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| ID | Type | Description | Link |
|---|---|---|---|
| 2017-002388-16 | EudraCT Number |
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Study terminated due to low probability of achieving a positive outcome on the primary endpoint.
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| Name | Class |
|---|---|
| Biomedical Advanced Research and Development Authority | FED |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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. |
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| 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. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| GSK2798745 | Drug | GSK2798745 will be available as white to slightly colored, round biconvex tablets to be administered via the oral route. |
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| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| Baseline Adjusted Total Cell Count of Neutrophils in BAL Samples at 24 Hours After Segmental LPS Challenge (26 Hours Post-first Dose) | Participants underwent segmental challenge to the lungs, via bronchoscopy, at 2 hours (Baseline) after the first dose of investigational medicinal product. BAL samples were taken, via bronchoscopy and total neutrophil cell count was measured. Baseline 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. Median and 95% CrI at indicated time point has been presented. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| GSK Clinical Trials | GlaxoSmithKline | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| GSK Investigational Site | Hanover | Lower Saxony | 30625 | Germany |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 33189900 | Background | 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. |
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IPD for this study is available via the Clinical Study Data Request site.
IPD is available via the Clinical Study Data Request site (copy the URL below to your browser)
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.
A total of 47 participants were randomized in the study. The study was terminated due to low probability of achieving a positive outcome on the primary endpoint.
This was a randomized, placebo-controlled, parallel group, double-blind (sponsor-open), segmental lipopolysaccharide (LPS) challenge study of GSK2798745 in healthy participants.
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| ID | Title | Description |
|---|---|---|
| FG000 | Placebo | Participants received two tablets of placebo in the morning on Day 1. Participants then underwent segmental challenge at 2 hours after first dose wherein LPS was instilled into the right middle segment and saline control into the lingula segment of the contralateral side. The second dose of placebo was administered 10 hours after LPS and saline challenge. |
| FG001 | GSK2798745 | Participants received two tablets of 2.4 milligrams (mg) GSK2798745 in the morning on Day 1. Participants then underwent segmental challenge at 2 hours after first dose wherein LPS was 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 mg GSK2798745 was administered 10 hours after LPS and saline challenge. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | Placebo | Participants received two tablets of placebo in the morning on Day 1. Participants then underwent segmental challenge at 2 hours after first dose wherein LPS was instilled into the right middle segment and saline control into the lingula segment of the contralateral side. The second dose of placebo was administered 10 hours after LPS and saline challenge. |
| Units | Counts |
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| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | All Subjects Population. |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | Evaluable Population. | Posted | Median | 95% Confidence Interval | Milligrams per liter | Baseline and at 26 hours post-first dose |
SAEs and non-SAEs were collected up to Day 9.
SAEs and non-SAEs were summarized for All Subjects Population
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Placebo | Participants received two tablets of placebo in the morning on Day 1. Participants then underwent segmental challenge at 2 hours after first dose wherein LPS was instilled into the right middle segment and saline control into the lingula segment of the contralateral side. The second dose of placebo was administered 10 hours after LPS and saline challenge. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Headache | Nervous system disorders | MedDRA 21.1 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| GSK Response Center | GlaxoSmithKline | 866-435-7343 | GSKClinicalSupportHD@gsk.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | May 21, 2018 | Nov 8, 2019 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Jun 23, 2018 | Nov 8, 2019 | SAP_001.pdf |
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| ID | Term |
|---|---|
| C000656065 | GSK2798745 |
| D012965 | Sodium Chloride |
| ID | Term |
|---|---|
| D002712 | Chlorides |
| D006851 | Hydrochloric Acid |
| D017606 | Chlorine Compounds |
| D007287 | Inorganic Chemicals |
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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.
