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

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01836471
• Collaborator: (none)
• Enrollment: 345
• Locations: 76
• Arms: 5
• Duration (Months): 33.1
• Patients Per Site: 4.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Asthma	Drug: QAW039; Drug: Placebo QAW039; Drug: Fluticasone 250 mcg; Drug: Fluticasone 100 mcg	Phase 2

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 345 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: May 1, 2013
• Actual Primary Completion Date: Feb 1, 2016
• Actual Study Completion Date: Feb 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: QAW039 450 mg qd Non-atopic 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; 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); Drug: Fluticasone 100 mcg; 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).
Placebo Comparator: Placebo Non-atopic 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; 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); Drug: Fluticasone 100 mcg; 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).
Experimental: QAW039 450 mg qd Atopic 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; 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); Drug: Fluticasone 100 mcg; 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).
Active Comparator: Fluticasone 150 mcg bid Atopic 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; 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); Drug: Fluticasone 250 mcg; 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).
Placebo Comparator: Placebo Atopic 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; 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); Drug: Fluticasone 100 mcg; 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).

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Trough FEV1 (L) in Non-atopic Patients at Week 12 - Full Analysis Set [baseline,12 weeks]

   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.

Secondary Outcome Measures

1. Change From Baseline in Trough FEV1 (L) in Atopic Patients at Week 12 - Full Analysis Set [baseline,12 weeks]

   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.

2. Change From Baseline in Trough FEV1 (L) in Non-atopic Compared to Atopic Patients at Week 12 - Full Analysis Set [baseline,12 weeks]

   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.

3. Change From Baseline in ACQ-6 Score at Week 12 Non-atopic and Atopic Patients at Week 12 - Full Analysis Set [baseline,12 weeks]

   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.

