AMPLIFY - D6571C00001 Duaklir USA Phase III Study

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02796677
• Collaborator: (none)
• Enrollment: 1,595
• Locations: 163
• Arms: 4
• Actual Duration (Months): 11.1
• Patients Per Site: 9.8
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

This is a multiple dose, randomized, parallel, double-blind, double-dummy, multicenter and multinational Phase III study to determine the efficacy and safety of Aclidinium bromide 400μg/Formoterol Fumarate (AB/FF) 12 μg compared to individual components and TIO (Tiotropium) 18 μg when administered to patients with stable chronic obstructive pulmonary disease (COPD).

Condition or Disease	Intervention/Treatment	Phase
Chronic Obstructive Pulmonary Disease	Drug: Aclidinium bromide 400 μg/Formoterol Fumarate 12 μg (AB/FF 400/12 μg); Drug: Aclidinium bromide 400 μg (AB 400 μg); Drug: Formoterol fumarate 12 μg (FF 12 μg); Other: Placebo to AB/FF 400/12 μg, AB 400 μg and FF 12 μg; Drug: Tiotropium 18 μg (TIO 18 μg); Other: Placebo to TIO 18 μg	Phase 3

Detailed Description

This study was conducted to assess the bronchodilator efficacy and safety as well as effect on health related quality of life of AB/FF 400/12 μg compared to the individual components (AB 400 μg and FF 12 μg) in COPD patients. The trial duration of 24 weeks allows the assessment of the effect on symptoms improvement of the combined treatments versus individual components as well as the long term bronchodilation comparison between AB 400 μg and TIO 18 μg in minimizing the risk of COPD exacerbations in current or former smokers, aged ≥40 in symptomatic COPD patients.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1595 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A 24 Week Treatment, Multicenter, Randomized, Double Blinded, Double Dummy, Parallel-group, Clinical Trial Evaluating the Efficacy and Safety of Aclidinium Bromide 400 μg/Formoterol Fumarate 12 μg Fixed-dose Combination BID Compared With Each Monotherapy (Aclidinium Bromide 400 μg BID and Formoterol Fumarate 12 μg BID) and Tiotropium 18 μg QD When Administered to Patients With Stable Chronic Obstructive Pulmonary Disease.
• Actual Study Start Date: Jul 5, 2016
• Actual Primary Completion Date: Jun 8, 2017
• Actual Study Completion Date: Jun 8, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: AB/FF 400/12 μg BID Participants were administered AB/FF 400/12 μg via Pressair®/Genuair® inhaler twice daily for 24 weeks of treatment.	Drug: Aclidinium bromide 400 μg/Formoterol Fumarate 12 μg (AB/FF 400/12 μg); Inhalation powder; Other Names: Oral Inhalation (by Pressair®/Genuair® Dry Powder Inhaler) ; Other: Placebo to AB/FF 400/12 μg, AB 400 μg and FF 12 μg; Inhalation powder; Other Names: Oral Inhalation (by Pressair®/Genuair® Dry Powder Inhaler)
Experimental: AB 400 μg BID Participants were administered AB 400 μg via Pressair®/Genuair® inhaler twice daily for 24 weeks of treatment.	Drug: Aclidinium bromide 400 μg (AB 400 μg); Inhalation powder; Other Names: Oral Inhalation (by Pressair®/Genuair® Dry Powder Inhaler) ; Other: Placebo to AB/FF 400/12 μg, AB 400 μg and FF 12 μg; Inhalation powder; Other Names: Oral Inhalation (by Pressair®/Genuair® Dry Powder Inhaler)
Experimental: FF 12 μg BID Participants were administered FF 12 μg via Pressair®/Genuair® inhaler twice daily for 24 weeks of treatment.	Drug: Formoterol fumarate 12 μg (FF 12 μg); Inhalation powder; Other Names: Oral Inhalation (by Pressair®/Genuair® Dry Powder Inhaler) ; Other: Placebo to AB/FF 400/12 μg, AB 400 μg and FF 12 μg; Inhalation powder; Other Names: Oral Inhalation (by Pressair®/Genuair® Dry Powder Inhaler)
Experimental: TIO 18 μg QD Participants were administered TIO 18 μg via Handihaler® inhale once daily for 24 weeks of treatment.	Drug: Tiotropium 18 μg (TIO 18 μg); Powder in capsules for oral inhalation; Other Names: Oral Inhalation (by Handihaler® Dry Powder Inhaler, DPI) ; Other: Placebo to TIO 18 μg; Powder in capsules for oral inhalation; Other Names: Oral Inhalation (by Handihaler® Dry Powder Inhaler, DPI)

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in 1-hour Morning Post-dose Dose Forced Expiratory Volume in 1 Second (FEV1) of AB/FF 400/12 μg Compared to AB 400 μg at Week 24 [At baseline 1-hour postdose and Week 24]

   To assess the bronchodilatory effect by evaluating the mean changes from baseline in FEV1 at 1 hour post-dose of AB/FF 400/12 µg compared to AB 400 μg after administration of oral inhalation powder BID via DIP to participants with COPD. Baseline was defined as the average of the two FEV1 values measured just prior to the administration of the first dose of investigational product (IP) at randomization Visit. If one of the two was missing, then the available one would be used as baseline value.

2. Change From Baseline in Morning Predose (Trough) FEV1 of AB/FF 400/12 μg Compared to FF 12 μg at Week 24 [At baseline morning predose and Week 24]

   To assess the bronchodilatory effect by evaluating the mean changes from baseline in FEV1 in morning pre-dose (trough) of AB/FF 400/12 µg compared to FF 12 μg after administration of oral inhalation powder BID via DPI to participants with COPD. Morning pre-dose (trough) FEV1 was defined as the average of the corresponding -30 minute and 0 minute before the morning study medication at Week 24. If one time-point was missing then the available one would be used as morning pre-dose.

3. Change From Baseline in Morning Predose (Trough) FEV1 at Week 24 Comparing AB 400 μg Versus TIO 18 μg to Demonstrate Non-inferiority [At baseline morning predose and Week 24]

   To assess the non-inferior bronchodilatory effect by evaluating the mean changes from baseline in FEV1 in morning pre-dose (trough)of AB 400 µg compared to TIO 18 μg after administration of oral inhalation powder BID via DPI to participants with COPD.

