Study of Efficacy and Safety of QAW039 in Patients With Severe Asthma Inadequately Controlled With Standard of Care Asthma Treatment.

Study Overview
=================
Brief Summary
-----------------
This study aimed to determine the efficacy and safety of QAW039 150 mg and QAW039 450 mg, compared with placebo, when added to GINA (Global Initiative for Asthma) steps 4 and 5 standard-of- care (SoC) asthma therapy (GINA 2016) in the following two populations: patient with inadequately controlled severe asthma and high eosinophil counts at baseline (eosinophil count at Visit 1 ≥250 cells/ µl) (sub-population) patients with inadequately controlled severe asthma (overall study population) Inadequate control is defined as partly controlled or uncontrolled asthma (GINA 2016).

Detailed Description
-----------------
This study used a randomized, multicenter, double-blind, placebo-controlled parallel-group design in which QAW039 150 mg or QA039 450 mg or placebo was added to standard of care, GINA steps 4 and 5 asthma therapy. The study included: Screening period of up to 2 weeks to assess eligibility; Run-in period of approximately 2 weeks and a maximum of 6 weeks on placebo to collect baseline data for efficacy variables and compliance with the Electronic Peak Flow/ eDiary device. Upon completion of the run-in period, all patients who met the eligibility criteria were randomized to one of three treatments: QAW039 150 mg or QAW039 450 mg or placebo once daily in a ratio of 1:1:1. Treatment period of 52 weeks (assessment period for all Primary and Secondary Outcome Measures). Clinic visits were scheduled approximately 4 weeks after randomization and then at approximately 8-week intervals during the active-treatment period. Phone calls occurred at specified time points between visits occurring at 8-week intervals. Patients who had successfully completed 52 weeks of treatment in this study were offered an optional participation in a safety study (CQAW039A2315). Follow-up period of 4 weeks, investigational and drug-free, following the last dose of study drug. A follow-up visit occurred approximately 4 weeks (i.e., approximately 30 days) following the last dose of study therapy to complete safety assessments and pregnancy testing (if applicable). the follow-up period applied to all patients except those patients who had entered the safety study (CQAW039A2315) directly after the Week 52 study visit.

Official Title
-----------------
A 52-week, Multicenter, Randomized, Double-blind, Placebo-controlled Study to Assess the Efficacy and Safety of QAW039 When Added to Existing Asthma Therapy in Patients With Uncontrolled Severe Asthma.

Conditions
-----------------
Asthma

Intervention / Treatment
-----------------
* Drug: QAW039
* Drug: QAW039
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Written informed consent and assent (if applicable). Male and female patients aged ≥12 years (or ≥lower age limit allowed by health authority and/or ethics committee/institutional review board approvals). A diagnosis of severe asthma, uncontrolled on GINA 4/5 asthma medication. Evidence of airway reversibility or airway hyper- reactivity. FEV1 of ≤80% of the predicted normal value for patients aged ≥18 years; FEV1 of ≤90% for patients aged 12 to <18 years An ACQ score ≥1.5. A history of 2 or more asthma exacerbations within the 12 months prior to entering the study. Exclusion Criteria: Use of other investigational drugs within 5 half-lives of study entry, or within 30 days, whichever is longer. Subjects who have participated in another trial of QAW039. A QTcF (Fridericia) ≥450 msec (male) or ≥460 msec (female). History of malignancy with the exception of local basal cell carcinoma of the skin. Pregnant or nursing (lactating) women. Serious co-morbidities. Patients on greater than 20 mg of simvastatin, greater than 40 mg of atorvastatin, greater than 40 mg of pravastatin, or greater than 2 mg of pitavastatin

