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 |
COPD, Chronic Bronchitis, Emphysema
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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 | 15.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10010952 |
E.1.2 | Term | COPD |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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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 this study is to evaluate the 24-hour spirometry effect (FEV1) of FF/VI 100/25 once daily compared with Fluticasone Propionate/Salmeterol 250/50mcg twice daily over a 12-week treatment period in subjects with COPD. |
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E.2.2 | Secondary objectives of the trial |
A secondary objective of the study is to characterize the time to onset (increase of 100mL above baseline in FEV1) on Treatment Day 1 of both FF/VI 100/25 and Fluticasone Propionate/Salmeterol 250/50mcg.
An additional secondary objective is to characterize the change from baseline in trough FEV1 at the end of 12 weeks of treatment on Treatment Day 85 (Visit 5) of both FF/VI 100/25 and Fluticasone Propionate/Salmeterol 250/50mcg. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subjects eligible for enrolment in the study must meet all of the following criteria:
1. Informed consent: Subjects must give their signed and dated written informed consent to participate.
2. Gender: Males or females. 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.
3. Age: ≥40 years of age at Screening (Visit 1)
4. 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 also produces significant systemic consequences.
5. Severity of Disease:
• Subject 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 ≤70% of predicted normal values calculated (via centralized vendor equipment) using NHANES III reference equations [Hankinson, 1999] at Screening (Visit 1).
Post-bronchodilator spirometry will be performed approximately 10-15 minutes after the subject has self-administered 4 inhalations (i.e., total 400mcg) of albuterol (salbutamol) via an MDI with a valved-holding chamber. The study-provided central spirometry equipment will calculate the FEV1/FVC ratio and FEV1 percent predicted values.
6. 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 cigarettes per day/20) x number of years smoked
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E.4 | Principal exclusion criteria |
Subjects meeting any of the following criteria must not be enrolled in the study:
1. 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)
2. Other respiratory disorders: Subjects with alpha1-antitrypsin deficiency as the underlying cause of COPD, active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, pulmonary fibrosis, pulmonary hypertension, interstitial lung diseases, or other active pulmonary diseases
3. Lung resection: Subjects with lung volume reduction surgery within the 12 months prior to Screening (Visit 1)
4. Hospitalization: Subjects who are hospitalized due to poorly controlled COPD within 12 weeks of Screening (Visit 1).
5. Poorly controlled COPD: Subjects with poorly controlled COPD, defined as the occurrence of the following in the 6 weeks prior to Screening (Visit 1):
Acute worsening of COPD that is managed by the subject with corticosteroids or antibiotics or that requires treatment prescribed by a physician.
6. Lower respiratory tract infection: Subjects with lower respiratory tract infection that required the use of antibiotics within 6 weeks prior to Screening (Visit 1).
7. COPD exacerbation/lower respiratory tract infection during Run-In Period: Subjects who experience a moderate/severe COPD exacerbation (see definitions in Section 6.3.12 of the protocol) and/or a lower respiratory infection (including pneumonia) during the Run-In period.
8. Abnormal and 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. The investigator will determine the medical significance of ECG abnormalities and whether they preclude the subject from entering the study.
9. Other diseases/abnormalities: Subjects with historical or current evidence of uncontrolled or clinically significant disease such as cardiovascular (i.e., patients requiring ICD or pacemaker requiring a rate set >60 bpm), hypertension, neurological, psychiatric, renal, hepatic, immunological, endocrine (including uncontrolled diabetes or thyroid disease), peptic ulcer disease, or haematological abnormalities. Significant is defined as any disease that, in the opinion of the investigator, would put the safety of the subject at risk through participation, or which would affect the efficacy or safety analysis if the disease/condition exacerbated during the study.
10. Cancer: Subjects with carcinoma that has not been in complete remission for at least 5 years. Carcinoma in situ of the cervix, squamous cell carcinoma and basal cell carcinoma of the skin would not be excluded if the subject has been considered cured within 5 years since diagnosis.
11. Drug/food allergy: Subjects with a history of hypersensitivity to any of the study medications (e.g., beta-agonists, corticosteroid) or components of the inhalation powder (e.g., lactose, magnesium stearate). In addition, subjects with a history of severe milk protein allergy that, in the opinion of the investigator, contraindicates the subject’s participation will also be excluded.
12. Drug/alcohol abuse: Subjects with a known or suspected history of alcohol or drug abuse within the last 2 years
13. Medication prior to spirometry: Subjects who are medically unable to withhold their albuterol (salbutamol) and/or their ipratropium for the 4-hour period required prior to spirometry testing at each study visit.
14. Additional medication: Use of specific medications within the pre-determined time intervals prior to Screening (Visit 1) or during the study (please see section 4.3 of the protocol).
15. Oxygen therapy: Subjects receiving treatment with long-term oxygen therapy or nocturnal oxygen therapy required for greater than 12 hours a day. Oxygen prn use (i.e., ≤12 hours per day) is not exclusionary.
16. Pulmonary rehabilitation: Subjects who have participated in the acute phase of a Pulmonary Rehabilitation Program within 4 weeks prior to Screening (Visit 1) or who will enter the acute phase of a Pulmonary Rehabilitation Program during the study. Subjects who are in the maintenance phase of a Pulmonary Rehabilitation Program are not excluded.
17. Potential of non-compliance: Subjects at risk of non-compliance/unable to comply with study procedures. Any infirmity, disability, or geographic location that would limit compliance for scheduled visits.
18. 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.
19. Pregnancy: Women who are pregnant or lactating or are planning on becoming pregnant during the study.
20. Previously randomized: to either the HZC113109 or HZC112352 clinical studies. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change from baseline trough in 24-hour weighted-mean serial FEV1 at the end of 12 weeks of treatment on Treatment Day 84 (Visit 5) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Visit 5 Days 84-85. Serial spirometry assessments will be taken 5 minutes prior to dosing then post dosing at 5, 15, 30 and 60 minutes and at 2, 4, 6, 8, 12, 13, 14, 16, 20 and 24 hours |
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E.5.2 | Secondary end point(s) |
Time to onset (increase of 100mL above baseline in FEV1) on Treatment Day 1 (Visit 2)
Change from baseline trough FEV1 at the end of 12 weeks of treatment on Treatment Day 85 (Visit 5)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Time to onset (increase of 100mL above baseline in FEV1) on Treatment Day 1 (Visit 2)
Change from baseline trough FEV1 at the end of 12 weeks of treatment on Treatment Day 85 (Visit 5)
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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 | 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 | Yes |
E.8.1.7.1 | Other trial design description |
Multicenter, Double-dummy |
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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 | 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 | 17 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 41 |
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 |
Germany |
Poland |
Romania |
Russian Federation |
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 | |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 11 |