Clinical trial NCT03207243: Efficacy and Safety Study of GSK3772847 in Subjects With Moderately Severe Asthma
Official title: A Randomized, Double-blind, Parallel Group, Multicenter, Stratified Study Evaluating the Efficacy and Safety of Repeat Doses of GSK3772847 Compared With Placebo in Participants With Moderately Severe Asthma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Asthma
Keywords: Severe asthma
Safety
GSK3772847
Efficacy
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2017-07-02
Enrollment: 165
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This will be a parallel intervention model in which GSK3772847 and placebo will be administered in parallel manner to randomized subjects.
Primary purpose: TREATMENT

Brief 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.

Primary outcomes:
measure: Percentage of Participants With Loss of Asthma Control Over Weeks 0-16
timeFrame: Up to Week 16
Secondary outcomes:
measure: Percentage of Participants With >=0.5 Point Asthma Control Questionnaire (ACQ-5) Score Increase From Baseline
timeFrame: Baseline and up to Week 16
measure: Percentage of Participants Who Have Pre-bronchodilator FEV1 Decrease From Baseline >7.5 %
timeFrame: Baseline and up to Week 16
measure: Percentage of Participants With Inability to Titrate Inhaled Corticosteroids (ICS)
timeFrame: Up to Week 16
measure: Percentage of Participants With Clinically Significant Asthma Exacerbation
timeFrame: Up to Week 16
measure: Percentage of Participants With Loss of Asthma Control Over Weeks 0-6
timeFrame: Up to Week 6
measure: Time to Loss of Asthma Control
timeFrame: Up to Week 16
measure: Percentage of Participants With Clinically Significant Asthma Exacerbation or Inability to Titrate
timeFrame: Up to Week 16
measure: Number of Participants Experiencing Asthma Related Hospitalization During the Study Period
timeFrame: Up to Week 16
measure: Rate Per 1000 Person-years of Participants With Hospitalization
timeFrame: Up to Week 16
measure: Number of Hospitalizations or Emergency Room Visits Per Participants
timeFrame: Up to Week 16
measure: Change From Baseline in Asthma Control Questionnaire (ACQ-5) Total Score
timeFrame: Baseline and Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and Week 16
measure: Percentage of Participants With <=-0.5 Point ACQ-5 Score Decrease From Baseline (Responder)
timeFrame: Baseline and Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and Week 16
measure: Change From Baseline in St George's Respiratory Questionnaire (SGRQ) Total Score
timeFrame: Baseline and Weeks 4, 8, 12 and 16
measure: Percentage of Participants With at Least a 4 Units Improvement From Baseline of St. George's Respiratory Questionnaire (SGRQ)
timeFrame: Baseline and Weeks 4, 8, 12 and 16
measure: Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in One Second (FEV1)
timeFrame: Baseline and Weeks 2, 4, 6, 8, 10, 12, 14 and 16
measure: Change From Baseline in Mean Morning Peak Expiratory Flow (PEF) and Mean Evening PEF
timeFrame: Baseline and Weeks 1-4; Weeks 5-8, Weeks 9-12 and Weeks 13-16.
measure: Change From Baseline in Mean Daytime Asthma Symptom Score Over Each Four Weeks of the 16 Week Treatment Period
timeFrame: Baseline and Weeks 1-4; Weeks 5-8, Weeks 9-12 and Weeks 13-16
measure: Change From Baseline in Mean Daily Rescue Medication Use (Albuterol/Salbutamol)
timeFrame: Baseline and Weeks 1-4; Weeks 5-8, Weeks 9-12 and Weeks 13-16
measure: Change From Baseline in Percent Night-time Awakenings Due to Asthma Symptoms Requiring Rescue Medication Use
timeFrame: Baseline and Weeks 1-4; Weeks 5-8, Weeks 9-12 and Weeks 13-16
measure: Percent Change From Baseline in Fractional Exhaled Nitric Oxide (FeNO)
timeFrame: Baseline and Weeks 1, 2, 4, 6, 8, 10, 12, 14 and 16
measure: Number of Participants Reporting Serious Adverse Events (SAEs) and Non-Serious Adverse Events (Non-SAEs)
timeFrame: Up to Week 16
measure: Change From Baseline in Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP)
timeFrame: Baseline and Week 0 (Post-dose), Week1, Week 2, Week 4 (Pre and Post dose), Week 6, Week 8 (Pre and Post dose), Week 10, Week 12 (Pre and Post dose), Week 14, Week 16, Week 20, Week 24 and Week 28
measure: Change From Baseline in Pulse Rate (PR)
timeFrame: Baseline and Week 0 (Post-dose), Week1, Week 2, Week 4 (Pre and Post dose), Week 6, Week 8 (Pre and Post dose), Week 10, Week 12 (Pre and Post dose), Week 14, Week 16, Week 20, Week 24 and Week 28
measure: Change From Baseline Between Post-dose and Pre-dose in DBP and SBP
timeFrame: Baseline and Weeks 0, 4, 8 and 12
measure: Change From Baseline Between Post-dose and Pre-dose in Pulse Rate
timeFrame: Baseline and Weeks 0, 4, 8 and 12
measure: Change From Baseline in PR Interval, QRS Duration, Uncorrected QT Interval, QT Corrected Interval-Fredericia [QTcF] Interval and RR Interval
timeFrame: Baseline and Week 0 (Post-dose), Week 4 (Pre and Post dose), Week 8 (Pre and Post dose), Week 12 (Pre and Post dose) and Week 16
measure: Change From Baseline in ECG Heart Rate
timeFrame: Baseline and Week 0 (Post-dose), Week 4 (Pre and Post dose), Week 8 (Pre and Post dose), Week 12 (Pre and Post dose) and Week 16
measure: Change From Baseline in QRS Axis
timeFrame: Baseline and Week 4 (Pre and Post dose), Week 8 (Pre and Post dose), Week 12 (Pre and Post dose) and Week 16
measure: Change Between Pre-dose and Post-dose of PR Interval, QRS Duration, Uncorrected QT Interval, QTcF Interval and RR Interval
timeFrame: Baseline and Weeks 0, 4, 8 and 12
measure: Change Between Pre-dose and Post-dose of Heart Rate
timeFrame: Baseline and Weeks 0, 4, 8 and 12
measure: Change Between Pre-dose and Post-dose of QRS Axis
timeFrame: Baseline and Weeks 0, 4, 8 and 12
measure: Change From Baseline in Maximum, Minimum and Average Changes in Heart Rate
timeFrame: Baseline and Weeks 0, 4 and 12
measure: Change From Baseline in Supraventricular Couplets, Supraventricular Ectopics, Supraventricular Runs, Supraventricular Singles, Ventricular Couplets, Ventricular Ectopics, Ventricular Runs, Ventricular Singles
timeFrame: Baseline and Weeks 0, 4 and 12
measure: Change From Baseline in Clinical Chemistry Parameter: Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), Gamma- Glutamyl Transferase (GGT) and Creatine Kinase (CK)
timeFrame: Baseline and Weeks 2, 4, 8, 12, 16 and 28
measure: Change From Baseline in Clinical Chemistry Parameters: Glucose, Potassium, Sodium, Calcium, Phosphate, Chloride, Urea and Carbon Dioxide (CO2)
timeFrame: Baseline and Weeks 2, 4, 8, 12, 16 and 28
measure: Change From Baseline in Clinical Chemistry Parameters: Creatinine, Total Bilirubin and Direct Bilirubin
timeFrame: Baseline and Weeks 2, 4, 8, 12, 16 and 28
measure: Change From Baseline in Clinical Chemistry Parameters: Total Protein and Albumin
timeFrame: Baseline and Weeks 2, 4, 8, 12, 16 and 28
measure: Change From Baseline in Hematology Parameters: Basophil, Eosinophils, Leukocytes, Lymphocytes, Neutrophils, Monocytes, and Platelets
timeFrame: Baseline and Weeks1, 2, 4, 6, 8, 10, 12, 14, 16 and 28
measure: Change From Baseline in Hematology Parameter: Erythrocyte Mean Corpuscular Volume
timeFrame: Baseline and Weeks1, 2, 4, 6, 8, 10, 12, 14, 16 and 28
measure: Change From Baseline in Hematology Parameter: Erythrocytes
timeFrame: Baseline and Weeks 1, 2, 4, 6, 8, 10, 12, 14, 16 and 28
measure: Change From Baseline in Hematology Parameter: Hemoglobin
timeFrame: Baseline and Weeks1, 2, 4, 6, 8, 10, 12, 14, 16 and 28
measure: Change From Baseline in Hematology Parameter: Hematocrit Level
timeFrame: Baseline and Weeks 1, 2, 4, 6, 8, 10, 12, 14, 16 and 28
measure: Change From Baseline in Hematology Parameter: Mean Corpuscular Hemoglobin
timeFrame: Baseline and Weeks 1, 2, 4, 6, 8, 10, 12, 14, 16 and 28
measure: Change From Baseline in Hematology Parameter: Mean Corpuscular Hemoglobin Concentration
timeFrame: Baseline and Weeks 1, 2, 4, 6, 8, 10, 12, 14, 16 and 28
measure: Change From Baseline in Hematology Parameter: Erythrocytes Distribution Width (%)
timeFrame: Baseline and Weeks1, 2, 4, 6, 8, 10, 12, 14, 16 and 28
measure: Change From Baseline in Cardiac Marker: N-Terminal ProB-type Natriuretic Peptide
timeFrame: Baseline and Weeks 1, 2, 4, 6, 8, 10, 12, 14, 16 and 28
measure: Change From Baseline in Cardiac Marker: Cardiac Troponin I
timeFrame: Baseline and Weeks 1, 2, 4, 6, 8, 10, 12, 14, 16 and 28
measure: Number of Participants With Incidence and Titres of Anti- GSK3772847 Antibodies
timeFrame: Baseline and Weeks 2, 4, 8, 12, 16, 20, 24 and 28
measure: Serum Concentrations of GSK3772847
timeFrame: Weeks 2, 4 (Pre-dose), 8 (Pre-dose), 12 (Pre-dose and Post-dose), 16, 20, 24 and 28
measure: Percent Change From Baseline in Free Soluble Suppressor of Tumorigenicity 2 (ST2) Concentration
timeFrame: Baseline and Week 4 (Pre-dose), Week 8 (Pre-dose), Week 12 (Pre-dose) and Week 16
measure: Percent Change From Baseline in Total Soluble ST2 Concentration
timeFrame: Baseline and Week 4 (Pre-dose), Week 8 (Pre-dose), Week 12 (Pre-dose) and Week 16
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: GSK Investigational Site
state: Alabama
city: Scottsboro
country: United States
facility: GSK Investigational Site
state: Alabama
city: Bakersfield
country: United States
facility: GSK Investigational Site
state: California
city: Long Beach
country: United States
facility: GSK Investigational Site
state: California
city: Los Angeles
country: United States
facility: GSK Investigational Site
state: California
city: Newport Beach
country: United States
facility: GSK Investigational Site
state: California
city: New Haven
country: United States
facility: GSK Investigational Site
state: Connecticut
city: Coral Gables
country: United States
facility: GSK Investigational Site
state: Florida
city: Hialeah
country: United States
facility: GSK Investigational Site
state: Florida
city: Miami
country: United States
facility: GSK Investigational Site
state: Florida
city: Miami
country: United States
facility: GSK Investigational Site
state: Florida
city: Miami
country: United States
facility: GSK Investigational Site
state: Florida
city: Miami
country: United States
facility: GSK Investigational Site
state: Florida
city: Miami
country: United States
facility: GSK Investigational Site
state: Florida
city: Miami
country: United States
facility: GSK Investigational Site
state: Florida
city: Miami
country: United States
facility: GSK Investigational Site
state: Florida
city: Winter Park
country: United States
facility: GSK Investigational Site
state: Florida
city: Adairsville
country: United States
facility: GSK Investigational Site
state: Georgia
city: Baltimore
country: United States
facility: GSK Investigational Site
state: Maryland
city: Ann Arbor
country: United States
facility: GSK Investigational Site
state: Michigan
city: Saint Louis
country: United States
facility: GSK Investigational Site
state: Missouri
city: Rochester
country: United States
facility: GSK Investigational Site
state: New York
city: Chapel Hill
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Charlotte
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Mooresville
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Cincinnati
country: United States
facility: GSK Investigational Site
state: Ohio
city: Toledo
country: United States
facility: GSK Investigational Site
state: Ohio
city: Tulsa
country: United States
facility: GSK Investigational Site
state: Oklahoma
city: Medford
country: United States
facility: GSK Investigational Site
state: Oregon
city: Pittsburgh
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Boerne
country: United States
facility: GSK Investigational Site
state: Texas
city: Williamsburg
country: United States
facility: GSK Investigational Site
state: Virginia
city: Madison
country: United States
facility: GSK Investigational Site
state: Wisconsin
city: Woodville South
country: Australia
facility: GSK Investigational Site
state: South Australia
city: Clayton
country: Australia
facility: GSK Investigational Site
state: Victoria
city: Melbourne
country: Australia
facility: GSK Investigational Site
state: Victoria
city: Parkville
country: Australia
facility: GSK Investigational Site
state: Victoria
city: Sherwood Park
country: Canada
facility: GSK Investigational Site
state: Alberta
city: Vancouver
country: Canada
facility: GSK Investigational Site
state: British Columbia
city: Vancouver
country: Canada
facility: GSK Investigational Site
state: British Columbia
city: Hamilton
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Ottawa
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Montreal
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Montréal
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Trois-Rivieres
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Québec
country: Canada
facility: GSK Investigational Site
city: Guadalajara
country: Mexico
facility: GSK Investigational Site
state: Jalisco
city: Cuernavaca
country: Mexico
facility: GSK Investigational Site
state: Morelos
city: Monterrey
country: Mexico
facility: GSK Investigational Site
state: Nuevo León
city: Villahermosa
country: Mexico
facility: GSK Investigational Site
state: Tabasco
city: Merida
country: Mexico
facility: GSK Investigational Site
state: Yucatán
city: Mexico City
country: Mexico
facility: GSK Investigational Site
city: México DF
country: Mexico
facility: GSK Investigational Site
city: Chelyabinsk
country: Russian Federation
facility: GSK Investigational Site
city: Kemerovo
country: Russian Federation
facility: GSK Investigational Site
city: Saint Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: Saint-Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: Samara
country: Russian Federation
facility: GSK Investigational Site
city: St. Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: Tomsk
country: Russian Federation
facility: GSK Investigational Site
city: Ulyanovsk
country: Russian Federation
facility: GSK Investigational Site
city: Kyiv
country: Ukraine
facility: GSK Investigational Site
city: Kyiv
country: Ukraine
facility: GSK Investigational Site
city: Kyiv
country: Ukraine
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: