Effects of GSK2798745 on Alveolar Barrier Disruption in a Segmental Lipopolysaccharide (LPS) Challenge Model
Condition: Healthy Volunteers
Intervention: GSK2798745; Placebo; Lipoplysaccharide from Escherichia Coli; Saline
Intervention description: GSK2798745 will be available as white to slightly colored, round biconvex tablets to be administered via the oral route.; Placebo matching to GSK2798745 will be available as white to slightly colored, round biconvex tablet to be administered via the oral route.; LPS will be used as challenge agent. About 4 nanogram per kilogram of LPS will be instilled into the right middle lung segment via bronchoscopy 2 hours after dosing with GSK2798745 or placebo on Day 1.; Sterile saline (0.9%) will be used as control challenge. Saline will be instilled into the lingula segment of contralateral side of lung via bronchoscopy 2 hours after dosing with GSK2798745 or placebo on Day 1.
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
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.
Masking: Triple (Participant, Care Provider, Investigator)
Masking description: This will be a double blind study where investigator, sub-investigators, other site staff and the subject will be blinded. Selected sponsor study team members will be unblinded to perform the interim analysis. This may include the medical monitor, study statistician, study programmer (and delegates) and study pharmacokineticist.
Enrollment: 47.0
Sex: All
Minimum age: 18 Years
Maximum age: 50 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Lipopolysaccharide; Pharmacodynamics; Healthy subjects; GSK2798745; Placebo; Segmental challenge

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].