A 12-week Treatment, Multi-center, Randomized, Double-blind, Parallel-group, Placebo and Active Controlled Study to Assess the Efficacy, Safety, and Tolerability of Indacaterol Maleate / Glycopyrronium Bromide in COPD Patients With Moderate to Severe Airflow Limitation

This study will assess the efficacy, safety and tolerability of indacaterol maleate/glycopyrronium bromide in patients with moderate to severe airflow limitation.

Study Overview

• Status: Completed
• Conditions: Chronic Obstructive Pulmonary Disease (COPD)
• Intervention / Treatment: Drug: QVA149; Drug: QAB149; Drug: NVA237; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 1001
• Phase: Phase 3

Contacts and Locations

Study Locations

• Colombia
  • Armenia, Colombia
    • Novartis Investigative Site
  • Barranquilla, Colombia
    • Novartis Investigative Site
  • Atlantico
    • Barranquilla, Atlantico, Colombia
      • Novartis Investigative Site
• Egypt
  • Alexandria, Egypt, 21131
    • Novartis Investigative Site
• France
  • Beuvry, France, 62660
    • Novartis Investigative Site
  • Nantes, France, 44000
    • Novartis Investigative Site
  • Paris, France, 75013
    • Novartis Investigative Site
  • Reims, France, 51092
    • Novartis Investigative Site
• Guatemala
  • Guatemala City, Guatemala, 01010
    • Novartis Investigative Site
  • Guatemala City, Guatemala, 01011
    • Novartis Investigative Site
  • Guatemala City, Guatemala, 01015
    • Novartis Investigative Site
• Hungary
  • Balassagyarmat, Hungary, 2660
    • Novartis Investigative Site
  • Debrecen, Hungary, 4032
    • Novartis Investigative Site
  • Deszk, Hungary, 6772
    • Novartis Investigative Site
  • Godollo, Hungary, 2100
    • Novartis Investigative Site
  • Gyor, Hungary, 9024
    • Novartis Investigative Site
  • Komarom, Hungary, 2900
    • Novartis Investigative Site
  • Mako, Hungary, 6900
    • Novartis Investigative Site
  • Miskolc, Hungary, 3529
    • Novartis Investigative Site
  • Szazhalombatta, Hungary, 2440
    • Novartis Investigative Site
  • Szombathely, Hungary, 9700
    • Novartis Investigative Site
  • Tatabanya, Hungary, 2800
    • Novartis Investigative Site
• Panama
  • Panamá
    • Panama City, Panamá, Panama
      • Novartis Investigative Site
• Slovakia
  • Galanta, Slovakia, 92422
    • Novartis Investigative Site
  • Kosice, Slovakia, 040 01
    • Novartis Investigative Site
  • Kosice, Slovakia, 04001
    • Novartis Investigative Site
  • Kralovsky Chlmec, Slovakia, 077 01
    • Novartis Investigative Site
  • Martin, Slovakia, 036 01
    • Novartis Investigative Site
  • Presov, Slovakia, 080 01
    • Novartis Investigative Site
  • Prievidza, Slovakia, 97101
    • Novartis Investigative Site
  • Spisská Nová Ves, Slovakia, 052 01
    • Novartis Investigative Site
  • Zvolen, Slovakia, 960 01
    • Novartis Investigative Site
  • Slovak Republic
    • Bardejov, Slovak Republic, Slovakia, 085 01
      • Novartis Investigative Site
    • Bojnice, Slovak Republic, Slovakia, 972 01
      • Novartis Investigative Site
    • Humenne, Slovak Republic, Slovakia, 066 01
      • Novartis Investigative Site
    • Liptovsky Hradok, Slovak Republic, Slovakia, 033 01
      • Novartis Investigative Site
    • Nitra, Slovak Republic, Slovakia, 949 01
      • Novartis Investigative Site
    • Vrable, Slovak Republic, Slovakia, 952 01
      • Novartis Investigative Site
• Slovenia
  • Golnik, Slovenia, 4204
    • Novartis Investigative Site
• United States
  • Alabama
    • Huntsville, Alabama, United States, 35801
      • Novartis Investigative Site
  • Arizona
    • *See Various Dept.'s*, Arizona, United States
      • Novartis Investigative Site
    • Tempe, Arizona, United States, 85283
      • Novartis Investigative Site
  • California
    • Buena Park, California, United States, 90620
      • Novartis Investigative Site
    • Fullerton, California, United States, 92835
      • Novartis Investigative Site
    • Palmdale, California, United States, 93551
      • Novartis Investigative Site
    • Riverside, California, United States, 92506
      • Novartis Investigative Site
    • San Diego, California, United States, 92120
      • Novartis Investigative Site
    • Sepulveda, California, United States, 91343
      • Novartis Investigative Site
  • Florida
    • Clearwater, Florida, United States, 33756
      • Novartis Investigative Site
