E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
subjects with moderate to very severe COPD |
|
E.1.1.1 | Medical condition in easily understood language |
subjects with moderate to very severe 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 | 17.1 |
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 |
To demonstrate that QVA149 (110/50 μg o.d.) is at least noninferior to salmeterol/fluticasone (50/500 μg b.i.d.) in terms of rate of COPD exacerbations (mild/moderate/severe) during 52 weeks of
treatment. |
|
E.2.2 | Secondary objectives of the trial |
To demonstrate that QVA149 (110/50 μg o.d.) is superior to salmeterol/fluticasone (50/500 μg b.i.d.) in terms of rate of all COPD exacerbations during 52 weeks of treatment.
To evaluate the effect of QVA149 compared to salmeterol/fluticasone during 52 weeks of treatment in terms of:
• Time to first COPD exacerbation (mild/moderate/severe).
• Rate and time to first moderate/severe COPD exacerbations.
To evaluate the effect of QVA149 compared to salmeterol/fluticasone in terms of:
• FEV1 (including morning pre-dose FEV1) and FVC on Day 1 and after 4, 12, 26, 38
and 52 weeks of treatment.
• Lung function in terms of standardized FEV1 AUC (0 – 12h), in a subset of patients.
• Total score of the St. George’s Respiratory Questionnaire (SGRQ-C) after 4, 12, 26,
38 and 52 weeks of treatment
• Mean use of rescue therapy over the 52 weeks treatment period.
|
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Written informed consent must be obtained before any assessment is performed.
2. Male or female adults aged ≥40 years.
3. Patients with stable COPD according to the current GOLD strategy (GOLD 2011).
4. Current or ex-smokers who have a smoking history of at least 10 pack years. (Ten packyears
are defined as 20 cigarettes a day for 10 years, or 10 cigarettes a day for 20 years).
5. Patients with a post-bronchodilator FEV1 ≥25 and < 60% of the predicted normal value,
and post-bronchodilator FEV1/FVC < 0.70 at Visit 101 (day -28).
(Post refers to 1 h after sequential inhalation of 84 μg (or equivalent dose) of ipratropium
bromide and 400 μg of salbutamol).
6. A documented history of at least 1 COPD exacerbation in the previous 12 months that
required treatment with systemic glucocorticosteroids and/or antibiotics.
7. Patients taking stable COPD medication (at least 60 days) prior to Visit 101.
8. Patients with an mMRC grade of at least 2 at Visit 101 (day -28). |
|
E.4 | Principal exclusion criteria |
1. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a
female after conception and until the termination of gestation, confirmed by a positive
hCG (human Chorionic Gonadotropin) laboratory test.
2. Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using effective methods of contraception during
dosing of study treatment. Effective contraception methods include:
• Total abstinence when this is in line with the preferred and usual lifestyle of the
subject (periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation
methods) and withdrawal are not acceptable methods of contraception).
• Female sterilization defined as surgical hysterectomy, bilateral oophorectomy, or
tubal ligation at least six weeks before taking the study treatment (Single
oophorectomy does not meet the definition of female sterilization).
• Male sterilization (at least 6 months prior to screening). For female subjects on the
study, the vasectomized male partner should be the sole partner for that subject.
• Barrier methods of contraception: condom or occlusive cap (diaphragm or
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository.
• Use of oral, injected or implanted hormonal methods of contraception or other forms
of hormonal contraception that have comparable efficacy (failure rate <1%), for
example hormone vaginal ring or transdermal hormone contraception. In case of use
of oral contraception women should have been stable on the same pill for a minimum
of 3 months before taking study treatment.
• Placement of an intrauterine device (IUD) or intrauterine system (IUS).
Women are considered post-menopausal and not of child bearing potential if they have
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical
profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical
bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six
weeks ago. In the case of oophorectomy alone, only when the reproductive status of
the woman has been confirmed by follow up hormone level assessment is she
considered not of child bearing potential.
3. Patients with Type I or uncontrolled Type II diabetes.
4. Patients with a history of long QT syndrome or whose QTc measured at Visit 101
(Fridericia method) is prolonged (>450 ms for males and females) and confirmed by a
central assessor. These patients should not be re-screened.
5. Patients who have a clinically significant ECG abnormality at Visit 101 or Visit 201.
(These patients should not be re-screened)
6. Patients who have a clinically significant laboratory abnormality at Visit 101.
7. Patients who have clinically significant renal, cardiovascular (such as but not limited to
unstable ischemic heart disease, NYHA Class III/IV left ventricular failure, myocardial
infarction), arrhythmia (see below for patients with atrial fibrillation), neurological,
endocrine, immunological, psychiatric, gastrointestinal, hepatic, or hematological
abnormalities which could interfere with the assessment of the efficacy and safety of the
study treatment.
8. Patients with paroxysmal (e.g. intermittent) atrial fibrillation are excluded. Patients with
persistent atrial fibrillation as defined by continuous atrial fibrillation for at least 6 months
and controlled with a rate control strategy (i.e., selective beta blocker, calcium channel
blocker, pacemaker placement, digoxin or ablation therapy) for at least 6 months may be considered for inclusion. In such patients, atrial fibrillation must be present at Visit 101
and Visit 102 with a resting ventricular rate < 100/min. At Visit 101 the atrial fibrillation
must be confirmed by central reading.
For more Exclusion criteria, please refer to the protocol. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Rate of COPD exacerbations (mild/moderate/severe) during 52 weeks of treatment |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
•Time to first COPD exacerbation (mild/moderate/severe).
•Rate and time to first moderate/severe COPD exacerbations.
•Rate and time to first moderate to severe COPD exacerbation requiring:
• systemic glucocorticosteroids during the treatment period
• antibiotics during the treatment period
• hospitalizations during the treatment period.
• rehospitilisation within 30 days during the treatment period.
•FEV1 (including morning pre-dose FEV1) and FVC on Day 1 and after 4, 12, 26, 38 and 52 weeks of treatment.
•Standardized FEV1 AUC (0 – 12h), in a subset of patients.
•Total score of the St. George’s Respiratory Questionnaire (SGRQ-C) after 4, 12, 26, 38 and 52 weeks of treatment
•Mean use of rescue therapy over the 52 weeks treatment period.
•Safety - ECG, laboratory tests, vital signs and adverse events
•24-hour weighted mean urine cortisol, in a sub-set of patients.
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
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 | Yes |
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) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | Yes |
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 | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 496 |
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 |
Argentina |
Austria |
Belgium |
Brazil |
Bulgaria |
Canada |
Chile |
China |
Colombia |
Croatia |
Czech Republic |
Denmark |
Egypt |
Estonia |
Finland |
France |
Germany |
Greece |
Guatemala |
Hong Kong |
Hungary |
Iceland |
India |
Italy |
Japan |
Korea, Republic of |
Latvia |
Lithuania |
Mexico |
Netherlands |
Norway |
Peru |
Philippines |
Poland |
Portugal |
Romania |
Russian Federation |
Serbia |
Slovakia |
South Africa |
Spain |
Sweden |
Switzerland |
Taiwan |
Thailand |
Turkey |
United Kingdom |
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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
|
|
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 | 3 |
E.8.9.1 | In the Member State concerned days | |
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 | 3 |