Chronic Obstructive Pulmonary Disease
Conditions
Keywords
COPD
Brief summary
The purpose of this study is to further figure out differences of glycopyrronium bromide compared to tiotropium in early bronchodilation measured by a comprehensive assessment of lung function that includes hyperinflation and specific airway resistance in patients with moderate to severe COPD.
Interventions
DRUGNVA237
NVA237 44 µg inhalation capsules once daily, delivered via single-dose dry-powder inhaler (SDDPI)
DRUGTiotropium
Tiotropium 18 μg once daily delivered via HandiHaler® device.
Placebo to NVA237 once daily, delivered via single-dose dry-powder inhaler (SDDPI).
Placebo to tiotropium once daily delivered via HandiHaler® device
DRUGSalbutamol
Used as resuce medication
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female adults aged ≥40 years * Patients with moderate to severe COPD defined by a post-bronchodilator Forced Expiratory Volume in One Second (FEV1)/(FVC) Forced Vital Capacity ratio of \<0.70 and a post-bronchodilator FEV1 of ≤70% and FEV1 ≥ 30% of predicted normal values. * Current or ex-smokers who have a smoking history of at least 10 pack years.
Exclusion criteria
* Pregnant or nursing (lactating) women * Patients who have a clinically significant laboratory abnormality at run-in * Patients with narrow-angle glaucoma, symptomatic benign prostatic hyperplasia or bladder-neck obstruction or moderate to severe renal impairment (GFR \<50 ml/min/1,732) or urinary retention. (BPH patients who are stable on treatment can be considered). * Patients with any history of asthma * Patients with pulmonary lobectomy or lung volume reduction surgery or lung transplantation * Patients receiving medications in the classes listed in the protocol as prohibited. Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Forced Expiratory Volume in One Second (FEV1) Area Under Curve (AUC) 0-2 | Day 1 | Standardized Forced Expiratory Volume in One Second (FEV1) AUC0-2h will be measured via spirometry. The AUC will be calculated from the FEV1 measurements obtained at timepoints between 0 min and 2h using the trapezoidal rule and will be standardized (=divided) by the measurement time (i.e. 2h). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Specific Airway Resistance (sRAW) | Day 1 | Specific Airway Resistance (sRAW) indicates volume and resistance-dependent work of breathing needed in order to generate a reference flow rate of 1 L/s, measured by kPa\*s. Whole body plethysmography (Bodybox) is used to measure SRaw. |
| Functional Resistance Capacity (FRCpleth) | Day 1 | Functional Resistance Capacity (FRCpleth) will be measured using whole body plethysmography (Bodybox). |
| Forced Expiratory Volume in One Second (FEV1) 15 Min Post Dose | Day 1 | Forced expiratory volume in 1 second (FEV1) is the amount of air that can be exhaled in one second. FEV1 will be measured by spirometry. All spirometry calibrations and evaluations will follow the recommendations of the American Thoracic Society / European Respiratory Society guidelines for acceptability. |
| Total Lung Capacity (TLC) | Day 1 | Total Lung Capacity (TLC) is the best vital capacity plus residual volume (RV). Whole body plethysmography (Bodybox) will be used to measure TLC. |
| Inspiratory Capacity (IC) | Day 1 | Inspiratory Capacity (IC) is the volume of air breathed in by a maximum inspiration at the end of a normal expiration. Whole body plethysmography (Bodybox) will be used to measure IC. |
| Residual Volume (RV) | Day 1 | Residual Volume (RV) will be measured using whole body plethysmography (Bodybox). |
Countries
Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| NVA237 Followed by Tiotropium Period 1: NVA237 plus placebo to tiotropium on day 1, followed by a 7 day washout. Period 2: tiotropium plus placebo to NVA237 on day 8. Salbutamol was used as rescue medication. | 76 |
| Tiotropium Followed by NVA237 Period 1: tiotropium plus placebo to NVA237 on day 1, followed by a 7 day washout. Period 2: NVA237 plus placebo to tiotropium on day 8. Salbutamol was used as rescue medication. | 76 |
| Total | 152 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| WASHOUT Period | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | NVA237 Followed by Tiotropium | Tiotropium Followed by NVA237 | Total |
|---|---|---|---|
| Age, Continuous | 61.9 years STANDARD_DEVIATION 7.2 | 61.7 years STANDARD_DEVIATION 8.2 | 61.8 years STANDARD_DEVIATION 7.7 |
| Sex: Female, Male Female | 28 Participants | 26 Participants | 54 Participants |
| Sex: Female, Male Male | 48 Participants | 50 Participants | 98 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 8 / 152 | 15 / 151 |
| serious Total, serious adverse events | 2 / 152 | 2 / 151 |
Outcome results
Primary
Forced Expiratory Volume in One Second (FEV1) Area Under Curve (AUC) 0-2
Standardized Forced Expiratory Volume in One Second (FEV1) AUC0-2h will be measured via spirometry. The AUC will be calculated from the FEV1 measurements obtained at timepoints between 0 min and 2h using the trapezoidal rule and will be standardized (=divided) by the measurement time (i.e. 2h).
