Effect of QVA149 Versus NVA237 and Tiotropium on Chronic Obstructive Pulmonary Disorder (COPD) Exacerbations
Condition: Chronic Obstructive Pulmonary Disease
MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive
Intervention: QVA149; NVA237; tiotropium; Salbutamol/albuterol
Intervention description: QVA149 110/50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks).; NVA237 50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks).; Open-label tiotropium bromide 18 μg capsules for inhalation once daily delivered via HandiHaler® device for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks).; As needed throughout the study
Intervention MeSH terms: Glycopyrrolate; Albuterol; Tiotropium Bromide
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 2224.0
Sex: All
Minimum age: 40 Years
Healthy volunteers: No
Keywords: QVA149; NVA237; COPD; exacerbation; combination bronchodilator

Summary:

      This study is designed to assess the effect of once-daily QVA149 on COPD exacerbations in
      patients with severe to very severe COPD.
    

Eligibility criteria:

        Inclusion Criteria :

          1. Male or female adults aged ≥40 years, who had signed an informed consent form prior to
             initiation of any study-related procedure.

          2. Patients with severe to very severe Chronic Obstructive Pulmonary Disease COPD (Stage
             III or IV) according to the Global Initiative for Chronic Obstructive Lung Disease
             (GOLD) Guidelines 2008.

          3. Current or ex-smokers with a smoking history of at least 10 pack years (Ten pack-years
             were defined as 20 cigarettes a day for 10 years, or 10 cigarettes a day for 20
             years).

          4. Patients with a post-bronchodilator Forced Expiratory Volume in one second ( FEV1)
             <50% of the predicted normal value, and post-bronchodilator FEV1/ Forced Vital
             Capacity (FVC) <0.70 at Visit 2 (day -14). (Post refers to 1 h after sequential
             inhalation of 84 µg (or equivalent dose) of ipratropium bromide and 400 µg of
             salbutamol).

          5. A documented history of at least 1 COPD exacerbation in the previous 12 months that
             required treatment with systemic glucocorticosteroids and/or antibiotics.

        Exclusion Criteria:

          1. Pregnant women or nursing mothers (pregnancy confirmed by positive urine pregnancy
             test).

          2. Women of child-bearing potential

          3. Patients requiring long term oxygen therapy (> 15 h a day) on a daily basis for
             chronic hypoxemia.

          4. Patients who had a COPD exacerbation that required treatment with antibiotics,
             systemic steroids (oral or intravenous) or hospitalization in the 6 weeks prior to
             visit 1 or between visit 1 (Day -21) and Visit 3 (Day 1).

          5. Patients who developed a COPD exacerbation during a period between visit 1 and 3 were
             ineligible but were permitted to be re-screened after a minimum of 6 weeks after the
             resolution of the COPD exacerbation.

          6. Patients who had a respiratory tract infection within 4 weeks prior to visit 1 (Day
             -21)

             • Patients who developed an upper or lower respiratory tract infection during the
             screening period (up to visit 3 (Day 1) were not eligible, but were permitted to be
             re-screened 4 weeks after the resolution of the respiratory tract infection

          7. Patients with concomitant pulmonary disease, e.g. pulmonary tuberculosis (unless
             confirmed by chest x-ray to be no longer active), clinically significant
             bronchiectasis, sarcoidosis, interstitial lung disorder or pulmonary hypertension.

          8. Patients with lung lobectomy, or lung volume reduction or lung transplantation.

          9. 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, history of myocardial
                  infarction, arrhythmia (excluding chronic stable Atrial Fibrillation (AF).
                  Patients with such events not considered clinically significant by the
                  investigator may be considered for inclusion in the study

               -  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

               -  uncontrolled hypo- or hyperthyroidism, hypokalemia or hyper adrenergic state

               -  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) were excluded from the study. Patients who underwent
                  full re-section of the prostate could be considered for the study, as well as
                  patients who were asymptomatic and stable on pharmacological treatment for the
                  condition).

               -  any condition which might have compromised patient safety or compliance,
                  interfered with evaluation, or precluded completion of the study

         10. Patients with any history of asthma indicated by (but not limited to) a blood
             eosinophil count > 600/mm3 (at visit 2), or onset of symptoms prior to 40 years.
             Patients without asthma were excluded if their eosinophil count was >600/mm3 at visit
             2.

         11. Patients with allergic rhinitis who used H1 antagonists or intranasal corticosteroids
             intermittently (treatment with a constant dose was permitted).

         12. Patients with eczema (atopic), known high immunoglobulin E (IgE) levels or a known
             positive skin prick test in the last 5 years.

         13. Patients with known history and diagnosis of alpha-1 antitrypsin deficiency.

         14. Patients who were participating in the active phase of a supervised pulmonary
             rehabilitation program.

         15. Patients with Type I or uncontrolled Type II diabetes.

         16. Patients contraindicated for treatment with, or having a history of reactions/
             hypersensitivity to any of the following inhaled drugs or drugs of a similar class or
             any component thereof:

               -  anticholinergic agents

               -  long and short acting beta-2 agonists

               -  sympathomimetic amines.

         17. Patients with a history of long QT syndrome or whose corrected QT interval (QTc)
             measured at visit 2 (Day -14) (Fridericia method) was prolonged (>450 ms for males and
             females) as confirmed by the central ECG assessor.

         18. Patients with a clinically significant abnormality on the screening or baseline ECG
             who in the judgment of the investigator would be at potential risk if enrolled into
             the study. (These patients could not be re-screened).

         19. Patients who needed treatments for COPD and allied conditions after the start of the
             study (visit 1)

         20. Patients who needed treatments for COPD and allied conditions (e.g. allergic rhinitis)
             unless they had been stabilized

         21. Patients taking other prohibited medications

         22. Patients unable to use a dry powder inhaler (e.g. single dose dry powder inhaler
             (SDDPI), HandiHaler® device, or pressurized Metered Dose Inhaler (MDI) (rescue
             medication).

         23. Patients unable to use an electronic patient diary.

         24. Patients who were, in the opinion of the investigator known to be unreliable or
             non-compliant.

         25. Patients who used other investigational drugs at the time of enrollment, or within 30
             days or 5 half-lives of visit 1 (day -21), whichever was longer.

         26. Patients who had live attenuated vaccination within 30 days prior to the screening
             visit or during the run-in period. Inactivated influenza vaccination, pneumococcal
             vaccination or any other inactivated vaccine was acceptable provided it was not
             administered within 48 hours prior to screening and randomization visits.

        No additional exclusions were applied by the investigator, in order to ensure that the
        study population was representative of all eligible patients.