Efficacy and Safety Study of GSK3772847 in Subjects With Moderately Severe Asthma

GlaxoSmithKline (GSK)

Status and phase: Completed; Phase 2

Conditions: Asthma

Treatments: Drug: GSK3772847; Drug: Fluticasone propionate/salmeterol; Drug: Fluticasone propionate; Drug: Placebo

Study type: Interventional

Funder types: Industry

Identifiers

NCT03207243

207597

2017-001072-34 (EudraCT Number)

Details and patient eligibility

About

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.

Enrollment: 165 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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165 participants in 2 patient groups, including a placebo group

Subjects receiving GSK3772847

Experimental group

Description:

Eligible subjects will receive GSK3772847 once every 4 weeks via IV route along with 500/50 mcg FP/Sal twice daily for first 2 weeks and dose of FP was reduced by approximately 50 percent at every 2 weeks until complete FP discontinuation.

Treatment:

Drug: Fluticasone propionate/salmeterol

Drug: GSK3772847

Drug: Fluticasone propionate

Subjects receiving placebo drug

Placebo Comparator group

Description:

Eligible subjects will receive placebo once every 4 weeks via IV route along with 500/50 mcg FP/Sal twice daily for first 2 weeks and dose of FP was reduced by approximately 50 percent at every 2 weeks until complete FP discontinuation.

Treatment:

Drug: Fluticasone propionate/salmeterol

Drug: Placebo

Drug: Fluticasone propionate