Study of GSK2862277 in Subjects Undergoing Oesophagectomy Surgery

A Placebo Controlled, Double-blind, Multi-centre, Single Dose, Parallel Group, Randomised Clinical Trial of GSK2862277 in Patients Undergoing Oesophagectomy Surgery

Status

Terminated

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02221037

Enrollment

Registered

2014-08-20

Start date

2015-04-28

Completion date

2017-06-28

Last updated

2020-10-27

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Lung Injury, Acute and Respiratory Distress Syndrome, Adult

Keywords

PaO2/FiO2, Peri-operative lung injury, EVLWI, ARDS, PVPI, SOFA scores, GSK2862277, Oesophagectomy

Brief summary

Lung injury in patients undergoing oesophagectomy may occur during surgery (peri-operatively) as a result of One Lung Ventilation (OLV) and/or during the immediate post-operative period when patients receive intensive care. This is reinforced by the observation that physiological markers of lung injury are most elevated immediately after completion of surgery, and the development of clinical Acute Respiratory Distress Syndrome (ARDS)occurs immediately post-operatively (within 72 hours of surgery), with the majority of cases reported 24-48 hours after completion of surgery. This study is designed to investigate the impact of pre-operative administration of GSK2862277 on biological and physiological markers of lung injury in patients undergoing surgical resection of oesophageal cancer in order to achieve optimal exposure at the site of injury following OLV and lung deflation. This study is a randomized placebo controlled, double-blind, multi-centre, single dose parallel group, design. There will be two treatment groups comprising one active and one placebo arm with approximately 40 patients per group. Patients enrolled in the study will be scheduled to undergo planned/elective trans-thoracic surgery for oesophagectomy. The primary endpoint for this study is the change in pulmonary vascular permeability index (PVPI) from pre-surgical levels to the end of surgery. GSK2862277 will be administered as an orally inhaled aerosol (single nebulized dose) over approximately 3 to 5 minutes (min) 1-3 hours prior to surgery. Subject will be monitored daily until discharge and followed up till day 28.

Interventions

DRUGGSK2862277

It is available as 26 milligrams (mg) white to off-white, uniform lyophilized cake that will be reconstituted (using reconstitution fluid formulated with polysorbate 80 in Water for Injection) to 40 mg/vial of Lyophile for reconstitution for inhalation with duration of nebulisation as approximately 3-5 min and will be administered using Pari eFlow with s30 mesh device.

DRUGPlacebo

It is a clear, colorless to pale yellow liquid, will be administered in volume to match active dose as solution for inhalation with duration of nebulisation as approximately 3-5 min and will be administered using Pari eFlow with s30 mesh device.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

ALL

Age

18 Years to 80 Years

Healthy volunteers

Inclusion criteria

* Subject has a planned elective transthoracic oesophagectomy * Male or female between 18 and 80 years of age inclusive, at the time of signing the informed consent. * Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form. * A female subject is eligible to participate if she is of: * Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea \[in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) \> 40 milli-International Units per milliliter and estradiol \< 40 picograms per milliliter (\<147 picomoles per liter) is confirmatory\]. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment. For most forms of HRT, at least 2-4 weeks should elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method. * Liver parameters according to the thresholds below: Aspartate aminotransferase and Alanine aminotransferase \< 5x Upper limit of normal (ULN); alkaline phosphatase and bilirubin \<=1.5xULN (isolated bilirubin \>1.5x ULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%). * QT duration corrected for heart rate by Bazett's formula (QTcB) or QT duration corrected for heart rate by Fridericia's formula (QTcF) \<= 480 milliseconds (msec) at screening * Either QTcB or QTcF, machine or manual over-read can be used. This applies to both males and females. The QT correction formula used to determine inclusion and discontinuation for an individual subject should be the same throughout the study. * Based on average QTc value of triplicate ECGs obtained over a brief recording period.

Exclusion criteria

* Positive screening test for pre-existing antibodies that bind GSK2862277. * Current evidence or history of pneumonia within 14 days before dosing. * Diagnosis of chronic respiratory disease with a forced expiratory volume in one second (FEV1) less than 50% predicted or resting oxygen saturations of less 92%. * 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 or GSK Medical Monitor, contraindicates their participation. * The subject has received an investigational product within the following time period prior to 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). * Use of corticosteroids (Intravenous, oral or Intramuscular) at a dose of \>= 10 Milligrams per day (mg/day) prednisolone (or equivalent) within 14 days prior to dosing, or anti-Tumor Necrosis Factor (anti-TNF) or anti-IL1 within 60 days prior to dosing. Criteria Based Upon Medical Histories * History or current evidence of clinically significant renal disease, diabetes mellitus/metabolic syndrome, hypertension, peripheral vascular disease or any other clinically significant respiratory, cardiovascular, neurological, endocrine, or hematological abnormalities that are uncontrolled on permitted therapy. Significant is defined as any disease that, in the opinion of the Investigator, would put the safety of the patients at risk through study participation, or which would affect the safety analysis or other analysis if the disease/condition exacerbated during the study. * Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). * History of regular alcohol consumption within 6 months of the study, defined as: an average weekly intake of \>28 units for males or \>14 units for females. One unit is equivalent to 8 grams of alcohol: a half-pint \[\ 240 milliliter (ml)\] of beer, 1 glass (125 ml) of wine or 1 (25 ml) measure of spirits Criteria Based Upon Diagnostic Assessments * Screens positive for Hepatitis B surface antigen, Hepatitis C antibody * Known Human Immunodeficiency Virus (HIV) positive; testing will be conducted in accordance with local procedures * Tests positive for Mycobacterium tuberculosis using QuantiFERON Gold Test. Other Criteria * Subject has received a live attenuated vaccine(s) within 3 weeks of randomisation or will require vaccination with a live attenuated vaccine prior to the end of the study (Day 28). * Unwillingness or inability to follow the procedures outlined in the protocol. * Subject is mentally or legally incapacitated.

Design outcomes

Primary

Measure	Time frame	Description
Baseline Adjusted Change in Pulmonary Vascular Permeability Index (PVPI) on Completion of Surgery	Baseline (Day 1 [immediately prior to start of surgery]) and Day 1 (on completion of surgery)	PVPI is a derived value from extra vascular lung water (EVLW), and is considered to be less variable than extra vascular lung water Index (EVLWI). PVPI was measured via single-indicator transpulmonary thermodilution with a patent indwelling Pulse Contour Cardiac Output (PiCCO) catheter. Baseline was Day 1 (immediately prior to start of surgery). Change from Baseline value was the post-Baseline value (on completion of surgery on Day 1) minus Baseline value. Per-Protocol 1 (PP1) Population comprised of all the participants in the Safety population for whom the treatment actually received was the same one when they were randomized to (both study drug and BAL sampling location).

