Comparative Study of Fluticasone Furoate(FF)/Umeclidinium Bromide (UMEC)/ Vilanterol (VI) Closed Therapy Versus FF/VI Plus UMEC Open Therapy in Subjects With Chronic Obstructive Pulmonary Disease (COPD)

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02729051
• Collaborator: (none)
• Enrollment: 1,055
• Locations: 127
• Arms: 2
• Actual Duration (Months): 10.8
• Patients Per Site: 8.3
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

This multicenter study will be conducted to compare the effect of FF/UMEC/VI with FF/VI plus UMEC on lung function after 24 weeks of treatment. This is a phase IIIB, 24-week, randomized, double-blind, parallel group multicenter study. This study will test the hypothesis that the difference in trough forced expiratory volume in one second (FEV1) between treatment groups is less than or equal to a pre-specified non-inferiority margin. Alternatively, this study will also test the hypothesis that the difference between treatment groups is greater than the margin. The triple therapy of FF/UMEC/VI in a single inhaler is being developed with the aim of providing a new treatment option for the management of advanced Global Initiative for Chronic Obstructive Lung Disease (GOLD) Group D COPD which will reduce the exacerbation frequency, allow for a reduced burden of polypharmacy, convenience, and improve lung function, health related quality of life (HRQoL) and symptom control over established dual/monotherapies. This study has a 2 week run in period where subjects will continue to have their existing COPD medications. At randomization, subjects will discontinue all existing COPD medications and will be assigned to treatment of FF/UMEC/VI, 100 microgram (mcg)/62.5 mcg/25 mcg and placebo or FF/VI, 100 mcg/25 mcg and UMEC, 62.5 mcg in a 1:1 ratio for 24 weeks. Subjects will have clinical visits at Pre-Screening (Visit 0), Screening (Visit 1), Randomization (Week 0, Visit 2), Week 4 (Visit 3), Week 12 (Visit 4) and Week 24 (Visit 5). A follow-up visit will be conducted at 1 week after the end of treatment period or after early withdrawal visit. Approximately, 1020 subjects will be enrolled in this study. There will be two pharmacokinetic (PK) groups (subset A and subset B). Approximately 120 subjects will be assigned to subset A and approximately 60 subjects will be assigned to subset B. The total duration of subject participation will be approximately 27 weeks, consisting of a 2-week run-in period, 24-week treatment period and a 1-week follow-up period.

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Disease, Chronic Obstructive	Drug: FF/UMEC/VI; Drug: FF/VI; Drug: UMEC; Drug: Placebo; Drug: Albuterol/salbutamol	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 1055 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase IIIB, 24-week Randomised, Double-blind Study to Compare 'Closed' Triple Therapy (FF/UMEC/VI) With 'Open' Triple Therapy (FF/VI + UMEC), in Subjects With Chronic Obstructive Pulmonary Disease (COPD)
• Actual Study Start Date: Jun 29, 2016
• Actual Primary Completion Date: May 23, 2017
• Actual Study Completion Date: May 23, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: FF/UMEC/VI closed triple therapy plus Placebo Subjects will receive FF/UMEC/VI, 100 mcg/62.5 mcg/25 mcg and placebo inhalation powder via the dry powder inhaler (DPI), once daily in the morning. Subjects will also receive albuterol/salbutamol as a rescue medication when needed during the treatment period.	Drug: FF/UMEC/VI; This intervention is provided in two strips. First strip contains FF blended with lactose. It is available as dry white powder, 100 mcg per blister. Second strip contains UMEC and VI blended with lactose and magnesium stearate. It is available as dry white powder, 62.5 mcg per blister UMEC, 25 mcg per blister VI. The intervention is inhaled via the DPI, once daily in the morning. DPI contains 30 doses (2 strips with 30 blisters per strip).; Drug: Placebo; This intervention is available in one strip. The strip contains lactose. The formulation is available as dry white powder. The intervention is inhaled via the DPI, once daily in the morning. DPI contains 30 doses (1 strip with 30 blisters).; Drug: Albuterol/salbutamol; This is a rescue medication administered via metered-dose inhaler (MDI) with a spacer which will be used when needed during the study.
Active Comparator: FF/VI plus UMEC open triple therapy Subjects will receive FF/VI, 100 mcg/25 mcg and UMEC, 62.5 mcg inhalation powder via the DPI, once daily in the morning. Subjects will also receive albuterol/salbutamol as a rescue medication when needed during the treatment period.	Drug: FF/VI; This intervention is provided in two strips. First strip contains FF blended with lactose. It is available as dry white powder, 100 mcg per blister. Second strip contains VI blended with lactose and magnesium stearate. It is available as dry white powder, 25 mcg per blister. The intervention is inhaled via the DPI, once daily in the morning. DPI contains 30 doses (2 strips with 30 blisters per strip).; Drug: UMEC; This intervention is available in one strip. The strip contains UMEC blended with lactose and magnesium stearate. The formulation is available as dry white powder, 62.5 mcg per blister. The intervention is inhaled via the DPI, once daily in the morning. DPI contains 30 doses (1 strip with 30 blisters).; Drug: Albuterol/salbutamol; This is a rescue medication administered via metered-dose inhaler (MDI) with a spacer which will be used when needed during the study.

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) at Week 24 [Baseline and Week 24]

   FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. It was measured using centralized spirometry. FEV1 values at Week 0, pre-dose were considered as Baseline values. Change from Baseline was calculated by subtracting Baseline value from the value at indicated time point. Modified Per Protocol (mPP) Population was used which comprised of all participants in the Intent-to-Treat (ITT) Population, who do not have a full protocol deviation considered to impact efficacy. Data following a moderate/severe COPD exacerbation or pneumonia was excluded from analysis due to the potential impact of the exacerbation or the medications used to treat it. Participants with partial protocol deviations considered to impact efficacy were included in the mPP Population but had their data excluded from analysis from the time of deviation onwards. Analysis was performed using a mixed model repeated measures (MMRM) method.

Secondary Outcome Measures

1. Percentage of Responders Based on the Saint (St) George Respiratory Questionnaire (SGRQ) Total Score at Week 24 [Week 24]

   SGRQ is a disease-specific questionnaire designed to measure impact of respiratory disease and its treatment on health related quality of life (HRQoL) of participants with COPD. It contains 14 questions with a total of 40 items grouped into domains (Symptoms, Activity and Impacts). SGRQ total score was calculated as 100 multiplied by summed weights from all positive items divided by sum of weights for all items in questionnaire. It ranges from 0 to 100, higher score indicates poor HRQoL. Response was defined as an SGRQ total score of >=4 units below Baseline. Non response was defined as a SGRQ total score <4 units below Baseline or a missing SGRQ total score with no subsequent on treatment scores. ITT Population comprised of randomized participants, excluding those who were randomized in error. A participant screened or run-in failure and also randomized was considered to be randomized in error. Analysis was performed using a generalized linear mixed model with a logit link function.

2. Change From Baseline in SGRQ Total Score at Week 24 [Baseline and Week 24]

   SGRQ is a disease-specific questionnaire designed to measure impact of respiratory disease and its treatment on HRQoL of participants with COPD. It contains 14 questions with a total of 40 items grouped into domains (Symptoms, Activity and Impacts). SGRQ total score was calculated as 100 multiplied by summed weights from all positive items divided by sum of weights for all items in questionnaire. It ranges from 0 to 100, higher score indicates poor HRQoL. Values at Week 0, pre-dose were considered as Baseline values. Change from Baseline was calculated by subtracting Baseline value from the value at indicated time point. Analysis was performed using a MMRM method including covariates of Baseline SGRQ Total score, stratum (number of long-acting bronchodilators per day during the run-in: 0/1 or 2), visit, geographical region, treatment, visit by treatment and visit by Baseline interaction.

3. Percentage of Responders Based on Transitional Dyspnea Index (TDI) Focal Score at Week 24 [Week 24]

   The TDI measures changes in the participant's dyspnea. TDI focal score was calculated as the sum of the ratings recorded for each of the 3 individual scales (Functional Impairment, Magnitude of Task, Magnitude of Effort). Each of these scales had a possible score ranging from -6 to +6. lower scores indicating more impairment. TDI focal score was calculated as the sum of the 3 individual scores and then divided by 2 (so the range of the TDI focal score is -9 to +9). The lower the score, the more deterioration in severity of dyspnea. If a score is missing for any of the three scales, then the TDI focal score was set to missing. A participant was considered as a responder if the on-treatment TDI focal score was at least 1 unit at that visit. Non-response was defined as a TDI focal score of less than 1 unit or a missing TDI focal score with no subsequent non-missing on-treatment scores. Analysis was performed using a generalized linear mixed model with a logit link function.

4. TDI Focal Score at Week 24 [Week 24]

   The TDI measures changes in the participant's dyspnoea. TDI focal score was calculated as the sum of the ratings recorded for each of the 3 individual scales (Functional Impairment, Magnitude of Task, Magnitude of Effort). Each of these scales had a possible score ranging from -6 to +6. lower scores indicating more impairment. TDI focal score was calculated as the sum of the 3 individual scores and then divided by 2 (so the range of the TDI focal score is -9 to +9). The lower the score, the more deterioration in severity of dyspnea. If a score is missing for any of the three scales, then the TDI focal score was set to missing. Analysis was performed using a repeated measures model.

5. Time to First Moderate or Severe Exacerbation [Up to 25 weeks]

   COPD exacerbations were identified based on the investigator's clinical judgment. Worsening symptoms of COPD that required treatment with oral/systemic corticosteroids and/or antibiotics were considered as moderate exacerbation. Worsening symptoms of COPD that required treatment with in-subject hospitalization was considered as severe exacerbation. Hazard ratio and 95% confidence interval (CI) is from a Cox proportional hazards model with covariates of treatment group, sex, exacerbation history (0, 1, >=2 moderate/severe exacerbations, prior year), smoking status (screening), stratum (number of long-acting bronchodilators per day during the run-in: 0/1 or 2), geographical region and percent predicted FEV1 at Baseline. Median and inter-quartile range (first and third quartile) have been presented.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

Informed Consent: A signed and dated written informed consent prior to study participation.

• Type of subject: Outsubject.

• Age: Subjects 40 years of age or older at Screening (Visit 1).

• Gender: Male or female subjects. A female subject is eligible to participate if she is not pregnant (as confirmed by a negative urine human chorionic gonadotrophin (hCG) test), not lactating, and at least one of the following conditions applies:

Non-reproductive potential defined as:

• Pre-menopausal females with one of the following: Documented tubal ligation, Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion; Hysterectomy; Documented Bilateral Oophorectomy.

• Postmenopausal defined as 12 months of spontaneous amenorrhea. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment.

Reproductive potential and agrees to follow one of the options listed in the Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP) from 30 days prior to the first dose of study treatmentand until after the last dose of study treatmentand completion of the follow-up visit.

• COPD Diagnosis: An established clinical history of COPD in accordance with the definition by the American Thoracic Society/European Respiratory Society.

• Smoking History: Current or former cigarette smokers with a history of cigarette smoking of >=10 pack-years at Screening (Visit 1) [number of pack years = (number of cigarettes per day divided by 20) x number of years smoked (e.g., 20 cigarettes per day for 10 years, or 10 cigarettes per day for 20 years)]. Previous smokers are defined as those who have stopped smoking for at least 6 months prior to Screening (Visit 1). Note: Pipe and/or cigar use cannot be used to calculate pack-year history.

• Severity of COPD symptoms: A score of >=10 on the COPD Assessment Test (CAT) at Screening (Visit1).

• Severity of COPD Disease: A post-albuterol/salbutamol FEV1/FVC ratio of <0.70 at Screening (Visit 1).

• Existing COPD maintenance treatment: Subject must be receiving daily maintenance treatment for their COPD for at least 3 months prior to Screening (Visit 1). Note: Subjects receiving only as needed COPD medications are not eligible.

• History of Exacerbations: Subjects must demonstrate: a post-bronchodilator FEV1 <50 percent predicted normal at Screening (Visit 1) and a documented history of >=1 moderate or severe COPD exacerbation in the 12 months prior to Screening or a post-bronchodilator 50 percent =< FEV1 <80 percent predicted normal at Screening (Visit 1) and a documented history of >=2 moderate exacerbations or a documented history of >=1 severe COPD exacerbation (hospitalised) in the 12 months prior to Screening (Visit 1). Notes: Percent predicted will be calculated using the European Respiratory Society Global Lung Function Initiative reference equations; A documented history of a COPD exacerbation (e.g., medical record verification) is a medical record of worsening COPD symptoms that required systemic/oral corticosteroids and/or antibiotics (for a moderate exacerbation) or hospitalisation (for a severe exacerbation). Prior use of antibiotics alone does not qualify as an exacerbation history unless the use was associated with treatment of worsening symptoms of COPD, such as increased dyspnoea, sputum volume, or sputum purulence (colour). Subject verbal reports are not acceptable.

• French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.

Exclusion Criteria:

• Pregnancy: Women who are pregnant or lactating or are planning on becoming pregnant during the study.

• Asthma: Subjects with a current diagnosis of asthma. (Subjects with a prior history of asthma are eligible if they have a current diagnosis of COPD, which is the primary cause of their respiratory symptoms).

• Alpha 1-antitrypsin deficiency: Subjects with alpha1-antitrypsin deficiency as the underlying cause of COPD.

• Other respiratory disorders: Subjects with active tuberculosis are excluded. Subjects with other respiratory disorders (e.g. clinically significant: bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension, interstitial lung diseases) are excluded if these conditions are the primary cause of their respiratory symptoms.

• Lung resection: Subjects with lung volume reduction surgery (including procedures such as endobronchial valves) within the 12 months prior to Screening (Visit 1).

• Risk Factors for Pneumonia: immune suppression (e.g. advanced human immune deficiency virus (HIV) with high viral load and low cluster of differentiation 4 (CD4) count, Lupus on immunosuppressants that would increase risk of pneumonia) or other risk factors for pneumonia (e.g. neurological disorders affecting control of the upper airway, such as Parkinson's Disease, Myasthenia Gravis). Notes: Subjects at a high risk for pneumonia (e.g. very low body mass index (BMI), severely malnourished or very low FEV1) will only be included at the discretion of the investigator.

• Pneumonia and/or moderate or severe COPD exacerbation that has not resolved at least 14 days prior to Screening (Visit 1) and at least 30 days following the last dose of oral/systemic corticosteroids (if applicable).

• Other Respiratory tract infections that have not resolved at least 7 days prior to Screening (Visit 1).

• Abnormal Chest x-ray: Chest x-ray reveals evidence of pneumonia or a clinically significant abnormality not believed to be due to the presence of COPD, or another condition that would hinder the ability to detect an infiltrate on chest x-ray (e.g. significant cardiomegaly, pleural effusion or scarring). All subjects will have a chest x-ray at Screening (Visit 1) [or historical radiograph or computerised tomography (CT) scan obtained within 3 months prior to Screening (Visit 1). Notes: Subjects who have experienced pneumonia and/or moderate or severe COPD exacerbation within 3 months of Screening (Visit 1) must provide a post pneumonia/exacerbation chest x-ray or have a chest x-ray conducted at Screening (Visit 1); For sites in Germany: If a chest x-ray (or CT scan) within 3 months prior to Screening (Visit 1) is not available, approval to conduct a diagnostic chest x-ray will need to be obtained from the Federal Office for Radiation Protection (BFS).

• Other diseases/abnormalities: Subjects with historical or current evidence of clinically significant cardiovascular, neurological, psychiatric, renal, hepatic, immunological, gastrointestinal, urogenital, nervous system, musculoskeletal, skin, sensory, endocrine (including uncontrolled diabetes or thyroid disease) or hematological abnormalities that are uncontrolled. Significant is defined as any disease that, in the opinion of the investigator, would put the safety of the subject at risk through participation, or which would affect the efficacy or safety analysis if the disease/condition exacerbated during the study.

• Unstable liver disease: ALT >2 times upper limit of normal (ULN); and bilirubin >1.5 times ULN (isolated bilirubin >1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin <35 percent). Current active liver or biliary disease (with the exception of Gilbert's syndrome or asymptomatic gallstones or otherwise stable chronic liver disease per investigator assessment). Notes: Stable chronic liver disease should generally be defined by the absence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, or persistent jaundice, or cirrhosis; Chronic stable hepatitis B and C (e.g., presence of hepatitis B surface antigen (HBsAg) or positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment) are acceptable if subject otherwise meets entry criteria.

• Unstable or life threatening cardiac disease: subjects with any of the following at Screening (Visit 1) would be excluded: Myocardial infarction or unstable angina in the last 6 months; Unstable or life threatening cardiac arrhythmia requiring intervention in the last 3 months; New York Heart Association (NYHA) Class 4 Heart failure.

• Abnormal and clinically significant 12-Lead ECG finding: Investigators will be provided with ECG reviews conducted by a centralized independent cardiologist to assist in evaluation of subject eligibility. The investigator will determine the clinical significance of each abnormal ECG finding in relation to the subject's medical history and exclude subjects who would be at undue risk by participating in the trial. An abnormal and clinically significant finding that would preclude a subject from entering the trial is defined as a 12-lead tracing that is interpreted as, but not limited to, any of the following: atrial fibrillation (AF) with rapid ventricular rate >120 beats per minute (BPM); sustained or nonsustained ventricular tachycardia (VT); Second degree heart block Mobitz type II and third degree heart block (unless pacemaker or defibrillator had been inserted).

• Contraindications: A history of allergy or hypersensitivity to any corticosteroid, anticholinergic/muscarinic receptor antagonist, beta2-agonist, lactose/milk protein or magnesium stearate or a medical condition such as narrow-angle glaucoma, prostatic hypertrophy or bladder neck obstruction that, in the opinion of the investigator contraindicates study participation.

• Cancer: Subjects with carcinoma that has not been in complete remission for at least 3 years. Subjects who have had carcinoma in situ of the cervix, squamous cell carcinoma and basal cell carcinoma of the skin would not be excluded based on the 3 year waiting period if the subject has been considered cured by treatment.

• Oxygen therapy: Use of long-term oxygen therapy (LTOT) described as resting oxygen therapy >3 Liters per minute (Oxygen use <= 3 Liters/minute flow is not exclusionary.)

• Medication prior to spirometry: Subjects who are medically unable to withhold their albuterol/salbutamol for the 4-hour period required prior to spirometry testing at each study visit.

• Drug/alcohol abuse: Subjects with a known or suspected history of alcohol or drug abuse within the last 2 years.

• Non-compliance: Subjects at risk of non-compliance, or unable to comply with the study procedures. Any infirmity, disability, or geographic location that would limit compliance for scheduled visits.

• Questionable validity of consent: Subjects with a history of psychiatric disease, intellectual deficiency, poor motivation or other conditions that will limit the validity of informed consent to participate in the study.

• Affiliation with investigator site: Study investigators, sub-investigators, and study coordinators, employees of a participating investigator or study site, or immediate family members of the aforementioned that is involved with this study.

• Inability to read: In the opinion of the investigator, any subject who is unable to read and/or would not be able to complete study related materials.

