A Study to Compare the Impact of Fulticasone Furoate/Vilanterol vs. Tiotropium on Arterial Stiffness in COPD

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01395888
• Collaborator: (none)
• Enrollment: 260
• Locations: 55
• Arms: 2
• Duration (Months): 13.2
• Patients Per Site: 4.7
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

This study is designed to evaluate the effect of fluticasone furoate (FF, GW685698)/vilanterol (VI, GW642444) Inhalation Powder once daily (QD) on arterial stiffness compared with Tiotropium QD over 12 week treatment period in subjects with COPD and aortic pulse wave velocity (aPWV) > 12.0 m/s at Visit 1. Arterial stiffness will be measured as aPWV. This is a comparator, randomised, double-blind, double-dummy, parallel group, multi-centre study. Subjects who meet the eligibility criteria at Screening and meet the randomization criteria at the end of a 2-week Run-In period will enter a 12-week treatment period. There will be an approximate 7-day Follow-up period after the treatment period.

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Disease, Chronic Obstructive	Drug: fluticasone furoate (FF, GW685698)/vilanterol (VI, GW642444) 100/25 mcg Novel Dry Powder Inhaler (NDPI); Drug: Tiotropium	Phase 3

Detailed Description

This is a Phase IIIb comparator, double-blind, double-dummy, randomised (1:1), parallel group, multi-centre study. At Visit 1 (Screening Visit), subjects who meet the pre-defined Inclusion Criteria and none of the Exclusion Criteria will enter a 2-week, single-blind placebo Run-in Period. The purpose of the Run-In Period is to monitor albuterol/salbutamol use at baseline, and to ensure that subjects' COPD is at a stable stage at randomization. Subject's adherence with study procedures, diary completion will also be evaluated during the Run-In Period. At the end of the Run-in period, subjects will be assessed and those who meet the randomisation criteria will receive one of the following two double-blind treatments for 12 weeks:

• FF (100 mcg)/VI (25 mcg) administered QD via a NDPI in the morning

• Tiotropium (18 mcg) administered QD via a HandiHaler in the morning

To ensure blinding of the treatments and to ensure a double-dummy design matching NDPI and HandiHaler will be utilised. Each subject will be instructed to self administer blinded study drug during the double blind treatment period as follows:

• Each morning take 1 inhalation from NDPI containing FF (100 mcg)/VI (25 mcg) followed by 1 inhalation from placebo capsule delivered via HandiHaler.

• Each morning take 1 inhalation from matching placebo NDPI followed by 1 inhalation from a capsule containing tiotropium 18 mcg delivered via HandiHaler.

An inhaled short acting beta2-receptor agonist, salbutamol/albuterol will be provided to subjects to use as needed throughout the Run-in and Treatment periods for relief of COPD symptoms. Ipratropium bromide is permitted if the subject is on a stable dose from Screening (Visit 1) and remains on the stable dose throughout the study. Subjects who experience an exacerbation of their COPD (which requires medication in addition to an increase in rescue medication) or a lower respiratory tract infection (LRTI) during the run-in period are not eligible to enter the treatment period. Any subject who experiences a similar COPD exacerbation (sec 4.4) or LRTI at any time on therapy will be withdrawn from the study. The aPWV will be measured at Screening and clinic Visits 3-5. Disease specific health status will be evaluated using the St. George's Respiratory Questionnaire (SGRQ-C), Euro Qol Questionnaire (EQ-5D) for COPD patients and the COPD Assessment Test (CAT) at Visit 2 (Day 1) and at Visit 5 (Weeks 12). The 12-lead ECG will be evaluated at Visit 1 (Screening) only. Vital signs (blood pressure and pulse rate), spirometry measurements, and clinical laboratory tests (hematology and chemistry) and other study-specific safety assessments will be obtained at selected clinic visits. A follow-up phone call will occur approximately 7 days after the last clinic visit. The overall study duration from Screening to Follow-up for each subject is approximately 15 weeks. Subjects will be considered to have completed the study upon completion of assessments and procedures up to and including completion of Follow-up Phone Contact (7 ± 2 days post Visit 5).

