Phase IIb Study of Umeclidinium (UMEC) Bromide Versus Placebo in Subjects With Asthma
Condition: Asthma
MeSH terms: Asthma
Intervention: Placebo; UMEC; Fluticasone Furoate; Albuterol/salbutamol
Intervention description: Placebo is a white powder to be administered using ELLIPTA DPI which hold two individual blister strips, both of which contains lactose monohydrate blended with magnesium stearate.; UMEC is a white powder to be administered using ELLIPTA DPI which hold two individual blister strips, one of which contains GSK573719 blended with lactose blended with magnesium stearate and another one contains lactose monohydrate blended with magnesium stearate.; FF is a white powder to be administered using ELLIPTA DPI which hold two individual blister strips, one of which contains GW685698 blended with lactose monohydrate and another one contains lactose monohydrate with magnesium stearate.; Albuterol/salbutamol is to be administered via metered-dose inhaler as a rescue drug on need basis throughout the study.
Intervention MeSH terms: Fluticasone; Xhance; Albuterol
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 425.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Respiratory; Efficacy; Umeclidinium bromide; Parallel; Asthma; Dry powder inhaler

Summary:

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

Eligibility criteria:

        Inclusion Criteria:

          -  18 years of age or older at the time of signing the informed consent.

          -  Subjects with a diagnosis of asthma as defined by the National Institutes of Health at
             least 6 months prior to Visit 0.

          -  Asthma Control Questionnaire (ACQ)-6 total score of >0.75 at Visit 1.

          -  Subjects are eligible if they have required daily Inhaled Corticosteroids (ICS)
             therapy >=100 milligram per day (mg/day) fluticasone propionate (FP) or equivalent
             with or without Long-Acting Beta-2-Agonists (LABA) or Long-Acting Muscarinic
             Antagonist (LAMA) for at least 12 weeks prior to Visit 0 and there have been no
             changes in maintenance asthma medications during the 4 weeks immediately prior to
             Visit 0. Dosing regimen (once or twice daily to equal the total daily dose) should be
             restricted to the current local product labels.

          -  A best pre-bronchodilator morning FEV1 <=85% of the predicted normal value. Predicted
             values will be based upon the European Respiratory Society (ERS) Global Lung Function
             Initiative. A best post-bronchodilator FEV1/ forced vital capacity (FVC) >=0.7 at
             Visit 1.

          -  Airway reversibility is defined as >=12% and >=200 mL increase in FEV1 between 20 and
             60 minutes following 4 inhalations of albuterol/salbutamol aerosol at Visit 1. Note:
             If the subject does not meet the above reversibility criteria at Visit 1 then the
             reversibility assessment may be repeated once within 7 days of Visit 1 if either
             criteria are met: The >=9% increase in FEV1 between 20 and 60 minutes following 4
             inhalations of albuterol/salbutamol aerosol at Visit 1; Documented evidence of a
             reversibility assessment within 1 year prior to Visit 1 which demonstrated a
             post-bronchodilator increase in FEV1 of >=12% and >=200 milliliter (mL). Should the
             subject successfully demonstrate airway reversibility (defined as >=12% and >=200 mL
             increase in FEV1 between 20 and 60 minutes following 4 inhalations of
             albuterol/salbutamol aerosol) at the second attempt then, provided that all other
             eligibility criteria assessed at Visit 1 are met, the subject may enter the 2-week
             run-in period.

          -  All subjects must be able to replace their current Short-Acting Beta-2-Agonists (SABA)
             inhaler with albuterol/salbutamol aerosol inhaler at Visit 1 as needed for the
             duration of the study. Subjects must be judged capable of withholding
             albuterol/salbutamol for at least 6 hours prior to study visits.

          -  Both male and female subjects are eligible to participate in the study. A female
             subject is eligible to participate if she is not pregnant, not breastfeeding, and at
             least one of the following conditions applies: Not a woman of childbearing potential
             (WOCBP) or a WOCBP who agrees to follow the contraceptive guidance during the
             treatment period and for at least 5 days after the last dose of study treatment.

          -  Able to give written informed consent prior to participation in the study, which will
             include the ability to comply with the requirements and restrictions listed in the
             consent form and in this protocol. Subjects must be able to read, comprehend, and
             write at a level sufficient to complete study related materials.

        Inclusion Criteria (for randomization)

          -  ACQ-6 total score of >0.75 at Visit 2.

          -  Spirometry: A best pre-bronchodilator morning FEV1 <=85% of the predicted normal value
             at Visit 2. Predicted values will be based upon the ERS Global Lung Function
             Initiative.

          -  Alanine aminotransferase (ALT) <=2 x upper limit of normal (ULN). Alkaline phosphatase
             <=1.5 x ULN. Bilirubin <=1.5 x ULN (isolated bilirubin >1.5 x ULN is acceptable if
             bilirubin is fractionated and direct bilirubin <35%).

          -  Compliance with completion of the Daily electronic diary (eDiary) reporting defined as
             completion of all questions/assessments on >=4 of the last 7 days during the run-in
             period.

        Exclusion Criteria:

          -  Chest X-ray documented pneumonia in the 12 weeks prior to Visit 1.

          -  Any severe asthma exacerbation, defined as deterioration of asthma requiring the use
             of systemic corticosteroids (oral, parenteral or depot) within 12 weeks of Visit 1, or
             an inpatient hospitalization or emergency department visit due to asthma that required
             systemic corticosteroids within 12 weeks of Visit 1.

          -  Current evidence of pneumonia, pneumothorax, atelectasis, pulmonary fibrotic disease,
             bronchopulmonary dysplasia, chronic bronchitis, emphysema, chronic obstructive
             pulmonary disease, lung cancer, or other respiratory abnormalities other than asthma.

