Clinical trial NCT03511105: Effects of GSK2798745 on Alveolar Barrier Disruption in a Segmental Lipopolysaccharide (LPS) Challenge Model
Official title: A Randomised, Placebo-controlled, Double-blind (Sponsor Open), Segmental LPS Challenge Study to Investigate the Pharmacodynamics of GSK2798745 in Healthy Participants
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Healthy Volunteers
Keywords: Lipopolysaccharide
Pharmacodynamics
Healthy subjects
GSK2798745
Placebo
Segmental challenge
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
Collaborators: name: Biomedical Advanced Research and Development Authority
First posted: 2018-04-27
Enrollment: 47
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This is a randomised, placebo-controlled, parallel-group study wherein, subjects will be randomised in a ratio of 1:1 to receive 2 single doses of either 4.8 milligrams GSK2798745, then 2.4 milligrams GSK2798745 12 hours later; or a dose of placebo, then another dose of placebo 12 hours later.
Primary purpose: TREATMENT

Brief summary: The primary objective of the study is to investigate the effect of GSK2798745 on alveolar-septal barrier permeability following LPS challenge in healthy subjects. The influx of protein-rich fluid into the lung due to damage to the alveolar capillary barrier, with resultant adverse effects on respiratory function, is a fundamental underlying defect in Acute Respiratory Distress Syndrome (ARDS). In this Phase 1, proof-of-mechanism study, a LPS challenge will be used as a surrogate injury model to investigate the effects of Transient receptor potential vanilloid 4 (TRPV4) channel blockade on alveolar-septal barrier permeability in man. This is a randomised, placebo-controlled, parallel group, double-blind (sponsor-open), segmental LPS challenge study of GSK2798745 in healthy subjects. Subjects will be randomised in a ratio of 1:1 to take 2 single doses of either 4.8 milligrams GSK2798745 followed by 2.4 milligrams GSK2798745 after 12 hours or a dose of placebo followed by another dose of placebo after 12 hours. The first dose will be administered on Day 1 at 2 hours before Baseline bronchoalveolar lavage (BAL) sampling from a segment in the left lower lobe of lung. LPS 4 nanogram per kilogram will subsequently be instilled into the right middle segment and saline control into the lingula segment of the contralateral side. The second dose of study treatment will be administered 10 hours after LPS challenge followed by post-dose BAL sampling on Day 2. Each subject will take approximately 5 weeks to complete the study.


Eligibility criteria: Inclusion Criteria:

* Subjects between 18 and 50 years of age inclusive, at the time of signing the informed consent.
* Subjects who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests (including a normal coagulation profile), ECGs, vital signs and spirometry. In the event of out-of-range results of safety tests, the tests may be repeated once within the screening window. If a retest result is again outside the reference range and considered clinically significant by the investigator and GlaxoSmithKline (GSK) medical monitor, the subject will be considered a screen failure.
* Normal spirometry (FEV1 \>=80% of predicted, FEV1/FVC ratio \>=70%) at Screening and before dosing.
* Body weight \>=50 kilogram (kg) and body mass index (BMI) within the range 19 to 29.9 kilogram per square meter (kg/m\^2)(inclusive).
* A male subject must agree to use contraception during the treatment period and for at least 7 days after the last dose of study treatment and refrain from donating sperm during this period.
* A female is eligible to participate if she is not of childbearing potential.
* Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and protocol.

Exclusion Criteria:

* Significant history of or current cardiovascular, respiratory (e.g., asthma, chronic obstructive pulmonary disorder (COPD), bronchiectasis, active Tuberculosis \[TB\]), hepatic, renal, gastrointestinal, endocrine, hematological, autoimmune or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study treatment; or interfering with the interpretation of data.
* Subject who, in the investigator/designee's judgement, poses a significant suicide risk. Evidence of serious suicide risk may include any history of suicidal behavior and/or any evidence of suicidal ideation on any questionnaires e.g., Type 4 or 5 on the Columbia Suicide Severity Rating Scale (C-SSRS) in the last 5 years.
* Active ulcer disease or gastrointestinal bleeding at the time of Screening (positive FOBT at Screening).
* Abnormal blood pressure as determined by the investigator.
* Alanine aminotransferase (ALT) or bilirubin \>1.5 times upper limit of normal (ULN) (isolated bilirubin \>1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).
* Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
* QT interval corrected for heart rate according Fridericia's formula (QTcF) \>450 milliseconds (msec).
* At risk of Torsades de pointes (e.g., a personal history or a family history of sudden unexplained death, long QT, familial cardiac syndrome, or cardiomyopathy).
* Chronic or acute infection within the 4 weeks before dosing, (e.g., upper and lower respiratory infection within the 4 weeks before dosing).
* Major (as per investigator judgment) surgery within the last 12 weeks prior to randomisation or planned within 3 months of Screening.
* Use of prescription or non-prescription drugs (except paracetamol), including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days or 5 half-lives (whichever is longer) before the first dose of study medication, unless, in the opinion of the investigator and GSK Medical Monitor, the medication will not interfere with the study procedures or compromise subject safety.
* History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator and/or GSK Medical Monitor, contraindicates their participation.
* Where participation in the study would result in donation of blood or blood products in excess of 500 milliliters (mL) within 3 months.
* The subject has participated in a clinical trial and has received an investigational product within the following time period before the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
* Exposure to more than four new chemical entities within 12 months before the first dosing day.
* Presence of hepatitis B surface antigen (HBsAg) at Screening.
* Positive hepatitis C antibody test result at Screening. Subjects with positive Hepatitis C antibody due to prior resolved disease can be enrolled, only if a confirmatory negative Hepatitis C Ribonucleic acid (RNA) test is obtained.
* Positive Hepatitis C RNA test result at screening or within 3 months prior to first dose of study treatment. Test is optional and subjects with negative Hepatitis C antibody test are not required to also undergo Hepatitis C RNA testing.
* A positive pre-study drug/alcohol/cotinine screen.
* A positive test for immunodeficiency virus (HIV) antibody.
* Regular use of known drugs of abuse.
* History of regular alcohol consumption within 6 months of the study defined as an average weekly intake of \>21 units for males or \>14 units for females. One unit is equivalent to 8 gram of alcohol: a half-pint (approximately 240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.
* Current smoker or a history of smoking within 6 months of screening, or a total pack year history of \>5 pack years. \[number of pack years = (number of cigarettes per day/20) x number of years smoked\].

Primary outcomes:
measure: Baseline Adjusted Total Protein Concentration in Broncho-alveolar (BAL) Samples at 24 Hours After Segmental LPS Challenge (26 Hours Post-first Dose)
timeFrame: Baseline and at 26 hours post-first dose
Secondary outcomes:
measure: Baseline Adjusted Total Cell Count of Neutrophils in BAL Samples at 24 Hours After Segmental LPS Challenge (26 Hours Post-first Dose)
timeFrame: Baseline and at 26 hours post-first dose
measure: Baseline Adjusted Differential Cell Count of Neutrophils in BAL Samples at 24 Hours After Segmental LPS Challenge (26 Hours Post-first Dose)
timeFrame: Baseline and at 26 hours post-first dose
measure: Number of Participants Reporting Serious Adverse Events (SAEs) and Non-SAEs
timeFrame: Up to Day 9 (FU/EW)
measure: Change From Baseline Values for Clinical Chemistry Parameters
timeFrame: Baseline (Day -1) and at Day 2 and Day 9 (FU/EW)
measure: Change From Baseline Values for Clinical Chemistry Parameters: Direct Bilirubin, Total Bilirubin and Creatinine
timeFrame: Baseline (Day -1) and at Day 2 and Day 9 (FU/EW)
measure: Change From Baseline Values for Clinical Chemistry Parameters: Calcium, Glucose, Potassium, Sodium and Urea/Blood Urea Nitrogen (BUN)
timeFrame: Baseline (Day -1) and at Day 2 and Day 9 (FU/EW)
measure: Change From Baseline Values for Clinical Chemistry Parameter-C Reactive Protein (CRP)
timeFrame: Baseline (Day -1) and at Day 2 and Day 9 (FU/EW)
measure: Change From Baseline Values for Clinical Chemistry Parameter-Total Protein
timeFrame: Baseline (Day -1) and at Day 2 and Day 9
measure: Change From Baseline Values for Hematology Parameters
timeFrame: Baseline (Day -1) and at Day 2 and Day 9 (FU/EW)
measure: Change From Baseline Values for Hematology Parameter: Hemoglobin
timeFrame: Baseline (Day -1) and at Day 2 and Day 9 (FU/EW)
measure: Change From Baseline Values for Hematology Parameters: Hematocrit and Reticulocytes
timeFrame: Baseline (Day -1) and at Day 2 and Day 9 (FU/EW)
measure: Change From Baseline Values for Hematology Parameter: Mean Corpuscular Hemogloblin (MCH)
timeFrame: Baseline (Day -1) and at Day 2 and Day 9 (FU/EW)
measure: Change From Baseline Values for Hematology Parameter: Mean Corpuscular Volume (MCV)
timeFrame: Baseline (Day -1) and at Day 2 and Day 9 (FU/EW)
measure: Change From Baseline Values for Hematology Parameter: Red Blood Cell (RBC) Count
timeFrame: Baseline (Day -1)and at Day 2 and Day 9 (FU/EW)
measure: Change From Baseline in Urine Potential of Hydrogen (pH)
timeFrame: Baseline (Day -1) and at Day 2 and Day 9 (FU/EW)
measure: Change From Baseline in Urine Specific Gravity
timeFrame: Baseline (Day -1) and at Day 2 and Day 9 (FU/EW)
measure: Number of Participants With Worst Case Post Baseline Abnormal Electrocardiogram (ECG) Findings
timeFrame: Up to Day 9 (FU/EW)
measure: Number of Participants With Abnormal Findings During Physical Examinations
timeFrame: Up to Day 9 (FU/EW)
measure: Change From Baseline in Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP)
timeFrame: Baseline (Day -1) and at 1, 6, 12, 14, 30 hours and Day 9 (FU/EW)
measure: Change From Baseline in Heart Rate
timeFrame: Baseline (Day -1) and at 1, 6, 12, 14, 30 hours and Day 9 (FU/EW)
measure: Change From Baseline in Temperature
timeFrame: Baseline (Day -1) and at 1, 2, 6, 8, 12, 14, 30 hours and Day 9 (FU/EW)
measure: Number of Participants With Positive Fecal Occult Blood Test (FOBT) Data
timeFrame: At Day 9
measure: Mean Forced Expiratory Volume in 1 Second (FEV1) and Mean Forced Vital Capacity (FVC)
timeFrame: Baseline (Day 1, Pre-dose) pre-bronchodilator and at Day 1 (pre-bronchodilator and 6 Hours), at Day 2 (25.5 and 30 Hours) and Day 9 pre-bronchodilator
measure: Area Under the Curve During 26 Hours of GSK2798745
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 6, 8, 12, 12.5, 13, 13.5, 14, 15, 24 and 26 hours post-dose
measure: Maximum Observed Plasma Concentration (Cmax) of GSK2798745
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 6, 8, 12, 12.5, 13, 13.5, 14, 15, 24 and 26 hours post-dose
Other outcomes:
Locations:
city: Hannover
country: Germany
facility: GSK Investigational Site
state: Niedersachsen
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Mole S, Harry A, Fowler A, Hotee S, Warburton J, Waite S, Beerahee M, Behm DJ, Badorrek P, Muller M, Faulenbach C, Lazaar AL, Hohlfeld JM. Investigating the effect of TRPV4 inhibition on pulmonary-vascular barrier permeability following segmental endotoxin challenge. Pulm Pharmacol Ther. 2020 Oct;64:101977. doi: 10.1016/j.pupt.2020.101977. Epub 2020 Nov 13.