Cross-Over Study in Subjects With COPD, Evaluating Lung F... | NCT01716520

Status Module

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Umeclidinium/Vilanterol 62.5/25 mcg	Experimental	Umeclidinium/Vilanterol 62.5/25 mcg once daily in the morning via novel dry powder inhaler (NDPI)	Device: Umeclidinium/Vilanterol 62.5/25 mcg
Umeclidinium 62.5 mcg	Experimental	Umeclidinium 62.5 mcg once daily in the morning via novel dry powder inhaler (NDPI)	Device: Umeclidinium 62.5 mcg
Vilanterol 25 mcg	Experimental	Vilanterol 25 mcg once daily in the morning via novel dry powder inhaler (NDPI)	Device: Vilanterol 25 mcg

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Umeclidinium/Vilanterol 62.5/25 mcg	Device	Umeclidinium/Vilanterol 62.5/25 mcg once daily in the morning via novel dry powder inhaler (NDPI)	Umeclidinium/Vilanterol 62.5/25 mcg

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Change From Baseline (BL) in Weighted Mean (WM) 0-6 Hour Forced Expiratory Volume in One Second (FEV1) Obtained Post-dose at Day 14 of Each Treatment Period (TP) by Response Type	FEV1 is a measure of lung function and the maximal amount of air that can be forcefully exhaled in one second. The WM FEV1 was derived by calculating the area under the FEV1/time curve (AUC) using the trapezoidal rule, and then dividing the value by the time interval over which the AUC was calculated. The WM FEV1 was calculated using 0-6 hour post-dose measurements at Day 14 of each TP, which included pre-dose (trough value for Day 14 [mean of the 23 and 24 hour assessments post Day 13 dosing]) and post-dose 15 minutes (min), 30 min, and 1, 3, and 6 hours. BL is the mean FEV1 values recorded 30 min and 5 min pre-dose on Day 1 of each TP, mean BL is the mean of the BLs for each participant, and period BL is the difference between the BL and the mean BL in each TP for each participant. Change from BL for each TP is the Day 14 value minus the BL value for that TP. Participants could have been classified as responders to both UMEC and VI.	Baseline and Day 14 of each treatment period (up to study day 83)

Secondary Outcomes

Measure	Description	Time Frame
Number of Participants (Par.) Who Were Responsive to UMEC/VI, UMEC, or VI According to FEV1 at Day 1 of Each Treatment Period (TP)	A responder is a par. with an increase from BL of >=12% and 200 milliliters (mL) at >=1 time point over 0-6 hours post-dose (PD) in FEV1 on Day 1. A non-responder (NR) is a par. with >=1 FEV1 assessment over 0-6 hours PD on Day 1 but no increase from BL of >=12% and 200 mL at any assessment(s). Missing: no FEV1 data recorded over 0-6 hours PD on Day 1. Response type is defined based on a par.'s response to each individual monotherapy treatment. A responder to UMEC is a par. who is a responder in the UMEC treatment period (TP) and either a NR or has missing data in the VI TP. A responder to VI is a par. who is a responder in the VI TP and either a NR or has missing data in the UMEC TP. A responder to UMEC and VI is a par. who is a responder in both the UMEC and VI TPs. A responder to neither is a par. who is a NR in both the UMEC and VI TPs. Missing: a par. who has missing data in both the UMEC and VI TPs, or who has missing data in one monotherapy period and is a NR in the other.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Type of Patient: Outpatient
Informed Consent: A signed and dated written informed consent prior to study participation
Age: Subjects 40 years of age or older at Visit 1
Gender: Male or female subjects.
COPD diagnosis: As defined by the American Thoracic Society/European Respiratory Society (ATS/ERS)
Severity of disease: A pre- and post-salbutamol FEV1/FVC ratio of <0.70 and a pre- and post-salbutamol FEV1 of ≤ 70% of predicted normal values at Visit 1
Smoking History: Current or former cigarette smokers with a history of cigarette smoking of ≥ 10 pack-years at Visit 1
Female subject of non child-bearing potential OR a female subject of child bearing potential, with a negative pregnancy test at screening, and agreeing to consistently and correctly use one of the acceptable contraceptive methods

Exclusion Criteria:

