Repeat Dose Study of GSK3772847 in Participants With Moderate to Severe Asthma With Allergic Fungal Airway Disease (AFAD)

Asthma Clinical Trial

Official title:

A Double Blind (Sponsor Open) Placebo-controlled, Stratified, Parallel Group Study to Evaluate the Efficacy and Safety of Repeat Doses of GSK3772847 in Participants With Moderate to Severe Asthma With Allergic Fungal Airway Disease (AFAD)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03393806
• Other study ID #: 207972
• Secondary ID: 2017-003544-20
• Status: Terminated
• Phase: Phase 2
• Start date: April 18, 2018
• Est. completion date: January 6, 2020

Study information

• Verified date: September 2020
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study is multicenter, double-blinded parallel group design, where participants with moderate to severe asthma with AFAD will be enrolled. Participants will receive three doses of 10 milligrams/kilogram (mg/kg) of GSK3772847 every 4 Weeks versus placebo along with standard of care. Participants will be randomized in 1:1 ratio to receive either 10 mg/kg GSK3772847 intravenously (IV) or matching placebo IV. Participants will receive study treatment on Week 0 (Day 1), Week 4 and Week 8. The total duration of the study will be 28 Weeks and approximately 46 participants will be randomized.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 17
• Est. completion date: January 6, 2020
• Est. primary completion date: October 9, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Participant must be at least 18 years of age inclusive, at the time of signing the informed consent.

• Documented history of physician diagnosed moderate or severe asthma for >=12 months based on Guidelines and treated with inhaled corticosteroid (ICS) and long-acting beta-2-agonist (LABA) for at least 4 months (>=500 micrograms/day [µg/day]) fluticasone propionate or equivalent as defined in the guidelines.

• Pre-bronchodilator FEV1 35-79% of predicted value for participant inclusive

• FeNO >= 25 parts per billion (ppb) at Screening

• ACQ-5 score >= 1.5 at Screening

• Blood eosinophil >=300 cells/microliter at Screening

• Evidence of allergic fungal airway disease like Fungal sensitization to any of the fungi Aspergillus fumigatus, Penicillium chrysogenum (notatum) at screening measured by serum-specific Immunoglobulin (Ig) E test. A history of exacerbations with at least 1 severe exacerbation (defined as requiring a minimum of 3 days of high-dose oral corticosteroids for asthma symptoms) in the previous 12 months.

• Body weight within 50-150 kilogram (kg)

• Both male and female gender. A female participant is eligible to participate if she is not pregnant not breastfeeding, 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 16 weeks after the last dose of study treatment.

• Capable of giving signed informed consent

Exclusion Criteria:

• Historical diagnosis of cystic fibrosis

• Concurrent respiratory diseases: Presence of a known pre-existing, clinically important respiratory conditions (example 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 or AFAD

• Has a history of chronic or recurrent non-pulmonary infectious disease or ongoing non-pulmonary infection including, but not limited to, chronic renal infection, chronic chest infection, recurrent urinary tract infection (example, recurrent pyelonephritis, chronic non-remitting cystitis), or open, draining skin wound or an ulcer

• Serious infection within 8 weeks of enrolment, including, but not limited to hepatitis, pneumonia, sepsis, or pyelonephritis; or has been hospitalized for an infection; or has been treated with IV antibiotics for an infection, within 8 weeks prior to the first administration of study drug.

• Evidence of poorly controlled chronic medical conditions other than asthma, example, participants with known, pre-existing, clinically significant endocrine, autoimmune, metabolic, neurological, renal, cardiovascular, gastrointestinal, hepatic, and hematological or any other system abnormalities that are uncontrolled with standard treatment.

• Cardiovascular disease: Clinically significant organic heart disease

• Participants with a diagnosis of malignancy or in the process of investigation for a malignancy. Participants with carcinoma that have not been in complete remission for at least 5 years. Participants 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 participant has been considered cured by treatment.

• Eosinophilic diseases: Other conditions that could lead to elevated eosinophil such as hyper-eosinophilic syndromes. Participants with a known, pre-existing parasitic infestation within 6 months prior to Screening (Visit 1)

• Prohibited medications is not permitted within the defined time intervals prior to Screening (Visit 1) and throughout the study.

• Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment.

• A known immunodeficiency such as human immunodeficiency virus infection.

• Hypersensitivity: significant allergies to humanized monoclonal antibodies or biologic or to any components of the formulation used in this study

• Clinically significant multiple or severe drug allergies, intolerance to topical corticosteroids, or severe post-treatment hypersensitivity reactions (including, but not limited to, erythema multiforme major, linear Ig A dermatosis, toxic epidermal necrolysis, and exfoliative dermatitis).

• Clinically significant abnormality on 12-lead ECG assessment at screening (Visit 1). Site investigators will be provided with ECG over-read conducted by a centralized independent cardiologist, to assist in evaluation of participant eligibility.

• Sinus bradycardia <45 beats per minute (bpm), sinus tachycardia >= 110 bpm, multifocal atrial tachycardia (wandering atrial pacemaker with rate >100bpm), evidence of Mobitz II second degree or third degree atrioventricular (AV) block, pathological Q waves (defined as wide [>0.04 seconds] and deep [>0.4 millivolts (mV) (4 millimeter [mm] with 10mm/mV setting)] or >25% of the height of the corresponding R wave, providing the R wave was >0.5mV [5mm with 10mm/mV setting], appearing in at least two contiguous leads, evidence of ventricular ectopic couplets, bigeminy, trigeminy or multifocal premature ventricular complexes, for participants without complete right bundle branch block: QTc for heart rate by Fridericia's formula QTc(F) >= 450 millisecond (msec) or an ECG that is unsuitable for QT measurements, for participants with complete right bundle branch block: QTc(F) >=480 msec or an ECG that is unsuitable for QT measurements, ST-T wave abnormalities, clinically significant conduction abnormalities and clinically significant arrhythmias.

• Smoking history: current smokers or former smokers with a smoking history >= 10 pack years

• History of alcohol or illegal substance abuse within 2 years prior to Screening (Visit1).

• Participants at risk of non-compliance, or unable to comply with the study procedures. Participants who are unable to follow study instructions such as visit schedule and paper diary completion. Participants 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.

Related Conditions & MeSH terms

• Asthma

Intervention

Drug:
• GSK3772847
GSK3772847 will be available as 100 mg/vial, white to yellow, uniform lyophilized cake in a 5 milliliter (mL) clear glass vial with closure sealed by red metal and yellow overseal.
• Placebo
Commercially sourced sterile normal saline will be provided as Placebo

Locations

Country	Name	City	State
France	GSK Investigational Site	Brest Cedex
France	GSK Investigational Site	Montpellier cedex 5
France	GSK Investigational Site	Nantes cedex 1
Netherlands	GSK Investigational Site	Amsterdam
Russian Federation	GSK Investigational Site	Izhevsk
Russian Federation	GSK Investigational Site	Kemerovo
Russian Federation	GSK Investigational Site	Moscow
Russian Federation	GSK Investigational Site	Moscow
Russian Federation	GSK Investigational Site	Saint Petersburg
Russian Federation	GSK Investigational Site	Saint Petersburg
Russian Federation	GSK Investigational Site	Saint-Petersburg
Russian Federation	GSK Investigational Site	Ulyanovsk
United Kingdom	GSK Investigational Site	Birmingham
United Kingdom	GSK Investigational Site	Bradford
United Kingdom	GSK Investigational Site	Edgbaston
United Kingdom	GSK Investigational Site	Leicester	Leicestershire
United Kingdom	GSK Investigational Site	Liverpool	Merseyside
United Kingdom	GSK Investigational Site	Wythenshawe	Greater Manchester

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Countries where clinical trial is conducted