• Medication prior to Screening: Use of the following medications within 30 days prior to Screening (Visit 1) or requirement for their use during the study: Use of long term continuous antibiotic therapy; systemic, oral, parenteral corticosteroids (Intra-spinal and intra-articular injections are allowed); use of any other investigational drug: within 30 days or 5 half lives whichever is longer.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	La Plata	Buenos Aires	Argentina
2	GSK Investigational Site	Mar del Plata	Buenos Aires	Argentina	7600
3	GSK Investigational Site	Buenos Aires		Argentina	C1425BEN
4	GSK Investigational Site	Ciudad Autónoma de Buenos Aires		Argentina	C1426ABP
5	GSK Investigational Site	Mendoza		Argentina	5500
6	GSK Investigational Site	Mendoza		Argentina	M5500CCG
7	GSK Investigational Site	San Miguel de Tucumán		Argentina	4000
8	GSK Investigational Site	Coffs Harbour	New South Wales	Australia	2450
9	GSK Investigational Site	Maroubra	New South Wales	Australia	2035
10	GSK Investigational Site	Randwick	New South Wales	Australia	2031
11	GSK Investigational Site	Westmead	New South Wales	Australia	2145
12	GSK Investigational Site	Woodville South	South Australia	Australia	5011
13	GSK Investigational Site	Footscray	Victoria	Australia	3011
14	GSK Investigational Site	Murdoch	Western Australia	Australia	6150
15	GSK Investigational Site	Golden Beach		Australia	4551
16	GSK Investigational Site	Brest Cedex		France	29609
17	GSK Investigational Site	Marseille cedex 03		France	13331
18	GSK Investigational Site	Nantes cedex 2		France	44277
19	GSK Investigational Site	Perpignan		France	66000
20	GSK Investigational Site	Pringy Cedex		France	74374
21	GSK Investigational Site	Toulouse		France	31400
22	GSK Investigational Site	Dillingen	Bayern	Germany	89407
23	GSK Investigational Site	Nuernberg	Bayern	Germany	90402
24	GSK Investigational Site	Cottbus	Brandenburg	Germany	03050
25	GSK Investigational Site	Ruedersdorf	Brandenburg	Germany	15562
26	GSK Investigational Site	Frankfurt	Hessen	Germany	60389
27	GSK Investigational Site	Fulda	Hessen	Germany	36039
28	GSK Investigational Site	Neu isenburg	Hessen	Germany	63263
29	GSK Investigational Site	Hannover	Niedersachsen	Germany	30173
30	GSK Investigational Site	Peine	Niedersachsen	Germany	31224
31	GSK Investigational Site	Wardenburg	Niedersachsen	Germany	26203
32	GSK Investigational Site	Dortmund	Nordrhein-Westfalen	Germany	44263
33	GSK Investigational Site	Gelsenkirchen	Nordrhein-Westfalen	Germany	45879
34	GSK Investigational Site	Rheine	Nordrhein-Westfalen	Germany	48431
35	GSK Investigational Site	Solingen	Nordrhein-Westfalen	Germany	42651
36	GSK Investigational Site	Warendorf	Nordrhein-Westfalen	Germany	48231
37	GSK Investigational Site	Leipzg	Sachsen	Germany	04109
38	GSK Investigational Site	Avellino	Campania	Italy	83100
39	GSK Investigational Site	Napoli	Campania	Italy	80131
40	GSK Investigational Site	Parma	Emilia-Romagna	Italy	43125
41	GSK Investigational Site	Palermo	Sicilia	Italy	90146
42	GSK Investigational Site	Pisa	Toscana	Italy	56124
43	GSK Investigational Site	San Sisto (PG)	Umbria	Italy	06156
44	GSK Investigational Site	Aichi		Japan	457-8511
45	GSK Investigational Site	Chiba		Japan	278-0004
46	GSK Investigational Site	Ehime		Japan	791-0281
47	GSK Investigational Site	Fukuoka		Japan	802-0083
48	GSK Investigational Site	Fukuoka		Japan	816-0813
49	GSK Investigational Site	Fukuoka		Japan	832-0059
50	GSK Investigational Site	Gifu		Japan	509-6134
51	GSK Investigational Site	Gunma		Japan	372-0831
52	GSK Investigational Site	Gunma		Japan	373-0807
53	GSK Investigational Site	Hokkaido		Japan	060-0033
54	GSK Investigational Site	Hokkaido		Japan	062-8618
55	GSK Investigational Site	Hokkaido		Japan	064-0801
56	GSK Investigational Site	Hyogo		Japan	664-8540
57	GSK Investigational Site	Hyogo		Japan	672-8064
58	GSK Investigational Site	Ibaraki		Japan	317-0077
59	GSK Investigational Site	Ibaraki		Japan	319-1113
60	GSK Investigational Site	Ishikawa		Japan	920-8530
61	GSK Investigational Site	Ishikawa		Japan	923-8560
62	GSK Investigational Site	Kagawa		Japan	760-8538
63	GSK Investigational Site	Kagawa		Japan	761-8073
64	GSK Investigational Site	Kagawa		Japan	762-8550
65	GSK Investigational Site	Kanagawa		Japan	210-0852
66	GSK Investigational Site	Kanagawa		Japan	232-0066
67	GSK Investigational Site	Kanagawa		Japan	236-0004
68	GSK Investigational Site	Kyoto		Japan	607-8062
69	GSK Investigational Site	Kyoto		Japan	615-8087
70	GSK Investigational Site	Mie		Japan	515-8544
71	GSK Investigational Site	Niigata		Japan	940-0856
72	GSK Investigational Site	Okayama		Japan	711-0921
73	GSK Investigational Site	Osaka		Japan	596-8501
74	GSK Investigational Site	Shizuoka		Japan	420-8527
75	GSK Investigational Site	Tokyo		Japan	103-0027
76	GSK Investigational Site	Tokyo		Japan	194-0023
77	GSK Investigational Site	Seoul		Korea, Republic of	130-709
78	GSK Investigational Site	Seoul		Korea, Republic of	152-703
79	GSK Investigational Site	Seoul		Korea, Republic of	156-755
80	GSK Investigational Site	Suwon		Korea, Republic of	442-723
81	GSK Investigational Site	Wonju, Gangwon-do,		Korea, Republic of	220-701
82	GSK Investigational Site	Ciudad de México	Estado De México	Mexico	03810
83	GSK Investigational Site	Guadalajara	Jalisco	Mexico	44100
84	GSK Investigational Site	Zapopan	Jalisco	Mexico	45070
85	GSK Investigational Site	Zapopan	Jalisco	Mexico	45200
86	GSK Investigational Site	Monterrey	Nuevo León	Mexico	64020
87	GSK Investigational Site	Monterrey	Nuevo León	Mexico	64460
88	GSK Investigational Site	Monterrey	Nuevo León	Mexico	64710
89	GSK Investigational Site	Aguascalientes		Mexico	20190
90	GSK Investigational Site	México DF		Mexico	14050
91	GSK Investigational Site	Elblag		Poland	82-300
92	GSK Investigational Site	Grudziadz		Poland	86-300
93	GSK Investigational Site	Kielce		Poland	25-751
94	GSK Investigational Site	Krakow		Poland	30-131
95	GSK Investigational Site	Ostrow Wilekopolski		Poland	63-400
96	GSK Investigational Site	Tarnów		Poland	33-100
97	GSK Investigational Site	Bucharest		Romania	020125
98	GSK Investigational Site	Bucharest		Romania	030303
99	GSK Investigational Site	Cluj Napoca		Romania	400371
100	GSK Investigational Site	Ramnicu Valcea		Romania	240564
101	GSK Investigational Site	Suceava		Romania	720284
102	GSK Investigational Site	Targu Mures		Romania	540156
103	GSK Investigational Site	Timisoara		Romania	300310
104	GSK Investigational Site	Arkhangelsk		Russian Federation	163000
105	GSK Investigational Site	Arkhangelsk		Russian Federation	163001
106	GSK Investigational Site	Barnaul		Russian Federation	656024
107	GSK Investigational Site	Barnaul		Russian Federation	656045
108	GSK Investigational Site	Irkutsk		Russian Federation	664033
109	GSK Investigational Site	Izhevsk		Russian Federation	426063
110	GSK Investigational Site	Kazan		Russian Federation	420008
111	GSK Investigational Site	Kazan		Russian Federation	420012
112	GSK Investigational Site	Moscow		Russian Federation	115 280
113	GSK Investigational Site	Moscow		Russian Federation	117574
114	GSK Investigational Site	Novosibirsk		Russian Federation	630102
115	GSK Investigational Site	Saint Petesburg		Russian Federation	195030
116	GSK Investigational Site	Saint-Petersburg		Russian Federation	193231
117	GSK Investigational Site	Saint-Petersburg		Russian Federation	194354
118	GSK Investigational Site	Saint-Petersburg		Russian Federation	198260
119	GSK Investigational Site	Saratov		Russian Federation	410028
120	GSK Investigational Site	Tomsk		Russian Federation	634034
121	GSK Investigational Site	Ufa		Russian Federation	450071
122	GSK Investigational Site	Laredo	Cantabria	Spain	39770
123	GSK Investigational Site	Barcelona		Spain	08003
124	GSK Investigational Site	Mérida (Badajoz)		Spain	06800
125	GSK Investigational Site	Pamplona		Spain	31008
126	GSK Investigational Site	Pozuelo De Alarcón/Madrid		Spain	28223
127	GSK Investigational Site	Zaragoza		Spain	50009

