Efficacy and Safety Study of Indacaterol Maleate/Glycopyrronium Bromide in Chronic Obstructive Pulmonary Disease (COPD) Patients.

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02487498
• Collaborator: (none)
• Enrollment: 355
• Locations: 53
• Arms: 2
• Actual Duration (Months): 13.4
• Patients Per Site: 6.7
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

The purpose of this study is to demonstrate that the efficacy of the combination product QVA149 is similar to the efficacy of the combination product umeclidinium/vilanterol on a pre-specified endpoint of FEV1 AUC0-24h while maintaining an acceptable safety profile.

Condition or Disease	Intervention/Treatment	Phase
Chronic Obstructive Pulmonary Disease	Drug: QVA149; Drug: Umeclidinium/vilanterol; Drug: Placebo (umeclidinium/vilanterol ); Drug: Placebo (QVA149)	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 355 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Multi-center, Randomized, Double-blind, Double-dummy, Active Controlled, Two-period Cross-over Study to Assess the Efficacy, Safety and Tolerability of Indacaterol Maleate/Glycopyrronium Bromide Compared to Umeclidinium Bromide/Vilanterol in COPD Patients With Moderate to Severe Airflow Limitation.
• Actual Study Start Date: Jul 27, 2015
• Actual Primary Completion Date: Sep 6, 2016
• Actual Study Completion Date: Sep 6, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: QVA149 QVA149 capsules for inhalation, delivered via QVA149 SDDPI	Drug: QVA149; QVA149 capsules for inhalation, delivered via QVA149 SDDPI; Drug: Placebo (umeclidinium/vilanterol ); Matching Placebo to umeclidinium/vilanterol for inhalation, delivered via ELLIPTA® inhaler
Experimental: Umeclidinium/vilanterol Umeclidinium/vilanterol for inhalation, delivered via ELLIPTA® inhaler	Drug: Umeclidinium/vilanterol; Umeclidinium/vilanterol for inhalation, delivered via ELLIPTA® inhaler; Drug: Placebo (QVA149); Matching Placebo to QVA149 capsules for inhalation, delivered via QVA149 SDDPI

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Forced Expiratory Volume (FEV1) Area Under the Curve (AUC) 0-24h [baseline, 0 to 24 hours post-dose at week 12]

   FEV1 was measured with spirometry conducted according to internationally accepted standards. The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time over an entire day (AUC 0-24h). A positive change from baseline indicates improvement.

Secondary Outcome Measures

1. Change From Baseline in Forced Expiratory Volume (FEV1) Area Under the Curve (AUC) 0-24h [baseline, 0 to 24 hours post-dose at week 12]

   FEV1 was measured with spirometry conducted according to internationally accepted standards. The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time over an entire day (AUC 0-24h). A positive change from baseline indicates improvement.

2. Superiority of QVA149 Compared to Umeclidinium/Vilanterol in Terms of Change From Baseline in Trough FEV1 (Mean of 23h 15 Minutes and 23 h 45 Minutes Post Previous Morning Dose) [baseline, 23 hours 15 minutes and 23 hours 45 minutes post previous morning dose at week 12]

   FEV1 was measured with spirometry conducted according to internationally accepted standards. Trough FEV1 was defined as the average of measurements made 23 hours 15 minutes and 23 hours 45 minutes post-dose for each treatment.

3. Change From Baseline in FEV1 AUC 12-24h [baseline, 12 hours to 24 hours post-dose at week 12]

   FEV1 was measured with spirometry conducted according to internationally accepted standards. The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time over 12 hours (AUC 12-24h).

4. Change From Baseline in FEV1 AUC 0-12h [baseline, 0 to 12 hours post-dose at week 12]

   FEV1 was measured with spirometry conducted according to internationally accepted standards. The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time over 12 hours (AUC 0-12h).

5. Change From Baseline in FEV1 AUC 0-4h, AUC 4-8h, AUC 8-12h, AUC 12-16h, AUC 16-20h and AUC 20-24h [baseline, 12 weeks]

   FEV1 was measured with spirometry conducted according to internationally accepted standards. The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time over 4 hour intervals FEV1 AUC 0-4h, AUC 4-8h, AUC 8-12h, AUC 12-16h, AUC 16-20h and AUC 20-24h.

6. QVA149 Compared to Umeclidinium/Vilanterol in Terms of Change From Baseline in Pre-dose Trough FEV1 (Mean of 15 Minutes and 45 Minutes Pre Morning Dose) [baseline, 12 weeks]

   FEV1 was measured with spirometry conducted according to internationally accepted standards. Pre-dose trough FEV1 was defined as the average of measurements made 15 minutes and 45 minutes pre morning dose for each treatment.

