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
Condition: Asthma
MeSH terms: Asthma
Intervention: FF/UMEC/VI (100/31.25/25) mcg; FF/UMEC/VI (100/62.5/25) mcg; FF/UMEC/VI (200/31.25/25) mcg; FF/UMEC/VI (200/62.5/25) mcg; FF/VI (100/25) mcg; FF/VI (200/25) mcg; Fluticasone/salmeterol (FSC); Albuterol/salbutamol; ELLIPTA DPI; DISKUS DPI; METERED-DOSE INHALER (MDI)
Intervention description: 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.; 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.; 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.; 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.; 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.; 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.; 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.; This is a rescue medication administered via metered-dose inhaler (MDI) which will be used when needed during the study.; 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.; 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.; Albuterol/salbutamol (rescue medication) will be delivered via metered-dose inhaler (MDI) will be used for reversibility testing.
Intervention MeSH terms: Fluticasone; Albuterol; Salmeterol Xinafoate; Fluticasone-Salmeterol Drug Combination
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Enrollment: 2436.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: umeclidinium bromide; fluticasone furoate; vilanterol; fixed dose combination; lung function; albuterol/salbutamol; asthma; closed triple therapy

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.
    

Eligibility criteria:

        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).