Secondary Outcome Measures

1. Change From Baseline in Normalized Area Under Curve 3hours Post-dose (nAUC0-3/3h) FEV1 of AB/FF 400/12 μg Compared to AB 400 μg and and FF 12 μg at Week 24 [At Day 1 and Day 169]

   To assess the bronchodilatory effect by evaluating the mean changes from baseline in nAUC0-3/3h FEV1 of AB/FF 400/12 µg compared to AB 400 μg and and FF 12 μg after administration of oral inhalation powder BID via DPI to participants with COPD.

2. Responder (Number of Participants) Analysis of St. George's Respiratory Questionnaire (SGRQ) Total Score With AB/FF 400/12 μg Versus AB 400 μg and FF 12 μg. [At baseline and Week 24]

   SGRQ was a A standardized self-completed tool used to measure impaired health and perceived well-being ("quality of life") in respiratory diseases. The questionnaire contained 50 items divided into 3 (symptoms, activity and impacts) dimensions. Each of the three dimensions of the questionnaire is scored separately in the range from 0 to 100%, zero score indicating no impairment of life quality. A summary score utilizing responses to all items is the total SGRQ score which also ranges from 0 to 100%. The SGRQ scores are calculated using weights attached to each item of the questionnaire which provides an estimate of the distress associated with the symptoms or state described in each item. Higher scores indicate poorer health. A decrease of at least 4 units in the SGRQ total score has been established as the criterion for minimal meaningful improvement. SGRQ responders will be those with a decrease in SGRQ total score of at least 4 units from baseline.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 130 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Adult male or non-pregnant, non-lactating female patients aged ≥40.

• Patients with diagnosis of moderate to very severe stable COPD: post-bronchodilator FEV1 < 80% of the predicted normal and post-bronchodilator FEV1/FVC < 70% at Screening Visit.

• Symptomatic patients with a CAT score ≥10 at Screening and Randomization visit (Visits 1 and 2).

• Current or former-smokers, with a smoking history of ≥ 10 pack-years.

• Patients able to perform acceptable and repeatable pulmonary function testing for FEV1 according to the American Thoracic Society (ATS)/European Respiratory Society (ERS) 2005 criteria at Visit 1.

• Patients eligible and able to participate in the study and who had signed an Informed Consent Form prior to initiation of any study-related procedures.

Exclusion Criteria:

• Involvement in the planning and/or conduct of the study (applies to AstraZeneca staff and/or site staff), or patients employed by or relatives of the employees of the site or sponsor.

• Previous randomization in the present study D6571C00001.

• Patients with predominant asthma.

• Any respiratory tract infection (including the upper respiratory tract) or COPD exacerbation (including the mild COPD exacerbation) within 6 weeks prior to screening or during the run-in period.

• Patients hospitalized for a COPD exacerbation (an emergency room visit for longer than 24 hours is considered a hospitalization) within 3 months prior to Screening Visit.

• Clinically significant respiratory conditions other than COPD.

• Patients who in the Investigator's opinion may need to start a pulmonary rehabilitation program during the study and/or patients who started/finished it within 3 months prior to Screening.

• Use of long-term oxygen therapy (≥ 15 hours/day).

• Patients who do not maintain regular day/night, waking/sleeping cycles including night shift workers.

• Clinically significant cardiovascular conditions.

• Patients with uncontrolled Type I or Type II diabetes, uncontrolled hypo-or hyperthyroidism, hypokalaemia, or hyperadrenergic state, uncontrolled hypertension.

• Patients with history of long QT syndrome or whose QTc (calculated according to Fridericia's Formula QTc=QT/RR1/3) > 470 ms as indicated in the centralised reading report assessed at Screening.

• Patients with clinically significant abnormalities in the laboratory tests, ECG parameters (other than QTc) or in the physical examination at Screening Visit that might comprise patient safety.

• Patient with known non-controlled history of infection with human immunodeficiency virus and/or active hepatitis.

• Patient with a history of hypersensitivity reaction to inhaled medication or any component thereof, including paradoxical bronchospasm.

• Patients with known narrow-angle glaucoma, symptomatic bladder neck obstruction, acute urinary retention or symptomatic non-stable prostate hypertrophy.

• History of malignancy of any organ system (including lung cancer), treated or untreated, within the past 5 years other than basal or squamous cell skin cancer.

• Patients with any other serious or uncontrolled physical or mental dysfunction.

• Patients with a history (within 2 years prior to screening) of drug and/or alcohol abuse that may prevent study compliance based on the Investigator judgment.

• Patients unlikely to be cooperative or that cannot comply with the study procedures.

• Patients treated with any investigational drug within 30 days (or 6 half-lives, whichever is longer) prior to Screening.

• Patients who intended to use any concomitant medication not permitted by this protocol or who had not undergone the required washout period for a particular prohibited medication.

• Patients unable to give consent, or patients of consenting age but under guardianship, or vulnerable patients. Patients who demonstrate < 80% compliance with the electronic diary during the run-in period.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Gulf Shores	Alabama	United States	36542
2	Research Site	Phoenix	Arizona	United States	85018
3	Research Site	Tucson	Arizona	United States	85712
4	Research Site	Corona	California	United States	92879
5	Research Site	Fresno	California	United States	93702
6	Research Site	Fullerton	California	United States	92835
7	Research Site	Lincoln	California	United States	95648
8	Research Site	San Diego	California	United States	92120
9	Research Site	Waterbury	Connecticut	United States	06708
10	Research Site	Clearwater	Florida	United States	33765
11	Research Site	Edgewater	Florida	United States	32132
12	Research Site	Hollywood	Florida	United States	33021
13	Research Site	Homestead	Florida	United States	33030
14	Research Site	Miami Lakes	Florida	United States	33016
15	Research Site	Miami	Florida	United States	33144
16	Research Site	Miami	Florida	United States	33186
17	Research Site	Ormond Beach	Florida	United States	32174
18	Research Site	Port Orange	Florida	United States	32129
19	Research Site	Saint Petersburg	Florida	United States	33704
20	Research Site	Saint Petersburg	Florida	United States	33709
21	Research Site	Sarasota	Florida	United States	34233
22	Research Site	Tampa	Florida	United States	33603
23	Research Site	Winter Park	Florida	United States	32789
24	Research Site	Blue Ridge	Georgia	United States	30513
25	Research Site	Woodstock	Georgia	United States	30189
26	Research Site	Chicago	Illinois	United States	60602
27	Research Site	Portage	Indiana	United States	46368
28	Research Site	Lafayette	Louisiana	United States	70508
29	Research Site	Fall River	Massachusetts	United States	02720
30	Research Site	Chelsea	Michigan	United States	48118
31	Research Site	Farmington Hills	Michigan	United States	48336
32	Research Site	Troy	Michigan	United States	48085
33	Research Site	Edina	Minnesota	United States	55435
34	Research Site	Fridley	Minnesota	United States	55432
35	Research Site	Minneapolis	Minnesota	United States	55407
36	Research Site	Woodbury	Minnesota	United States	55125
37	Research Site	Saint Charles	Missouri	United States	63301
38	Research Site	Saint Louis	Missouri	United States	63117
39	Research Site	Saint Louis	Missouri	United States	63141
40	Research Site	Fremont	Nebraska	United States	68025
41	Research Site	Omaha	Nebraska	United States	68114
42	Research Site	Omaha	Nebraska	United States	68134
43	Research Site	Las Vegas	Nevada	United States	89102
44	Research Site	Bronx	New York	United States	10455
45	Research Site	Brooklyn	New York	United States	11230
46	Research Site	Buffalo	New York	United States	14215
47	Research Site	New York	New York	United States	10036
48	Research Site	Rochester	New York	United States	14618
49	Research Site	Charlotte	North Carolina	United States	28207
50	Research Site	Charlotte	North Carolina	United States	28277
51	Research Site	Gastonia	North Carolina	United States	28054
52	Research Site	Wilmington	North Carolina	United States	28401
53	Research Site	Canton	Ohio	United States	44718
54	Research Site	Cincinnati	Ohio	United States	45231
55	Research Site	Cincinnati	Ohio	United States	45242
56	Research Site	Cincinnati	Ohio	United States	45246
57	Research Site	Columbus	Ohio	United States	43207
58	Research Site	Columbus	Ohio	United States	43215
59	Research Site	Dublin	Ohio	United States	43016
60	Research Site	Grove City	Ohio	United States	43123
61	Research Site	Edmond	Oklahoma	United States	73034
62	Research Site	Midwest City	Oklahoma	United States	73110
63	Research Site	Oklahoma City	Oklahoma	United States	73104
64	Research Site	Medford	Oregon	United States	97504
65	Research Site	Altoona	Pennsylvania	United States	16602
66	Research Site	Pittsburgh	Pennsylvania	United States	15243
67	Research Site	Wyomissing	Pennsylvania	United States	19610
68	Research Site	East Providence	Rhode Island	United States	02914
69	Research Site	Columbia	South Carolina	United States	29204
70	Research Site	Gaffney	South Carolina	United States	29340
71	Research Site	Mount Pleasant	South Carolina	United States	29464
72	Research Site	Spartanburg	South Carolina	United States	29303
73	Research Site	Union	South Carolina	United States	29379
74	Research Site	Arlington	Texas	United States	76012
75	Research Site	Baytown	Texas	United States	77521
76	Research Site	Boerne	Texas	United States	78006
77	Research Site	Dallas	Texas	United States	75225
78	Research Site	Fort Worth	Texas	United States	76104
79	Research Site	Houston	Texas	United States	77074
80	Research Site	Lewisville	Texas	United States	75067
81	Research Site	McKinney	Texas	United States	75069
82	Research Site	Tomball	Texas	United States	77375
83	Research Site	Midvale	Utah	United States	84047
84	Research Site	Abingdon	Virginia	United States	24210
85	Research Site	Newport News	Virginia	United States	23606
86	Research Site	Dimitrovgrad		Bulgaria	6400
87	Research Site	Gabrovo		Bulgaria	5300
88	Research Site	Roman		Bulgaria	3130
89	Research Site	Ruse		Bulgaria	7002
90	Research Site	Sevlievo		Bulgaria	5400
91	Research Site	Sliven		Bulgaria	8800
92	Research Site	Sofia		Bulgaria	1002
93	Research Site	Sofia		Bulgaria	1431
94	Research Site	Stara Zagora		Bulgaria	6003
95	Research Site	Vidin		Bulgaria	3700
96	Research Site	Jaromer		Czechia	544 01
97	Research Site	Jindrichuv Hradec		Czechia	377 01
98	Research Site	Praha 8		Czechia	182 00
99	Research Site	Rokycany		Czechia	33722
100	Research Site	Strakonice		Czechia	38601
101	Research Site	Berlin		Germany	10117
102	Research Site	Berlin		Germany	10629
103	Research Site	Berlin		Germany	10717
104	Research Site	Berlin		Germany	10787
105	Research Site	Berlin		Germany	12627
106	Research Site	Bochum		Germany	44787
107	Research Site	Dortmund		Germany	44263
108	Research Site	Dresden		Germany	01069
109	Research Site	Frankfurt		Germany	60596
110	Research Site	Grosshansdorf		Germany	20927
111	Research Site	Hamburg		Germany	20253
112	Research Site	Hamburg		Germany	20354
113	Research Site	Hamburg		Germany	D-22143
114	Research Site	Hannover		Germany	30159
115	Research Site	Leipzig		Germany	04103
116	Research Site	Leipzig		Germany	04275
117	Research Site	Luebeck		Germany	23552
118	Research Site	Marburg		Germany	35037
119	Research Site	München		Germany	80539
120	Research Site	Schwerin		Germany	19055
121	Research Site	Balassagyarmat		Hungary	2660
122	Research Site	Budapest		Hungary	1036
123	Research Site	Debrecen		Hungary	4031
124	Research Site	Gödöllő		Hungary	2100
125	Research Site	Komló		Hungary	7300
126	Research Site	Nyíregyháza		Hungary	4400
127	Research Site	Pécs		Hungary	7635
128	Research Site	Szigetszentmiklós		Hungary	2310
129	Research Site	Szombathely		Hungary	9700
130	Research Site	Jerusalem		Israel	91120
131	Research Site	Petach Tikva		Israel	49100
132	Research Site	Rehovot		Israel	76100
133	Research Site	Bialystok		Poland	15-003
134	Research Site	Częstochowa		Poland	42-200
135	Research Site	Gdańsk		Poland	80-382
136	Research Site	Gdynia		Poland	81-384
137	Research Site	Inowrocław		Poland	88-100
138	Research Site	Katowice		Poland	40-040
139	Research Site	Ostrowiec Świętokrzyski		Poland	27-400
140	Research Site	Pabianice		Poland	95-200
141	Research Site	Szczecin		Poland	70-111
142	Research Site	Warszawa		Poland	01-192
143	Research Site	Wrocław		Poland	50-088
144	Research Site	Zabrze		Poland	41-800
145	Research Site	Alicante		Spain	03004
146	Research Site	Barcelona		Spain	08830
147	Research Site	Lleida		Spain	25198
148	Research Site	Ivano-Frankivsk		Ukraine	76012
149	Research Site	Kharkiv		Ukraine	61035
150	Research Site	Kharkiv		Ukraine	61039
151	Research Site	Odessa		Ukraine	65009
152	Research Site	Poltava		Ukraine	36024
153	Research Site	Sumy		Ukraine	40030
154	Research Site	Uzhhorod		Ukraine	88017
155	Research Site	Vinnytsia		Ukraine	21018
156	Research Site	Zhytomyr		Ukraine	10002
157	Research Site	Birmingham		United Kingdom	B15 2SQ
158	Research Site	Cardiff		United Kingdom	CF14 5GJ
159	Research Site	Chorley		United Kingdom	PR7 7NA
160	Research Site	Glasgow		United Kingdom	G20 OSP
161	Research Site	Hexham		United Kingdom	NE46 1QJ
162	Research Site	Liverpool		United Kingdom	L22 0LG
163	Research Site	Manchester		United Kingdom	M15 6SX