4. Change From Baseline in ACQ-6 Score at Week 12 Non-atopic Compared to Atopic Patients at Week 12 - Full Analysis Set [baseline,12 weeks]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Encinitas	California	United States	92024
2	Novartis Investigative Site	Huntington Beach	California	United States	92647
3	Novartis Investigative Site	Los Angeles	California	United States	90025
4	Novartis Investigative Site	Los Angeles	California	United States	90048
5	Novartis Investigative Site	Mission Viejo	California	United States	92691
6	Novartis Investigative Site	Orange	California	United States	92868
7	Novartis Investigative Site	Palmdale	California	United States	93551
8	Novartis Investigative Site	Riverside	California	United States	92506
9	Novartis Investigative Site	Rolling Hills Estates	California	United States	90274
10	Novartis Investigative Site	San Diego	California	United States	92123
11	Novartis Investigative Site	San Jose	California	United States	95117
12	Novartis Investigative Site	Stockton	California	United States	95207
13	Novartis Investigative Site	Colorado Springs	Colorado	United States	80907
14	Novartis Investigative Site	Denver	Colorado	United States	80206
15	Novartis Investigative Site	Denver	Colorado	United States	80230
16	Novartis Investigative Site	Sarasota	Florida	United States	34233
17	Novartis Investigative Site	Owensboro	Kentucky	United States	42301
18	Novartis Investigative Site	North Dartmouth	Massachusetts	United States	02747
19	Novartis Investigative Site	Minneapolis	Minnesota	United States	55402
20	Novartis Investigative Site	St. Louis	Missouri	United States	63128
21	Novartis Investigative Site	St. Louis	Missouri	United States	63141
22	Novartis Investigative Site	Papillion	Nebraska	United States	68046
23	Novartis Investigative Site	Skillman	New Jersey	United States	08558
24	Novartis Investigative Site	Charlotte	North Carolina	United States	28207
25	Novartis Investigative Site	Cincinnati	Ohio	United States	45231
26	Novartis Investigative Site	Medford	Oregon	United States	97504-8741
27	Novartis Investigative Site	Portland	Oregon	United States	97213
28	Novartis Investigative Site	Lincoln	Rhode Island	United States	02865
29	Novartis Investigative Site	Charleston	South Carolina	United States	29407
30	Novartis Investigative Site	Seattle	Washington	United States	98104
31	Novartis Investigative Site	Erpent		Belgium	5100
32	Novartis Investigative Site	Liege		Belgium	4000
33	Novartis Investigative Site	Barranquilla	Atlantico	Colombia
34	Novartis Investigative Site	Bogotá	Cundinamarca	Colombia
35	Novartis Investigative Site	Barranquilla		Colombia
36	Novartis Investigative Site	Medellín		Colombia
37	Novartis Investigative Site	Hradec Kralove	CZE	Czech Republic	500 05
38	Novartis Investigative Site	Karlovy Vary-Stara Rokle	CZE	Czech Republic	360 17
39	Novartis Investigative Site	Teplice	CZE	Czech Republic	415 01
40	Novartis Investigative Site	Trutnov		Czech Republic	541 01
41	Novartis Investigative Site	Berlin		Germany	10717
42	Novartis Investigative Site	Frankfurt		Germany	60596
43	Novartis Investigative Site	Leipzig		Germany	04357
44	Novartis Investigative Site	Lübeck		Germany	23552
45	Novartis Investigative Site	Marburg		Germany	D-35037
46	Novartis Investigative Site	Wiesbaden		Germany	65187
47	Novartis Investigative Site	Witten		Germany	58452
48	Novartis Investigative Site	Hyderabad	Andhra Pradesh	India	500 068
49	Novartis Investigative Site	Panjim	Goa	India	403 002
