The Effect of QVA149 on Patient Reported Dyspnea in Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD) (BLAZE)

A Multicenter, Randomized, Blinded, Double-dummy, Placebo-controlled, 3-period Cross-over Study to Evaluate the Effect of QVA149 on Patient Reported Dyspnea in Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD), Using Tiotropium as an Active Control

This study assessed the effect of QVA149 on patient-reported dyspnea in moderate to severe Chronic Obstructive Pulmonary Disease (COPD) patients.

Study Overview

• Status: Completed
• Conditions: Chronic Obstructive Pulmonary Disease
• Intervention / Treatment: Drug: QVA149; Drug: Placebo to tiotropium; Drug: Salbutamol/albuterol; Drug: Tiotropium; Drug: Placebo to QVA149

Detailed Description

This study used a multi-center, randomized, blinded, double-dummy placebo controlled, three-period crossover design to assess the effect of once daily QVA149 q.d vs. placebo and tiotropium 18 μg q.d. in terms of patient reported dyspnea as assessed by Baseline Dyspnea Index (BDI)/Transient Dyspnea Index (TDI)(SAC version) in patients with moderate to severe COPD.

• Study Type: Interventional
• Enrollment (Actual): 247
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Bruxelles, Belgium, 1000
    • Novartis Investigative Site
  • Gilly, Belgium, 6060
    • Novartis Investigative Site
  • Jambes, Belgium, 5100
    • Novartis Investigative Site
  • Jette, Belgium, 1090
    • Novartis Investigative Site
  • Leuven, Belgium, 3000
    • Novartis Investigative Site
  • Liege, Belgium, 4000
    • Novartis Investigative Site
  • Oostende, Belgium, 8400
    • Novartis Investigative Site
  • Wavre, Belgium, 1301
    • Novartis Investigative Site
• Canada
  • Ontario
    • Burlington, Ontario, Canada, L7N 3V2
      • Novartis Investigative Site
    • Mississauga, Ontario, Canada, L5M 2V8
      • Novartis Investigative Site
    • Toronto, Ontario, Canada, M6H 3M2
      • Novartis Investigative Site
    • Toronto, Ontario, Canada, M5G1N8
      • Novartis Investigative Site
  • Quebec
    • Laval, Quebec, Canada, H7S 2M5
      • Novartis Investigative Site
    • Mirabel, Quebec, Canada, J7J 2K8
      • Novartis Investigative Site
    • St-Charles-Borromée, Quebec, Canada, J6E 6J2
      • Novartis Investigative Site
• Germany
  • Aschaffenburg, Germany, 63739
    • Novartis Investigative Site
  • Berlin, Germany, 12203
    • Novartis Investigative Site
  • Berlin, Germany, 13156
    • Novartis Investigative Site
  • Berlin, Germany, 10789
    • Novartis Investigative Site
  • Berlin, Germany, 12099
    • Novartis Investigative Site
  • Frankfurt, Germany, 60389
    • Novartis Investigative Site
  • Halle, Germany, 06108
    • Novartis Investigative Site
  • Hannover, Germany, 30317
    • Novartis Investigative Site
  • Leipzig, Germany, 04207
    • Novartis Investigative Site
  • Leipzig, Germany, 04357
    • Novartis Investigative Site
  • Leipzig, Germany, 04103
    • Novartis Investigative Site
  • Leipzig, Germany, 04275
    • Novartis Investigative Site
  • Mainz, Germany, D-55101
    • Novartis Investigative Site
  • Potsdam, Germany, 14467
    • Novartis Investigative Site
  • Potsdam, Germany, 14478
    • Novartis Investigative Site
  • Rheine, Germany, 48431
    • Novartis Investigative Site
  • Rüdersdorf, Germany, 15562
    • Novartis Investigative Site
  • Sachsen
    • Cottbus, Sachsen, Germany, 03050
      • Novartis Investigative Site
• Spain
  • Madrid, Spain, 28007
    • Novartis Investigative Site
  • Andalucia
    • Malaga, Andalucia, Spain, 29010
      • Novartis Investigative Site
  • Badajoz
    • Mérida, Badajoz, Spain, 06800
      • Novartis Investigative Site
  • Barcelona
    • Badalona, Barcelona, Spain, 08914
      • Novartis Investigative Site
  • Leon
    • Ponferrada, Leon, Spain, 24400
      • Novartis Investigative Site
• United Kingdom
  • Bradford, United Kingdom, BD9 6RJ
    • Novartis Investigative Site
  • Glasgow, United Kingdom, G11 6NT
    • Novartis Investigative Site
  • Newcastle-upon-Tyne, United Kingdom, NE7 7DN
    • Novartis Investigative Site
  • Portsmouth, United Kingdom, PO6 3AD
    • Novartis Investigative Site
  • Manchester
    • Salford, Manchester, United Kingdom, M6 8HD
      • 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:

