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

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02563067
• Collaborator: (none)
• Enrollment: 877
• Locations: 163
• Arms: 3
• Actual Duration (Months): 44
• Patients Per Site: 5.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This study aimed to determine the efficacy and safety of QAW039 and QAW039 450 mg compared to 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 (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)

Condition or Disease	Intervention/Treatment	Phase
Asthma	Drug: QAW039; Drug: QAW039; Drug: Placebo	Phase 3

Detailed Description

This study used a randomized, multicenter, double-blind, placebo-controlled parallel-group design in which QAW039 (150 mg and 450 mg) or placebo was added to 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 optional safety study (CQAW039A2315) directly after the Week 52 study visit

Study Design

• Study Type: Interventional
• Actual Enrollment: 877 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• 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.
• Actual Study Start Date: Dec 3, 2015
• Actual Primary Completion Date: Jul 4, 2019
• Actual Study Completion Date: Aug 2, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: QAW039 150 mg QAW039 150 mg once daily	Drug: QAW039; QAW039 150 mg once daily
Experimental: QAW039 450 mg QAW039 450 mg once daily	Drug: QAW039; QAW039 450 mg once daily
Placebo Comparator: Placebo Placebo once daily	Drug: Placebo; Placebo once daily

Outcome Measures

Primary Outcome Measures

1. Rate of Moderate-to-severe Asthma Exacerbations During the 52-week Treatment Period in High Eosinophils Subpopulation [52 weeks]

   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.

2. Rate of Moderate-to-severe Asthma Exacerbations During the 52-week Treatment Period in Overall Population [52 weeks]

   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).

Secondary Outcome Measures

1. 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 [Baseline, Week 52]

   AQLQ is a 32-item instrument administered as a self-assessment. AQLQ+12 is a modified version of AQLQ developed to measure functional impairments of participants aged 12-70 years. It is divided into 4 domains: activity limitation, symptoms, emotional function, and environmental stimuli. Participants were asked to recall their experiences during the last 2 weeks and respond to each question on a 7-point scale (1=severe impairment, 7=no impairment), where higher scores indicated "better quality of life." Overall AQLQ+12 score is the mean of all 32 responses. The high eosinophils subpopulation consists of all patients with blood eosinophil count ≥ 250 cells/μL at baseline.

2. Change From Baseline to Week 52 in Asthma Control Questionnaire-5 (ACQ-5) Score in High Eosinophils Subpopulation [Baseline, Week 52]

   The ACQ-5 is a five-item, self-completed questionnaire, which is used as a measure of asthma control of a participant. The five questions (concerning nocturnal awakening, waking in the morning, activity limitation, shortness of breath and wheeze) enquire about the frequency and/or severity of symptoms over the previous week. The response options for all these questions range from zero (no impairment/limitation) to six (total impairment/ limitation) scale. The ACQ-5 score is the average of the individual item scores and ranges from 0 to 6. Higher scores indicates worsening of condition. The high eosinophils subpopulation consists of all patients with blood eosinophil count ≥ 250 cells/μL at baseline.

3. Change From Baseline to Week 52 in Pre-dose Forced Expiratory Volume in 1 Second (FEV1) in High Eosinophils Subpopulation [Baseline, Week 52]

   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.

4. Change From Baseline to Week 52 in Asthma Quality of Life Questionnaire for Participants 12 Years and Older (AQLQ+12) Score in Overall Population [Baseline, Week 52]

   AQLQ is a 32-item instrument administered as a self-assessment. AQLQ+12 is a modified version of AQLQ developed to measure functional impairments of participants aged 12-70 years. It is divided into 4 domains: activity limitation, symptoms, emotional function, and environmental stimuli. Participants were asked to recall their experiences during the last 2 weeks and respond to each question on a 7-point scale (1=severe impairment, 7=no impairment), where higher scores indicated "better quality of life." Overall AQLQ+12 score is the mean of all 32 responses.