7. QVA149 Compared to Umeclidinium/Vilanterol in Terms of Change From Baseline in FEV1 at Any Time Point [Day 1 (5min, 15min, 30min, hours 1, 2, 4, 8, 11h 55min, 23h 15min, 23h 45min); week 6 (-45min, -15min); week 12 (-45min, -15min, 5min, 15min, 30min, hours 1, 2, 4, 8, 11h 55min, 12h 5min, 12h 15min, 12h 30min, 13, 14, 16, 20, 23h 15min, 23h 45min)]

   FEV1 was measured with spirometry conducted according to internationally accepted standards.

8. QVA149 Compared to Umeclidinium/Vilanterol in Terms of Change From Baseline in Forced Vital Capacity (FVC) at Any Time Point [Day 1 (5min, 15min, 30 min, hours 1, 2, 4, 8, 11h 55min, 23h 15min, 23h 45min); week 6 (-45min, -15min); week 12 (-45min, -15min, 5min, 15min, 30min, hours 1, 2, 4, 8, 11h 55min, 12h 5min, 12h 15min, 12h 30min, 13, 14, 16, 20, 23h 15min, 23h 45min)]

   FEV1 was measured with spirometry conducted according to internationally accepted standards.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male or female adults aged ≥40 yrs

• Smoking history of at least 10 pack years

• Diagnosis of stable Chronic Obstructive Pulmonary Disease (COPD) as classified by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) Guidelines, 2015)

• Post-bronchodilator Forced Expiratory Volume in 1 Second (FEV1)< 80% and ≥ 30% of the predicted normal value and post-bronchodilator FEV1/FVC (forced vital capacity) <70%

• Modified Medical Research Council questionnaire grade of 2 or higher

Exclusion Criteria:

• Patients who have had a respiratory tract infection within 4 weeks prior to Visit 1

• Patients with concomitant pulmonary disease

• Patients with a history of asthma

• Any patient with lung cancer or a history of lung cancer

• Patients with a history of certain cardiovascular co-morbid conditions

• Patients with a known history and diagnosis of alpha-1 antitrypsin deficiency

• Patients in the active phase of a supervised pulmonary rehabilitation program

• Patients contraindicated for inhaled anticholinergic agents and β2 agonists

• Other protocol-defined inclusion/exclusion criteria may apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Anaheim	California	United States	92801
2	Novartis Investigative Site	Escondido	California	United States	92025
3	Novartis Investigative Site	Riverside	California	United States	92506
4	Novartis Investigative Site	San Diego	California	United States	92103-8415
5	Novartis Investigative Site	San Diego	California	United States	92117
6	Novartis Investigative Site	San Diego	California	United States	92120
7	Novartis Investigative Site	Chiefland	Florida	United States	32626
8	Novartis Investigative Site	Clearwater	Florida	United States	33765
9	Novartis Investigative Site	Gainesville	Florida	United States	32607
10	Novartis Investigative Site	Miami	Florida	United States	33144
11	Novartis Investigative Site	Miami	Florida	United States	33169
12	Novartis Investigative Site	Winter Park	Florida	United States	32789
13	Novartis Investigative Site	Florence	Kentucky	United States	41042
14	Novartis Investigative Site	Owensboro	Kentucky	United States	42303
15	Novartis Investigative Site	North Dartmouth	Massachusetts	United States	02747
16	Novartis Investigative Site	Livonia	Michigan	United States	48152
17	Novartis Investigative Site	Saint Charles	Missouri	United States	63301
18	Novartis Investigative Site	Saint Louis	Missouri	United States	63141
19	Novartis Investigative Site	Lincoln	Nebraska	United States	68510
20	Novartis Investigative Site	Omaha	Nebraska	United States	68134
21	Novartis Investigative Site	Skillman	New Jersey	United States	08558
22	Novartis Investigative Site	Gastonia	North Carolina	United States	28054
23	Novartis Investigative Site	Monroe	North Carolina	United States	28112
24	Novartis Investigative Site	New Bern	North Carolina	United States	28562
25	Novartis Investigative Site	Raleigh	North Carolina	United States	27607
26	Novartis Investigative Site	Shelby	North Carolina	United States	28150
27	Novartis Investigative Site	Wilmington	North Carolina	United States	28401
28	Novartis Investigative Site	Cincinnati	Ohio	United States	45231
29	Novartis Investigative Site	Cincinnati	Ohio	United States	45245
30	Novartis Investigative Site	Eugene	Oregon	United States	97404
31	Novartis Investigative Site	Pottstown	Pennsylvania	United States	19464
32	Novartis Investigative Site	Anderson	South Carolina	United States	29621
33	Novartis Investigative Site	Charleston	South Carolina	United States	29406-7108
34	Novartis Investigative Site	Charleston	South Carolina	United States	29407
35	Novartis Investigative Site	Easley	South Carolina	United States	29640
36	Novartis Investigative Site	Fort Mill	South Carolina	United States	29707
37	Novartis Investigative Site	Gaffney	South Carolina	United States	29340
38	Novartis Investigative Site	Greenville	South Carolina	United States	29615
39	Novartis Investigative Site	Mount Pleasant	South Carolina	United States	29464
40	Novartis Investigative Site	Rock Hill	South Carolina	United States	29732
41	Novartis Investigative Site	Seneca	South Carolina	United States	29678
42	Novartis Investigative Site	Simpsonville	South Carolina	United States	29681
43	Novartis Investigative Site	Spartanburg	South Carolina	United States	29303
44	Novartis Investigative Site	Union	South Carolina	United States	29379
45	Novartis Investigative Site	Amarillo	Texas	United States	79106-4165
46	Novartis Investigative Site	Boerne	Texas	United States	78006
47	Novartis Investigative Site	El Paso	Texas	United States	79903
48	Novartis Investigative Site	Fort Worth	Texas	United States	76104
49	Novartis Investigative Site	Kingwood	Texas	United States	77339
50	Novartis Investigative Site	Plano	Texas	United States	75093
51	Novartis Investigative Site	San Antonio	Texas	United States	78299
52	Novartis Investigative Site	Richmond	Virginia	United States	23225
53	Novartis Investigative Site	Greenfield	Wisconsin	United States	53228

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02487498
• Other Study ID Numbers: CQVA149A2350
• First Posted: Jul 1, 2015
• Last Update Posted: Apr 2, 2018
• Last Verified: Mar 1, 2018

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: Chronic Obstructive Pulmonary Disease (COPD)
• Additional relevant MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Glycopyrrolate

Study Results

Participant Flow

Pre-assignment Detail	Participants were randomized to 1 of 2 sequences in a 1:1 ratio.

Arm/Group Title	First QVA149, Then Umeclidinium/Vilanterol	First Umeclidinium/Vilanterol, Then QVA149
Arm/Group Description	Participants received QVA149 27.5/12.5 ug via inhalation twice daily (b.i.d.) for 12 weeks. Then after 3 weeks washout, participants received Umeclidinium/vilanterol 62.5/25 ug via inhalation once daily for 12 weeks.	Participants received Umeclidinium/vilanterol 62.5/25 ug via inhalation once daily for 12 weeks. Then after 3 weeks washout, participants received QVA149 27.5/12.5 ug via inhalation twice daily (b.i.d.) for 12 weeks.
Period Title: Period: Period 1
STARTED	178	177
COMPLETED	172	166
NOT COMPLETED	6	11
Period Title: Period: Period 1
STARTED	172	166
COMPLETED	170	159
NOT COMPLETED	2	7
Period Title: Period: Period 1
STARTED	170	159
COMPLETED	164	154
NOT COMPLETED	6	5

Baseline Characteristics

Arm/Group Title	Overall Participants
Arm/Group Description	Participants received QVA149 27.5/12.5 ug via inhalation twice daily (b.i.d.) for 12 weeks and Umeclidinium/vilanterol 62.5/25 ug via inhalation once daily for 12 weeks.
Overall Participants	355
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	63.9 (8.30)
Sex: Female, Male (Count of Participants)
Female	163 45.9%
Male	192 54.1%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Forced Expiratory Volume (FEV1) Area Under the Curve (AUC) 0-24h
Description	FEV1 was measured with spirometry conducted according to internationally accepted standards. The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time over an entire day (AUC 0-24h). A positive change from baseline indicates improvement.
Time Frame	baseline, 0 to 24 hours post-dose at week 12

Outcome Measure Data

Analysis Population Description

The full analysis, which included all randomized patients who received at least one dose of double-blind treatment, was considered for the analysis. Only participants with a value at both baseline and the post-baseline time point were included in the analysis.

Arm/Group Title	First QVA149, Then Umeclidinium/Vilanterol	First Umeclidinium/Vilanterol, Then QVA149
Arm/Group Description	Participants received QVA149 27.5/12.5 ug via inhalation twice daily (b.i.d.) for 12 weeks. Then after 3 weeks washout, participants received Umeclidinium/vilanterol 62.5/25 ug via inhalation once daily for 12 weeks.	Participants received Umeclidinium/vilanterol 62.5/25 ug via inhalation once daily for 12 weeks. Then after 3 weeks washout, participants received QVA149 27.5/12.5 ug via inhalation twice daily (b.i.d.) for 12 weeks.
Measure Participants	319	326
Least Squares Mean (Standard Error) [Liters]	0.1846 (0.01193)	0.2028 (0.01188)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	First QVA149, Then Umeclidinium/Vilanterol, First Umeclidinium/Vilanterol, Then QVA149
	Comments	Ho: QVA149 27.5/12.5 μg b.i.d. is inferior to umeclidinium/vilanterol 62.5/25 μg q.d; Ha: QVA149 27.5/12.5 μg b.i.d. is non-inferior to umeclidinium/vilanterol 62.5/25 μg q.d.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority was demonstrated if the lower limit (LL) of the 97.5% one -sided confidence interval (CI) > -20 mL
Statistical Test of Hypothesis	p-Value	0.415
	Comments
	Method	Linear Mixed Model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.0182
	Confidence Interval	(2-Sided) 95%; -0.0342 to -0.0023
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.00813
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in Forced Expiratory Volume (FEV1) Area Under the Curve (AUC) 0-24h
Description	FEV1 was measured with spirometry conducted according to internationally accepted standards. The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time over an entire day (AUC 0-24h). A positive change from baseline indicates improvement.
Time Frame	baseline, 0 to 24 hours post-dose at week 12