    • Clearwater, Florida, United States, 33765
      • Novartis Investigative Site
    • Deland, Florida, United States, 32720
      • Novartis Investigative Site
    • Ft. Lauderdale, Florida, United States, 33316-192
      • Novartis Investigative Site
    • Miami, Florida, United States, 33186
      • Novartis Investigative Site
    • Miami, Florida, United States, 33156
      • Novartis Investigative Site
    • Orlando, Florida, United States, 32806
      • Novartis Investigative Site
    • Pensacola, Florida, United States, 32503
      • Novartis Investigative Site
    • Pensacola, Florida, United States, 32504
      • Novartis Investigative Site
    • Port Orange, Florida, United States, 32127
      • Novartis Investigative Site
    • Sarasota, Florida, United States, 34233
      • Novartis Investigative Site
    • Tamarac, Florida, United States, 33321
      • Novartis Investigative Site
    • Tampa, Florida, United States, 33603
      • Novartis Investigative Site
    • Winter Park, Florida, United States, 32789
      • Novartis Investigative Site
  • Georgia
    • Lawrenceville, Georgia, United States, 30046
      • Novartis Investigative Site
  • Louisiana
    • Opelousas, Louisiana, United States, 70570
      • Novartis Investigative Site
  • Nevada
    • Henderson, Nevada, United States, 89014
      • Novartis Investigative Site
    • Las Vegas, Nevada, United States, 89119
      • Novartis Investigative Site
    • Reno, Nevada, United States, 89520
      • Novartis Investigative Site
  • New Jersey
    • Brandon, New Jersey, United States, 33511
      • Novartis Investigative Site
  • North Carolina
    • Charlotte, North Carolina, United States, 28207
      • Novartis Investigative Site
    • Huntersville, North Carolina, United States, 28078
      • Novartis Investigative Site
    • Raleigh, North Carolina, United States, 27607
      • Novartis Investigative Site
    • Shelby, North Carolina, United States, 28152
      • Novartis Investigative Site
    • Shelby, North Carolina, United States, 28150
      • Novartis Investigative Site
  • South Carolina
    • Charleston, South Carolina, United States, 29406-7108
      • Novartis Investigative Site
    • Charleston, South Carolina, United States, 29412
      • Novartis Investigative Site
    • Columbia, South Carolina, United States, 29201
      • Novartis Investigative Site
    • Easley, South Carolina, United States, 29640
      • Novartis Investigative Site
    • Gaffney, South Carolina, United States, 29340
      • Novartis Investigative Site
    • Greenville, South Carolina, United States, 29615
      • Novartis Investigative Site
    • Pelzer, South Carolina, United States, 29669
      • Novartis Investigative Site
    • Rock Hll, South Carolina, United States, 29732
      • Novartis Investigative Site
    • Seneca, South Carolina, United States, 29678
      • Novartis Investigative Site
    • Simpsonville, South Carolina, United States, 29681
      • Novartis Investigative Site
    • Spartanburg, South Carolina, United States, 29303
      • Novartis Investigative Site
    • Union, South Carolina, United States, 29379
      • Novartis Investigative Site
  • Tennessee
    • Johnson City, Tennessee, United States, 37601
      • Novartis Investigative Site
  • Texas
    • Arlington, Texas, United States, 76012
      • Novartis Investigative Site
    • Corsicana, Texas, United States, 75110
      • Novartis Investigative Site
    • Dallas, Texas, United States, 75216
      • Novartis Investigative Site
    • Dallas, Texas, United States, 75235
      • Novartis Investigative Site
    • Fort Worth, Texas, United States, 76107
      • Novartis Investigative Site
    • Ft. Worth, Texas, United States, 76104
      • Novartis Investigative Site
    • Lufkin, Texas, United States, 75904
      • Novartis Investigative Site
    • McKinney, Texas, United States, 75069
      • Novartis Investigative Site
    • Tyler, Texas, United States, 75708
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male and female patients that have signed informed consent and are >/= 40 years of age.
• Patients with stable COPD according to GOLD 2011.
• Patients with a post-bronchodilator FEV1 of >/= 30% and < 80% predicted and a post-bronchodilator FEV1/FVC <0.70.
• Current or ex-smokers who have a smoking history of at least 10 pack years.
• Patients with an mMRC grade 2 or greater.