          -  Women who are pregnant or lactating or are planning to become pregnant during the
             study.

          -  Immune suppression (e.g., Human Immunodeficiency Virus [HIV], Lupus) or other risk
             factors for pneumonia (e.g., neurological disorders affecting control of the upper
             airway, such as Parkinson's disease, Myasthenia Gravis). Subjects at potentially high
             risk (e.g., very low Body Mass Index [BMI], severely malnourished, or very low FEV1)
             will only be included at the discretion of the Investigator

          -  Subjects with historical or current evidence of clinically significant cardiovascular,
             neurological, psychiatric, renal, hepatic, immunological, gastrointestinal,
             urogenital, nervous system, musculoskeletal, skin, sensory, endocrine (including
             uncontrolled diabetes or thyroid disease) or hematological abnormalities that are
             uncontrolled. Significant is defined as any disease that, in the opinion of the
             Investigator, would put the safety of the subject at risk through participation, or
             which would affect the efficacy or safety analysis if the disease/condition
             exacerbated during the study.

          -  Unstable liver disease as defined by the presence of ascites, encephalopathy,
             coagulopathy, hypoalbuminaemia, esophageal or gastric varices or persistent jaundice,
             cirrhosis, known biliary abnormalities (with the exception of Gilbert's syndrome or
             asymptomatic gallstones). Note: Chronic stable hepatitis B and C is acceptable if the
             subject otherwise meets entry criteria.

          -  Evidence of a clinically significant abnormality in the 12-lead ECG performed during
             screening or run-in. The Principal Investigator will determine the clinical
             significance of each abnormal ECG finding in relation to the subject's medical history
             and exclude subjects who would be at undue risk by participating in the trial. An
             abnormal and clinically significant finding is defined as a 12-lead tracing that is
             interpreted as, but not limited to, any of the following: Atrial fibrillation (AF)
             with rapid ventricular rate >120 beats per minute (BPM); Sustained or nonsustained
             ventricular tachycardia (VT); Second degree heart block Mobitz type II and third
             degree heart block (unless pacemaker or defibrillator had been inserted); QT interval
             corrected for heart rate by Fridericia's formula (QTcF) >=500 millisecond (msec) in
             subjects with QRS <120 msec and QTcF >=530 msec in subjects with QRS >=120 msec.

          -  Subjects with any of the following at Screening (Visit 1) would be excluded:
             Myocardial infarction or unstable angina in the last 6 months; Unstable or life
             threatening cardiac arrhythmia requiring intervention in the last 3 months; New York
             Heart Association (NYHA) Class IV Heart failure.

          -  Subjects with a medical condition such as narrow-angle glaucoma, urinary retention,
             prostatic hypertrophy or bladder neck obstruction should only be included if in the
             opinion of the Investigator the benefit outweighs the risk and that the condition
             would not contraindicate study participation.

          -  Subjects with carcinoma that has not been in complete remission for at least 5 years.
             Subjects who have had carcinoma in situ of the cervix, squamous cell carcinoma and
             basal cell carcinoma of the skin would not be excluded based on the 5 year waiting
             period if the subject has been considered cured by treatment.

          -  Subjects with a history of psychiatric disease, intellectual deficiency, poor
             motivation or other conditions that will limit the validity of informed consent to
             participate in the study.

          -  Subjects who are medically unable to withhold their albuterol/salbutamol for the
             6-hour period required prior to spirometry testing at each study visit.

          -  Current smoker or a smoking history of >=10 pack years (e.g., 20 cigarettes/day for 10
             years). A subject may not have used inhaled tobacco products within the past 12 months
             (i.e., cigarettes, e-cigarettes/vaping, cigars or pipe tobacco).

          -  Subjects with a known or suspected history of alcohol or drug abuse within the last 2
             years. This includes marijuana, which is considered an abused drug.

          -  A history of allergy or hypersensitivity to any corticosteroid,
             anticholinergic/muscarinic receptor antagonist, beta2-agonist, lactose/milk protein or
             magnesium stearate.

          -  Subjects at risk of non-compliance, or unable to comply with the study procedures. Any
             infirmity, disability, or geographic location that would limit compliance for
             scheduled visits.

          -  Study investigators, sub-investigators, study coordinators, employees of a
             participating investigator or study site, or immediate family members of the
             aforementioned that is involved with this study.

          -  In the opinion of the Investigator, any subject who is unable to read and/or would not
             be able to complete study related materials.

        Exclusion Criteria (for randomization)

          -  Occurrence of a culture-documented or suspected bacterial or viral infection of the
             upper or lower respiratory tract, sinus or middle ear during the run-in period that
             led to a change in asthma management or, in the opinion of the Investigator, is
             expected to affect the subject's asthma status or the subject's ability to participate
             in the study.

          -  Evidence of a moderate asthma exacerbation leading to a change in therapy or severe
             exacerbation during screening or the run-in period, defined as deterioration of asthma
             requiring the use of systemic corticosteroids (tablets, suspension, or injection) or
             an in-patient hospitalization or emergency department visit due to asthma that
             required systemic corticosteroids.

          -  Changes in asthma medication (excluding changes after Visit 0 or run-in medication and
             albuterol/salbutamol inhalation aerosol provided at Visit 1).

          -  Evidence of clinically significant abnormal laboratory tests during screening or
             run-in, which are still abnormal upon repeat analysis and are not believed to be due
             to disease(s) present. Each Investigator will use his/her own discretion in
             determining the clinical significance of the abnormality.