Outcome Measure Data

Analysis Population Description

The full analysis, which included all randomized patients who received at least one dose of double-blind treatment, was considered for the analysis. Only participants with a value at both baseline and post-baseline time point were included in the analysis

Arm/Group Title	First QVA149, Then Umeclidinium/Vilanterol	First Umeclidinium/Vilanterol, Then QVA149
Arm/Group Description	Participants received QVA149 27.5/12.5 ug via inhalation twice daily (b.i.d.) for 12 weeks. Then after 3 weeks washout, participants received Umeclidinium/vilanterol 62.5/25 ug via inhalation once daily for 12 weeks.	Participants received Umeclidinium/vilanterol 62.5/25 ug via inhalation once daily for 12 weeks. Then after 3 weeks washout, participants received QVA149 27.5/12.5 ug via inhalation twice daily (b.i.d.) for 12 weeks.
Measure Participants	319	326
Least Squares Mean (Standard Error) [Liters]	0.1846 (0.01193)	0.2028 (0.01188)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	First QVA149, Then Umeclidinium/Vilanterol, First Umeclidinium/Vilanterol, Then QVA149
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.0182
	Confidence Interval	(2-Sided) 95%; -0.0342 to -0.0023
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.00813
	Estimation Comments

3. Secondary Outcome

Title	Superiority of QVA149 Compared to Umeclidinium/Vilanterol in Terms of Change From Baseline in Trough FEV1 (Mean of 23h 15 Minutes and 23 h 45 Minutes Post Previous Morning Dose)
Description	FEV1 was measured with spirometry conducted according to internationally accepted standards. Trough FEV1 was defined as the average of measurements made 23 hours 15 minutes and 23 hours 45 minutes post-dose for each treatment.
Time Frame	baseline, 23 hours 15 minutes and 23 hours 45 minutes post previous morning dose at week 12

Outcome Measure Data

Analysis Population Description

The full analysis, which included all randomized patients who received at least one dose of double-blind treatment, was considered for the analysis. Only participants with a value at both baseline and the post-baseline time point were included in the analysis.

Arm/Group Title	First QVA149, Then Umeclidinium/Vilanterol	First Umeclidinium/Vilanterol, Then QVA149
Arm/Group Description	Participants received QVA149 27.5/12.5 ug via inhalation twice daily (b.i.d.) for 12 weeks. Then after 3 weeks washout, participants received Umeclidinium/vilanterol 62.5/25 ug via inhalation once daily for 12 weeks.	Participants received Umeclidinium/vilanterol 62.5/25 ug via inhalation once daily for 12 weeks. Then after 3 weeks washout, participants received QVA149 27.5/12.5 ug via inhalation twice daily (b.i.d.) for 12 weeks.
Measure Participants	312	312
Least Squares Mean (Standard Error) [Liters]	0.1676 (0.01112)	0.1767 (0.01111)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	First QVA149, Then Umeclidinium/Vilanterol, First Umeclidinium/Vilanterol, Then QVA149
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.0091
	Confidence Interval	(2-Sided) 95%; -0.0313 to 0.0131
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.01132
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline in FEV1 AUC 12-24h
Description	FEV1 was measured with spirometry conducted according to internationally accepted standards. The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time over 12 hours (AUC 12-24h).
Time Frame	baseline, 12 hours to 24 hours post-dose at week 12

Outcome Measure Data

Analysis Population Description

The full analysis, which included all randomized patients who received at least one dose of double-blind treatment, was considered for the analysis. Only participants with a value at both baseline and the post-baseline time point were included in the analysis

Arm/Group Title	First QVA149, Then Umeclidinium/Vilanterol	First Umeclidinium/Vilanterol, Then QVA149
Arm/Group Description	Participants received QVA149 27.5/12.5 ug via inhalation twice daily (b.i.d.) for 12 weeks. Then after 3 weeks washout, participants received Umeclidinium/vilanterol 62.5/25 ug via inhalation once daily for 12 weeks.	Participants received Umeclidinium/vilanterol 62.5/25 ug via inhalation once daily for 12 weeks. Then after 3 weeks washout, participants received QVA149 27.5/12.5 ug via inhalation twice daily (b.i.d.) for 12 weeks.
Measure Participants	317	323
Least Squares Mean (Standard Error) [Liters]	0.1625 (0.01216)	0.1539 (0.01210)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	First QVA149, Then Umeclidinium/Vilanterol, First Umeclidinium/Vilanterol, Then QVA149
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.0086
	Confidence Interval	(2-Sided) 95%; -0.0086 to 0.0258
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.00874
	Estimation Comments

5. Secondary Outcome

Title	Change From Baseline in FEV1 AUC 0-12h
Description	FEV1 was measured with spirometry conducted according to internationally accepted standards. The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time over 12 hours (AUC 0-12h).
Time Frame	baseline, 0 to 12 hours post-dose at week 12

Outcome Measure Data

Analysis Population Description

The full analysis, which included all randomized patients who received at least one dose of double-blind treatment, was considered for the analysis. Only participants with a value at both baseline and the post-baseline time point were included in the analysis

Arm/Group Title	First QVA149, Then Umeclidinium/Vilanterol	First Umeclidinium/Vilanterol, Then QVA149
Arm/Group Description	Participants received QVA149 27.5/12.5 ug via inhalation twice daily (b.i.d.) for 12 weeks. Then after 3 weeks washout, participants received Umeclidinium/vilanterol 62.5/25 ug via inhalation once daily for 12 weeks.	Participants received Umeclidinium/vilanterol 62.5/25 ug via inhalation once daily for 12 weeks. Then after 3 weeks washout, participants received QVA149 27.5/12.5 ug via inhalation twice daily (b.i.d.) for 12 weeks.
Measure Participants	319	326
Least Squares Mean (Standard Error) [Liters]	0.2077 (0.01082)	0.2496 (0.01075)

6. Secondary Outcome

Title	Change From Baseline in FEV1 AUC 0-4h, AUC 4-8h, AUC 8-12h, AUC 12-16h, AUC 16-20h and AUC 20-24h
Description	FEV1 was measured with spirometry conducted according to internationally accepted standards. The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time over 4 hour intervals FEV1 AUC 0-4h, AUC 4-8h, AUC 8-12h, AUC 12-16h, AUC 16-20h and AUC 20-24h.
Time Frame	baseline, 12 weeks

Outcome Measure Data

Analysis Population Description

The full analysis, which included all randomized patients who received at least one dose of double-blind treatment, was considered for the analysis. Only participants with a value at both baseline and the post-baseline time points were included in the analysis

Arm/Group Title	First QVA149, Then Umeclidinium/Vilanterol	First Umeclidinium/Vilanterol, Then QVA149
Arm/Group Description	Participants received QVA149 27.5/12.5 ug via inhalation twice daily (b.i.d.) for 12 weeks. Then after 3 weeks washout, participants received Umeclidinium/vilanterol 62.5/25 ug via inhalation once daily for 12 weeks.	Participants received Umeclidinium/vilanterol 62.5/25 ug via inhalation once daily for 12 weeks. Then after 3 weeks washout, participants received QVA149 27.5/12.5 ug via inhalation twice daily (b.i.d.) for 12 weeks.
Measure Participants	337	347
0-4h	0.2663 (0.01082)	0.2938 (0.01077)
4-8h	0.1970 (0.01132)	0.2519 (0.01123)
8-12h	0.1513 (0.01143)	0.2015 (0.01132)
12-16h	0.2120 (0.01292)	0.1842 (0.01285)
16-20h	0.1383 (0.01292)	0.1340 (0.01287)
20-24h	0.1374 (0.01197)	0.1445 (0.01190)

7. Secondary Outcome

Title	QVA149 Compared to Umeclidinium/Vilanterol in Terms of Change From Baseline in Pre-dose Trough FEV1 (Mean of 15 Minutes and 45 Minutes Pre Morning Dose)
Description	FEV1 was measured with spirometry conducted according to internationally accepted standards. Pre-dose trough FEV1 was defined as the average of measurements made 15 minutes and 45 minutes pre morning dose for each treatment.
Time Frame	baseline, 12 weeks

Outcome Measure Data

Analysis Population Description

The full analysis, which included all randomized patients who received at least one dose of double-blind treatment, was considered for the analysis. Only participants with a value at both baseline and the post-baseline time point were included in the analysis

Arm/Group Title	First QVA149, Then Umeclidinium/Vilanterol	First Umeclidinium/Vilanterol, Then QVA149
Arm/Group Description	Participants received QVA149 27.5/12.5 ug via inhalation twice daily (b.i.d.) for 12 weeks. Then after 3 weeks washout, participants received Umeclidinium/vilanterol 62.5/25 ug via inhalation once daily for 12 weeks.	Participants received Umeclidinium/vilanterol 62.5/25 ug via inhalation once daily for 12 weeks. Then after 3 weeks washout, participants received QVA149 27.5/12.5 ug via inhalation twice daily (b.i.d.) for 12 weeks.
Measure Participants	319	326
Least Squares Mean (Standard Error) [Liters]	0.1827 (0.01183)	0.2043 (0.01177)

8. Secondary Outcome

Title	QVA149 Compared to Umeclidinium/Vilanterol in Terms of Change From Baseline in FEV1 at Any Time Point
Description	FEV1 was measured with spirometry conducted according to internationally accepted standards.
Time Frame	Day 1 (5min, 15min, 30min, hours 1, 2, 4, 8, 11h 55min, 23h 15min, 23h 45min); week 6 (-45min, -15min); week 12 (-45min, -15min, 5min, 15min, 30min, hours 1, 2, 4, 8, 11h 55min, 12h 5min, 12h 15min, 12h 30min, 13, 14, 16, 20, 23h 15min, 23h 45min)