Study Design

• Study Type: Interventional
• Actual Enrollment: 260 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A 12 Week Study to Evaluate the Effect of Fluticasone Furoate (FF, GW685698)/Vilanterol (VI, GW642444) 100/25 mcg Inhalation Powder Delivered Once Daily Via a Novel Dry Powder Inhaler (NDPI) on Arterial Stiffness Compared With Tiotropium Bromide 18 mcg Delivered Once Daily Via a HandiHaler in Subjects With Chronic Obstructive Pulmonary Disease (COPD).
• Study Start Date: Jun 30, 2011
• Actual Primary Completion Date: Aug 1, 2012
• Actual Study Completion Date: Aug 6, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Relovair Inhaled long-acting bronchodilator and corticosteroid combination	Drug: fluticasone furoate (FF, GW685698)/vilanterol (VI, GW642444) 100/25 mcg Novel Dry Powder Inhaler (NDPI); fluticasone furoate (FF, GW685698)/vilanterol (VI, GW642444) 100/25 mcg Inhalation Powder delivered once daily via a Novel Dry Powder Inhaler (NDPI)
Active Comparator: Tiotropium Inhaled long-acting anticholinergic	Drug: Tiotropium; • Tiotropium (18 mcg) administered QD via a HandiHaler

Outcome Measures

Primary Outcome Measures

1. Mean Change From Baseline (BL) in Aortic Pulse Wave Velocity (aPWV) at the End of the 12-week Treatment Period (Day 84) [Baseline to Day 84 (Early Withdrawal)]

   PWV is defined as the speed of travel of the pressure pulse along an arterial segment and can be obtained for any arterial segment accessible to palpation. aPWV is measured with tonometers positioned transcutaneously at the base of the common carotid artery and over the femoral artery. PWV increases with arterial stiffness and is defined by the Moens-Korteweg equation: PWV=square root of Eh/2pR, where E is Young's modulus of the arterial wall, h is the wall thickness, R is the arterial radius at the end of diastole, and p is the blood density. Change from Baseline was calculated as the Day 84 value minus the Baseline value. The analysis was performed using a repeated measures model with covariates of treatment, visit, age, gender, smoking status at screening, geographical region, Baseline aPWV, and interaction terms of Baseline by visit and treatment by visit.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Type of subject: Outpatient

• Informed consent: Subjects must give their signed and dated written informed consent to participate.

• Gender: Male or female subjects.

• Age: greater then or equal to 40 years of age at Screening (Visit 1)

• COPD diagnosis: Subjects with a clinical history of COPD in accordance with the following definition by the American Thoracic Society (ATS) /European Respiratory Society(ERS).

• Subjects with a current or prior history ofgreater then or equal to 10 pack-years of cigarette smoking at Screening (Visit 1).

• Subjects with a measured post-albuterol/salbutamol FEV1 less then 70% of predicted at Screening (Visit 1).

• Subjects with a measured post-albuterol/salbutamol FEV1/FVC ratio of less then or equal to 0.70 at Screening (Visit 1).

• Exacerbation History: Subjects who have been hospitalised or have been treated with oral corticosteroids or antibiotics for their COPD within the last 3 years prior to Screening (V1).

• Baseline aPWV: subjects with a measured aPWV greater then 12.0 m/s at Screening (Visit 1).

Exclusion Criteria:

