Efficacy, Safety, and Tolerability of NVA237 Compared to Tiotropium in Patients With Chronic Obstructive Pulmonary Disease (COPD)

Study Overview
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Brief Summary
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This study compared the efficacy and safety of NVA237 with tiotropium in patients with moderate to severe COPD. Tiotropium belongs to the same drug class as NVA237.

Detailed Description
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This was a randomized, blinded, double-dummy, parallel-group 12-week study to assess the efficacy, safety, and tolerability of NVA237 (50 μg o.d.) compared to tiotropium (18 μg o.d.) in patients with chronic obstructive pulmonary disease (COPD).

Official Title
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A 12-week Treatment, Randomized, Blinded, Double-dummy, Parallel-group Study to Assess the Efficacy, Safety, and Tolerability of NVA237 (50 µg o.d.) Compared to Tiotropium (18 µg o.d.) in Patients With Chronic Obstructive Pulmonary Disease (COPD)

Conditions
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Chronic Obstructive Pulmonary Disease

Intervention / Treatment
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* Drug: NVA237
* Drug: Tiotropium
* Drug: Placebo to tiotropium
* Drug: Placebo to NVA237
* Drug: salbutamol/albuterol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with moderate to severe stable COPD (Stage II or Stage III) according to the current GOLD Guidelines (GOLD 2010). Patients with a post-bronchodilator Forced Expiratory Volume in 1 second (FEV1) ≥ 30% and < 80% of the predicted normal, and a post-bronchodilator FEV1/ Forced Vital Capacity (FVC) < 0.70 at screening Current or ex-smokers who have a smoking history of at least 10 pack years (e.g. 10 pack years = 1 pack/day x 10 yrs, or ½ pack/day x 20 yrs). Symptomatic patients, according to daily electronic diary data between Visit 2 (Day -14) and Visit 3 (Day 1), with a total score of 1 or more on at least 4 of the last 7 days prior to Visit 3. Exclusion Criteria: Pregnant or nursing (lactating) women Patients who, in the judgment of the investigator, or the responsible Novartis personnel, have a clinically relevant laboratory abnormality or a clinically significant condition before Visit 1. Patients with narrow-angle glaucoma, symptomatic benign prostatic hyperplasia or bladder-neck obstruction or moderate to severe renal impairment or urinary retention. (BPH patients who are stable on treatment can be considered). Patients receiving medications in the classes listed in the protocol as prohibited. Other protocol-defined inclusion/exclusion criteria apply and can be found in the study protocol