• Patients with moderate to severe stable chronic obstructive pulmonary disease
• Smoking history of 10 pack years
• Post-bronchodilator Forced Expiratory Volume in 1 second (FEV1) between 30 - 80%
• Patients must be able to use computer mouse and display
• mMRC grade>2

Exclusion Criteria:

• Patients with a history of long QT syndrome
• Patients with Type I or uncontrolled Type II diabetes
• Patients who have had a COPD exacerbation or respiratory tract infection within 6 weeks prior to screening
• Patients with any history of asthma
• Patients with pulmonary lobectomy, lung volume reduction surgery, or lung transplantation
• Patients with concomitant pulmonary disease
• Patients requiring long term oxygen therapy (>15 h a day)

Other protocol-defined inclusion/exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: DOUBLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: QVA149 + placebo to tiotropium; Participants received QVA149 plus placebo to tiotropium during 1 of 3 treatment periods, once a day for 6 weeks. Participants were provided with a salbutamol/albuterol inhaler to use as rescue medication.	Drug: QVA149; QVA149 110/50 μg hard non-gelatin capsule, inhalation/blister once a day via SDDPI; Drug: Placebo to tiotropium; Placebo 0 mg hard gelatin capsule, inhalation/ blister once a day via HandiHaler® device; Drug: Salbutamol/albuterol; salbutamol/albuterol (containing CFC-free propellant -HFA 134a) inhaler used as rescue medication when needed.
ACTIVE_COMPARATOR: Tiotropium + placebo to QVA149; Participants received tiotropium 18 μg plus placebo to QVA149 during 1 of 3 treatment periods once a day for 6 weeks. Participants were provided with a salbutamol/albuterol inhaler to use as rescue medication.	Drug: Salbutamol/albuterol; salbutamol/albuterol (containing CFC-free propellant -HFA 134a) inhaler used as rescue medication when needed.; Drug: Tiotropium; Tiotropium 18 ug hard gelatin capsule, inhalation/ blister once a day via HandiHaler® device; Drug: Placebo to QVA149; Placebo 0 mg hard non-gelatin capsule, inhalation/ blister once a day via SDDPI
PLACEBO_COMPARATOR: Placebo; Participants received placebo to QVA149 plus placebo to tiotropium during 1 of 3 treatment periods once a day for 6 weeks. Participants were provided with a salbutamol/albuterol inhaler to use as rescue medication.	Drug: Placebo to tiotropium; Placebo 0 mg hard gelatin capsule, inhalation/ blister once a day via HandiHaler® device; Drug: Salbutamol/albuterol; salbutamol/albuterol (containing CFC-free propellant -HFA 134a) inhaler used as rescue medication when needed.; Drug: Placebo to QVA149; Placebo 0 mg hard non-gelatin capsule, inhalation/ blister once a day via SDDPI