Secondary

Measure	Time frame	Description
Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)	Up to Day 31	AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with use of a medicinal product (MP), whether or not considered related to MP. AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with use of MP. SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect or is medically significant or all events of possible drug induced liver injury with hyperbilirubinemia. Safety Population comprised of all participants who received at least one complete dose of study treatment.
Number of Participants With Hematology Abnormalities of Potential Clinical Importance	Up to Day 8	Hematology parameters included basophils, eosinophils, hematocrit, hemoglobin, lymphocytes, monocytes, neutrophils, neutrophil bands, platelets, red blood cell (RBC) count, segmented neutrophils and white blood cell (WBC) count. The potential clinical concern values were: hematocrit (low: \<0.3 fraction and high: \>0.54 fraction), Hemoglobin (low: \<90 gram per Liter and high: \>180 gram per Liter), lymphocytes (low: \<0.6 x 10\^9 cells/Liter and high: \>3.0 x 10\^9 cells/Liter), neutrophils: (low: \<1.5 x 10\^9 cells/Liter and high: \>20 x 10\^9 cells/Liter), platelets: (low: \<100 x 10\^9 cells/Liter and high: \>600 x 10\^9 cells/Liter) and WBC: (low: \<3 x 10\^9 cells/Liter and high: \>20 x 10\^9 cells/Liter). Only those participants for which at least one value of potential clinical concern was reported are summarized.
Number of Participants With Clinical Chemistry Abnormalities of Potential Clinical Importance	Up to Day 8	Clinical chemistry parameters and their potential clinical concern values were: albumin (low: \<25 millimole \[mmol\]/L and high: \>60 mmol/L), calcium (low: \<1.8 mmoL/L and high: \>2.75 mmol/L), creatinine (low: \<30 mmol/L and high: \>160 mmol/L), glucose (low: \<3 mmol/L and high: \>9 mmol/L), potassium (low: \<2.5 mmol/L and high: \>5.5 mmol/L), sodium (low: \<120 mmol/L and high: \>160 mmol/L), total carbon dioxide content (low: \<16 mmol/L and high: \>35 mmol/L) and blood urea nitrogen (low: \<3 mmol/L and high: \>15 mmol/L). Number of participants with clinical chemistry abnormalities of potential clinical importance are presented.
Number of Participants With Abnormal Urinalysis Parameters	Day 1 (pre-dose) and Day 8	Urinalysis included dipstick urine test which was used to screen for glucose, ketones, occult blood and protein on Day 1 (pre-dose) and Day 8. The dipstick test gives results in a semi-quantitative manner, and results for urinalysis parameters of urine glucose, ketones, occult blood and protein can be read as Trace, 1+, 2+ and 3+, indicating proportional concentrations in the urine sample.
Number of Participants With Electrocardiogram (ECG) Values of Potential Clinical Importance	Days 1, 2, 4 and 8	Single 12-lead ECGs were obtained thereafter during the study, using an ECG machine that automatically calculated the heart rate and measured PR, QRS, QT, RR and corrected QT (QTc) intervals. Number of participants with ECG values of potential clinical importance are presented.
Number of Participants With Vital Signs of Potential Clinical Importance	Up to Day 31	Vital sign measurements included systolic and diastolic blood pressure, pulse rate, temperature and respiratory rate. Vital sign measurements were measured in a semi-recumbent or supine position after 5 minutes rest. The potential clinical concern range for systolic blood pressure: \<85 and \>160 millimeters of mercury, for diastolic: \<45 and \>100 millimeters of mercury and heart rate: \<40 and \>110 beats per minute. Number of participants with vital signs of potential clinical importance are presented.
Baseline Adjusted Change in PaO2/FiO2 on Completion of Surgery	Baseline (Day 1 [immediately prior to start of surgery]) and Day 1 (on completion of surgery)	Oxygenation and function of gas exchange was assessed by the comparison of partial pressure of oxygen arterially (PaO2) divided by the fraction of oxygen that is being inspired (FiO2), sometimes referred to simply as the 'P to F ratio'. The P to F ratio was assessed at time points during the period of intubation and mechanical ventilation. An arterial blood sample was required for determination of the partial pressure of oxygen and the percentage of O2 which is being inspired was recorded at the corresponding time point. Baseline was Day 1 (immediately prior to start of surgery). Change from Baseline value was the post-Baseline value (on completion of surgery on Day 1) minus Baseline value.
Levels of BAL Biomarkers on Completion of Surgery	Day 1 (on completion of surgery)	Samples were collected to determine concentrations of biomarkers in BAL using an appropriately validated assay on Day 1 after completion of surgery. BAL biomarkers included soluble tumor necrosis factor receptor (STNFR) type I, free, STNFR type I, total, tumor necrosis factor alpha, interleukin 6, interleukin 8, interleukin 1 beta, monocyte chemotactic protein-1, macrophage inflammatory protein 1 alpha, macrophage inflammatory protein 1 beta, interleukin 10 and soluble receptor for advanced glycation end (sRAGE) products. Any value below limit of quantification was replaced with half the lower limit of quantification (LLQ) prior to deriving the summary measures. Mean levels of BAL biomarkers on completion of surgery are presented. Only those participants available at the specified time points were analyzed represented by n=X,X,X,X in the category titles.
Levels of BAL Biomarkers (C-reactive Protein and Total Proteins) on Completion of Surgery	Day 1 (on completion of surgery)	Samples were collected to determine concentrations of biomarkers in BAL using an appropriately validated assay. BAL biomarkers included C-reactive protein and total proteins. Any value below limit of quantification was replaced with half the LLQ prior to deriving the summary measures. All BAL C-reactive protein samples were below limit of quantification and all were assigned to half the LLQ prior to deriving the summary measures. Mean levels of BAL biomarkers on completion of surgery are presented. Only those participants available at the specified time points were analyzed represented by n=X,X,X,X in the category titles.
Maximum Observed Concentration (Cmax)	Day 1 (pre-dose, 1 hour post-dose and on completion of surgery), Day 2 (24 to 26 hours post-dose) and Day 3 (46 to 50 hours post-dose)	Blood samples for pharmacokinetic analysis of GSK2862277 were collected at the indicated time points.
Baseline Adjusted Change in EVLWI on Completion of Surgery	Baseline (Day 1 [immediately prior to start of surgery]) and Day 1 (on completion of surgery)	EVLW refers to the fluid within the lung but outside the vascular compartment. It includes extravasated plasma, intracellular water, lymphatic fluid, and surfactant. EVLWI was measured by trans-pulmonary thermodilution via a PiCCO hemodynamic monitor. Baseline was Day 1 (immediately prior to start of surgery). Change from Baseline value was the post-Baseline value (on completion of surgery on Day 1) minus Baseline value. Only those participants with data available at the specified time points were analyzed.
Change Over Time in PaO2/FiO2 Post-operatively on Day 2 Through to Day 4	Baseline (Day 1 [immediately prior to start of surgery]) to Days 2, 3 and 4	Oxygenation and function of gas exchange was assessed by the comparison of PaO2 divided by the FiO2, sometimes referred to simply as the 'P to F ratio'. The P to F ratio was assessed at time points during the period of intubation and mechanical ventilation. An arterial blood sample was required for determination of the partial pressure of oxygen and the percentage of O2 which is being inspired was recorded at the corresponding time point. Baseline was Day 1 (immediately prior to start of surgery). Change from Baseline value was the post-Baseline value (on completion of surgery on Day 1) minus Baseline value. PP1 Population was analyzed. Only those participants available at the specified time points were analyzed represented by n=X,X in the category titles.
Change Over Time in PVPI Post-operatively on Day 2 Through to Day 4	Baseline (Day 1 [immediately prior to start of surgery]) to Days 2, 3 and 4	PVPI is a derived value from EVLW, and is considered to be less variable than EVLWI. PVPI was measured via single-indicator transpulmonary thermodilution as long as the participant remained in the ICU with a patent indwelling PiCCO catheter. Baseline was Day 1 (immediately prior to start of surgery). Change from Baseline value was the post-Baseline value minus Baseline value. PP1 Population was analyzed. Only those participants available at the specified time points were analyzed represented by n=X,X,X,X in the category titles.
Change Over Time in EVLWI Post-operatively on Day 2 Through to Day 4	Baseline (Day 1 [immediately prior to start of surgery]) to Days 2, 3 and 4	EVLW refers to the fluid within the lung but outside the vascular compartment. It includes extravasated plasma, intracellular water, lymphatic fluid, and surfactant. EVLWI was measured by trans-pulmonary thermodilution via a PiCCO hemodynamic monitor. Change from Baseline value was the post-Baseline value minus Baseline value. PP1 Population was analyzed. Only those participants available at the specified time points were analyzed represented by n=X,X,X,X in the category titles.
Daily Sequential Organ Failure Assessment (SOFA) Scores on Day 2 Through to Day 4	Day 2 to Day 4	The SOFA score defines the presence and severity of dysfunction within 6 organ systems (cardiovascular, respiratory, coagulation, liver, renal, and nervous system) with a value of 0 for assigned to normal function to a maximum value of 4 for severe dysfunction in each of the organ systems. Each component of the SOFA score was added together, ranging from 0 indicating no organ dysfunction in any of the 6 organ systems, to 24 indicating maximal organ dysfunction across all 6 organ systems. Per-Protocol (PP) 2 Population comprised of all the participants in the Safety population for whom the study drug actually received was the same one they were randomized to (study drug).
Area Under the Concentration-time Curve From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration (AUC [0 to t])	Day 1 (pre-dose, 1 hour post-dose and on completion of surgery), Day 2 (24 to 26 hours post-dose) and Day 3 (46 to 50 hours post-dose)	Blood samples for pharmacokinetic analysis of GSK2862277 were collected at the indicated time points. Pharmacokinetic (PK) Population comprised of all participants in the Safety population for whom a pharmacokinetic sample (plasma and/or BAL) was obtained and analyzed.
Derived Pharmacokinetic Parameter- Half-life (t1/2) and Time of Occurrence of Cmax (Tmax)	Day 1 (pre-dose, 1 hour post-dose and on completion of surgery), Day 2 (24 to 26 hours post-dose) and Day 3 (46 to 50 hours post-dose)	Half-life (t1⁄2) is the time required for a quantity to reduce to half its initial value. t1/2 was not determined in all cases due to insufficient data in the terminal phase. Blood samples for pharmacokinetic analysis of GSK2862277 were collected at the indicated time points. Only those participants available at the specified time points were analyzed represented by n=X,X in the category titles.
Ratio of Total Protein Derived From BAL and Plasma Values	Day 1 (on completion of surgery)	BAL sampling and plasma sampling was done on Day 1 (on completion of surgery). Raw summary statistics for the derived ratio were not produced. Only statistical modeling was performed that produced a posterior distribution for each treatment. Summary measure for the posterior distribution was the median. The quantity being modeled was the mean treatment effect (pooling data from BAL Collapsed and Ventilated Lungs). The standard deviation is capturing the dispersion of the estimate for the mean effect. Ratio of total protein (Ratio was derived from BAL and Plasma values) is presented.
Number of Participants With Positive Immunogenicity Results Post-dosing	Day 8 and Day 31	Serum samples were obtained to determine incidence and titers of serum anti-GSK2862277 antibodies at the specified time points. The binding antibody detection assay was performed at the specified time points. Number of participants with positive immunogenicity results post-dosing is presented.
BAL Concentrations of GSK2862277	Day 1 (on completion of surgery)	BAL samples were collected on Day 1 (on completion of surgery) and BAL concentrations of GSK2862277 and derived PK parameters were determined. Only those participants available at the specified time points were analyzed.
Levels of BAL Biomarkers (Surfactant Protein and Clara Cell Secretory Protein) on Completion of Surgery	Day 1 (on completion of surgery)	Samples were collected to determine concentrations of biomarkers in BAL using an appropriately validated assay. BAL biomarkers included surfactant protein D and clara cell secretory protein. Any value below limit of quantification was replaced with half the LLQ prior to deriving the summary measures. Mean levels of BAL biomarkers on completion of surgery are presented. Only those participants available at the specified time points were analyzed represented by n=X,X,X,X in the category titles.

