Efficacy and Safety of QMF149 vs. Salmeterol Xinafoate/Fluticasone Propionate in Patients With Chronic Obstructive Pulmonary Disease (COPD)

Study Overview
=================
Brief Summary
-----------------
To compare the efficacy, safety and pharmacokinetics of QMF149 delivered via Concept1 to salmeterol xinafoate/fluticasone propionate delivered via Accuhaler in adult patients with COPD

Official Title
-----------------
A Randomized, Double-blind, 12-week Treatment, Parallel-group Study to Evaluate the Efficacy and Safety of QMF149 (150 µg/160 µg o.d.) Compared With Salmeterol Xinafoate/Fluticasone Propionate (50 µg/500 µg b.i.d.) in Patients With Chronic Obstructive Pulmonary Disease

Conditions
-----------------
COPD

Intervention / Treatment
-----------------
* Drug: QMF149
* Drug: Salmeterol


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients with moderate to very severe COPD (GOLD 2 to GOLD 4) according to the 2011 Global Initiative for Chronic Obstructive Lung Disease (GOLD) Guidelines Patients with a post-bronchodilator FEV1 < 70% of the predicted normal, and a post-bronchodilator FEV1/FVC < 0.70 at run-in (Visit 101). Current or ex-smokers who have a smoking history of at least 10 pack years (defined as the number of packs of 20 cigarettes smoked per day multiplied by number of years the patient smoked. e.g.10 pack years = 1 pack /day x 10 yrs, or ½ pack/day x 20 yrs). An ex-smoker may be defined as a subject who has not smoked for ≥ 6 months at screening. Exclusion Criteria: Patients who have had a COPD exacerbation that required treatment with antibiotics and/or oral corticosteroids and/or hospitalization in the 6 weeks prior to screening (Visit 1). Patients who develop a COPD exacerbation between screening (Visit 1) and treatment (Visit 201) will not be eligible but will be permitted to be re-screened after a minimum of 6 weeks after the resolution of the COPD exacerbation. Patients who have had a respiratory tract infection within 4 weeks prior to screening Visit 1. Patients who develop a respiratory tract infection between screening (Visit 1) and treatment (Visit 201) will not be eligible, but will be permitted to be re-screened 4 weeks after the resolution of the respiratory tract infection. Patients requiring long term oxygen therapy prescribed for >12 hours per day. Patients with, a) any history of asthma or, b) onset of respiratory symptoms prior to age 40 years. 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: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: QMF149<br>QMF149 (Indacaterol acetate/Mometasone furoate) 150/160 µg o.d. delivered via Concept1 device | Drug: QMF149<br>* delivered via Concept1 device<br>|
| Active Comparator: Salmeterol xinafoate/fluticasone propionate<br>Salmeterol xinafoate/fluticasone propionate 50/500 µg b.i.d, delivered via Accuhaler® | Drug: Salmeterol<br>* delivered via Accuhaler®<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mixed Model for Repeated Measures (MMRM): Between-treatment Comparisons for Trough FEV1 (L) on Day 85 | Spirometry is conducted according to the global standard. Trough FEV1 is defined as the average of the 23 hour 10 minute and 23 hour 45 minute post dose FEV1 readings. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patient Reported Outcome Measures: SGRQ (St. George's Respiratory Questionnaire) | A Total and three component scores are calculated: Symptoms; Activity; Impacts. Each component of the questionnaire is scored separately:The score for each component is calculated separately by dividing the summed weights by the maximum possible weight for that component and expressing the result as a percentage: Score = 100 x Summed weights from all positive items in that component divided by Sum of weights for all items in that component The Total score is calculated in similar way: Score = 100 x Summed weights from all positive items in the questionnaire divided by Sum of weights for all items in the questionnaire Sum of maximum possible weights for each component and Total: Symptoms 566.2 Activity 982.9 Impacts 1652.8 Total (sum of maximum for all three components) 3201.9 The proportion of patients who achieve a clinically important improvement of at least 4 units in the total SGRQ will be analyzed. The higher the score the more symptoms of disease are present. | 4 and 12 weeks | 
| Analysis of the Proportion of Subjects With a Clinically Important Improvement of >=1 Point in the TDI (Transitional Dyspnoea Index)Focal Score by Visit | A TDI focal score of ≥1 is considered to be a clinically important improvement from baseline. Analysis of the proportion of subjects with a clinically important improvement of >=1 point in the TDI focal score, by visit | 4 and 12 weeks | 
| Patient Reported Outcome Measures: COPD Assessment Test | It consists of eight items, each presented as a semantic 6-point differential scale, providing a total score out of 40. A higher score indicates a worse health status. Scores of 0 - 10, 11 - 20, 21 - 30 and 31 - 40 represent a mild, moderate, severe or very severe clinical impact of COPD upon the patient. | Baseline, 4 and 12 weeks | 
