Efficacy, Tolerability and Safety of NVA237 in Patients With Chronic Obstructive Pulmonary Disease

Study Overview
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Brief Summary
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This study will assess the efficacy, tolerability and safety of NVA237 compared to tiotropium when added on to fluticasone/salmeterol in patients with chronic obstructive pulmonary disease.

Official Title
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A Multicenter, Randomized, Blinded, Active-controlled, Parallel-group Study to Compare the Efficacy, Tolerability and Safety of NVA237 Compared to Tiotropium Added on to Fluticasone/Salmeterol in Patients With Chronic Obstructive Pulmonary Disease

Conditions
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Chronic Obstructive Pulmonary Disease

Intervention / Treatment
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* Drug: NVA237 50µg once daily
* Drug: Tiotropium 18µg once daily
* Drug: Flu/Sal
* Drug: NVA237 placebo + Tiotropium placebo.


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with Moderate to Severe COPD (Stage II or Stage III) according to the GOLD 2010 guideline Current or ex-smokers who have a smoking history of at least 10 pack years Qualifying FEV1 at Visit 2 (day -7) Exclusion Criteria: Patients with a history of asthma or a history of high blood eosinophil count (>600/mm³) Patients with concomitant pulmonary disease Patients with lung lobectomy or lung volume reduction or lung transplantation Patients with α-1 antitrypsin deficiency Patients who have had live attenuated vaccinations within 30 days prior to screening visit or during run-in period Other protocol-defined inclusion/exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NVA237 + Fluticasone/Salmeterol (Flu/Sal)<br>NVA237 50 µg once daily (NVA237 + Tiotropium placebo + Flu/Sal). NVA237 50 μg o.d., delivered via single-dose dry-powder inhaler (SDDPI) o.d. plus Placebo to tiotropium o.d. delivered via a proprietary inhalation device plus Flu/Sal 500/50 μg b.i.d. delivered via a proprietary inhalation device. In addition, at Visit 1, all participants were provided with a short acting β2-agonist (salbutamol) which they were instructed to use throughout the study as rescue medication. | Drug: NVA237 50µg once daily<br>* NVA237 50 μg o.d., delivered via single-dose dry-powder inhaler (SDDPI)<br>Drug: Flu/Sal<br>* Flu/Sal 500/50 μg b.i.d. delivered via a proprietary inhalation device<br>Drug: NVA237 placebo + Tiotropium placebo.<br>* Tiotropium 18 μg o.d. delivered via a proprietary inhalation device<br>|
| Active Comparator: Tiotropium + Flu/Sal<br>Tiotropium 18µg once daily (NVA237 placebo + Tiotropium + Flu/Sal). Tiotropium 18 μg o.d. delivered via a proprietary inhalation device plus Placebo to NVA237 o.d. delivered via single-dose dry-powder inhaler (SDDPI) plus Flu/Sal 500/50 μg b.i.d. delivered via a proprietary inhalation device. In addition, at Visit 1, all participants were provided with a short acting β2-agonist (salbutamol) which they were instructed to use throughout the study as rescue medication. | Drug: Tiotropium 18µg once daily<br>* Tiotropium 18 μg o.d. delivered via a proprietary inhalation device<br>Drug: Flu/Sal<br>* Flu/Sal 500/50 μg b.i.d. delivered via a proprietary inhalation device<br>Drug: NVA237 placebo + Tiotropium placebo.<br>* Tiotropium 18 μg o.d. delivered via a proprietary inhalation device<br>|
| Placebo Comparator: Flu/Sal<br>Placebo (NVA237 placebo + Tiotropium placebo + Flu/Sal). Placebo to tiotropium o.d. delivered via a proprietary inhalation device plus Placebo to NVA237 o.d. delivered via single-dose dry-powder inhaler (SDDPI) plus Flu/Sal 500/50 μg b.i.d. delivered via a proprietary inhalation device. In addition, at Visit 1, all participants were provided with a short acting β2-agonist (salbutamol) which they were instructed to use throughout the study as rescue medication. | Drug: Flu/Sal<br>* Flu/Sal 500/50 μg b.i.d. delivered via a proprietary inhalation device<br>Drug: NVA237 placebo + Tiotropium placebo.