5. Change From Baseline to Week 52 in Asthma Control Questionnaire-5 (ACQ-5) Score in Overall Population [Baseline, Week 52]

   The ACQ-5 is a five-item, self-completed questionnaire, which is used as a measure of asthma control of a participant. The five questions (concerning nocturnal awakening, waking in the morning, activity limitation, shortness of breath and wheeze) enquire about the frequency and/or severity of symptoms over the previous week. The response options for all these questions range from zero (no impairment/limitation) to six (total impairment/ limitation) scale. The ACQ-5 score is the average of the individual item scores and ranges from 0 to 6. Higher scores indicates worsening of condition.

6. Change From Baseline to Week 52 in Pre-dose Forced Expiratory Volume in 1 Second (FEV1) in Overall Population [Baseline, Week 52]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Written informed consent.

• Male and female patients aged ≥12 years.

• A diagnosis of severe asthma, uncontrolled on GINA 4/5 asthma medication.

• Evidence of airway reversibility or airway hyper- reactivity.

• FEV1 ≤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 >20 mg of simvastatin, > 40 mg of atorvastatin, >40 mg of pravastatin, or

2 mg of pitavastatin.

Contacts and Locations

Locations

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144	Novartis Investigative Site	Vysne Hagy		Slovakia	5984
145	Novartis Investigative Site	Tygerberg	Cape Town	South Africa	7505
146	Novartis Investigative Site	Mowbray		South Africa	7700
147	Novartis Investigative Site	Panorama		South Africa	7500
148	Novartis Investigative Site	Malaga	Andalucia	Spain	29009
149	Novartis Investigative Site	Jerez	Cadiz	Spain	11407
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158	Novartis Investigative Site	Madrid		Spain	28046
159	Novartis Investigative Site	Santiago de Compostela		Spain	15706
160	Novartis Investigative Site	Zaragoza		Spain	50009
161	Novartis Investigative Site	Taichung	Taiwan ROC	Taiwan	40201
162	Novartis Investigative Site	Taichung		Taiwan	40447
163	Novartis Investigative Site	Taichung		Taiwan	40705

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Feb 10, 2017
• Statistical Analysis Plan - Aug 26, 2019

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02563067
• Other Study ID Numbers: CQAW039A2314; 2015-003172-67
• First Posted: Sep 29, 2015
• Last Update Posted: May 3, 2021
• Last Verified: Apr 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: Asthma; QAW039
• Additional relevant MeSH terms: Asthma; Indoleacetic Acids

Study Results

Participant Flow

Recruitment Details	Participants were recruited from centers in Argentina (18), Canada (5), Czech Republic (7), Greece (6), India (12), Israel (5), Italy (22), Japan (16), Lebanon (3), Malaysia (4), Mexico (3), Netherlands (4), Russian Federation (11), Serbia (4), Slovakia (11), South Africa (3), Spain (13), Taiwan (3) and the United States (19).
Pre-assignment Detail	The study included a Screening period of up to 2 weeks and a Placebo Run-in period of 2 to 6 weeks, during which eligibility for randomization was determined

Arm/Group Title	QAW039 150 mg	QAW039 450 mg	Placebo
Arm/Group Description	QAW039 150 mg once daily	QAW039 450 mg once daily	Placebo once daily
Period Title: Overall Study
STARTED	296	294	287
FAS/SAF: High Eosinophils Subpopulation	198	196	193
FAS/SAF: Overall Population	296	293	287
COMPLETED	277	268	267
NOT COMPLETED	19	26	20

Baseline Characteristics

Arm/Group Title	QAW039 150 mg	QAW039 450 mg	Placebo	Total
Arm/Group Description	QAW039 150 mg once daily	QAW039 450 mg once daily	Placebo once daily	Total of all reporting groups
Overall Participants	296	294	287	877
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	49.8 (14.60)	49.6 (15.25)	50.9 (14.16)	50.1 (14.68)
Sex: Female, Male (Count of Participants)
Female	165 55.7%	178 60.5%	177 61.7%	520 59.3%
Male	131 44.3%	116 39.5%	110 38.3%	357 40.7%
Race/Ethnicity, Customized (Count of Participants)
Caucasian	234 79.1%	235 79.9%	227 79.1%	696 79.4%
Black	6 2%	4 1.4%	1 0.3%	11 1.3%
Asian	44 14.9%	41 13.9%	41 14.3%	126 14.4%
Native American	2 0.7%	2 0.7%	4 1.4%	8 0.9%
Unknown	2 0.7%	2 0.7%	3 1%	7 0.8%
Other	8 2.7%	10 3.4%	11 3.8%	29 3.3%