Time frame: Day 1
Population: The Full Analysis Set (FAS) consisted of all randomized patients who applied at least one dose of study medication during at least one study period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NVA237 | Forced Expiratory Volume in One Second (FEV1) Area Under Curve (AUC) 0-2 | 1.490 liters per hour | Standard Deviation 0.4232 |
| Tiotropium | Forced Expiratory Volume in One Second (FEV1) Area Under Curve (AUC) 0-2 | 1.453 liters per hour | Standard Deviation 0.4135 |
Secondary
Forced Expiratory Volume in One Second (FEV1) 15 Min Post Dose
Forced expiratory volume in 1 second (FEV1) is the amount of air that can be exhaled in one second. FEV1 will be measured by spirometry. All spirometry calibrations and evaluations will follow the recommendations of the American Thoracic Society / European Respiratory Society guidelines for acceptability.
Time frame: Day 1
Population: The Full Analysis Set (FAS) consisted of all randomized patients who applied at least one dose of study medication during at least one study period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NVA237 | Forced Expiratory Volume in One Second (FEV1) 15 Min Post Dose | 1.433 liters per hour | Standard Deviation 0.411 |
| Tiotropium | Forced Expiratory Volume in One Second (FEV1) 15 Min Post Dose | 1.398 liters per hour | Standard Deviation 0.4092 |
Secondary
Functional Resistance Capacity (FRCpleth)
Functional Resistance Capacity (FRCpleth) will be measured using whole body plethysmography (Bodybox).
Time frame: Day 1
Population: The Full Analysis Set (FAS) consisted of all randomized patients who applied at least one dose of study medication during at least one study period.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| NVA237 | Functional Resistance Capacity (FRCpleth) | -45 min (n=152, 150) | 5.211 Liters | Standard Deviation 1.3086 |
| NVA237 | Functional Resistance Capacity (FRCpleth) | 30 min (n=150, 151) | 4.823 Liters | Standard Deviation 1.2517 |
| NVA237 | Functional Resistance Capacity (FRCpleth) | 1 hr (n=151, 149) | 4.769 Liters | Standard Deviation 1.2571 |
| NVA237 | Functional Resistance Capacity (FRCpleth) | 1 hr 30 min (n=151, 149) | 4.756 Liters | Standard Deviation 1.2366 |
| NVA237 | Functional Resistance Capacity (FRCpleth) | 2 h 30 min (n= 150, 149) | 4.736 Liters | Standard Deviation 1.1545 |
| NVA237 | Functional Resistance Capacity (FRCpleth) | 3 h 30 min (n= 150, 148) | 4.761 Liters | Standard Deviation 1.2286 |
| Tiotropium | Functional Resistance Capacity (FRCpleth) | 2 h 30 min (n= 150, 149) | 4.676 Liters | Standard Deviation 1.2243 |
| Tiotropium | Functional Resistance Capacity (FRCpleth) | -45 min (n=152, 150) | 5.142 Liters | Standard Deviation 1.2656 |
| Tiotropium | Functional Resistance Capacity (FRCpleth) | 1 hr 30 min (n=151, 149) | 4.714 Liters | Standard Deviation 1.1523 |
| Tiotropium | Functional Resistance Capacity (FRCpleth) | 30 min (n=150, 151) | 4.852 Liters | Standard Deviation 1.1812 |
| Tiotropium | Functional Resistance Capacity (FRCpleth) | 3 h 30 min (n= 150, 148) | 4.704 Liters | Standard Deviation 1.1911 |
| Tiotropium | Functional Resistance Capacity (FRCpleth) | 1 hr (n=151, 149) | 4.725 Liters | Standard Deviation 1.1496 |
Secondary
Inspiratory Capacity (IC)
Inspiratory Capacity (IC) is the volume of air breathed in by a maximum inspiration at the end of a normal expiration. Whole body plethysmography (Bodybox) will be used to measure IC.
