| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Obstructive Pulmonary Disease COPD |
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| E.1.1.1 | Medical condition in easily understood language |
| Chronic Obstructive Pulmonary Disease |
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| 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 | 10010952 |
| E.1.2 | Term | COPD |
| E.1.2 | System Organ Class | 100000004855 |
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| 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 |
| The primary objective of the study is to evaluate the contribution on lung function (as measured by trough FEV1) of FF 100 mcg to FF/VI 100/25mcg QD by the comparison of the latter with VI 25mcg QD (each administered via the ELLIPTA™ inhaler) and the safety of FF/VI 100/25 mcg QD over a 12-week treatment period in subjects with COPD. |
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| E.2.2 | Secondary objectives of the trial |
•Evaluate the effect of FF/VI 100/25 mcg QD compared with VI 25 mcg QD on subject-recordings of rescue medication (albuterol [salbutamol]) use and symptoms of COPD (breathlessness, cough and sputum) production
•Evaluate the effect of FF/VI 100/25 mcg QD compared with VI 25 mcg QD on health-related quality of life using the St. George’s Respiratory Questionnaire – Chronic Obstructive Pulmonary Disorder (SGRQ-C)
•Evaluate the effect of FF/VI 100/25 mcg QD compared with VI 25 mcg QD on COPD health status using the COPD Assessment Test (CAT)
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Type of subject: Outpatient
2. Informed consent: Subjects must give their signed and dated written informed consent to participate.
3. Gender: Male subjects or female subjects
Female subjects must be post-menopausal or using a highly effective method for avoidance of pregnancy. The decision to include or exclude women of childbearing potential may be made at the discretion of the investigator in accordance with local practice in relation to adequate contraception.
4. Age: ≥ 40 years of age at Screening (Visit 1)
5. COPD diagnosis: Subjects with a clinical history of COPD in accordance with the following definition by the American Thoracic Society/European Respiratory Society [Celli, 2004]:
COPD is a preventable and treatable disease characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and is associated with an abnormal inflammatory response of the lungs to noxious particles or gases, primarily caused by cigarette smoking. Although COPD affects the lungs, it is also associated with significant systemic consequences.
6. Severity of disease:
• Subjects with a measured post-albuterol (salbutamol) FEV1/FVC ratio of <=0.70 at Screening (Visit 1) [Pelligrino, 2005]
• Subjects with a measured post- albuterol (salbutamol) FEV1 ≥30 to <=70% of predicted normal values calculated (via standardized spirometry equipment provided by a centralized vendor) using Global Lung Function Initiative (GLI) 2012 reference equations [Quanjer, 2012] at Screening (Visit 1)
Note: For reporting purposes, in addition to the Quanjer values, the NHANES III predicted values [Hankinson, 1999; Hankinson, 2010] at Screening (Visit 1) will be presented for consistency with previous Phase IIIa-b studies with FF/VI in subjects with COPD.
Post-bronchodilator spirometry will be performed approximately 10-15 minutes after the subject has self-administered 4 inhalations (i.e., total of 400mcg) of albuterol (salbutamol) via an MDI with a valved-holding chamber. The study-provided standardized spirometry equipment will calculate the FEV1/FVC ratio and FEV1 percent predicted values.
7. Tobacco use: Subjects with a current or prior history of ≥10 pack-years of cigarette smoking at Screening (Visit 1). Former smokers are defined as those who have stopped smoking for at least 6 months prior to Visit 1.
Note: Pipe and/or cigar use cannot be used to calculate pack-year history.
Number of pack years = (number of cigarette per day/20)) x number of years smoked
8. History of COPD exacerbation: A documented history (e.g., medical record verification) of at least one COPD exacerbation in the 12 months prior to Screening (Visit 1) that required either systemic/oral corticosteroids, antibiotics and/or hospitalization
Note: Prior use of antibiotics alone does not qualify as an exacerbation history, unless the use was associated with treatment of worsening symptoms of COPD, such as increased dyspnea, cough or sputum volume, or sputum purulence (color), onset or worsening of chest tightness. Subject verbal reports are not acceptable.
9. Current symptoms of COPD: A Subject Diary combined symptom score (combination of breathlessness, cough, sputum, and nighttime awakenings requiring treatment with albuterol [salbutamol]) of ≥4 on at least 5 of the 7 days immediately preceding Visit 2 (Randomization)
10. QTc Criteria: QTc <450msec or QTc <480msec for patients with bundle branch block. The QTc is the QT interval corrected for heart rate according to either Bazett’s formula (QTcB), Fridericia’s formula (QTcF), or another method, machine or manual overread.
• For eligibility and withdrawal, ideally the same QT correction formula will be used for all subjects. However, because this is not always possible, the same QT
correction formula must be used for each individual subject to determine eligibility for and withdrawal from the study.
• The specific formula that will be used to determine eligibility and withdrawal for an individual subject should be determined prior to initiation of the study. Note that the QT correction formula used is usually site-dependent since not all ECG machines are programmed by the manufacturer with the same formula.
The QTc should be based on single or averaged QTc values of triplicate electrocardiograms (ECGs) obtained over a brief recording period. |
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| E.4 | Principal exclusion criteria |
1. Pregnancy: Women who are pregnant or lactating or are planning on becoming pregnant during the study.
2. Asthma: Subjects with a current diagnosis of asthma. (Subjects with a prior history of asthma are eligible if they have a current diagnosis of COPD).
