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A Phase III Parallel Group Study, Comparing the Efficacy, Safety and Tolerability of the Fixed Dose Combination (FDC) of Fluticasone Furoate+Umeclidinium Bromide+Vilanterol (FF/UMEC/VI) With the FDC of FF/VI in Subjects With Inadequately Controlled Asthma

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ClinicalTrials.gov Identifier: NCT02924688
Recruitment Status : Completed
First Posted : October 5, 2016
Last Update Posted : March 20, 2019
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Tracking Information
First Submitted Date  ICMJE September 12, 2016
First Posted Date  ICMJE October 5, 2016
Last Update Posted Date March 20, 2019
Actual Study Start Date  ICMJE October 13, 2016
Actual Primary Completion Date February 22, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 3, 2016)
Mean change from baseline in trough Forced Expiratory Volume in 1 second (FEV1) at Week 24 [ Time Frame: Baseline and 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. Trough FEV1 on treatment is defined as the highest FEV1 value obtained prior to the morning dose of investigational product. Rescue medication should be withheld for at least 6 hours prior to measuring trough FEV1.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02924688 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: October 27, 2017)
  • Number of on treatment moderate and/or severe asthma exacerbations [ Time Frame: Up to Week 52 ]
    Annual rate of on-treatment moderate and severe exacerbations will be compared between FF/UMEC/VI with FF/VI. Moderate exacerbation is defined as deterioration in asthma symptoms, deterioration in lung function, or increased rescue bronchodilator use lasting for at least 2 days or more and requiring a change in asthma treatment. Severe exacerbation will be defined as deterioration of asthma requiring the use of systemic corticosteroids for at least 3 days or an inpatient hospitalization or emergency department visit due to asthma that required systemic corticosteroids.
  • Mean change from baseline in clinic FEV1 at 3 hours post study treatment at Week 24 [ Time Frame: Baseline and Week 24 ]
    Post-dose FEV1 is defined as the highest FEV1 value obtained 3 hours (+/- 15 minutes) after the morning dose of investigational product. Rescue medication should be withheld for at least 6 hours prior to the pre-dose spirometry assessments until after completion of the 3 hour post-dose spirometry assessments.
  • Mean change from baseline in Asthma Control Questionnaire-7 (ACQ-7) total score at Week 24 [ Time Frame: Baseline and Week 24 ]
    The 7-item ACQ is a participant-reported questionnaire assessing asthma symptoms (night-time waking, symptoms on waking, activity limitation, shortness of breath, wheezing) and daily rescue bronchodilator use. Participants will be asked to recall how their asthma had been during the previous week. Questions will be weighted equally and scored from 0 (totally controlled) to 6 (severely uncontrolled). The mean ACQ score is the mean of the responses. Mean scores of =<0.75 indicate well-controlled asthma, scores between 0.76 and <1.5 indicate partly controlled asthma, and a score >=1.5 indicates uncontrolled asthma. Individual changes of at least 0.5 are considered to be clinically meaningful.
  • Mean change from baseline in St. George's Respiratory Questionnaire (SGRQ) total score at Week 24 [ Time Frame: Baseline and Week 24 ]
    The SGRQ is designed to measure Quality of Life in patients with diseases of airway obstruction, measuring symptoms, impact, and activity over the past 3 months. Higher scores indicate worse health status, and a change of 4 points is considered a clinically relevant change.
  • Mean change from baseline in Evaluating Respiratory Symptoms (E-RS) total score over Weeks 21 to 24 (inclusive) of the treatment period [ Time Frame: Baseline and Week 24 ]
    The Evaluating Respiratory Symptoms (E-RS) instrument consists of 11 items from the14 item Exacerbations of COPD patient reported outcome instrument (EXACT-PRO). The E-RS is intended to capture information related to respiratory symptoms (i.e. breathlessness, cough, sputum production, chest congestion and chest tightness). The instrument is to be completed daily each night prior to going to bed; the daily recording of information allows an assessment of the underlying day-to-day variability of a patient's symptoms. The E-RS has a scoring range of 0-40 and the responder threshold is a ≥ 2 points improvement from baseline in the total score.
  • Incidence and type of adverse events (AE) and serious adverse event (SAE) [ Time Frame: Up to Week 52 ]
    An AE is any untoward medical occurrence in a subject, 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 or any other situation according to medical or scientific judgment will be categorized as an SAE.
  • Electrocardiogram (ECG) measurements as a measure of safety [ Time Frame: Up to Week 52 ]
    A single 12-lead ECG will be measured in a supine position having rested in this position for approximately 5 minutes before each reading.
  • Systolic and diastolic blood pressure assessment as a measure of safety [ Time Frame: Up to Week 52 ]
    Blood pressure will be measured in the sitting position after 5 minutes rest.
  • Pulse rate assessment as a measure of safety [ Time Frame: Up to Week 52 ]
    Pulse rate will be measured in the sitting position after 5 minutes rest.
  • Number of participants with abnormal clinical chemistry parameters [ Time Frame: Up to Week 52 ]
    Blood samples will be collected to analyze albumin, alkaline phosphatase, alanine aminotransferase (SGPT), aspartate amino-transferase (SGOT), direct bilirubin, total bilirubin, calcium, creatinine, glucose, potassium, total protein, sodium, blood urea nitrogen, and total serum immunoglobulin E (IgE).
  • Number of participants with abnormal hematological parameters [ Time Frame: Up to Week 52 ]
    Blood samples will be collected to analyze hemoglobin, hematocrit, platelet count, white blood cells (WBC) count, neutrophils, basophils, eosinophils, lymphocytes, monocytes, red blood cells (RBC) count, mean corpuscular volume (MCV), and mean corpuscular hemoglobin (MCH).
Original Secondary Outcome Measures  ICMJE
 (submitted: October 3, 2016)
  • Number of on treatment moderate and/or severe asthma exacerbations [ Time Frame: Up to Week 52 ]
    Annual rate of on-treatment moderate and severe exacerbations will be compared between FF/UMEC/VI with FF/VI. Moderate exacerbation is defined as deterioration in asthma symptoms, deterioration in lung function, or increased rescue bronchodilator use lasting for at least 2 days or more and requiring a change in asthma treatment. Severe exacerbation will be defined as deterioration of asthma requiring the use of systemic corticosteroids for at least 3 days or an inpatient hospitalization or emergency department visit due to asthma that required systemic corticosteroids.
  • Mean change from baseline in clinic FEV1 at 3 hours post study treatment at Week 24 [ Time Frame: Baseline and Week 24 ]
    Post-dose FEV1 is defined as the highest FEV1 value obtained 3 hours (+/- 15 minutes) after the morning dose of investigational product. Rescue medication should be withheld for at least 6 hours prior to the pre-dose spirometry assessments until after completion of the 3 hour post-dose spirometry assessments.
  • Mean change from baseline in Asthma Control Questionnaire-7 (ACQ-7) total score at Week 24 [ Time Frame: Baseline and Week 24 ]
    The 7-item ACQ is a participant-reported questionnaire assessing asthma symptoms (night-time waking, symptoms on waking, activity limitation, shortness of breath, wheezing) and daily rescue bronchodilator use. Participants will be asked to recall how their asthma had been during the previous week. Questions will be weighted equally and scored from 0 (totally controlled) to 6 (severely uncontrolled). The mean ACQ score is the mean of the responses. Mean scores of =<0.75 indicate well-controlled asthma, scores between 0.76 and <1.5 indicate partly controlled asthma, and a score >=1.5 indicates uncontrolled asthma. Individual changes of at least 0.5 are considered to be clinically meaningful.
  • Mean change from baseline in St. George's Respiratory Questionnaire (SGRQ) total score at Week 24 [ Time Frame: Baseline and Week 24 ]
    The SGRQ is designed to measure Quality of Life in patients with diseases of airway obstruction, measuring symptoms, impact, and activity over the past 3 months. Higher scores indicate worse health status, and a change of 4 points is considered a clinically relevant change.
  • Mean change from baseline in Evaluating Respiratory Symptoms (E-RS) total score over the first 24 weeks of the treatment period [ Time Frame: Baseline and Week 24 ]
    The Evaluating Respiratory Symptoms (E-RS) instrument consists of 11 items from the14 item Exacerbations of COPD patient reported outcome instrument (EXACT-PRO). The E-RS is intended to capture information related to respiratory symptoms (i.e. breathlessness, cough, sputum production, chest congestion and chest tightness). The instrument is to be completed daily each night prior to going to bed; the daily recording of information allows an assessment of the underlying day-to-day variability of a patient's symptoms. The E-RS has a scoring range of 0-40 and the responder threshold is a ≥ 2 points improvement from baseline in the total score.
  • Incidence and type of adverse events (AE) and serious adverse event (SAE) [ Time Frame: Up to Week 52 ]
    An AE is any untoward medical occurrence in a subject, 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 or any other situation according to medical or scientific judgment will be categorized as an SAE.
  • Electrocardiogram (ECG) measurements as a measure of safety [ Time Frame: Up to Week 52 ]
    A single 12-lead ECG will be measured in a supine position having rested in this position for approximately 5 minutes before each reading.
  • Systolic and diastolic blood pressure assessment as a measure of safety [ Time Frame: Up to Week 52 ]
    Blood pressure will be measured in the sitting position after 5 minutes rest.
  • Pulse rate assessment as a measure of safety [ Time Frame: Up to Week 52 ]
    Pulse rate will be measured in the sitting position after 5 minutes rest.
  • Number of participants with abnormal clinical chemistry parameters [ Time Frame: Up to Week 52 ]
    Blood samples will be collected to analyze albumin, alkaline phosphatase, alanine aminotransferase (SGPT), aspartate amino-transferase (SGOT), direct bilirubin, total bilirubin, calcium, creatinine, glucose, potassium, total protein, sodium, blood urea nitrogen, and total serum immunoglobulin E (IgE).
  • Number of participants with abnormal hematological parameters [ Time Frame: Up to Week 52 ]
    Blood samples will be collected to analyze hemoglobin, hematocrit, platelet count, white blood cells (WBC) count, neutrophils, basophils, eosinophils, lymphocytes, monocytes, red blood cells (RBC) count, mean corpuscular volume (MCV), and mean corpuscular hemoglobin (MCH).
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Phase III Parallel Group Study, Comparing the Efficacy, Safety and Tolerability of the Fixed Dose Combination (FDC) of Fluticasone Furoate+Umeclidinium Bromide+Vilanterol (FF/UMEC/VI) With the FDC of FF/VI in Subjects With Inadequately Controlled Asthma
Official Title  ICMJE A Phase III, Randomized, Double-blind, Active Controlled, Parallel Group Study, Comparing the Efficacy, Safety and Tolerability of the Fixed Dose Combination FF/UMEC/VI With the Fixed Dose Dual Combination of FF/VI, Administered Once-daily Via a Dry Powder Inhaler in Subjects With Inadequately Controlled Asthma
Brief Summary A once-daily 'closed' triple FDC therapy of FF/UMEC/VI via a single ELLIPTA® dry powder inhaler (DPI) is being developed by GlaxoSmithKline (GSK) 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 is a phase III, multi-center, active-controlled, double-blind, parallel-group study to compare the efficacy, safety and tolerability of the FDC of FF/UMEC/VI with the FDC of FF/VI. This study has 5 phases: Pre-Screening (Visit 0), Screening/Run-in, Enrolment/Stabilization, Randomization/Treatment, and Follow up. At Visit 1 (Screening), subjects meeting all protocol defined inclusion/exclusion criteria will enter a 3-week run-in period and will receive fixed dose inhaled corticosteroid/long-acting beta agonist (ICS/LABA) (fluticasone/salmeterol, 250/50 micrograms (mcg), via the DISKUS® DPI) one inhalation twice a day. At Visit 2 (Enrolment), eligible subjects will be enrolled into the 2-week stabilization period to receive FF/VI (100/25 mcg via the ELLIPTA DPI once a day, in the morning). At the conclusion of the stabilization period (Visit 3), all subjects who meet the pre-defined randomization criteria will be randomized 1:1:1:1:1:1 during the treatment period to receive either FF/UMEC/VI (100/62.5/25 mcg; 200/62.5/25 mcg; 100/31.25/25 mcg; 200/31.25/25 mcg) or FF/VI (100/25 mcg; 200/25 mcg) via the ELLIPTA DPI once daily in the morning. The duration of the treatment period is variable but will be a minimum of 24 weeks and a maximum of 52 weeks. Subjects will have up to 6 on-treatment clinic visits scheduled at Visits 3, 4, 5, 6, 7 and 8/End of Study (EOS) (Weeks 0, 4, 12, 24, 36 and 52, respectively). A follow-up visit will be conducted approximately 7 days after the end of treatment period or, if applicable, after the early withdrawal visit. Subjects will be provided with short acting albuterol/salbutamol to be used on an as-needed basis (rescue medication) throughout the study. Approximately 2250 subjects will be randomized, with approximately 375 subjects randomized to each of the 6 double-blind treatment arms to ensure approximately 337 evaluable subjects per treatment arm. DISKUS and ELLIPTA are registered trademarks of GSK groups of companies.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Asthma
Intervention  ICMJE
  • Drug: FF/UMEC/VI (100/31.25/25) mcg
    Dry white powder delivered via the ELLIPTA DPI (one inhalation once-daily [QD] in the morning). The ELLIPTA DPI 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 31.25 mcg and VI 25 mcg in each blister.
  • Drug: FF/UMEC/VI (100/62.5/25) mcg
    Dry white powder delivered via the ELLIPTA DPI (one inhalation, QD in the morning). The ELLIPTA DPI 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.
  • Drug: FF/UMEC/VI (200/31.25/25) mcg
    Dry white powder delivered via the ELLIPTA DPI (one inhalation, QD in the morning). The ELLIPTA DPI 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 31.25 mcg and VI 25 mcg in each blister.
  • Drug: FF/UMEC/VI (200/62.5/25) mcg
    Dry white powder delivered via the ELLIPTA DPI (one inhalation, QD in the morning). The ELLIPTA DPI 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.
  • Drug: FF/VI (100/25) mcg
