A Long-term Safety Study of Fixed Dose Combination Therapy Fluticasone Furoate/Umeclidinium Bromide/Vilanterol Trifenatate in Japanese Subjects With Asthma

Study Overview
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Brief Summary
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Despite availability of treatments and published guidelines, subjects may have asthma that is inadequately controlled. GlaxoSmithKline is currently developing a once-daily 'closed' triple therapy of an Inhaled Corticosteroids/Long-Acting Beta-2-Agonists/Long-Acting Muscarinic Antagonist (ICS/LAMA/LABA) combination (Fluticasone Furoate/Umeclidinium Bromide/Vilanterol Trifenatate [FF/UMEC/VI]) in a single device, with the aim of providing a new treatment option for the management of asthma by improving lung function, health-related quality of life (HRQoL) and symptom control over established combination therapies. This study has 3 study periods: Run-in, Treatment period and a Follow-up period. Eligible subjects who meet the pre-defined criteria at screening (Visit 1) will enter into a 2-week run-in period. Subjects will continue their pre-screening inhaled medications for asthma (ICS+LABA or ICS+LABA+LAMA) without any change in regimen/dosage until day before Visit 2. At Visit 2 subjects will be allocated to either FF/UMEC/VI 100/62.5/25 or FF/UMEC/VI 200/62.5/25 micrograms (mcg) treatment depending on the asthma control status for 52 weeks. Switching medication from FF/UMEC/VI 100/62.5/25 to FF/UMEC/VI 200/62.5/25 will be permitted in accordance with the control status of the subject assessed by Asthma Control Questionnaire (ACQ)-7 at Week 24 of the treatment period. A follow-up visit will be conducted for approximately 1 week. Subjects will be provided with salbutamol as a rescue medication throughout the study.

Official Title
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A Phase III, 52-week, Open-label Study to Evaluate Long-term Safety of Fixed Dose Combination Therapy Fluticasone Furoate/Umeclidinium Bromide/Vilanterol Trifenatate in Japanese Patients With Asthma

Conditions
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Asthma

Intervention / Treatment
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* Drug: FF/UMEC/VI 100/62.5/25 mcg
* Drug: FF/UMEC/VI 200/62.5/25 mcg
* Drug: Salbutamol
* Other: ACQ-7


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria at the time of informed consent (Visit 0) and at screening (Visit 1). Age: Participant must be 18 years of age or older at the time of signing the informed consent. Ethnicity: Japanese Diagnosis: Subjects with a diagnosis of asthma as defined by the National Institutes of Health at least one year prior to providing informed consent. Current Asthma Maintenance Therapy: Outpatients are eligible if they have received ICS+LABA or ICS+LABA＋LAMA with asthma control status as Not well controlled with ICS (mid-dose) +LABA ; Not well controlled with ICS (high-dose) +LABA or Controlled with ICS (mid-dose) +LABA + LAMA; Not well controlled with ICS (mid-dose) +LABA + LAMA; Controlled with ICS (high-dose) +LABA + LAMA respectively in stable regimen and dosage for at least 4 weeks prior to screening visit (Visit 1) (with medium to high dose of ICS defined by the Japanese Guidelines [JGL]). Asthma Control Questionnaire (ACQ-6) will be used for the assessment of control status of asthma at Visit 1 (screening Visit) (i.e., less than or equal to 0.75 points shows controlled and > 0.75 shows not well controlled). Short-Acting Beta Agonists (SABAs): All subjects must be able to replace their current SABA inhaler with salbutamol aerosol inhaler at Visit 1 as needed for the duration of the study. Subjects should be able to withhold salbutamol for at least 6 hours prior to clinic visit. Sex: Male and/or female: A female participant 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 from the screening visit until after the last dose of study medication and completion of the follow-up visit. Informed Consent: capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF). Exclusion Criteria at the time of informed consent (Visit 0) and at screening (Visit 1). Pneumonia: Chest X-ray documented pneumonia in the 6 weeks prior to Visit 1. Asthma Exacerbation: Any asthma exacerbation requiring a change in maintenance asthma therapy in the 6 weeks prior to Visit 1. COPD: Subjects with the diagnosis of chronic obstructive pulmonary disease, as per Global Initiative for Chronic Obstructive Lung Disease (GOLD 2016) guidelines, including history of exposure to risk factors (i.e., especially tobacco smoke, occupational dusts and chemicals, smoke from home cooking and heating fuels) (for tobacco smoke); post- salbutamol Forced Expiratory Volume in 1 second (FEV1)/forced vital capacity (FVC) ratio of <0.70 and a post- salbutamol FEV1 of less than or equal to 70% of predicted normal values (diagnosis prior to Visit 1 acceptable);Onset of disease greater than or equal to 40 years of age. Concurrent respiratory disorders: Subjects with current evidence of pneumonia, active tuberculosis, lung cancer, significant bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension, interstitial lung diseases or other active pulmonary diseases or abnormalities other than asthma. Risk Factors for Pneumonia: Immune suppression (e.g., 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). Patients 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. Other diseases/abnormalities: 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, hypoalbuminemia, 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 are acceptable if the subject otherwise meets entry criteria. Clinically significant ECG abnormality: Evidence of a clinically significant abnormality in the 12-lead ECG performed during screening. The 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) greater than or equal to 500 milliseconds (msec) in patients with QRS <120 msec and QTcF greater than or equal to 530 msec in patients with QRS greater than or equal to 120 msec. Unstable or life threatening cardiac disease: 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 Antimuscarinic effects: 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. Cancer: 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. Questionable validity of consent: 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. Medication prior to spirometry: Subjects who are medically unable to withhold their salbutamol for the 6-hour period required prior to spirometry testing at each study visit. Drug/alcohol abuse: Subjects with a known or suspected history of alcohol or drug abuse within the last 2 years. Allergy or hypersensitivity: A history of allergy or hypersensitivity to any corticosteroid, anticholinergic/muscarinic receptor antagonist, beta-agonist, lactose/severe milk protein or magnesium stearate. Tobacco use: Subjects who are: Current smokers (defined as subjects who have used inhaled tobacco products within the 12 months prior to Visit 1 [i.e., cigarettes, e-cigarettes/vaping, cigars or pipe tobacco]); Former smokers with a smoking history of greater than equal to 10 pack years (e.g., greater than equal to 20 cigarettes/day for 10 years). Non-compliance: 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. Affiliation with Investigator site: 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. Inability to read: In the opinion of the Investigator, any subject who is unable to read and/or would not be able to complete study related materials. Inclusion Criteria end of the run-in period (Visit 2) Asthma maintenance therapy: No changes in asthma maintenance therapy (excluding salbutamol inhalation aerosol provided at Visit 1) and control status during the run-in period. Asthma Control Questionnaire (ACQ-6 at screening and ACQ-7 at the end of the run-in period) will be used for the assessment of control status of asthma, i.e., 0.75 points shows controlled and >0.75 shows not well controlled. Concurrent conditions/medical history: Liver function test at Visit1 ALT <2 x upper limit of normal (ULN) ALP less than or equal to 1.5 x ULN Bilirubin less than or equal to 1.5 x ULN (isolated bilirubin >1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%) Exclusion Criteria end of the run-in period (Visit 2) Respiratory Infection: 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. Severe asthma exacerbation: Evidence of a severe exacerbation during screening or the run-in period, defined as deterioration of asthma requiring the use of systemic corticosteroids (tablets, suspension, or injection) for at least 3 days or an in-patient hospitalization or emergency department visit due to asthma that required systemic corticosteroids. Laboratory test abnormalities: Evidence of clinically significant abnormal laboratory tests during screening or the run-in period 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. There is no restriction on diet in this study. Use of tobacco products will not be allowed from screening until after the final follow-up visit. Caffeine and alcohol is allowed ad libitum. There is no restriction on activity in this study.

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FF/UMEC/VI 100/62.5/25 mcg closed triple therapy<br>Subjects will receive FF/UMEC/VI 100/62.5/25 mcg inhalation powder via ELLIPTA, once daily, 1 puff/time, in the morning. Subjects may receive salbutamol as a rescue medication when needed throughout the run-in and treatment period. | Drug: FF/UMEC/VI 100/62.5/25 mcg<br>* Subjects will self-administer the study treatment via the ELLIPTA device. The ELLIPTA holds 2 individual blister strips with 30 blisters on each strip: the first strip contains FF 100 mcg in each blister and the second strip contains UMEC 62.5 mcg and VI 25 mcg in each blister. ELLIPTA is a registered trademark of GSK groups of companies.<br>Drug: Salbutamol<br>* Salbutamol is a rescue medication administered via metered-dose inhaler (MDI) which will be used when needed during the study.<br>Other: ACQ-7<br>* ACQ-7 will be used for the assessment of control status of asthma.<br>|
| Experimental: FF/UMEC/VI 200/62.5/25 mcg closed triple therapy<br>Subjects will receive FF/UMEC/VI 200/62.5/25 mcg inhalation powder via ELLIPTA, once daily, 1 puff/time, in the morning. Subjects may receive salbutamol as a rescue medication when needed throughout the run-in and treatment period. | Drug: FF/UMEC/VI 200/62.5/25 mcg<br>* Subjects will self-administer the study treatment via the ELLIPTA device. The ELLIPTA holds 2 individual blister strips with 30 blisters on each strip: the first strip contains FF 200 mcg in each blister and the second strip contains UMEC 62.5 mcg and VI 25 mcg in each blister. ELLIPTA is a registered trademark of GSK groups of companies.<br>Drug: Salbutamol<br>* Salbutamol is a rescue medication administered via metered-dose inhaler (MDI) which will be used when needed during the study.<br>Other: ACQ-7<br>* ACQ-7 will be used for the assessment of control status of asthma.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Non-serious Adverse Events (Non-SAEs) and Serious Adverse Events (SAEs) | An adverse event (AE) is any untoward medical occurrence in clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. A SAE is defined as any untoward medical occurrence that, at any dose: result in death, life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, congenital anomaly/birth defect, other important medical events that may jeopardize the participant or require medical or surgical intervention to prevent one of the outcome mentioned before. Intent-To-Treat (ITT) Population comprised of all participants who received at least one dose of study treatment in the treatment period. | Up to Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | Blood pressure was measured in seated position after 5 minutes rest for participants at indicated time points. Baseline is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated as relevant visit value minus Baseline value. | Baseline (Day 1), Weeks 4, 12, 24, 36 and 52 | 
| Change From Baseline in Pulse Rate | Pulse rate was measured in seated position after 5 minutes rest for participants at indicated time points. Baseline is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated as relevant visit value minus Baseline value. | Baseline (Day 1), Weeks 4, 12, 24, 36 and 52 | 
| Change From Baseline in PR Interval and QT Interval Corrected for Heart Rate According to Fridericia's Formula (QTcF) | Single 12-lead electrocardiograms (ECG) were obtained using an automated ECG machine that measured PR Interval and QTcF Interval. Baseline is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated as relevant visit value minus Baseline value. | Baseline (Day 1), Weeks 4, 24 and 52 | 
| Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Hemoglobin | Blood samples were collected to analyze the hematology parameter: erythrocytes mean corpuscular hemoglobin. Baseline is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated as relevant visit value minus Baseline value. | Baseline (Day 1), Weeks 12, 24 and 52 | 
| Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Volume | Blood samples were collected to analyze the hematology parameter: erythrocytes mean corpuscular volume. Baseline is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated as relevant visit value minus Baseline value. | Baseline (Day 1), Weeks 12, 24 and 52 | 
| Change From Baseline in Hematology Parameter: Erythrocytes | Blood samples were collected to analyze the hematology parameter: erythrocytes. Baseline is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated as relevant visit value minus Baseline value. | Baseline (Day 1), Weeks 12, 24 and 52 | 
