Asthma
Conditions
Keywords
asthma,, NVA237,, glycopyrronium bromide, allergic asthma,, allergy triggered asthma,, reactive asthma,, asthma attack,, difficulty breathing
Brief summary
The purpose of this trial is to characterize the bronchodilator effects and safety of 25 ug and 50 ug o.d. NVA237 (glycopyrronium bromide) doses compared to placebo in asthma patients
Detailed description
This study uses a randomized, double-blind, placebo controlled, 3-period cross-over clinical trial design. During a screening epoch patient eligibility will be assessed. The screening epoch will be followed by a 21-day Run-in epoch during which patients will continue their inhaled corticosteroids use but be withdrawn from LABA-treatment and switched to short-acting bronchodilator-rescue medication. After the Run-in period patients will be randomized to one of the 6 treatment sequences and enter the first 7-day study treatment period. Treatment period one is followed by a 10 to 14 days washout period after which patients begin the second 7-day treatment period which is then followed by a second 10 to 14 days washout period followed by the third 7-day treatment period. At the end of each treatment period spirometry will be performed to assess the primary endpoint in terms of trough FEV1. The study population will consist of approximately 144 patients with asthma who have been treated in a stable regimen of ICS/LABA for at least 4 weeks prior to screening.
Interventions
DRUGNVA237 (glycopyrronium bromide)
In each treatment arm, patient will receive NVA237 (glycopyrronium bromide) 25 ug and 50 ug dose
DRUGPlacebo
In each treatment arm, patient will receive placebo
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Male and female adult patients aged \>= 18 or =\< 65 years * Patients with a diagnosis of asthma for a period of at least 1 year receiving daily treatment of ICS/LABA in a stable regimen for \>= 4 weeks * Pre-bronchodilator FEV1 of \>= 50% and =\< 80% of the predicted normal value and an increase in FEV1 of 12% and \>= 200 ml during reversibility testing Key
Exclusion criteria
* Patients who have had an asthma exacerbation that required either treatment with systemic corticosteroids for at least 3 days, or an emergency room visit, or hospital treatment within 6 weeks prior to screening and patients with a history of life-threatening asthma attacks * Patients who have had a respiratory tract infection within 4 weeks prior to screening. * Patients who have smoked or inhaled tobacco products within the past 6 month of screening. * Patients with a history of chronic lung diseases other than asthma, including (but not limited to) chronic obstructive pulmonary disease, bronchiectasis, sarcoidosis, interstitial lung disease, cystic fibrosis, and tuberculosis (unless tuberculosis is confirmed as no longer active by imaging). * Patients on Maintenance Immunotherapy (desensitization) for allergies for at least 3 months prior to Run-in who are expected to change therapy throughout the course of the study. * Patients who during the Run-in period are shown to be intolerable to LABA withdrawal. * Patients who have discontinued LAMA therapy in the past (e.g. due to intolerance or perceived lack of efficacy).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Trough FEV1 After One Week of Treatment, Point Estimate | Following 1 week of treatment | To evaluate the bronchodilator effects of NVA237 (25 ug and 50 ug) compared to placebo in terms of trough FEV1 (mean of 23h 15 min and 23 h 45 min post -dose) following 1 week of treatment in the respective treatment period. Trough FEV1 was assessed by performing spirometry measurements in the clinic for each treatment period. For the primary efficacy variable, trough FEV1 is the mean of two measurements taken at 23h 15 min and 23h 45 min post dose. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| FEV1 AUC (5 Min-4 h) After One Week of Treatment | Following 1 week of treatment | To evaluate the bronchodilator effects of NVA237 (25 ug and 50 ug) compared with placebo in terms of Standardized FEV1 AUC following 1 week of treatment in the respective treatment period. FEV1 was measured with spirometry conducted according to internationally accepted standards. The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time over an entire day (AUC 5min-4h) |
| FEV1 AUC (5 Min - 23 h 45 Min) After One Week of Treatment | Following 1 week of treatment | To evaluate the bronchodilator effects of NVA237 (25 ug and 50 ug) compared with placebo in terms of Standardized FEV1 AUC following 1 week of treatment in the respective treatment period. FEV1 was measured with spirometry conducted according to internationally accepted standards. The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time over an entire day AUC (5 min - 23 h 45 min) |