50	Novartis Investigative Site	Nagpur	Maharashtra	India	400 012
51	Novartis Investigative Site	Nagpur	Maharashtra	India	440010
52	Novartis Investigative Site	Coimbatore	Tamil Nadu	India	641 045
53	Novartis Investigative Site	Cheongju-si	Chungcheongbuk-do	Korea, Republic of	28644
54	Novartis Investigative Site	Bucheon-Si	Gyeonggi-Do	Korea, Republic of	14584
55	Novartis Investigative Site	Suwon	Gyeonggi-do	Korea, Republic of	443-721
56	Novartis Investigative Site	Seoul	Korea	Korea, Republic of	06591
57	Novartis Investigative Site	Gwangju		Korea, Republic of	501-757
58	Novartis Investigative Site	Bialystok		Poland	15-010
59	Novartis Investigative Site	Bialystok		Poland	15-044
60	Novartis Investigative Site	Lodz		Poland	90-153
61	Novartis Investigative Site	Wroclaw		Poland	50-349
62	Novartis Investigative Site	Bucuresti	District 1	Romania	10457
63	Novartis Investigative Site	Bucharest	District 3	Romania	030303
64	Novartis Investigative Site	Bucharest	District 3	Romania	030317
65	Novartis Investigative Site	Craiova	Dolj	Romania	200515
66	Novartis Investigative Site	Arad		Romania	310013
67	Novartis Investigative Site	Craiova		Romania	200515
68	Novartis Investigative Site	Deva		Romania	330162
69	Novartis Investigative Site	Timisoara		Romania	300736
70	Novartis Investigative Site	Cape Town		South Africa	7500
71	Novartis Investigative Site	Cape Town		South Africa	7531
72	Novartis Investigative Site	Cape Town		South Africa	7925
73	Novartis Investigative Site	Cape Town		South Africa	8001
74	Novartis Investigative Site	Durban		South Africa	4001
75	Novartis Investigative Site	Gatesville		South Africa	7764
76	Novartis Investigative Site	Pretoria		South Africa	0181

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Richard Kay, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01836471
• Other Study ID Numbers: CQAW039A2214; 2012-003995-38
• First Posted: Apr 22, 2013
• Last Update Posted: Mar 20, 2017
• Last Verified: Jan 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Asthma; Fluticasone; Xhance; Indoleacetic Acids

Study Results

Participant Flow

Pre-assignment Detail	Total of 939 subjects were screened, 679 entered the inhaled corticosteroid (ICS) tapering run-in, 345 subjects were randomized; eleven randomized subjects discontinued the study prior to start of study drug. Patient disposition and baseline characteristics were presented for 334 subjects (received study drug)

Arm/Group Title	QAW039 450 mg qd Non-atopic	Placebo Non-atopic	QAW039 450 mg qd Atopic	Fluticasone 150 µg Bid Atopic	Placebo Atopic
Arm/Group Description	QAW039 450 mg qd plus background ICS (100 μg fluticasone, bid). Non-atopic patients randomized in ratio of approximately 1:1 to QAW039 or placebo.	Placebo to QAW039 450 mg qd plus background ICS (100 μg fluticasone, bid). Non-atopic patients randomized in ratio of approximately 1:1 to QAW039 or placebo.	QAW039 450 mg qd plus background ICS (100 μg fluticasone, bid). Atopic patients randomized in ratio of approximately 1:1:1 to QAW039 or fluticasone or placebo.	Fluticasone 150 µg plus background ICS (100 μg fluticasone, bid). Atopic patients randomized in ratio of approximately 1:1:1 to QAW039 or fluticasone or placebo.	Placebo to QAW039 450 mg qd plus background ICS (100 μg fluticasone, bid). Atopic patients randomized in ratio of approximately 1:1:1 to QAW039 or fluticasone or placebo.
Period Title: Overall Study
STARTED	93	94	51	42	54
COMPLETED	82	85	49	40	49
NOT COMPLETED	11	9	2	2	5

