Efficacy and Safety Study of GSK3772847 in Subjects With Moderately Severe Asthma
Condition: Asthma
MeSH terms: Asthma
Intervention: GSK3772847; Placebo; Fluticasone propionate/salmeterol; Fluticasone propionate
Intervention description: GSK3772847 10 mg/kg will be administered as IV infusion once every 4 weeks to randomized subjects.; Placebo sterile normal saline will be administered as IV infusion once every 4 weeks to randomized subjects.; FP/Sal 500/50 mcg will be administered via inhalation route twice daily to all subjects.; FP 500, 250, 100 or 50 mcg will be administered via inhalation route twice daily to all subjects.
Intervention MeSH terms: Fluticasone; Xhance; Salmeterol Xinafoate
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: This will be a parallel intervention model in which GSK3772847 and placebo will be administered in parallel manner to randomized subjects.
Masking: Double (Participant, Investigator)
Masking description: This is a double blind study and subjects and investigator will be masked.
Enrollment: 165.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Severe asthma; Safety; GSK3772847; Efficacy

Summary:

      GSK3772847, an anti-interleukin (IL)33 receptor monoclonal antibody, is a novel treatment for
      asthma. This is a phase 2a study which aims to evaluate efficacy, safety, tolerability,
      pharmacokinetic (PK) and pharmacodynamic (PD) profiles of GSK3772847 in subjects with
      moderately severe asthma. The study will be conducted in 4 phases including screening, run-in
      phase, treatment phase and follow-up. In treatment phase, eligible subjects will be
      randomized to receive either GSK3772847 or placebo administered via intravenous (IV) route
      every 4 weeks in addition to open-label background therapy of fluticasone propionate/
      salmeterol (FP/Sal) 500/50 micrograms (mcg) twice daily. During the treatment phase, the
      background therapy will be switched to FP 500 mcg for 2 weeks and the dose of FP will be
      reduced by approximately 50 percent at every 2 weeks until complete FP discontinuation. The
      total duration of study will be approximately 33 weeks and approximately 165 subjects with
      moderately severe asthma who are maintained on high-dose of inhaled corticosteroids/
      Long-Acting Beta-2-Agonists (ICS/LABA) will be randomized.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Age: At least 18 years of age at the time of signing the informed consent.

          -  Males and females: 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 highly effective
             contraceptive methods from 4 weeks prior to the first dose of study medication and
             until at least 16 weeks after the last dose of study medication and completion of the
             follow-up visit.

          -  Capable of giving signed informed consent which includes compliance with the
             requirements and restrictions listed in the consent form and in this protocol.

          -  A subject with a documented diagnosis of moderate severe asthma based on Global
             Initiative for Asthma (GINA) 2016 Guidelines, whose asthma has been managed with
             regular treatment of high dose ICS defined as FP 500 mcg twice daily (i.e. 1000 mcg
             total daily dose) or equivalent, and LABA for at least 4 months. Additional therapy
             with a leukotriene receptor antagonist (LTRA) is permissible.

          -  Airway reversibility of at least 12 percent and 200 milliliter (mL) in FEV1 at
             Screening (Visit 1), or documented reversibility prior to Screening (Visit 1), or
             documented history of bronchial hyper reactivity (e.g. fall in FEV1 from baseline of
             more than or equal to 20percent with standard doses of methacholine or histamine, or
             more than or equal to 15 percent with standardized hyperventilation, hypertonic saline
             or mannitol challenge) from a bronchoprovocation study [e.g. methacholine challenge
             prior to Screening (Visit 1)].

          -  ACQ-5 score more than or equal to 1.0 and less than 4.0 at Screening (Visit 1).

          -  Had at least one asthma exacerbation within 12 months prior to screening that required
             treatment with systemic corticosteroid and/or hospitalization.

          -  All subjects must be able to replace their current Short-Acting Beta2-Agonists (SABA)
             treatment with albuterol/salbutamol aerosol inhaler at Visit 1 for use as needed, per
             product label, for the duration of the study.

        Randomization inclusion criteria:

          -  ACQ-5 score more than or equal to 1.0 and less than 4.0 at Visit 2.

          -  Compliance with completion of the Daily eDiary reporting defined as completion of all
             questions/assessments on more than or equal to 4 of the last 7 days during the run-in
             period.

        Exclusion Criteria:

          -  Current smokers or former smokers with a smoking history more than or equal to 10 pack
             years.

          -  Presence of a known pre-existing, clinically important respiratory conditions (e.g.
             pneumonia, pneumothorax, atelectasis segmental or larger, pulmonary fibrotic disease,
             bronchopulmonary dysplasia, chronic bronchitis, emphysema, chronic obstructive
             pulmonary disease, or other respiratory abnormalities) other than asthma.

          -  A pre-bronchodilator FEV1 less than 50 percent predicted of normal value at Screening
             (Visit 1).

          -  Subjects with a diagnosis of malignancy or in the process of investigation for a
             malignancy. Subjects with carcinoma that have 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.

          -  Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test
             result at Screening (Visit 1) or within 3 months prior to first dose of study
             treatment.

          -  Site investigators will be provided with ECG over-read conducted by a centralized
             independent cardiologist, to assist in evaluation of subject eligibility.

          -  Weight: less than 50 kilograms (kg) and more than 150 kg.

          -  Regular use of systemic corticosteroids for conditions including asthma within 3
             months prior to Screening (Visit 1).

          -  Subjects with high parasympathetic tone (e.g. trained athletes with baseline
             bradycardia) or chronic conditions associated with parasympathetic surges (e.g.
             migraines).

          -  Other conditions that could lead to elevated eosinophils such as hypereosinophilic
             syndromes. Subjects with a known, pre-existing parasitic infestation within 6 months
             prior to Screening (Visit 1).

          -  Clinically significant organic heart disease [e.g. Coronary artery disease (CAD), New
             York Heart Association (NYHA) Class III/IV heart failure].

          -  Ongoing infections (i.e. not resolved within 7 days prior to Screening [Visit 1]) or
             recurrent infections (i.e. requiring treatment for an identical diagnosis within 3
             months) requiring systemic antibiotics Known, pre-existing parasitic infestations
             within 6 months prior to Screening.

          -  A subject must not have any clinically significant, uncontrolled condition, or disease
             state that, in the opinion of the investigator, would put the safety of the subject at
             risk through study participation or would confound the interpretation of the efficacy
             results if the condition/disease exacerbated during the study.

          -  A known immunodeficiency such as human immunodeficiency virus infection.

          -  Subjects with allergy or intolerance to a monoclonal antibody or biologic or to any
             components of the formulation used in this study.

          -  Subjects with a history (or suspected history) of alcohol misuse or substance abuse
             within 2 years prior to Screening (Visit 1).

          -  Subjects who are unable to follow study instructions such as visit schedule, dosing
             directions, study eDiary completion, or use of a standard metered dose inhaler.
             Subjects who have known evidence of lack of adherence to controller medication and/or
             ability to follow physician's recommendations. Any infirmity, disability, or
             geographic location that would limit compliance for scheduled visits.

          -  Subjects who have previously participated in a study of GSK3772847.

          -  Use of the prohibited medications is not permitted within the defined time intervals
             prior to Screening (Visit 1) and throughout the study. Potential subjects should not
             be washed out of their medication solely for the purpose on enrolling in the trial.

          -  A subject will not be eligible for this study if he/she is an immediate family member
             of the participating investigator, sub investigator, study coordinator, or employee of
             the participating investigator.

          -  In the opinion of the investigator, any subject who is unable to read and/or would not
             be able to complete a diary card/questionnaire.

          -  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.

        Randomization exclusion criteria:

          -  Evidence of clinically significant abnormal laboratory tests during screening 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.

          -  Evidence of clinically significant abnormal ECG findings at Visit 2.

          -  An abnormal and significant finding from 24-hour Holter monitoring at Screening (Visit
             1). Investigators will be provided with Holter reviews conducted by an independent
             cardiologist to assist in evaluation of subject eligibility.

          -  Liver function at screening (Visit 1): ALT more than 2 x upper limit of normal (ULN)
             and bilirubin more than 1.5xULN (isolated bilirubin more than 1.5xULN is acceptable if
             bilirubin is fractionated and direct bilirubin less than 35 percent); Current or
             chronic history of liver disease, or known hepatic or biliary abnormalities (with the
             exception of Gilbert's syndrome or asymptomatic gallstones).

          -  Subjects with ongoing asthma exacerbation at the time of Visit 2.

          -  A pre-bronchodilator FEV1 less than 50 percent predicted of normal value at Visit 2.

          -  Positive pregnancy test at Visit 0, Screening (Visit 1) or Visit 2.

          -  Ongoing or recurrent infections requiring systemic antibiotics.