| Peak FEV1 During 4 Hours Post-dose After 1 Week of Treatment | Following 1 week of treatment | To evaluate the bronchodilator effects of NVA237 (25 ug and 50 ug) compared with placebo in terms of Peak FEV1 following 1 week of treatment in the respective treatment period. FEV1 was measured with spirometry conducted according to internationally accepted standards. The peak effect following 1 week of treatment was defined as the maximum FEV1 during the first 4 hour on that day. |
| Trough Forced Vital Capacity (FVC) After 1 Week of Treatment | Following 1 week of treatment | To evaluate the bronchodilator effects of NVA237 (25 ug and 50 ug) compared with placebo in terms of FVC following 1 week of treatment in respective treatment period. Trough Forced Vital Capacity (FVC) following 7 Days. 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 |
| FEV1 AUC (5 Min-1 h) After One Week of Treatment | Following 1 week of treatment | To evaluate the bronchodilator effects of NVA237 (25 ug and 50 ug) compared with placebo in terms of Standardized FEV1 AUC following 1 week of treatment in the respective treatment period. FEV1 was measured with spirometry conducted according to internationally accepted standards. The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time over an entire day (AUC 5min-1h) |
| Mean Morning Peak Expiratory Flow (PEF) Following the 1-week Treatment Period | Following 1 week of treatment | A Peak Expiratory Flow (PEF) meter was distributed to patients at Visit 1, to be used to measure PEF twice-daily as directed. During the Screening and Treatment Periods, PEF was measured in the morning and evening every day. the morning PEF was performed within 15 minutes after waking, and the evening PEF approximately 12 hours later. Patients were encouraged to perform morning and evening PEF measurements before the use of any LABA or rescue medication. The highest of 3 values was recorded as the daily personal best. The personal best was used to calculate the mean morning PEF and mean evening PEF value |
| Mean Evening Peak Expiratory Flow Rate (PEF) Following 1-week Treatment | Following 1 week of treatment | A Peak Expiratory Flow (PEF) meter was distributed to patients at Visit 1, to be used to measure PEF twice-daily as directed. During the Screening and Treatment Periods, PEF was measured in the morning and evening every day. the morning PEF was performed within 15 minutes after waking, and the evening PEF approximately 12 hours later. Patients were encouraged to perform morning and evening PEF measurements before the use of any LABA or rescue medication. The highest of 3 values was recorded as the daily personal best. The personal best was used to calculate the mean morning PEF and mean evening PEF value collected between assessment Visits. LS Mean of change from baseline in mean morning PEF is calculated with the ANCOVA model using treatment, stratification group, dosing schedule, gender, center grouping, smoking status, and baseline mean morning PEF as covariates |
| Mean Daily Number of Puffs of Rescue Medication During 1 Week of Treatment | Following 1 week of 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. daytime and nighttime (combined) number of puffs is defined as the average of the respective number of puffs. |
| Percent Change From Baseline in FEV1/FVC Ratio | Following 1 week of treatment | To evaluate the bronchodilator effects of NVA237 (25 ug and 50 ug) compared with placebo in terms of FEV1/FVC ratio following 1 week of treatment in respective treatment period |
Countries
Belgium, Germany, Japan, Latvia, Lithuania, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Participants All participants randomized to one of six treatment sequences | 148 |
| Total | 148 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Non-compliance with study treatment | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Subject/guardian decision | 1 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous | 47.3 Years STANDARD_DEVIATION 11.8 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 16 Participants |
| Race (NIH/OMB) Black or African American | 12 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 120 Participants |
| Sex: Female, Male Female | 75 Participants |
| Sex: Female, Male Male | 73 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 147 | 1 / 146 | 0 / 146 |
| other Total, other adverse events | 10 / 147 | 11 / 146 | 11 / 146 |
| serious Total, serious adverse events | 1 / 147 | 1 / 146 | 0 / 146 |
Outcome results
Primary
Trough FEV1 After One Week of Treatment, Point Estimate
To evaluate the bronchodilator effects of NVA237 (25 ug and 50 ug) compared to placebo in terms of trough FEV1 (mean of 23h 15 min and 23 h 45 min post -dose) following 1 week of treatment in the respective treatment period. Trough FEV1 was assessed by performing spirometry measurements in the clinic for each treatment period. For the primary efficacy variable, trough FEV1 is the mean of two measurements taken at 23h 15 min and 23h 45 min post dose.
