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

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

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.

Official Title
-----------------
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

Conditions
-----------------
Chronic Obstructive Pulmonary Disease

Intervention / Treatment
-----------------
* Drug: QVA149
* Drug: Tiotropium
* Drug: Placebo to QVA149
* Drug: Placebo to tiotropium
* Drug: Salbutamol/albuterol


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 40 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: QVA149 + placebo to tiotropium<br>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<br>* QVA149 110/50 μg hard non-gelatin capsule, inhalation/blister once a day via SDDPI<br>Drug: Placebo to tiotropium<br>* Placebo 0 mg hard gelatin capsule, inhalation/ blister once a day via HandiHaler® device<br>Drug: Salbutamol/albuterol<br>* salbutamol/albuterol (containing CFC-free propellant -HFA 134a) inhaler used as rescue medication when needed.<br>|
| Active Comparator: Tiotropium + placebo to QVA149<br>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: Tiotropium<br>* Tiotropium 18 ug hard gelatin capsule, inhalation/ blister once a day via HandiHaler® device<br>Drug: Placebo to QVA149<br>* Placebo 0 mg hard non-gelatin capsule, inhalation/ blister once a day via SDDPI<br>Drug: Salbutamol/albuterol<br>* salbutamol/albuterol (containing CFC-free propellant -HFA 134a) inhaler used as rescue medication when needed.<br>|
| Placebo Comparator: Placebo<br>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 QVA149<br>* Placebo 0 mg hard non-gelatin capsule, inhalation/ blister once a day via SDDPI<br>Drug: Placebo to tiotropium<br>* Placebo 0 mg hard gelatin capsule, inhalation/ blister once a day via HandiHaler® device<br>Drug: Salbutamol/albuterol<br>* salbutamol/albuterol (containing CFC-free propellant -HFA 134a) inhaler used as rescue medication when needed.<br>|

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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
COPD, Dyspnea, QVA149, tiotropium