France,  Netherlands,  Russian Federation,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percent Change From Baseline in Blood Eosinophils Over Time	Blood samples were collected at the indicated time points for assessment of blood eosinophil cell count. Baseline is the most recent recorded value before dosing on Day 1. Percent change from Baseline is calculated as (Ratio to Baseline minus 1)*100, where ratio to Baseline is the value at specified time point divided by Baseline value.	Baseline (Day 1, pre-dose), Weeks 2, 4, 8 and 12
Primary	Percent Change From Baseline in Fractional Exhaled Nitric Oxide (FeNO) Over Time	FeNO was assessed using a handheld electronic device. The measurements were obtained in accordance with the American Thoracic Society and the European Respiratory Society Recommendations for Standardized Procedures for the Online and Offline Measurement of Exhaled Lower Respiratory Nitric Oxide and Nasal Nitric Oxide. Participants did not use their rescue medication for at least 6 hours before each FeNO assessment, unless essential for clinical need. Baseline is the most recent recorded value before dosing on Day 1. Percent change from Baseline is calculated as (Ratio to Baseline minus 1)*100, where ratio to Baseline is the value at specified time point divided by Baseline value.	Baseline (Day 1, pre-dose), Weeks 2, 4, 8 and 12
Secondary	Serum Concentrations of GSK3772847	Whole blood samples were collected at indicated time points for measurement of serum concentrations of GSK3772847.	Week 0 (post-dose), Week 2, Week 4 (pre-dose), Week 8 (pre-dose and post-dose), Week 12 and Week 24
Secondary	Serum Levels of Free Suppressor of Tumorigenicity 2 (ST2)	Serum samples were collected at indicated time points for assessment of free ST2 levels. Baseline is the most recent recorded value before dosing on Day 1 (Week 0).	Baseline, Week 0 (post-dose), Week 2, Week 4 (pre-dose), Week 8 (pre-dose and post-dose) and Week 12
Secondary	Serum Levels of Total Soluble ST2	Serum samples were collected at indicated time points for assessment of total soluble ST2 levels. Baseline is the most recent recorded value before dosing on Day 1 (Week 0).	Baseline, Week 0 (post-dose), Week 2, Week 4 (pre-dose), Week 8 (pre-dose and post-dose) and Week 12
Secondary	Number of Participants With Positive Anti-GSK3772847 Antibodies Post-dosing	Serum samples were collected at indicated time points and tested for the presence of antibodies that bind to GSK3772847. The presence of anti-GSK3772847 antibodies was assessed using a tiered approach including a screening assay, a confirmation assay and calculation of titre. Data for participants who showed positive results for confirmation assay has been presented.	Weeks 0, 2, 4, 8, 12 and 24
Secondary	Number of Participants for Whom Titers of Anti-GSK3772847 Antibodies Was Performed	Serum samples were collected at indicated time points and tested for the presence of antibodies that bind to GSK3772847. The presence of anti-GSK3772847 antibodies was assessed using a tiered approach including a screening assay, a confirmation assay and calculation of titer. Data for number of participants for whom titers of anti-GSK3772847 antibodies was performed is presented.	Weeks 0, 2, 4, 8, 12 and 24
Secondary	Change From Baseline in Asthma Control Questionnaire-5 (ACQ-5) Absolute Score at Weeks 2, 4, 8 and 12	The ACQ-5 is a five-item, self-completed questionnaire, which measures a participant's asthma control. The questions enquire about the frequency and/or severity of symptoms (nocturnal awakening, activity limitation, shortness of breath and wheeze) over the previous week. The response options for all these questions range from zero (no impairment/limitation) to six (total impairment/limitation) scale. ACQ-5 score is the mean of the five questions and ranges from 0 (totally controlled) to 6 (severely uncontrolled). Baseline value is defined as the ACQ-5 assessment on Day 1. Change from Baseline is calculated as the post-dose value minus Baseline value.	Baseline (Day 1), Weeks 2, 4, 8 and 12
Secondary	Change From Baseline in Asthma Quality of Life Questionnaire (AQLQ) Total and Domain Scores at Weeks 2, 4, 8 and 12	The AQLQ is a disease-specific, self-administered quality of life questionnaire that was developed to evaluate the impact of asthma treatments on the quality of life of asthma sufferers. The AQLQ contains 32 items in four domains: activity limitation (11 items), symptoms (12 items), emotional function (five items), and environmental stimuli (four items). Participants were asked to recall their experience over the previous 14 days and respond to each question on a seven-point scale where a value of 1 indicates 'total impairment' and 7 indicates 'no impairment'. The total score is the mean of responses to all 32 questions and each individual domain score was calculated as the mean of the items within that domain. Hence, the total and domain scores were each defined on a range from 1 to 7 with higher scores indicating a higher quality of life. Baseline value is defined as the AQLQ assessment on Day 1. Change from Baseline is calculated as the post-dose value minus Baseline value.	Baseline (Day 1), Weeks 2, 4, 8 and 12
Secondary	Percentage of Responders to ACQ-5 at Weeks 2, 4, 8 and 12	The ACQ-5 is a five-item, self-completed questionnaire, which measures a participant's asthma control. The questions enquire about the frequency and/or severity of symptoms (nocturnal awakening, activity limitation, shortness of breath and wheeze) over the previous week. The response options for all these questions range from zero (no impairment/limitation) to six (total impairment/limitation) scale. ACQ-5 score is the mean of the five questions and ranges from 0 (totally controlled) to 6 (severely uncontrolled). A responder to ACQ-5 is defined as a participant who has a decrease from Baseline in ACQ-5 score of 0.5 or more at Weeks 2, 4, 8 and 12.	Weeks 2, 4, 8 and 12
Secondary	Percentage of Responders to AQLQ at Weeks 2, 4, 8 and 12	The AQLQ is a disease-specific, self-administered quality of life questionnaire that was developed to evaluate the impact of asthma treatments on the quality of life of asthma sufferers. The AQLQ contains 32 items in four domains: activity limitation (11 items), symptoms (12 items), emotional function (five items), and environmental stimuli (four items). Participants were asked to recall their experience over the previous 14 days and respond to each question on a seven-point scale where a value of 1 indicates 'total impairment' and 7 indicates 'no impairment'. The total score is the mean of responses to all 32 questions. The total score was defined on a range from 1 to 7 with higher scores indicating a higher quality of life. A responder to AQLQ is defined as a participant who has an increase from Baseline in AQLQ score of 0.5 or more at Weeks 2, 4, 8 and 12.	Weeks 2, 4, 8 and 12
Secondary	Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1)	FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. FEV1 is measured using spirometry. Baseline is the most recent recorded value before dosing on Day 1. Change from Baseline is calculated as the post-dose value minus the Baseline value.	Baseline (Day 1, pre-dose), Weeks 2, 4, 8 and 12
Secondary	Change From Baseline in Forced Vital Capacity (FVC)	FVC is the maximal amount of air that can be forcibly exhaled from lungs after taking the deepest breath possible. FVC is measured by spirometry. Baseline is the most recent recorded value before dosing on Day 1. Change from Baseline is calculated as the post-dose value minus the Baseline value.	Baseline (Day 1, pre-dose), Weeks 2, 4, 8 and 12
Secondary	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. An SAE is defined as any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent disability/incapacity; is a congenital anomaly/birth defect; other important medical events that may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed before.	Up to Week 24
Secondary	Number of Participants With Worst Case Post-Baseline Chemistry Results Relative to Normal Range at Baseline	Blood samples were collected for the assessment of following clinical chemistry parameters: alanine aminotransferase, albumin, alkaline phosphatase, aspartate aminotransferase, bilirubin, calcium, carbon dioxide, chloride, creatine kinase, creatinine, direct bilirubin, gamma glutamyl transferase, glucose, phosphate, potassium, protein, sodium and urea. Participants were counted in the worst case category that their value changed to (low, normal or high), unless there was no change in their category. Participants whose value category was unchanged (e.g., High to High), or whose value became normal, are recorded in the "To Normal or No Change" category. Participants were counted twice if the participant had values that changed 'To Low' and 'To High', so the percentages may not add to 100 percent (%). 'To Low' rows are not presented for tests that have lower limit of normal = 0.	Up to Week 24
Secondary	Number of Participants With Worst Case Post-Baseline Hematology Results Relative to Normal Range at Baseline	Blood samples were collected for the assessment of following hematology parameters: basophils, eosinophils, erythrocyte (Ery. ) mean hemoglobin concentration (MCHC), Ery. mean corpuscular hemoglobin (MCH), Ery mean corpuscular volume (MCV), erythrocytes, erythrocytes distribution width, hematocrit, hemoglobin, leukocytes, lymphocytes, monocytes, neutrophils and platelets. Participants were counted in the worst case category that their value changed to (low, normal or high), unless there was no change in their category. Participants whose value category was unchanged (e.g., High to High), or whose value became normal, are recorded in the "To Normal or No Change" category. Participants were counted twice if the participant had values that changed 'To Low' and 'To High', so the percentages may not add to 100%. 'To Low' rows are not presented for tests that have lower limit of normal = 0.	Up to Week 24
Secondary	Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)	SBP and DBP were measured in the supine position after five minutes of rest for the participant. Baseline is the most recent recorded value before dosing on Day 1 (Week 0). Change from Baseline is calculated as post-dose visit value minus Baseline value.	Baseline (Day 1, pre-dose), Week 0 (post-dose), Weeks 4 and 8 (pre-dose and post-dose) Weeks 12 and 24
Secondary	Change From Baseline in Pulse Rate	Pulse rate was measured in the supine position after five minutes of rest for the participant. Baseline is the most recent recorded value before dosing on Day 1 (Week 0). Change from Baseline is calculated as post-dose visit value minus Baseline value.	Baseline (Day 1, pre-dose), Week 0 (post-dose), Weeks 4 and 8 (pre-dose and post-dose) Weeks 12 and 24
Secondary	Number of Participants With Abnormal Electrocardiogram (ECG) Findings	Twelve lead ECGs were obtained using a standardized ECG machine that measured heart rate, PR, QRS, QT and corrected QT interval (QTc). ECG measurements were done with the participant in a supine position having rested in this position for approximately 5 minutes before each reading. Clinically significant (CS) and not clinically significant (NCS) abnormal ECG findings at worst-case post-Baseline are presented. CS abnormal findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition. Data for worst-case post-Baseline is presented.	Up to Week 12
Secondary	Number of Participants With Abnormal 24-hour Holter Findings	A Holter monitor is a type of continuous ambulatory ECG device used for quantitative assessment of abnormal rhythm events. Number of participants with abnormal 24-hour Holter findings is presented. Data was summarized for participants with at least 16 hours of data.	Week 0