A Long-term Safety Study of Fixed Dose Combination Therapy Fluticasone Furoate/Umeclidinium Bromide/Vilanterol Trifenatate in Japanese Subjects With Asthma
Condition: Asthma
MeSH terms: Asthma
Intervention: FF/UMEC/VI 100/62.5/25 mcg; FF/UMEC/VI 200/62.5/25 mcg; Salbutamol; ACQ-7
Intervention description: 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.; 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.; Salbutamol is a rescue medication administered via metered-dose inhaler (MDI) which will be used when needed during the study.; ACQ-7 will be used for the assessment of control status of asthma.
Intervention MeSH terms: Albuterol
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 111.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: fluticasone furoate; fixed dose combination; Japanese subjects; vilanterol; asthma; umeclidinium bromide; closed triple therapy

Summary:

      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.
    

Eligibility criteria:

        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.