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<br>NVA237 50 μg once a day and placebo to tiotropium once a day during 85 days. Salbutamol/albuterol was provided as rescue medication. | Drug: NVA237<br>* NVA237 50 μg inhalation capsules once a day, delivered via SDDPI<br>Drug: Placebo to tiotropium<br>* Placebo to tiotropium 18 μg o.d. once a day delivered via HandiHaler® device.<br>Drug: salbutamol/albuterol<br>* salbutamol/albuterol given as a rescue medication via inhaler when needed<br>|
| Active Comparator: Tiotropium<br>Tiotropium 18 μg once a day and placebo to NVA237 once a day during 85 days. Salbutamol/albuterol was provided as rescue medication. | Drug: Tiotropium<br>* Tiotropium 18 μg once a day delivered via HandiHaler® device<br>Drug: Placebo to NVA237<br>* Placebo to NVA237 50 μg once a day delivered via SDDPI<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Trough Forced Expiratory Volume in 1 Second (FEV1) After 12 Weeks of Treatment (Non-inferiority Analysis) | Forced Expiratory Volume in 1 second (FEV1) is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation, measured through spirometry testing. The trough in FEV1 was defined as the mean of two measurements at 23hours 15min and 23 hours 45min post dosing. ANCOVA model: Trough FEV1 = treatment + baseline FEV1 + baseline Inhaled corticosteroid (ICS) use (Yes/No) + FEV1 reversibility components + baseline smoking status + region + center (region). This analysis excluded values within 6 hours of rescue medication use or 7 days of systemic corticosteroid use. | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Trough Forced Expiratory Volume in 1 Second (FEV1) After 12 Weeks of Treatment (Analysis of Superiority) | FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation, measured through spirometry testing. The trough in FEV1 was defined as the mean of two measurements at 23h 15min and 23h 45min post dosing. ANCOVA model: Trough FEV1 = treatment + baseline FEV1 + baseline Inhaled corticosteroid (ICS) use (Yes/No) + FEV1 reversibility components + baseline smoking status + region + center(region). This analysis excluded values within 6 hours of rescue medication use or 7 days of systemic corticosteroid. | Week 12 | 
| Transition Dyspnea Index (TDI) Focal Score After 4 Weeks and 12 Weeks of Treatment | Transition Dyspnea Index (TDI) captures changes from baseline. The TDI score is based on three domains with each domain scored from -3 (major deterioration) to +3 (major improvement), to give an overall score of -9 to +9, a negative score indicating a deterioration from baseline. A TDI focal score of 1 is considered to be a clinically significant improvement from baseline. ANCOVA model: TDI focal score = treatment + Baseline dyspnea index (BDI) + baseline Inhaled corticosteroid (ICS) use (Yes/No) + FEV1 reversibility components + baseline smoking status + region + center(region). Center is included as a random effect nested within region. | Weeks 4 and 12 | 
| St. George's Respiratory Questionnaire Total Score After 12 Weeks of Treatment | St. George's Respiratory Questionnaire (SGRQ) is a health related quality of life questionnaire consisting of 51 items in three areas: symptoms (respiratory symptoms and severity), activity (activities that cause or are limited by breathlessness) and impacts (social functioning and psychological disturbances due to airway disease). The total score is 0 to 100 with a higher score indicating poorer health status. ANCOVA model: SGRQ total score = treatment + baseline SGRQ score + baseline ICS use (Yes/No) + FEV1 reversibility components + baseline smoking status + region + center (region). | Week 12 | 
| Change From Baseline in Mean Daily Number of Puffs of Rescue Medication Used Over the 12 Week Treatment | A day with no rescue medication use is defined from the diary data as any day where the patient recorded no rescue medicine use during the previous 12 hours. Baseline mean daily, daytime and nighttime (combined) number of puffs is defined as the average of the respective number of puffs. Only patients with a value at both baseline and post-baseline visits were included. | Baseline and Day 1 to Week 12 | 
| Trough Forced Expiratory Volume in 1 Second (FEV1) at Day 1 and Week 4 | FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation, measured through spirometry testing. Trough FEV1 is defined as the average of the post-dose 23 h 15 min and the 23 h 45 min FEV1 values. Trough assessments taken outside 22 h 45 min - 24 h 15 min are excluded from this analysis. ANCOVA model: Trough FEV1 = treatment + baseline FEV1 + baseline Inhaled corticosteroid (ICS) use (Yes/No) + FEV1 reversibility components + baseline smoking status + region + center(region). Center is included as a random effect nested within region. | Day 1 and Week 4 | 