Sponsors and Collaborators

• AstraZeneca

Investigators

• Principal Investigator: Sanjay Sethi, 3495 Bailey Ave , Buffalo NY14215, USA

Study Documents (Full-Text)

• Study Protocol - Mar 21, 2016
• Statistical Analysis Plan - Jul 4, 2017

More Information

Additional Information:

• Protocol
• SAP

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT02796677
• Other Study ID Numbers: D6571C00001
• First Posted: Jun 13, 2016
• Last Update Posted: Nov 9, 2018
• Last Verified: Nov 1, 2018

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: Yes
• Product Manufactured in and Exported from the U.S.: Yes
• Keywords provided by AstraZeneca: Safety; Efficacy; Aclidinium bromide; Formoterol fumarate; Tiotropium; Bronchodilation; COPD
• Additional relevant MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Bromides; Formoterol Fumarate; Tiotropium Bromide

Study Results

Participant Flow

Recruitment Details	Study was conducted on participants with stable chronic obstructive pulmonary disease (COPD), in 11 countries: United States (US), Germany, Poland, Hungary, Bulgaria, Ukraine, United Kingdom (UK), Czech Republic, Spain, Israel & Russia (was not finally started). First participant enrolled was 05 July 2016 & participant last visit was 08 June 2017
Pre-assignment Detail	Eligible Participants signed informed consent form (ICF) & entered screening (Run-in) period (14 ± 3 days), inclusion/exclusion criteria were checked by medical & COPD history, physical examination, laboratory analysis, electrocardiogram, & COPD severity (COPD Assessment Test [CAT] & post-bronchodilator forced expiratory volume in 1 second [FEV1])

Arm/Group Title	Aclidinium Bromide (AB)/Formoterol Fumarate (FF) 400/12 μg	AB 400 μg	FF 12 μg	Tiotropium (TIO) 18 μg
Arm/Group Description	Randomized participants received AB 400 μg/FF 12 μg oral inhalation powder twice daily (BID) via dry powder inhaler (DPI).	Randomized participants received AB 400 μg oral inhalation powder BID via DPI.	Randomized participants received FF 12 μg oral inhalation powder BID via DPI.	Randomized participants received TIO 18 μg oral inhalation powder in capsule BID via DPI.
Period Title: Overall Study
STARTED	317	478	320	479
Completed Treatment and Follow-up	279	405	267	403
COMPLETED	279	405	267	405
NOT COMPLETED	38	73	53	74

Baseline Characteristics

Arm/Group Title	Aclidinium Bromide (AB)/Formoterol Fumarate (FF) 400/12 μg	AB 400 μg	FF 12 μg	Tiotropium (TIO) 18 μg	Total
Arm/Group Description	Randomized participants received AB 400 μg/FF 12 μg oral inhalation powder twice daily (BID) via dry powder inhaler (DPI).	Randomized participants received AB 400 μg oral inhalation powder BID via DPI.	Randomized participants received FF 12 μg oral inhalation powder BID via DPI.	Randomized participants received TIO 18 μg oral inhalation powder in capsule BID via DPI.	Total of all reporting groups
Overall Participants	314	475	319	475	1583
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	64.4 (8.5)	64.4 (8.1)	64.7 (8.3)	64.0 (8.6)	64.3 (8.4)
Sex: Female, Male (Count of Participants)
Female	121 38.5%	171 36%	129 40.4%	199 41.9%	620 39.2%
Male	193 61.5%	304 64%	190 59.6%	276 58.1%	963 60.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	1 0.2%	0 0%	0 0%	1 0.1%
Asian	0 0%	2 0.4%	0 0%	2 0.4%	4 0.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	17 5.4%	28 5.9%	16 5%	16 3.4%	77 4.9%
White	297 94.6%	444 93.5%	303 95%	457 96.2%	1501 94.8%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in 1-hour Morning Post-dose Dose Forced Expiratory Volume in 1 Second (FEV1) of AB/FF 400/12 μg Compared to AB 400 μg at Week 24
Description	To assess the bronchodilatory effect by evaluating the mean changes from baseline in FEV1 at 1 hour post-dose of AB/FF 400/12 µg compared to AB 400 μg after administration of oral inhalation powder BID via DIP to participants with COPD. Baseline was defined as the average of the two FEV1 values measured just prior to the administration of the first dose of investigational product (IP) at randomization Visit. If one of the two was missing, then the available one would be used as baseline value.
Time Frame	At baseline 1-hour postdose and Week 24

Outcome Measure Data

Analysis Population Description

Intention-to Treat (ITT) population: All randomized participants who took at least one dose of IP and had at least a baseline FEV1, under the ITT principle and regardless the adherence to the randomized treatment.