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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.
| Placebo | Drug | Placebo matching to GSK2798745 will be available as white to slightly colored, round biconvex tablet to be administered via the oral route. |
|
| 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. |
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| 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. |
|
| 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) | Participants underwent segmental challenge to the lungs, via bronchoscopy, at 2 hours after the first dose of investigational medicinal product. BAL samples were taken, via bronchoscopy and total neutrophil cell count was measured. Baseline 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 hour (26 hours post-first dose) after the LPS and saline challenges, from the challenged segments. Median and 95% CrI at the indicated time point has been presented. | Baseline and at 26 hours post-first dose |
| Number of Participants Reporting Serious Adverse Events (SAEs) and Non-SAEs | An AE is any untoward medical occurrence in a clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability, is a congenital anomaly/ birth effect and other important medical events. All Subjects Population consists of all randomized participants who received at least one dose of study treatment. This population was based on the treatment the participant actually received. SAEs and non-SAEs were analyzed up to follow-up or early withdrawal (FU/EW) of Day 9. | Up to Day 9 (FU/EW) |
| Change From Baseline Values for Clinical Chemistry Parameters | Blood samples were collected for the analysis of clinical chemistry parameters including alkaline phosphate (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and creatinine kinase (CK). Baseline values were defined as the latest pre-treatment assessment with a non-missing value. Change from Baseline value is calculated as the value at the post-dose visit minus the Baseline value. | 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 | Blood samples were collected for the analysis of clinical chemistry parameters direct bilirubin, total bilirubin and creatinine. Baseline values were defined as the latest pre-treatment assessment with a non-missing value. Change from Baseline value is calculated as the value at the post-dose visit minus the Baseline value. | Baseline (Day -1) and at Day 2 and Day 9 (FU/EW) |
| Change From Baseline Values for Clinical Chemistry Parameters: Calcium, Glucose, Potassium, Sodium and Urea/Blood Urea Nitrogen (BUN) | Blood samples were collected for the analysis of clinical chemistry parameters including calcium, glucose, potassium, sodium and urea/BUN. Baseline values were defined as the latest pre-treatment assessment with a non-missing value. Change from Baseline value is calculated as the value at the post-dose visit minus the Baseline value. | Baseline (Day -1) and at Day 2 and Day 9 (FU/EW) |
| Change From Baseline Values for Clinical Chemistry Parameter-C Reactive Protein (CRP) | Blood samples were collected for the analysis of clinical chemistry parameter- CRP. Baseline values were defined as the latest pre-treatment assessment with a non-missing value. Change from Baseline value is calculated as the value at the post-dose visit minus the Baseline value. | Baseline (Day -1) and at Day 2 and Day 9 (FU/EW) |
| Change From Baseline Values for Clinical Chemistry Parameter-Total Protein | Blood samples were collected for the analysis of clinical chemistry parameter- total protein. Baseline values were defined as the latest pre-treatment assessment with a non-missing value. Change from Baseline value is calculated as the value at the post-dose visit minus the Baseline value. | Baseline (Day -1) and at Day 2 and Day 9 |
| Change From Baseline Values for Hematology Parameters | Blood samples were collected for the analysis of hematology parameters including basophils, eosinophils, lymphocytes, monocytes, total neutrophils, platelet count and white blood cell (WBC) count. Baseline values were defined as the latest pre-treatment assessment with a non-missing value. Change from Baseline value is calculated as the value at the post-dose visit minus the Baseline value. | Baseline (Day -1) and at Day 2 and Day 9 (FU/EW) |
| Change From Baseline Values for Hematology Parameter: Hemoglobin | Blood samples were collected for the analysis of hematology parameter: hemoglobin. Baseline values were defined as the latest pre-treatment assessment with a non-missing value. Change from Baseline value is calculated as the value at the post-dose visit minus the Baseline value. | Baseline (Day -1) and at Day 2 and Day 9 (FU/EW) |
| Change From Baseline Values for Hematology Parameters: Hematocrit and Reticulocytes | Blood samples were collected for the analysis of hematology parameters: hematocrit and reticulocytes. Baseline values were defined as the latest pre-treatment assessment with a non-missing value. Change from Baseline value is calculated as the value at the post-dose visit minus the Baseline value. | Baseline (Day -1) and at Day 2 and Day 9 (FU/EW) |
| Change From Baseline Values for Hematology Parameter: Mean Corpuscular Hemogloblin (MCH) | Blood samples were collected for the analysis of hematology parameter: MCH. Baseline values were defined as the latest pre-treatment assessment with a non-missing value. Change from Baseline value is calculated as the value at the post-dose visit minus the Baseline value. | Baseline (Day -1) and at Day 2 and Day 9 (FU/EW) |
| Change From Baseline Values for Hematology Parameter: Mean Corpuscular Volume (MCV) | Blood samples were collected for the analysis of hematology parameter: MCV. Baseline values were defined as the latest pre-treatment assessment with a non-missing value. Change from Baseline value is calculated as the value at the post-dose visit minus the Baseline value. | Baseline (Day -1) and at Day 2 and Day 9 (FU/EW) |
| Change From Baseline Values for Hematology Parameter: Red Blood Cell (RBC) Count | Blood samples were collected for the analysis of hematology parameter: RBC count. Baseline values were defined as the latest pre-treatment assessment with a non-missing value. Change from Baseline value is calculated as the value at the post-dose visit minus the Baseline value. | Baseline (Day -1)and at Day 2 and Day 9 (FU/EW) |
| Change From Baseline in Urine Potential of Hydrogen (pH) | Urine samples were collected for measurement of urine pH at indicated time points. pH is a measure of hydrogen ion concentration and used to determine the acidity or alkalinity of urine. pH is measured on a numeric scale ranging from 0 to 14; values on the scale refer to the degree of alkalinity or acidity. A pH of 7 is neutral. A pH less than 7 is acidic, and a pH greater than 7 is basic. Baseline values were defined as the latest pre-treatment assessment with a non-missing value. Change from Baseline value is calculated as the value at the post-dose visit minus the Baseline value. | Baseline (Day -1) and at Day 2 and Day 9 (FU/EW) |
| Change From Baseline in Urine Specific Gravity | Urine samples were collected for the analysis of urine specific gravity. Urine specific gravity is a measure of the concentration of solutes in the urine and provides information on the kidney's ability to concentrate urine. The dipstick test gives results in a semi-quantitative manner. Baseline values were defined as the latest pre-treatment assessment with a non-missing value. Change from Baseline value is calculated as the value at the post-dose visit minus the Baseline value. | Baseline (Day -1) and at Day 2 and Day 9 (FU/EW) |
| Number of Participants With Worst Case Post Baseline Abnormal Electrocardiogram (ECG) Findings | A single 12-lead ECG was performed at the specified timepoints during the study where the participant was instructed to be in semi-recumbent position for 5 minutes before obtaining the ECG. An ECG machine that automatically calculated the heart rate and measures like the PR, QRS, QT, and corrected QT intervals. Number of participants with worst-case post-Baseline abnormal clinically significant findings and abnormal not clinically significant findings in ECG results has been reported. The decision if an ECG abnormality is clinically significant or not-clinically significant was in the discretion of the investigator, based on her/his clinical judgement. Baseline values is defined as the latest pre-treatment assessment with a non-missing value. | Up to Day 9 (FU/EW) |
| Number of Participants With Abnormal Findings During Physical Examinations | A complete physical examination included, at a minimum, assessments of the skin, cardiovascular, respiratory, gastrointestinal and neurological systems. Height and weight were also measured and recorded. A brief physical examination included, at a minimum, assessments of the skin, lungs, cardiovascular system, and abdomen (liver and spleen). | Up to Day 9 (FU/EW) |
| Change From Baseline in Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP) | The DBP and SBP were measured in participants in a semi-supine position after 5 minutes rest. Baseline values were defined as the latest pre-treatment assessment with a non-missing value. Change from Baseline value is calculated as the value at the post-dose visit minus the Baseline value. | Baseline (Day -1) and at 1, 6, 12, 14, 30 hours and Day 9 (FU/EW) |
| Change From Baseline in Heart Rate | Heart rate was measured at indicated time points in supine position after 5 minutes rest for the participants. Baseline values were defined as the latest pre-treatment assessment with a non-missing value. Change from Baseline value is calculated as the value at the post-dose visit minus the Baseline value. | Baseline (Day -1) and at 1, 6, 12, 14, 30 hours and Day 9 (FU/EW) |