Sponsors and Collaborators

• GlaxoSmithKline

Investigators

• Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

• Study Protocol - Jun 29, 2016
• Statistical Analysis Plan - Jun 22, 2017

More Information

Additional Information:

• IPD for this study will be made available via the Clinical Study Data Request site.

Publications

• Bremner PR, Birk R, Brealey N, Ismaila AS, Zhu CQ, Lipson DA. Single-inhaler fluticasone furoate/umeclidinium/vilanterol versus fluticasone furoate/vilanterol plus umeclidinium using two inhalers for chronic obstructive pulmonary disease: a randomized non-inferiority study. Respir Res. 2018 Jan 25;19(1):19. doi: 10.1186/s12931-018-0724-0.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT02729051
• Other Study ID Numbers: 200812; 2015-005212-14
• First Posted: Apr 6, 2016
• Last Update Posted: Jul 15, 2019
• Last Verified: May 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by GlaxoSmithKline: Chronic Obstructive Pulmonary Disease (COPD); fluticasone furoate/umeclidinium bromide/vilanterol (FF/UMEC/VI); Umeclidinium bromide (UMEC); Closed triple therapy; Placebo; Open triple therapy; fluticasone furoate/vilanterol (FF/VI)
• Additional relevant MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Albuterol

Study Results

Participant Flow

Recruitment Details	This was a 24-week, randomized, double-blind, parallel group multicenter study to compare closed triple therapy Fluticasone Furoate/ Umeclidinium/ Vilanterol Trifenatate (FF/UMEC/VI) with open triple therapy (FF/VI + UMEC), in participants with chronic obstructive pulmonary disease (COPD). This study was conducted across 12 countries.
Pre-assignment Detail	A total of 1311 participants were pre-screened, of which 1278 participants were screened (33 pre-screen failures). There were 175 screen failures and 48 Run-in failures. A total of 1055 participants were randomized and received the study treatment.

Arm/Group Title	FF/UMEC/VI 100/62.5/25	FF/VI 100/25 + UMEC 62.5
Arm/Group Description	Participants received FF/UMEC/VI, 100 micrograms (mcg)/62.5 mcg/25 mcg via ELLIPTA dry powder inhaler (DPI) once daily in morning and placebo inhalation powder via ELLIPTA DPI, once daily in the morning. Participants also received albuterol/salbutamol as a rescue medication when needed during the treatment period.	Participants received FF/VI, 100 mcg/25 mcg via ELLIPTA DPI once daily in morning and UMEC 62.5 mcg inhalation powder via ELLIPTA DPI, once daily in the morning. Participants also received albuterol/salbutamol as a rescue medication when needed during the treatment period.
Period Title: Overall Study
STARTED	527	528
COMPLETED	497	496
NOT COMPLETED	30	32

Baseline Characteristics

Arm/Group Title	FF/UMEC/VI 100/62.5/25	FF/VI 100/25 + UMEC 62.5	Total
Arm/Group Description	Participants received FF/UMEC/VI, 100 mcg/62.5 mcg/25 mcg via ELLIPTA DPI once daily in morning and placebo inhalation powder via ELLIPTA DPI, once daily in the morning. Participants also received albuterol/salbutamol as a rescue medication when needed during the treatment period.	Participants received FF/VI, 100 mcg/25 mcg via ELLIPTA DPI once daily in morning and UMEC 62.5 mcg inhalation powder via ELLIPTA DPI, once daily in the morning. Participants also received albuterol/salbutamol as a rescue medication when needed during the treatment period.	Total of all reporting groups
Overall Participants	527	528	1055
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	66.7 (8.46)	65.9 (8.77)	66.3 (8.62)
Sex: Female, Male (Count of Participants)
Female	136 25.8%	134 25.4%	270 25.6%
Male	391 74.2%	394 74.6%	785 74.4%
Race/Ethnicity, Customized (Count of Participants)
American Indian or Alaska Native	18 3.4%	14 2.7%	32 3%
Asian - East Asian Heritage	29 5.5%	30 5.7%	59 5.6%
Asian - Japanese Heritage	41 7.8%	38 7.2%	79 7.5%
Asian - South East Asian Heritage	2 0.4%	0 0%	2 0.2%
White - Arabic/North African Heritage	1 0.2%	4 0.8%	5 0.5%
White - White/Caucasian/European Heritage	416 78.9%	416 78.8%	832 78.9%
American Indian/Alaska Native and Asian and White	0 0%	1 0.2%	1 0.1%
American Indian or Alaska Native and White	20 3.8%	25 4.7%	45 4.3%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) at Week 24
Description	FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. It was measured using centralized spirometry. FEV1 values at Week 0, pre-dose were considered as Baseline values. Change from Baseline was calculated by subtracting Baseline value from the value at indicated time point. Modified Per Protocol (mPP) Population was used which comprised of all participants in the Intent-to-Treat (ITT) Population, who do not have a full protocol deviation considered to impact efficacy. Data following a moderate/severe COPD exacerbation or pneumonia was excluded from analysis due to the potential impact of the exacerbation or the medications used to treat it. Participants with partial protocol deviations considered to impact efficacy were included in the mPP Population but had their data excluded from analysis from the time of deviation onwards. Analysis was performed using a mixed model repeated measures (MMRM) method.
Time Frame	Baseline and Week 24