    Dry white powder delivered via the ELLIPTA DPI (one inhalation, QD in the morning). The ELLIPTA DPI 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 VI 25 mcg in each blister.
  • Drug: FF/VI (200/25) mcg
    Dry white powder delivered via the ELLIPTA DPI (one inhalation, QD in the morning). The ELLIPTA DPI 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 VI 25 mcg in each blister.
  • Drug: Fluticasone/salmeterol (FSC)
    Dry white powder delivered via the DISKUS DPI (one inhalation twice daily: one in the morning and one in the evening). The DISKUS DPI holds a strip of 60 blisters; each blister contains FP 250 mcg and 50 mcg of salmeterol.
  • Drug: Albuterol/salbutamol
    This is a rescue medication administered via metered-dose inhaler (MDI) which will be used when needed during the study.
  • Device: ELLIPTA DPI
    The ELLIPTA device will be used during the stabilization period and the treatment period. The ELLIPTA DPI is a moulded plastic two-sided device that can hold two individual blister strips which contain powder formulation for oral inhalation.
  • Device: DISKUS DPI
    The DISKUS device will be used during the run-in period. The DISKUS DPI is a plastic inhalation delivery system containing a single-foil blister strip of a powder formulation of FSC for oral inhalation.
  • Device: METERED-DOSE INHALER (MDI)
    Albuterol/salbutamol (rescue medication) will be delivered via metered-dose inhaler (MDI) will be used for reversibility testing.
Study Arms  ICMJE
  • Experimental: FF/UMEC/VI (100/31.25/25) mcg closed triple therapy
    Subjects will receive FF/UMEC/VI (100/31.25/25) mcg inhalation powder via DPI, once daily in the morning. Subjects may receive albuterol/salbutamol as a rescue medication when needed during the treatment period.
    Interventions:
    • Drug: FF/UMEC/VI (100/31.25/25) mcg
    • Drug: FF/VI (100/25) mcg
    • Drug: Fluticasone/salmeterol (FSC)
    • Drug: Albuterol/salbutamol
    • Device: ELLIPTA DPI
    • Device: DISKUS DPI
    • Device: METERED-DOSE INHALER (MDI)
  • Experimental: FF/UMEC/VI (100/62.5/25) mcg closed triple therapy
    Subjects will receive FF/UMEC/VI (100/62.5/25) mcg inhalation powder via DPI, once daily in the morning. Subjects will also receive albuterol/salbutamol as a rescue medication when needed during the treatment period.
    Interventions:
    • Drug: FF/UMEC/VI (100/62.5/25) mcg
    • Drug: FF/VI (100/25) mcg
    • Drug: Fluticasone/salmeterol (FSC)
    • Drug: Albuterol/salbutamol
    • Device: ELLIPTA DPI
    • Device: DISKUS DPI
    • Device: METERED-DOSE INHALER (MDI)
  • Experimental: FF/UMEC/VI (200/31.25/25) mcg closed triple therapy
    Subjects will receive FF/UMEC/VI (200/31.25/25) mcg inhalation powder via DPI, once daily in the morning. Subjects may receive albuterol/salbutamol as a rescue medication when needed during the treatment period.
    Interventions:
    • Drug: FF/UMEC/VI (200/31.25/25) mcg
    • Drug: FF/VI (100/25) mcg
    • Drug: Fluticasone/salmeterol (FSC)
    • Drug: Albuterol/salbutamol
    • Device: ELLIPTA DPI
    • Device: DISKUS DPI
    • Device: METERED-DOSE INHALER (MDI)
  • Experimental: FF/UMEC/VI (200/62.5/25) mcg closed triple therapy
    Subjects may receive FF/UMEC/VI (200/62.5/25) mcg inhalation powder via DPI, once daily in the morning. Subjects may receive albuterol/salbutamol as a rescue medication when needed during the treatment period.
    Interventions:
    • Drug: FF/UMEC/VI (200/62.5/25) mcg
    • Drug: FF/VI (100/25) mcg
    • Drug: Fluticasone/salmeterol (FSC)
    • Drug: Albuterol/salbutamol
    • Device: ELLIPTA DPI
    • Device: DISKUS DPI
    • Device: METERED-DOSE INHALER (MDI)
  • Active Comparator: FF/VI (100/25) mcg dual combination therapy
    Subjects will receive FF/VI (100/25) mcg inhalation powder via DPI, once daily in the morning. Subjects may receive albuterol/salbutamol as a rescue medication when needed during the treatment period.
    Interventions:
    • Drug: FF/VI (100/25) mcg
    • Drug: Fluticasone/salmeterol (FSC)
    • Drug: Albuterol/salbutamol
    • Device: ELLIPTA DPI
    • Device: DISKUS DPI
    • Device: METERED-DOSE INHALER (MDI)
  • Active Comparator: FF/VI (200/25) mcg dual combination therapy
    Subjects will receive FF/VI (200/25) mcg inhalation powder via DPI, once daily in the morning. Subjects may receive albuterol/salbutamol as a rescue medication when needed during the treatment period.
    Interventions:
    • Drug: FF/VI (100/25) mcg
    • Drug: FF/VI (200/25) mcg
    • Drug: Fluticasone/salmeterol (FSC)
    • Drug: Albuterol/salbutamol
    • Device: ELLIPTA DPI
    • Device: DISKUS DPI
    • Device: METERED-DOSE INHALER (MDI)
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 18, 2019)
2544
Original Estimated Enrollment  ICMJE
 (submitted: October 3, 2016)
2250
Actual Study Completion Date  ICMJE February 22, 2019
Actual Primary Completion Date February 22, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria for Screening