• Body Mass Index of less then or equal to 35

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Ciudad Autonoma de Buenos Aires	Buenos Aires	Argentina	C1056ABJ
2	GSK Investigational Site	Rosario	Santa Fe	Argentina	S2000JKR
3	GSK Investigational Site	Buenos Aires		Argentina	C1424BSF
4	GSK Investigational Site	Buenos Aires		Argentina	C1425BEN
5	GSK Investigational Site	Ciudad Autónoma de Buenos Aires		Argentina	C1426ABP
6	GSK Investigational Site	Mendoza		Argentina	5500
7	GSK Investigational Site	Mendoza		Argentina	M5500CCG
8	GSK Investigational Site	San Juan		Argentina	5400
9	GSK Investigational Site	Tucuman		Argentina	4000
10	GSK Investigational Site	Tucumán		Argentina	T4000DGF
11	GSK Investigational Site	Bethune Cedex		France	62408
12	GSK Investigational Site	Grenoble Cedex 09		France	38043
13	GSK Investigational Site	Lille		France	59000
14	GSK Investigational Site	Montpellier cedex 5		France	34295
15	GSK Investigational Site	Reims Cedex		France	51092
16	GSK Investigational Site	Saint-Michel		France	16470
17	GSK Investigational Site	Immenhausen	Hessen	Germany	34376
18	GSK Investigational Site	Schwerin	Mecklenburg-Vorpommern	Germany	19055
19	GSK Investigational Site	Hannover	Niedersachsen	Germany	30159
20	GSK Investigational Site	Goch	Nordrhein-Westfalen	Germany	47574
21	GSK Investigational Site	Magdeburg	Sachsen-Anhalt	Germany	39112
22	GSK Investigational Site	Geesthacht	Schleswig-Holstein	Germany	21502
23	GSK Investigational Site	Berlin		Germany	10787
24	GSK Investigational Site	Berlin		Germany	10789
25	GSK Investigational Site	Berlin		Germany	13125
26	GSK Investigational Site	Hamburg		Germany	20354
27	GSK Investigational Site	Eboli (SA)	Campania	Italy	84025
28	GSK Investigational Site	Bologna	Emilia-Romagna	Italy	40138
29	GSK Investigational Site	Crema	Lombardia	Italy	26013
30	GSK Investigational Site	Pavia	Lombardia	Italy	27100
31	GSK Investigational Site	Cassano Murge (BA)	Puglia	Italy	70020
32	GSK Investigational Site	Bergen		Norway	5017
33	GSK Investigational Site	Bergen		Norway	N-5021
34	GSK Investigational Site	Drammen		Norway	3004
35	GSK Investigational Site	Fredrikstad		Norway	1606
36	GSK Investigational Site	Skedsmokorset		Norway	N-2020
37	GSK Investigational Site	Chita		Russian Federation	672000
38	GSK Investigational Site	Kemerovo		Russian Federation	650002
39	GSK Investigational Site	Kokhma		Russian Federation	153511
40	GSK Investigational Site	Moscow		Russian Federation	105077
41	GSK Investigational Site	Moscow		Russian Federation	115093
42	GSK Investigational Site	Penza		Russian Federation	440067
43	GSK Investigational Site	Saratov		Russian Federation	410053
44	GSK Investigational Site	St. Petersburg		Russian Federation	197022
45	GSK Investigational Site	Vladivostok, Primorskiy Kray		Russian Federation	690022
46	GSK Investigational Site	Voronezh		Russian Federation	394018
47	GSK Investigational Site	Yaroslavl		Russian Federation	150003
48	GSK Investigational Site	Yaroslavl		Russian Federation	150062
49	GSK Investigational Site	Cherkassy		Ukraine	18009
50	GSK Investigational Site	Donetsk		Ukraine	83099
51	GSK Investigational Site	Kharkiv		Ukraine	61035
52	GSK Investigational Site	Kiev		Ukraine	03680
53	GSK Investigational Site	Kyiv		Ukraine	03038
54	GSK Investigational Site	Kyiv		Ukraine	03049
55	GSK Investigational Site	Yalta		Ukraine	98603

Sponsors and Collaborators

• GlaxoSmithKline

Investigators

• Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

Publications

None provided.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT01395888
• Other Study ID Numbers: 115247
• First Posted: Jul 18, 2011
• Last Update Posted: Feb 15, 2018
• Last Verified: Jan 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Additional relevant MeSH terms: Lung Diseases; Pulmonary Disease, Chronic Obstructive; Fluticasone; Xhance; Tiotropium Bromide

Study Results

Participant Flow

Recruitment Details	A total of 260 participants were randomized. Three of these participants were randomized in error (they were determined not to have met entry criteria and were classified as run-in/screen failures); thus, they did not receive investigational product and are not captured in the Treatment Period table of the Participant Flow module.
Pre-assignment Detail	At Visit (V) 1, eligible participants (par.) entered a 2-week, single-blind placebo Run-in Period (RIP) to establish a stable baseline. At V 2, eligible par. were randomized to a 12-week, double-blind, double-dummy Treatment Period. 802 par. were screened, 279 par. entered the RIP, and 257 par. were randomized and received >=1 study treatment dose.

