A Study to Assess the Effect of QAW039 in Non-atopic Asthmatic Patients

Study Overview
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Brief Summary
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The purpose of the study was to assess the clinical effect of QAW039 in non-atopic asthmatics taking low dose Inhaled Corticosteroid (ICS) as background therapy.

Detailed Description
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This was a multi-centre, randomised, placebo-controlled, double blind, 3-arm study designed to compare the efficacy and safety of a once daily dose of QAW039 with placebo in non-atopic and atopic asthmatics both inadequately controlled despite receiving a low dose ICS background therapy, over a 12 week treatment period. Efficacy and safety of a once daily dose of QAW039 was also compared with an increased dose of ICS in atopic asthmatics taking low dose ICS as background therapy.

Official Title
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A Double-blind, Placebo-controlled, Study Examining the Effect of Orally Administered QAW039 (450 mg QD) on FEV1 and ACQ in Non-atopic, Asthmatic Patients With a Baseline, Pre-bronchodilator FEV1 of 40-80% Predicted, Inadequately Controlled With Low Dose ICS Therapy

Conditions
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Asthma

Intervention / Treatment
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* Drug: QAW039
* Drug: Placebo QAW039
* Drug: Fluticasone 250 mcg
* Drug: Fluticasone 100 mcg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent must be obtained before any assessment is performed Patients with a diagnosis of persistent asthma (according to Global Initiative for Asthma 2011) for a period of at least 6 months prior to screening Patients with a pre-bronchodilator Forced Expiratory Volume In One Second (FEV1) value of 40% to 80% of individual predicted value at screening and prior to treatment An Asthma Control Questionnaire score ≥ 1.5 prior to treatment Demonstration of reversible airway obstruction Exclusion Criteria: Pregnant or nursing (lactating) women Acute illness other than asthma at the start of the study Patients with clinically significant laboratory abnormalities at screening Patients with clinically significant condition which may compromise subject safety or interfere with study evaluation Use of other investigational drugs at the time of enrollment