Outcome Measure Data

Analysis Population Description

mPP Population

Arm/Group Title	FF/UMEC/VI 100/62.5/25	FF/VI 100/25 + UMEC 62.5
Arm/Group Description	Participants received FF/UMEC/VI, 100 mcg/62.5 mcg/25 mcg via ELLIPTA DPI once daily in morning and placebo inhalation powder via ELLIPTA DPI, once daily in the morning. Participants also received albuterol/salbutamol as a rescue medication when needed during the treatment period.	Participants received FF/VI, 100 mcg/25 mcg via ELLIPTA DPI once daily in morning and UMEC 62.5 mcg inhalation powder via ELLIPTA DPI, once daily in the morning. Participants also received albuterol/salbutamol as a rescue medication when needed during the treatment period.
Measure Participants	307	287
Least Squares Mean (Standard Error) [Liter]	0.113 (0.0112)	0.095 (0.0116)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FF/UMEC/VI 100/62.5/25, FF/VI 100/25 + UMEC 62.5
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	If the lower bound of the two-sided 95% confidence interval around the (FF/UMEC/VI versus FF/VI+UMEC) treatment difference is above -50 milliliter (mL) then FF/UMEC/VI was to be considered non-inferior to FF/VI+UMEC.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.018
	Confidence Interval	(2-Sided) 95%; -0.013 to 0.050
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.0161
	Estimation Comments	MMRM method included covariates of Baseline FEV1, stratum (number of long-acting bronchodilators per day during the run-in: 0/1 or 2), visit, geographical region, treatment, visit by treatment and visit by Baseline interaction.

2. Secondary Outcome

Title	Percentage of Responders Based on the Saint (St) George Respiratory Questionnaire (SGRQ) Total Score at Week 24
Description	SGRQ is a disease-specific questionnaire designed to measure impact of respiratory disease and its treatment on health related quality of life (HRQoL) of participants with COPD. It contains 14 questions with a total of 40 items grouped into domains (Symptoms, Activity and Impacts). SGRQ total score was calculated as 100 multiplied by summed weights from all positive items divided by sum of weights for all items in questionnaire. It ranges from 0 to 100, higher score indicates poor HRQoL. Response was defined as an SGRQ total score of >=4 units below Baseline. Non response was defined as a SGRQ total score <4 units below Baseline or a missing SGRQ total score with no subsequent on treatment scores. ITT Population comprised of randomized participants, excluding those who were randomized in error. A participant screened or run-in failure and also randomized was considered to be randomized in error. Analysis was performed using a generalized linear mixed model with a logit link function.
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

ITT Population. Only those participants with data available at the specified time points were analyzed.

Arm/Group Title	FF/UMEC/VI 100/62.5/25	FF/VI 100/25 + UMEC 62.5
Arm/Group Description	Participants received FF/UMEC/VI, 100 mcg/62.5 mcg/25 mcg via ELLIPTA DPI once daily in morning and placebo inhalation powder via ELLIPTA DPI, once daily in the morning. Participants also received albuterol/salbutamol as a rescue medication when needed during the treatment period.	Participants received FF/VI, 100 mcg/25 mcg via ELLIPTA DPI once daily in morning and UMEC 62.5 mcg inhalation powder via ELLIPTA DPI, once daily in the morning. Participants also received albuterol/salbutamol as a rescue medication when needed during the treatment period.
Measure Participants	489	483
Number [Percentage of Participants]	50 9.5%	51 9.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FF/UMEC/VI 100/62.5/25, FF/VI 100/25 + UMEC 62.5
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.92
	Confidence Interval	(2-Sided) 95%; 0.71 to 1.20
	Parameter Dispersion	Type: Value:
	Estimation Comments	Analysis included covariates of treatment group, stratum (number of long-acting bronchodilators per day during the run-in: 0/1 or 2), geographical region, visit, Baseline, Baseline by visit and treatment by visit interactions.

3. Secondary Outcome

Title	Change From Baseline in SGRQ Total Score at Week 24
Description	SGRQ is a disease-specific questionnaire designed to measure impact of respiratory disease and its treatment on HRQoL of participants with COPD. It contains 14 questions with a total of 40 items grouped into domains (Symptoms, Activity and Impacts). SGRQ total score was calculated as 100 multiplied by summed weights from all positive items divided by sum of weights for all items in questionnaire. It ranges from 0 to 100, higher score indicates poor HRQoL. Values at Week 0, pre-dose were considered as Baseline values. Change from Baseline was calculated by subtracting Baseline value from the value at indicated time point. Analysis was performed using a MMRM method including covariates of Baseline SGRQ Total score, stratum (number of long-acting bronchodilators per day during the run-in: 0/1 or 2), visit, geographical region, treatment, visit by treatment and visit by Baseline interaction.
Time Frame	Baseline and Week 24

Outcome Measure Data

Analysis Population Description

ITT Population. Only those participants with data available at the specified time points were analyzed.

Arm/Group Title	FF/UMEC/VI 100/62.5/25	FF/VI 100/25 + UMEC 62.5
Arm/Group Description	Participants received FF/UMEC/VI, 100 mcg/62.5 mcg/25 mcg via ELLIPTA DPI once daily in morning and placebo inhalation powder via ELLIPTA DPI, once daily in the morning. Participants also received albuterol/salbutamol as a rescue medication when needed during the treatment period.	Participants received FF/VI, 100 mcg/25 mcg via ELLIPTA DPI once daily in morning and UMEC 62.5 mcg inhalation powder via ELLIPTA DPI, once daily in the morning. Participants also received albuterol/salbutamol as a rescue medication when needed during the treatment period.
Measure Participants	489	483
Least Squares Mean (Standard Error) [Scores on a scale]	-5.841 (0.5870)	-4.935 (0.5904)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FF/UMEC/VI 100/62.5/25, FF/VI 100/25 + UMEC 62.5
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	-0.906
	Confidence Interval	(2-Sided) 95%; -2.540 to 0.728
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.8327
	Estimation Comments	Analysis performed using a repeated measures model with covariates of Baseline SGRQ, stratum (number of long-acting bronchodilators per day during the run-in: 0/1 or 2), visit, geographical region, treatment, visit by treatment and visit by Baseline.

4. Secondary Outcome

Title	Percentage of Responders Based on Transitional Dyspnea Index (TDI) Focal Score at Week 24
Description	The TDI measures changes in the participant's dyspnea. TDI focal score was calculated as the sum of the ratings recorded for each of the 3 individual scales (Functional Impairment, Magnitude of Task, Magnitude of Effort). Each of these scales had a possible score ranging from -6 to +6. lower scores indicating more impairment. TDI focal score was calculated as the sum of the 3 individual scores and then divided by 2 (so the range of the TDI focal score is -9 to +9). The lower the score, the more deterioration in severity of dyspnea. If a score is missing for any of the three scales, then the TDI focal score was set to missing. A participant was considered as a responder if the on-treatment TDI focal score was at least 1 unit at that visit. Non-response was defined as a TDI focal score of less than 1 unit or a missing TDI focal score with no subsequent non-missing on-treatment scores. Analysis was performed using a generalized linear mixed model with a logit link function.
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

ITT Population. Only those participants with data available at the specified time points were analyzed.