| Change From Baseline in Temperature | Temperature was measured at indicated time points in supine position after 5 minutes rest for the participants. Baseline values were defined as the latest pre-treatment assessment with a non-missing value. Change from Baseline value is calculated as the value at the post-dose visit minus the Baseline value. | Baseline (Day -1) and at 1, 2, 6, 8, 12, 14, 30 hours and Day 9 (FU/EW) |
| Number of Participants With Positive Fecal Occult Blood Test (FOBT) Data | Based on the preclinical finding of gastric erosions, FOBT was performed before and after dosing at screening and follow-up and any positive hemoglobin measurement was recorded as potentially clinically important. Participants with at least one recorded result has been reported. | At Day 9 |
| Mean Forced Expiratory Volume in 1 Second (FEV1) and Mean Forced Vital Capacity (FVC) | Spirometric assessments including FEV1 and FVC were conducted from screening and up to Day 9. Measurements were made in triplicate and the highest FEV1 and FVC were recorded in the case report form (CRF). Mean FEV1 and FVC values along with 95% confidence interval (CI) at indicated timepoints has been presented. Baseline values is defined as the latest pre-treatment assessment with a non-missing value. | 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 |
| Area Under the Curve During 26 Hours of GSK2798745 | Blood samples were collected at indicated time points. The 2 and 26-hour blood samples were taken immediately before BAL sampling. Pharmacokinetic (PK) Population consists of all participants in the All Subjects Population who had at least one non-missing PK assessment (Non-quantifiable [NQ] values will be considered as non-missing values). | 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 |
| Maximum Observed Plasma Concentration (Cmax) of GSK2798745 | Blood samples were collected at indicated time points. The 2- and 26-hour blood samples were taken immediately before BAL sampling. | 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 |
| BG001 |
| GSK2798745 |
Participants received two tablets of 2.4 milligrams (mg) GSK2798745 in the morning on Day 1. Participants then underwent segmental challenge at 2 hours after first dose wherein LPS was 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 mg GSK2798745 was administered 10 hours after LPS and saline challenge. |
| BG002 | Total | Total of all reporting groups |
| Standard Deviation |
| Years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| ID | Title | Description |
|---|---|---|
| OG000 | Placebo | Participants received two tablets of placebo in the morning on Day 1. Participants then underwent segmental challenge at 2 hours after first dose wherein LPS was instilled into the right middle segment and saline control into the lingula segment of the contralateral side. The second dose of placebo was administered 10 hours after LPS and saline challenge. |
| OG001 | GSK2798745 | Participants received two tablets of 2.4 milligrams (mg) GSK2798745 in the morning on Day 1. Participants then underwent segmental challenge at 2 hours after first dose wherein LPS was 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 mg GSK2798745 was administered 10 hours after LPS and saline challenge. |
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| Secondary | Baseline Adjusted Total Cell Count of Neutrophils in BAL Samples at 24 Hours After Segmental LPS Challenge (26 Hours Post-first Dose) | Participants underwent segmental challenge to the lungs, via bronchoscopy, at 2 hours (Baseline) after the first dose of investigational medicinal product. BAL samples were taken, via bronchoscopy and total neutrophil cell count was measured. Baseline 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. Median and 95% CrI at indicated time point has been presented. | Evaluable Population. | Posted | Median | 95% Confidence Interval | 10^6 cells per milliliter | Baseline and at 26 hours post-first dose |
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| Secondary | Baseline Adjusted Differential Cell Count of Neutrophils in BAL Samples at 24 Hours After Segmental LPS Challenge (26 Hours Post-first Dose) | Participants underwent segmental challenge to the lungs, via bronchoscopy, at 2 hours after the first dose of investigational medicinal product. BAL samples were taken, via bronchoscopy and total neutrophil cell count was measured. Baseline 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 hour (26 hours post-first dose) after the LPS and saline challenges, from the challenged segments. Median and 95% CrI at the indicated time point has been presented. | Evaluable Population. | Posted | Median | 95% Confidence Interval | Percentage of total cell count | Baseline and at 26 hours post-first dose |
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| Secondary | Number of Participants Reporting Serious Adverse Events (SAEs) and Non-SAEs | An AE is any untoward medical occurrence in a clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability, is a congenital anomaly/ birth effect and other important medical events. All Subjects Population consists of all randomized participants who received at least one dose of study treatment. This population was based on the treatment the participant actually received. SAEs and non-SAEs were analyzed up to follow-up or early withdrawal (FU/EW) of Day 9. | All Subjects Population. | Posted | Count of Participants | Participants | Up to Day 9 (FU/EW) |