Pregnancy: Women who are pregnant or lactating or are planning on becoming pregnant during the study
Asthma: A current diagnosis of asthma
Other Respiratory Disorders: Known alpha-1 antitrypsin deficiency, active lung infections (such as tuberculosis), and lung cancer are absolute exclusionary conditions.
Other Diseases/Abnormalities: Subjects with historical or current evidence of clinically significant cardiovascular, neurological, psychiatric, renal, hepatic, immunological, endocrine (including uncontrolled diabetes or thyroid disease) or hematological abnormalities that are uncontrolled and/or a previous history of cancer in remission for < 5 years prior to Visit 1
Contraindications: A history of allergy or hypersensitivity to any anticholinergic/muscarinic receptor antagonist, beta2-agonist, lactose/milk protein or magnesium stearate or a medical condition such as of narrow-angle glaucoma, prostatic hypertrophy or bladder neck obstruction that, in the opinion of the study physician contraindicates study participation or use of an inhaled anticholinergic.
Hospitalization: Hospitalization for COPD or pneumonia within 12 weeks prior to Visit 1.
Lung Resection: Subjects with lung volume reduction surgery within the 12 months prior to Visit 1.
12-Lead ECG: An abnormal and significant ECG finding from the 12-lead ECG conducted at Visit 1
Screening Labs: Significantly abnormal finding from clinical chemistry or hematology tests at Visit 1 as determined by the study investigator.
Medication Prior to Spirometry: Unable to withhold salbutamol for the 4 hour period required prior to spirometry testing at each study visit and at each spirometry test performed at home.
Medications Prior to Screening: Use of the prohibited medications according to defined time intervals prior to Visit 1
Oxygen: Use of long-term oxygen therapy (LTOT) described as oxygen therapy prescribed for greater than 12 hours a day. As-needed oxygen use (i.e., ≤ 12 hours per day) is not exclusionary.
Nebulized Therapy: Regular use (prescribed for use every day, not for as-needed use) of short-acting bronchodilators (e.g., salbutamol, ipratropium bromide) via nebulized therapy
Pulmonary Rehabilitation Program: Participation in the acute phase of a pulmonary rehabilitation program within 4 weeks prior to Visit 1. Subjects who are in the maintenance phase of a pulmonary rehabilitation program are not excluded.
Drug or Alcohol Abuse: A known or suspected history of alcohol or drug abuse within 2 years prior to Visit 1.
Affiliation with Investigator Site: Is an investigator, sub-investigator, study coordinator, employee of a participating investigator or study site, or immediate family member of the aforementioned that is involved in 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 a questionnaire

Name	Affiliation	Role
GSK Clinical Trials	GlaxoSmithKline	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
GSK Investigational Site		Haapsalu		90502	Estonia
GSK Investigational Site

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

ID	Type	URL	Comment
116133	Individual Participant Data Set	View IPD

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Sequence 1: UMEC 62.5 µg, VI 25 µg, UMEC/VI 62.5/25 µg	Participants received umeclidinium (UMEC) 62.5 micrograms (µg), vilanterol (VI) 25 µg, and UMEC/VI 62.5/25 µg in Treatment Periods 1, 2, and 3, respectively. Participants received all treatments once a day (QD) for 14 days from a Dry Powder Inhaler (DPI). The three treatment periods were separated by a washout period of 10 to 14 days.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Change From Baseline (BL) in Weighted Mean (WM) 0-6 Hour Forced Expiratory Volume in One Second (FEV1) Obtained Post-dose at Day 14 of Each Treatment Period (TP) by Response Type

FEV1 is a measure of lung function and the maximal amount of air that can be forcefully exhaled in one second. The WM FEV1 was derived by calculating the area under the FEV1/time curve (AUC) using the trapezoidal rule, and then dividing the value by the time interval over which the AUC was calculated. The WM FEV1 was calculated using 0-6 hour post-dose measurements at Day 14 of each TP, which included pre-dose (trough value for Day 14 [mean of the 23 and 24 hour assessments post Day 13 dosing]) and post-dose 15 minutes (min), 30 min, and 1, 3, and 6 hours. BL is the mean FEV1 values recorded 30 min and 5 min pre-dose on Day 1 of each TP, mean BL is the mean of the BLs for each participant, and period BL is the difference between the BL and the mean BL in each TP for each participant. Change from BL for each TP is the Day 14 value minus the BL value for that TP. Participants could have been classified as responders to both UMEC and VI.