Ages Eligible for Study
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Minimum Age: 18 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: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: QAW039 450 mg qd Non-atopic<br>QAW039 450 mg (3 capsules of QAW039 150 mg) qd combined with background ICS (100 μg fluticasone, bid). Non-atopic patients randomized in ratio of approximately 1:1. | Drug: QAW039<br>* QAW039 supplied as hard gelatin capsule in unit dose strength of 150 mg. Patient took 450 mg once daily (3 capsules taken with food in the morning) for the approximate period of the study (12 weeks)<br>Drug: Fluticasone 100 mcg<br>* Background therapy - fluticasone was supplied in inhalers with dose strength of 100 mcg. All patients in the study other than the Atopic Fluticasone 150 mcg arm were given the 100 mcg dose strength inhalers and took fluticasone 100 mcg bid (taken morning and evening with approximately 12 hours between doses) as background therapy for the approximate period of the study (12 weeks).<br>|
| Placebo Comparator: Placebo Non-atopic<br>Placebo to QAW039 (3 capsules of Placebo of QAW039 150 mg) combined with background ICS (100 μg fluticasone, bid). Non-atopic randomized in ratio of approximately 1:1. | Drug: Placebo QAW039<br>* Matching placebo for QAW039 supplied as hard gelatin capsule were identical in appearance to their active counterparts. Patients took 3 QAW039 matching placebo capsules once a day ( taken with food in the morning) for the approximate period of the study (12 weeks)<br>Drug: Fluticasone 100 mcg<br>* Background therapy - fluticasone was supplied in inhalers with dose strength of 100 mcg. All patients in the study other than the Atopic Fluticasone 150 mcg arm were given the 100 mcg dose strength inhalers and took fluticasone 100 mcg bid (taken morning and evening with approximately 12 hours between doses) as background therapy for the approximate period of the study (12 weeks).<br>|
| Experimental: QAW039 450 mg qd Atopic<br>QAW039 450 mg (3 capsules of QAW039 150 mg) qd combined with background ICS (100 μg fluticasone, bid). Atopic patients randomized in a ratio of approximate 1:1:1 | Drug: QAW039<br>* QAW039 supplied as hard gelatin capsule in unit dose strength of 150 mg. Patient took 450 mg once daily (3 capsules taken with food in the morning) for the approximate period of the study (12 weeks)<br>Drug: Fluticasone 100 mcg<br>* Background therapy - fluticasone was supplied in inhalers with dose strength of 100 mcg. All patients in the study other than the Atopic Fluticasone 150 mcg arm were given the 100 mcg dose strength inhalers and took fluticasone 100 mcg bid (taken morning and evening with approximately 12 hours between doses) as background therapy for the approximate period of the study (12 weeks).<br>|
| Active Comparator: Fluticasone 150 mcg bid Atopic<br>Placebo to QAW039 (3 capsules of Placebo of QAW039 150 mg) combined with 150 μg ICS and with background ICS (100 μg fluticasone, bid). As a consequence total ICS was 250 μg fluticasone bid. Atopic patients randomized in ratio of approximately 1:1:1 | Drug: Placebo QAW039<br>* Matching placebo for QAW039 supplied as hard gelatin capsule were identical in appearance to their active counterparts. Patients took 3 QAW039 matching placebo capsules once a day ( taken with food in the morning) for the approximate period of the study (12 weeks)<br>Drug: Fluticasone 250 mcg<br>* Fluticasone was supplied in inhalers with dose strength of 250 mcg. Patients took 250 mcg bid (morning and evening approximately 12 hours between doses) for a total dose of 500 mcg daily for the approximate period of the study (12 weeks).<br>|
| Placebo Comparator: Placebo Atopic<br>Placebo to QAW039 (3 capsules of Placebo of QAW039 150 mg) combined with background ICS (100 μg fluticasone, bid). Atopic patients andomized in ratio of approximately 1:1:1 | Drug: Placebo QAW039<br>* Matching placebo for QAW039 supplied as hard gelatin capsule were identical in appearance to their active counterparts. Patients took 3 QAW039 matching placebo capsules once a day ( taken with food in the morning) for the approximate period of the study (12 weeks)<br>Drug: Fluticasone 100 mcg<br>* Background therapy - fluticasone was supplied in inhalers with dose strength of 100 mcg. All patients in the study other than the Atopic Fluticasone 150 mcg arm were given the 100 mcg dose strength inhalers and took fluticasone 100 mcg bid (taken morning and evening with approximately 12 hours between doses) as background therapy for the approximate period of the study (12 weeks).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Trough FEV1 (L) in Non-atopic Patients at Week 12 - Full Analysis Set | Forced Expiratory Volume in one second (FEV1) is calculated as the volume of air forcibly exhaled in one second as measured by a spirometer. Baseline is defined as the last available FEV1 measurement taken prior to the first dose of randomized study drug. Data within 6 hr of rescue medication use is excluded from this analysis. For subjects with missing trough FEV1 (L) at Week 12, the last post baseline observation were used (LOCF). Estimates are from a mixed effects model with treatment, subject population (non-atopic vs. atopic), treatment by subject population interaction, baseline trough FEV1 and region as fixed effects and center nested within region as random effects. Full analysis set included all randomized subjects who received at least one dose of study drug. | baseline,12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Trough FEV1 (L) in Atopic Patients at Week 12 - Full Analysis Set | Forced Expiratory Volume in one second (FEV1) is calculated as the volume of air forcibly exhaled in one second as measured by a spirometer. Baseline is defined as the FEV1 measurement taken prior to the first dose of randomized study drug. Data within 6 hr of rescue medication use is excluded from this analysis. For subjects with missing trough FEV1 (L) at Week 12, the last post baseline observation were used (LOCF). Estimates are from a mixed effects model with treatment, subject population (non-atopic vs. atopic), treatment by subject population interaction, baseline trough FEV1 and region as fixed effects and center nested within region as random effects. Full analysis set included all randomized subjects who received at least one dose of study drug. | baseline,12 weeks | 
| Change From Baseline in Trough FEV1 (L) in Non-atopic Compared to Atopic Patients at Week 12 - Full Analysis Set | Forced Expiratory Volume in one second (FEV1) is calculated as the volume of air forcibly exhaled in one second as measured by a spirometer. Baseline is defined as the FEV1 measurement taken prior to the first dose of randomized study drug. Data within 6 hr of rescue medication use is excluded from this analysis. For subjects with missing trough FEV1 (L) at Week 12, the last post baseline observation were used (LOCF). Estimates are from a mixed effects model with treatment, subject population, treatment by subject population interaction, baseline trough FEV1 and region as fixed effects and center nested within region as random effects. Full analysis set included all randomized subjects who received at least one dose of study drug. | baseline,12 weeks | 
| Change From Baseline in ACQ-6 Score at Week 12 Non-atopic and Atopic Patients at Week 12 - Full Analysis Set | ACQ-6 consists of:5 items on symptoms, 1 item on rescue bronchodilator use, and 1 item on airway caliber (FEV1 % predicted). The ACQ was fully validated, including a minimal important difference (MID) or smallest change that could be considered clinically important (0.5). The ACQ was self-administered at the clinic and patients scored each item on a 7-point response scale: 0 = 'totally controlled' and 6 = 'severely uncontrolled.' Study staff scored question 7 based on % predicted FEV1 (ideally pre-bronchodilator). The total score=average of first 6 questions. Baseline=the ACQ-6 measurement taken prior to first dose of randomized study drug. The single missing score was interpolated by utilizing prior or subsequent completions of the questionnaire. Estimates were from a mixed effects model with treatment, subject population (non-atopic vs. atopic), treatment by subject population interaction, baseline ACQ-6 and region as fixed effects and center nested within region as random effects. | baseline,12 weeks | 
| Change From Baseline in ACQ-6 Score at Week 12 Non-atopic Compared to Atopic Patients at Week 12 - Full Analysis Set | ACQ-6 consists of:5 items on symptoms, 1 item on rescue bronchodilator use, and 1 item on airway caliber (FEV1 % predicted). The ACQ was fully validated, including a minimal important difference (MID) or smallest change that could be considered clinically important (0.5). The ACQ was self-administered at the clinic and patients scored each item on a 7-point response scale: 0 = 'totally controlled' and 6 = 'severely uncontrolled.' Study staff scored question 7 based on % predicted FEV1 (ideally pre-bronchodilator). The total score=average of first 6 questions. Baseline=the ACQ-6 measurement taken prior to first dose of randomized study drug. The single missing score was interpolated by utilizing prior or subsequent completions of the questionnaire. Estimates were from a mixed effects model with treatment, subject population (non-atopic vs. atopic), treatment by subject population interaction, baseline ACQ-6 and region as fixed effects and center nested within region as random effects. | baseline,12 weeks |