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| Secondary | Change From Baseline Values for Clinical Chemistry Parameters | Blood samples were collected for the analysis of clinical chemistry parameters including alkaline phosphate (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and creatinine kinase (CK). Baseline values were defined as the latest pre-treatment assessment with a non-missing value. Change from Baseline value is calculated as the value at the post-dose visit minus the Baseline value. | All Subjects Population. | Posted | Mean | Standard Deviation | International units per liter | Baseline (Day -1) and at Day 2 and Day 9 (FU/EW) |
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| Secondary | Change From Baseline Values for Clinical Chemistry Parameters: Direct Bilirubin, Total Bilirubin and Creatinine | Blood samples were collected for the analysis of clinical chemistry parameters direct bilirubin, total bilirubin and creatinine. Baseline values were defined as the latest pre-treatment assessment with a non-missing value. Change from Baseline value is calculated as the value at the post-dose visit minus the Baseline value. | All Subjects Population. | Posted | Mean | Standard Deviation | Micromoles per liter | Baseline (Day -1) and at Day 2 and Day 9 (FU/EW) |
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| Secondary | Change From Baseline Values for Clinical Chemistry Parameters: Calcium, Glucose, Potassium, Sodium and Urea/Blood Urea Nitrogen (BUN) | Blood samples were collected for the analysis of clinical chemistry parameters including calcium, glucose, potassium, sodium and urea/BUN. Baseline values were defined as the latest pre-treatment assessment with a non-missing value. Change from Baseline value is calculated as the value at the post-dose visit minus the Baseline value. | All Subjects Population. | Posted | Mean | Standard Deviation | Millimoles per liter | Baseline (Day -1) and at Day 2 and Day 9 (FU/EW) |
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| Secondary | Change From Baseline Values for Clinical Chemistry Parameter-C Reactive Protein (CRP) | Blood samples were collected for the analysis of clinical chemistry parameter- CRP. Baseline values were defined as the latest pre-treatment assessment with a non-missing value. Change from Baseline value is calculated as the value at the post-dose visit minus the Baseline value. | All Subjects Population. | Posted | Mean | Standard Deviation | Milligrams per liter | Baseline (Day -1) and at Day 2 and Day 9 (FU/EW) |
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| Secondary | Change From Baseline Values for Clinical Chemistry Parameter-Total Protein | Blood samples were collected for the analysis of clinical chemistry parameter- total protein. Baseline values were defined as the latest pre-treatment assessment with a non-missing value. Change from Baseline value is calculated as the value at the post-dose visit minus the Baseline value. | All Subjects Population. | Posted | Mean | Standard Deviation | Grams per liter | Baseline (Day -1) and at Day 2 and Day 9 |
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| Secondary | Change From Baseline Values for Hematology Parameters | Blood samples were collected for the analysis of hematology parameters including basophils, eosinophils, lymphocytes, monocytes, total neutrophils, platelet count and white blood cell (WBC) count. Baseline values were defined as the latest pre-treatment assessment with a non-missing value. Change from Baseline value is calculated as the value at the post-dose visit minus the Baseline value. | All Subjects Population. | Posted | Mean | Standard Deviation | Giga cells per liter | Baseline (Day -1) and at Day 2 and Day 9 (FU/EW) |
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| Secondary | Change From Baseline Values for Hematology Parameter: Hemoglobin | Blood samples were collected for the analysis of hematology parameter: hemoglobin. Baseline values were defined as the latest pre-treatment assessment with a non-missing value. Change from Baseline value is calculated as the value at the post-dose visit minus the Baseline value. | All Subjects Population. | Posted | Mean | Standard Deviation | Grams per liter | Baseline (Day -1) and at Day 2 and Day 9 (FU/EW) |
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| Secondary | Change From Baseline Values for Hematology Parameters: Hematocrit and Reticulocytes | Blood samples were collected for the analysis of hematology parameters: hematocrit and reticulocytes. Baseline values were defined as the latest pre-treatment assessment with a non-missing value. Change from Baseline value is calculated as the value at the post-dose visit minus the Baseline value. | All Subjects Population. | Posted | Mean | Standard Deviation | Percentage of red blood cells in blood | Baseline (Day -1) and at Day 2 and Day 9 (FU/EW) |