Exclusion Criteria:

• Patients with Type I or uncontrolled Type II diabetes - 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.)
• Patients who have a clinically significant ECG abnormality at Visit 101 or Visit 102. (These patients should not be re-screened.)
• Patients with a history of malignancy of any organ system, treated or untreated, within the last five years.
• Patients with narrow-angle glaucoma, BPH or bladder-neck obstruction or moderate-severe renal impairment or urinary retention.
• Patients who had a COPD exacerbation within 6 weeks prior to screening.
• Patients who have a respiratory tract infection within 4 weeks prior to screening.
• Patients requiring long term oxygen therapy prescribed for more than 12 hr per day.
• Patients with a history of asthma. 8. Patients with an onset of respiratory symptoms, including COPD diagnosis, prior to age 40 years.
• Patients with a blood eosinophil count of greater than 600 mm/3 during run-in.
• Patients with concomitant pulmonary disease.
• Patients with a diagnosis of alpha-1 anti-trypsin deficiency.
• Patients with active pulmonary tuberculosis.
• Patients in the active phase of a pulmonary rehabilitation programme.
• Other protocol-defined inclusion/exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: QVA149; 27.5/12.5 ug twice daily (b.i.d.) Single Dose Dry Powder Inhaler (SDDPI	Drug: QVA149; QVA149 was supplied in a capsule form in blister packs for use in the Novartis Concept1 SDDPI
Active Comparator: QAB149; 27.5 ug b.i.d.	Drug: QAB149; QAB149 was supplied in capsule form in blister packs for use in the Novartis Concept1 SDDPI.
Active Comparator: NVA237; 12.5 ug b.i.d.	Drug: NVA237; NVA237 was supplied in capsule form in blister packs for use in the Novartis Concept1 SDDPI.
Placebo Comparator: Placebo; b.i.d.	Drug: Placebo; Placebo was supplied in capsule form in blister packs for use in the Novartis Concept1 SDDPI.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Primary: Change From Baseline in Standardized Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve (AUC) (0-12 Hours (h))	Pulmonary function assessments were performed using centralized spirometry according to international standards. Baseline FEV1 was defined as the average of the pre-dose FEV1 measured at -45 minutes (min) and -15 min at day 1. A mixed model for repeated measures (MMRM), used for this analysis, included terms of treatment, baseline FEV1 measurements, smoking status at baseline, baseline inhaled corticosteroid (ICS) use, region, baseline FEV1 * visit interaction, and visit, treatment * visit interaction. Missing values of FEV1 AUC0-12 at Day 1 and Week 12 will not imputed. The trapezoidal rule was used to calculate FEV1 AUC and then normalized to the length of time.	baseline (BL), 12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) Total Score	Participants reported change in health status by using the SGRQ. The SGRQ contains 50 items divided into 2 parts covering 3 aspects of health related to COPD: Part I covers "Symptoms" and is concerned with respiratory symptoms, their frequency and severity; Part II covers "Activity" and is concerned with activities that cause or are limited by breathlessness; Part II is also concerned with "Impacts", which covers a range of aspects concerned with social functioning and psychological disturbances resulting from airways disease. A score was calculated for each of these 3 subscales and a "Total" score was calculated. In each case the lowest possible value is zero and the highest 100. Higher values correspond to greater impairment of health status. Missing week 12 data were imputed with Last Observation Carried Forward (LOCF) method but only if measured at day >= 29. A negative change from baseline indicates improvement.	BL, 12 Weeks