3. Other respiratory disorders: Subjects with alpha 1-antitrypsin deficiency as the underlying cause of COPD active tuberculosis, lung cancer, bronchiectasis primary pulmonary hypertension, interstitial lung diseases, or other active pulmonary diseases. Please view protocol for further information.
4. Lung resection: Subjects with lung volume reduction surgery within the 12 months prior to Screening (Visit 1).
5. Chest X-ray (or CT scan): Subjects with a chest X-ray (or CT scan) that reveals evidence of clinically significant abnormalities not believed to be due to the presence of COPD. Please view protocol for further information.
6. Hospitalization: Subjects who are hospitalized due to poorly controlled COPD that has not resolved at least 4 weeks prior to Screening (Visit 1) and at least 6 weeks following the last dose of systemic corticosteroids.
7. Poorly controlled COPD: Subjects with poorly controlled COPD, defined as the occurrence of any of the following in the 6 weeks prior to Screening (Visit 1): please view protocol for further information.
8. Lower respiratory tract infection: Subjects with lower respiratory tract infection that required the use of antibiotics within 6 weeks prior to Screening (Visit 1).
9. COPD exacerbation/lower respiratory tract infection during Run-In Period: Subjects who experience a moderate/severe COPD exacerbation, please view protocol for further information.
10. Abnormal clinically significant laboratory finding: Subjects who have an abnormal clinical significant finding in any liver chemistry test at Screening (Visit 1) or upon repeat prior to randomization.
11. Abnormal clinically significant 12-Lead ECG at Screening (Visit 1): Subjects who have an abnormal, clinically significant ECG finding at Screening (Visit 1) or upon repeat prior to randomization. Please view protocol for further information.
12. Other diseases/abnormalities: Subjects with historical or current evidence of clinically significant and unstable disease such as cardiovascular (e.g., patients requiring ICD, pacemaker requiring a rate set >60bpm, uncontrolled hypertension, Please view protocol for further information.
13. Liver Disease: Subjects who have unstable liver disease please view protocol for further information.
14. Cancer: Subjects with carcinoma that has not been in complete remission for at least 5 years. Please view protocol for further information.
15. Contraindications: Subjects with a history of allergy or hypersensitivity to any of the study medications please view protocol for further information.
16. Drug/alcohol abuse: Subjects with a known or suspected history of alcohol or drug abuse within the last 2 years
17. Medication prior to spirometry: Subjects who are medically unable to withhold their albuterol (salbutamol) or their ipratropium bromide for the 4-hour period required prior to spirometry testing at each study visit.
18. Additional medication: Use of the following medications within the following time intervals prior to Screening (Visit 1) or during the study: Please view protocol for further information.
19. Oxygen therapy: Subjects receiving treatment with long-term oxygen therapy please view protocol for further information.
20. Sleep apnea: Subjects with clinically significant sleep apnea who require use of continuous positive airway pressure (CPAP) device or non-invasive positive pressure ventilation (NIPPV).
21. Pulmonary rehabilitation: Subjects who have participated in the acute phase of a Pulmonary Rehabilitation Program within 4 weeks prior to Screening please view protocol for further information.
22. Non-Compliance during Run-In Period: Failure to demonstrate adequate compliance defined as completion of Diary Card please view protocol for further information.
23. Potential of non-compliance: Subjects at risk of non-compliance, or unable to comply with the study procedures. Any infirmity, disability, or geographic location that would limit compliance for scheduled visits.
24. Questionable validity of consent: Subjects with a history of psychiatric disease, intellectual deficiency, poor motivation or other conditions that will limit the validity of informed consent to participate in the study.
25. Prior use of study medication/other investigational drugs: Subjects who have received an investigational drug within 30 days of entry into this, please view protocol for further information.
26. Affiliation with investigator site: Study investigators, sub-investigators, study coordinators, employees of a participating investigator or immediate family members of the aforementioned are excluded from participating in this study. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is change from baseline in Clinic Visit trough (pre-bronchodilator and pre-dose) FEV1, (to evaluate the contribution of FF) on Treatment Day 84 (Visit 7)
Trough FEV1 on Treatment Day 84 is defined as the mean of the FEV1 values obtained 23 and 24 hours after dosing on Treatment Day 83, measured at Visit 7.
Baseline FEV1 is the mean of the two assessments made 30 minutes pre-dose and immediately pre-dose on Treatment Day 1.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Treatment Day 84 (Visit 7) |
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| E.5.2 | Secondary end point(s) |
The secondary endpoints are:
• Percentage of rescue-free 24-hour periods over the entire 12-week Treatment Period
• Time to first moderate/severe COPD exacerbation
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
For rescue-free 24-hour periods the timepoint is over the entire 12-week Treatment Period.
For time to first moderate/severe COPD exacerbation, the timepoint is whenever this occurs during the 12-week Treatment Period. |
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| 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 | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
assessing Health Outcomes with the following questionnaires: SGRQ-C, CAT and CASA-Q.
CASA-Q will not be used in Poland. |
|
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| stratified -reversible/non-reversible) |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| unlicensed comparator Vilanterol |
|
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 49 |
| 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 |
| Germany |
| Japan |
| Korea, Republic of |
| Poland |
| Romania |
| Russian Federation |
| South Africa |
| Taiwan |
| Ukraine |
| United States |
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| 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
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| 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 | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 21 |
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