| Patient Reported Outcome Measures: Medical Outcome Study (MOS) Sleep Scale: Without Quantity Subscale | Scoring the MOS Sleep Survey is a two-step process:• All items are scored so that a high score reflects more of the attribute implied by the scale name. Each item is converted to a 0 to 100 possible range so that the lowest and highest possible scores are set at 0 and 100, respectively. In this format, scores represent the achieved percentage of the total possible score. For example, a score of 50 represents 50% of the highest possible score. • Second, items within each scale are averaged together to create the 7 scale scores. Scales with at least one item answered can be used to generate a scale score. Items that are left blank (missing data) are not taken into account when calculating the scale scores. Scores represent the average for all items in the scale that the respondent answered. An additional measure is based on the average number of hours sleep each night during the past 4 weeks and are described in outcome measure 15. | Baseline, 4 and 12 weeks | 
| Patient Reported Outcome Measures: Medical Outcome Study (MOS) Sleep Scale: Sleep Quantity Subscale | The sleep quantity subscale,which refers to question 2 of the PRO: On average, how many hours did you sleep each night during the past 4 weeks. More hours of sleep indicate better outcome. | Baseline, 4 and 12 weeks | 
| Summary Statistics of COPD Exacerbations over12 Weeks as Defined by Chronic Pulmonary Disease Tool (EXACT) | The EXACT is a 14-item electronic questionnaire designed to detect the frequency, severity, and duration of exacerbations in patients with COPD. | 12 weeks | 
| Time to First COPD Exacerbation | Time-to-event variables will be analyzed by the Kaplan-Meier estimates and the stratified Cox proportional hazard model by smoking status and COPD severity. The model will include treatment and country as factors, and FEV1 prior to inhalation and FEV1 15 min post inhalation of salbutamol/albuterol as covariates. The reported measure will detail the percentage of participants that were event free of a specified event. | 12 weeks | 
| Annual Rate of COPD Exacerbations | Time-to-event variables will be analyzed by the Kaplan-Meier estimates and the stratified Cox proportional hazard model by smoking status and COPD severity. The model will include treatment and country as factors, and FEV1 prior to inhalation and FEV1 15 min post inhalation of salbutamol/albuterol as covariates. | 12 weeks | 
| Duration (in Days) of COPD Exacerbations | Duration and number of the COPD exacerbation will be analyzed by the negative binomial regression model including treatment, country, smoking status, and COPD severity as factors and FEV1 prior to inhalation and FEV1 15 min post inhalation of salbutamol/albuterol as covariates. | 12 weeks | 
| Percentage of Patients With at Least One Exacerbation up to Week 12 | Time-to-event variables will be analyzed by the Kaplan-Meier estimates and the stratified Cox proportional hazard model by smoking status and COPD severity. The model will include treatment and country as factors, and FEV1 prior to inhalation and FEV1 15 min post inhalation of salbutamol/albuterol as covariates. The reported measure will detail the percentage of participants that had an exacerbation up to week 12. Less exacerbations reflect a better outcome. | 12 weeks | 
| Time (in Days) to Permanent Study Discontinuation Due to COPD Exacerbation | Time-to-event variables will be analyzed by the Kaplan-Meier estimates and the stratified Cox proportional hazard model by smoking status and COPD severity. The model will include treatment and country as factors, and FEV1 prior to inhalation and FEV1 15 min post inhalation of salbutamol/albuterol as covariates. | 12 weeks | 
| The Percentage of Patients Who Permanently Discontinued Due to COPD Exacerbation | Time-to-event variables will be analyzed by the Kaplan-Meier estimates and the stratified Cox proportional hazard model by smoking status and COPD severity. The model will include treatment and country as factors, and FEV1 prior to inhalation and FEV1 15 min post inhalation of salbutamol/albuterol as covariates. | 12 weeks | 
| Total Amount (in Doses) of Systemic Corticosteroid Used to Treat COPD Exacerbation During the 12 Week Treatment Period | Total amount (in doses) of systemic corticosteroid used to treat COPD exacerbation will be summarized descriptively by treatment group per each systemic corticosteroid. | 12 weeks | 
| Plasma Cortisol Concentrations at Each Timepoint | Plasma cortisol to be measured in a subset of approximately 60 patients via central laboratory. Blood sample for Plasma cortisol is collected at pre-dose and post dose up to 4 hour on Day 1, up to 12 hours post-dose on Day 28 and Day 84, and 23 hour 35 minute on Day 2, Day 29, and Day 85, and at pre-dose 25 minute on Day 28, and Day 84. | Day 1, Day 28, Day 84 | 