Intent-to-Treat (ITT) Population: all participants (par.) randomized to treatment who received >=1 dose of randomized study medication in a TP. Only par. available at the specified time points were analyzed. Different par. may have been analyzed for different parameters; the overall number of par, analyzed reflects everyone in the ITT Population.

Posted

Least Squares Mean

Standard Error

Liters

Baseline and Day 14 of each treatment period (up to study day 83)

ID	Title	Description
OG000	UMEC 62.5 µg	Participants received UMEC 62.5 µg inhalation powder QD from the DPI for 14 days during one of the three treatment periods. Each treatment period was followed by a washout period of 10-14 days.
OG001	VI 25 µg	Participants received VI 25 µg inhalation powder QD from the DPI for 14 days during one of the three treatment periods. Each treatment period was followed by a washout period of 10-14 days.
OG002	UMEC/VI 62.5/25 µg	Participants received UMEC/VI 62.5/25 µg inhalation powder QD from the DPI for 14 days during one of the three treatment periods. Each treatment period was followed by a washout period of 10-14 days.

Units	Counts
Participants	OG000171 OG001171 OG002173

Title

Denominators

Categories

Responder to UMEC, n=90, 90, 88

Title	Measurements
	OG0000.216± 0.0166 OG0010.201± 0.0167 OG0020.337± 0.0166

Responder to VI, n=99, 102, 100

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG002		ANCOVA		<0.001	Analysis was performed using an Analysis of Covariance (ANCOVA) model with covariates of treatment, period, mean Baseline, period Baseline, response type and treatment by response type interaction.	Mean Difference (Final Values)	0.121			2-Sided	95	0.085	0.157			Responders to UMEC=responders to UMEC or to both monotherapies, as defined by a participant with an increase from Baseline of >=12% and 200 milliliters (mL) at >=1 time point over 0-6 hours post-dose in FEV1 on Day 1.	No	Superiority or Other

Secondary

Number of Participants (Par.) Who Were Responsive to UMEC/VI, UMEC, or VI According to FEV1 at Day 1 of Each Treatment Period (TP)

A responder is a par. with an increase from BL of >=12% and 200 milliliters (mL) at >=1 time point over 0-6 hours post-dose (PD) in FEV1 on Day 1. A non-responder (NR) is a par. with >=1 FEV1 assessment over 0-6 hours PD on Day 1 but no increase from BL of >=12% and 200 mL at any assessment(s). Missing: no FEV1 data recorded over 0-6 hours PD on Day 1. Response type is defined based on a par.'s response to each individual monotherapy treatment. A responder to UMEC is a par. who is a responder in the UMEC treatment period (TP) and either a NR or has missing data in the VI TP. A responder to VI is a par. who is a responder in the VI TP and either a NR or has missing data in the UMEC TP. A responder to UMEC and VI is a par. who is a responder in both the UMEC and VI TPs. A responder to neither is a par. who is a NR in both the UMEC and VI TPs. Missing: a par. who has missing data in both the UMEC and VI TPs, or who has missing data in one monotherapy period and is a NR in the other.

ITT Population

Posted

Number

participants

Baseline (BL) and 0-6 hours post-dose (15 minutes, 30 minutes, and 1, 3, and 6 hours post-dose) on Day 1 of each treatment period (up to study day 71)

ID	Title	Description
OG000	UMEC 62.5 µg	Participants received UMEC 62.5 µg inhalation powder QD from the DPI for 14 days during one of the three treatment periods. Each treatment period was followed by a washout period of 10-14 days.
OG001

Secondary

Number of Participants With a Larger Change From Baseline in 0-6 Hour Weighted Mean FEV1 at Day 14 of Each Treatment Period With UMEC/VI Compared With UMEC and VI Alone

The number of participants with a larger change from Baseline in weighted mean FEV1 with UMEC/VI compared with UMEC and VI alone was recorded. Participants who improved on UMEC/VI had a larger change from Baseline difference in 0-6 hour weighted mean FEV1 on Day 14 on UMEC/VI compared to UMEC or VI alone. Baseline is the mean FEV1 values recorded 30 min and 5 min pre-dose on Day 1 of each treatment period, mean Baseline is the mean of the Baselines for each participant, and period Baseline is the difference between the Baseline and the mean Baseline in each treatment period for each participant. Change from Baseline for each treatment period is the Day 14 value minus the Baseline value for that treatment period.

ITT Population. Only those participants available at the specified time point were analyzed.