Arm/Group Title	FF/UMEC/VI 100/62.5/25	FF/VI 100/25 + UMEC 62.5
Arm/Group Description	Participants received FF/UMEC/VI, 100 mcg/62.5 mcg/25 mcg via ELLIPTA DPI once daily in morning and placebo inhalation powder via ELLIPTA DPI, once daily in the morning. Participants also received albuterol/salbutamol as a rescue medication when needed during the treatment period.	Participants received FF/VI, 100 mcg/25 mcg via ELLIPTA DPI once daily in morning and UMEC 62.5 mcg inhalation powder via ELLIPTA DPI, once daily in the morning. Participants also received albuterol/salbutamol as a rescue medication when needed during the treatment period.
Measure Participants	482	481
Number [Percentage of Participants]	56 10.6%	56 10.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FF/UMEC/VI 100/62.5/25, FF/VI 100/25 + UMEC 62.5
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.95
	Confidence Interval	(2-Sided) 95%; 0.72 to 1.25
	Parameter Dispersion	Type: Value:
	Estimation Comments	Include covariates of treatment group, stratum (number of long-acting bronchodilators/ day during the run-in: 0/1 or 2), geographical region, visit, Baseline dyspnea index (BDI) focal score, BDI focal score/ visit and treatment/ visit interactions.

5. Secondary Outcome

Title	TDI Focal Score at Week 24
Description	The TDI measures changes in the participant's dyspnoea. TDI focal score was calculated as the sum of the ratings recorded for each of the 3 individual scales (Functional Impairment, Magnitude of Task, Magnitude of Effort). Each of these scales had a possible score ranging from -6 to +6. lower scores indicating more impairment. TDI focal score was calculated as the sum of the 3 individual scores and then divided by 2 (so the range of the TDI focal score is -9 to +9). The lower the score, the more deterioration in severity of dyspnea. If a score is missing for any of the three scales, then the TDI focal score was set to missing. Analysis was performed using a repeated measures model.
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

ITT Population. Only those participants with data available at the specified time points were analyzed.

Arm/Group Title	FF/UMEC/VI 100/62.5/25	FF/VI 100/25 + UMEC 62.5
Arm/Group Description	Participants received FF/UMEC/VI, 100 mcg/62.5 mcg/25 mcg via ELLIPTA DPI once daily in morning and placebo inhalation powder via ELLIPTA DPI, once daily in the morning. Participants also received albuterol/salbutamol as a rescue medication when needed during the treatment period.	Participants received FF/VI, 100 mcg/25 mcg via ELLIPTA DPI once daily in morning and UMEC 62.5 mcg inhalation powder via ELLIPTA DPI, once daily in the morning. Participants also received albuterol/salbutamol as a rescue medication when needed during the treatment period.
Measure Participants	482	481
Least Squares Mean (Standard Error) [Scores on a scale]	2.029 (0.1252)	1.892 (0.1254)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FF/UMEC/VI 100/62.5/25, FF/VI 100/25 + UMEC 62.5
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.137
	Confidence Interval	(2-Sided) 95%; -0.211 to 0.485
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.1773
	Estimation Comments	Analysis included covariates of BDI focal score, stratum (number of long-acting bronchodilators per day during the run-in: 0/1 or 2), visit, geographical region, treatment, visit by treatment and visit by BDI Focal score interactions.

6. Secondary Outcome

Title	Time to First Moderate or Severe Exacerbation
Description	COPD exacerbations were identified based on the investigator's clinical judgment. Worsening symptoms of COPD that required treatment with oral/systemic corticosteroids and/or antibiotics were considered as moderate exacerbation. Worsening symptoms of COPD that required treatment with in-subject hospitalization was considered as severe exacerbation. Hazard ratio and 95% confidence interval (CI) is from a Cox proportional hazards model with covariates of treatment group, sex, exacerbation history (0, 1, >=2 moderate/severe exacerbations, prior year), smoking status (screening), stratum (number of long-acting bronchodilators per day during the run-in: 0/1 or 2), geographical region and percent predicted FEV1 at Baseline. Median and inter-quartile range (first and third quartile) have been presented.
Time Frame	Up to 25 weeks

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	FF/UMEC/VI 100/62.5/25	FF/VI 100/25 + UMEC 62.5
Arm/Group Description	Participants received FF/UMEC/VI, 100 mcg/62.5 mcg/25 mcg via ELLIPTA DPI once daily in morning and placebo inhalation powder via ELLIPTA DPI, once daily in the morning. Participants also received albuterol/salbutamol as a rescue medication when needed during the treatment period.	Participants received FF/VI, 100 mcg/25 mcg via ELLIPTA DPI once daily in morning and UMEC 62.5 mcg inhalation powder via ELLIPTA DPI, once daily in the morning. Participants also received albuterol/salbutamol as a rescue medication when needed during the treatment period.
Measure Participants	527	528
Median (Inter-Quartile Range) [Days]	NA	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FF/UMEC/VI 100/62.5/25, FF/VI 100/25 + UMEC 62.5
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.87
	Confidence Interval	(2-Sided) 95%; 0.68 to 1.12
	Parameter Dispersion	Type: Value:
	Estimation Comments	Analysis was performed using a Cox proportional hazards model.

