| 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) |
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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 | 14.1 |
| 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 |
| To demonstrate non-inferiority of QVA149 110/50 µg to tiotropium 18 µg q.d. plus formoterol 12µg b.i.d. in terms of health related quality of life as assessed by St George’s Respiratory Questionnaire (SGRQ-C) after 26 weeks of treatment in moderate to severe COPD patients. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate QVA149 110/50 µg q.d. as compared to tiotropium 18 µg q.d. plus formoterol 12µg b.i.d. following 26 weeks of treatment in terms of improvement of dyspnea as assessed by BDI/TDI.
To evaluate QVA149 110/50 µg q.d. as compared to tiotropium plus formoterol during 26 weeks of treatment in terms of
• Rate of moderate/severe COPD exacerbations requiring systemic corticosteroids and/or antibiotics or hospitalization
• Time to first moderate/severe COPD exacerbation during the treatment period
• Lung function assessed by trough FEV1
• Lung function assessed by FEV1 30 min
• Symptoms reported by the patients using component score of Part I “Symptoms” of the St George’s Respiratory Questionnaire (SGRQ-C).
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female adults aged ≥40 years, who have signed an Informed Consent Form prior to initiation of any study-related procedure.
2. Patients with moderate to severe stable COPD (Stage II or Stage III) according to the GOLD Guidelines 2010.
3. Current or ex-smokers who have a smoking history of at least 10 pack years. (Ten pack-years are defined as 20 cigarettes a day for 10 years, or 10 cigarettes a day for 20 years etc.)
4. Patients with a post-bronchodilator FEV1 ≥30% and < 80% of the predicted normal, and post-bronchodilator FEV1/FVC < 0.7 at Visit 2.
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| E.4 | Principal exclusion criteria |
1. Women who are pregnant or breast feeding
2. Women of child-bearing potential must use effective contraception
3. Patients with conditions contraindicated for treatment with, or having a history of reactions/hypersensitivity to any of the following inhaled drugs, drugs of a similar class or any component thereof
• anticholinergics
• long and short acting beta-2 agonists
• sympathomimetic amines
• lactose or any of the other excipients
4. Patients with a history of long QT syndrome or whose QTc measured at Visit 2 is prolonged (>450 ms for males and females).
5. Patients who have a clinically significant abnormality on the ECG at Visit 2, who in the judgment of the investigator would be at potential risk if enrolled into the study. (These patients should not be re-screened).
6. Patients with paroxysmal (e.g. intermittent) atrial fibrillation are excluded.
7. Patients with Type I or uncontrolled Type II diabetes including patients with a history of blood glucose levels consistently outside the normal range or HbA1c> 8.0% of a total Hb measured at screening (Visit 2).
8. Patients with narrow-angle glaucoma, symptomatic prostatic hyperplasia or bladder-neck obstruction or moderate to severe renal impairment or urinary retention. (Patients with a transurethral resection of prostate (TURP) are excluded from the study. Patients who have undergone full re-section of the prostate may be considered for the study, as well as patients who are asymptomatic and stable on pharmacological treatment for the condition).
9. Patients with a history of malignancy of any organ system (including lung cancer), treated or untreated, within the past 5 years whether or not there is evidence of local recurrence or metastases, with the exception of localized basal cell carcinoma of the skin. Patients with non-melanoma skin carcinoma may be considered for the study.
10. Patients who, in the judgment of the investigator, have a clinically relevant laboratory abnormality or a clinically significant condition such as (but not limited to):
• unstable ischemic heart disease, left ventricular failure (NYHA Class III & IV), history of myocardial infarction, arrhythmia (excluding chronic stable AF). Patients with such events not considered clinically significant by the investigator may be considered for inclusion in the study.
• uncontrolled hypo-or hyperthyroidism, hypokalemia or hyperadrenergic state
• any condition which might compromise patient safety or compliance, interfere with evaluation, or preclude completion of the study
11. Patients who are, in the opinion of the investigator known to be unreliable or non-compliant.
12. Patients with a body mass index (BMI) of more than 40 kg/m2.
COPD specific exclusion
13. Patients requiring long term oxygen therapy (> 15 h a day) on a daily basis for chronic hypoxemia.
14. Patients who have had a COPD exacerbation that required treatment with antibiotics, systemic steroids (oral or intravenous) or hospitalization in the 6 weeks prior to pre-screening.
15. Patients who develop a COPD exacerbation between the pre-screening and the randomization visit will not be eligible but will be permitted to be re-screened after a minimum of 6 weeks after the resolution of the COPD exacerbation.
16. Patients who have had a respiratory tract infection within 6 weeks prior to pre-screening (Visit 1).
17. Patients who develop a respiratory tract infection between pre-screening and randomization (up to Visit 3) will not be eligible, but will be permitted to be re-screened 6 weeks after the resolution of the respiratory tract infection.
18. Patients with concomitant pulmonary disease
19. Patients with active pulmonary tuberculosis
20. Patients with pulmonary lobectomy, lung volume reduction surgery, or lung transplantation.
21. Patients with any history of asthma/COPD indicated by or onset of symptoms prior to 40 years.
22. Patients with a blood eosinophil count >600/mm3 at screening (Visit 2) will not be eligible, but will be permitted to be re-screened in case the high blood eosinophil count derived from an infection. The re-screen should be performed 6 weeks after the resolution of the infection
23. Patients with eczema (atopic), known high IgE levels, or a confirmed allergy history within the last 5 years
24. Patients with allergic rhinitis who use a H1 antagonist or intra-nasal corticosteroids intermittently
25. Patients with a history and diagnosis of α-1 antitrypsin deficiency.
26. Patients participating in or planning to participate in a supervised pulmonary rehabilitation program (“Disease Management Program” is permitted).
27. Patients receiving any medications in the class listed in Table 5-1, 5-2 or 5-3
28. Use of other investigational drugs (approved or unapproved) at the time of enrolment, or within 30 days of 5 half-lives of Visit 1
29. Patients unable to use a dry powder inhaler. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy variable, is the change from baseline of quality of life as assessed St George’s Respiratory Questionnaire (SGRQ-C) at the end of the study. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
| All continuous secondary endpoints BDI/TDI, CAT, Part I “Symptoms” of the St George’s Respiratory Questionnaire (SGRQ-C) and FEV1 (pre- and post-dose measurements) will be analyzed analogous to the primary endpoint (i.e. ANCOVA models with factors treatment, center and baseline). Rates of exacerbations will be displayed descriptively (# (%) of Pts with- # of exacerbations), the same display will be used for patients requiring corticosteroids/antibiotics. Time to exacerbation will be displayed using Kaplan-Meier plots. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
| 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 | 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 | 96 |
| 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
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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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
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