Time frame: Following 1 week of treatment
Population: The Full Analysis Set (FAS) consisted of all patients in the randomized Set (RAN) who received at least one dose of study medication. Following the intent-to-treat principle, patients in the FAS were analyzed according to the treatment they were randomized to in the assigned treatment sequence.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| NVA237 50 ug | Trough FEV1 After One Week of Treatment, Point Estimate | 2.392 Liters | Standard Error 0.0249 |
| NVA237 25 ug | Trough FEV1 After One Week of Treatment, Point Estimate | 2.392 Liters | Standard Error 0.025 |
| Placebo | Trough FEV1 After One Week of Treatment, Point Estimate | 2.303 Liters | Standard Error 0.0247 |
p-value: <0.00195% CI: [0.047, 0.132]Linear Mixed Model
p-value: <0.00195% CI: [0.047, 0.132]Linear Mixed Model
Secondary
FEV1 AUC (5 Min-1 h) After One Week of Treatment
To evaluate the bronchodilator effects of NVA237 (25 ug and 50 ug) compared with placebo in terms of Standardized FEV1 AUC following 1 week of treatment in the respective treatment period. FEV1 was measured with spirometry conducted according to internationally accepted standards. The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time over an entire day (AUC 5min-1h)
Time frame: Following 1 week of treatment
Population: The Full Analysis Set (FAS) consisted of all patients in the randomized Set (RAN) who received at least one dose of study medication. Following the intent-to-treat principle, patients in the FAS were analyzed according to the treatment they were randomized to in the assigned treatment sequence.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| NVA237 50 ug | FEV1 AUC (5 Min-1 h) After One Week of Treatment | 2.489 Liters | Standard Error 0.0226 |
| NVA237 25 ug | FEV1 AUC (5 Min-1 h) After One Week of Treatment | 2.492 Liters | Standard Error 0.0228 |
| Placebo | FEV1 AUC (5 Min-1 h) After One Week of Treatment | 2.324 Liters | Standard Error 0.0227 |
p-value: <0.00195% CI: [0.127, 0.203]Linear Mixed Model
p-value: <0.00195% CI: [0.129, 0.206]Linear Mixed Model
Secondary
FEV1 AUC (5 Min - 23 h 45 Min) After One Week of Treatment
To evaluate the bronchodilator effects of NVA237 (25 ug and 50 ug) compared with placebo in terms of Standardized FEV1 AUC following 1 week of treatment in the respective treatment period. FEV1 was measured with spirometry conducted according to internationally accepted standards. The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time over an entire day AUC (5 min - 23 h 45 min)
Time frame: Following 1 week of treatment
Population: The Full Analysis Set (FAS) consisted of all patients in the randomized Set (RAN) who received at least one dose of study medication. Following the intent-to-treat principle, patients in the FAS were analyzed according to the treatment they were randomized to in the assigned treatment sequence.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| NVA237 50 ug | FEV1 AUC (5 Min - 23 h 45 Min) After One Week of Treatment | 2.443 Liters | Standard Error 0.0226 |
| NVA237 25 ug | FEV1 AUC (5 Min - 23 h 45 Min) After One Week of Treatment | 2.450 Liters | Standard Error 0.0227 |
| Placebo | FEV1 AUC (5 Min - 23 h 45 Min) After One Week of Treatment | 2.304 Liters | Standard Error 0.0226 |
p-value: <0.00195% CI: [0.106, 0.173]Linear Mixed Model
p-value: <0.00195% CI: [0.112, 0.179]Linear Mixed Model
Secondary
FEV1 AUC (5 Min-4 h) After One Week of Treatment
To evaluate the bronchodilator effects of NVA237 (25 ug and 50 ug) compared with placebo in terms of Standardized FEV1 AUC following 1 week of treatment in the respective treatment period. FEV1 was measured with spirometry conducted according to internationally accepted standards. The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time over an entire day (AUC 5min-4h)
Time frame: Following 1 week of treatment
Population: The Full Analysis Set (FAS) consisted of all patients in the randomized Set (RAN) who received at least one dose of study medication. Following the intent-to-treat principle, patients in the FAS were analyzed according to the treatment they were randomized to in the assigned treatment sequence.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| NVA237 50 ug | FEV1 AUC (5 Min-4 h) After One Week of Treatment | 2.522 Liters | Standard Error 0.0223 |
| NVA237 25 ug | FEV1 AUC (5 Min-4 h) After One Week of Treatment | 2.525 Liters | Standard Error 0.0224 |
| Placebo | FEV1 AUC (5 Min-4 h) After One Week of Treatment | 2.346 Liters | Standard Error 0.0223 |
p-value: <0.00195% CI: [0.141, 0.212]Linear Mixed Model
p-value: <0.00195% CI: [0.144, 0.215]Linear Mixed Model
Secondary
Mean Daily Number of Puffs of Rescue Medication During 1 Week of 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. daytime and nighttime (combined) number of puffs is defined as the average of the respective number of puffs.