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| Secondary | Change From Baseline Values for Hematology Parameter: Mean Corpuscular Hemogloblin (MCH) | Blood samples were collected for the analysis of hematology parameter: MCH. Baseline values were defined as the latest pre-treatment assessment with a non-missing value. Change from Baseline value is calculated as the value at the post-dose visit minus the Baseline value. | All Subjects Population. | Posted | Mean | Standard Deviation | Picograms | Baseline (Day -1) and at Day 2 and Day 9 (FU/EW) |
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| Secondary | Change From Baseline Values for Hematology Parameter: Mean Corpuscular Volume (MCV) | Blood samples were collected for the analysis of hematology parameter: MCV. Baseline values were defined as the latest pre-treatment assessment with a non-missing value. Change from Baseline value is calculated as the value at the post-dose visit minus the Baseline value. | All Subjects Population. | Posted | Mean | Standard Deviation | Femtoliters | Baseline (Day -1) and at Day 2 and Day 9 (FU/EW) |
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| Secondary | Change From Baseline Values for Hematology Parameter: Red Blood Cell (RBC) Count | Blood samples were collected for the analysis of hematology parameter: RBC count. Baseline values were defined as the latest pre-treatment assessment with a non-missing value. Change from Baseline value is calculated as the value at the post-dose visit minus the Baseline value. | All Subjects Population. | Posted | Mean | Standard Deviation | Tera cells per liter | Baseline (Day -1)and at Day 2 and Day 9 (FU/EW) |
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| Secondary | Change From Baseline in Urine Potential of Hydrogen (pH) | Urine samples were collected for measurement of urine pH at indicated time points. pH is a measure of hydrogen ion concentration and used to determine the acidity or alkalinity of urine. pH is measured on a numeric scale ranging from 0 to 14; values on the scale refer to the degree of alkalinity or acidity. A pH of 7 is neutral. A pH less than 7 is acidic, and a pH greater than 7 is basic. Baseline values were defined as the latest pre-treatment assessment with a non-missing value. Change from Baseline value is calculated as the value at the post-dose visit minus the Baseline value. | All Subjects Population. | Posted | Mean | Standard Deviation | pH | Baseline (Day -1) and at Day 2 and Day 9 (FU/EW) |
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| Secondary | Change From Baseline in Urine Specific Gravity | Urine samples were collected for the analysis of urine specific gravity. Urine specific gravity is a measure of the concentration of solutes in the urine and provides information on the kidney's ability to concentrate urine. The dipstick test gives results in a semi-quantitative manner. Baseline values were defined as the latest pre-treatment assessment with a non-missing value. Change from Baseline value is calculated as the value at the post-dose visit minus the Baseline value. | All Subjects Population. | Posted | Mean | Standard Deviation | Ratio | Baseline (Day -1) and at Day 2 and Day 9 (FU/EW) |
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| Secondary | Number of Participants With Worst Case Post Baseline Abnormal Electrocardiogram (ECG) Findings | A single 12-lead ECG was performed at the specified timepoints during the study where the participant was instructed to be in semi-recumbent position for 5 minutes before obtaining the ECG. An ECG machine that automatically calculated the heart rate and measures like the PR, QRS, QT, and corrected QT intervals. Number of participants with worst-case post-Baseline abnormal clinically significant findings and abnormal not clinically significant findings in ECG results has been reported. The decision if an ECG abnormality is clinically significant or not-clinically significant was in the discretion of the investigator, based on her/his clinical judgement. Baseline values is defined as the latest pre-treatment assessment with a non-missing value. | All Subjects Population. | Posted | Count of Participants | Participants | Up to Day 9 (FU/EW) |
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| Secondary | Number of Participants With Abnormal Findings During Physical Examinations | A complete physical examination included, at a minimum, assessments of the skin, cardiovascular, respiratory, gastrointestinal and neurological systems. Height and weight were also measured and recorded. A brief physical examination included, at a minimum, assessments of the skin, lungs, cardiovascular system, and abdomen (liver and spleen). | Safety Population. This analysis was not planned and data was not collected and captured in the database. | Posted | Up to Day 9 (FU/EW) |
