Effects of GSK2798745 on Alveolar Barrier Disruption in a Segmental Lipopolysaccharide (LPS) Challenge Model

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. \[number of pack years = (number of cigarettes per day/20) x number of years smoked\].