A Randomised, Placebo-controlled, Double-blind (Sponsor Open), Segmental LPS Challenge Study to Investigate the Pharmacodynamics of GSK2798745 in Healthy Participants

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.