Adverse Events

Time Frame	On-treatment serious adverse events (SAEs) and non-serious AEs (nSAEs) were collected from start of study treatment (Week 0) until Week 25 including 1 Week of follow-up.
Adverse Event Reporting Description	On-treatment SAEs and nSAEs were reported for ITT Population.
Arm/Group Title	FF/UMEC/VI 100/62.5/25		FF/VI 100/25 + UMEC 62.5
Arm/Group Description	Participants received FF/UMEC/VI, 100 mcg/62.5 mcg/25 mcg via ELLIPTA DPI once daily in morning and placebo inhalation powder via ELLIPTA DPI, once daily in the morning. Participants also received albuterol/salbutamol as a rescue medication when needed during the treatment period.		Participants received FF/VI, 100 mcg/25 mcg via ELLIPTA DPI once daily in morning and UMEC 62.5 mcg inhalation powder via ELLIPTA DPI, once daily in the morning. Participants also received albuterol/salbutamol as a rescue medication when needed during the treatment period.
All Cause Mortality
	FF/UMEC/VI 100/62.5/25		FF/VI 100/25 + UMEC 62.5
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/527 (1.3%)		5/528 (0.9%)
Serious Adverse Events
	FF/UMEC/VI 100/62.5/25		FF/VI 100/25 + UMEC 62.5
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	55/527 (10.4%)		60/528 (11.4%)
Cardiac disorders
Acute myocardial infarction	2/527 (0.4%)		1/528 (0.2%)
Aortic valve incompetence	0/527 (0%)		1/528 (0.2%)
Atrial fibrillation	2/527 (0.4%)		0/528 (0%)
Cardiac failure	1/527 (0.2%)		1/528 (0.2%)
Cardiac failure acute	1/527 (0.2%)		0/528 (0%)
Cardio-respiratory arrest	0/527 (0%)		1/528 (0.2%)
Cardiogenic shock	1/527 (0.2%)		1/528 (0.2%)
Cardiomyopathy	1/527 (0.2%)		0/528 (0%)
Cardiopulmonary failure	1/527 (0.2%)		0/528 (0%)
Coronary artery disease	1/527 (0.2%)		0/528 (0%)
Degenerative aortic valve disease	0/527 (0%)		1/528 (0.2%)
Mitral valve incompetence	0/527 (0%)		1/528 (0.2%)
Myocardial ischaemia	1/527 (0.2%)		0/528 (0%)
Prinzmetal angina	1/527 (0.2%)		0/528 (0%)
Sinus bradycardia	1/527 (0.2%)		0/528 (0%)
Stress cardiomyopathy	0/527 (0%)		1/528 (0.2%)
Ear and labyrinth disorders
Sudden hearing loss	1/527 (0.2%)		0/528 (0%)
Gastrointestinal disorders
Gastritis hypertrophic	1/527 (0.2%)		0/528 (0%)
Gastrointestinal polyp haemorrhage	0/527 (0%)		1/528 (0.2%)
Gastrointestinal hypomotility	1/527 (0.2%)		0/528 (0%)
General disorders
Chest pain	1/527 (0.2%)		0/528 (0%)
Death	1/527 (0.2%)		0/528 (0%)
Hepatobiliary disorders
Cholecystitis	1/527 (0.2%)		0/528 (0%)
Cholecystitis acute	2/527 (0.4%)		1/528 (0.2%)
Cholelithiasis	0/527 (0%)		1/528 (0.2%)
Infections and infestations
Cholecystitis infective	1/527 (0.2%)		0/528 (0%)
Enteritis infectious	0/527 (0%)		1/528 (0.2%)
Gastroenteritis	0/527 (0%)		1/528 (0.2%)
Infective exacerbation of chronic obstructive airways disease	3/527 (0.6%)		2/528 (0.4%)
Influenza	1/527 (0.2%)		1/528 (0.2%)
Pneumonia	9/527 (1.7%)		13/528 (2.5%)
Pneumonia bacterial	0/527 (0%)		2/528 (0.4%)
Pyelonephritis	0/527 (0%)		1/528 (0.2%)
Respiratory tract infection bacterial	0/527 (0%)		1/528 (0.2%)
Sepsis	0/527 (0%)		1/528 (0.2%)
Septic shock	0/527 (0%)		1/528 (0.2%)
Staphylococcal infection	0/527 (0%)		1/528 (0.2%)
Superinfection	0/527 (0%)		1/528 (0.2%)
Toxic shock syndrome	1/527 (0.2%)		0/528 (0%)
Urinary tract infection	0/527 (0%)		1/528 (0.2%)
Injury, poisoning and procedural complications
Ankle fracture	0/527 (0%)		1/528 (0.2%)
Contusion	1/527 (0.2%)		0/528 (0%)
Craniocerebral injury	1/527 (0.2%)		0/528 (0%)
Femoral neck fracture	1/527 (0.2%)		0/528 (0%)
Procedural complication	1/527 (0.2%)		0/528 (0%)
Rib fracture	1/527 (0.2%)		0/528 (0%)
Spinal compression fracture	0/527 (0%)		1/528 (0.2%)
Spinal fracture	0/527 (0%)		1/528 (0.2%)
Tibia fracture	0/527 (0%)		1/528 (0.2%)
Investigations
X-ray abnormal	1/527 (0.2%)		0/528 (0%)
Metabolism and nutrition disorders
Dehydration	1/527 (0.2%)		0/528 (0%)
Diabetes mellitus	0/527 (0%)		1/528 (0.2%)
Hyponatraemia	1/527 (0.2%)		0/528 (0%)
Musculoskeletal and connective tissue disorders
Back pain	0/527 (0%)		1/528 (0.2%)
Pseudarthrosis	1/527 (0.2%)		0/528 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Angiosarcoma	0/527 (0%)		1/528 (0.2%)
Benign hepatic neoplasm	0/527 (0%)		1/528 (0.2%)
Bladder cancer	1/527 (0.2%)		0/528 (0%)
Colon cancer	0/527 (0%)		1/528 (0.2%)
Glioblastoma	1/527 (0.2%)		0/528 (0%)
Oesophageal adenocarcinoma	1/527 (0.2%)		0/528 (0%)
Prostate cancer	0/527 (0%)		1/528 (0.2%)
Nervous system disorders
Brain injury	1/527 (0.2%)		0/528 (0%)
Cerebrovascular accident	1/527 (0.2%)		0/528 (0%)
Intensive care unit acquired weakness	1/527 (0.2%)		0/528 (0%)
Ischaemic stroke	0/527 (0%)		1/528 (0.2%)
Syncope	1/527 (0.2%)		0/528 (0%)
Psychiatric disorders
Organic brain syndrome	1/527 (0.2%)		0/528 (0%)
Reproductive system and breast disorders
Vaginal prolapse	1/527 (0.2%)		0/528 (0%)
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema	1/527 (0.2%)		0/528 (0%)
Atelectasis	0/527 (0%)		1/528 (0.2%)
Chronic obstructive pulmonary disease	24/527 (4.6%)		32/528 (6.1%)
Haemoptysis	1/527 (0.2%)		0/528 (0%)
Pneumothorax spontaneous	0/527 (0%)		1/528 (0.2%)
Pulmonary fibrosis	0/527 (0%)		1/528 (0.2%)
Respiratory acidosis	0/527 (0%)		1/528 (0.2%)
Respiratory failure	0/527 (0%)		2/528 (0.4%)
Vascular disorders
Aortic aneurysm	0/527 (0%)		1/528 (0.2%)
Hypertension	0/527 (0%)		1/528 (0.2%)
Other (Not Including Serious) Adverse Events
	FF/UMEC/VI 100/62.5/25		FF/VI 100/25 + UMEC 62.5
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	122/527 (23.1%)		125/528 (23.7%)
Infections and infestations
Viral upper respiratory tract infection	56/527 (10.6%)		52/528 (9.8%)
Upper respiratory tract infection	18/527 (3.4%)		24/528 (4.5%)
Influenza	16/527 (3%)		17/528 (3.2%)
Pharyngitis	12/527 (2.3%)		16/528 (3%)
Nervous system disorders
Headache	32/527 (6.1%)		33/528 (6.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.