Baseline Characteristics

Arm/Group Title	QAW039 450 mg qd Non-atopic	Placebo Non-atopic	QAW039 450 mg qd Atopic	Fluticasone 150 µg Bid Atopic	Placebo Atopic	Total
Arm/Group Description	QAW039 450 mg qd plus background ICS (100 μg fluticasone, bid). Non-atopic patients randomized in ratio of approximately 1:1 to QAW039 or placebo.	Placebo to QAW039 450 mg qd plus background ICS (100 μg fluticasone, bid). Non-atopic patients randomized in ratio of approximately 1:1 to QAW039 or placebo.	QAW039 450 mg qd plus background ICS (100 μg fluticasone, bid). Atopic patients randomized in ratio of approximately 1:1:1 to QAW039 or fluticasone or placebo.	Fluticasone 150 µg plus background ICS (100 μg fluticasone, bid). Atopic patients randomized in ratio of approximately 1:1:1 to QAW039 or fluticasone or placebo.	Placebo to QAW039 450 mg qd plus background ICS (100 μg fluticasone, bid). Atopic patients randomized in ratio of approximately 1:1:1 to QAW039 or fluticasone or placebo.	Total of all reporting groups
Overall Participants	93	94	51	42	54	334
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	51.9 (14.33)	53.5 (14.37)	50.3 (12.75)	48.2 (12.16)	48.2 (13.58)	51.0 (13.81)
Sex: Female, Male (Count of Participants)
Female	60 64.5%	60 63.8%	26 51%	23 54.8%	25 46.3%	194 58.1%
Male	33 35.5%	34 36.2%	25 49%	19 45.2%	29 53.7%	140 41.9%
Race/Ethnicity, Customized (participants) [Number]
American Indian or Alaska Native	2 2.2%	3 3.2%	3 5.9%	3 7.1%	2 3.7%	13 3.9%
Asian	15 16.1%	16 17%	4 7.8%	6 14.3%	3 5.6%	44 13.2%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	1 1.9%	1 0.3%
Black or African American	6 6.5%	6 6.4%	3 5.9%	3 7.1%	4 7.4%	22 6.6%
White	68 73.1%	68 72.3%	40 78.4%	29 69%	43 79.6%	248 74.3%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Other	2 2.2%	1 1.1%	1 2%	1 2.4%	1 1.9%	6 1.8%
Duration of asthma (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	14.88 (12.349)	12.82 (12.196)	24.69 (17.446)	27.78 (18.039)	24.09 (16.055)	18.91 (15.648)
Subject population (Number) [Number]
Non-atopic	93 100%	94 100%	0 0%	0 0%	0 0%	187 56%
Atopic	0 0%	0 0%	51 100%	42 100%	54 100%	147 44%
Percentage of predicted FEV1 (%) pre-bronchodilator (Percentage) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Percentage]	67.5446 (11.81404)	65.7286 (13.94056)	69.0662 (12.16292)	68.7483 (10.52156)	64.8709 (12.97729)	66.9849 (12.56166)
ACQ-6 score (points) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [points]	1.70 (0.762)	1.53 (0.745)	1.55 (0.665)	1.68 (0.749)	1.72 (0.675)	1.63 (0.728)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Trough FEV1 (L) in Non-atopic Patients at Week 12 - Full Analysis Set
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. 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.
Time Frame	baseline,12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	QAW039 450 mg qd Non-atopic	Placebo Non-atopic
Arm/Group Description	QAW039 450 mg qd plus background ICS (100 μg fluticasone, bid). Non-atopic patients randomized in ratio of approximately 1:1 to QAW039 or placebo.	Placebo to QAW039 450 mg qd plus background ICS (100 μg fluticasone, bid). Non-atopic patients randomized in ratio of approximately 1:1 to QAW039 or placebo.
Measure Participants	91	93
Least Squares Mean (Standard Error) [liter]	0.05 (0.029)	0.03 (0.029)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	QAW039 450 mg qd Non-atopic, Placebo Non-atopic
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7269
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	least squares mean
	Estimated Value	0.01
	Confidence Interval	(2-Sided) 90%; -0.5 to 0.08
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.038
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in Trough FEV1 (L) in Atopic Patients at Week 12 - Full Analysis Set
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 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.
Time Frame	baseline,12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	QAW039 450 mg qd Atopic	Fluticasone 150 µg Bid Atopic	Placebo Atopic
Arm/Group Description	QAW039 450 mg qd plus background ICS (100 μg fluticasone, bid). Atopic patients randomized in ratio of approximately 1:1:1 to QAW039 or fluticasone or placebo.	Fluticasone 150 µg plus background ICS (100 μg fluticasone, bid). Atopic patients randomized in ratio of approximately 1:1:1 to QAW039 or fluticasone or placebo.	Placebo to QAW039 450 mg qd plus background ICS (100 μg fluticasone, bid). Atopic patients randomized in ratio of approximately 1:1:1 to QAW039 or fluticasone or placebo.
Measure Participants	50	41	52
Least Squares Mean (Standard Error) [liter]	0.06 (0.038)	0.01 (0.042)	0.05 (0.037)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	QAW039 450 mg qd Non-atopic, Placebo Atopic
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	least sqares mean
	Estimated Value	0.01
	Confidence Interval	(2-Sided) 90%; -0.08 to 0.09
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.050
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	QAW039 450 mg qd Non-atopic, Placebo Non-atopic
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	least squares mean
	Estimated Value	0.04
	Confidence Interval	(2-Sided) 90%; -0.04 to 0.13
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.054
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo Non-atopic, Placebo Atopic
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	least squares mean
	Estimated Value	-0.04
	Confidence Interval	(2-Sided) 90%; -0.13 to 0.05
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.053
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline in Trough FEV1 (L) in Non-atopic Compared to Atopic Patients at Week 12 - Full Analysis Set
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 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.
Time Frame	baseline,12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	QAW039 450 mg qd Non-atopic	Placebo Non-atopic	QAW039 450 mg qd Atopic	Fluticasone 150 µg Bid Atopic	Placebo Atopic
Arm/Group Description	QAW039 450 mg qd plus background ICS (100 μg fluticasone, bid). Non-atopic patients randomized in ratio of approximately 1:1 to QAW039 or placebo.	Placebo to QAW039 450 mg qd plus background ICS (100 μg fluticasone, bid). Non-atopic patients randomized in ratio of approximately 1:1 to QAW039 or placebo.	QAW039 450 mg qd plus background ICS (100 μg fluticasone, bid). Atopic patients randomized in ratio of approximately 1:1:1 to QAW039 or fluticasone or placebo.	Fluticasone 150 µg plus background ICS (100 μg fluticasone, bid). Atopic patients randomized in ratio of approximately 1:1:1 to QAW039 or fluticasone or placebo.	Placebo to QAW039 450 mg qd plus background ICS (100 μg fluticasone, bid). Atopic patients randomized in ratio of approximately 1:1:1 to QAW039 or fluticasone or placebo.
Measure Participants	91	93	50	41	52
Least Squares Mean (Standard Error) [liter]	0.05 (0.029)	0.03 (0.029)	0.06 (0.038)	0.01 (0.042)	0.05 (0.037)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	QAW039 450 mg qd Non-atopic, Placebo Non-atopic, Placebo Atopic, Fluticasone 150 µg Bid Atopic, Placebo Atopic
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9179
	Comments
	Method	Mixed Models Analysis
	Comments