Countries

United Kingdom

Participant flow

Recruitment details

The study was conducted at 8 centers in the United Kingdom from 28-Apr-2015 to 28-Jun-2017.

Pre-assignment details

A total of 54 participants (included 2 participants who were screen-failures and were re-screened) were screened, of which 21 participants (2 re-entered study) were screen-failures (SF). Reasons for SF: study procedure could not be performed (4), inclusion/exclusion criteria not met (14), study closed/terminated (1) and investigator discretion (2).

Participants by arm

Arm	Count
Placebo (BAL Collapsed Lung) Eligible participants received a single dose of matching placebo on Day 1 via oral inhalation route over approximately 3 to 5 minutes; approximately 1 to 3 hours prior to scheduled surgery. After surgery, participants in this arm underwent collapsed lung BAL procedure on Day 1.	5
Placebo (BAL Ventilated Lung) Eligible participants received a single dose of matching placebo on Day 1 via oral inhalation route over approximately 3 to 5 minutes; approximately 1 to 3 hours prior to scheduled surgery. After surgery, participants in this arm underwent ventilated lung BAL procedure on Day 1.	11
GSK2862277 26 mg (BAL Collapsed Lung) Eligible participants received a single dose of GSK2862277 26 mg on Day 1 via oral inhalation route over approximately 3 to 5 minutes; approximately 1 to 3 hours prior to scheduled surgery. After surgery, participants in this arm underwent collapsed lung BAL procedure on Day 1.	8
GSK2862277 26 mg (BAL Ventilated Lung) Eligible participants received a single dose of GSK2862277 26 mg on Day 1 via oral inhalation route over approximately 3 to 5 minutes; approximately 1 to 3 hours prior to scheduled surgery. After surgery, participants in this arm underwent ventilated lung BAL procedure on Day 1.	9
Total	33

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003
Overall Study	Physician Decision	0	0	1	0

Baseline characteristics

Characteristic	Placebo (BAL Collapsed Lung)	Placebo (BAL Ventilated Lung)	GSK2862277 26 mg (BAL Collapsed Lung)	GSK2862277 26 mg (BAL Ventilated Lung)	Total
Age, Continuous	63.0 Years STANDARD_DEVIATION 9.7	63.5 Years STANDARD_DEVIATION 10.47	62.0 Years STANDARD_DEVIATION 4.69	59.3 Years STANDARD_DEVIATION 10.76	61.9 Years STANDARD_DEVIATION 9.09
Race/Ethnicity, Customized White	5 Participants	11 Participants	8 Participants	9 Participants	33 Participants
Sex: Female, Male Female	0 Participants	4 Participants	0 Participants	2 Participants	6 Participants
Sex: Female, Male Male	5 Participants	7 Participants	8 Participants	7 Participants	27 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	0 / 5	0 / 11	0 / 8	0 / 9
other Total, other adverse events	5 / 5	10 / 11	5 / 8	8 / 9
serious Total, serious adverse events	3 / 5	5 / 11	5 / 8	4 / 9

Outcome results

Primary

Baseline Adjusted Change in Pulmonary Vascular Permeability Index (PVPI) on Completion of Surgery

PVPI is a derived value from extra vascular lung water (EVLW), and is considered to be less variable than extra vascular lung water Index (EVLWI). PVPI was measured via single-indicator transpulmonary thermodilution with a patent indwelling Pulse Contour Cardiac Output (PiCCO) catheter. Baseline was Day 1 (immediately prior to start of surgery). Change from Baseline value was the post-Baseline value (on completion of surgery on Day 1) minus Baseline value. Per-Protocol 1 (PP1) Population comprised of all the participants in the Safety population for whom the treatment actually received was the same one when they were randomized to (both study drug and BAL sampling location).

Time frame: Baseline (Day 1 [immediately prior to start of surgery]) and Day 1 (on completion of surgery)

Population: PP1 Population.

Arm	Measure	Value (MEAN)	Dispersion
Placebo (BAL Collapsed Lung)	Baseline Adjusted Change in Pulmonary Vascular Permeability Index (PVPI) on Completion of Surgery	0.00 Ratio	Standard Deviation 0.367
Placebo (BAL Ventilated Lung)	Baseline Adjusted Change in Pulmonary Vascular Permeability Index (PVPI) on Completion of Surgery	0.11 Ratio	Standard Deviation 0.664
GSK2862277 26 mg (BAL Collapsed Lung)	Baseline Adjusted Change in Pulmonary Vascular Permeability Index (PVPI) on Completion of Surgery	-0.18 Ratio	Standard Deviation 0.536
GSK2862277 26 mg (BAL Ventilated Lung)	Baseline Adjusted Change in Pulmonary Vascular Permeability Index (PVPI) on Completion of Surgery	0.21 Ratio	Standard Deviation 0.449

Secondary

Area Under the Concentration-time Curve From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration (AUC [0 to t])

Blood samples for pharmacokinetic analysis of GSK2862277 were collected at the indicated time points. Pharmacokinetic (PK) Population comprised of all participants in the Safety population for whom a pharmacokinetic sample (plasma and/or BAL) was obtained and analyzed.