Time frame: Following 1 week of treatment
Population: The Full Analysis Set (FAS) consisted of all patients in the randomized Set (RAN) who received at least one dose of study medication. Following the intent-to-treat principle, patients in the FAS were analyzed according to the treatment they were randomized to in the assigned treatment sequence
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| NVA237 50 ug | Mean Daily Number of Puffs of Rescue Medication During 1 Week of Treatment | 0.98 Puffs/day | Standard Error 0.094 |
| NVA237 25 ug | Mean Daily Number of Puffs of Rescue Medication During 1 Week of Treatment | 1.02 Puffs/day | Standard Error 0.094 |
| Placebo | Mean Daily Number of Puffs of Rescue Medication During 1 Week of Treatment | 1.13 Puffs/day | Standard Error 0.094 |
p-value: 0.05395% CI: [-0.31, 0]Linear Mixed Model
p-value: 0.16395% CI: [-0.27, 0.05]Linear Mixed Model
Secondary
Mean Evening Peak Expiratory Flow Rate (PEF) Following 1-week Treatment
A Peak Expiratory Flow (PEF) meter was distributed to patients at Visit 1, to be used to measure PEF twice-daily as directed. During the Screening and Treatment Periods, PEF was measured in the morning and evening every day. the morning PEF was performed within 15 minutes after waking, and the evening PEF approximately 12 hours later. Patients were encouraged to perform morning and evening PEF measurements before the use of any LABA or rescue medication. The highest of 3 values was recorded as the daily personal best. The personal best was used to calculate the mean morning PEF and mean evening PEF value collected between assessment Visits. LS Mean of change from baseline in mean morning PEF is calculated with the ANCOVA model using treatment, stratification group, dosing schedule, gender, center grouping, smoking status, and baseline mean morning PEF as covariates
Time frame: Following 1 week of treatment
Population: The Full Analysis Set (FAS) consisted of all patients in the randomized Set (RAN) who received at least one dose of study medication. Following the intent-to-treat principle, patients in the FAS were analyzed according to the treatment they were randomized to in the assigned treatment sequence
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| NVA237 50 ug | Mean Evening Peak Expiratory Flow Rate (PEF) Following 1-week Treatment | 409.66 L/min | Standard Error 2.928 |
| NVA237 25 ug | Mean Evening Peak Expiratory Flow Rate (PEF) Following 1-week Treatment | 408.08 L/min | Standard Error 2.934 |
| Placebo | Mean Evening Peak Expiratory Flow Rate (PEF) Following 1-week Treatment | 378.72 L/min | Standard Error 2.949 |
p-value: <0.00195% CI: [25.07, 36.82]Linear Mixed Model
p-value: <0.00195% CI: [23.47, 35.26]Linear Mixed Model
Secondary
Mean Morning Peak Expiratory Flow (PEF) Following the 1-week Treatment Period
A Peak Expiratory Flow (PEF) meter was distributed to patients at Visit 1, to be used to measure PEF twice-daily as directed. During the Screening and Treatment Periods, PEF was measured in the morning and evening every day. the morning PEF was performed within 15 minutes after waking, and the evening PEF approximately 12 hours later. Patients were encouraged to perform morning and evening PEF measurements before the use of any LABA or rescue medication. The highest of 3 values was recorded as the daily personal best. The personal best was used to calculate the mean morning PEF and mean evening PEF value
Time frame: Following 1 week of treatment
Population: The Full Analysis Set (FAS) consisted of all patients in the randomized Set (RAN) who received at least one dose of study medication. Following the intent-to-treat principle, patients in the FAS were analyzed according to the treatment they were randomized to in the assigned treatment sequence
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| NVA237 50 ug | Mean Morning Peak Expiratory Flow (PEF) Following the 1-week Treatment Period | 395.09 L/min | Standard Error 2.948 |
| NVA237 25 ug | Mean Morning Peak Expiratory Flow (PEF) Following the 1-week Treatment Period | 393.87 L/min | Standard Error 2.962 |
| Placebo | Mean Morning Peak Expiratory Flow (PEF) Following the 1-week Treatment Period | 369.58 L/min | Standard Error 2.958 |
p-value: <0.00195% CI: [19.22, 31.79]Linear Mixed Model
p-value: <0.00195% CI: [17.99, 30.59]Linear Mixed Model
Secondary
Peak FEV1 During 4 Hours Post-dose After 1 Week of Treatment
To evaluate the bronchodilator effects of NVA237 (25 ug and 50 ug) compared with placebo in terms of Peak FEV1 following 1 week of treatment in the respective treatment period. FEV1 was measured with spirometry conducted according to internationally accepted standards. The peak effect following 1 week of treatment was defined as the maximum FEV1 during the first 4 hour on that day.
