Assess Bronchodilator Effect and Safety of Two Doses of QVM149 Compared to a Fixed Dose Combination of Salmeterol/Fluticasone in Patients With Asthma.

Study Overview
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Brief Summary
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The purpose of this study is to assess peak FEV1 of two doses of QVM149 compared to a fixed-dose combination of salmeterol/fluticasone (50/500μg b.i.d.) and to characterize the respective 24 hour bronchodilator effect profiles in patients with asthma. Data from this study will complement lung function data obtained in the pivotal QVM149 phase 3 program by assessing the bronchodilatory effect of QVM149 at multiple time-points over an entire dosing interval of 24 hours.

Official Title
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A Randomized, Double-blind, Double-dummy, Active-controlled, 3-period Complete Cross-over Study to Assess the Bronchodilator Effect and Safety of Two Doses of QVM149 Compared to a Fixed Dose Combination of Salmeterol/Fluticasone in Patients With Asthma

Conditions
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Asthma

Intervention / Treatment
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* Drug: QVM149 150/50/80 μg o.d.
* Drug: QVM149 150/50/160 μg o.d.
* Drug: salmeterol/fluticasone FDC 50/500 μg b.i.d.


Participation Criteria
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Eligibility Criteria
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Key Inclusion criteria Male and female adult patients ≥ 18 years old and ≤ 75 years. Patients with a documented physician diagnosis of asthma for a period of at least 12 months prior to Visit 1 (Screening). Patients who have used ICS and LABA combinations for asthma for at least 3 month and at a stable medium or high dose of ICS for at least 1 month prior to Visit 1 (Screening). Pre-bronchodilator FEV1 of < 80 % of the predicted normal value at screening Visit 1 (spirometry will not be repeated at baseline prior to randomization). Patients who demonstrate an increase in FEV1 of ≥ 12 % and 200 mL after administration of 400 µg salbutamol/360 µg albuterol (or equivalent do se) at Visit 1 (Screening). All patients must perform a reversibility test at Visit 1 (Screening). If reversibility is not demonstrated at Visit 1 (Screening), then, reversibility testing may be repeated once during the screening period. If reversibility is not demonstrated at Visit 1 (retesting allowed once), patients must be screen failed. Spacer devices are not permitted during reversibility testing Key Exclusion criteria Patients who have smoked or inhaled tobacco products within the 6 month period prior to Visit 1 Patients who have had an asthma attack/exacerbation requiring systemic steroids or hospitalization or emergency room visit within 6 weeks of Visit 1 Patients with narrow-angle glaucoma, symptomatic benign prostatic hyperplasia (BPH) or bladder-neck obstruction or severe renal impairment or urinary retention Patients who have had a respiratory tract infection or asthma worsening within 4 weeks prior to Visit 1 Patients with any chronic conditions affecting the upper respiratory tract Patients with a history of chronic lung diseases other than asthma, including (but not limited to) COPD, sarcoidosis, interstitial lung disease, cystic fibrosis, clinically significant bronchiectasis and active tuberculosis. Patients with Type I diabetes or uncontrolled Type II diabetes (HbA1c >9% at screening). Patients who have a clinically significant ECG abnormality at Visit 1 Patients with a history of hypersensitivity or intolerance to any of the study drugs (including excipients) Patients with narcolepsy and/or insomnia. Patients on Maintenance Immunotherapy (desensitization) for allergies for less than 3 months prior to Visit 2 or patients on Maintenance Immunotherapy for more than 3 months prior to Visit 2 but expected to change throughout the course of the study. Pregnant or nursing (lactating) women Women of child-bearing potential must use Highly effective contraception methods Patients who have discontinued LAMA therapy in the past for any safety, tolerability or perceived lack of efficacy reason. History of paradoxical bronchospasm in response to inhaled medicines. Patients with a history of clinically relevant bronchoconstriction upon repeated forced expiratory maneuvers. Patient with a serum potassium level below the laboratory limit of normal at screening.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Sequence 1<br>A-B-C | Drug: QVM149 150/50/80 μg o.d.<br>* A<br>Drug: QVM149 150/50/160 μg o.d.<br>* B<br>Drug: salmeterol/fluticasone FDC 50/500 μg b.i.d.<br>* C<br>|