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total Total Transient Dyspnea Index (TDI) Score After 6 Weeks of Treatment QVA149 Compared to Placebo	Total Transient Dyspnea Index (TDI) is part of the BDI/TDI questionnaire where participants indicated whether they improved or deteriorated since their Baseline Dyspnea Index (BDI). The BDI and TDI each had 3 domains: activities, tasks, and effort. BDI domains were rated from 0 (very severe) to 4 (none) and the rates summed for the total BDI score ranging from 0 to 12; the lower the score the worse the severity of dyspnea. TDI domains were rated from -6 (major deterioration) to 6 (major improvement) and the rates summed for the total TDI score ranging from -18 to 18. However, to ensure comparability with the TDI paper version, all TDI values were divided by 2 before the analysis. If data was missing or insufficient for any one of the domains a BDI/TDI was calculated. BDI = Baseline Dyspnea Index taken 75 min prior to the first dose in each treatment period. TDI = Transition Dyspnea Index taken after 6 weeks of treatment 75 min prior to the last dose in each treatment period.	Baseline and 6 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total Total Transient Dyspnea Index (TDI) Score After 6 Weeks of Treatment QVA149 Compared to Tiotropium	Total Transient Dyspnea Index (TDI) is part of the BDI/TDI questionnaire where participants indicated whether they improved or deteriorated since their Baseline Dyspnea Index (BDI). The BDI and TDI each had 3 domains: activities, tasks, and effort. BDI domains were rated from 0 (very severe) to 4 (none) and the rates summed for the total BDI score ranging from 0 to 12; the lower the score the worse the severity of dyspnea. TDI domains were rated from -6 (major deterioration) to 6 (major improvement) and the rates summed for the total TDI score ranging from -18 to 18. However, to ensure comparability with the TDI paper version, all TDI values were divided by 2 before the analysis. If data was missing or insufficient for any one of the domains a BDI/TDI was calculated. BDI = Baseline Dyspnea Index taken 75 min prior to the first dose in each treatment period. TDI = Transition Dyspnea Index taken after 6 weeks of treatment 75 min prior to the last dose in each treatment period.	Baseline and 6 weeks
Standardized Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve (AUC) 5min-4h After First Dose and 6 Weeks of Treatment With QVA149 Compared to Placebo and Tiotropium	Forced Expiratory Volume in 1 second (FEV1) was measured with spirometry conducted according to internationally accepted standards. Measurements were taken at 5 min- 4hr post-dose of day 1 and week 6. The standardized FEV1 Area under the curve (AUC) was calculated as the sum of trapezoids divided by the length of time.	5min-4hr at day 1 and week 6 post-dose
Standardized Forced Vital Capacity (FVC) Area Under the Curve (AUC) 5min-4 Hrs After First Dose and 6 Weeks of Treatment With QVA149 Compared to Placebo and Tiotropium	Forced Vital Capacity (FVC) is the total amount of air that can be exhaled by the patient after a full inhalation. The FVC was measured via spirometry conducted according to internationally accepted standards at 5 min-4 hr post dose of day 1 and week 6.	5min-4hr at day 1 and week 6 post-dose
Change From Baseline in The Capacity of Daily Living During the Morning (CDLM) Score Averaged Over 6 Weeks of Treatment	The Capacity of Daily Living during the Morning (CDLM) is a self-administered daily assessment. The CDLM asks COPD patients to (i) report their ability to carry out 6 morning activities and (ii) rate the difficulty in performing those activities on a five point Likert-type scale ranging from "not at all difficult" to "extremely difficult". For each of the six morning activities a score ranging from 0 (=so difficult that they could not carry out the activity by themselves) to 5 (not at all difficult to carry out the activity by themselves) is calculated by using the responses from the two questions for each activity. Daily CDLM is calculated using the scores average from the 6 morning activities. CDLM is calculated as the average daily CDLM score over 6 weeks of treatment. The change from baseline in CDLM score over 6 weeks is analyzed using a MIXED model with baseline CDLM score as a covariate. A CDLM score of 0.20 is considered to be a minimal clinically important difference.	Baseline and 6 weeks
Change From Baseline in the Mean Daily Number of Puffs of Rescue Medication Used Over the 6 Weeks of Treatment	The number of puffs of rescue medication taken by participants, were collected each day during the study via entries in e-diaries	Baseline and 6 weeks

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Mahler DA, Decramer M, D'Urzo A, Worth H, White T, Alagappan VK, Chen H, Gallagher N, Kulich K, Banerji D. Dual bronchodilation with QVA149 reduces patient-reported dyspnoea in COPD: the BLAZE study. Eur Respir J. 2014 Jun;43(6):1599-609. doi: 10.1183/09031936.00124013. Epub 2013 Oct 31.

Study record dates

Study Major Dates

• Study Start: October 1, 2011
• Primary Completion (ACTUAL): August 1, 2012
• Study Completion (ACTUAL): August 1, 2012

Study Registration Dates

• First Submitted: November 15, 2011
• First Submitted That Met QC Criteria: December 8, 2011
• First Posted (ESTIMATE): December 12, 2011

Study Record Updates

• Last Update Posted (ESTIMATE): December 24, 2013
• Last Update Submitted That Met QC Criteria: November 5, 2013
• Last Verified: November 1, 2013

More Information

Terms related to this study

• Keywords: COPD; Dyspnea; QVA149; tiotropium
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Respiration Disorders; Signs and Symptoms, Respiratory; Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Dyspnea; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Parasympatholytics; Autonomic Agents; Peripheral Nervous System Agents; Muscarinic Antagonists; Cholinergic Antagonists; Cholinergic Agents; Adrenergic Agonists; Adjuvants, Anesthesia; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Reproductive Control Agents; Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists; Tocolytic Agents; Albuterol; Glycopyrrolate; Tiotropium Bromide
• Other Study ID Numbers: CQVA149A2322; 2011-000229-63 (EUDRACT_NUMBER)