A 64-week Treatment, Multi-center, Randomized, Double-blind, Parallel-group, Active Controlled Study to Evaluate the Effect of QVA149 (110/50 μg o.d.) vs NVA237 (50 μg o.d.) and Open-label Tiotropium (18 μg o.d.) on COPD Exacerbations in Patients With Severe to Very Severe Chronic Obstructive Pulmonary Disease (COPD)
Trial Snapshot
- Phase
- Phase 3
- Status
- Completed
- Sponsor
- Novartis Pharmaceuticals
- Enrollment
- 2,224
- Locations
- 1
- Primary Endpoint
- Rate of Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations in QVA149 and NVA237 Treatment Arms During the Treatment Period.
Study Overview
Brief Summary
This study is designed to assess the effect of once-daily QVA149 on COPD exacerbations in patients with severe to very severe COPD.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Eligibility Criteria
- Ages
- 40 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- Not provided
Exclusion Criteria
- •Pregnant women or nursing mothers (pregnancy confirmed by positive urine pregnancy test).
- •Women of child-bearing potential
- •Patients requiring long term oxygen therapy (> 15 h a day) on a daily basis for chronic hypoxemia.
- •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).
- •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.
- •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
- •Patients with concomitant pulmonary disease, e.g. pulmonary tuberculosis (unless confirmed by chest x-ray to be no longer active), clinically significant bronchiectasis, sarcoidosis, interstitial lung disorder or pulmonary hypertension.
- •Patients with lung lobectomy, or lung volume reduction or lung transplantation.
- •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
- •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
- •Patients with allergic rhinitis who used H1 antagonists or intranasal corticosteroids intermittently (treatment with a constant dose was permitted).
- •Patients with eczema (atopic), known high immunoglobulin E (IgE) levels or a known positive skin prick test in the last 5 years.
- •Patients with known history and diagnosis of alpha-1 antitrypsin deficiency.
- •Patients who were participating in the active phase of a supervised pulmonary rehabilitation program.
- •Patients with Type I or uncontrolled Type II diabetes.
- •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.
- •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.
- •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).
- •Patients who needed treatments for COPD and allied conditions after the start of the study (visit 1)
- •Patients who needed treatments for COPD and allied conditions (e.g. allergic rhinitis) unless they had been stabilized
- •Patients taking other prohibited medications
- •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).
- •Patients unable to use an electronic patient diary.
- •Patients who were, in the opinion of the investigator known to be unreliable or non-compliant.
- •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.
- •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.
Arms & Interventions
QVA149
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). Salbutamol/albuterol was available for rescue medication use throughout the study.
Intervention: QVA149 (Drug)
QVA149
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). Salbutamol/albuterol was available for rescue medication use throughout the study.
Intervention: Salbutamol/albuterol (Drug)
NVA237
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). Salbutamol/albuterol was available for rescue medication use throughout the study.
Intervention: NVA237 (Drug)
NVA237
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). Salbutamol/albuterol was available for rescue medication use throughout the study.
Intervention: Salbutamol/albuterol (Drug)
open-label tiotropium
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). Salbutamol/albuterol was available for rescue medication use throughout the study.
Intervention: tiotropium (Drug)
open-label tiotropium
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). Salbutamol/albuterol was available for rescue medication use throughout the study.
Intervention: Salbutamol/albuterol (Drug)
Outcomes
Primary Outcomes
Rate of Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations in QVA149 and NVA237 Treatment Arms During the Treatment Period.
Time Frame: 64 weeks
A Chronic Obstructive Pulmonary Disease (COPD) exacerbation was defined as a worsening of two or more of the following major symptoms for at least 2 consecutive days: dyspnea, sputum volume or sputum purulence OR a worsening of any 1 major symptom together with an increase in any 1 of the following minor symptoms for at least 2 consecutive days: sore throat, colds (nasal discharge and/or nasal congestion), fever without other cause, cough or wheezing. A COPD exacerbation was considered of moderate severity if treatment with systemic glucocorticosteroids or antibiotics or both was required and severe if hospitalization was required. An emergency room (ER) visit of longer than 24 hours was considered a hospitalization. Rate of moderate or severe exacerbations per year = total number of moderate or severe exacerbations / total number of treatment years
Secondary Outcomes
- Rate of Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations in QVA149 and Open-label Tiotropium Treatment Arms During the Treatment Period.(76 weeks)
- Time to First Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbation Between QVA149, NVA237 and Open Label Tiotropium During the Treatment Period(64 weeks)
- Rate of Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations Requiring the Use of Both Systemic Glucocorticosteroids and Antibiotics(64 weeks)
- Number of Days With Moderate or Severe Exacerbation That Required Treatment With Systemic Corticosteroids and Antibiotics(64 weeks)
- Time to Study Withdrawal or Premature Discontinuation for Any Reason Between QVA149 (110/50 µg q.d.), NVA237 (50 µg q.d.) and Open Label Tiotropium (18 µg q.d.) During the Treatment Period.(64 weeks)
- Percentage of Patients With Study Withdrawal or Premature Discontinuation for Any Reason Between QVA149 (110/50 µg q.d.), NVA237 (50 µg q.d.) and Open Label Tiotropium (18 µg q.d.)During the Treatment Period(64 weeks)
- Cumulative Rates of Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations for Multiple COPD Exacerbation at Different Time Points(26, 52, 64, 76 weeks)
- Pre-dose Forced Expiratory Volume in 1 Second (FEV-1) After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium(4, 12, 26, 38, 52 and 64 weeks)
- Pre-dose Forced Vital Capacity (FVC)After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium(4, 12, 26, 38, 52 and 64 weeks)
- Change in Mean Daily Use (Number of Puffs) of Rescue Therapy Between QVA149, NVA237 and Open Label Tiotropium From Baseling Over the 64 Week Treatment Period(Baseline (14 day run-in), 64 weeks)
- Change From Baseline of Percentage of Days Without Rescue Therapy Use Between QVA149,NVA237 and Open Label Tiotropium Over the 64 Week Treatment Period(Baseline (14 day run-in), 64 weeks)
- St. George's Respiratory Questionnaire (SGRQ) Scores Between QVA149, NVA237 and Open Label Tiotropium Over 12, 26, 38, 52 and 64 Weeks of Treatment(12, 26, 38, 52 and 64 weeks)