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

NCT03511105 | Terminated Phase 1 Results

• 2 other identifiers: 2074642017-002388-16
• Study Type: interventional
• Target: 47
• Locations: 1 country
• Sites: 1

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.

Conditions

Healthy Volunteers

Keywords

Lipopolysaccharide; Pharmacodynamics; Healthy subjects; GSK2798745; Placebo; Segmental challenge

Outcome Measures

Primary Outcomes (1)

• Baseline Adjusted Total Protein Concentration in Broncho-alveolar (BAL) Samples at 24 Hours After Segmental LPS Challenge (26 Hours Post-first Dose)

  Participants underwent segmental challenge to lungs, via bronchoscopy, at 2 hours after first dose of investigational medicinal product. BAL samples were taken, via bronchoscopy and total protein was measured. Baseline (2 hours) samples were taken immediately before the LPS and saline challenges, from a segment in the left lower lobe, and post-challenge samples were taken at 24 hours (26 hours post-first dose) after the LPS and saline challenges, from the challenged segments. Evaluable Population consists of all participants for whom results of the primary analysis can be determined i.e. all randomized participants who received two correct doses of study treatment, received LPS and saline segmental challenge (in contralateral lobes) and for which results of both baseline (2 hours) and LPS lobe (26 hours) BAL samples are evaluable. This population will be based on treatment the participant actually received. Median and 95% credible interval (CrI) has been presented.

  Baseline and at 26 hours post-first dose

Secondary Outcomes (25)

• Baseline Adjusted Total Cell Count of Neutrophils in BAL Samples at 24 Hours After Segmental LPS Challenge (26 Hours Post-first Dose)

  Baseline and at 26 hours post-first dose

• Baseline Adjusted Differential Cell Count of Neutrophils in BAL Samples at 24 Hours After Segmental LPS Challenge (26 Hours Post-first Dose)

  Baseline and at 26 hours post-first dose

• Number of Participants Reporting Serious Adverse Events (SAEs) and Non-SAEs

  Up to Day 9 (FU/EW)

• Change From Baseline Values for Clinical Chemistry Parameters

  Baseline (Day -1) and at Day 2 and Day 9 (FU/EW)

• Change From Baseline Values for Clinical Chemistry Parameters: Direct Bilirubin, Total Bilirubin and Creatinine

  Baseline (Day -1) and at Day 2 and Day 9 (FU/EW)

Study Arms (2)

Subjects receiving GSK2798745

EXPERIMENTAL

Eligible subjects will receive two tablets of 2.4 milligrams GSK2798745 on the morning of Day 1. Subjects will then undergo segmental challenge at 2 hours after first dose wherein LPS will be instilled into the right middle segment and saline control into the lingula segment of the contralateral side. The second dose of a single tablet of 2.4 milligrams of GSK2798745 will be administered 10 hours after LPS and saline challenge.

Drug: GSK2798745; Drug: Lipoplysaccharide from Escherichia Coli; Drug: Saline

Subjects receiving matching Placebo

PLACEBO COMPARATOR

Eligible subjects will receive two tablets of placebo on the morning of Day 1. Subjects will then undergo segmental challenge at 2 hours after first dose wherein LPS will be instilled into the right middle segment and saline control into the lingula segment of the contralateral side. The second dose placebo will be administered 10 hours after LPS and saline challenge.

Drug: Placebo; Drug: Lipoplysaccharide from Escherichia Coli; Drug: Saline

Interventions

GSK2798745 DRUG

GSK2798745 will be available as white to slightly colored, round biconvex tablets to be administered via the oral route.

Subjects receiving GSK2798745

Placebo DRUG

Placebo matching to GSK2798745 will be available as white to slightly colored, round biconvex tablet to be administered via the oral route.

Subjects receiving matching Placebo

Lipoplysaccharide from Escherichia Coli DRUG

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.

Subjects receiving GSK2798745; Subjects receiving matching Placebo

Saline DRUG

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.

Subjects receiving GSK2798745; Subjects receiving matching Placebo

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead
• Biomedical Advanced Research and Development Authority: collaborator

Study Sites (1)

GSK Investigational Site

Hanover, Lower Saxony, 30625, Germany

Location

Related Publications (1)

• 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.

  PMID: 33189900 BACKGROUND

MeSH Terms

Interventions

GSK2798745; Sodium Chloride

Intervention Hierarchy (Ancestors)

Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: April 24, 2018
• First Posted: April 27, 2018
• Study Start: June 25, 2018
• Primary Completion: December 18, 2018
• Study Completion: December 18, 2018
• Last Updated: March 29, 2021
• Results First Posted: February 5, 2020

Record last verified: 2021-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD is available via the Clinical Study Data Request site (copy the URL below to your browser)
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.

Locations

DE (1)