Chronic Obstructive Pulmonary Disease
Conditions
Keywords
NVA237, COPD, bronchodilator, exercise endurance
Brief summary
The ability for patients with COPD to exercise is limited due to the deterioration of their lung function. NVA237 is being developed to treat COPD. This study is designed to look at how well NVA237 improves the ability to exercise in patients with moderate to severe COPD.
Interventions
DRUGNVA237
50 μg via NEOHALER inhaler device single dose dry powder inhaler (SDDPI) once daily
DRUGPlacebo
Matching placebo via NEOHALER inhaler device single dose dry powder inhaler (SDDPI) once daily
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients who signed an Informed Consent Form prior to initiation of any study-related procedure * Patients with moderate to severe stable COPD (clinical diagnosis in compliance with GOLD 2008) * Current or ex-smokers with a smoking history ≥ 10 pack years. (Ten pack-years were defined as 20 cigarettes a day for 10 years, or 10 cigarettes a day for 20 years etc.). * Patients with a post-bronchodilator FEV1 ≥ 40 and \< 70% of the predicted normal, and postbronchodilator FEV1/FVC \< 0.7 during screening. (Post referred to the highest post-bronchodilator value after inhalation of 80 μg ipratropium bromide) * Increase in FEV1 from pre- to post-bronchodilator assessment of ≥ 5%
Exclusion criteria
* Pregnant women or nursing mothers * Women of child-bearing potential * Patients who had a COPD exacerbation (whether hospitalized or not) in the 6 weeks prior to Visit 1 or between Visit 1 and Visit 4 * Patients who had a lower respiratory tract infection in the 6 weeks prior to Visit 1 * Patients requiring long term oxygen therapy on a daily basis for chronic hypoxemia * Patients with resting (5 min) oxygen SaO2 (or SpO2) saturation on room air of \< 85% * Patients with a maximum workload (Wmax) value \< 20 W (as determined by the incremental cycle endurance test) at Visit 2. * Patients whose exercise endurance time at sub-maximal workload was above 25 min at baseline * Patients with a clinically significant abnormality on the screening or baseline ECG who in the judgment of the investigator would have been at potential risk if enrolled into the study * Patients with a history of long QT syndrome or whose QTc was prolonged (\> 450 ms for males and \> 470 ms females) at screening (Fredericia's correction) Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Exercise Endurance Time During a Sub-maximal Constant-load Cycle Ergometry Test (SMETT) After 3 Weeks (Day 21) of Treatment | Day 21 | SMETT is an exercise procedure where the patient cycles at 80% of the maximum workload (Wmax )value achieved at the Incremental exercise test. During this test, the patient will cycle at a constant load. Exercise endurance time was from commencement of loaded pedaling to stopping exercise. The analysis-of covariance model included the sequence, period, and treatment as fixed factors, the baseline value as covariate and the patient as a random effect. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Inspiratory Capacity (IC) at Rest (1 Hour Post Dose) and at Peak (End of Exercise) During Sub-maximal Constant-load Cycle Ergometry Test (SMETT) After 3 Weeks of Treatment | Day 21 | IC at peak was observed using spirometry. However, two different methodologies (whole body plethysmography (Bodybox) and spirometry) were used to observe IC at rest. The analysis of covariance model included the sequence, period, and treatment as fixed factors, the baseline value as covariate and the patient as a random effect. |
| Peak and Trough (24 h Post Dose) Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) | Day 21 | FEV1 is the amount of air that can be exhaled in one second. FEV1 was measured with spirometry conducted according to internationally accepted standards. FVC is the volume of air that can forcibly be blown out after full inspiration and is used in spirometry tests. The trough effects of Day 1 treatment are derived from values prior to morning dosing on the next treatment day (Day 2 of the corresponding period). The analysis-of covariance model included the sequence, period, and treatment as fixed factors, the baseline value as covariate and the patient as a random effect. |
| Slow Vital Capacity (SVC) and Total Lung Capacity (TLC) | Day 21 | Vital Capacity is the amount of air that can be forcibly exhaled from the lungs after a full inhalation. Slow Vital Capacity (SVC) test is performed by having the patient slowly and completely blow out all of the air from their lungs. Total Lung Capacity (TLC) is the best vital capacity plus residual volume. Whole body plethysmography (Bodybox) was used to measure SVC and TLC. The trough effects of Day 1 treatment are derived from values prior to morning dosing on the next treatment day (Day 2 of the corresponding period). |
| Isotime Inspiratory Capacity (IC) During Sub-maximal Constant-load Cycle Ergometry Test (SMETT) After 3 Weeks of Treatment | Day 21 | Isotime is the last matching timepoint in the submaximal exercise tolerance test (SMETT) at which for both periods the patient has a test result. The analysis-of covariance model included the sequence, period, and treatment as fixed factors, the baseline value as covariate and the patient as a random effect. |
| Exertional Dyspnea (Borg CR10 Scale) During Sub-maximal Constant-load Cycle Ergometry Test (SMETT) After 3 Weeks Treatment | Day 21 | The Borg CR10 Scale consists of 12-point score that the patients pointed to so as to indicate their level of dyspnea before and during exercise testing (where 0 indicates no breathlessness at all and 12 indicates maximum breathlessness). A reduction in this score indicates an improvement. The analysis-of covariance model included the sequence, period, and treatment as fixed factors, the baseline value as covariate and the patient as a random effect. |
| Leg Discomfort (Borg CR10 Scale) During Sub-maximal Constant-load Cycle Ergometry Test (SMETT) After 3 Weeks Treatment | Day 21 | The modified Borg CR10 Scale consists of 12-point score that the patients pointed to so as to indicate their level of leg discomfort before and during exercise testing (where 0 indicates no breathlessness at all and 12 indicates maximum breathlessness). A reduction in this score indicates an improvement. The analysis-of covariance model included the sequence, period, and treatment as fixed factors, the baseline value as covariate and the patient as a random effect. |
| Exercise Endurance Time During a Sub-maximal Constant-load Cycle Ergometry Test (SMETT) on Treatment Day 1 | Day 1 | SMETT is an exercise procedure where the patient cycles at 80% of the maximum workload (Wmax )value achieved at the Incremental exercise test. During this test, the patient will cycle at a constant load. Exercise endurance time was from commencement of loaded pedaling to stopping exercise. The analysis-of covariance model included the sequence, period, and treatment as fixed factors, the baseline value as covariate and the patient as a random effect. |
| Specific Airways Conductance (SGaw) | Day 21 | SGaw is a measure of how hard it is to get air into the lungs, measured by (Sec(-1)\*kP). Whole body plethysmography (Bodybox) was used to measure SGaw. The analysis-of covariance model included the sequence, period, and treatment as fixed factors, the baseline value as covariate and the patient as a random effect. |
Countries
Germany, Italy, Romania, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| NVA237 Followed by Placebo Period 1: 50 μg NVA237 via NEOHALER inhaler device for 21 days.
Period 2: Matching placebo via NEOHALER inhaler device for 21 days
The washout period ran for 14 to 28 days between treatment periods. Daily inhaled corticosteroid treatment (if applicable) was allowed to remain stable throughout the study.
Salbutamol (albuterol) was used as rescue medication throughout the study. | 55 |
| Placebo Followed by NVA237 Period 1: Matching placebo of NVA237 via NEOHALER inhaler device for 21 days
Period 2: 50 μg NVA237 via NEOHALER inhaler device for 21 days.
The washout period ran for 14 to 28 days between treatment periods. Daily inhaled corticosteroid treatment (if applicable) was allowed to remain stable throughout the study.
Salbutamol (albuterol) was used as rescue medication throughout the study. | 53 |
| Total | 108 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 1 (21 Days) | Adverse Event | 3 | 4 |
| Period 1 (21 Days) | Withdrawal by Subject | 0 | 2 |
| Period 2 (21 Days) | Protocol Deviation | 0 | 1 |
| Washout (14 - 28 Days) | Abnormal Test Procedure | 1 | 0 |
| Washout (14 - 28 Days) | Adverse Event | 2 | 0 |
Baseline characteristics
| Characteristic | NVA237 Followed by Placebo | Placebo Followed by NVA237 | Total |
|---|---|---|---|
| Age Continuous | 61.3 years STANDARD_DEVIATION 8.5 | 59.7 years STANDARD_DEVIATION 8.78 | 60.5 years STANDARD_DEVIATION 8.64 |
| Sex: Female, Male Female | 25 Participants | 20 Participants | 45 Participants |
| Sex: Female, Male Male | 30 Participants | 33 Participants | 63 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 102 | 0 / 102 |
| serious Total, serious adverse events | 1 / 102 | 0 / 102 |
Outcome results
Primary
Exercise Endurance Time During a Sub-maximal Constant-load Cycle Ergometry Test (SMETT) After 3 Weeks (Day 21) of Treatment
SMETT is an exercise procedure where the patient cycles at 80% of the maximum workload (Wmax )value achieved at the Incremental exercise test. During this test, the patient will cycle at a constant load. Exercise endurance time was from commencement of loaded pedaling to stopping exercise. The analysis-of covariance model included the sequence, period, and treatment as fixed factors, the baseline value as covariate and the patient as a random effect.
Time frame: Day 21
Population: Pharmacodynamics (PD) set consisted of participants who completed at least one treatment period, had an evaluable PD assessment on Day 21 of this period and had no major protocol deviation impacting the primary PD assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| NVA237 | Exercise Endurance Time During a Sub-maximal Constant-load Cycle Ergometry Test (SMETT) After 3 Weeks (Day 21) of Treatment | 505.63 seconds |
| Placebo | Exercise Endurance Time During a Sub-maximal Constant-load Cycle Ergometry Test (SMETT) After 3 Weeks (Day 21) of Treatment | 416.70 seconds |
Secondary
Exercise Endurance Time During a Sub-maximal Constant-load Cycle Ergometry Test (SMETT) on Treatment Day 1
SMETT is an exercise procedure where the patient cycles at 80% of the maximum workload (Wmax )value achieved at the Incremental exercise test. During this test, the patient will cycle at a constant load. Exercise endurance time was from commencement of loaded pedaling to stopping exercise. The analysis-of covariance model included the sequence, period, and treatment as fixed factors, the baseline value as covariate and the patient as a random effect.
Time frame: Day 1
Population: Pharmacodynamics (PD) set consisted of participants who completed at least one treatment period, had an evaluable PD assessment on Day 21 of this period and had no major protocol deviation impacting the primary PD assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| NVA237 | Exercise Endurance Time During a Sub-maximal Constant-load Cycle Ergometry Test (SMETT) on Treatment Day 1 | 490.92 Seconds |
| Placebo | Exercise Endurance Time During a Sub-maximal Constant-load Cycle Ergometry Test (SMETT) on Treatment Day 1 | 447.78 Seconds |
Secondary
Exertional Dyspnea (Borg CR10 Scale) During Sub-maximal Constant-load Cycle Ergometry Test (SMETT) After 3 Weeks Treatment
The Borg CR10 Scale consists of 12-point score that the patients pointed to so as to indicate their level of dyspnea before and during exercise testing (where 0 indicates no breathlessness at all and 12 indicates maximum breathlessness). A reduction in this score indicates an improvement. The analysis-of covariance model included the sequence, period, and treatment as fixed factors, the baseline value as covariate and the patient as a random effect.
Time frame: Day 21
Population: Pharmacodynamics (PD) set consisted of participants who completed at least one treatment period, had an evaluable PD assessment on Day 21 of this period and had no major protocol deviation impacting the primary PD assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| NVA237 | Exertional Dyspnea (Borg CR10 Scale) During Sub-maximal Constant-load Cycle Ergometry Test (SMETT) After 3 Weeks Treatment | 5.64 units on a scale |
| Placebo | Exertional Dyspnea (Borg CR10 Scale) During Sub-maximal Constant-load Cycle Ergometry Test (SMETT) After 3 Weeks Treatment | 6.80 units on a scale |
Secondary
Inspiratory Capacity (IC) at Rest (1 Hour Post Dose) and at Peak (End of Exercise) During Sub-maximal Constant-load Cycle Ergometry Test (SMETT) After 3 Weeks of Treatment
IC at peak was observed using spirometry. However, two different methodologies (whole body plethysmography (Bodybox) and spirometry) were used to observe IC at rest. The analysis of covariance model included the sequence, period, and treatment as fixed factors, the baseline value as covariate and the patient as a random effect.
Time frame: Day 21
Population: Pharmacodynamics (PD) set consisted of participants who completed at least one treatment period, had an evaluable PD assessment on Day 21 of this period and had no major protocol deviation impacting the primary PD assessment. n indicates number of participants with observation at each time-point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| NVA237 | Inspiratory Capacity (IC) at Rest (1 Hour Post Dose) and at Peak (End of Exercise) During Sub-maximal Constant-load Cycle Ergometry Test (SMETT) After 3 Weeks of Treatment | IC at peak (Spirometry), Day 21 (n = 93, 90) | 2.22 Litres |
| NVA237 | Inspiratory Capacity (IC) at Rest (1 Hour Post Dose) and at Peak (End of Exercise) During Sub-maximal Constant-load Cycle Ergometry Test (SMETT) After 3 Weeks of Treatment | IC at rest (Bodybox) Day 21 (n= 97, 96) | 2.49 Litres |
| NVA237 | Inspiratory Capacity (IC) at Rest (1 Hour Post Dose) and at Peak (End of Exercise) During Sub-maximal Constant-load Cycle Ergometry Test (SMETT) After 3 Weeks of Treatment | IC at rest (Spirometry), Day 21 (n= 98, 96) | 2.39 Litres |
| Placebo | Inspiratory Capacity (IC) at Rest (1 Hour Post Dose) and at Peak (End of Exercise) During Sub-maximal Constant-load Cycle Ergometry Test (SMETT) After 3 Weeks of Treatment | IC at peak (Spirometry), Day 21 (n = 93, 90) | 2.03 Litres |
| Placebo | Inspiratory Capacity (IC) at Rest (1 Hour Post Dose) and at Peak (End of Exercise) During Sub-maximal Constant-load Cycle Ergometry Test (SMETT) After 3 Weeks of Treatment | IC at rest (Bodybox) Day 21 (n= 97, 96) | 2.26 Litres |
| Placebo | Inspiratory Capacity (IC) at Rest (1 Hour Post Dose) and at Peak (End of Exercise) During Sub-maximal Constant-load Cycle Ergometry Test (SMETT) After 3 Weeks of Treatment | IC at rest (Spirometry), Day 21 (n= 98, 96) | 2.17 Litres |
Secondary
Isotime Inspiratory Capacity (IC) During Sub-maximal Constant-load Cycle Ergometry Test (SMETT) After 3 Weeks of Treatment
Isotime is the last matching timepoint in the submaximal exercise tolerance test (SMETT) at which for both periods the patient has a test result. The analysis-of covariance model included the sequence, period, and treatment as fixed factors, the baseline value as covariate and the patient as a random effect.
Time frame: Day 21
Population: Pharmacodynamics (PD) set consisted of participants who completed at least one treatment period, had an evaluable PD assessment on Day 21 of this period and had no major protocol deviation impacting primary the PD assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| NVA237 | Isotime Inspiratory Capacity (IC) During Sub-maximal Constant-load Cycle Ergometry Test (SMETT) After 3 Weeks of Treatment | 2.22 Liters |
| Placebo | Isotime Inspiratory Capacity (IC) During Sub-maximal Constant-load Cycle Ergometry Test (SMETT) After 3 Weeks of Treatment | 2.02 Liters |
Secondary
Leg Discomfort (Borg CR10 Scale) During Sub-maximal Constant-load Cycle Ergometry Test (SMETT) After 3 Weeks Treatment
The modified Borg CR10 Scale consists of 12-point score that the patients pointed to so as to indicate their level of leg discomfort before and during exercise testing (where 0 indicates no breathlessness at all and 12 indicates maximum breathlessness). A reduction in this score indicates an improvement. The analysis-of covariance model included the sequence, period, and treatment as fixed factors, the baseline value as covariate and the patient as a random effect.
Time frame: Day 21
Population: Pharmacodynamics (PD) set consisted of participants who completed at least one treatment period, had an evaluable PD assessment on Day 21 of this period and had no major protocol deviation impacting the primary PD assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| NVA237 | Leg Discomfort (Borg CR10 Scale) During Sub-maximal Constant-load Cycle Ergometry Test (SMETT) After 3 Weeks Treatment | 6.21 units on a scale |
| Placebo | Leg Discomfort (Borg CR10 Scale) During Sub-maximal Constant-load Cycle Ergometry Test (SMETT) After 3 Weeks Treatment | 7.05 units on a scale |
Secondary
Peak and Trough (24 h Post Dose) Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC)
FEV1 is the amount of air that can be exhaled in one second. FEV1 was measured with spirometry conducted according to internationally accepted standards. FVC is the volume of air that can forcibly be blown out after full inspiration and is used in spirometry tests. The trough effects of Day 1 treatment are derived from values prior to morning dosing on the next treatment day (Day 2 of the corresponding period). The analysis-of covariance model included the sequence, period, and treatment as fixed factors, the baseline value as covariate and the patient as a random effect.
Time frame: Day 21
Population: Pharmacodynamics (PD) set consisted of participants who completed at least one treatment period, had an evaluable PD assessment on Day 21 of this period and had no major protocol deviation impacting the primary PD assessment.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| NVA237 | Peak and Trough (24 h Post Dose) Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) | FEV1 at peak, Day 21 | 1.60 Litres |
| NVA237 | Peak and Trough (24 h Post Dose) Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) | FEV1 at trough, Day 21 | 1.44 Litres |
| NVA237 | Peak and Trough (24 h Post Dose) Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) | FVC at peak, Day 21 | 3.37 Litres |
| NVA237 | Peak and Trough (24 h Post Dose) Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) | FVC at trough, Day 21 | 3.17 Litres |
| Placebo | Peak and Trough (24 h Post Dose) Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) | FVC at trough, Day 21 | 2.96 Litres |
| Placebo | Peak and Trough (24 h Post Dose) Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) | FEV1 at peak, Day 21 | 1.35 Litres |
| Placebo | Peak and Trough (24 h Post Dose) Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) | FVC at peak, Day 21 | 3.00 Litres |
| Placebo | Peak and Trough (24 h Post Dose) Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) | FEV1 at trough, Day 21 | 1.33 Litres |
Secondary
Slow Vital Capacity (SVC) and Total Lung Capacity (TLC)
Vital Capacity is the amount of air that can be forcibly exhaled from the lungs after a full inhalation. Slow Vital Capacity (SVC) test is performed by having the patient slowly and completely blow out all of the air from their lungs. Total Lung Capacity (TLC) is the best vital capacity plus residual volume. Whole body plethysmography (Bodybox) was used to measure SVC and TLC. The trough effects of Day 1 treatment are derived from values prior to morning dosing on the next treatment day (Day 2 of the corresponding period).
Time frame: Day 21
Population: Pharmacodynamics (PD) set consisted of participants who completed at least one treatment period, had an evaluable PD assessment on Day 21 of this period and had no major protocol deviation impacting the primary PD assessment. n indicates number of participants with observation at each time-point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| NVA237 | Slow Vital Capacity (SVC) and Total Lung Capacity (TLC) | SVC at trough, Day 21 (n= 98, 96) | 3.21 Litres |
| NVA237 | Slow Vital Capacity (SVC) and Total Lung Capacity (TLC) | SVC at peak, Day 21 (n= 97, 96) | 3.40 Litres |
| NVA237 | Slow Vital Capacity (SVC) and Total Lung Capacity (TLC) | TLC at trough, Day 21 (n= 98, 96) | 6.99 Litres |
| NVA237 | Slow Vital Capacity (SVC) and Total Lung Capacity (TLC) | TLC at peak, Day 21 (n= 97, 96) | 6.86 Litres |
| Placebo | Slow Vital Capacity (SVC) and Total Lung Capacity (TLC) | TLC at peak, Day 21 (n= 97, 96) | 7.10 Litres |
| Placebo | Slow Vital Capacity (SVC) and Total Lung Capacity (TLC) | SVC at trough, Day 21 (n= 98, 96) | 3.14 Litres |
| Placebo | Slow Vital Capacity (SVC) and Total Lung Capacity (TLC) | TLC at trough, Day 21 (n= 98, 96) | 7.17 Litres |
| Placebo | Slow Vital Capacity (SVC) and Total Lung Capacity (TLC) | SVC at peak, Day 21 (n= 97, 96) | 3.14 Litres |
Secondary
Specific Airways Conductance (SGaw)
SGaw is a measure of how hard it is to get air into the lungs, measured by (Sec(-1)\*kP). Whole body plethysmography (Bodybox) was used to measure SGaw. The analysis-of covariance model included the sequence, period, and treatment as fixed factors, the baseline value as covariate and the patient as a random effect.
Time frame: Day 21
Population: Pharmacodynamics (PD) set consisted of participants who completed at least one treatment period, had an evaluable PD assessment on Day 21 of this period and had no major protocol deviation impacting the primary PD assessment.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| NVA237 | Specific Airways Conductance (SGaw) | SGaw at trough, Day 21 (n= 98, 96) | 0.48 litres/(Second*kpa); kpa = kilopascal |
| NVA237 | Specific Airways Conductance (SGaw) | SGaw at peak, Day 21 (n= 97, 96) | 0.66 litres/(Second*kpa); kpa = kilopascal |
| Placebo | Specific Airways Conductance (SGaw) | SGaw at trough, Day 21 (n= 98, 96) | 0.40 litres/(Second*kpa); kpa = kilopascal |
| Placebo | Specific Airways Conductance (SGaw) | SGaw at peak, Day 21 (n= 97, 96) | 0.42 litres/(Second*kpa); kpa = kilopascal |