Time frame: Day 1 (pre-dose, 1 hour post-dose and on completion of surgery), Day 2 (24 to 26 hours post-dose) and Day 3 (46 to 50 hours post-dose)

Population: PK Population.

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Placebo (BAL Collapsed Lung)	Area Under the Concentration-time Curve From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration (AUC [0 to t])	340505.15 Hours*picograms/milliliter	Geometric Coefficient of Variation 45.284
Placebo (BAL Ventilated Lung)	Area Under the Concentration-time Curve From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration (AUC [0 to t])	290102.64 Hours*picograms/milliliter	Geometric Coefficient of Variation 76.45

Secondary

BAL Concentrations of GSK2862277

BAL samples were collected on Day 1 (on completion of surgery) and BAL concentrations of GSK2862277 and derived PK parameters were determined. Only those participants available at the specified time points were analyzed.

Time frame: Day 1 (on completion of surgery)

Population: PK Population.

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Placebo (BAL Collapsed Lung)	BAL Concentrations of GSK2862277	11220.00 Nanograms per milliliter	—
Placebo (BAL Ventilated Lung)	BAL Concentrations of GSK2862277	74155.37 Nanograms per milliliter	Geometric Coefficient of Variation 377

Secondary

Baseline Adjusted Change in EVLWI on Completion of Surgery

EVLW refers to the fluid within the lung but outside the vascular compartment. It includes extravasated plasma, intracellular water, lymphatic fluid, and surfactant. EVLWI was measured by trans-pulmonary thermodilution via a PiCCO hemodynamic monitor. Baseline was Day 1 (immediately prior to start of surgery). Change from Baseline value was the post-Baseline value (on completion of surgery on Day 1) minus Baseline value. Only those participants with data available at the specified time points were analyzed.

Time frame: Baseline (Day 1 [immediately prior to start of surgery]) and Day 1 (on completion of surgery)

Population: PP1 Population.

Arm	Measure	Value (MEAN)	Dispersion
Placebo (BAL Collapsed Lung)	Baseline Adjusted Change in EVLWI on Completion of Surgery	0.462 Milliliters per kilograms	Standard Deviation 1.4731
Placebo (BAL Ventilated Lung)	Baseline Adjusted Change in EVLWI on Completion of Surgery	-0.317 Milliliters per kilograms	Standard Deviation 1.3436
GSK2862277 26 mg (BAL Collapsed Lung)	Baseline Adjusted Change in EVLWI on Completion of Surgery	0.008 Milliliters per kilograms	Standard Deviation 1.2527
GSK2862277 26 mg (BAL Ventilated Lung)	Baseline Adjusted Change in EVLWI on Completion of Surgery	-0.300 Milliliters per kilograms	Standard Deviation 3.8403

Secondary

Baseline Adjusted Change in PaO2/FiO2 on Completion of Surgery

Oxygenation and function of gas exchange was assessed by the comparison of partial pressure of oxygen arterially (PaO2) divided by the fraction of oxygen that is being inspired (FiO2), sometimes referred to simply as the 'P to F ratio'. The P to F ratio was assessed at time points during the period of intubation and mechanical ventilation. An arterial blood sample was required for determination of the partial pressure of oxygen and the percentage of O2 which is being inspired was recorded at the corresponding time point. Baseline was Day 1 (immediately prior to start of surgery). Change from Baseline value was the post-Baseline value (on completion of surgery on Day 1) minus Baseline value.

Time frame: Baseline (Day 1 [immediately prior to start of surgery]) and Day 1 (on completion of surgery)

Population: PP1 Population.

Arm	Measure	Value (MEAN)	Dispersion
Placebo (BAL Collapsed Lung)	Baseline Adjusted Change in PaO2/FiO2 on Completion of Surgery	8.9 Millimiters of Mercury	Standard Deviation 141.1
Placebo (BAL Ventilated Lung)	Baseline Adjusted Change in PaO2/FiO2 on Completion of Surgery	18.5 Millimiters of Mercury	Standard Deviation 160.82
GSK2862277 26 mg (BAL Collapsed Lung)	Baseline Adjusted Change in PaO2/FiO2 on Completion of Surgery	-47.5 Millimiters of Mercury	Standard Deviation 252.16
GSK2862277 26 mg (BAL Ventilated Lung)	Baseline Adjusted Change in PaO2/FiO2 on Completion of Surgery	11.2 Millimiters of Mercury	Standard Deviation 98.12

Secondary

Change Over Time in EVLWI Post-operatively on Day 2 Through to Day 4

EVLW refers to the fluid within the lung but outside the vascular compartment. It includes extravasated plasma, intracellular water, lymphatic fluid, and surfactant. EVLWI was measured by trans-pulmonary thermodilution via a PiCCO hemodynamic monitor. Change from Baseline value was the post-Baseline value minus Baseline value. PP1 Population was analyzed. Only those participants available at the specified time points were analyzed represented by n=X,X,X,X in the category titles.

Time frame: Baseline (Day 1 [immediately prior to start of surgery]) to Days 2, 3 and 4

Population: PP1 Population.

Arm	Measure	Group	Value (MEAN)	Dispersion
Placebo (BAL Collapsed Lung)	Change Over Time in EVLWI Post-operatively on Day 2 Through to Day 4	Day 2, n=5,6,3,5	-0.033 Millimeters per kilograms	Standard Deviation 1.1203
Placebo (BAL Collapsed Lung)	Change Over Time in EVLWI Post-operatively on Day 2 Through to Day 4	Day 4, n=3,5,2,4	-0.621 Millimeters per kilograms	Standard Deviation 0.2646
Placebo (BAL Collapsed Lung)	Change Over Time in EVLWI Post-operatively on Day 2 Through to Day 4	Day 3, n=4,5,3,5	0.062 Millimeters per kilograms	Standard Deviation 1.2468
Placebo (BAL Ventilated Lung)	Change Over Time in EVLWI Post-operatively on Day 2 Through to Day 4	Day 2, n=5,6,3,5	-1.120 Millimeters per kilograms	Standard Deviation 2.4825
Placebo (BAL Ventilated Lung)	Change Over Time in EVLWI Post-operatively on Day 2 Through to Day 4	Day 4, n=3,5,2,4	0.828 Millimeters per kilograms	Standard Deviation 4.1772
Placebo (BAL Ventilated Lung)	Change Over Time in EVLWI Post-operatively on Day 2 Through to Day 4	Day 3, n=4,5,3,5	-0.190 Millimeters per kilograms	Standard Deviation 1.4762
GSK2862277 26 mg (BAL Collapsed Lung)	Change Over Time in EVLWI Post-operatively on Day 2 Through to Day 4	Day 3, n=4,5,3,5	-0.203 Millimeters per kilograms	Standard Deviation 2.3349
GSK2862277 26 mg (BAL Collapsed Lung)	Change Over Time in EVLWI Post-operatively on Day 2 Through to Day 4	Day 2, n=5,6,3,5	-0.694 Millimeters per kilograms	Standard Deviation 0.871
GSK2862277 26 mg (BAL Collapsed Lung)	Change Over Time in EVLWI Post-operatively on Day 2 Through to Day 4	Day 4, n=3,5,2,4	0.311 Millimeters per kilograms	Standard Deviation 1.9297
GSK2862277 26 mg (BAL Ventilated Lung)	Change Over Time in EVLWI Post-operatively on Day 2 Through to Day 4	Day 2, n=5,6,3,5	0.604 Millimeters per kilograms	Standard Deviation 1.337
GSK2862277 26 mg (BAL Ventilated Lung)	Change Over Time in EVLWI Post-operatively on Day 2 Through to Day 4	Day 4, n=3,5,2,4	1.981 Millimeters per kilograms	Standard Deviation 2.8449
GSK2862277 26 mg (BAL Ventilated Lung)	Change Over Time in EVLWI Post-operatively on Day 2 Through to Day 4	Day 3, n=4,5,3,5	0.755 Millimeters per kilograms	Standard Deviation 1.4801

Secondary

Change Over Time in PaO2/FiO2 Post-operatively on Day 2 Through to Day 4

Oxygenation and function of gas exchange was assessed by the comparison of PaO2 divided by the FiO2, sometimes referred to simply as the 'P to F ratio'. The P to F ratio was assessed at time points during the period of intubation and mechanical ventilation. An arterial blood sample was required for determination of the partial pressure of oxygen and the percentage of O2 which is being inspired was recorded at the corresponding time point. Baseline was Day 1 (immediately prior to start of surgery). Change from Baseline value was the post-Baseline value (on completion of surgery on Day 1) minus Baseline value. PP1 Population was analyzed. Only those participants available at the specified time points were analyzed represented by n=X,X in the category titles.

Time frame: Baseline (Day 1 [immediately prior to start of surgery]) to Days 2, 3 and 4

Population: PP1 Population.

Arm	Measure	Group	Value (MEAN)	Dispersion
Placebo (BAL Collapsed Lung)	Change Over Time in PaO2/FiO2 Post-operatively on Day 2 Through to Day 4	Day 2, n=5,8,5,6	-15.1 Millimeters of Mercury	Standard Deviation 171.84
Placebo (BAL Collapsed Lung)	Change Over Time in PaO2/FiO2 Post-operatively on Day 2 Through to Day 4	Day 4, n=5,8,5,5	-36.3 Millimeters of Mercury	Standard Deviation 139.18
Placebo (BAL Collapsed Lung)	Change Over Time in PaO2/FiO2 Post-operatively on Day 2 Through to Day 4	Day 3, n=5,8,5,5	-53.7 Millimeters of Mercury	Standard Deviation 120.35
Placebo (BAL Ventilated Lung)	Change Over Time in PaO2/FiO2 Post-operatively on Day 2 Through to Day 4	Day 2, n=5,8,5,6	-103.3 Millimeters of Mercury	Standard Deviation 87.24
Placebo (BAL Ventilated Lung)	Change Over Time in PaO2/FiO2 Post-operatively on Day 2 Through to Day 4	Day 4, n=5,8,5,5	-123.6 Millimeters of Mercury	Standard Deviation 68.14
Placebo (BAL Ventilated Lung)	Change Over Time in PaO2/FiO2 Post-operatively on Day 2 Through to Day 4	Day 3, n=5,8,5,5	-43.0 Millimeters of Mercury	Standard Deviation 179.64
GSK2862277 26 mg (BAL Collapsed Lung)	Change Over Time in PaO2/FiO2 Post-operatively on Day 2 Through to Day 4	Day 3, n=5,8,5,5	-9.5 Millimeters of Mercury	Standard Deviation 325.46
GSK2862277 26 mg (BAL Collapsed Lung)	Change Over Time in PaO2/FiO2 Post-operatively on Day 2 Through to Day 4	Day 2, n=5,8,5,6	38.9 Millimeters of Mercury	Standard Deviation 312.28
GSK2862277 26 mg (BAL Collapsed Lung)	Change Over Time in PaO2/FiO2 Post-operatively on Day 2 Through to Day 4	Day 4, n=5,8,5,5	-22.3 Millimeters of Mercury	Standard Deviation 342.46
GSK2862277 26 mg (BAL Ventilated Lung)	Change Over Time in PaO2/FiO2 Post-operatively on Day 2 Through to Day 4	Day 2, n=5,8,5,6	-79.3 Millimeters of Mercury	Standard Deviation 199.85
GSK2862277 26 mg (BAL Ventilated Lung)	Change Over Time in PaO2/FiO2 Post-operatively on Day 2 Through to Day 4	Day 4, n=5,8,5,5	-56.5 Millimeters of Mercury	Standard Deviation 123.31
GSK2862277 26 mg (BAL Ventilated Lung)	Change Over Time in PaO2/FiO2 Post-operatively on Day 2 Through to Day 4	Day 3, n=5,8,5,5	-119.0 Millimeters of Mercury	Standard Deviation 148.67

Secondary

Change Over Time in PVPI Post-operatively on Day 2 Through to Day 4

PVPI is a derived value from EVLW, and is considered to be less variable than EVLWI. PVPI was measured via single-indicator transpulmonary thermodilution as long as the participant remained in the ICU with a patent indwelling PiCCO catheter. Baseline was Day 1 (immediately prior to start of surgery). Change from Baseline value was the post-Baseline value minus Baseline value. PP1 Population was analyzed. Only those participants available at the specified time points were analyzed represented by n=X,X,X,X in the category titles.

Time frame: Baseline (Day 1 [immediately prior to start of surgery]) to Days 2, 3 and 4

Population: PP1 Population.

Arm	Measure	Group	Value (MEAN)	Dispersion
Placebo (BAL Collapsed Lung)	Change Over Time in PVPI Post-operatively on Day 2 Through to Day 4	Day 2, n=5,6,3,5	-0.22 Ratio	Standard Deviation 0.259
Placebo (BAL Collapsed Lung)	Change Over Time in PVPI Post-operatively on Day 2 Through to Day 4	Day 4, n=3,5,2,4	-0.40 Ratio	Standard Deviation 0.2
Placebo (BAL Collapsed Lung)	Change Over Time in PVPI Post-operatively on Day 2 Through to Day 4	Day 3, n=4,6,3,5	-0.20 Ratio	Standard Deviation 0.648
Placebo (BAL Ventilated Lung)	Change Over Time in PVPI Post-operatively on Day 2 Through to Day 4	Day 2, n=5,6,3,5	-0.27 Ratio	Standard Deviation 0.427
Placebo (BAL Ventilated Lung)	Change Over Time in PVPI Post-operatively on Day 2 Through to Day 4	Day 4, n=3,5,2,4	-0.24 Ratio	Standard Deviation 0.666
Placebo (BAL Ventilated Lung)	Change Over Time in PVPI Post-operatively on Day 2 Through to Day 4	Day 3, n=4,6,3,5	-0.23 Ratio	Standard Deviation 0.516
GSK2862277 26 mg (BAL Collapsed Lung)	Change Over Time in PVPI Post-operatively on Day 2 Through to Day 4	Day 3, n=4,6,3,5	-0.30 Ratio	Standard Deviation 0.529
GSK2862277 26 mg (BAL Collapsed Lung)	Change Over Time in PVPI Post-operatively on Day 2 Through to Day 4	Day 2, n=5,6,3,5	-0.50 Ratio	Standard Deviation 0.346
GSK2862277 26 mg (BAL Collapsed Lung)	Change Over Time in PVPI Post-operatively on Day 2 Through to Day 4	Day 4, n=3,5,2,4	-0.20 Ratio	Standard Deviation 0
GSK2862277 26 mg (BAL Ventilated Lung)	Change Over Time in PVPI Post-operatively on Day 2 Through to Day 4	Day 2, n=5,6,3,5	-0.42 Ratio	Standard Deviation 0.63
GSK2862277 26 mg (BAL Ventilated Lung)	Change Over Time in PVPI Post-operatively on Day 2 Through to Day 4	Day 4, n=3,5,2,4	-0.08 Ratio	Standard Deviation 0.85
GSK2862277 26 mg (BAL Ventilated Lung)	Change Over Time in PVPI Post-operatively on Day 2 Through to Day 4	Day 3, n=4,6,3,5	-0.32 Ratio	Standard Deviation 0.756

Secondary

Daily Sequential Organ Failure Assessment (SOFA) Scores on Day 2 Through to Day 4

The SOFA score defines the presence and severity of dysfunction within 6 organ systems (cardiovascular, respiratory, coagulation, liver, renal, and nervous system) with a value of 0 for assigned to normal function to a maximum value of 4 for severe dysfunction in each of the organ systems. Each component of the SOFA score was added together, ranging from 0 indicating no organ dysfunction in any of the 6 organ systems, to 24 indicating maximal organ dysfunction across all 6 organ systems. Per-Protocol (PP) 2 Population comprised of all the participants in the Safety population for whom the study drug actually received was the same one they were randomized to (study drug).

Time frame: Day 2 to Day 4

Population: PP 2 Population.

Arm	Measure	Group	Value (MEAN)	Dispersion
Placebo (BAL Collapsed Lung)	Daily Sequential Organ Failure Assessment (SOFA) Scores on Day 2 Through to Day 4	Day 2	1.0 Scores on a Scale	Standard Deviation 2.24
Placebo (BAL Collapsed Lung)	Daily Sequential Organ Failure Assessment (SOFA) Scores on Day 2 Through to Day 4	Day 4	2.2 Scores on a Scale	Standard Deviation 3.96
Placebo (BAL Collapsed Lung)	Daily Sequential Organ Failure Assessment (SOFA) Scores on Day 2 Through to Day 4	Day 3	3.4 Scores on a Scale	Standard Deviation 4.72
Placebo (BAL Ventilated Lung)	Daily Sequential Organ Failure Assessment (SOFA) Scores on Day 2 Through to Day 4	Day 2	1.6 Scores on a Scale	Standard Deviation 1.39
Placebo (BAL Ventilated Lung)	Daily Sequential Organ Failure Assessment (SOFA) Scores on Day 2 Through to Day 4	Day 4	1.3 Scores on a Scale	Standard Deviation 0.9
Placebo (BAL Ventilated Lung)	Daily Sequential Organ Failure Assessment (SOFA) Scores on Day 2 Through to Day 4	Day 3	1.5 Scores on a Scale	Standard Deviation 1.8
GSK2862277 26 mg (BAL Collapsed Lung)	Daily Sequential Organ Failure Assessment (SOFA) Scores on Day 2 Through to Day 4	Day 3	1.8 Scores on a Scale	Standard Deviation 2.86
GSK2862277 26 mg (BAL Collapsed Lung)	Daily Sequential Organ Failure Assessment (SOFA) Scores on Day 2 Through to Day 4	Day 2	1.5 Scores on a Scale	Standard Deviation 2.54
GSK2862277 26 mg (BAL Collapsed Lung)	Daily Sequential Organ Failure Assessment (SOFA) Scores on Day 2 Through to Day 4	Day 4	1.3 Scores on a Scale	Standard Deviation 3.56
GSK2862277 26 mg (BAL Ventilated Lung)	Daily Sequential Organ Failure Assessment (SOFA) Scores on Day 2 Through to Day 4	Day 2	2.1 Scores on a Scale	Standard Deviation 1.92
GSK2862277 26 mg (BAL Ventilated Lung)	Daily Sequential Organ Failure Assessment (SOFA) Scores on Day 2 Through to Day 4	Day 4	1.6 Scores on a Scale	Standard Deviation 1.69
GSK2862277 26 mg (BAL Ventilated Lung)	Daily Sequential Organ Failure Assessment (SOFA) Scores on Day 2 Through to Day 4	Day 3	1.6 Scores on a Scale	Standard Deviation 1.43

Secondary

Derived Pharmacokinetic Parameter- Half-life (t1/2) and Time of Occurrence of Cmax (Tmax)

Half-life (t1⁄2) is the time required for a quantity to reduce to half its initial value. t1/2 was not determined in all cases due to insufficient data in the terminal phase. Blood samples for pharmacokinetic analysis of GSK2862277 were collected at the indicated time points. Only those participants available at the specified time points were analyzed represented by n=X,X in the category titles.

Time frame: Day 1 (pre-dose, 1 hour post-dose and on completion of surgery), Day 2 (24 to 26 hours post-dose) and Day 3 (46 to 50 hours post-dose)

Population: PK Population.

Arm	Measure	Group	Value (GEOMETRIC_MEAN)	Dispersion
Placebo (BAL Collapsed Lung)	Derived Pharmacokinetic Parameter- Half-life (t1/2) and Time of Occurrence of Cmax (Tmax)	Tmax, n=3,6	7.584 Hours	Geometric Coefficient of Variation 11.4958
Placebo (BAL Ventilated Lung)	Derived Pharmacokinetic Parameter- Half-life (t1/2) and Time of Occurrence of Cmax (Tmax)	Tmax, n=3,6	7.583 Hours	Geometric Coefficient of Variation 11.4119
Unknown	Derived Pharmacokinetic Parameter- Half-life (t1/2) and Time of Occurrence of Cmax (Tmax)	t1/2, n=0,0	— Hours	—

Secondary

Levels of BAL Biomarkers (C-reactive Protein and Total Proteins) on Completion of Surgery

Samples were collected to determine concentrations of biomarkers in BAL using an appropriately validated assay. BAL biomarkers included C-reactive protein and total proteins. Any value below limit of quantification was replaced with half the LLQ prior to deriving the summary measures. All BAL C-reactive protein samples were below limit of quantification and all were assigned to half the LLQ prior to deriving the summary measures. Mean levels of BAL biomarkers on completion of surgery are presented. Only those participants available at the specified time points were analyzed represented by n=X,X,X,X in the category titles.

Time frame: Day 1 (on completion of surgery)

Population: PP1 Population.

Arm	Measure	Group	Value (MEAN)	Dispersion
Placebo (BAL Collapsed Lung)	Levels of BAL Biomarkers (C-reactive Protein and Total Proteins) on Completion of Surgery	C-reactive protein, n=5,9,5,8	0.04650 Milligrams per Liter	Standard Deviation 0
Placebo (BAL Collapsed Lung)	Levels of BAL Biomarkers (C-reactive Protein and Total Proteins) on Completion of Surgery	Total proteins, n=5,10,5,8	423.6 Milligrams per Liter	Standard Deviation 182.8
Placebo (BAL Ventilated Lung)	Levels of BAL Biomarkers (C-reactive Protein and Total Proteins) on Completion of Surgery	Total proteins, n=5,10,5,8	605.1 Milligrams per Liter	Standard Deviation 670.6
Placebo (BAL Ventilated Lung)	Levels of BAL Biomarkers (C-reactive Protein and Total Proteins) on Completion of Surgery	C-reactive protein, n=5,9,5,8	0.04650 Milligrams per Liter	Standard Deviation 0
GSK2862277 26 mg (BAL Collapsed Lung)	Levels of BAL Biomarkers (C-reactive Protein and Total Proteins) on Completion of Surgery	C-reactive protein, n=5,9,5,8	0.04650 Milligrams per Liter	Standard Deviation 0
GSK2862277 26 mg (BAL Collapsed Lung)	Levels of BAL Biomarkers (C-reactive Protein and Total Proteins) on Completion of Surgery	Total proteins, n=5,10,5,8	136.8 Milligrams per Liter	Standard Deviation 108.33
GSK2862277 26 mg (BAL Ventilated Lung)	Levels of BAL Biomarkers (C-reactive Protein and Total Proteins) on Completion of Surgery	C-reactive protein, n=5,9,5,8	0.04650 Milligrams per Liter	Standard Deviation 0
GSK2862277 26 mg (BAL Ventilated Lung)	Levels of BAL Biomarkers (C-reactive Protein and Total Proteins) on Completion of Surgery	Total proteins, n=5,10,5,8	303.0 Milligrams per Liter	Standard Deviation 274.85

Secondary

Levels of BAL Biomarkers on Completion of Surgery

Samples were collected to determine concentrations of biomarkers in BAL using an appropriately validated assay on Day 1 after completion of surgery. BAL biomarkers included soluble tumor necrosis factor receptor (STNFR) type I, free, STNFR type I, total, tumor necrosis factor alpha, interleukin 6, interleukin 8, interleukin 1 beta, monocyte chemotactic protein-1, macrophage inflammatory protein 1 alpha, macrophage inflammatory protein 1 beta, interleukin 10 and soluble receptor for advanced glycation end (sRAGE) products. Any value below limit of quantification was replaced with half the lower limit of quantification (LLQ) prior to deriving the summary measures. Mean levels of BAL biomarkers on completion of surgery are presented. Only those participants available at the specified time points were analyzed represented by n=X,X,X,X in the category titles.

Time frame: Day 1 (on completion of surgery)

Population: PP1 Population.

Arm	Measure	Group	Value (MEAN)	Dispersion
Placebo (BAL Collapsed Lung)	Levels of BAL Biomarkers on Completion of Surgery	STNFR type I, Free, n=5,9,5,8	645.5400 Picograms per milliliter	Standard Deviation 398.14834
Placebo (BAL Collapsed Lung)	Levels of BAL Biomarkers on Completion of Surgery	Interleukin 6, n=5,9,5,8	63.580 Picograms per milliliter	Standard Deviation 66.8285
Placebo (BAL Collapsed Lung)	Levels of BAL Biomarkers on Completion of Surgery	Macrophage inflammatory protein 1 alpha, n=5,9,5,8	63.348 Picograms per milliliter	Standard Deviation 54.8461
Placebo (BAL Collapsed Lung)	Levels of BAL Biomarkers on Completion of Surgery	STNFR I, Total, n=5,9,5,8	299.4000 Picograms per milliliter	Standard Deviation 168.92556
Placebo (BAL Collapsed Lung)	Levels of BAL Biomarkers on Completion of Surgery	Monocyte chemotactic protein-1, n=5,9,5,8	118.1600 Picograms per milliliter	Standard Deviation 124.52553
Placebo (BAL Collapsed Lung)	Levels of BAL Biomarkers on Completion of Surgery	Interleukin 8, n=5,9,5,8	8041.600 Picograms per milliliter	Standard Deviation 16369.4998
Placebo (BAL Collapsed Lung)	Levels of BAL Biomarkers on Completion of Surgery	Tumor necrosis factor alpha, n=5,9,5,7	3.5110 Picograms per milliliter	Standard Deviation 2.68376
Placebo (BAL Collapsed Lung)	Levels of BAL Biomarkers on Completion of Surgery	sRAGE products, n=5,9,5,8	1440.2 Picograms per milliliter	Standard Deviation 1144.89
Placebo (BAL Collapsed Lung)	Levels of BAL Biomarkers on Completion of Surgery	Interleukin 10, n=5,9,5,8	1.7098 Picograms per milliliter	Standard Deviation 1.93498
Placebo (BAL Collapsed Lung)	Levels of BAL Biomarkers on Completion of Surgery	Interleukin 1 beta, n=5,9,5,8	70.2376 Picograms per milliliter	Standard Deviation 123.55622
Placebo (BAL Collapsed Lung)	Levels of BAL Biomarkers on Completion of Surgery	Macrophage inflammatory protein 1 beta, n=5,9,5,8	142.040 Picograms per milliliter	Standard Deviation 132.7086
Placebo (BAL Ventilated Lung)	Levels of BAL Biomarkers on Completion of Surgery	Interleukin 1 beta, n=5,9,5,8	66.3749 Picograms per milliliter	Standard Deviation 99.46797
Placebo (BAL Ventilated Lung)	Levels of BAL Biomarkers on Completion of Surgery	Macrophage inflammatory protein 1 beta, n=5,9,5,8	219.891 Picograms per milliliter	Standard Deviation 264.1694
Placebo (BAL Ventilated Lung)	Levels of BAL Biomarkers on Completion of Surgery	Monocyte chemotactic protein-1, n=5,9,5,8	122.2649 Picograms per milliliter	Standard Deviation 170.65326
Placebo (BAL Ventilated Lung)	Levels of BAL Biomarkers on Completion of Surgery	Macrophage inflammatory protein 1 alpha, n=5,9,5,8	165.300 Picograms per milliliter	Standard Deviation 203.2446
Placebo (BAL Ventilated Lung)	Levels of BAL Biomarkers on Completion of Surgery	Tumor necrosis factor alpha, n=5,9,5,7	24.3850 Picograms per milliliter	Standard Deviation 33.67945
Placebo (BAL Ventilated Lung)	Levels of BAL Biomarkers on Completion of Surgery	sRAGE products, n=5,9,5,8	2121.7 Picograms per milliliter	Standard Deviation 2078.47
Placebo (BAL Ventilated Lung)	Levels of BAL Biomarkers on Completion of Surgery	Interleukin 6, n=5,9,5,8	138.917 Picograms per milliliter	Standard Deviation 217.3948
Placebo (BAL Ventilated Lung)	Levels of BAL Biomarkers on Completion of Surgery	Interleukin 10, n=5,9,5,8	5.2672 Picograms per milliliter	Standard Deviation 8.39023
Placebo (BAL Ventilated Lung)	Levels of BAL Biomarkers on Completion of Surgery	Interleukin 8, n=5,9,5,8	3822.170 Picograms per milliliter	Standard Deviation 6270.8199
Placebo (BAL Ventilated Lung)	Levels of BAL Biomarkers on Completion of Surgery	STNFR I, Total, n=5,9,5,8	310.8136 Picograms per milliliter	Standard Deviation 307.29751
Placebo (BAL Ventilated Lung)	Levels of BAL Biomarkers on Completion of Surgery	STNFR type I, Free, n=5,9,5,8	278.2529 Picograms per milliliter	Standard Deviation 201.58668
GSK2862277 26 mg (BAL Collapsed Lung)	Levels of BAL Biomarkers on Completion of Surgery	Interleukin 10, n=5,9,5,8	0.5130 Picograms per milliliter	Standard Deviation 0
GSK2862277 26 mg (BAL Collapsed Lung)	Levels of BAL Biomarkers on Completion of Surgery	STNFR type I, Free, n=5,9,5,8	106.1600 Picograms per milliliter	Standard Deviation 168.39828
GSK2862277 26 mg (BAL Collapsed Lung)	Levels of BAL Biomarkers on Completion of Surgery	STNFR I, Total, n=5,9,5,8	175.5660 Picograms per milliliter	Standard Deviation 167.67312
GSK2862277 26 mg (BAL Collapsed Lung)	Levels of BAL Biomarkers on Completion of Surgery	Tumor necrosis factor alpha, n=5,9,5,7	6.1040 Picograms per milliliter	Standard Deviation 12.51974
GSK2862277 26 mg (BAL Collapsed Lung)	Levels of BAL Biomarkers on Completion of Surgery	Interleukin 6, n=5,9,5,8	15.844 Picograms per milliliter	Standard Deviation 30.5243
GSK2862277 26 mg (BAL Collapsed Lung)	Levels of BAL Biomarkers on Completion of Surgery	Interleukin 8, n=5,9,5,8	126.340 Picograms per milliliter	Standard Deviation 145.1019
GSK2862277 26 mg (BAL Collapsed Lung)	Levels of BAL Biomarkers on Completion of Surgery	Interleukin 1 beta, n=5,9,5,8	1.1674 Picograms per milliliter	Standard Deviation 0.78732
GSK2862277 26 mg (BAL Collapsed Lung)	Levels of BAL Biomarkers on Completion of Surgery	Monocyte chemotactic protein-1, n=5,9,5,8	53.4260 Picograms per milliliter	Standard Deviation 75.21106
GSK2862277 26 mg (BAL Collapsed Lung)	Levels of BAL Biomarkers on Completion of Surgery	Macrophage inflammatory protein 1 alpha, n=5,9,5,8	9.140 Picograms per milliliter	Standard Deviation 0
GSK2862277 26 mg (BAL Collapsed Lung)	Levels of BAL Biomarkers on Completion of Surgery	Macrophage inflammatory protein 1 beta, n=5,9,5,8	28.292 Picograms per milliliter	Standard Deviation 41.4424
GSK2862277 26 mg (BAL Collapsed Lung)	Levels of BAL Biomarkers on Completion of Surgery	sRAGE products, n=5,9,5,8	1966.0 Picograms per milliliter	Standard Deviation 2734.6
GSK2862277 26 mg (BAL Ventilated Lung)	Levels of BAL Biomarkers on Completion of Surgery	Interleukin 1 beta, n=5,9,5,8	18.6054 Picograms per milliliter	Standard Deviation 38.61022
GSK2862277 26 mg (BAL Ventilated Lung)	Levels of BAL Biomarkers on Completion of Surgery	sRAGE products, n=5,9,5,8	1044.6 Picograms per milliliter	Standard Deviation 1560.45
GSK2862277 26 mg (BAL Ventilated Lung)	Levels of BAL Biomarkers on Completion of Surgery	Macrophage inflammatory protein 1 beta, n=5,9,5,8	48.413 Picograms per milliliter	Standard Deviation 82.2684
GSK2862277 26 mg (BAL Ventilated Lung)	Levels of BAL Biomarkers on Completion of Surgery	Interleukin 8, n=5,9,5,8	432.513 Picograms per milliliter	Standard Deviation 731.0601
GSK2862277 26 mg (BAL Ventilated Lung)	Levels of BAL Biomarkers on Completion of Surgery	Interleukin 6, n=5,9,5,8	43.828 Picograms per milliliter	Standard Deviation 64.0092
GSK2862277 26 mg (BAL Ventilated Lung)	Levels of BAL Biomarkers on Completion of Surgery	Tumor necrosis factor alpha, n=5,9,5,7	3.7814 Picograms per milliliter	Standard Deviation 5.33211
GSK2862277 26 mg (BAL Ventilated Lung)	Levels of BAL Biomarkers on Completion of Surgery	Interleukin 10, n=5,9,5,8	1.8123 Picograms per milliliter	Standard Deviation 3.23279
GSK2862277 26 mg (BAL Ventilated Lung)	Levels of BAL Biomarkers on Completion of Surgery	STNFR I, Total, n=5,9,5,8	183.9000 Picograms per milliliter	Standard Deviation 229.72939
GSK2862277 26 mg (BAL Ventilated Lung)	Levels of BAL Biomarkers on Completion of Surgery	STNFR type I, Free, n=5,9,5,8	67.7713 Picograms per milliliter	Standard Deviation 69.69634
GSK2862277 26 mg (BAL Ventilated Lung)	Levels of BAL Biomarkers on Completion of Surgery	Macrophage inflammatory protein 1 alpha, n=5,9,5,8	23.942 Picograms per milliliter	Standard Deviation 32.7837
GSK2862277 26 mg (BAL Ventilated Lung)	Levels of BAL Biomarkers on Completion of Surgery	Monocyte chemotactic protein-1, n=5,9,5,8	51.5713 Picograms per milliliter	Standard Deviation 59.72512

Secondary

Levels of BAL Biomarkers (Surfactant Protein and Clara Cell Secretory Protein) on Completion of Surgery

Samples were collected to determine concentrations of biomarkers in BAL using an appropriately validated assay. BAL biomarkers included surfactant protein D and clara cell secretory protein. Any value below limit of quantification was replaced with half the LLQ prior to deriving the summary measures. Mean levels of BAL biomarkers on completion of surgery are presented. Only those participants available at the specified time points were analyzed represented by n=X,X,X,X in the category titles.

Time frame: Day 1 (on completion of surgery)

Population: PP1 Population.

Arm	Measure	Group	Value (MEAN)	Dispersion
Placebo (BAL Collapsed Lung)	Levels of BAL Biomarkers (Surfactant Protein and Clara Cell Secretory Protein) on Completion of Surgery	Surfactant Protein D, n=5,9,5,8	411.92 Nanograms per milliliter	Standard Deviation 472.487
Placebo (BAL Collapsed Lung)	Levels of BAL Biomarkers (Surfactant Protein and Clara Cell Secretory Protein) on Completion of Surgery	Clara cell secretory protein, n=5,7,5,7	3635.40 Nanograms per milliliter	Standard Deviation 2575.875
Placebo (BAL Ventilated Lung)	Levels of BAL Biomarkers (Surfactant Protein and Clara Cell Secretory Protein) on Completion of Surgery	Clara cell secretory protein, n=5,7,5,7	2131.66 Nanograms per milliliter	Standard Deviation 3217.852
Placebo (BAL Ventilated Lung)	Levels of BAL Biomarkers (Surfactant Protein and Clara Cell Secretory Protein) on Completion of Surgery	Surfactant Protein D, n=5,9,5,8	760.04 Nanograms per milliliter	Standard Deviation 898.224
GSK2862277 26 mg (BAL Collapsed Lung)	Levels of BAL Biomarkers (Surfactant Protein and Clara Cell Secretory Protein) on Completion of Surgery	Surfactant Protein D, n=5,9,5,8	872.88 Nanograms per milliliter	Standard Deviation 848.358
GSK2862277 26 mg (BAL Collapsed Lung)	Levels of BAL Biomarkers (Surfactant Protein and Clara Cell Secretory Protein) on Completion of Surgery	Clara cell secretory protein, n=5,7,5,7	1000.40 Nanograms per milliliter	Standard Deviation 1167.704
GSK2862277 26 mg (BAL Ventilated Lung)	Levels of BAL Biomarkers (Surfactant Protein and Clara Cell Secretory Protein) on Completion of Surgery	Surfactant Protein D, n=5,9,5,8	551.31 Nanograms per milliliter	Standard Deviation 943.64
GSK2862277 26 mg (BAL Ventilated Lung)	Levels of BAL Biomarkers (Surfactant Protein and Clara Cell Secretory Protein) on Completion of Surgery	Clara cell secretory protein, n=5,7,5,7	1409.21 Nanograms per milliliter	Standard Deviation 2358.501

Secondary

Maximum Observed Concentration (Cmax)

Blood samples for pharmacokinetic analysis of GSK2862277 were collected at the indicated time points.

Time frame: Day 1 (pre-dose, 1 hour post-dose and on completion of surgery), Day 2 (24 to 26 hours post-dose) and Day 3 (46 to 50 hours post-dose)

Population: PK Population.

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Placebo (BAL Collapsed Lung)	Maximum Observed Concentration (Cmax)	31123.58 Picograms per milliliters	Geometric Coefficient of Variation 64.452
Placebo (BAL Ventilated Lung)	Maximum Observed Concentration (Cmax)	25469.14 Picograms per milliliters	Geometric Coefficient of Variation 93.307

Secondary

Number of Participants With Abnormal Urinalysis Parameters

Urinalysis included dipstick urine test which was used to screen for glucose, ketones, occult blood and protein on Day 1 (pre-dose) and Day 8. The dipstick test gives results in a semi-quantitative manner, and results for urinalysis parameters of urine glucose, ketones, occult blood and protein can be read as Trace, 1+, 2+ and 3+, indicating proportional concentrations in the urine sample.

Time frame: Day 1 (pre-dose) and Day 8