Time frame: Day 1
Population: The Full Analysis Set (FAS) consisted of all randomized patients who applied at least one dose of study medication during at least one study period.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| NVA237 | Inspiratory Capacity (IC) | -45 min (n=152, 150) | 2.169 Liters | Standard Deviation 0.5548 |
| NVA237 | Inspiratory Capacity (IC) | 30 min (n=150, 151) | 2.433 Liters | Standard Deviation 0.5934 |
| NVA237 | Inspiratory Capacity (IC) | 1hr (n=151, 149) | 2.455 Liters | Standard Deviation 0.6001 |
| NVA237 | Inspiratory Capacity (IC) | 1hr 30 min (n=151, 150) | 2.472 Liters | Standard Deviation 0.62 |
| NVA237 | Inspiratory Capacity (IC) | 2hr 30 min (n=150, 149) | 2.467 Liters | Standard Deviation 0.5929 |
| NVA237 | Inspiratory Capacity (IC) | 3hr 30 min (n=150, 149) | 2.479 Liters | Standard Deviation 0.6036 |
| Tiotropium | Inspiratory Capacity (IC) | 2hr 30 min (n=150, 149) | 2.474 Liters | Standard Deviation 0.6051 |
| Tiotropium | Inspiratory Capacity (IC) | -45 min (n=152, 150) | 2.193 Liters | Standard Deviation 0.5583 |
| Tiotropium | Inspiratory Capacity (IC) | 1hr 30 min (n=151, 150) | 2.457 Liters | Standard Deviation 0.5883 |
| Tiotropium | Inspiratory Capacity (IC) | 30 min (n=150, 151) | 2.422 Liters | Standard Deviation 0.5996 |
| Tiotropium | Inspiratory Capacity (IC) | 3hr 30 min (n=150, 149) | 2.449 Liters | Standard Deviation 0.5907 |
| Tiotropium | Inspiratory Capacity (IC) | 1hr (n=151, 149) | 2.435 Liters | Standard Deviation 0.5908 |
Secondary
Residual Volume (RV)
Residual Volume (RV) will be measured using whole body plethysmography (Bodybox).
Time frame: Day 1
Population: The Full Analysis Set (FAS) consisted of all randomized patients who applied at least one dose of study medication during at least one study period.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| NVA237 | Residual Volume (RV) | -45 min (n=152, 150) | 4.433 Liters | Standard Deviation 1.2596 |
| NVA237 | Residual Volume (RV) | 30 min (n=150, 151) | 3.996 Liters | Standard Deviation 1.1862 |
| NVA237 | Residual Volume (RV) | 1 hr (n=151, 149) | 3.891 Liters | Standard Deviation 1.1997 |
| NVA237 | Residual Volume (RV) | 1 hr 30 min (n=151, 149) | 3.910 Liters | Standard Deviation 1.1534 |
| NVA237 | Residual Volume (RV) | 2 h 30 min (n= 150, 149) | 3.893 Liters | Standard Deviation 1.0486 |
| NVA237 | Residual Volume (RV) | 3 h 30 min (n= 150, 148) | 3.970 Liters | Standard Deviation 1.1576 |
| Tiotropium | Residual Volume (RV) | 2 h 30 min (n= 150, 149) | 3.861 Liters | Standard Deviation 1.1058 |
| Tiotropium | Residual Volume (RV) | -45 min (n=152, 150) | 4.344 Liters | Standard Deviation 1.1707 |
| Tiotropium | Residual Volume (RV) | 1 hr 30 min (n=151, 149) | 3.903 Liters | Standard Deviation 1.0281 |
| Tiotropium | Residual Volume (RV) | 30 min (n=150, 151) | 4.035 Liters | Standard Deviation 1.0689 |
| Tiotropium | Residual Volume (RV) | 3 h 30 min (n= 150, 148) | 3.895 Liters | Standard Deviation 1.074 |
| Tiotropium | Residual Volume (RV) | 1 hr (n=151, 149) | 3.913 Liters | Standard Deviation 1.0281 |
Secondary
Specific Airway Resistance (sRAW)
Specific Airway Resistance (sRAW) indicates volume and resistance-dependent work of breathing needed in order to generate a reference flow rate of 1 L/s, measured by kPa\*s. Whole body plethysmography (Bodybox) is used to measure SRaw.
