A 52-week treatment, multi-center, randomized, double blind, double dummy, parallel-group, active controlled study to compare the effect of QVA149 (indacaterol maleate / glycopyrronium bromide) with salmeterol/fluticasone on the rate of exacerbations in subjects with moderate to very severe COPD

Study Objective

Primary study objective
• To demonstrate that QVA149 (110/50 μg o.d.) is at least non-inferior to salmeterol/fluticasone (50/500 μg b.i.d) in terms of rate of COPD exacerbations (mild/moderate/severe) during 52 weeks of treatment.

Secondary study objectives
• To demonstrate that QVA149 is superior to salmeterol/fluticasone 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: 

1. Time to first COPD exacerbation (mild/moderate/severe).
2. Rate and time to first moderate/severe COPD exacerbations.
3. Rate and time to first moderate to severe COPD exacerbation requiring systemic glucocorticosteroids, antibiotics, hospitalizations and/or rehospitalization within 30 days during the treatment period.

• To evaluate the effect of QVA149 compared to salmeterol/fluticasone in terms of:

1. FEV1 and FVC on Day 1 and after 4, 12, 26, 38 and 52 weeks of treatment.
2. Lung function in terms of standardized FEV1 AUC (0-12h), in a subset of patients.
3. Total score of the St. George’s Respiratory Questionnaire (SGRQ-C) after 4, 12, 26, 38 and 52 weeks of treatment.
4. Mean use of rescue therapy over the 52 weeks treatment period.
5. To assess the safety and tolerability of QVA149 (110/50 μg o.d.) vs fluticasone/salmeterol (500/50 μg b.i.d.) over the 52 weeks of treatment.
6. To assess the safety of QVA149 (110/50 μg o.d.) in terms of HPA axis function, as determined by 24-hour weighted mean urine cortisol, in a subset of patients.

Participation conditions

Inclusion criteria

Patients eligible for inclusion in this study have to fulfill all of the following criteria:
• Male and female adults aged ≥ 40 years, who have signed Inform Consent Form prior to initiation of any study-related procedure.
• Patients with stable COPD according to the current GOLD strategy (GOLD 2011) with an mMRC grade 2 or greater at Visit 101.
• Current or ex-smokers who have a smoking history of at least 10 pack years.
• Patients with a post-bronchodilator FEV1 ≥ 25 and < 60% of the predicted normal value, and post-bronchodilator FEV1/FVC < 0.70 at Visit 101.
• A documented history of at least 1 COPD exacerbation in the previous 12 months that required treatment with systemic glucocorticosteroids and/or antibiotics.
• Patients taking stable COPD medication (at least 60 days) prior to Visit 101.

Exclusion criteria

 Patients fulfilling any of the following criteria are not eligible for inclusion in this study:
• Pregnant or nursing 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.
• 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, female sterilization, male sterilization, barrier methods of contraception, use of oral, injected, or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS).
• Patients with Type I or uncontrolled Type II diabetes.
• Patients with a history of long QTc syndrome or QTc > 450 ms or a clinically significant ECG abnormality at Visit 101 or Visit 201.
• Patients who have a clinically significant lab abnormality, renal, cardiovascular (such as unstable ischemic heart disease, NYHA Class III/IV left ventricular failure, myocardial infarction) arrhythmia, neurological, endocrine, immunological, psychiatric, gastrointestinal, hepatic or hematological abnormalities.
• Patients with paroxysmal atrial fibrillation. Patients with persistent atrial fibrillation (continuous and controlled for at least 6 months) may be considered.
• Patients contraindicated for treatment with, or having a history of reactions/hypersensitivity with anticholinergic agents, long and short acting β2-agonists, sympathomimetic amines and/or lactose or any of the other excipients of trial medication.
• Patients with a history of malignancy of any organ system in the past 5 years (localized basal cell carcinoma is allowed).
• Patients who have not achieved an acceptable spirometry results at Visit 101 in accordance with American Thoracic Society (ATS)/European Respiratory Society (ERS) criteria for acceptability (one retest).
• Patients who have had a COPD exacerbation requiring antibiotics, systemic corticosteroids and/or hospitalization 6 weeks prior to Visit 1.
• Patients who develop a COPD exacerbation of any severity between screening and treatment (re-screened is allowed after a minimum of 6 weeks).
• Patients with any history of asthma or onset of respiratory symptoms, including a COPD diagnosis prior to age 40 years (blood eosinophils > 600/mm3 at Visit 101).
• Patients with concomitant pulmonary disease (e.g. lung fibrosis, sarcoidosis, interstitial lung disease, pulmonary hypertension).
• Patients with clinically significant bronchiectasis, pulmonary tuberculosis, lung volume reduction surgery or lung transplantation.
• Patients unable to use an electronic patient diary.

Centre Hospitalier de Luxembourg (CHL), Department of Pneumology