Outcome Measures

1. Primary Outcome

Title	Rate of Moderate-to-severe Asthma Exacerbations During the 52-week Treatment Period in High Eosinophils Subpopulation
Description	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.
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) in high eosinophils subpopulation (count ≥ 250 cells/μL)

Arm/Group Title	QAW039 150 mg	QAW039 450 mg	Placebo
Arm/Group Description	QAW039 150 mg once daily	QAW039 450 mg once daily	Placebo once daily
Measure Participants	198	196	193
Least Squares Mean (95% Confidence Interval) [Events/year]	0.73	0.76	1.06

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	QAW039 150 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.059
	Comments
	Method	negative binomial regression model
	Comments	adjusted p-value, closed testing procedure across the primary and key secondary null hypotheses. Overall type I error rate controlled at two-sided 5%.
Method of Estimation	Estimation Parameter	Rate Ratio
	Estimated Value	0.69
	Confidence Interval	(2-Sided) 95%; 0.50 to 0.96
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	QAW039 450 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.114
	Comments
	Method	negative binomial regression model
	Comments	adjusted p-value, closed testing procedure across the primary and key secondary null hypotheses. Overall type I error rate controlled at two-sided 5%.
Method of Estimation	Estimation Parameter	Rate Ratio
	Estimated Value	0.72
	Confidence Interval	(2-Sided) 95%; 0.52 to 1.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	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
Description	AQLQ is a 32-item instrument administered as a self-assessment. AQLQ+12 is a modified version of AQLQ developed to measure functional impairments of participants aged 12-70 years. It is divided into 4 domains: activity limitation, symptoms, emotional function, and environmental stimuli. Participants were asked to recall their experiences during the last 2 weeks and respond to each question on a 7-point scale (1=severe impairment, 7=no impairment), where higher scores indicated "better quality of life." Overall AQLQ+12 score is the mean of all 32 responses. The high eosinophils subpopulation consists of all patients with blood eosinophil count ≥ 250 cells/μL at baseline.
Time Frame	Baseline, Week 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) in high eosinophils subpopulation (count ≥ 250 cells/μL)

Arm/Group Title	QAW039 150 mg	QAW039 450 mg	Placebo
Arm/Group Description	QAW039 150 mg once daily	QAW039 450 mg once daily	Placebo once daily
Measure Participants	198	196	193
Least Squares Mean (Standard Error) [units on a scale]	0.73 (0.061)	0.71 (0.062)	0.58 (0.062)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	QAW039 150 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.369
	Comments
	Method	ANCOVA
	Comments	adjusted p-value, closed testing procedure across the primary and key secondary null hypotheses. Overall type I error rate controlled at two-sided 5%.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.15
	Confidence Interval	(2-Sided) 95%; -0.02 to 0.32
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	QAW039 450 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.824
	Comments
	Method	ANCOVA
	Comments	adjusted p-value, closed testing procedure across the primary and key secondary null hypotheses. Overall type I error rate controlled at two-sided 5%.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.13
	Confidence Interval	(2-Sided) 95%; -0.04 to 0.30
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline to Week 52 in Asthma Control Questionnaire-5 (ACQ-5) Score in High Eosinophils Subpopulation
Description	The ACQ-5 is a five-item, self-completed questionnaire, which is used as a measure of asthma control of a participant. The five questions (concerning nocturnal awakening, waking in the morning, activity limitation, shortness of breath and wheeze) enquire about the frequency and/or severity of symptoms over the previous week. The response options for all these questions range from zero (no impairment/limitation) to six (total impairment/ limitation) scale. The ACQ-5 score is the average of the individual item scores and ranges from 0 to 6. Higher scores indicates worsening of condition. The high eosinophils subpopulation consists of all patients with blood eosinophil count ≥ 250 cells/μL at baseline.
Time Frame	Baseline, Week 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) in high eosinophils subpopulation (count ≥ 250 cells/μL)