Percentage of Participants With a Clinically Important Improvement of at Least 4 Units in the SGRQ Total Score	Participants reported change in health status by using the SGRQ. The SGRQ contains 50 items divided into 2 parts covering 3 aspects of health related to COPD: Part I covers "Symptoms" and is concerned with respiratory symptoms, their frequency and severity; Part II covers "Activity" and is concerned with activities that cause or are limited by breathlessness; Part II is also concerned with "Impacts", which covers a range of aspects concerned with social functioning and psychological disturbances resulting from airways disease. A score was calculated for each of these 3 subscales and a "Total" score was calculated. In each case the lowest possible value is zero and the highest 100. Higher values correspond to greater impairment of health status.	12 weeks
Change From Baseline in Trough FEV1	Pulmonary function assessments were performed using centralized spirometry according to international standards. Trough FEV1 was analyzed using the same MMRM as specified for FEV1. Trough FEV1 was defined as the mean of FEV1 at 23 h 15 min and 23 h 45 min after the morning dose of the previous day. Before the mean was calculated, a time window of 10 - 13 hours post-evening dose was applied to these 2 measurements. Recordings outside the time window were set to missing.	BL, day 2, day 86
Change From Baseline in Pre-dose Trough FEV1	Pulmonary function assessments were performed using centralized spirometry according to international standards. Pre-dose trough FEV1 was analyzed using the same MMRM as specified for FEV1. Pre-dose trough FEV1 was defined as the mean of FEV1 at -45 min and -15 min before the morning dose. Since the time of evening dose of the previous day was not recorded at these visits, no time window was applied.	BL, day 85
Change From Baseline in FEV1	Pulmonary function assessments were performed using centralized spirometry according to international standards. Baseline FEV1 was defined as the average of the pre-dose FEV1 measured at -45 minutes (min) and -15 min at day 1. A mixed model for repeated measures (MMRM), used for this analysis, included terms of treatment, baseline FEV1 measurements, smoking status at baseline, baseline inhaled corticosteroid (ICS) use, region, baseline FEV1 * visit interaction, and visit, treatment * visit interaction.	BL, Day 1: 5min, 15min, 1h, 2h, 4h, 6h, 8h, 11h55 min; Day 2: 23h15min, 23h45min; Day 15: -45min, -15min, 1h; Day 29: -45 min, -15min, 1h; Day 57: -45min, -15min, 1h; day 85: -45min, -15min, 5min, 15min, 1h, 2h, 4h, 6h, 8h, 11h; day 86: 23h15min; 23h45min
Change From Baseline in FVC	Pulmonary function assessments were performed using centralized spirometry according to international standards. Baseline FVC was defined as the average of the pre-dose FVC measured at -45 minutes (min) and -15 min at day 1. A mixed model for repeated measures (MMRM), used for this analysis, included terms of treatment, baseline FVC measurements, smoking status at baseline, baseline inhaled corticosteroid (ICS) use, region, baseline FEV1 * visit interaction, and visit, treatment * visit interaction.	BL, Day 1: 5min, 15min, 1h, 2h, 4h, 6h, 8h, 11h55 min; Day 2: 23h15min, 23h45min; Day 15: -45min, -15min, 1h; Day 29: -45 min, -15min, 1h; Day 57: -45min, -15min, 1h; day 85: -45min, -15min, 5min, 15min, 1h, 2h, 4h, 6h, 8h, 11h; day 86: 23h15min; 23h45min