  • Age: 18 years of age or older at the time of signing the informed consent.
  • Diagnosis: Subjects with a diagnosis of asthma as defined by the National Institutes of Health at least one year prior to Visit 0.
  • Symptomatic: Subjects with inadequately controlled asthma (ACQ-6 score >=1.5) despite ICS/LABA maintenance therapy at Visit 1.
  • Asthma Control: In the 1 year prior to Visit 1

    • A documented healthcare contact for acute asthma symptoms or
    • A documented temporary change in asthma therapy for acute asthma symptoms, according to a pre-specified asthma action plan (or equivalent)
  • Current Asthma Maintenance Therapy: Subjects are eligible if they have required daily ICS/LABA for at least 12 weeks prior to Visit 0 with no changes to maintenance asthma medications during the 6 weeks immediately prior to Visit 0 (including no changes to a stable total dose of ICS of >250 mcg/day fluticasone proprionate [FP, or equivalent]).
  • Spirometry: A best pre-bronchodilator morning (ante meridian [AM]) FEV1 >=30% and <85% of the predicted normal value at Visit 1. Predicted values will be based upon the European Respiratory Society (ERS) Global Lung Function Initiative.
  • Reversibility of Disease: airway reversibility defined as >=12% and >=200 milliliter (mL) increase in FEV1 between 20 and 60 minutes following 4 inhalations of albuterol/salbutamol aerosol at Visit 1.
  • 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 a) or b) are met: a) >=9% increase in FEV1 between 20 and 60 minutes following 4 inhalations of albuterol/salbutamol aerosol at Visit 1. b) 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 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 3-week run-in period.