| Change From Baseline in Hematology Parameter: Hematocrit | Blood samples were collected to analyze the hematology parameter: hematocrit. Baseline is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated as relevant visit value minus Baseline value. | Baseline (Day 1), Weeks 12, 24 and 52 | 
| Change From Baseline in Hematology Parameter: Hemoglobin | Blood samples were collected to analyze the hematology parameter: hemoglobin. Baseline is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated as relevant visit value minus Baseline value. | Baseline (Day 1), Weeks 12, 24 and 52 | 
| Change From Baseline in Hematology Parameter: Platelet Count | Blood samples were collected to analyze the hematology parameter: platelet count. Baseline is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated as relevant visit value minus Baseline value. | Baseline (Day 1), Weeks 12, 24 and 52 | 
| Change From Baseline in Hematology Parameter: Basophils/Leukocytes | Blood samples were collected to analyze the hematology parameter: Basophils/Leukocytes. Baseline is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated as relevant visit value minus Baseline value. | Baseline (Day 1), Weeks 12, 24 and 52 | 
| Change From Baseline in Hematology Parameter: Eosinophils/Leukocytes | Blood samples were collected to analyze the hematology parameter: Eosinophils/Leukocytes. Baseline is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated as relevant visit value minus Baseline value. | Baseline (Day 1), Weeks 12, 24 and 52 | 
| Change From Baseline in Hematology Parameter: Lymphocytes/Leukocytes | Blood samples were collected to analyze the hematology parameter: Lymphocytes/Leukocytes. Baseline is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated as relevant visit value minus Baseline value. | Baseline (Day 1), Weeks 12, 24 and 52 | 
| Change From Baseline in Hematology Parameter: Monocytes/Leukocytes | Blood samples were collected to analyze the hematology parameter: Monocytes/Leukocytes. Baseline is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated as relevant visit value minus Baseline value. | Baseline (Day 1), Weeks 12, 24 and 52 | 
| Change From Baseline in Hematology Parameter: Neutrophils/Leukocytes | Blood samples were collected to analyze the hematology parameter: Neutrophils/Leukocytes. Baseline is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated as relevant visit value minus Baseline value. | Baseline (Day 1), Weeks 12, 24 and 52 | 
| Change From Baseline in Chemistry Parameters: Alanine Aminotransferase, Alkaline Phosphatase, Aspartate Aminotransferase | Blood samples were collected to analyze the chemistry parameters: alanine aminotransferase, alkaline phosphatase and aspartate aminotransferase. Baseline is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated as relevant visit value minus Baseline value. | Baseline (Day 1), Weeks 12, 24 and 52 | 
| Change From Baseline in Chemistry Parameters: Albumin, Protein | Blood samples were collected to analyze the chemistry parameters: albumin and protein. Baseline is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated as relevant visit value minus Baseline value. | Baseline (Day 1), Weeks 12, 24 and 52 | 
| Change From Baseline in Chemistry Parameters: Bilirubin, Creatinine, Direct Bilirubin | Blood samples were collected to analyze the chemistry parameters: bilirubin, creatinine and direct bilirubin. Baseline is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated as relevant visit value minus Baseline value. | Baseline (Day 1), Weeks 12, 24 and 52 | 
| Change From Baseline in Chemistry Parameters: Calcium, Glucose, Potassium, Sodium, Urea | Blood samples were collected to analyze the chemistry parameters: calcium, glucose, potassium, sodium and urea. Baseline is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated as relevant visit value minus Baseline value. | Baseline (Day 1), Weeks 12, 24 and 52 | 
| Number of Participants With Worst Case Post-Baseline Urinalysis Results Relative to Baseline | Urine samples were collected for analysis of presence of occult blood and protein in urine using dipstick method. The dipstick test gives results in a semi-quantitative manner, and results for urinalysis parameter of occult blood and protein can be read as Trace, 1+, 2+ and 3+ indicating proportional concentrations in the urine sample. Baseline is the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. | Baseline (Day 1) and up to Week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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asthma, fluticasone furoate, fixed dose combination, Japanese subjects, vilanterol, umeclidinium bromide, closed triple therapy