<br>* Tiotropium 18 μg o.d. delivered via a proprietary inhalation device<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Mean Trough Forced Expiratory Volume in 1 Second (FEV1) (NVA237 Versus Tiotropium) | Spirometry was conducted according to internationally accepted standards. Trough FEV1 referred to the mean of FEV1 at 23:15 hours and 23:45 hours after the morning dose of study drug. The baseline was defined as the average of FEV1 values taken in the clinic 45 min and 15 min prior to the first dose of randomized treatment at Visit 3. A mixed model was used and contained treatment as a fixed effect with the baseline measurement of trough FEV1, FEV1 prior to inhalation of short acting bronchodilators, and FEV1 post-inhalation of bronchodilators and stratification factors as covariates. A positive change from baseline indicates improvement. | baseline, 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Mean Trough FEV1 (Flu/Sal Versus NVA237/Tiotropium+Flu/Sal) | Spirometry was conducted according to internationally accepted standards. Trough FEV1 referred to the mean of FEV1 at 23:15h and 23:45h after the morning dose of study drug. The baseline was defined as the average of FEV1 values taken in the clinic 45min and 15min prior to the first dose of randomized treatment at Visit 3. A mixed model was used and contained treatment as a fixed effect with the baseline measurement of trough FEV1, FEV1 prior to inhalation of short acting bronchodilators, and FEV1 post-inhalation of bronchodilators and stratification factors as covariates. A positive change from baseline indicates improvement. | baseline, 4 weeks, 8 weeks, 12 weeks | 
| Change From Baseline in Mean Trough FEV1 | Spirometry was conducted according to internationally accepted standards. Trough FEV1 referred to the mean of FEV1 at 23:15h and 23:45h after the morning dose of study drug. The baseline was defined as the average of FEV1 values taken in the clinic 45min and 15min prior to the first dose of randomized treatment at Visit 3. A mixed model was used and contained treatment as a fixed effect with the baseline measurement of trough FEV1, FEV1 prior to inhalation of short acting bronchodilators, and FEV1 post-inhalation of bronchodilators and stratification factors as covariates. A positive change from baseline indicates improvement. | baseline, 4 weeks, 8 weeks, 12 weeks | 
| Change From Baseline in Total Score of the St George's Respiratory Questionnaire for COPD Patients (SGRQ-C) After 12 Weeks of Treatment | SGRQ-C is a health related quality of life questionnaire consisting of 40 items divided into two components: 1) symptoms, 2) activity& impacts. The lowest possible value is zero and the highest is 100. Higher values corresponded to greater impairment in quality of life. An analysis model included terms for treatment, baseline total SGRQ score, FEV1 and baseline smoking status. The model also contained as fixed effects the baseline total SGRQ score, FEV1 prior to inhalation of short acting bronchodilator, FEV1 post inhalation of short acting bronchodilator and stratification factors as covariates. A negative change from baseline indicates improvement. | 12 weeks | 
| Change From Baseline in the Mean Daily Number of Puffs of Rescue Medication Use | The total number of puffs of rescue medication used over the last 12 h recorded in the morning (nighttime use) and in the evening (daytime use) over the full 12 weeks was divided by the total number of days with non-missing rescue data to derive the mean daytime and nighttime number of puffs of rescue medication. Change from baseline in the mean daytime and nighttime number of puffs of rescue medication was analyzed as for the change from baseline in the mean daily number of puffs of rescue medication. | baseline, 12 weeks | 
| Mean Percentage of Nights With 'no Nighttime Awakenings' | A night with 'no nighttime awakenings' is defined from diary data as any night where patient did not wake up due to symptoms. Total number of nights with 'no nighttime awakenings' over treatment period was divided by total number of nights where diary recordings have been made in order to derive percentage of 'no nighttime awakenings' which will be summarized by treatment and analyzed using a similar mixed model as specified for primary analysis. Diary data recorded during the 7 day run-in period was used to calculate baseline percentage of nights 'no nighttime awakenings'. | 12 weeks | 
| Mean Percentage of Days With Performance of Usual Activities | A 'day able to perform usual daily activities' was defined from diary data as any day where the patient was not prevented from performing their usual daily activities due to respiratory symptoms. The percentage of 'days able to perform usual daily activities' was derived and analyzed using a similar mixed model as specified for primary analysis as for the percentage of nights with 'no nighttime awakenings'. | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Obstructive Pulmonary Disease,, NVA 237,, glycopyrronium,, COPD