4. Secondary Outcome

Title	Change From Baseline in ACQ-6 Score at Week 12 Non-atopic and Atopic Patients at Week 12 - Full Analysis Set
Description	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.
Time Frame	baseline,12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	QAW039 450 mg qd Non-atopic	Placebo Non-atopic	QAW039 450 mg qd Atopic	Fluticasone 150 µg Bid Atopic	Placebo Atopic
Arm/Group Description	QAW039 450 mg qd plus background ICS (100 μg fluticasone, bid). Non-atopic patients randomized in ratio of approximately 1:1 to QAW039 or placebo.	Placebo to QAW039 450 mg qd plus background ICS (100 μg fluticasone, bid). Non-atopic patients randomized in ratio of approximately 1:1 to QAW039 or placebo.	QAW039 450 mg qd plus background ICS (100 μg fluticasone, bid). Atopic patients randomized in ratio of approximately 1:1:1 to QAW039 or fluticasone or placebo.	Fluticasone 150 µg plus background ICS (100 μg fluticasone, bid). Atopic patients randomized in ratio of approximately 1:1:1 to QAW039 or fluticasone or placebo.	Placebo to QAW039 450 mg qd plus background ICS (100 μg fluticasone, bid). Atopic patients randomized in ratio of approximately 1:1:1 to QAW039 or fluticasone or placebo.
Measure Participants	80	85	48	40	48
Least Squares Mean (Standard Error) [score]	-0.05 (0.077)	-0.03 (0.073)	-0.25 (0.096)	-0.35 (0.104)	-0.18 (0.096)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	QAW039 450 mg qd Non-atopic, Placebo Non-atopic
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	least squares mean
	Estimated Value	-0.02
	Confidence Interval	(2-Sided) 95%; -0.22 to 0.17
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.098
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo Atopic, Placebo Atopic
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	least sqares mean
	Estimated Value	-0.07
	Confidence Interval	(2-Sided) 95%; -0.32 to 0.19
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.128
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo Atopic, Fluticasone 150 µg Bid Atopic
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	least squares mean
	Estimated Value	0.10
	Confidence Interval	(2-Sided) 95%; -0.16 to 0.37
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.134
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Fluticasone 150 µg Bid Atopic, Placebo Atopic
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	least squares mean
	Estimated Value	-0.17
	Confidence Interval	(2-Sided) 95%; -0.43 to 0.09
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.134
	Estimation Comments

5. Secondary Outcome

Title	Change From Baseline in ACQ-6 Score at Week 12 Non-atopic Compared to Atopic Patients at Week 12 - Full Analysis Set
Description	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.
Time Frame	baseline,12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	QAW039 450 mg qd Non-atopic	Placebo Non-atopic	QAW039 450 mg qd Atopic	Fluticasone 150 µg Bid Atopic	Placebo Atopic
Arm/Group Description	QAW039 450 mg qd plus background ICS (100 μg fluticasone, bid). Non-atopic patients randomized in ratio of approximately 1:1 to QAW039 or placebo.	Placebo to QAW039 450 mg qd plus background ICS (100 μg fluticasone, bid). Non-atopic patients randomized in ratio of approximately 1:1 to QAW039 or placebo.	QAW039 450 mg qd plus background ICS (100 μg fluticasone, bid). Atopic patients randomized in ratio of approximately 1:1:1 to QAW039 or fluticasone or placebo.	Fluticasone 150 µg plus background ICS (100 μg fluticasone, bid). Atopic patients randomized in ratio of approximately 1:1:1 to QAW039 or fluticasone or placebo.	Placebo to QAW039 450 mg qd plus background ICS (100 μg fluticasone, bid). Atopic patients randomized in ratio of approximately 1:1:1 to QAW039 or fluticasone or placebo.
Measure Participants	80	85	48	40	48
Least Squares Mean (Standard Error) [score]	-0.05 (0.077)	-0.03 (0.073)	-0.25 (0.096)	-0.35 (0.104)	-0.18 (0.096)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	QAW039 450 mg qd Non-atopic, Placebo Non-atopic, Placebo Atopic, Fluticasone 150 µg Bid Atopic, Placebo Atopic
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7930
	Comments
	Method	Mixed Models Analysis
	Comments

Adverse Events

Time Frame	Timeframe for AE
Adverse Event Reporting Description	AE additional description
Arm/Group Title	QAW039 450 mg qd		Fluticasone 150 mcg Bid		Placebo
Arm/Group Description	QAW039 450 mg qd		Fluticasone 150 mcg bid		Placebo
All Cause Mortality
	QAW039 450 mg qd		Fluticasone 150 mcg Bid		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	QAW039 450 mg qd		Fluticasone 150 mcg Bid		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/145 (1.4%)		0/42 (0%)		3/147 (2%)
Cardiac disorders
CORONARY ARTERY DISEASE	0/145 (0%)		0/42 (0%)		1/147 (0.7%)
Hepatobiliary disorders
HEPATIC STEATOSIS	0/145 (0%)		0/42 (0%)		1/147 (0.7%)
Immune system disorders
ANAPHYLACTIC REACTION	1/145 (0.7%)		0/42 (0%)		0/147 (0%)
Nervous system disorders
PRESYNCOPE	0/145 (0%)		0/42 (0%)		1/147 (0.7%)
Reproductive system and breast disorders
OVARIAN CYST	1/145 (0.7%)		0/42 (0%)		0/147 (0%)
Other (Not Including Serious) Adverse Events
	QAW039 450 mg qd		Fluticasone 150 mcg Bid		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	36/145 (24.8%)		19/42 (45.2%)		35/147 (23.8%)
Gastrointestinal disorders
DENTAL CARIES	0/145 (0%)		1/42 (2.4%)		0/147 (0%)
NAUSEA	1/145 (0.7%)		1/42 (2.4%)		1/147 (0.7%)
Infections and infestations
ACUTE SINUSITIS	0/145 (0%)		0/42 (0%)		3/147 (2%)
BRONCHITIS	3/145 (2.1%)		0/42 (0%)		4/147 (2.7%)
CONJUNCTIVITIS VIRAL	0/145 (0%)		1/42 (2.4%)		0/147 (0%)
INFLUENZA	2/145 (1.4%)		0/42 (0%)		3/147 (2%)
NASOPHARYNGITIS	5/145 (3.4%)		1/42 (2.4%)		3/147 (2%)
ORAL CANDIDIASIS	0/145 (0%)		1/42 (2.4%)		1/147 (0.7%)
PHARYNGITIS	1/145 (0.7%)		1/42 (2.4%)		0/147 (0%)
RHINITIS	2/145 (1.4%)		2/42 (4.8%)		0/147 (0%)
SINUSITIS BACTERIAL	3/145 (2.1%)		0/42 (0%)		0/147 (0%)
SKIN INFECTION	0/145 (0%)		1/42 (2.4%)		0/147 (0%)
TONSILLITIS	0/145 (0%)		1/42 (2.4%)		0/147 (0%)
UPPER RESPIRATORY TRACT INFECTION	7/145 (4.8%)		1/42 (2.4%)		5/147 (3.4%)
VIRAL UPPER RESPIRATORY TRACT INFECTION	2/145 (1.4%)		1/42 (2.4%)		3/147 (2%)
Injury, poisoning and procedural complications
LIGAMENT SPRAIN	0/145 (0%)		1/42 (2.4%)		0/147 (0%)
WOUND	0/145 (0%)		1/42 (2.4%)		0/147 (0%)
Investigations
BLOOD TRIGLYCERIDES INCREASED	1/145 (0.7%)		1/42 (2.4%)		0/147 (0%)
ELECTROCARDIOGRAM QT PROLONGED	1/145 (0.7%)		2/42 (4.8%)		0/147 (0%)
Musculoskeletal and connective tissue disorders
ARTHRALGIA	1/145 (0.7%)		1/42 (2.4%)		1/147 (0.7%)
ARTHRITIS	0/145 (0%)		1/42 (2.4%)		0/147 (0%)
MUSCULOSKELETAL PAIN	0/145 (0%)		1/42 (2.4%)		0/147 (0%)
SYNOVIAL CYST	0/145 (0%)		1/42 (2.4%)		0/147 (0%)
Nervous system disorders
HEADACHE	1/145 (0.7%)		0/42 (0%)		3/147 (2%)
SYNCOPE	0/145 (0%)		1/42 (2.4%)		0/147 (0%)
Renal and urinary disorders
HAEMATURIA	0/145 (0%)		1/42 (2.4%)		0/147 (0%)
Reproductive system and breast disorders
DYSMENORRHOEA	0/145 (0%)		1/42 (2.4%)		1/147 (0.7%)
Respiratory, thoracic and mediastinal disorders
ASTHMA	10/145 (6.9%)		2/42 (4.8%)		13/147 (8.8%)
COUGH	3/145 (2.1%)		0/42 (0%)		1/147 (0.7%)
PRODUCTIVE COUGH	1/145 (0.7%)		0/42 (0%)		3/147 (2%)
Skin and subcutaneous tissue disorders
DERMATITIS CONTACT	0/145 (0%)		2/42 (4.8%)		0/147 (0%)
ECZEMA	0/145 (0%)		1/42 (2.4%)		0/147 (0%)
ERYTHEMA	0/145 (0%)		1/42 (2.4%)		0/147 (0%)

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 (i.e., data from all sites) in the clinical trial.