Arm/Group Title	AB/FF 400/12 μg	AB 400 μg	FF 12 μg	TIO 18 μg
Arm/Group Description	Randomized participants received orally AB 400 μg/FF 12 μg inhalation powder twice daily (BID) via dry powder inhaler (DPI).	Randomized participants received AB 400 μg oral inhalation powder BID via DPI.	Randomized participants received orally FF 12 μg inhalation powder BID via DPI.	Edit Randomized participants received orally TIO 18 μg inhalation powder in capsule BID via DPI.
Measure Participants	314	475	319	475
Least Squares Mean (Standard Error) [Litres]	0.253 (0.013)	0.169 (0.011)	0.168 (0.013)	0.161 (0.011)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	AB/FF 400/12 μg, AB 400 μg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.084
	Confidence Interval	(2-Sided) 95%; 0.051 to 0.117
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Change From Baseline in Morning Predose (Trough) FEV1 of AB/FF 400/12 μg Compared to FF 12 μg at Week 24
Description	To assess the bronchodilatory effect by evaluating the mean changes from baseline in FEV1 in morning pre-dose (trough) of AB/FF 400/12 µg compared to FF 12 μg after administration of oral inhalation powder BID via DPI to participants with COPD. Morning pre-dose (trough) FEV1 was defined as the average of the corresponding -30 minute and 0 minute before the morning study medication at Week 24. If one time-point was missing then the available one would be used as morning pre-dose.
Time Frame	At baseline morning predose and Week 24

Outcome Measure Data

Analysis Population Description

ITT population: All randomized participants who took at least one dose of IP and had at least a baseline FEV1, under the ITT principle and regardless the adherence to the randomized treatment.

Arm/Group Title	AB/FF 400/12 μg	AB 400 μg	FF 12 μg	TIO 18 μg
Arm/Group Description	Randomized participants received orally AB 400 μg/FF 12 μg inhalation powder twice daily (BID) via dry powder inhaler (DPI).	Randomized participants received AB 400 μg oral inhalation powder BID via DPI.	Randomized participants received orally FF 12 μg inhalation powder BID via DPI.	Edit Randomized participants received orally TIO 18 μg inhalation powder in capsule BID via DPI.
Measure Participants	314	475	319	475
Least Squares Mean (Standard Error) [Litres]	0.080 (0.014)	0.066 (0.012)	0.025 (0.014)	0.060 (0.012)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	AB/FF 400/12 μg, FF 12 μg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0009
	Comments
	Method	Mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.055
	Confidence Interval	(2-Sided) 95%; 0.023 to 0.088
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Change From Baseline in Morning Predose (Trough) FEV1 at Week 24 Comparing AB 400 μg Versus TIO 18 μg to Demonstrate Non-inferiority
Description	To assess the non-inferior bronchodilatory effect by evaluating the mean changes from baseline in FEV1 in morning pre-dose (trough)of AB 400 µg compared to TIO 18 μg after administration of oral inhalation powder BID via DPI to participants with COPD.
Time Frame	At baseline morning predose and Week 24

Outcome Measure Data

Analysis Population Description

Per-Protocol (PP) population: A subset of the ITT population, consisted of participants who met all inclusion/exclusion criteria liable to affect the efficacy assessment, had sufficient treatment compliance, and did not present serious deviations of the protocol that might affect efficacy.

Arm/Group Title	AB 400 μg	TIO 18 μg
Arm/Group Description	Randomized participants received orally AB 400 μg/FF 12 μg inhalation powder twice daily (BID) via dry powder inhaler (DPI).	Randomized participants received orally TIO 18 μg inhalation powder in capsule BID via DPI.
Measure Participants	423	419
Least Squares Mean (Standard Error) [Litres]	0.064 (0.013)	0.057 (0.013)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	AB/FF 400/12 μg, AB 400 μg
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority was established by showing that the lower bound of the two-sided 95% confidence interval for change from baseline in morning pre-dose (trough) FEV1 at week 24 when compared AB 400 μg versus TIO 18 μg was higher than -50 mL (non-inferiority limit).
Statistical Test of Hypothesis	p-Value	0.6377
	Comments
	Method	Mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.007
	Confidence Interval	(2-Sided) 95%; -0.021 to 0.035
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline in Normalized Area Under Curve 3hours Post-dose (nAUC0-3/3h) FEV1 of AB/FF 400/12 μg Compared to AB 400 μg and and FF 12 μg at Week 24
Description	To assess the bronchodilatory effect by evaluating the mean changes from baseline in nAUC0-3/3h FEV1 of AB/FF 400/12 µg compared to AB 400 μg and and FF 12 μg after administration of oral inhalation powder BID via DPI to participants with COPD.
Time Frame	At Day 1 and Day 169

Outcome Measure Data

Analysis Population Description

ITT population: All randomized participants who took at least one dose of IP and had at least a baseline FEV1, under the ITT principle and regardless the adherence to the randomized treatment.