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| Secondary | Change From Baseline in Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP) | The DBP and SBP were measured in participants in a semi-supine position after 5 minutes rest. Baseline values were defined as the latest pre-treatment assessment with a non-missing value. Change from Baseline value is calculated as the value at the post-dose visit minus the Baseline value. | All Subjects Population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). | Posted | Mean | Standard Deviation | Millimeters of mercury | Baseline (Day -1) and at 1, 6, 12, 14, 30 hours and Day 9 (FU/EW) |
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| Secondary | Change From Baseline in Heart Rate | Heart rate was measured at indicated time points in supine position after 5 minutes rest for the participants. Baseline values were defined as the latest pre-treatment assessment with a non-missing value. Change from Baseline value is calculated as the value at the post-dose visit minus the Baseline value. | All Subjects Population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). | Posted | Mean | Standard Deviation | Beats per minute | Baseline (Day -1) and at 1, 6, 12, 14, 30 hours and Day 9 (FU/EW) |
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| Secondary | Change From Baseline in Temperature | Temperature was measured at indicated time points in supine position after 5 minutes rest for the participants. Baseline values were defined as the latest pre-treatment assessment with a non-missing value. Change from Baseline value is calculated as the value at the post-dose visit minus the Baseline value. | All Subjects Population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). | Posted | Mean | Standard Deviation | Degree celsius | Baseline (Day -1) and at 1, 2, 6, 8, 12, 14, 30 hours and Day 9 (FU/EW) |
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| Secondary | Number of Participants With Positive Fecal Occult Blood Test (FOBT) Data | Based on the preclinical finding of gastric erosions, FOBT was performed before and after dosing at screening and follow-up and any positive hemoglobin measurement was recorded as potentially clinically important. Participants with at least one recorded result has been reported. | All Subjects Population. | Posted | Count of Participants | Participants | At Day 9 |
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| Secondary | Mean Forced Expiratory Volume in 1 Second (FEV1) and Mean Forced Vital Capacity (FVC) | Spirometric assessments including FEV1 and FVC were conducted from screening and up to Day 9. Measurements were made in triplicate and the highest FEV1 and FVC were recorded in the case report form (CRF). Mean FEV1 and FVC values along with 95% confidence interval (CI) at indicated timepoints has been presented. Baseline values is defined as the latest pre-treatment assessment with a non-missing value. | All Subjects Population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). | Posted | Mean | 95% Confidence Interval | Liters | 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 |
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| Secondary | Area Under the Curve During 26 Hours of GSK2798745 | Blood samples were collected at indicated time points. The 2 and 26-hour blood samples were taken immediately before BAL sampling. Pharmacokinetic (PK) Population consists of all participants in the All Subjects Population who had at least one non-missing PK assessment (Non-quantifiable [NQ] values will be considered as non-missing values). | PK Population. | Posted | Geometric Mean | Geometric Coefficient of Variation | Hour*nanograms per milliliter | 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 |
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| Secondary | Maximum Observed Plasma Concentration (Cmax) of GSK2798745 | Blood samples were collected at indicated time points. The 2- and 26-hour blood samples were taken immediately before BAL sampling. | PK Population. | Posted | Geometric Mean | Geometric Coefficient of Variation | Nanograms per milliliter | 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 |
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| 0 |
| 25 |
| 0 |
| 25 |
| 10 |
| 25 |
| EG001 | GSK2798745 | Participants received two tablets of 2.4 milligrams (mg) GSK2798745 in the morning on Day 1. Participants then underwent segmental challenge at 2 hours after first dose wherein LPS was 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 mg GSK2798745 was administered 10 hours after LPS and saline challenge. | 0 | 22 | 0 | 22 | 7 | 22 |
| Pyrexia | General disorders | MedDRA 21.1 | Systematic Assessment |
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| Nasopharyngitis | Infections and infestations | MedDRA 21.1 | Systematic Assessment |
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GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.
| D017670 |
| Sodium Compounds |
| Percentage change |
| 7.31 |
| Standard Error of the Mean |
| 22.837 |
| 2-Sided |
| 95 |
| -48.20 |
| 41.64 |
Percentage change on GSK2798745 relative to placebo has been presented. |
| Other |
| Percentage change |
| 0.10 |
| Standard Error of the Mean |
| 5.429 |
| 2-Sided |
| 95 |
| -11.15 |
| 10.16 |
Percentage change on GSK2798745 relative to placebo has been presented. |
| Other |
| ALT, Day 2 |
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| ALT, Day 9 |
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| AST, Day 2 |
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| AST, Day 9 |
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| CK, Day 2 |
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| CK, Day 9 |
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| Total bilirubin, Day 2 |
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| Total bilirubin, Day 9 |
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| Creatinine, Day 2 |
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| Creatinine, Day 9 |
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| Glucose, Day 2 |
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| Glucose, Day 9 |
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| Potassium, Day 2 |
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| Potassium, Day 9 |
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| Sodium, Day 2 |
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| Sodium, Day 9 |
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| Urea, Day 2 |
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| Urea, Day 9 |
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| Eosinophils, Day 2 |
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| Eosinophils, Day 9 |
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| Lymphocytes, Day 2 |
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| Lymphocytes, Day 9 |
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| Monocytes, Day 2 |
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| Monocytes, Day 9 |
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| Neutrophils, Day 2 |
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| Neutrophils, Day 9 |
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| Platelet count, Day 2 |
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| Platelet count, Day 9 |
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| WBC count, Day 2 |
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| WBC count, Day 9 |
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| Reticulocytes, Day 2 |
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| Reticulocytes, Day 9 |
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| DBP, 6 hours, n=25, 22 |
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| DBP, 12 hours, n=25, 22 |
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| DBP, 14 hours, n=24, 22 |
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| DBP, 30 hours, n=25, 22 |
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| DBP, Day 9, n=25, 22 |
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| SBP, 1 hour, n=25, 22 |
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| SBP, 6 hours, n=25, 22 |
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| SBP, 12 hours, n=25, 22 |
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| SBP, 14 hours, n=24, 22 |
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| SBP, 30 hours, n=25, 22 |
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| SBP, Day 9, n=25, 22 |
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| 6 hours, n=25, 22 |
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| 12 hours, n=25, 22 |
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| 14 hours, n=24, 22 |
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| 30 hours, n=25, 22 |
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| Day 9, n=25, 22 |
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| 2 hours, n=25, 22 |
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| 6 hours, n=25, 22 |
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| 8 hours, n=25, 22 |
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| 12 hours, n=25, 22 |
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| 14 hours, n=24, 22 |
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| 30 hours, n=25, 22 |
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| Day 9, n=25, 22 |
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| FEV1, Day 1, 6 Hours, n=25, 22 |
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| FEV1, Day 2, 25.5 Hours, n=23, 22 |
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| FEV1, Day 2, 30 Hours, n=23, 22 |
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| FEV1, Day 9, pre-bronchodilator, n=25, 22 |
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| FVC, Day 1, Pre-bronchodilator, n=25, 22 |
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| FVC, Day 1, 6 Hours, n=25, 22 |
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| FVC, Day 2, 25.5 Hours, n=23, 22 |
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| FVC, Day 2, 30 Hours, n=23, 22 |
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| FVC, Day 9, pre-bronchodilator, n=25, 22 |
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