Arm/Group Title	Salb/Alb + IBr	FF/VI 100/25 µg	Tiotropium Bromide 18 µg
Arm/Group Description	Participants were provided with an inhaled short-acting beta2-receptor agonist, salbutamol/albuterol (Salb/Alb), for use as needed throughout the Run-in Period for relief of chronic obstructive pulmonary disease (COPD) symptoms. Ipratropium bromide (IBr) was permitted during the Run-in Period and for up to 4 hours prior to Randomization (Visit 2) if the participant was on a stable dose prior to Screening (Visit 1). Following randomization, IBr was not permitted during exposure to study treatment.	Participants (par.) self-administered one inhalation of Fluticasone Furoate /Vilanterol (FF/VI) 100/25 micrograms (µg) via a dry powder inhaler (DPI) followed by 2 inhalations from a single placebo capsule delivered via a HandiHaler in the morning for 12 weeks. An inhaled short-acting beta2-receptor agonist, salbutamol/albuterol, was provided for participants to use as needed throughout the Treatment Period for relief of Chronic Obstructive Pulmonary Disease (COPD) symptoms.	Participants self-administered one inhalation of placebo via an DPI followed by 2 inhalations from a single capsule containing Tiotropiuum Bromide 18 µg via a HandiHaler. An inhaled short-acting beta2-receptor agonist, salbutamol/albuterol, was provided for participants to use as needed throughout the Treatment Period for relief of COPD symptoms.
Period Title: 2-week Run-in Period
STARTED	279	0	0
COMPLETED	257	0	0
NOT COMPLETED	22	0	0
Period Title: 2-week Run-in Period
STARTED	0	127	130
Completed the Treatment Period	0	112	113
COMPLETED	0	112	113
NOT COMPLETED	0	15	17

Baseline Characteristics

Arm/Group Title	FF/VI 100/25 µg	Tiotropium Bromide 18 µg	Total
Arm/Group Description	Participants self-administered one inhalation of Fluticasone Furoate /Vilanterol (FF/VI) 100/25 micrograms (µg) via a dry powder inhaler (DPI) followed by 2 inhalations from a single placebo capsule delivered via a HandiHaler in the morning for 12 weeks. An inhaled short-acting beta2-receptor agonist, salbutamol/albuterol, was provided for participants to use as needed throughout the Treatment Period for relief of Chronic Obstructive Pulmonary Disease (COPD) symptoms.	Participants self-administered one inhalation of placebo via an DPI followed by 2 inhalations from a single capsule containing Tiotropiuum Bromide 18 µg via a HandiHaler. An inhaled short-acting beta2-receptor agonist, salbutamol/albuterol, was provided for participants to use as needed throughout the Treatment Period for relief of COPD symptoms.	Total of all reporting groups
Overall Participants	127	130	257
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	66.7 (7.20)	67.7 (7.34)	67.3 (7.28)
Sex: Female, Male (Count of Participants)
Female	19 15%	18 13.8%	37 14.4%
Male	108 85%	112 86.2%	220 85.6%
Race/Ethnicity, Customized (participants) [Number]
White - White/Caucasian/European	127 100%	130 100%	257 100%

Outcome Measures

1. Primary Outcome

Title	Mean Change From Baseline (BL) in Aortic Pulse Wave Velocity (aPWV) at the End of the 12-week Treatment Period (Day 84)
Description	PWV is defined as the speed of travel of the pressure pulse along an arterial segment and can be obtained for any arterial segment accessible to palpation. aPWV is measured with tonometers positioned transcutaneously at the base of the common carotid artery and over the femoral artery. PWV increases with arterial stiffness and is defined by the Moens-Korteweg equation: PWV=square root of Eh/2pR, where E is Young's modulus of the arterial wall, h is the wall thickness, R is the arterial radius at the end of diastole, and p is the blood density. Change from Baseline was calculated as the Day 84 value minus the Baseline value. The analysis was performed using a repeated measures model with covariates of treatment, visit, age, gender, smoking status at screening, geographical region, Baseline aPWV, and interaction terms of Baseline by visit and treatment by visit.
Time Frame	Baseline to Day 84 (Early Withdrawal)

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) Population: all participants (par.) who were randomized to and received >=1 dose of randomized medication in the TP. The analysis model included all par. in the ITT Population without missing covariate information (MCI) and with >=1 post-BL measurement. Par. presented represent those with data available at Day 84 without MCI.

