Bronchodilator Effects and Safety of Glycopyrronium Bromide (25 ug and 50 ug o.d.) in Asthma

Study Overview
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Brief Summary
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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
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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will be followed by a 21-day Run-in epoch during which patients will continue their inhaled corticosteroids use but be withdrawn from LABA-treatment and switched to short-acting bronchodilator-rescue medication.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.

Official Title
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A Multicenter, Randomized, Double-blind, Placebo-controlled 3-period Complete Cross-over Study to Assess the Bronchodilator Effects and Safety of Glycopyrronium Bromide (NVA237) (25 ug and 50 ug o.d.) in Asthma Patients.

Conditions
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Asthma

Intervention / Treatment
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* Drug: NVA237 (glycopyrronium bromide)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: 1(NVA237 50 ug/NVA237 25 ug/placebo)<br>Treatment sequence: NVA 237 50 ug, 25 ug and placebo | Drug: NVA237 (glycopyrronium bromide)<br>* In each treatment arm, patient will receive NVA237 (glycopyrronium bromide) 25 ug and 50 ug dose<br>Drug: Placebo<br>* In each treatment arm, patient will receive placebo<br>|
| Other: 2(NVA237 50 ug/placebo/NVA237 25 ug)<br>Treatment sequence: NVA 237 50 ug, placebo and 25 ug | Drug: NVA237 (glycopyrronium bromide)<br>* In each treatment arm, patient will receive NVA237 (glycopyrronium bromide) 25 ug and 50 ug dose<br>Drug: Placebo<br>* In each treatment arm, patient will receive placebo<br>|
| Other: 3 (NVA237 25 ug/NVA237 50 ug/placebo)<br>Treatment sequence: NVA237 25 ug, 50 ug and placebo | Drug: NVA237 (glycopyrronium bromide)<br>* In each treatment arm, patient will receive NVA237 (glycopyrronium bromide) 25 ug and 50 ug dose<br>Drug: Placebo<br>* In each treatment arm, patient will receive placebo<br>|
| Other: 4 (NVA237 25 ug/placebo/NVA237 50 ug)<br>Treatment sequence: NVA 237 25 ug, placebo and 50 ug | Drug: NVA237 (glycopyrronium bromide)<br>* In each treatment arm, patient will receive NVA237 (glycopyrronium bromide) 25 ug and 50 ug dose<br>Drug: Placebo<br>* In each treatment arm, patient will receive placebo<br>|
| Other: 5 (placebo/NVA237 50 ug/ NVA237 25 ug)<br>Treatment sequence: Placebo, NVA237 50 ug and 25 ug | Drug: NVA237 (glycopyrronium bromide)<br>* In each treatment arm, patient will receive NVA237 (glycopyrronium bromide) 25 ug and 50 ug dose<br>Drug: Placebo<br>* In each treatment arm, patient will receive placebo<br>|
| Other: 6 (placebo/ NVA237 25 ug/NVA237 50 ug)<br>Treatment sequence: placebo, NVA237 25 ug and 50 ug | Drug: NVA237 (glycopyrronium bromide)<br>* In each treatment arm, patient will receive NVA237 (glycopyrronium bromide) 25 ug and 50 ug dose<br>Drug: Placebo<br>* In each treatment arm, patient will receive placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Following 1 week of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | Following 1 week of treatment | 
| 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) | Following 1 week of treatment | 
| 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) | Following 1 week of treatment | 
| 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. | Following 1 week of treatment | 
| 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 | Following 1 week of treatment | 
| 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 | Following 1 week of treatment | 
| 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 | Following 1 week of treatment | 
| 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 | Following 1 week of treatment | 
| 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. | Following 1 week of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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asthma,, NVA237,, glycopyrronium bromide, allergic asthma,, allergy triggered asthma,, reactive asthma,, asthma attack,, difficulty breathing