Outcome Measure Data

Analysis Population Description

The full analysis, which included all randomized patients who received at least one dose of double-blind treatment, was considered for the analysis. Only participants with a value at both baseline and the post-baseline time points were included in the analysis

Arm/Group Title	First QVA149, Then Umeclidinium/Vilanterol	First Umeclidinium/Vilanterol, Then QVA149
Arm/Group Description	Participants received QVA149 27.5/12.5 ug via inhalation twice daily (b.i.d.) for 12 weeks. Then after 3 weeks washout, participants received Umeclidinium/vilanterol 62.5/25 ug via inhalation once daily for 12 weeks.	Participants received Umeclidinium/vilanterol 62.5/25 ug via inhalation once daily for 12 weeks. Then after 3 weeks washout, participants received QVA149 27.5/12.5 ug via inhalation twice daily (b.i.d.) for 12 weeks.
Measure Participants	337	347
Day 1, 5 minutes	0.1134 (0.00996)	0.1117 (0.00984)
Day 1, 15 minutes	0.1448 (0.01081)	0.1591 (0.01053)
Day 1, 30 minutes	0.1630 (0.01080)	0.1836 (0.01071)
Day 1, 1 hour	0.1742 (0.01133)	0.2000 (0.01121)
Day 1, 2 hours	0.1723 (0.01152)	0.2138 (0.01136)
Day 1, 4 hours	0.1487 (0.01179)	0.2168 (0.01165)
Day 1, 8 hours	0.0908 (0.01160)	0.1781 (0.01145)
Day 1, 11 hours 55 minutes	0.0521 (0.01203)	0.1537 (0.01185)
Day 1, 23 hours 15 minutes	0.1422 (0.01109)	0.1573 (0.01099)
Day 1, 23 hours 45 minutes	0.1702 (0.01156)	0.1821 (0.01145)
Week 6, -45 minutes	0.1819 (0.01197)	0.2071 (0.01188)
Week 6, -15 minutes	0.2111 (0.01225)	0.2343 (0.01214)
Week 12, -45 minutes	0.1750 (0.01195)	0.1957 (0.01191)
Week 12, -15 minutes	0.1914 (0.01217)	0.2112 (0.01214)
Week 12, 5 minutes	0.2421 (0.01020)	0.2563 (0.01015)
Week 12, 15 minutes	0.2681 (0.01086)	0.2865 (0.01084)
Week 12, 30 minutes	0.2819 (0.01097)	0.2940 (0.01090)
Week 12, 1 hour	0.2919 (0.01149)	0.3053 (0.01141)
Week 12, 2 hours	0.2740 (0.01168)	0.2994 (0.01158)
Week 12, 4 hours	0.2316 (0.01192)	0.2823 (0.01185)
Week 12, 8 hours	0.1631 (0.01176)	0.2201 (0.01167)
Week 12, 11 hours 55 minutes	0.1320 (0.01236)	0.1812 (0.01193)
Week 12, 12 hours 5 minutes	0.1974 (0.01375)	0.1893 (0.01364)
Week 12, 12 hours 15 minutes	0.2107 (0.01375)	0.1959 (0.01368)
Week 12, 12 hours 30 minutes	0.2296 (0.01355)	0.1934 (0.01350)
Week 12, 13 hours	0.2341 (0.01376)	0.1953 (0.01364)
Week 12, 14 hours	0.2308 (0.01372)	0.1966 (0.01357)
Week 12, 16 hours	0.1705 (0.01382)	0.1582 (0.01381)
Week 12, 20 hours	0.1078 (0.01338)	0.1158 (0.01338)
Week 12, 23 hours 15 minutes	0.1573 (0.01117)	0.1648 (0.01115)
Week 12, 23 hours 45 minutes	0.1798 (0.01163)	0.1892 (0.01167)

9. Secondary Outcome

Title	QVA149 Compared to Umeclidinium/Vilanterol in Terms of Change From Baseline in Forced Vital Capacity (FVC) at Any Time Point
Description	FEV1 was measured with spirometry conducted according to internationally accepted standards.
Time Frame	Day 1 (5min, 15min, 30 min, hours 1, 2, 4, 8, 11h 55min, 23h 15min, 23h 45min); week 6 (-45min, -15min); week 12 (-45min, -15min, 5min, 15min, 30min, hours 1, 2, 4, 8, 11h 55min, 12h 5min, 12h 15min, 12h 30min, 13, 14, 16, 20, 23h 15min, 23h 45min)

Outcome Measure Data

Analysis Population Description

The full analysis, which included all randomized patients who received at least one dose of double-blind treatment, was considered for the analysis. Only participants with a value at both baseline and the post-baseline time points were included in the analysis.