| Peak Forced Expiratory Volume in 1 Second (FEV1) During 5 Min to 4 Hours Post-dose, at Day 1 and Week 12 | Spirometry was conducted according to internationally accepted standards. Peak FEV1 is the maximum FEV1 recorded during first 4 hours post dose. ANCOVA model: Peak FEV1 = treatment + baseline FEV1 + baseline Inhaled corticosteroid (ICS) use (Yes/No) + FEV1 reversibility components + baseline smoking status + region + center (region). Center is included as a random effect nested within region. This analysis excludes values within 6 hours of rescue medication use or 7 days of systemic corticosteroid use. | 5 min to 4 hours post-dose at Day 1 and Week 12 | 
| Inspiratory Capacity (IC) at Each Time-point, by Visit | IC was measured with spirometry conducted according to internationally accepted standards. ANCOVA model: IC = treatment + baseline IC + baseline Inhaled corticosteroid (ICS) use (Yes/No) + FEV1 reversibility components + baseline smoking status + region + center(region). Center is included as a random effect nested within region. | (25 min, 1 h 55 min, 3 h 55 min, 23 h 40 min Day 1), (-20 min, 25 min, 23 h 40 min Week 4),(-20 min, 25 min, 1 h 55 min, 3 h 55 min, 23 h 40 min Week 12) | 
| Forced Expiratory Volume in 1 Second (FEV1) at Each Time-point by Visit | Forced Expiratory Volume in 1 second (FEV1) is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. FEV1 was analyzed using Analysis of Covariance (ANCOVA) model: FEV1 = treatment + baseline FEV1 + baseline Inhaled corticosteroid (ICS) use (Yes/No) + FEV1 reversibility components + baseline smoking status + region + center(region). Center is included as a random effect nested within region. | (5,15,30 min, 1, 2,3,4 h, 23h 15 min and 23h 45 min postdose of Day 1), (-45, -15 min predose, 5,15,30 min, 1h, 23h 15 min and 23h 45 min postdose of Week 4), (-45, -15 min predose, 5,15,30 min, 1, 2, 3,4 h, 23h 15 min and 23h 45 min postdose of Week 12) | 
| Forced Vital Capacity (FVC) at Each Time-point by Visit | Forced Vital Capacity (FVC) is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. FVC was assessed via spirometry. ANCOVA model: FVC = treatment + baseline FVC + baseline Inhaled corticosteroid (ICS) use (Yes/No) + FEV1 reversibility components + baseline smoking status + region + center(region). Center is included as a random effect nested within region. | (5,15,30 min, 1, 2,3,4 h, 23h 15 min and 23h 45 min postdose of Day 1), (-45, -15 min predose, 5,15,30 min, 1h, 23h 15 min and 23h 45 min postdose of Week 4), (-45, -15 min predose, 5,15,30 min, 1, 2, 3,4 h, 23h 15 min and 23h 45 min postdose of Week 12) | 
| Standardized Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) (5 Min-4 h) Post-dose | Forced Expiratory Volume in one second (FEV1) was measured with spirometry conducted according to internationally accepted standards. Area Under the Curve (AUC) is calculated using the trapezoidal rule using the existing FEV1 measurements (i.e., the missing FEV1 measurements are not interpolated). ANCOVA model: FEV1 AUC = treatment + baseline FEV1 + baseline Inhaled corticosteroid (ICS) use (Yes/No) + FEV1 reversibility components + baseline smoking status + region + center(region). Center is included as a random effect nested within region. | Day 1 and week 12 | 
| Event Free Rate at Weeks 4, 8 and 12 After Treatment | Event free rate was calculated as a percentage of participants who did not experience any moderate or severe COPD exacerbation leading to hospitalization/treatment with systemic corticosteroids/treatment with antibiotics. The event free rate reflects the percent of patients who did NOT have an exacerbation by 4, 8 and 12 weeks. Event-free rates are calculated at the end of the specified weeks (i.e. Day 29, Day 57 and Day 85) by the Kaplan Meier method. | Weeks 4, 8 and 12 | 
| Mean Daily, Daytime and Nighttime (Combined) Symptom Scores Over the 12 Week Treatment Period | Participants completed eDiaries providing scores 0 to 3 for symptoms: Cough and wheeze (none, mild, moderate, severe); sputum volume (none, less than 5 mL, 5-25 mL, >25 mL); sputum color (none, white-grey, yellow, green); lowest level of activity causing breathlessness (never or only when running, when walking uphill or upstairs, when walking on flat ground, at rest). Symptoms in the morning, for the previous night (no waking due to symptoms, woke up once due to symptoms, woke up more than once due to symptoms, woke up frequently or could not sleep due to symptoms). Symptoms experienced during the day that had prevented them for performing normal activities (not at all, a little, quite a lot, completely). The mean change from baseline in the total scores and in the individual scores was summarized by treatment. Only participants with a value at both baseline and post-baseline were included. Possible total scores 0-18 (night); 0-36 (day). A higher score means worsening of symptoms. | 12 weeks | 

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