| Active Comparator: Sequence 2<br>A-C-B | Drug: QVM149 150/50/80 μg o.d.<br>* A<br>Drug: QVM149 150/50/160 μg o.d.<br>* B<br>Drug: salmeterol/fluticasone FDC 50/500 μg b.i.d.<br>* C<br>|
| Active Comparator: Sequence 3<br>B-C-A | Drug: QVM149 150/50/80 μg o.d.<br>* A<br>Drug: QVM149 150/50/160 μg o.d.<br>* B<br>Drug: salmeterol/fluticasone FDC 50/500 μg b.i.d.<br>* C<br>|
| Active Comparator: Sequence 4<br>B-A-C | Drug: QVM149 150/50/80 μg o.d.<br>* A<br>Drug: QVM149 150/50/160 μg o.d.<br>* B<br>Drug: salmeterol/fluticasone FDC 50/500 μg b.i.d.<br>* C<br>|
| Active Comparator: Sequence 5<br>C-A-B | Drug: QVM149 150/50/80 μg o.d.<br>* A<br>Drug: QVM149 150/50/160 μg o.d.<br>* B<br>Drug: salmeterol/fluticasone FDC 50/500 μg b.i.d.<br>* C<br>|
| Active Comparator: Sequence 6<br>C-B-A | Drug: QVM149 150/50/80 μg o.d.<br>* A<br>Drug: QVM149 150/50/160 μg o.d.<br>* B<br>Drug: salmeterol/fluticasone FDC 50/500 μg b.i.d.<br>* C<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak FEV1 (L) Defined as the Highest Bronchodilatory Effect on FEV1 During a Period of 5 Min to 4 h After the Last Evening Dose of Each Treatment Period | The highest bronchodilator effect on FEV1 during a period of 5 min to 4 h after the last evening dose of each treatment period . To demonstrate superiority in peak bronchodilator effect of QVM149 at a dose of 150/50/160 μg o.d. and 150/50/80 μg o.d. compared to a FDC of salmeterol/fluticasone at a dose of 50/500 μg b.i.d. after 3 weeks of treatment in patients with asthma | 3 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| FEV1 Over 24 h After 21 Days of Treatment in Relation to Evening Dose | To evaluate the bronchodilator effect of each dose of QVM149 compared to salmeterol/fluticasone FDC after 3 weeks of treatment at -45 min, -15 min, 5 min, 15 min, 30 min, 1 h, 2 h, 3h, 4 h, 8 h, 10 h, 11 h 55 min, 14 h, 18 h, 21 h, 23 h 15 min, 23 h 45 min. | -45 min, -15 min, 5 min, 15 min, 30 min, 1 h, 2 h, 3h, 4 h, 8 h, 10 h, 11 h 55 min, 14 h, 18 h, 21 h, 23 h 15 min, 23 h 45 min at 3 weeks | 
| FVC Over 24 h After 21 Days of Treatment in Relation to Evening Dose | To evaluate the bronchodilator effect of each dose of QVM149 compared to salmeterol/fluticasone FDC after 3 weeks of treatment at -45 min, -15 min, 5 min, 15 min, 30 min, 1 h, 2 h, 3h, 4 h, 8 h, 10 h, 11 h 55 min, 14 h, 18 h, 21 h, 23 h 15 min, 23 h 45 min. | -45 min, -15 min, 5 min, 15 min, 30 min, 1 h, 2 h, 3h, 4 h, 8 h, 10 h, 11 h 55 min, 14 h, 18 h, 21 h, 23 h 15 min, 23 h 45 min at 3 weeks | 
| FEV1/FVC Ratio Over 24 h After 21 Days of Treatment in Relation to Evening Dose | To evaluate the bronchodilator effect of each dose of QVM149 compared to salmeterol/fluticasone FDC after 3 weeks of treatment at -45 min, -15 min, 5 min, 15 min, 30 min, 1 h, 2 h, 3h, 4 h, 8 h, 10 h, 11 h 55 min, 14 h, 18 h, 21 h, 23 h 15 min, 23 h 45 min. | -45 min, -15 min, 5 min, 15 min, 30 min, 1 h, 2 h, 3h, 4 h, 8 h, 10 h, 11 h 55 min, 14 h, 18 h, 21 h, 23 h 15 min, 23 h 45 min at 3 weeks | 
| FEV1 AUC 5 Min - 1 h (Day 21) FEV1 AUC 5 Min - 4 h (Day 21) and FEV1 AUC 5 Min - 23 h 45 Min (Day 21) | To evaluate the bronchodilator effect of each dose of QVM149 compared to salmeterol/ fluticasone FDC by measuring standardized FEV1 AUCs after 3 weeks of treatment respective period. | 3 weeks | 
| Trough FEV1 After 21 Days of Treatment | To evaluate post-dose trough bronchodilator effect of each dose of QVM149 compared to salmeterol/fluticasone FDC after 3 weeks of treatment in the respective treatment period. The trough FEV1 is the mean value of FEV1 at 23 h 15 min and 23 h 45 min post-dose | 3 weeks |