| Plasma Drug Concentrations (Pharmacokinetics) at Each Timepoint | Plasma indacaterol and mometasone furoate is to be measured in a subset of approximately 60 patients via central laboratory. Blood samples are collected at pre-dose on Day 1, 29, and 84; and post dose up to 4 hour on Day 1, up to 12 hours on Day 28 and 84. For sparse pharmacokinetic testing, blood samples will be collected at 23h 35 min post-dose following morning dose administration on Day 28 and 84, in all patients participating in this study. | Day 1, 29, 84 | 
| Pharmacokinetic Parameter: Cmax | Maximum observed plasma concentration after drug administration is to be measured in a subset of approximately 60 patients via central laboratory, and will be determined for indacaterol and MF following morning dosing on Days 28 and 84. | Day 28, 84 | 
| Pharmacokinetic Parameter--Tmax | Time to reach the maximum plasma concentration after drug administration is to be measured in a subset of approximately 60 patients via central laboratory, and will be determined for indacaterol and MF following morning dosing on Days 28 and 84. | Day 28, 84 | 
| Pharmacokinetic Parameter--AUC0-t | Area under the plasma concentration time curve from time zero to time t post-dose is to be measured in a subset of approximately 60 patients via central laboratory, and will be determined for indacaterol and MF following morning dosing on Days 28 and 84. | Day 28, 84 | 
| Trough FEV1 After First Dose and After 4 Weeks of Treatment | Spirometry is conducted according to the global standard. FEV1 is measured at pre-dose and post dose up to 1 hours on Day 1 and Day 28; 24 hours post-dose on Day 29 and 85. In a subset of approximately 60 patients, FEV1 is measured up to 20 hours postdose on Day 28 and Day 84. | Day 1 and Day 85 | 
| Mixed Model for Repeated Measures (MMRM): Between-treatment Comparisons for FEV1 (L), by Visit and Timepoint |  | Day 1 through day 85 | 
| Forced Vital Capacity (FVC) at Each Timepoint | Spirometry is conducted according to the global standard. FVC is measured at pre-dose and post dose up to 4 hour on Day 1, Day 28, and Day 84, at post dose 12 hour, 23 hour 10 minute and 23 hour 45 minutes on Day 2 and Day 29, and at pre-dose 50 min and 15 min on Day 2, Day 28, and Day 84. | Day 1, Day 2, Day 28, Day , Day 29, Day 84, Day 85 | 
| FEV1/FVC at Each Timepoint | Spirometry is conducted according to the global standard. FEV1/FVC is measured at pre-dose and post dose up to 4 hour on Day 1, Day 28, and Day 84, at post dose 12 hour, 23 hour 10 minute and 23 hour 45 minutes on Day 2 and Day 29, and at pre-dose 50 min and 15 min on Day 2, Day 28, and Day 84. | Day 1, Day 2, Day 28, Day , Day 29, Day 84, Day 85 | 
| FEV1 (L) on Day 1 Between-treatment Comparisons of AUC (5min - 4h) | Spirometry is conducted according to the global standard. FEV1 AUC (5 min-4 h), Scheduled (not actual) time points are to be used. The standardized AUC(5 min - 4 h) for FEV1 will be summarized by treatment. | Day 1 | 
| FEV1 AUC (5 Min-4 h), | Spirometry is conducted according to the global standard. FEV1 AUC (5 min-4 h), (5 min-24 h) is measured after the first dose on Day 1 and on Day 28 and Day 84 in a subset of approximately 60 patients. Scheduled (not actual) time points are to be used. The interpretation of FEV1 at time 0 is the baseline value at the randomization visit and the latest pre-dose value (-50 min or -15 min) at subsequent visits. The standardized AUC(5 min - 4 h) for FEV1 will be summarized by treatment. The same will be repeated for standardized AUC for FEV1 between 5 min and 24 hours post morning dose. | Day 1(Baseline), Day 28, Day 84 | 
| Mixed Model for Repeated Measures (MMRM): Between-treatment Comparisons for AUC (5 Min - 23 h 45 Min) for FEV1 (L) on Day 28 and Day 84 (Full Analysis Set, 24-h Profiling Subgroup) | Spirometry is conducted according to the global standard. FEV1 AUC (5 min-4 h), (5 min-24 h) is measured after the first dose on Day 1 and on Day 28 and Day 84 in a subset of approximately 60 patients. Scheduled (not actual) time points are to be used. The interpretation of FEV1 at time 0 is the baseline value at the randomization visit and the latest pre-dose value (-50 min or -15 min) at subsequent visits. The standardized AUC(5 min - 4 h) for FEV1 will be summarized by treatment. The same will be repeated for standardized AUC for FEV1 between 5 min and 24 hours post morning dose. | Day 28, Day 84 | 
| The Usage of Rescue Medication (Short Acting β2-agonist) | Participants record the number of puffs of rescue medication taken in the previous 12 hours each morning and evening throughout the 12 week treatment period. | 12 weeks | 
| The Overall Change in Usage of Rescue Medication (Short Acting β2-agonist) . | This value represents the percent of days in the study where no rescue medication was needed. | Baseline to 12 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
COPD