Arm/Group Title	QAW039 150 mg	QAW039 450 mg	Placebo
Arm/Group Description	QAW039 150 mg once daily	QAW039 450 mg once daily	Placebo once daily
Measure Participants	198	196	193
Least Squares Mean (Standard Error) [units on a scale]	-0.92 (0.067)	-0.84 (0.068)	-0.75 (0.069)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	QAW039 150 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.369
	Comments
	Method	ANCOVA
	Comments	adjusted p-value, closed testing procedure across the primary and key secondary null hypotheses. Overall type I error rate controlled at two-sided 5%.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.17
	Confidence Interval	(2-Sided) 95%; -0.36 to 0.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	QAW039 450 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.824
	Comments
	Method	ANCOVA
	Comments	adjusted p-value, closed testing procedure across the primary and key secondary null hypotheses. Overall type I error rate controlled at two-sided 5%.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.09
	Confidence Interval	(2-Sided) 95%; -0.28 to 0.10
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline to Week 52 in Pre-dose Forced Expiratory Volume in 1 Second (FEV1) in High Eosinophils Subpopulation
Description	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.
Time Frame	Baseline, Week 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) in high eosinophils subpopulation (count ≥ 250 cells/μL)

Arm/Group Title	QAW039 150 mg	QAW039 450 mg	Placebo
Arm/Group Description	QAW039 150 mg once daily	QAW039 450 mg once daily	Placebo once daily
Measure Participants	198	196	193
Least Squares Mean (Standard Error) [Liter]	0.192 (0.0306)	0.162 (0.0311)	0.124 (0.0313)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	QAW039 150 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.369
	Comments
	Method	ANCOVA
	Comments	adjusted p-value, closed testing procedure across the primary and key secondary null hypotheses. Overall type I error rate controlled at two-sided 5%.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.068
	Confidence Interval	(2-Sided) 95%; -0.018 to 0.154
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	QAW039 450 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.824
	Comments
	Method	ANCOVA
	Comments	adjusted p-value, closed testing procedure across the primary and key secondary null hypotheses. Overall type I error rate controlled at two-sided 5%.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.038
	Confidence Interval	(2-Sided) 95%; -0.048 to 0.124
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Primary Outcome

Title	Rate of Moderate-to-severe Asthma Exacerbations During the 52-week Treatment Period in Overall Population
Description	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).
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS), including all randomized patients who received at least one dose of study drug.

Arm/Group Title	QAW039 150 mg	QAW039 450 mg	Placebo
Arm/Group Description	QAW039 150 mg once daily	QAW039 450 mg once daily	Placebo once daily
Measure Participants	296	293	287
Least Squares Mean (95% Confidence Interval) [Events/year]	0.76	0.70	0.93

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	QAW039 150 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.369
	Comments
	Method	negative binomial regression model
	Comments	adjusted p-value, closed testing procedure across the primary and key secondary null hypotheses. Overall type I error rate controlled at two-sided 5%.
Method of Estimation	Estimation Parameter	Rate Ratio
	Estimated Value	0.82
	Confidence Interval	(2-Sided) 95%; 0.62 to 1.07
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	QAW039 450 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.348
	Comments
	Method	negative binomial regression model
	Comments	adjusted p-value, closed testing procedure across the primary and key secondary null hypotheses. Overall type I error rate controlled at two-sided 5%.
Method of Estimation	Estimation Parameter	Rate Ratio
	Estimated Value	0.76
	Confidence Interval	(2-Sided) 95%; 0.58 to 1.00
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Change From Baseline to Week 52 in Asthma Quality of Life Questionnaire for Participants 12 Years and Older (AQLQ+12) Score in Overall Population
Description	AQLQ is a 32-item instrument administered as a self-assessment. AQLQ+12 is a modified version of AQLQ developed to measure functional impairments of participants aged 12-70 years. It is divided into 4 domains: activity limitation, symptoms, emotional function, and environmental stimuli. Participants were asked to recall their experiences during the last 2 weeks and respond to each question on a 7-point scale (1=severe impairment, 7=no impairment), where higher scores indicated "better quality of life." Overall AQLQ+12 score is the mean of all 32 responses.
Time Frame	Baseline, Week 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS), including all randomized patients who received at least one dose of study drug.

Arm/Group Title	QAW039 150 mg	QAW039 450 mg	Placebo
Arm/Group Description	QAW039 150 mg once daily	QAW039 450 mg once daily	Placebo once daily
Measure Participants	296	293	287
Least Squares Mean (Standard Error) [units on a scale]	0.62 (0.050)	0.67 (0.050)	0.55 (0.051)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	QAW039 150 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.824
	Comments
	Method	ANCOVA
	Comments	adjusted p-value, closed testing procedure across the primary and key secondary null hypotheses. Overall type I error rate controlled at two-sided 5%.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.07
	Confidence Interval	(2-Sided) 95%; -0.07 to 0.21
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	QAW039 450 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.824
	Comments
	Method	ANCOVA
	Comments	adjusted p-value, closed testing procedure across the primary and key secondary null hypotheses. Overall type I error rate controlled at two-sided 5%.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.12
	Confidence Interval	(2-Sided) 95%; -0.02 to 0.26
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Change From Baseline to Week 52 in Asthma Control Questionnaire-5 (ACQ-5) Score in Overall Population
Description	The ACQ-5 is a five-item, self-completed questionnaire, which is used as a measure of asthma control of a participant. The five questions (concerning nocturnal awakening, waking in the morning, activity limitation, shortness of breath and wheeze) enquire about the frequency and/or severity of symptoms over the previous week. The response options for all these questions range from zero (no impairment/limitation) to six (total impairment/ limitation) scale. The ACQ-5 score is the average of the individual item scores and ranges from 0 to 6. Higher scores indicates worsening of condition.
Time Frame	Baseline, Week 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS), including all randomized patients who received at least one dose of study drug.

Arm/Group Title	QAW039 150 mg	QAW039 450 mg	Placebo
Arm/Group Description	QAW039 150 mg once daily	QAW039 450 mg once daily	Placebo once daily
Measure Participants	296	293	287
Least Squares Mean (Standard Error) [units on a scale]	-0.83 (0.055)	-0.77 (0.055)	-0.70 (0.055)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	QAW039 150 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.824
	Comments
	Method	ANCOVA
	Comments	adjusted p-value, closed testing procedure across the primary and key secondary null hypotheses. Overall type I error rate controlled at two-sided 5%.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.12
	Confidence Interval	(2-Sided) 95%; -0.28 to 0.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	QAW039 450 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.824
	Comments
	Method	ANCOVA
	Comments	adjusted p-value, closed testing procedure across the primary and key secondary null hypotheses. Overall type I error rate controlled at two-sided 5%.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.07
	Confidence Interval	(2-Sided) 95%; -0.23 to 0.08
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Change From Baseline to Week 52 in Pre-dose Forced Expiratory Volume in 1 Second (FEV1) in Overall Population
Description	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.
Time Frame	Baseline, Week 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS), including all randomized patients who received at least one dose of study drug.

Arm/Group Title	QAW039 150 mg	QAW039 450 mg	Placebo
Arm/Group Description	QAW039 150 mg once daily	QAW039 450 mg once daily	Placebo once daily
Measure Participants	296	293	287
Least Squares Mean (Standard Error) [Liter]	0.153 (0.0247)	0.164 (0.0249)	0.103 (0.0250)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	QAW039 150 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.369
	Comments
	Method	ANCOVA
	Comments	adjusted p-value, closed testing procedure across the primary and key secondary null hypotheses. Overall type I error rate controlled at two-sided 5%.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.050
	Confidence Interval	(2-Sided) 95%; -0.019 to 0.119
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	QAW039 450 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.595
	Comments
	Method	ANCOVA
	Comments	adjusted p-value, closed testing procedure across the primary and key secondary null hypotheses. Overall type I error rate controlled at two-sided 5%.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.061
	Confidence Interval	(2-Sided) 95%; -0.008 to 0.130
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Post-Hoc Outcome

Title	All Collected Deaths
Description	Total Deaths are presented from first dose of study treatment until discontinuation of trial, up to maximum duration of 56 weeks. Deaths on-treatment are presented from first dose of study treatment until last dose of study treatment plus 30 days, up to maximum duration of 56 weeks.
Time Frame	up to 56 weeks

Outcome Measure Data

Analysis Population Description

Safety Set (SAF), including all randomized patients who received at least one dose of study drug

Arm/Group Title	QAW039 150 mg	QAW039 450 mg	Placebo
Arm/Group Description	QAW039 150 mg once daily	QAW039 450 mg once daily	Placebo once daily
Measure Participants	296	293	287
Total Deaths	1 0.3%	1 0.3%	1 0.3%
Deaths on-treatment	0 0%	1 0.3%	1 0.3%

Adverse Events

Time Frame	Adverse events (AEs) are presented from first dose of study treatment until last dose of study treatment plus 7 days post treatment. Serious AEs (including the All-Cause Mortality data table) are presented from first dose of study treatment until last dose of study treatment plus 30 days post treatment, up to maximum duration of 56 weeks.
Adverse Event Reporting Description	Any sign or symptom that occurs during the study treatment plus 7 days post treatment for adverse events and 30 days post treatment for serious adverse events.
Arm/Group Title	QAW039 150 mg		QAW039 450 mg		Placebo
Arm/Group Description	QAW039 150 mg		QAW039 450 mg		Placebo
All Cause Mortality
	QAW039 150 mg		QAW039 450 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/296 (0%)		1/293 (0.3%)		1/287 (0.3%)
Serious Adverse Events
	QAW039 150 mg		QAW039 450 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	20/296 (6.8%)		20/293 (6.8%)		18/287 (6.3%)
Blood and lymphatic system disorders
Anaemia	0/296 (0%)		0/293 (0%)		1/287 (0.3%)
Cardiac disorders
Arteriosclerosis coronary artery	0/296 (0%)		0/293 (0%)		1/287 (0.3%)
Eye disorders
Ulcerative keratitis	1/296 (0.3%)		0/293 (0%)		0/287 (0%)
Gastrointestinal disorders
Abdominal discomfort	0/296 (0%)		0/293 (0%)		1/287 (0.3%)
Abdominal pain upper	1/296 (0.3%)		0/293 (0%)		0/287 (0%)
Inguinal hernia	0/296 (0%)		0/293 (0%)		1/287 (0.3%)
Pancreatitis	1/296 (0.3%)		0/293 (0%)		0/287 (0%)
Rectal haemorrhage	0/296 (0%)		0/293 (0%)		1/287 (0.3%)
Vomiting	1/296 (0.3%)		0/293 (0%)		0/287 (0%)
General disorders
Non-cardiac chest pain	1/296 (0.3%)		0/293 (0%)		0/287 (0%)
Hepatobiliary disorders
Cholelithiasis	0/296 (0%)		1/293 (0.3%)		0/287 (0%)
Liver disorder	0/296 (0%)		1/293 (0.3%)		0/287 (0%)
Infections and infestations
Appendicitis	1/296 (0.3%)		0/293 (0%)		1/287 (0.3%)
Bronchitis	0/296 (0%)		1/293 (0.3%)		1/287 (0.3%)
Escherichia sepsis	0/296 (0%)		1/293 (0.3%)		0/287 (0%)
Gastroenteritis	0/296 (0%)		1/293 (0.3%)		1/287 (0.3%)
Gastrointestinal viral infection	0/296 (0%)		0/293 (0%)		1/287 (0.3%)
Influenza	0/296 (0%)		0/293 (0%)		1/287 (0.3%)
Pneumonia	2/296 (0.7%)		4/293 (1.4%)		3/287 (1%)
Sinusitis	1/296 (0.3%)		0/293 (0%)		0/287 (0%)
Tonsillitis	0/296 (0%)		0/293 (0%)		1/287 (0.3%)
Upper respiratory tract infection	0/296 (0%)		0/293 (0%)		1/287 (0.3%)
Urinary tract infection	0/296 (0%)		1/293 (0.3%)		0/287 (0%)
Viral upper respiratory tract infection	0/296 (0%)		1/293 (0.3%)		0/287 (0%)
Injury, poisoning and procedural complications
Femur fracture	0/296 (0%)		1/293 (0.3%)		0/287 (0%)
Fracture displacement	0/296 (0%)		1/293 (0.3%)		0/287 (0%)
Hip fracture	0/296 (0%)		0/293 (0%)		1/287 (0.3%)
Humerus fracture	1/296 (0.3%)		0/293 (0%)		0/287 (0%)
Lower limb fracture	1/296 (0.3%)		0/293 (0%)		0/287 (0%)
Lumbar vertebral fracture	1/296 (0.3%)		0/293 (0%)		0/287 (0%)
Radius fracture	0/296 (0%)		1/293 (0.3%)		0/287 (0%)
Seroma	0/296 (0%)		1/293 (0.3%)		0/287 (0%)
Ulna fracture	1/296 (0.3%)		0/293 (0%)		0/287 (0%)
Musculoskeletal and connective tissue disorders
Gouty arthritis	0/296 (0%)		0/293 (0%)		1/287 (0.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant melanoma	1/296 (0.3%)		0/293 (0%)		0/287 (0%)
Ovarian neoplasm	1/296 (0.3%)		0/293 (0%)		0/287 (0%)
Parathyroid tumour benign	1/296 (0.3%)		0/293 (0%)		0/287 (0%)
Renal neoplasm	0/296 (0%)		1/293 (0.3%)		0/287 (0%)
Squamous cell carcinoma of skin	0/296 (0%)		0/293 (0%)		1/287 (0.3%)
Nervous system disorders
Brain hypoxia	0/296 (0%)		1/293 (0.3%)		0/287 (0%)
Renal and urinary disorders
Acute kidney injury	0/296 (0%)		1/293 (0.3%)		0/287 (0%)
Renal failure	1/296 (0.3%)		0/293 (0%)		0/287 (0%)
Reproductive system and breast disorders
Uterine enlargement	0/296 (0%)		0/293 (0%)		1/287 (0.3%)
Uterine prolapse	0/296 (0%)		1/293 (0.3%)		0/287 (0%)
Respiratory, thoracic and mediastinal disorders
Asthma	8/296 (2.7%)		6/293 (2%)		6/287 (2.1%)
Atelectasis	0/296 (0%)		1/293 (0.3%)		0/287 (0%)
Nasal polyps	0/296 (0%)		2/293 (0.7%)		0/287 (0%)
Pulmonary embolism	0/296 (0%)		1/293 (0.3%)		0/287 (0%)
Vascular disorders
Arterial thrombosis	1/296 (0.3%)		0/293 (0%)		0/287 (0%)
Lymphoedema	0/296 (0%)		1/293 (0.3%)		0/287 (0%)
Other (Not Including Serious) Adverse Events
	QAW039 150 mg		QAW039 450 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	181/296 (61.1%)		183/293 (62.5%)		180/287 (62.7%)
Infections and infestations
Bronchitis	37/296 (12.5%)		30/293 (10.2%)		32/287 (11.1%)
Influenza	17/296 (5.7%)		18/293 (6.1%)		13/287 (4.5%)
Nasopharyngitis	33/296 (11.1%)		42/293 (14.3%)		26/287 (9.1%)
Rhinitis	10/296 (3.4%)		15/293 (5.1%)		13/287 (4.5%)
Upper respiratory tract infection	18/296 (6.1%)		16/293 (5.5%)		14/287 (4.9%)
Upper respiratory tract infection bacterial	10/296 (3.4%)		8/293 (2.7%)		14/287 (4.9%)
Viral upper respiratory tract infection	20/296 (6.8%)		28/293 (9.6%)		24/287 (8.4%)
Musculoskeletal and connective tissue disorders
Back pain	13/296 (4.4%)		5/293 (1.7%)		9/287 (3.1%)
Nervous system disorders
Headache	19/296 (6.4%)		21/293 (7.2%)		9/287 (3.1%)
Respiratory, thoracic and mediastinal disorders
Asthma	129/296 (43.6%)		119/293 (40.6%)		145/287 (50.5%)
Rhinitis allergic	13/296 (4.4%)		8/293 (2.7%)		9/287 (3.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.