Secondary: Change From Baseline in Standardized FEV1 AUC (0-4 h), FEV1 AUC (4-8h), FEV1 AUC (8-12h) and FEV1 AUC (0-12 h)	Pulmonary function assessments were performed using centralized spirometry according to international standards. Baseline FEV1 was defined as the average of the pre-dose FEV1 measured at -45 minutes (min) and -15 min at day 1. A mixed model for repeated measures (MMRM), used for this analysis, included terms of treatment, baseline FEV1 measurements, smoking status at baseline, baseline inhaled corticosteroid (ICS) use, region, baseline FEV1 * visit interaction, and visit, treatment * visit interaction. The trapezoidal rule was used to calculate FEV1 AUC and then normalized to the length of time.	BL, day 1, 12 weeks
Transitional Dyspnea Index (TDI) Focal Score	The Baseline Dyspnea Index (BDI) / TDI is an instrument used to assess a participant's level of dyspnea. The BDI and TDI each have three domains: functional impairment, magnitude of task and magnitude of effort. BDI domains were rated from 0 (severe) to 4 (unimpaired) and rates summed for baseline focal score ranged from 0 to 12; lower scores mean worse severity. TDI domains were rated from -3 (major deterioration) to 3 (major improvement) and rates summed for transition focal score ranged from -9 to 9; negative scores indicate deterioration. A TDI focal score of ≥1 was defined as a clinically important improvement from baseline.	BL, 12 weeks
Secondary: Change From Baseline in Mean Daily Number of Puffs of Rescue Medication	Participants completed an electronic diary (eDiary) twice daily at the same time in the morning and evening to record the number of puffs of rescue medication taken in the previous 12 hours. A negative change from baseline indicates improvement.	BL, 12 weeks
Secondary: Change From Baseline in Mean Total Daily Symptom Score, Mean Daytime Total Symptom Score and Mean Nighttime Total Symptom Score	The participant recorded symptom scores twice daily in the eDiary. The daily clinical symptoms included: cough, wheezing, shortness of breath, sputum volume, sputum color, and night time awakening. The range of scores for each assessment is 0 to 3 where 0 indications No symptom and 3 indicates a Severe symptom. The maximum daytime total score is 27 and the maximum nighttime total score is 27. The total daily symptom score is obtained by adding the scores for the morning and evening symptoms for each day. The maximum possible total daily score is 54. A negative change from baseline indicated improvement.	BL, 12 weeks

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Mahler DA, Kerwin E, Murray L, Dembek C. The Impact of Twice-Daily Indacaterol/Glycopyrrolate on the Components of Health-Related Quality of Life and Dyspnea in Patients with Moderate-to-Severe Chronic Obstructive Pulmonary Disease. Chronic Obstr Pulm Dis. 2019 Oct 23;6(4):308-20. doi: 10.15326/jcopdf.6.4.2019.0131.

Study record dates

Study Major Dates

• Study Start: December 1, 2012
• Primary Completion (Actual): February 1, 2014
• Study Completion (Actual): February 1, 2014

Study Registration Dates

• First Submitted: October 19, 2012
• First Submitted That Met QC Criteria: October 22, 2012
• First Posted (Estimate): October 23, 2012

Study Record Updates

• Last Update Posted (Estimate): July 15, 2015
• Last Update Submitted That Met QC Criteria: July 13, 2015
• Last Verified: July 1, 2015

More Information

Terms related to this study

• Keywords: COPD, QVA149
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Muscarinic Antagonists; Cholinergic Antagonists; Cholinergic Agents; Adjuvants, Anesthesia; Glycopyrrolate
• Other Study ID Numbers: CQVA149A2337