  • Short-Acting beta2 Agonists (SABAs): All subjects must be able to replace their current 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.
  • Male or eligible Female, defined as having documentation of non-reproductive potential or reproductive potential as follows:

A female subject is eligible to participate if she is not pregnant (as confirmed by a negative serum human chorionic gonadotrophin (hCG) test), not lactating, is not planning on becoming pregnant during the study and at least one of the following conditions applies: Non-reproductive potential defined as pre-menopausal females with documented tubal ligation or documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion or hysterectomy or documented bilateral oophorectomy; Postmenopausal defined as 12 months of spontaneous amenorrhea with an appropriate clinical profile (e.g., age appropriate, >45 years, in the absence of hormone replacement therapy). In questionable cases for women <60 years of age, a blood sample with simultaneous follicle stimulating hormone and estradiol falling into the central laboratory's postmenopausal reference range is confirmatory. Females under 60 years of age, who are on hormone replacement therapy (HRT) and whose menopausal status is in doubt, are required to use a highly effective method to avoid pregnancy if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment. For most forms of HRT, at least 2 to 4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, subjects can resume use of HRT during the study without use of a highly effective method to avoid pregnancy; Reproductive potential and agrees to follow one of the options listed in the Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP) from the screening visit until after the last dose of study medication and completion of the follow-up visit. The Investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception.

  • Informed Consent: 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.

Exclusion Criteria for Screening

  • 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. Note: Subjects requiring a temporary change in asthma therapy (e.g., oral corticosteroids or increased dose of ICS) to treat an exacerbation in the 6 weeks prior to Visit 1 are not explicitly excluded at Visit 1 provided that, at the Investigator's discretion, the subject's condition is stable after they have resumed their pre-exacerbation maintenance asthma therapy (without modification) and they are considered appropriate for enrolment into this study of up to 12 month's duration.
  • Chronic Obstructive Pulmonary Disease: Subjects with the diagnosis of chronic obstructive pulmonary disease, as per Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, including history of exposure to risk factors (i.e., especially tobacco smoke, occupational dusts and chemicals, smoke from home cooking and heating fuels) and a post-albuterol/salbutamol FEV1/Forced Vital Capacity (FVC) ratio of <0.70 and a post-albuterol/salbutamol FEV1 of =<70% of predicted normal values and onset of disease >=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., human immunodeficiency virus, 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 Electrocardiogram 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 non-sustained 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 milliseconds (msec) in subjects with QRS <120 msec and QTcF >=530 msec in subjects with QRS >=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 albuterol/salbutamol for the 6-hour period required prior to spirometry testing at each study visit.
  • 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]) or former smokers with a smoking history of >=10 pack years (e.g., >=20 cigarettes/day for 10 years).
  • 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, beta2-agonist, lactose/milk protein or magnesium stearate.
  • 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 for Enrolment

  • Inadequately controlled asthma: Subjects with inadequately controlled asthma (ACQ-6 score >=1.5) at Visit 2.
  • Percent-predicted FEV1: A best pre-bronchodilator morning (AM) FEV1 >=30% and <90% of the predicted normal value at Visit 2. Predicted values will be based upon the ERS Global Lung Function Initiative
  • Liver function tests at Visit 1: alanine aminotransferase (ALT) <2 x upper limit of normal (ULN); alkaline phosphatase <=1.5xULN; bilirubin <=1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%)
  • Compliance with completion of the Daily eDiary reporting defined as completion of all questions/assessments on >=4 of the last 7 days during the run-in period.

Exclusion Criteria for Enrolment

  • 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.
  • Asthma medication: Changes in asthma medication (excluding run-in medication and albuterol/salbutamol inhalation aerosol provided at Visit 1).
  • Laboratory test abnormalities: 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.

Inclusion Criteria for Randomization

  • Compliance with completion of the Daily eDiary reporting defined as completion of all questions/assessments on >=4 of the last 7 days during the stabilization period.

Exclusion Criteria for Randomization

  • 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 stabilization 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 enrolment or the stabilization period, defined as deterioration of asthma requiring the use of systemic corticosteroids (tablets, suspension, or injection) for at least 3 days or an inpatient hospitalization or emergency department visit due to asthma that required systemic corticosteroids.
  • Asthma medication: Changes in asthma medication (excluding stabilization period medication provided at Visit 2 and albuterol/salbutamol inhalation aerosol provided at Visit 1).
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Argentina,   Australia,   Canada,   Germany,   Italy,   Japan,   Korea, Republic of,   Netherlands,   Poland,   Romania,   Russian Federation,   South Africa,   Spain,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02924688
Other Study ID Numbers  ICMJE 205715
2016-001304-37 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party GlaxoSmithKline
Study Sponsor  ICMJE GlaxoSmithKline
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: GSK Clinical Trials GlaxoSmithKline
PRS Account GlaxoSmithKline
Verification Date March 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP