questionnaire for COPD
• COPD Assessment Test Score
• Study Rescue Medication Use
• Percentage Change in Awakening-free nights
• EXACT-RS dyspnoea score and EXACT-RS total score
• Other Pulmonary Function Parameters
• Time to Each COPD Exacerbation
• Other Annualised Rates of COPD Exacerbations
• Discontinuations Due to Lack of Efficacy
• Average Change in Sleep Disturbance Scores
• Days of Hospitalisaton
• Treatment Compliance Analyses |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| At the end of the treatment. |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| 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) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| 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 | Yes |
| 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 | 3 |
| 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 | 15 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 227 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Bulgaria |
| Czech Republic |
| Germany |
| Hungary |
| Latvia |
| Lithuania |
| Macedonia, the former Yugoslav Republic of |
| Poland |
| Romania |
| Russian Federation |
| Slovakia |
| South Africa |
| Spain |
| Ukraine |
| United Kingdom |
|
| 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
|
| The end of study is defined as last patient last visit. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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