Evaluation of Umeclidinium Bromide in Combination With Fluticasone Furoate in COPD Subjects With an Asthmatic Component

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the dose-response of 4 doses of umeclidinium bromide in combination with fluticasone furoate compared with fluticasone furoate monotherapy in chronic obstructive pulmonary disease participants with an asthmatic component. The fluticasone furoate/umeclidinium bromide treatments will also be compared to the once-daily inhaled corticosteroid/long-acting beta agonist combination fluticasone furoate/vilanterol.

Official Title
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200699: A Clinical Study to Evaluate Four Doses of Umeclidinium Bromide in Combination With Fluticasone Furoate in COPD Subjects With an Asthmatic Component

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Drug: FF
* Drug: UMEC
* Drug: VI


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 years of age or older COPD with evidence of an asthmatic component as demonstrated by spirometry, reversibility and current therapy at screening as follows: Post-bronchodilator morning (AM) FEV1 >=50% and <=80% of the predicted normal value at Visit 1 Pre- and post-bronchodilator FEV1/FVC ratio <0.7. Demonstrated reversibility by >=12% and >=200 mL increase in FEV1 following albuterol at Visit 1. A need for regular controller therapy (i.e., inhaled corticosteroids alone or in combination with a long-acting beta-agonist or leukotriene modifier, etc.) for a minimum of 12 weeks prior to Visit 1. Outpatient subjects who are smokers or non-smokers. Exclusion Criteria: History of life-threatening respiratory event within the last 5 years. Unresolved respiratory infection Recent Severe COPD or Asthma Exacerbation Risk factors for pneumonia Hospitalization for pneumonia within 3 months Concurrent respiratory disease other than chronic obstructive pulmonary disease or asthma. Other uncontrolled condition or disease state that, in the opinion of the investigator, would put the safety of the subject at risk through study participation or would confound the interpretation of the efficacy results if the condition/disease exacerbated during the study. Viral hepatitis or HIV Current or chronic history of liver disease, known hepatic or biliary abnormalities Drug or milk protein allergy Administration of prescription or over-the-counter medication that would significantly affect the course of COPD or asthma, or interact with study drug Subjects with lung volume reduction surgery within 12 months prior to screening. Use of long-term oxygen therapy (LTOT) Requirement for nebulized therapy Participation in the acute phase of a pulmonary rehabilitation program within 4 weeks Unstable or life-threatening cardiac disease Abnormal and clinically significant 12-Lead Electrocardiogram (ECG) finding Diseases preventing the use of anticholinergics

Ages Eligible for Study
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Minimum Age: 18 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: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Phase A<br>Eligible subjects will enter a 4-week run-in period and will receive fluticasone propionate/salmeterol. Subjects will then be randomized to receive fluticasone furoate 100 mcg, fluticasone furoate/umeclidinium bromide 100/15.6 mcg, fluticasone furoate/umeclidinium bromide 100/62.5 mcg, fluticasone furoate/umeclidinium bromide 100/125 mcg, fluticasone furoate/umeclidinium bromide 100/250 mcg, or fluticasone furoate/vilanterol 100/25 mcg, respectively for 4 weeks | Drug: FF<br>* Fluticasone furoate is available as fluticasone furoate inhalation powder (100 mcg per blister), combination of fluticasone furoate/umeclidinium bromide inhalation powder (fluticasone furoate: 100 mcg per blister, umeclidinium bromide: 15.6, 62.5, 125, or 250 mcg per blister) and combination of fluticasone furoate/vilanterol inhalation powder (fluticasone furoate: 100 mcg per blister, vilanterol: 25 mcg per blister)<br>Drug: UMEC<br>* Umeclidinium bromide is available as combination of fluticasone furoate/umeclidinium bromide inhalation powder (fluticasone furoate: 100 mcg per blister, umeclidinium bromide: 15.6, 62.5, 125, or 250 mcg per blister)<br>Drug: VI<br>* Vilanterol is available as vilanterol inhalation powder (25 mcg per blister) and combination of fluticasone furoate/vilanterol inhalation powder (fluticasone furoate: 100 mcg per blister, vilanterol: 25 mcg per blister)<br>|
| Experimental: Treatment Phase B<br>Subjects completing Treatment Phase A will be randomized to receive either fluticasone furoate/umeclidinium bromide100/250 mcg or fluticasone furoate/umeclidinium bromide/vilanterol 100/250/25 mcg for 1 week. | Drug: FF<br>* Fluticasone furoate is available as fluticasone furoate inhalation powder (100 mcg per blister), combination of fluticasone furoate/umeclidinium bromide inhalation powder (fluticasone furoate: 100 mcg per blister, umeclidinium bromide: 15.6, 62.5, 125, or 250 mcg per blister) and combination of fluticasone furoate/vilanterol inhalation powder (fluticasone furoate: 100 mcg per blister, vilanterol: 25 mcg per blister)<br>Drug: UMEC<br>* Umeclidinium bromide is available as combination of fluticasone furoate/umeclidinium bromide inhalation powder (fluticasone furoate: 100 mcg per blister, umeclidinium bromide: 15.6, 62.5, 125, or 250 mcg per blister)<br>Drug: VI<br>* Vilanterol is available as vilanterol inhalation powder (25 mcg per blister) and combination of fluticasone furoate/vilanterol inhalation powder (fluticasone furoate: 100 mcg per blister, vilanterol: 25 mcg per blister)<br>|
| Experimental: Treatment Phase C<br>Subjects completing Treatment Phase B will be randomized to receive either the same treatment as in Treatment Phase B, or the same treatment minus the umeclidinium bromide component, for 1 week. | Drug: FF<br>* Fluticasone furoate is available as fluticasone furoate inhalation powder (100 mcg per blister), combination of fluticasone furoate/umeclidinium bromide inhalation powder (fluticasone furoate: 100 mcg per blister, umeclidinium bromide: 15.6, 62.5, 125, or 250 mcg per blister) and combination of fluticasone furoate/vilanterol inhalation powder (fluticasone furoate: 100 mcg per blister, vilanterol: 25 mcg per blister)<br>Drug: UMEC<br>* Umeclidinium bromide is available as combination of fluticasone furoate/umeclidinium bromide inhalation powder (fluticasone furoate: 100 mcg per blister, umeclidinium bromide: 15.6, 62.5, 125, or 250 mcg per blister)<br>Drug: VI<br>* Vilanterol is available as vilanterol inhalation powder (25 mcg per blister) and combination of fluticasone furoate/vilanterol inhalation powder (fluticasone furoate: 100 mcg per blister, vilanterol: 25 mcg per blister)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Clinic Trough Forced Expiratory Volume in One Second (FEV1) at the End of Treatment Phase A (Visit 6/Day 29) | FEV1 is defined as forced expiratory volume in one second and measured in the morning at Visits 1 through 8 between 6:00 and 11:00 electronically by spirometry. Change from Baseline in trough FEV1 is defined as the difference in the value obtained at Visit 6 (24 hours post-dose on Visit 5) and the last acceptable/borderline acceptable value obtained prior to randomization (from Visit 2 pre-bronchodilator or Visit 3 pre-dose). Trough FEV1 is defined as the acceptable/borderline acceptable FEV1 value obtained at Visit 6, approximately 24 hours after morning dosing on Visit 5. ITT population is comprised of all participants randomized to treatment who received at least one dose of randomized study medication in the treatment period. All comparisons for statistical purposes are with the FF 100 µg arm. | Baseline and Day 29 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in Rescue Medication Use at the End of Treatment Phase A | All participants received the albuterol/salbutamol via MDI as a rescue medication on an as-needed basis. Total daily rescue medication use for a given day is the sum of daytime albuterol/salbutamol use recorded in PM and nighttime albuterol/salbutamol use recorded in AM the next day. The number of puffs of albuterol (salbutamol) MDI used in the last 12 hours for relief of symptoms were recorded morning and evening in the eDiary by the participants. End of Treatment Phase A is the last 7 days of Treatment Phase A. Change from Baseline at the end of Treatment Phase is the difference between the end of Treatment Phase value and the appropriate baseline week. Analysis performed using analysis of covariance with covariates of treatment, age, sex, baseline rescue medication use, pack years smoked per randomization stratification and age when first treated with an inhaler per randomization stratification. Baseline is the last 7 days of the run-in period prior to randomization | Baseline and End of Treatment Phase A (The end of Treatment Phase A was defined as the last 7 days of Treatment Phase A, including the AM assessments on the date of Visit 6) | 
| Mean Change From Baseline in E-RS Total Scores at the End of Treatment Phase A | A daily symptoms score for exacerbations of chronic pulmonary disease tool - Respiratory Symptoms (E-RS) is derived by summing the 11 item-level E-RS scores and has a theoretical range of 0-40, with higher values indicating more severe respiratory symptoms. The Baseline E-RS score is defined as the mean within-subject daily score over the 7 days prior to randomization, with data present for a minimum of 4 of the 7 days. Change from Baseline at the end of Treatment Phase is the difference between the end of Treatment Phase value and the appropriate Baseline week. Analysis performed using analysis of covariance with covariates of treatment, age, sex, baseline score, pack years smoked per randomization stratification and age when first treated with an inhaler per randomization stratification. Baseline is the last 7 days of the run-in period prior to randomization. All comparisons for statistical purposes are with the FF 100 µg arm. | Baseline and End of Treatment Phase A (The end of Treatment Phase A was defined as the last 7 days of Treatment Phase A, including the AM assessments on the date of Visit 6) | 
| Change From Baseline in Daily Morning (AM) PEF (Pre-dose and Pre-rescue Bronchodilator) Measured at Home and Averaged Over the Last 21 Days of Treatment Phase A | Peak expiratory flow (PEF) stability limit was calculated from AM PEF measurements on the 7 days preceding Visit 3 as mean AM PEF from the available 7 days preceding Visit 3 x 80%. PEF stability limit serves as a benchmark of the participants run-in COPD status and used for comparison during the treatment phase to assess subject safety. Change from Baseline over the last 21 days of Treatment Phase A is the difference between the last 21 days of Treatment Phase A and the appropriate Baseline week. The last 21 days of Treatment Phase A include the AM assessments on the date of Visit 6. AM assessments include the date of Visit 6 and the 20 consecutive days preceding the date of Visit. Analysis performed using analysis of covariance with covariates of treatment, age, sex, Baseline AM PEF, pack years smoked per randomization stratification and age when first treated with an inhaler per randomization stratification. Baseline is the last 7 days of the run-in period prior to randomization | Baseline and from Day 8 through Day 29 | 
| Change From Trough in Clinic Forced Expiratory Volume (FEV1) at 3 Hours Post-study Treatment at Visit 5/Day 28 | FEV1 was measured in the morning by spirometry. At Visit 5, after trough FEV1 is measured, subject received investigational product. 3 hours post-dose, spirometry was repeated and subject then received 2 puffs of albuterol/salbutamol. After 30 minutes,spirometry was repeated.. Change from Baseline in clinic trough (pre-dose) FEV1 is the difference in the trough value at 3 hours post-dose peak FEV1 and the Baseline value. If the trough value or the Baseline was missing, then change from Baseline was considered as missing. Baseline value of clinic FEV1 is the last acceptable/borderline acceptable (pre-dose) FEV1 value obtained prior to randomization (from Visit 3 pre-dose or from Visit 2 pre-bronchodilator). Analysis done using analysis of covariance with covariates of treatment, age, sex, baseline clinic trough FEV1, pre-dose trough FEV1 at Visit 5, pack years smoked per randomization stratification and age when first treated with an inhaler per randomization stratification. | Baseline and Day 28 | 
| Change in Clinic FEV1 Following 2 Puffs of Albuterol/Salbutamol Given 3 Hours Post-study Treatment Dose at Visit 5/Day 28 | FEV1 is defined as forced expiratory volume in one second and measured in the morning at Visits 1 through 8 between 6:00 and 11:00 electronically by spirometry. Reversibility was measured at Visit 1 and Visit 2 for study eligibility by change in clinic FEV1 within 20 to 60 minutes following 4 inhalations of albuterol/salbutamol and again measured 3 hours after dosing at Visit 5 by change in clinic FEV1 30 minutes following 2 inhalations of albuterol/salbutamol. Baseline value of clinic FEV1 is the last acceptable/borderline acceptable (pre-dose) FEV1 value obtained prior to randomization (either from Visit 3 pre-dose or from Visit 2 pre-bronchodilator). Analysis performed using analysis of covariance with covariates of treatment, age, sex, baseline clinic trough FEV1, pre-albuterol/salbutamol FEV1 at Visit 5, pack years smoked per randomization stratification and age when first treated with an inhaler per randomization stratification. | Baseline and Day 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GSK573719, asthma, UMEC, FF, GSK2829332, persistent obstruction, GW685698, Fluticasone Furoate, COPD, umeclidinium bromide