Arm/Group Title	AB/FF 400/12 μg	AB 400 μg	FF 12 μg	TIO 18 μg
Arm/Group Description	Randomized participants received orally AB 400 μg/FF 12 μg inhalation powder twice daily (BID) via dry powder inhaler (DPI).	Randomized participants received AB 400 μg oral inhalation powder BID via DPI.	Randomized participants received orally FF 12 μg inhalation powder BID via DPI.	Edit Randomized participants received orally TIO 18 μg inhalation powder in capsule BID via DPI.
Measure Participants	314	475	319	475
Least Squares Mean (Standard Error) [Litres]	0.237 (0.013)	0.162 (0.010)	0.149 (0.013)	0.151 (0.010)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	AB/FF 400/12 μg, AB 400 μg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.075
	Confidence Interval	(2-Sided) 95%; 0.043 to 0.107
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	AB/FF 400/12 μg, FF 12 μg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.087
	Confidence Interval	(2-Sided) 95%; 0.052 to 0.122
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Responder (Number of Participants) Analysis of St. George's Respiratory Questionnaire (SGRQ) Total Score With AB/FF 400/12 μg Versus AB 400 μg and FF 12 μg.
Description	SGRQ was a A standardized self-completed tool used to measure impaired health and perceived well-being ("quality of life") in respiratory diseases. The questionnaire contained 50 items divided into 3 (symptoms, activity and impacts) dimensions. Each of the three dimensions of the questionnaire is scored separately in the range from 0 to 100%, zero score indicating no impairment of life quality. A summary score utilizing responses to all items is the total SGRQ score which also ranges from 0 to 100%. The SGRQ scores are calculated using weights attached to each item of the questionnaire which provides an estimate of the distress associated with the symptoms or state described in each item. Higher scores indicate poorer health. A decrease of at least 4 units in the SGRQ total score has been established as the criterion for minimal meaningful improvement. SGRQ responders will be those with a decrease in SGRQ total score of at least 4 units from baseline.
Time Frame	At baseline and Week 24

Outcome Measure Data

Analysis Population Description

ITT population: All randomized participants who took at least one dose of IP and had at least a baseline FEV1, under the ITT principle and regardless the adherence to the randomized treatment.