Posted

Number

participants

Baseline and Day 14 of each treatment period (up to study day 83)

ID	Title	Description
OG000	UMEC 62.5 µg	Participants received UMEC 62.5 µg inhalation powder QD from the DPI for 14 days during one of the three treatment periods. Each treatment period was followed by a washout period of 10-14 days.
OG001	VI 25 µg	Participants received VI 25 µg inhalation powder QD from the DPI for 14 days during one of the three treatment periods. Each treatment period was followed by a washout period of 10-14 days.

Secondary

Change From Baseline in Trough FEV1 on Day 15 of Each Treatment Period

Trough FEV1 on Treatment Day 15 is defined as the mean of the FEV1 values obtained at 23 and 24 hours after dosing on Day 14. Analysis was performed using an ANCOVA model with covariates of treatment, period, mean Baseline (BL), period BL, response type, and treatment by response type interaction. A participant is a reponder to UMEC if they were a responder to UMEC monotherapy or a responder to both UMEC monotherapy and VI monotherapy. A participant is a responder to VI if they were a responder to VI monotherapy or a responder to both UMEC monotherapy or VI monotherapy. BL is the mean FEV1 recorded 30 min and 5 min pre-dose on Day 1 of each treatment period, mean BL is the mean of the BLs for each participant, and period BL is the difference between BL and the mean BL in each treatment period for each participant. Change from BL for each treatment period is the Day 15 value minus the BL value for that treatment period.

ITT Population. Only those participants available at the specified time points were analyzed. Different participants may have been analyzed for different parameters; the overall number of participants analyzed reflects everyone in the ITT Population.

Posted

Least Squares Mean

Standard Error

Liters

Baseline and Day 15 of each treatment period (up to study day 84)

ID	Title	Description
OG000	UMEC 62.5 µg	Participants received UMEC 62.5 µg inhalation powder QD from the DPI for 14 days during one of the three treatment periods. Each treatment period was followed by a washout period of 10-14 days.
OG001

Arm/Groups

ID	Title	Description	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	UMEC 62.5 µg	Participants received UMEC 62.5 µg inhalation powder QD from the DPI for 14 days during one of the three treatment periods. Each treatment period was followed by a washout period of 10-14 days.	3	171	8	171
EG001	VI 25 µg	Participants received VI 25 µg inhalation powder QD from the DPI for 14 days during one of the three treatment periods. Each treatment period was followed by a washout period of 10-14 days.	1	171	13	171
EG002	UMEC/VI 62.5/25 µg	Participants received UMEC/VI 62.5/25 µg inhalation powder QD from the DPI for 14 days during one of the three treatment periods. Each treatment period was followed by a washout period of 10-14 days.	3	173	13	173

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Bladder cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA	Systematic Assessment	EG0000 affected171 at risk EG0010 affected171 at risk EG0021 affected173 at risk
Oesophageal carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA	Systematic Assessment	EG0001 affected171 at risk EG0010 affected171 at risk EG0020 affected173 at risk
Pancreatic carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA	Systematic Assessment	EG0001 affected171 at risk EG0010 affected171 at risk EG0020 affected173 at risk
Chronic obstructive pulmonary disease	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0002 affected171 at risk EG0010 affected171 at risk EG0020 affected173 at risk
Angina pectoris	Cardiac disorders	MedDRA	Systematic Assessment	EG0000 affected171 at risk EG0010 affected171 at risk EG0021 affected173 at risk
Abscess limb	Infections and infestations	MedDRA	Systematic Assessment	EG0000 affected171 at risk EG0010 affected171 at risk EG0021 affected173 at risk
Spinal fracture	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0000 affected171 at risk EG0011 affected171 at risk EG0020 affected173 at risk

ID	Term
D008173	Lung Diseases, Obstructive
D008171	Lung Diseases
D012140	Respiratory Tract Diseases
D002908	Chronic Disease
D020969	Disease Attributes
D010335	Pathologic Processes
D013568	Pathological Conditions, Signs and Symptoms

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Nasopharyngitis	Infections and infestations	MedDRA	Systematic Assessment		EG0005 affected171 at risk EG00111 affected171 at risk EG0027 affected173 at risk
Headache	Nervous system disorders	MedDRA	Systematic Assessment		EG0003 affected171 at risk EG0012 affected171 at risk EG0026 affected173 at risk