Ages Eligible for Study
-----------------
Minimum Age: 12 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: QAW039 150 mg<br>QAW039 150 mg once daily | Drug: QAW039<br>* QAW039 150 mg once daily<br>|
| Experimental: QAW039 450 mg<br>QAW039 450 mg once daily | Drug: QAW039<br>* QAW039 450 mg once daily<br>|
| Placebo Comparator: Placebo<br>Placebo once daily | Drug: Placebo<br>* Placebo once daily<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Moderate-to-severe Asthma Exacerbations During the 52-week Treatment Period in High Eosinophils Subpopulation | A severe asthma exacerbation is defined as treatment with 'rescue' systemic corticosteroids for greater than or equal to 3 days and hospitalization; or treatment with 'rescue' systemic corticosteroids for greater than or equal to 3 days and emergency department visit (greater than 24 hours*); or death due to asthma. A moderate asthma exacerbation is defined as treatment with 'rescue' systemic corticosteroids for greater than or equal to 3 days either as an outpatient or in emergency department visits (Emergency department visit less than or equal to 24 hours). The high eosinophils subpopulation consists of all patients with blood eosinophil count ≥ 250 cells/μL at baseline. | Baseline, Week 52 | 
| Rate of Moderate-to-severe Asthma Exacerbations During the 52-week Treatment Period in Overall Population | A severe asthma exacerbation is defined as treatment with 'rescue' systemic corticosteroids for greater than or equal to 3 days and hospitalization; or treatment with 'rescue' systemic corticosteroids for greater than or equal to 3 days and emergency department visit (greater than 24 hours*); or death due to asthma. A moderate asthma exacerbation is defined as treatment with 'rescue' systemic corticosteroids for greater than or equal to 3 days either as an outpatient or in emergency department visits (Emergency department visit less than or equal to 24 hours). | Baseline, Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 52 in Asthma Quality of Life Questionnaire for Participants 12 Years and Older (AQLQ+12) Score in High Eosinophils Subpopulation | The AQLQ+12 is comprised of a total of 32 individual questions that span a total of four domains: symptoms, activity limitation, emotional function, and environmental stimuli. Patients were asked to recall their experiences during the previous 2 weeks and to score each item on a 7-point scale (7 = not at all impaired to 1 = severely impaired). The AQLQ+12 yields individual domain scores, which is the mean of all items in each domain, and an overall score, which is the mean of all 32 individual responses. Higher scores indicate less impairment in health-related quality of life. The high eosinophils subpopulation consists of all patients with blood eosinophil count ≥ 250 cells/μL at baseline. | 52 weeks | 
| Change From Baseline to Week 52 in Asthma Control Questionnaire-5(ACQ-5) Score in High Eosinophils Subpopulation | The ACQ-5 is a five-item, self-completed questionnaire, which is used as a measure of asthma control of a participant. Patients were asked to recall how their asthma had been during the previous week and to respond to the symptom questions on a 7-point scale (0=no impairment, 6=maximum impairment). The questions are equally weighted and the ACQ-5 score is the mean of the 5 questions: therefore, between 0 (totally controlled) and 6 (severely uncontrolled). The high eosinophils subpopulation consists of all patients with blood eosinophil count ≥ 250 cells/μL at baseline. | Baseline, Week 52 | 
| Change From Baseline to Week 52 in Pre-dose Forced Expiratory Volume in 1 Second (FEV1) in High Eosinophils Subpopulation | 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. The high eosinophils subpopulation consists of all patients with blood eosinophil count ≥ 250 cells/μL at baseline. | Baseline, Week 52 | 
| Change From Baseline to Week 52 in Asthma Quality of Life Questionnaire for Participants 12 Years and Older (AQLQ+12) Score in Overall Population | The AQLQ+12 is comprised of a total of 32 individual questions that span a total of four domains: symptoms, activity limitation, emotional function, and environmental stimuli. Patients were asked to recall their experiences during the previous 2 weeks and to score each item on a 7-point scale (7 = not at all impaired to 1 = severely impaired). The AQLQ+12 yields individual domain scores, which is the mean of all items in each domain, and an overall score, which is the mean of all 32 individual responses. Higher scores indicate less impairment in health-related quality of life. | Baseline, Week 52 | 
| Change From Baseline to Week 52 in Asthma Control Questionnaire-5(ACQ-5) Score in Overall Population | The ACQ-5 is a five-item, self-completed questionnaire, which is used as a measure of asthma control of a participant. Patients were asked to recall how their asthma had been during the previous week and to respond to the symptom questions on a 7-point scale (0=no impairment, 6=maximum impairment). The questions are equally weighted and the ACQ-5 score is the mean of the 5 questions: therefore, between 0 (totally controlled) and 6 (severely uncontrolled). | Baseline, Week 52 | 
| Change From Baseline to Week 52 in Pre-dose Forced Expiratory Volume in 1 Second (FEV1) in Overall Population | 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. | Baseline, Week 52 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Asthma, QAW039, allergic asthma, allergy triggered asthma, reactive asthma, asthma attack, difficulty breathing