Phase IIb Study of Umeclidinium (UMEC) Bromide Versus Placebo in Subjects With Asthma

Study Overview
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Brief Summary
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This study is conducted to evaluate the effects of UMEC 62.5 microgram (mcg) and UMEC 31.25 mcg on lung function versus placebo after 24 weeks of treatment. This study will provide important information regarding the efficacy and safety of UMEC when administered in a separate inhaler to subjects on a background of fluticasone furoate (FF). This is a Phase IIb, randomized, double-blind, placebo controlled study that will compare the efficacy, safety and tolerability of UMEC (62.5 mcg and 31.25 mcg) administered once-daily in subjects with asthma that is not well controlled. Eligible subjects will be requested to participate in the study for a maximum of approximately 31 weeks with 4 phases (pre screening, screening/run-in, randomization/treatment and safety follow-up). The total number of randomized subjects required is approximately 384, with 128 subjects randomized 1:1:1 to each of the 3 double-blind treatment arms.

Official Title
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A Phase IIb, 24 Week, Randomized, Double-blind, 3 Arm Parallel Group Study, Comparing the Efficacy, Safety and Tolerability of Two Doses of Umeclidinium Bromide Administered Once-daily Via a Dry Powder Inhaler, Versus Placebo, in Participants With Asthma

Conditions
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Asthma

Intervention / Treatment
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* Drug: Placebo
* Drug: UMEC
* Drug: Fluticasone Furoate
* Drug: Albuterol/salbutamol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 years of age or older at the time of signing the informed consent. Subjects with a diagnosis of asthma as defined by the National Institutes of Health at least 6 months prior to Visit 0. Asthma Control Questionnaire (ACQ)-6 total score of >0.75 at Visit 1. Subjects are eligible if they have required daily Inhaled Corticosteroids (ICS) therapy >=100 milligram per day (mg/day) fluticasone propionate (FP) or equivalent with or without Long-Acting Beta-2-Agonists (LABA) or Long-Acting Muscarinic Antagonist (LAMA) for at least 12 weeks prior to Visit 0 and there have been no changes in maintenance asthma medications during the 4 weeks immediately prior to Visit 0. Dosing regimen (once or twice daily to equal the total daily dose) should be restricted to the current local product labels. A best pre-bronchodilator morning FEV1 <=85% of the predicted normal value. Predicted values will be based upon the European Respiratory Society (ERS) Global Lung Function Initiative. A best post-bronchodilator FEV1/ forced vital capacity (FVC) >=0.7 at Visit 1. Airway reversibility is defined as >=12% and >=200 mL increase in FEV1 between 20 and 60 minutes following 4 inhalations of albuterol/salbutamol aerosol at Visit 1. Note: If the subject does not meet the above reversibility criteria at Visit 1 then the reversibility assessment may be repeated once within 7 days of Visit 1 if either criteria are met: The >=9% increase in FEV1 between 20 and 60 minutes following 4 inhalations of albuterol/salbutamol aerosol at Visit 1; Documented evidence of a reversibility assessment within 1 year prior to Visit 1 which demonstrated a post-bronchodilator increase in FEV1 of >=12% and >=200 milliliter (mL). Should the subject successfully demonstrate airway reversibility (defined as >=12% and >=200 mL increase in FEV1 between 20 and 60 minutes following 4 inhalations of albuterol/salbutamol aerosol) at the second attempt then, provided that all other eligibility criteria assessed at Visit 1 are met, the subject may enter the 2-week run-in period. All subjects must be able to replace their current Short-Acting Beta-2-Agonists (SABA) inhaler with albuterol/salbutamol aerosol inhaler at Visit 1 as needed for the duration of the study. Subjects must be judged capable of withholding albuterol/salbutamol for at least 6 hours prior to study visits. Both male and female subjects are eligible to participate in the study. A female subject is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: Not a woman of childbearing potential (WOCBP) or a WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 5 days after the last dose of study treatment. Able to give written informed consent prior to participation in the study, which will include the ability to comply with the requirements and restrictions listed in the consent form and in this protocol. Subjects must be able to read, comprehend, and write at a level sufficient to complete study related materials. Inclusion Criteria (for randomization) ACQ-6 total score of >0.75 at Visit 2. Spirometry: A best pre-bronchodilator morning FEV1 <=85% of the predicted normal value at Visit 2. Predicted values will be based upon the ERS Global Lung Function Initiative. Alanine aminotransferase (ALT) <=2 x upper limit of normal (ULN). Alkaline phosphatase <=1.5 x ULN. Bilirubin <=1.5 x ULN (isolated bilirubin >1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%). Compliance with completion of the Daily electronic diary (eDiary) reporting defined as completion of all questions/assessments on >=4 of the last 7 days during the run-in period. Exclusion Criteria: Chest X-ray documented pneumonia in the 12 weeks prior to Visit 1. Any severe asthma exacerbation, defined as deterioration of asthma requiring the use of systemic corticosteroids (oral, parenteral or depot) within 12 weeks of Visit 1, or an inpatient hospitalization or emergency department visit due to asthma that required systemic corticosteroids within 12 weeks of Visit 1. Current evidence of pneumonia, pneumothorax, atelectasis, pulmonary fibrotic disease, bronchopulmonary dysplasia, chronic bronchitis, emphysema, chronic obstructive pulmonary disease, lung cancer, or other respiratory abnormalities other than asthma. Women who are pregnant or lactating or are planning to become pregnant during the study. Immune suppression (e.g., Human Immunodeficiency Virus [HIV], Lupus) or other risk factors for pneumonia (e.g., neurological disorders affecting control of the upper airway, such as Parkinson's disease, Myasthenia Gravis). Subjects at potentially high risk (e.g., very low Body Mass Index [BMI], severely malnourished, or very low FEV1) will only be included at the discretion of the Investigator 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 as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, esophageal or gastric varices or persistent jaundice, cirrhosis, known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). Note: Chronic stable hepatitis B and C is acceptable if the subject otherwise meets entry criteria. Evidence of a clinically significant abnormality in the 12-lead ECG performed during screening or run-in. The Principal 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 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); QT interval corrected for heart rate by Fridericia's formula (QTcF) >=500 millisecond (msec) in subjects with QRS <120 msec and QTcF >=530 msec in subjects with QRS >=120 msec. 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 IV Heart failure. Subjects with a medical condition such as narrow-angle glaucoma, urinary retention, prostatic hypertrophy or bladder neck obstruction should only be included if in the opinion of the Investigator the benefit outweighs the risk and that the condition would not contraindicate study participation. Subjects with carcinoma that has not been in complete remission for at least 5 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 5 year waiting period if the subject has been considered cured by treatment. 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. Subjects who are medically unable to withhold their albuterol/salbutamol for the 6-hour period required prior to spirometry testing at each study visit. Current smoker or a smoking history of >=10 pack years (e.g., 20 cigarettes/day for 10 years). A subject may not have used inhaled tobacco products within the past 12 months (i.e., cigarettes, e-cigarettes/vaping, cigars or pipe tobacco). Subjects with a known or suspected history of alcohol or drug abuse within the last 2 years. This includes marijuana, which is considered an abused drug. A history of allergy or hypersensitivity to any corticosteroid, anticholinergic/muscarinic receptor antagonist, beta2-agonist, lactose/milk protein or magnesium stearate. 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. Study investigators, sub-investigators, study coordinators, employees of a participating investigator or study site, or immediate family members of the aforementioned that is involved with this study. In the opinion of the Investigator, any subject who is unable to read and/or would not be able to complete study related materials. Exclusion Criteria (for randomization) Occurrence of a culture-documented or suspected bacterial or viral infection of the upper or lower respiratory tract, sinus or middle ear during the run-in period that led to a change in asthma management or, in the opinion of the Investigator, is expected to affect the subject's asthma status or the subject's ability to participate in the study. Evidence of a moderate asthma exacerbation leading to a change in therapy or severe exacerbation during screening or the run-in period, defined as deterioration of asthma requiring the use of systemic corticosteroids (tablets, suspension, or injection) or an in-patient hospitalization or emergency department visit due to asthma that required systemic corticosteroids. Changes in asthma medication (excluding changes after Visit 0 or run-in medication and albuterol/salbutamol inhalation aerosol provided at Visit 1). Evidence of clinically significant abnormal laboratory tests during screening or run-in, which are still abnormal upon repeat analysis and are not believed to be due to disease(s) present. Each Investigator will use his/her own discretion in determining the clinical significance of the abnormality.

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 |
| --- | --- |
| Placebo Comparator: Placebo<br>Subjects will be administered placebo once daily via the ELLIPTA® dry powder inhaler (DPI) for 24 weeks. Subjects will also receive FF 100 mcg once daily, in the morning for 24 weeks. ELLIPTA is a registered trademark of the GSK group of companies. | Drug: Placebo<br>* Placebo is a white powder to be administered using ELLIPTA DPI which hold two individual blister strips, both of which contains lactose monohydrate blended with magnesium stearate.<br>Drug: Fluticasone Furoate<br>* FF is a white powder to be administered using ELLIPTA DPI which hold two individual blister strips, one of which contains GW685698 blended with lactose monohydrate and another one contains lactose monohydrate with magnesium stearate.<br>Drug: Albuterol/salbutamol<br>* Albuterol/salbutamol is to be administered via metered-dose inhaler as a rescue drug on need basis throughout the study.<br>|
| Experimental: UMEC 62.5 mcg<br>Subjects will be administered UMEC 62.5 mcg once daily via the ELLIPTA dry powder inhaler (DPI) for 24 weeks. Subjects will also receive FF 100 mcg once daily, in the morning for 24 weeks. | Drug: UMEC<br>* UMEC is a white powder to be administered using ELLIPTA DPI which hold two individual blister strips, one of which contains GSK573719 blended with lactose blended with magnesium stearate and another one contains lactose monohydrate blended with magnesium stearate.<br>Drug: Fluticasone Furoate<br>* FF is a white powder to be administered using ELLIPTA DPI which hold two individual blister strips, one of which contains GW685698 blended with lactose monohydrate and another one contains lactose monohydrate with magnesium stearate.<br>Drug: Albuterol/salbutamol<br>* Albuterol/salbutamol is to be administered via metered-dose inhaler as a rescue drug on need basis throughout the study.<br>|
| Experimental: UMEC 31.25 mcg<br>Subjects will be administered UMEC 31.25 mcg once daily via the ELLIPTA dry powder inhaler (DPI) for 24 weeks. Subjects will also receive FF 100 mcg once daily, in the morning for 24 weeks. | Drug: UMEC<br>* UMEC is a white powder to be administered using ELLIPTA DPI which hold two individual blister strips, one of which contains GSK573719 blended with lactose blended with magnesium stearate and another one contains lactose monohydrate blended with magnesium stearate.<br>Drug: Fluticasone Furoate<br>* FF is a white powder to be administered using ELLIPTA DPI which hold two individual blister strips, one of which contains GW685698 blended with lactose monohydrate and another one contains lactose monohydrate with magnesium stearate.<br>Drug: Albuterol/salbutamol<br>* Albuterol/salbutamol is to be administered via metered-dose inhaler as a rescue drug on need basis throughout the study.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in Clinic Trough Forced Expiratory Volume in 1 Second (FEV1) at Week 24 | FEV1 is measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. The highest of 3 technically acceptable measurements were recorded at each Visit. The Baseline value of clinic FEV1 was last acceptable/borderline acceptable (pre-dose) FEV1 value obtained prior to randomized treatment start date. Change from Baseline was calculated as FEV1 value at Week 24 minus FEV1 value at Baseline. Treatment policy estimand was assessed, including all on- and post-treatment data. Intent-to-Treat Population comprised all randomized participants, excluding those who were randomized in error, who did not receive the study drug. Least square (LS) mean and standard error (SE) data is presented. Different participants may have been analyzed at different time points; thus, overall number of participants analyzed reflects everyone in ITT Population without missing covariate information, with Baseline, at least one post-Baseline measurement. | Baseline (Day 1 pre-dose) and Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in Clinic FEV1 at 3 Hours Post Dose at 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. The highest of 3 technically acceptable measurements were recorded at each Visit. The Baseline value of clinic FEV1 was the last acceptable/borderline acceptable (pre-dose) FEV1 value obtained prior to randomization (either from Visit 2 pre-dose or from Visit 1 pre-bronchodilator). Change from Baseline was calculated as FEV1 value at Week 24 (recorded at 3 hours post dose) minus FEV1 value at Baseline. The analysis only including data collected on-treatment. LS mean change and SE data is presented. | Baseline (Day 1 pre-dose) and Week 24 | 
| Number of Participants With On-treatment Adverse Events (AE), Non-serious Adverse Events (Non-SAE) | An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment or all events of possible drug-induced liver injury with hyperbilirubinemia were categorized as SAE. Number of participants with on-treatment AEs and SAEs and serious adverse events (SAE) and common (>=3%)non-SAEs have been reported. | Up to Week 24 | 
| Number of Participants With On-treatment Abnormal Electrocardiograms (ECG) Findings | A single 12-lead ECG and rhythm strip was recorded after measurement of vital signs and spirometry at given time points. All ECG measurements were measured with participants in supine position after >=5 minutes rest. All ECGs were electronically transmitted to an independent and treatment-blinded cardiologist for the measurement. ECG was obtained 15 minutes to 45 minutes after the administration of study treatment. Data for number of participants with abnormal ECG Findings have been reported. | Week 4 and Week 24 | 
| Mean Change From Baseline in On-treatment Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | Blood pressure was measured at every clinic visit, starting at Visit 1, and prior to conducting spirometry. Blood pressure was measured with participant in sitting position after approximately 5 minutes rest. Baseline value was defined as the latest vital signs assessment prior to randomized treatment start, including unscheduled visits. Change from Baseline was calculated by subtracting Baseline value from the value at specified time point. LS mean and SE data is presented. Different participants may have data available at different time points; thus, the overall number of participants analyzed reflects everyone in the ITT Population without missing covariate information and with a Baseline and at least one post-Baseline measurement. | Baseline (Day 1 pre-dose), Weeks 4, 12 and 24 | 
| Mean Change From Baseline in On-treatment Pulse Rate | Pulse rate was measured at every clinic visit, starting at Visit 1, and prior to conducting spirometry. Pulse rate was measured with participant in sitting position after approximately 5 minutes rest. Baseline value was defined as the latest vital signs assessment prior to randomized treatment start, including unscheduled visits. Change from Baseline was calculated by subtracting Baseline value from the value at specified time point. LS mean and SE data is presented. | Baseline (Day 1 pre-dose), Weeks 4, 12 and 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Respiratory, Efficacy, Umeclidinium bromide, Parallel, Asthma, Dry powder inhaler