Time frame: Following 1 week of treatment
Population: The Full Analysis Set (FAS) consisted of all patients in the randomized Set (RAN) who received at least one dose of study medication. Following the intent-to-treat principle, patients in the FAS were analyzed according to the treatment they were randomized to in the assigned treatment sequence
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| NVA237 50 ug | Peak FEV1 During 4 Hours Post-dose After 1 Week of Treatment | 2.621 Liters | Standard Error 0.0228 |
| NVA237 25 ug | Peak FEV1 During 4 Hours Post-dose After 1 Week of Treatment | 2.630 Liters | Standard Error 0.0229 |
| Placebo | Peak FEV1 During 4 Hours Post-dose After 1 Week of Treatment | 2.457 Liters | Standard Error 0.0228 |
p-value: <0.00195% CI: [0.127, 0.201]Linear Mixed Model
p-value: <0.00195% CI: [0.137, 0.211]Linear Mixed Model
Secondary
Percent Change From Baseline in FEV1/FVC Ratio
To evaluate the bronchodilator effects of NVA237 (25 ug and 50 ug) compared with placebo in terms of FEV1/FVC ratio following 1 week of treatment in respective treatment period
Time frame: Following 1 week of treatment
Population: The Full Analysis Set (FAS) consisted of all patients in the randomized Set (RAN) who received at least one dose of study medication. Following the intent-to-treat principle, patients in the FAS were analyzed according to the treatment they were randomized to in the assigned treatment sequence
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NVA237 50 ug | Percent Change From Baseline in FEV1/FVC Ratio | 0.018 Percent change | Standard Deviation 0.0421 |
| NVA237 25 ug | Percent Change From Baseline in FEV1/FVC Ratio | 0.016 Percent change | Standard Deviation 0.0438 |
| Placebo | Percent Change From Baseline in FEV1/FVC Ratio | 0.003 Percent change | Standard Deviation 0.0398 |
Secondary
Trough Forced Vital Capacity (FVC) After 1 Week of Treatment
To evaluate the bronchodilator effects of NVA237 (25 ug and 50 ug) compared with placebo in terms of FVC following 1 week of treatment in respective treatment period. Trough Forced Vital Capacity (FVC) following 7 Days. 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
Time frame: Following 1 week of treatment
Population: The Full Analysis Set (FAS) consisted of all patients in the randomized Set (RAN) who received at least one dose of study medication. Following the intent-to-treat principle, patients in the FAS were analyzed according to the treatment they were randomized to in the assigned treatment sequence
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| NVA237 50 ug | Trough Forced Vital Capacity (FVC) After 1 Week of Treatment | 3.509 Liters | Standard Error 0.0268 |
| NVA237 25 ug | Trough Forced Vital Capacity (FVC) After 1 Week of Treatment | 3.530 Liters | Standard Error 0.0269 |
| Placebo | Trough Forced Vital Capacity (FVC) After 1 Week of Treatment | 3.472 Liters | Standard Error 0.0267 |
p-value: 0.07995% CI: [-0.004, 0.077]Linear Mixed Model
p-value: 0.00695% CI: [0.017, 0.099]Linear Mixed Model