Arm/Group Title	FF/VI 100/25 µg	Tiotropium Bromide 18 µg
Arm/Group Description	Participants self-administered one inhalation of Fluticasone Furoate /Vilanterol (FF/VI) 100/25 micrograms (µg) via a dry powder inhaler (DPI) followed by 2 inhalations from a single placebo capsule delivered via a HandiHaler in the morning for 12 weeks. An inhaled short-acting beta2-receptor agonist, salbutamol/albuterol, was provided for participants to use as needed throughout the Treatment Period for relief of Chronic Obstructive Pulmonary Disease (COPD) symptoms.	Participants self-administered one inhalation of placebo via an DPI followed by 2 inhalations from a single capsule containing Tiotropiuum Bromide 18 µg via a HandiHaler. An inhaled short-acting beta2-receptor agonist, salbutamol/albuterol, was provided for participants to use as needed throughout the Treatment Period for relief of COPD symptoms.
Measure Participants	106	102
Least Squares Mean (Standard Error) [meters per second (m/sec)]	-0.859 (0.2590)	-1.118 (0.2620)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FF/VI 100/25 µg, Tiotropium Bromide 18 µg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.484
	Comments
	Method	Mixed Models Analysis
	Comments	Restricted maximum likelihood (REML)-based repeated measures approach (MMRM)
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.259
	Confidence Interval	(2-Sided) 95%; -0.468 to 0.986
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Arm/Group Title	FF/VI 100/25 µg		Tiotropium Bromide 18 µg
Arm/Group Description	Participants self-administered one inhalation of Fluticasone Furoate /Vilanterol (FF/VI) 100/25 micrograms (µg) via a dry powder inhaler (DPI) followed by 2 inhalations from a single placebo capsule delivered via a HandiHaler in the morning for 12 weeks. An inhaled short-acting beta2-receptor agonist, salbutamol/albuterol, was provided for participants to use as needed throughout the Treatment Period for relief of Chronic Obstructive Pulmonary Disease (COPD) symptoms.		Participants self-administered one inhalation of placebo via an DPI followed by 2 inhalations from a single capsule containing Tiotropiuum Bromide 18 µg via a HandiHaler. An inhaled short-acting beta2-receptor agonist, salbutamol/albuterol, was provided for participants to use as needed throughout the Treatment Period for relief of COPD symptoms.
All Cause Mortality
	FF/VI 100/25 µg		Tiotropium Bromide 18 µg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	FF/VI 100/25 µg		Tiotropium Bromide 18 µg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/127 (5.5%)		8/130 (6.2%)
Gastrointestinal disorders
Acute abdomen	1/127 (0.8%)		0/130 (0%)
Pancreatolithiasis	1/127 (0.8%)		0/130 (0%)
General disorders
Pyrexia	1/127 (0.8%)		0/130 (0%)
Hepatobiliary disorders
Bile duct obstruction	1/127 (0.8%)		0/130 (0%)
Infections and infestations
Pneumonia	2/127 (1.6%)		0/130 (0%)
Peritonsillar abscess	0/127 (0%)		1/130 (0.8%)
Injury, poisoning and procedural complications
Multiple injuries	0/127 (0%)		1/130 (0.8%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bronchial carcinoma	1/127 (0.8%)		0/130 (0%)
Nervous system disorders
Altered state of consciousness	1/127 (0.8%)		0/130 (0%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	2/127 (1.6%)		5/130 (3.8%)
Pulmonary embolism	0/127 (0%)		1/130 (0.8%)
Skin and subcutaneous tissue disorders
Skin ulcer	0/127 (0%)		1/130 (0.8%)
Other (Not Including Serious) Adverse Events
	FF/VI 100/25 µg		Tiotropium Bromide 18 µg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/127 (6.3%)		8/130 (6.2%)
Infections and infestations
Nasopharyngitis	5/127 (3.9%)		4/130 (3.1%)
Nervous system disorders
Headache	3/127 (2.4%)		5/130 (3.8%)

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.