Cross-Over Study in Subjects With COPD, Evaluating Lung Function Response After Treatment With Once Daily Umeclidinium 62.5mcg, Vilanterol 25mcg, and Umeclidinium/Vilanterol 62.5/25mcg

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the lung function response to UMEC/VI, UMEC, and VI in individual patients using a cross-over design. This is a multicenter, randomized, double-blind, 3-way crossover study. Eligible subjects will be randomized to a sequence of UMEC 62.5mcg, VI 25mcg, and UMEC/VI 62.5/25mcg. All subjects will receive each treatment once-daily for 14 days, and each treatment will be separated by a 10-14 day washout period. There will be a 5-7 day run-in period prior to randomization.

Official Title
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A Randomized, Double-Blind, 3-Way, Cross-Over Study to Evaluate Lung Function Response After Treatment With Umeclidinium 62.5mcg, Vilanterol 25mcg, and Umeclidinium/Vilanterol 62.5/25mcg Once-Daily in Subjects With Chronic Obstructive Pulmonary Disease (COPD)

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Device: Umeclidinium/Vilanterol 62.5/25 mcg
* Device: Umeclidinium 62.5 mcg
* Device: Vilanterol 25 mcg


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Umeclidinium/Vilanterol 62.5/25 mcg<br>Umeclidinium/Vilanterol 62.5/25 mcg once daily in the morning via novel dry powder inhaler (NDPI) | Device: Umeclidinium/Vilanterol 62.5/25 mcg<br>* Umeclidinium/Vilanterol 62.5/25 mcg once daily in the morning via novel dry powder inhaler (NDPI)<br>|
| Experimental: Umeclidinium 62.5 mcg<br>Umeclidinium 62.5 mcg once daily in the morning via novel dry powder inhaler (NDPI) | Device: Umeclidinium 62.5 mcg<br>* Umeclidinium 62.5 mcg once daily in the morning via novel dry powder inhaler (NDPI)<br>|
| Experimental: Vilanterol 25 mcg<br>Vilanterol 25 mcg once daily in the morning via novel dry powder inhaler (NDPI) | Device: Vilanterol 25 mcg<br>* Vilanterol 25 mcg once daily in the morning via novel dry powder inhaler (NDPI)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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 Outcome Measures

| Outcome Measure | 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. | 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) | 
| 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. | Baseline and Day 14 of each treatment period (up to study day 83) | 
| 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. | Baseline and Day 15 of each treatment period (up to study day 84) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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umeclidinium, long-acting muscarinic antagonist, long-acting beta-agonist, Chronic Obstructive Pulmonary Disease, vilanterol