Time frame: Day 1
Population: The Full Analysis Set (FAS) consisted of all randomized patients who applied at least one dose of study medication during at least one study period.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| NVA237 | Specific Airway Resistance (sRAW) | -45 min (n=152, 150) | 4.203 kilopascal (kPa) | Standard Deviation 1.8102 |
| NVA237 | Specific Airway Resistance (sRAW) | 30 min (n=150, 151) | 2.904 kilopascal (kPa) | Standard Deviation 1.4759 |
| NVA237 | Specific Airway Resistance (sRAW) | 1 hr (n=151, 149) | 2.656 kilopascal (kPa) | Standard Deviation 1.3062 |
| NVA237 | Specific Airway Resistance (sRAW) | 1 hr 30 min (n=151, 150) | 2.632 kilopascal (kPa) | Standard Deviation 1.3152 |
| NVA237 | Specific Airway Resistance (sRAW) | 2 hr 30 min (n=150, 149) | 2.643 kilopascal (kPa) | Standard Deviation 1.3146 |
| NVA237 | Specific Airway Resistance (sRAW) | 3 hr 30 min (n=150, 149) | 2.779 kilopascal (kPa) | Standard Deviation 1.4496 |
| Tiotropium | Specific Airway Resistance (sRAW) | 2 hr 30 min (n=150, 149) | 2.756 kilopascal (kPa) | Standard Deviation 1.4091 |
| Tiotropium | Specific Airway Resistance (sRAW) | -45 min (n=152, 150) | 4.105 kilopascal (kPa) | Standard Deviation 1.8338 |
| Tiotropium | Specific Airway Resistance (sRAW) | 1 hr 30 min (n=151, 150) | 2.811 kilopascal (kPa) | Standard Deviation 1.4065 |
| Tiotropium | Specific Airway Resistance (sRAW) | 30 min (n=150, 151) | 3.089 kilopascal (kPa) | Standard Deviation 1.4555 |
| Tiotropium | Specific Airway Resistance (sRAW) | 3 hr 30 min (n=150, 149) | 2.828 kilopascal (kPa) | Standard Deviation 1.4534 |
| Tiotropium | Specific Airway Resistance (sRAW) | 1 hr (n=151, 149) | 2.877 kilopascal (kPa) | Standard Deviation 1.413 |
Secondary
Total Lung Capacity (TLC)
Total Lung Capacity (TLC) is the best vital capacity plus residual volume (RV). Whole body plethysmography (Bodybox) will be used to measure TLC.
Time frame: Day 1
Population: The Full Analysis Set (FAS) consisted of all randomized patients who applied at least one dose of study medication during at least one study period.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| NVA237 | Total Lung Capacity (TLC) | 30 min (n=150, 151) | 7.255 Liters | Standard Deviation 1.4628 |
| NVA237 | Total Lung Capacity (TLC) | -45 min (n=152, 150) | 7.380 Liters | Standard Deviation 1.4781 |
| NVA237 | Total Lung Capacity (TLC) | 2hr 30 min (n=150, 149) | 7.203 Liters | Standard Deviation 1.37 |
| NVA237 | Total Lung Capacity (TLC) | 1hr (n=151, 149) | 7.224 Liters | Standard Deviation 1.4294 |
| NVA237 | Total Lung Capacity (TLC) | 3hr 30 min (n=150, 148) | 7.240 Liters | Standard Deviation 1.4297 |
| NVA237 | Total Lung Capacity (TLC) | 1hr 30 min (n=151, 149) | 7.227 Liters | Standard Deviation 1.4383 |
| Tiotropium | Total Lung Capacity (TLC) | 3hr 30 min (n=150, 148) | 7.149 Liters | Standard Deviation 1.3963 |
| Tiotropium | Total Lung Capacity (TLC) | -45 min (n=152, 150) | 7.335 Liters | Standard Deviation 1.4328 |
| Tiotropium | Total Lung Capacity (TLC) | 30 min (n=150, 151) | 7.274 Liters | Standard Deviation 1.4032 |
| Tiotropium | Total Lung Capacity (TLC) | 1hr (n=151, 149) | 7.161 Liters | Standard Deviation 1.4015 |
| Tiotropium | Total Lung Capacity (TLC) | 1hr 30 min (n=151, 149) | 7.165 Liters | Standard Deviation 1.369 |
| Tiotropium | Total Lung Capacity (TLC) | 2hr 30 min (n=150, 149) | 7.149 Liters | Standard Deviation 1.4476 |