Arm/Group Title	First QVA149, Then Umeclidinium/Vilanterol	First Umeclidinium/Vilanterol, Then QVA149
Arm/Group Description	Participants received QVA149 27.5/12.5 ug via inhalation twice daily (b.i.d.) for 12 weeks. Then after 3 weeks washout, participants received Umeclidinium/vilanterol 62.5/25 ug via inhalation once daily for 12 weeks.	Participants received Umeclidinium/vilanterol 62.5/25 ug via inhalation once daily for 12 weeks. Then after 3 weeks washout, participants received QVA149 27.5/12.5 ug via inhalation twice daily (b.i.d.) for 12 weeks.
Measure Participants	337	347
Day 1, 5 minutes	0.1994 (0.01672)	0.2054 (0.01655)
Day 1, 15 minutes	0.2454 (0.01764)	0.2589 (0.01724)
Day 1, 30 minutes	0.2734 (0.01806)	0.3028 (0.01792)
Day 1, 1 hour	0.2841 (0.01937)	0.3136 (0.01917)
Day 1, 2 hours	0.2708 (0.01928)	0.3334 (0.01904)
Day 1, 4 hours	0.2333 (0.01914)	0.3405 (0.01892)
Day 1, 8 hours	0.1728 (0.01923)	0.3067 (0.01900)
Day 1, 11 hours 55 minutes	0.1291 (0.01971)	0.2654 (0.01944)
Day 1, 23 hours 15 minutes	0.2387 (0.01789)	0.2363 (0.01775)
Day 1, 23 hours 45 minutes	0.2821 (0.01886)	0.2940 (0.01868)
Week 6, -45 minutes	0.2666 (0.01958)	0.3045 (0.01942)
Week 6, -15 minutes	0.2860 (0.01963)	0.3372 (0.01943)
Week 12, -45 minutes	0.2264 (0.01956)	0.2737 (0.01947)
Week 12, -15 minutes	0.2468 (0.01949)	0.2844 (0.01943)
Week 12, 5 minutes	0.3386 (0.01711)	0.3489 (0.01701)
Week 12, 15 minutes	0.3616 (0.01771)	0.3811 (0.01768)
Week 12, 30 minutes	0.3796 (0.01830)	0.4019 (0.01821)
Week 12, 1 hour	0.3935 (0.01962)	0.4085 (0.01949)
Week 12, 2 hours	0.3708 (0.01953)	0.4050 (0.01937)
Week 12, 4 hours	0.3261 (0.01933)	0.3845 (0.01924)
Week 12, 8 hours	0.2259 (0.01950)	0.3152 (0.01936)
Week 12, 11 hours 55 minutes	0.1900 (0.02023)	0.2749 (0.01956)
Week 12, 12 hours 5 minutes	0.2817 (0.02157)	0.2711 (0.02141)
Week 12, 12 hours 15 minutes	0.3010 (0.02177)	0.2762 (0.02165)
Week 12, 12 hours 30 minutes	0.3279 (0.02155)	0.2786 (0.02146)
Week 12, 13 hours	0.3381 (0.02210)	0.2909 (0.02189)
Week 12, 14 hours	0.3445 (0.02233)	0.2984 (0.02208)
Week 12, 16 hours	0.2496 (0.02191)	0.2514 (0.02188)
Week 12, 20 hours	0.1600 (0.02168)	0.1845 (0.02169)
Week 12, 23 hours 15 minutes	0.2026 (0.01802)	0.2251 (0.01800)
Week 12, 23 hours 45 minutes	0.2415 (0.01897)	0.2662 (0.01903)