Arm/Group Title	AB/FF 400/12 μg	AB 400 μg	FF 12 μg	TIO 18 μg
Arm/Group Description	Randomized participants received orally AB 400 μg/FF 12 μg inhalation powder twice daily (BID) via dry powder inhaler (DPI).	Randomized participants received AB 400 μg oral inhalation powder BID via DPI.	Randomized participants received orally FF 12 μg inhalation powder BID via DPI.	Edit Randomized participants received orally TIO 18 μg inhalation powder in capsule BID via DPI.
Measure Participants	270	383	258	389
Number of responders -Yes	130 41.4%	188 39.6%	128 40.1%	197 41.5%
Number of responders- NO	140 44.6%	195 41.1%	130 40.8%	192 40.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	AB/FF 400/12 μg, AB 400 μg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8714
	Comments
	Method	Logistic random-effect model
	Comments
Method of Estimation	Estimation Parameter	Odds ratio
	Estimated Value	0.96
	Confidence Interval	(2-Sided) 95%; 0.61 to 1.51
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	AB/FF 400/12 μg, FF 12 μg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8873
	Comments
	Method	Logistic random-effect model
	Comments
Method of Estimation	Estimation Parameter	Odds ratio
	Estimated Value	0.97
	Confidence Interval	(2-Sided) 95%; 0.59 to 1.58
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	From time of signature of the ICF throughout the treatment period and including the follow-up period (14 days after the last study drug administration)
Adverse Event Reporting Description	An adverse event was the development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition might be symptoms, signs or the abnormal results of an investigation. The safety population was defined as all randomized patients who took at least one dose of IMP.
Arm/Group Title	AB/FF 400/12 μg		AB 400 μg		FF 12 μg		TIO 18 μg
Arm/Group Description	Randomized participants received orally AB 400 μg/FF 12 μg inhalation powder twice daily (BID) via dry powder inhaler (DPI).		Randomized participants received AB 400 μg oral inhalation powder BID via DPI.		Randomized participants received orally FF 12 μg inhalation powder BID via DPI.		Randomized participants received orally TIO 18 μg inhalation powder in capsule BID via DPI.
All Cause Mortality
	AB/FF 400/12 μg		AB 400 μg		FF 12 μg		TIO 18 μg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/314 (0.3%)		1/475 (0.2%)		4/319 (1.3%)		2/475 (0.4%)
Serious Adverse Events
	AB/FF 400/12 μg		AB 400 μg		FF 12 μg		TIO 18 μg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	23/314 (7.3%)		41/475 (8.6%)		22/319 (6.9%)		37/475 (7.8%)
Blood and lymphatic system disorders
Polycythaemia	0/314 (0%)	0	1/475 (0.2%)	1	0/319 (0%)	0	0/475 (0%)	0
Cardiac disorders
Coronary artery stenosis	0/314 (0%)	0	0/475 (0%)	0	1/319 (0.3%)	1	0/475 (0%)	0
Cardiac failure acute	0/314 (0%)	0	2/475 (0.4%)	2	0/319 (0%)	0	0/475 (0%)	0
Cardiac failure congestive	0/314 (0%)	0	2/475 (0.4%)	3	0/319 (0%)	0	0/475 (0%)	0
Angina pectoris	1/314 (0.3%)	1	0/475 (0%)	0	0/319 (0%)	0	1/475 (0.2%)	1
Acute myocardial infarction	0/314 (0%)	0	0/475 (0%)	0	0/319 (0%)	0	1/475 (0.2%)	1
Angina unstable	0/314 (0%)	0	0/475 (0%)	0	0/319 (0%)	0	1/475 (0.2%)	1
Myocardial infarction	0/314 (0%)	0	0/475 (0%)	0	0/319 (0%)	0	3/475 (0.6%)	3
Cor pulmonale chronic	0/314 (0%)	0	0/475 (0%)	0	0/319 (0%)	0	1/475 (0.2%)	1
Atrial tachycardia	1/314 (0.3%)	1	0/475 (0%)	0	0/319 (0%)	0	0/475 (0%)	0
Atrial fibrillation	0/314 (0%)	0	1/475 (0.2%)	1	0/319 (0%)	0	2/475 (0.4%)	2
Supraventricular tachycardia	0/314 (0%)	0	1/475 (0.2%)	1	0/319 (0%)	0	1/475 (0.2%)	1
Endocrine disorders
Hypercalcaemia of malignancy	0/314 (0%)	0	0/475 (0%)	0	1/319 (0.3%)	1	0/475 (0%)	0
Gastrointestinal disorders
Abdominal hernia	0/314 (0%)	0	0/475 (0%)	0	0/319 (0%)	0	1/475 (0.2%)	1
Diarrhoea	0/314 (0%)	0	0/475 (0%)	0	0/319 (0%)	0	1/475 (0.2%)	1
Abdominal pain upper	0/314 (0%)	0	0/475 (0%)	0	0/319 (0%)	0	1/475 (0.2%)	1
General disorders
Complication associated with device	0/314 (0%)	0	0/475 (0%)	0	1/319 (0.3%)	1	0/475 (0%)	0
Death	0/314 (0%)	0	0/475 (0%)	0	1/319 (0.3%)	1	0/475 (0%)	0
Impaired healing	0/314 (0%)	0	1/475 (0.2%)	1	0/319 (0%)	0	0/475 (0%)	0
Chest pain	0/314 (0%)	0	0/475 (0%)	0	0/319 (0%)	0	1/475 (0.2%)	1
Hepatobiliary disorders
Cholelithiasis	0/314 (0%)	0	0/475 (0%)	0	0/319 (0%)	0	1/475 (0.2%)	1
Infections and infestations
Pneumonia	4/314 (1.3%)	4	3/475 (0.6%)	3	1/319 (0.3%)	1	2/475 (0.4%)	2
Appendicitis	1/314 (0.3%)	1	0/475 (0%)	0	0/319 (0%)	0	0/475 (0%)	0
Diverticulitis	0/314 (0%)	0	1/475 (0.2%)	1	0/319 (0%)	0	0/475 (0%)	0
Pneumonia bacterial	0/314 (0%)	0	1/475 (0.2%)	1	0/319 (0%)	0	0/475 (0%)	0
Post procedural infection	0/314 (0%)	0	1/475 (0.2%)	1	0/319 (0%)	0	0/475 (0%)	0
Sepsis	1/314 (0.3%)	1	0/475 (0%)	0	0/319 (0%)	0	0/475 (0%)	0
Septic shock	0/314 (0%)	0	1/475 (0.2%)	1	0/319 (0%)	0	0/475 (0%)	0
Staphylococcal infection	0/314 (0%)	0	0/475 (0%)	0	1/319 (0.3%)	1	0/475 (0%)	0
Laryngitis	0/314 (0%)	0	0/475 (0%)	0	0/319 (0%)	0	1/475 (0.2%)	1
Peritonsillar abscess	0/314 (0%)	0	1/475 (0.2%)	1	0/319 (0%)	0	0/475 (0%)	0
Gastritis viral	0/314 (0%)	0	0/475 (0%)	0	0/319 (0%)	0	1/475 (0.2%)	1
Injury, poisoning and procedural complications
Arterial bypass occlusion	0/314 (0%)	0	1/475 (0.2%)	1	0/319 (0%)	0	0/475 (0%)	0
Radius fracture	1/314 (0.3%)	1	0/475 (0%)	0	0/319 (0%)	0	0/475 (0%)	0
Femur fracture	0/314 (0%)	0	1/475 (0.2%)	1	0/319 (0%)	0	0/475 (0%)	0
Humerus fracture	0/314 (0%)	0	0/475 (0%)	0	1/319 (0.3%)	1	1/475 (0.2%)	1
Tibia fracture	0/314 (0%)	0	1/475 (0.2%)	1	0/319 (0%)	0	0/475 (0%)	0
Tendon rupture	1/314 (0.3%)	1	0/475 (0%)	0	0/319 (0%)	0	0/475 (0%)	0
Foreign body	1/314 (0.3%)	1	0/475 (0%)	0	0/319 (0%)	0	0/475 (0%)	0
Road traffic accident	1/314 (0.3%)	1	1/475 (0.2%)	1	0/319 (0%)	0	0/475 (0%)	0
Alcohol poisoning	0/314 (0%)	0	0/475 (0%)	0	0/319 (0%)	0	1/475 (0.2%)	1
Intervertebral disc injury	0/314 (0%)	0	0/475 (0%)	0	0/319 (0%)	0	1/475 (0.2%)	1
Thermal burn	0/314 (0%)	0	0/475 (0%)	0	0/319 (0%)	0	1/475 (0.2%)	1
Rib fracture	1/314 (0.3%)	1	0/475 (0%)	0	0/319 (0%)	0	0/475 (0%)	0
Metabolism and nutrition disorders
Hyperglycaemia	0/314 (0%)	0	0/475 (0%)	0	0/319 (0%)	0	1/475 (0.2%)	1
Hyponatraemia	0/314 (0%)	0	0/475 (0%)	0	0/319 (0%)	0	1/475 (0.2%)	1
Musculoskeletal and connective tissue disorders
Intervertebral disc protrusion	1/314 (0.3%)	1	1/475 (0.2%)	1	0/319 (0%)	0	0/475 (0%)	0
Lumbar spinal stenosis	0/314 (0%)	0	0/475 (0%)	0	0/319 (0%)	0	1/475 (0.2%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
B-cell lymphoma	1/314 (0.3%)	1	0/475 (0%)	0	0/319 (0%)	0	0/475 (0%)	0
Neuroendocrine carcinoma	0/314 (0%)	0	1/475 (0.2%)	1	0/319 (0%)	0	0/475 (0%)	0
Spinal meningioma benign	0/314 (0%)	0	1/475 (0.2%)	1	0/319 (0%)	0	0/475 (0%)	0
Metastatic neoplasm	0/314 (0%)	0	0/475 (0%)	0	1/319 (0.3%)	1	0/475 (0%)	0
Squamous cell carcinoma of lung	1/314 (0.3%)	1	0/475 (0%)	0	0/319 (0%)	0	0/475 (0%)	0
Oesophageal carcinoma	0/314 (0%)	0	1/475 (0.2%)	1	0/319 (0%)	0	0/475 (0%)	0
Pancreatic carcinoma stage IV	0/314 (0%)	0	0/475 (0%)	0	1/319 (0.3%)	1	0/475 (0%)	0
Renal cell carcinoma	0/314 (0%)	0	1/475 (0.2%)	1	0/319 (0%)	0	0/475 (0%)	0
Nervous system disorders
Cerebrovascular accident	1/314 (0.3%)	1	0/475 (0%)	0	0/319 (0%)	0	0/475 (0%)	0
Cerebellar infarction	0/314 (0%)	0	0/475 (0%)	0	1/319 (0.3%)	1	0/475 (0%)	0
Lacunar stroke	0/314 (0%)	0	0/475 (0%)	0	1/319 (0.3%)	1	0/475 (0%)	0
Subarachnoid haemorrhage	0/314 (0%)	0	1/475 (0.2%)	1	0/319 (0%)	0	0/475 (0%)	0
Carotid artery stenosis	0/314 (0%)	0	0/475 (0%)	0	1/319 (0.3%)	1	0/475 (0%)	0
Syncope	1/314 (0.3%)	1	1/475 (0.2%)	1	1/319 (0.3%)	1	0/475 (0%)	0
Hydrocephalus	0/314 (0%)	0	1/475 (0.2%)	1	0/319 (0%)	0	0/475 (0%)	0
Sciatica	0/314 (0%)	0	1/475 (0.2%)	1	0/319 (0%)	0	0/475 (0%)	0
Dizziness	1/314 (0.3%)	1	0/475 (0%)	0	0/319 (0%)	0	0/475 (0%)	0
Epilepsy	0/314 (0%)	0	0/475 (0%)	0	0/319 (0%)	0	1/475 (0.2%)	1
Transient ischaemic attack	0/314 (0%)	0	1/475 (0.2%)	1	0/319 (0%)	0	0/475 (0%)	0
Psychiatric disorders
Anxiety	1/314 (0.3%)	1	0/475 (0%)	0	0/319 (0%)	0	0/475 (0%)	0
Bipolar disorder	0/314 (0%)	0	1/475 (0.2%)	1	0/319 (0%)	0	0/475 (0%)	0
Renal and urinary disorders
Chronic kidney disease	0/314 (0%)	0	1/475 (0.2%)	1	0/319 (0%)	0	0/475 (0%)	0
Oliguria	0/314 (0%)	0	1/475 (0.2%)	1	0/319 (0%)	0	0/475 (0%)	0
End stage renal disease	0/314 (0%)	0	1/475 (0.2%)	1	0/319 (0%)	0	0/475 (0%)	0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	7/314 (2.2%)	8	11/475 (2.3%)	11	10/319 (3.1%)	10	14/475 (2.9%)	14
Dyspnoea	0/314 (0%)	0	1/475 (0.2%)	1	0/319 (0%)	0	0/475 (0%)	0
Hypoxia	1/314 (0.3%)	1	0/475 (0%)	0	0/319 (0%)	0	0/475 (0%)	0
Atelectasis	0/314 (0%)	0	1/475 (0.2%)	1	0/319 (0%)	0	0/475 (0%)	0
Pulmonary embolism	1/314 (0.3%)	1	1/475 (0.2%)	1	1/319 (0.3%)	1	1/475 (0.2%)	1
Respiratory failure	1/314 (0.3%)	1	0/475 (0%)	0	0/319 (0%)	0	0/475 (0%)	0
Pulmonary mass	0/314 (0%)	0	0/475 (0%)	0	1/319 (0.3%)	1	0/475 (0%)	0
Vascular disorders
Hypertensive crisis	1/314 (0.3%)	1	0/475 (0%)	0	0/319 (0%)	0	0/475 (0%)	0
Arteriosclerosis	1/314 (0.3%)	1	0/475 (0%)	0	0/319 (0%)	0	0/475 (0%)	0
Deep vein thrombosis	0/314 (0%)	0	1/475 (0.2%)	1	0/319 (0%)	0	0/475 (0%)	0
Peripheral artery stenosis	1/314 (0.3%)	1	0/475 (0%)	0	0/319 (0%)	0	0/475 (0%)	0
Peripheral arterial occlusive disease	0/314 (0%)	0	0/475 (0%)	0	1/319 (0.3%)	1	0/475 (0%)	0
Varicose vein	0/314 (0%)	0	0/475 (0%)	0	0/319 (0%)	0	1/475 (0.2%)	1
Other (Not Including Serious) Adverse Events
	AB/FF 400/12 μg		AB 400 μg		FF 12 μg		TIO 18 μg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	173/314 (55.1%)		222/475 (46.7%)		178/319 (55.8%)		241/475 (50.7%)
Gastrointestinal disorders
Diarrhoea	6/314 (1.9%)	6	9/475 (1.9%)	9	7/319 (2.2%)	7	7/475 (1.5%)	7
Infections and infestations
Nasopharyngitis	36/314 (11.5%)	42	47/475 (9.9%)	56	39/319 (12.2%)	45	64/475 (13.5%)	67
Upper respiratory tract infection	8/314 (2.5%)	9	13/475 (2.7%)	15	7/319 (2.2%)	7	17/475 (3.6%)	21
Sinusitis	8/314 (2.5%)	8	10/475 (2.1%)	10	6/319 (1.9%)	6	7/475 (1.5%)	7
Pneumonia	4/314 (1.3%)	4	1/475 (0.2%)	1	6/319 (1.9%)	6	6/475 (1.3%)	6
Urinary tract infection	4/314 (1.3%)	4	5/475 (1.1%)	5	8/319 (2.5%)	8	3/475 (0.6%)	3
Musculoskeletal and connective tissue disorders
Back pain	15/314 (4.8%)	22	7/475 (1.5%)	7	8/319 (2.5%)	12	7/475 (1.5%)	8
Arthralgia	8/314 (2.5%)	9	4/475 (0.8%)	4	3/319 (0.9%)	4	8/475 (1.7%)	10
Nervous system disorders
Headache	16/314 (5.1%)	27	19/475 (4%)	20	17/319 (5.3%)	19	25/475 (5.3%)	31
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary	49/314 (15.6%)	60	79/475 (16.6%)	90	58/319 (18.2%)	74	61/475 (12.8%)	70
Dyspnoea	6/314 (1.9%)	6	13/475 (2.7%)	18	6/319 (1.9%)	7	12/475 (2.5%)	12
Cough	6/314 (1.9%)	7	7/475 (1.5%)	7	4/319 (1.3%)	4	17/475 (3.6%)	19
Vascular disorders
Hypertension	7/314 (2.2%)	7	8/475 (1.7%)	8	9/319 (2.8%)	10	7/475 (1.5%)	9

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

All clinical study findings and documents will be regarded as confidential. The investigator and members of his/her research team must not disclose such information without prior written approval from the sponsor.