Adverse Events

Adverse Event Reporting Description	Since this is a cross-over design study, all patients were randomized to receive both treatments, either in sequence QVA/UV or sequence UV/QVA. The number of patients on each treatment does not add up to the total number of patients.
Arm/Group Title	QVA 27.5/12.5 Bid		U/V 62.5/25 od		All Patients
Arm/Group Description	QVA149 capsules for inhalation, delivered via QVA149 SDDPI		Umeclidinium/vilanterol for inhalation, delivered via ELLIPTA® inhaler		All Patients
All Cause Mortality
	QVA 27.5/12.5 Bid		U/V 62.5/25 od		All Patients
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	QVA 27.5/12.5 Bid		U/V 62.5/25 od		All Patients
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	17/337 (5%)		10/347 (2.9%)		26/355 (7.3%)
Cardiac disorders
Acute coronary syndrome	1/337 (0.3%)		0/347 (0%)		1/355 (0.3%)
Coronary artery disease	2/337 (0.6%)		0/347 (0%)		2/355 (0.6%)
Myocardial infarction	1/337 (0.3%)		1/347 (0.3%)		2/355 (0.6%)
Gastrointestinal disorders
Pancreatitis acute	1/337 (0.3%)		0/347 (0%)		1/355 (0.3%)
Infections and infestations
Bronchitis	0/337 (0%)		1/347 (0.3%)		1/355 (0.3%)
Clostridium difficile infection	0/337 (0%)		1/347 (0.3%)		1/355 (0.3%)
Escherichia urinary tract infection	1/337 (0.3%)		0/347 (0%)		1/355 (0.3%)
Lower respiratory tract infection	0/337 (0%)		1/347 (0.3%)		1/355 (0.3%)
Pneumonia	1/337 (0.3%)		2/347 (0.6%)		3/355 (0.8%)
Pneumonia staphylococcal	1/337 (0.3%)		0/347 (0%)		1/355 (0.3%)
Metabolism and nutrition disorders
Hypokalaemia	0/337 (0%)		1/347 (0.3%)		1/355 (0.3%)
Hyponatraemia	1/337 (0.3%)		0/347 (0%)		1/355 (0.3%)
Musculoskeletal and connective tissue disorders
Rhabdomyolysis	1/337 (0.3%)		0/347 (0%)		1/355 (0.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	0/337 (0%)		1/347 (0.3%)		1/355 (0.3%)
Breast cancer	0/337 (0%)		1/347 (0.3%)		1/355 (0.3%)
Cervix carcinoma stage iii	0/337 (0%)		1/347 (0.3%)		1/355 (0.3%)
Papillary thyroid cancer	1/337 (0.3%)		0/347 (0%)		1/355 (0.3%)
Squamous cell carcinoma of lung	1/337 (0.3%)		0/347 (0%)		1/355 (0.3%)
Squamous cell carcinoma of the oral cavity	1/337 (0.3%)		0/347 (0%)		1/355 (0.3%)
Tonsil cancer	0/337 (0%)		1/347 (0.3%)		1/355 (0.3%)
Nervous system disorders
Encephalopathy	1/337 (0.3%)		0/347 (0%)		1/355 (0.3%)
Seizure	0/337 (0%)		1/347 (0.3%)		1/355 (0.3%)
Renal and urinary disorders
Ureterolithiasis	1/337 (0.3%)		0/347 (0%)		1/355 (0.3%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	1/337 (0.3%)		0/347 (0%)		1/355 (0.3%)
Chronic obstructive pulmonary disease	8/337 (2.4%)		2/347 (0.6%)		10/355 (2.8%)
Hypoxia	1/337 (0.3%)		0/347 (0%)		1/355 (0.3%)
Vascular disorders
Arteriosclerosis	1/337 (0.3%)		0/347 (0%)		1/355 (0.3%)
Peripheral artery occlusion	1/337 (0.3%)		0/347 (0%)		1/355 (0.3%)
Thrombosis	1/337 (0.3%)		0/347 (0%)		1/355 (0.3%)
Vascular insufficiency	1/337 (0.3%)		0/347 (0%)		1/355 (0.3%)
Other (Not Including Serious) Adverse Events
	QVA 27.5/12.5 Bid		U/V 62.5/25 od		All Patients
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	78/337 (23.1%)		89/347 (25.6%)		140/355 (39.4%)
Infections and infestations
Acute sinusitis	3/337 (0.9%)		1/347 (0.3%)		4/355 (1.1%)
Bronchitis	11/337 (3.3%)		6/347 (1.7%)		16/355 (4.5%)
Gastroenteritis viral	3/337 (0.9%)		1/347 (0.3%)		4/355 (1.1%)
Lower respiratory tract infection	4/337 (1.2%)		3/347 (0.9%)		7/355 (2%)
Nasopharyngitis	3/337 (0.9%)		4/347 (1.2%)		7/355 (2%)
Oral candidiasis	4/337 (1.2%)		2/347 (0.6%)		6/355 (1.7%)
Sinusitis	6/337 (1.8%)		5/347 (1.4%)		11/355 (3.1%)
Upper respiratory tract infection	5/337 (1.5%)		8/347 (2.3%)		13/355 (3.7%)
Upper respiratory tract infection bacterial	4/337 (1.2%)		7/347 (2%)		9/355 (2.5%)
Viral upper respiratory tract infection	3/337 (0.9%)		8/347 (2.3%)		11/355 (3.1%)
Injury, poisoning and procedural complications
Laceration	2/337 (0.6%)		2/347 (0.6%)		4/355 (1.1%)
Musculoskeletal and connective tissue disorders
Back pain	3/337 (0.9%)		2/347 (0.6%)		5/355 (1.4%)
Nervous system disorders
Headache	2/337 (0.6%)		3/347 (0.9%)		4/355 (1.1%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	50/337 (14.8%)		51/347 (14.7%)		89/355 (25.1%)
Cough	1/337 (0.3%)		7/347 (2%)		8/355 (2.3%)
Dyspnoea	3/337 (0.9%)		4/347 (1.2%)		6/355 (1.7%)
Nasal congestion	1/337 (0.3%)		4/347 (1.2%)		5/355 (1.4%)
Productive cough	3/337 (0.9%)		2/347 (0.6%)		4/355 (1.1%)

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 (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety