Trial Outcomes & Findings for Study of GSK1278863 to Reduce Ischemic Events in Patients Undergoing Thoracic Aortic Aneurysm Repair (NCT NCT01920594)

NCT ID: NCT01920594

Last Updated: 2017-12-07

Results Overview

S100 beta is a CSF biomarker that rise significantly in participants with neurologic injury following DTA/TAAA surgery. CSF samples were collected at Baseline and within 48 hours following DTA/TAAA repair to assess peak change from Baseline in CSF S100 beta. Baseline was defined at Day 0. Change from Baseline was calculated as post-Baseline value minus Baseline value.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

57 participants

Primary outcome timeframe

Baseline (Day 0) to 48 hours following DTA/TAAA repair

Results posted on

2017-12-07

Participant Flow

This study was conducted across 10 centers in the United States and 2 centers in Canada from 31 October 2013 to 08 October 2014.

A total of 55 participants were randomized in the study and were included in All Subjects Population. Participants were stratified according to intervention type (surgical or endovascular repair, with the latter limited to 50% of the total study population).

Participant milestones

Participant milestones
Measure	GSK1278863 300 mg Loading + 100 mg QD Eligible participants received GSK1278863 300 milligrams (mg) on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by GSK1278863 100 mg once daily (QD) for 4 days starting from Day 0 (surgical day).	Placebo Eligible participants received Placebo matching GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by Placebo matching GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).
Overall Study STARTED	27	28
Overall Study COMPLETED	20	25
Overall Study NOT COMPLETED	7	3

Reasons for withdrawal

Reasons for withdrawal
Measure	GSK1278863 300 mg Loading + 100 mg QD Eligible participants received GSK1278863 300 milligrams (mg) on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by GSK1278863 100 mg once daily (QD) for 4 days starting from Day 0 (surgical day).	Placebo Eligible participants received Placebo matching GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by Placebo matching GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).
Overall Study Adverse Event	4	2
Overall Study Lost to Follow-up	1	0
Overall Study Recovery	2	0
Overall Study Investigator discretion	0	1

Baseline Characteristics

Study of GSK1278863 to Reduce Ischemic Events in Patients Undergoing Thoracic Aortic Aneurysm Repair

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	GSK1278863 300 mg Loading + 100 mg QD n=27 Participants Eligible participants received GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).	Placebo n=28 Participants Eligible participants received Placebo matching GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by Placebo matching GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).	Total n=55 Participants Total of all reporting groups
Age, Customized 21 to 88 years	27 Participants n=93 Participants	28 Participants n=4 Participants	55 Participants n=27 Participants
Sex: Female, Male Female	9 Participants n=93 Participants	10 Participants n=4 Participants	19 Participants n=27 Participants
Sex: Female, Male Male	18 Participants n=93 Participants	18 Participants n=4 Participants	36 Participants n=27 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Asian	1 Participants n=93 Participants	2 Participants n=4 Participants	3 Participants n=27 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Black or African American	2 Participants n=93 Participants	7 Participants n=4 Participants	9 Participants n=27 Participants
Race (NIH/OMB) White	24 Participants n=93 Participants	19 Participants n=4 Participants	43 Participants n=27 Participants
Race (NIH/OMB) More than one race	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants

PRIMARY outcome

Timeframe: Baseline (Day 0) to 48 hours following DTA/TAAA repair

Population: Pharmacodynamic (PD) population comprised of all participants from whom PD data was available. For the change from Baseline assessment, only those with both evaluable Baseline and post-dose values (so that the change could be calculated) were included in the analysis.

Outcome measures

Outcome measures
Measure	GSK1278863 300 mg Loading + 100 mg QD n=27 Participants Eligible participants received GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).	Placebo n=27 Participants Eligible participants received Placebo matching GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by Placebo matching GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).
Change From Baseline to Peak in Cerebrospinal Fluid (CSF) S100 Beta Within 48 Hours Following Descending Thoracic Aorta/Thoracoabdominal Aortic Aneurysm (DTA/TAAA) Repair	2748.19 Nanograms per liter (ng/L) Standard Deviation 6212.035	566.78 Nanograms per liter (ng/L) Standard Deviation 1897.172

PRIMARY outcome

Timeframe: Baseline (Day 0) to 48 hours following DTA/TAAA repair

Population: PD population. For the change from Baseline assessment, only those with both evaluable Baseline and post-dose values (so that the change could be calculated) were included in the analysis.

GFAP is a CSF biomarker that rise significantly in participants with neurologic injury following DTA/TAAA surgery. CSF samples for the analysis of GFAP was collected at Baseline and within 48 hours following DTA/TAAA repair to assess peak change from Baseline in CSF GFAP. Baseline was defined at Day 0. Change from Baseline was calculated as post-Baseline value minus Baseline value.

Outcome measures

Outcome measures
Measure	GSK1278863 300 mg Loading + 100 mg QD n=27 Participants Eligible participants received GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).	Placebo n=27 Participants Eligible participants received Placebo matching GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by Placebo matching GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).
Change From Baseline to Peak in CSF Glial Fibrillary Acidic Protein (GFAP) Within 48 Hours Following DTA/TAAA Repair	1078.61 Microgram per liter (µg/L) Standard Deviation 2894.129	283.03 Microgram per liter (µg/L) Standard Deviation 1092.448

SECONDARY outcome

Timeframe: Up to Follow-up (Day 45)

Population: All Subjects Population comprised of all participants who received at least one dose of study drug (GSK1278863 or placebo).

An AE is any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An 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, considered to be medically significant or is associated with liver injury and impaired liver function.

Outcome measures

Outcome measures
Measure	GSK1278863 300 mg Loading + 100 mg QD n=27 Participants Eligible participants received GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).	Placebo n=28 Participants Eligible participants received Placebo matching GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by Placebo matching GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) Any AEs	26 Participants	23 Participants
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) Any SAEs	20 Participants	14 Participants

SECONDARY outcome

Timeframe: Up to Follow-up (Day 45)

Population: All Subjects Population.

Vital sign measurements included systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse rate. Criteria for vital sign values meeting PCI included: SBP \< 70 millimeters of mercury (mmHg) and \> 160 mmHg; DBP \< 45 mmHg and \> 110 mmHg. Data for participants with vital signs values outside the potential clinical importance range has been presented. Only those parameters for which at least one value of PCI was reported are summarized.

Outcome measures

Outcome measures
Measure	GSK1278863 300 mg Loading + 100 mg QD n=27 Participants Eligible participants received GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).	Placebo n=28 Participants Eligible participants received Placebo matching GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by Placebo matching GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).
Number of Participants With Vital Signs of Potential Clinical Importance (PCI) SBP	2 Participants	1 Participants
Number of Participants With Vital Signs of Potential Clinical Importance (PCI) DBP	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Up to Follow-up (Day 45)

Population: All Subjects Population.

Single 12-lead ECGs was obtained at each time point during the study using an ECG machine that automatically calculated the heart rate and measures PR, QRS, QT, and QT interval corrected for heart rate intervals. Data for participants with abnormal-clinical significant (CS) and abnormal-not clinically significant (NCS) ECG findings on post-operative Days 1, 2, 3, 4, 5, 6, 7 and during Follow-up Visits has been presented.

Outcome measures

Outcome measures
Measure	GSK1278863 300 mg Loading + 100 mg QD n=27 Participants Eligible participants received GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).	Placebo n=28 Participants Eligible participants received Placebo matching GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by Placebo matching GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).
Number of Participants With Abnormal Electrocardiography (ECG) Parameters Post-operative Day 1, Abnormal-NCS	18 Participants	18 Participants
Number of Participants With Abnormal Electrocardiography (ECG) Parameters Post-operative Day 2, Abnormal-NCS	18 Participants	17 Participants
Number of Participants With Abnormal Electrocardiography (ECG) Parameters Post-operative Day 3, Abnormal-NCS	17 Participants	16 Participants
Number of Participants With Abnormal Electrocardiography (ECG) Parameters Post-operative Day 3, Abnormal-CS	1 Participants	1 Participants
Number of Participants With Abnormal Electrocardiography (ECG) Parameters Post-operative Day 4, Abnormal-NCS	13 Participants	18 Participants
Number of Participants With Abnormal Electrocardiography (ECG) Parameters Post-operative Day 5, Abnormal-NCS	14 Participants	17 Participants
Number of Participants With Abnormal Electrocardiography (ECG) Parameters Post-operative Day 6, Abnormal-NCS	14 Participants	10 Participants
Number of Participants With Abnormal Electrocardiography (ECG) Parameters Post-operative Day 7, Abnormal-NCS	15 Participants	15 Participants
Number of Participants With Abnormal Electrocardiography (ECG) Parameters Follow-up, Abnormal-NCS	11 Participants	13 Participants

SECONDARY outcome

Timeframe: Up to post-operative Day 7

Population: All Subjects Population.

Blood samples for assessment of clinical chemistry parameters aspartate amino transferase (AST), alanine amino transferase (ALT), gamma glutamyl transferase (GGT), alkaline phosphatase, blood urea nitrogen (BUN), creatinine, glucose, sodium, creatine phosphokinase, potassium, chloride, total carbon dioxide, calcium, total and direct bilirubin, uric acid, albumin and total protein was done at Randomization, Day 0 (done prior to 100 mg on-call dosing), 1, 2, 3, 4, 5, 6 and 7. Only those parameters for which at least one value of PCI was reported are summarized. Data for participants with clinical chemistry values outside the PCI range has been presented.

Outcome measures

Outcome measures
Measure	GSK1278863 300 mg Loading + 100 mg QD n=27 Participants Eligible participants received GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).	Placebo n=28 Participants Eligible participants received Placebo matching GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by Placebo matching GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).
Number of Participants With Clinical Chemistry Parameters of PCI	19 Participants	18 Participants

SECONDARY outcome

Timeframe: Up to post-operative Day 7

Population: All Subjects Population.

Blood samples for assessment of hematology parameters platelet count, red blood cell count, white blood cell count, reticulocyte count, hemoglobin, hematocrit, mean corpuscle volume, mean corpuscle hemoglobin, mean corpuscle hemoglobin concentration, neutrophils, lymphocytes, monocytes, eosinophils and basophils was done at Randomization, Day 0 (done prior to 100 mg on-call dosing), 1, 2, 3, 4, 5, 6 and 7. Only those parameters for which at least one value of PCI was reported are summarized. Data for participants with hematology values outside the PCI range has been presented.

Outcome measures

Outcome measures
Measure	GSK1278863 300 mg Loading + 100 mg QD n=27 Participants Eligible participants received GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).	Placebo n=28 Participants Eligible participants received Placebo matching GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by Placebo matching GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).
Number of Participants With Hematology Parameters of PCI	25 Participants	16 Participants

SECONDARY outcome

Timeframe: Baseline(Day 0) to 48 hours following DTA/TAAA repair

Population: PD Population.

S100 beta was a CSF biomarker that rise significantly in participants with neurologic injury following DTA/TAAA surgery. AUC for CSF S100 beta from Baseline to 48 hours following DTA/TAAA repair was assessed to measure central nervous system injury. AUC was determined using the linear trapezoidal rule for increasing concentrations and the logarithmic trapezoidal rule for decreasing concentrations. Baseline was defined at Day 0. Change from Baseline was calculated as post-Baseline minus Baseline value.

Outcome measures

Outcome measures
Measure	GSK1278863 300 mg Loading + 100 mg QD n=27 Participants Eligible participants received GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).	Placebo n=28 Participants Eligible participants received Placebo matching GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by Placebo matching GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).
Change From Baseline in Area Under Curve (AUC) for CSF S100 Beta to 48 Hours	17263.25 Hournanogram per liter (hourng/L) Geometric Coefficient of Variation 316.40	9758.27 Hournanogram per liter (hourng/L) Geometric Coefficient of Variation 221.85

SECONDARY outcome

Timeframe: Baseline(Day 0) to 48 hours following DTA/TAAA repair

Population: PD Population.

GFAP was a CSF biomarker that rise significantly in participants with neurologic injury following DTA/TAAA surgery. AUC for CSF GFAP from Baseline to 48 hours following DTA/TAAA repair was assessed to measure central nervous system injury. AUC was determined using the linear trapezoidal rule for increasing concentrations and the logarithmic trapezoidal rule for decreasing concentrations. Baseline was defined at Day 0. Change from Baseline was calculated as post-Baseline minus Baseline value.

Outcome measures

Outcome measures
Measure	GSK1278863 300 mg Loading + 100 mg QD n=27 Participants Eligible participants received GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).	Placebo n=28 Participants Eligible participants received Placebo matching GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by Placebo matching GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).
Change From Baseline in AUC for CSF GFAP to 48 Hours	182.35 Hourmicrogram per liter (hourµg/L) Geometric Coefficient of Variation 15899.84	58.32 Hourmicrogram per liter (hourµg/L) Geometric Coefficient of Variation 1413.66

SECONDARY outcome

Timeframe: Baseline (Day 0) to 48 hours following DTA/TAAA repair

CSF biomarker erythropoietin samples were collected for the analysis of ischemic neurologic injury. CSF samples were collected at Baseline and within 48 hours following DTA/TAAA repair to assess peak change from Baseline in CSF erythropoietin. Baseline was defined at Day 0. Change from Baseline was calculated as post-Baseline value minus Baseline value.

Outcome measures

Outcome measures
Measure	GSK1278863 300 mg Loading + 100 mg QD n=27 Participants Eligible participants received GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).	Placebo n=27 Participants Eligible participants received Placebo matching GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by Placebo matching GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).
Change From Baseline to Peak in CSF Biomarker Erythropoietin Within 48 Hours Following DTA/TAAA Repair	1.34 International units per liter (IU/L) Standard Deviation 137.411	0.61 International units per liter (IU/L) Standard Deviation 1.582

SECONDARY outcome

Timeframe: Baseline (Day 0) to 48 hours following DTA/TAAA repair

Population: PD Population. For the change from Baseline assessment, only those with both evaluable Baseline and post-dose values (so that the change could be calculated) were included in the analysis.

CSF biomarker lactate dehydrogenase samples were collected for the analysis of ischemic neurologic injury. CSF samples were collected at Baseline and within 48 hours following DTA/TAAA repair to assess peak change from Baseline in CSF lactate dehydrogenase. Baseline was defined at Day 0. Change from Baseline was calculated as post-Baseline value minus Baseline value.

Outcome measures

Outcome measures
Measure	GSK1278863 300 mg Loading + 100 mg QD n=27 Participants Eligible participants received GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).	Placebo n=27 Participants Eligible participants received Placebo matching GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by Placebo matching GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).
Change From Baseline to Peak in CSF Biomarker Lactate Dehydrogenase Within 48 Hours Following DTA/TAAA Repair	1.82 Millimoles per liter (mmol/L) Standard Deviation 2.021	1.28 Millimoles per liter (mmol/L) Standard Deviation 1.160

SECONDARY outcome

Timeframe: Baseline (Day 0) to 48 hours following DTA/TAAA repair

CSF biomarker tau protein samples were collected for the analysis of ischemic neurologic injury. CSF samples were collected at Baseline and within 48 hours following DTA/TAAA repair to assess peak change from Baseline in CSF tau protein. Baseline was defined at Day 0. Change from Baseline was calculated as post-Baseline minus Baseline value.

Outcome measures

Outcome measures
Measure	GSK1278863 300 mg Loading + 100 mg QD n=27 Participants Eligible participants received GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).	Placebo n=27 Participants Eligible participants received Placebo matching GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by Placebo matching GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).
Change From Baseline to Peak in CSF Biomarker Tau Protein Within 48 Hours Following DTA/TAAA Repair	1729.25 ng/L Standard Deviation 2177.526	751.21 ng/L Standard Deviation 1053.951

SECONDARY outcome

Timeframe: Baseline (Day 0) to 48 hours following DTA/TAAA repair

CSF biomarker NSE samples were collected for the analysis of ischemic neurologic injury. CSF samples were collected at Baseline and within 48 hours following DTA/TAAA repair to assess peak change from Baseline in CSF NSE. Baseline was defined at Day 0. Change from Baseline was calculated as post-Baseline minus Baseline value.

Outcome measures

Outcome measures
Measure	GSK1278863 300 mg Loading + 100 mg QD n=27 Participants Eligible participants received GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).	Placebo n=27 Participants Eligible participants received Placebo matching GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by Placebo matching GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).
Change From Baseline to Peak in CSF Biomarker Neuron-specific Enolase (NSE) Within 48 Hours Following DTA/TAAA Repair	9.31 µg/L Standard Deviation 9.717	5.65 µg/L Standard Deviation 7.214

SECONDARY outcome

Timeframe: Surgical Day (Day 0), Post-operative Day 1, 2, 7 and follow-up (Day 45)

Population: PD population. Only those participants available at the indicated time points were analyzed.

The NIHSS was a systematic assessment tool that provided a quantitative measure of stroke-related neurologic deficit. A trained observer rates the participant's ability to answer questions and perform activities. Ratings for each item are scored with 0 as normal, and there was an allowance for untestable items. The NIHSS scores were categorized as: No event (NIHSS score=0), Mild (NIHSS score 1-4), Moderate (NIHSS score 5-15), or Severe (NIHSS score \>15). The single participant assessment required less than 10 minutes to complete. Data for participants with NIHSS administrated at surgical day, post-operative Day 1, Day 2, Day 7 and Follow-up Visit has been reported.

Outcome measures

Outcome measures
Measure	GSK1278863 300 mg Loading + 100 mg QD n=27 Participants Eligible participants received GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).	Placebo n=28 Participants Eligible participants received Placebo matching GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by Placebo matching GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).
Number of Participants With Neurologic Outcomes Assessed by the National Institutes of Health Stroke Scale (NIHSS) Surgical Day, No event (Score=0)	27 Participants	23 Participants
Number of Participants With Neurologic Outcomes Assessed by the National Institutes of Health Stroke Scale (NIHSS) Surgical Day, Mild (Score 1-4)	0 Participants	3 Participants
Number of Participants With Neurologic Outcomes Assessed by the National Institutes of Health Stroke Scale (NIHSS) Post-operative Day 1, No event (Score=0)	11 Participants	14 Participants
Number of Participants With Neurologic Outcomes Assessed by the National Institutes of Health Stroke Scale (NIHSS) Post-operative Day 1, Mild (Score 1-4)	4 Participants	7 Participants
Number of Participants With Neurologic Outcomes Assessed by the National Institutes of Health Stroke Scale (NIHSS) Post-operative Day 1, Moderate (Score 5-15)	4 Participants	1 Participants
Number of Participants With Neurologic Outcomes Assessed by the National Institutes of Health Stroke Scale (NIHSS) Post-operative Day 1, Severe (Score >15)	6 Participants	1 Participants
Number of Participants With Neurologic Outcomes Assessed by the National Institutes of Health Stroke Scale (NIHSS) Post-operative Day 2, No event (Score=0)	11 Participants	15 Participants
Number of Participants With Neurologic Outcomes Assessed by the National Institutes of Health Stroke Scale (NIHSS) Post-operative Day 2, Mild (Score 1-4)	4 Participants	3 Participants
Number of Participants With Neurologic Outcomes Assessed by the National Institutes of Health Stroke Scale (NIHSS) Post-operative Day 2, Moderate (Score 5-15)	3 Participants	3 Participants
Number of Participants With Neurologic Outcomes Assessed by the National Institutes of Health Stroke Scale (NIHSS) Post-operative Day 2, Severe (Score >15)	6 Participants	1 Participants
Number of Participants With Neurologic Outcomes Assessed by the National Institutes of Health Stroke Scale (NIHSS) Post-operative Day 7, No event (Score=0)	10 Participants	16 Participants
Number of Participants With Neurologic Outcomes Assessed by the National Institutes of Health Stroke Scale (NIHSS) Post-operative Day 7, Mild (Score 1-4)	2 Participants	7 Participants
Number of Participants With Neurologic Outcomes Assessed by the National Institutes of Health Stroke Scale (NIHSS) Post-operative Day 7, Moderate (Score 5-15)	4 Participants	1 Participants
Number of Participants With Neurologic Outcomes Assessed by the National Institutes of Health Stroke Scale (NIHSS) Post-operative Day 7, Severe (Score >15)	4 Participants	0 Participants
Number of Participants With Neurologic Outcomes Assessed by the National Institutes of Health Stroke Scale (NIHSS) Follow-up, No event (Score=0)	13 Participants	17 Participants
Number of Participants With Neurologic Outcomes Assessed by the National Institutes of Health Stroke Scale (NIHSS) Follow-up, Mild (Score 1-4)	1 Participants	6 Participants
Number of Participants With Neurologic Outcomes Assessed by the National Institutes of Health Stroke Scale (NIHSS) Follow-up, Moderate (Score 5-15)	4 Participants	2 Participants

SECONDARY outcome

Timeframe: Post-operative Day 7 and follow-up (Day 45)

Population: PD population. Only those participants available at the indicated time points were analyzed.

The mRS was a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. The mRS was a 6 point disability scale with possible scores ranging from 0 up to 5. A separate category (of 6) was added for participants who died. The mRS scores were categorized as mild (mRS score 0-1), moderate (mRS score 2-3), or severe (mRS score \>=4).

Outcome measures

Outcome measures
Measure	GSK1278863 300 mg Loading + 100 mg QD n=27 Participants Eligible participants received GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).	Placebo n=28 Participants Eligible participants received Placebo matching GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by Placebo matching GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).
Number of Participants With Neurologic Outcomes Assessed by Modified Rankin Scale (mRS) Post-operative Day 7, Mild (Score 0-1)	9 Participants	11 Participants
Number of Participants With Neurologic Outcomes Assessed by Modified Rankin Scale (mRS) Post-operative Day 7, Moderate (Score 2-3)	1 Participants	8 Participants
Number of Participants With Neurologic Outcomes Assessed by Modified Rankin Scale (mRS) Post-operative Day 7, Severe (Score >=4)	10 Participants	5 Participants
Number of Participants With Neurologic Outcomes Assessed by Modified Rankin Scale (mRS) Follow-up, Mild (Score 0-1)	8 Participants	14 Participants
Number of Participants With Neurologic Outcomes Assessed by Modified Rankin Scale (mRS) Follow-up, Moderate (Score 2-3)	4 Participants	7 Participants
Number of Participants With Neurologic Outcomes Assessed by Modified Rankin Scale (mRS) Follow-up, Severe (Score >=4)	6 Participants	4 Participants

SECONDARY outcome

Timeframe: Surgical Day (Day 0), Post-operative Day 1, 2, 7 and follow-up (Day 45)

Population: PD population. Only those participants available at the indicated time points were analyzed.

The ASIA score was developed by the American Spinal Injury Association for the neurologic assessment of participants with a spinal injury. In this study, only the ASIA lower extremity motor score was assessed. This comprised five muscle groups scored from 0-5 on both the left and right lower extremities, for a maximal total score of 50. The ASIA scores were categorized as: mild (ASIA score 41-50), moderate (ASIA score 26-40), or severe (ASIA score \<=25).

Outcome measures

Outcome measures
Measure	GSK1278863 300 mg Loading + 100 mg QD n=27 Participants Eligible participants received GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).	Placebo n=28 Participants Eligible participants received Placebo matching GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by Placebo matching GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).
Number of Participants With Neurologic Outcomes Assessed by the American Spinal Injury Association (ASIA) Lower Extremity Motor Outcome Scale Surgical Day, Mild (Score 41-50)	26 Participants	26 Participants
Number of Participants With Neurologic Outcomes Assessed by the American Spinal Injury Association (ASIA) Lower Extremity Motor Outcome Scale Surgical Day, Moderate (Score 26-40)	1 Participants	0 Participants
Number of Participants With Neurologic Outcomes Assessed by the American Spinal Injury Association (ASIA) Lower Extremity Motor Outcome Scale Post-operative Day 1, Mild (Score 41-50)	15 Participants	19 Participants
Number of Participants With Neurologic Outcomes Assessed by the American Spinal Injury Association (ASIA) Lower Extremity Motor Outcome Scale Post-operative Day 1, Moderate (Score 26-40)	2 Participants	2 Participants
Number of Participants With Neurologic Outcomes Assessed by the American Spinal Injury Association (ASIA) Lower Extremity Motor Outcome Scale Post-operative Day 1, Severe (Score <=25)	8 Participants	2 Participants
Number of Participants With Neurologic Outcomes Assessed by the American Spinal Injury Association (ASIA) Lower Extremity Motor Outcome Scale Post-operative Day 2, Mild (Score 41-50)	14 Participants	21 Participants
Number of Participants With Neurologic Outcomes Assessed by the American Spinal Injury Association (ASIA) Lower Extremity Motor Outcome Scale Post-operative Day 2, Moderate (Score 26-40)	1 Participants	0 Participants
Number of Participants With Neurologic Outcomes Assessed by the American Spinal Injury Association (ASIA) Lower Extremity Motor Outcome Scale Post-operative Day 2, Severe (Score <=25)	8 Participants	1 Participants
Number of Participants With Neurologic Outcomes Assessed by the American Spinal Injury Association (ASIA) Lower Extremity Motor Outcome Scale Post-operative Day 7, Mild (Score 41-50)	13 Participants	22 Participants
Number of Participants With Neurologic Outcomes Assessed by the American Spinal Injury Association (ASIA) Lower Extremity Motor Outcome Scale Post-operative Day 7, Moderate (Score 26-40)	1 Participants	1 Participants
Number of Participants With Neurologic Outcomes Assessed by the American Spinal Injury Association (ASIA) Lower Extremity Motor Outcome Scale Post-operative Day 7, Severe (Score <=25)	6 Participants	1 Participants
Number of Participants With Neurologic Outcomes Assessed by the American Spinal Injury Association (ASIA) Lower Extremity Motor Outcome Scale Follow-up, Mild (Score 41-50)	14 Participants	24 Participants
Number of Participants With Neurologic Outcomes Assessed by the American Spinal Injury Association (ASIA) Lower Extremity Motor Outcome Scale Follow-up, Moderate (Score 26-40)	2 Participants	0 Participants
Number of Participants With Neurologic Outcomes Assessed by the American Spinal Injury Association (ASIA) Lower Extremity Motor Outcome Scale Follow-up, Severe (Score <=25)	2 Participants	1 Participants

SECONDARY outcome

Timeframe: Up to Follow-up (Day 45)

Population: All Subjects Population.

The clinical composite event rate included all-cause mortality (death), stroke, spinal infarction (paraplegia which was due to spinal infarct a result of the surgery, myocardial infarction, and the need for dialysis or sustained doubling of serum creatinine (acute kidney injury). The clinical composite endpoint used a first occurrence approach, i.e. a composite event was recorded at the time of first occurrence of any component of the composite.

Outcome measures

Outcome measures
Measure	GSK1278863 300 mg Loading + 100 mg QD n=27 Participants Eligible participants received GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).	Placebo n=28 Participants Eligible participants received Placebo matching GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by Placebo matching GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).
Number of Participants With Clinical Composite of All Cause Mortality, Stroke, Spinal Infarction, MI, Need for Dialysis/Sustained Doubling of Serum Creatinine Acute Kidney Injury	13 Participants	10 Participants
Number of Participants With Clinical Composite of All Cause Mortality, Stroke, Spinal Infarction, MI, Need for Dialysis/Sustained Doubling of Serum Creatinine Myocardial Infarction	1 Participants	0 Participants
Number of Participants With Clinical Composite of All Cause Mortality, Stroke, Spinal Infarction, MI, Need for Dialysis/Sustained Doubling of Serum Creatinine Paraplegia	6 Participants	4 Participants
Number of Participants With Clinical Composite of All Cause Mortality, Stroke, Spinal Infarction, MI, Need for Dialysis/Sustained Doubling of Serum Creatinine Stroke	1 Participants	2 Participants
Number of Participants With Clinical Composite of All Cause Mortality, Stroke, Spinal Infarction, MI, Need for Dialysis/Sustained Doubling of Serum Creatinine Death	6 Participants	2 Participants
Number of Participants With Clinical Composite of All Cause Mortality, Stroke, Spinal Infarction, MI, Need for Dialysis/Sustained Doubling of Serum Creatinine Composite Above	16 Participants	12 Participants

SECONDARY outcome

Timeframe: Baseline (Day 0) and 8 to 48 hours following DTA/TAAA repair

Population: PD population. Only those participants available at the indicated time points were analyzed.

AUC from 8 hours post surgery (up to 48 hours post surgery) was derived for markers of ischemic organ injury troponin I and troponin T. AUC was determined using the linear trapezoidal rule for increasing concentrations and the logarithmic trapezoidal rule for decreasing concentrations.

Outcome measures

Outcome measures
Measure	GSK1278863 300 mg Loading + 100 mg QD n=27 Participants Eligible participants received GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).	Placebo n=28 Participants Eligible participants received Placebo matching GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by Placebo matching GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).
Assessment in AUC for Markers of Ischemic Organ Injury Including Tropinin Within 48 Hours Troponin I	13.29 µg*hour/L Geometric Coefficient of Variation 0.615	7.23 µg*hour/L Geometric Coefficient of Variation 0.650
Assessment in AUC for Markers of Ischemic Organ Injury Including Tropinin Within 48 Hours Troponin T	3.14 µg*hour/L Geometric Coefficient of Variation 0.879	4.19 µg*hour/L Geometric Coefficient of Variation 0.750

SECONDARY outcome

Timeframe: Up to Follow-up (Day 45)

Population: PD Population.

The NIHSS was a systematic assessment tool that provided a quantitative measure of stroke-related neurologic deficit. Ratings for each item are scored with 0 as normal, and there was an allowance for untestable items. The NIHSS scores were categorized as: No event (NIHSS score=0), Mild (NIHSS score 1-4), Moderate (NIHSS score 5-15), or Severe (NIHSS score \>15). The ASIA score was developed by the American Spinal Injury Association for the neurologic assessment of participants with a spinal injury. In this study, only the ASIA lower extremity motor score was assessed. This comprised five muscle groups scored from 0-5 on both the left and right lower extremities, for a maximal total score of 50. The ASIA scores were categorized as: mild (ASIA score 41-50), moderate (ASIA score 26-40), or severe (ASIA score \<=25). "Composite above" includes participants with NIHSS\>5 or ASIA\<40 at the 30-day Follow-up or Death.

Outcome measures

Outcome measures
Measure	GSK1278863 300 mg Loading + 100 mg QD n=27 Participants Eligible participants received GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).	Placebo n=28 Participants Eligible participants received Placebo matching GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by Placebo matching GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).
Number of Participants With Composite Index of All Cause Mortality and Disability (NIHSS>5/ASIA<40) ASIA <40	4 Participants	1 Participants
Number of Participants With Composite Index of All Cause Mortality and Disability (NIHSS>5/ASIA<40) NIHSS >5	4 Participants	2 Participants
Number of Participants With Composite Index of All Cause Mortality and Disability (NIHSS>5/ASIA<40) Death	6 Participants	2 Participants
Number of Participants With Composite Index of All Cause Mortality and Disability (NIHSS>5/ASIA<40) Composite Above	11 Participants	4 Participants

SECONDARY outcome

Timeframe: Pre-dose, 1 to 3 hours post-dose, every 5 hours for 24 hours, 1, 3, 8 and 24 hours post-dose on Day 1 and 3

Population: PK Population. Only those participants available at the indicated time points were analyzed.

Blood samples for PK analysis AUC(0-t) were collected at pre-dose (prior to the 100 mg dose), 1-3 hours after study drug was administered and then every 5 hours for 24 hours. On Days 1 and 3 samples were collected at pre-dose then 1, 3, 8 and 24 hours post dose. AUC (0-t) was determined using the linear trapezoidal rule for increasing concentrations and the logarithmic trapezoidal rule for decreasing concentrations.

Outcome measures

Outcome measures
Measure	GSK1278863 300 mg Loading + 100 mg QD n=27 Participants Eligible participants received GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).	Placebo Eligible participants received Placebo matching GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by Placebo matching GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).
Pharmacokinetic (PK) Parameters in Blood: AUC(0-t) of GSK1278863 Blood, Surgical Day	3591.449 Hour*ng/mL Geometric Coefficient of Variation 50.23	—
Pharmacokinetic (PK) Parameters in Blood: AUC(0-t) of GSK1278863 Blood, Post-operative Day 1	2858.165 Hour*ng/mL Geometric Coefficient of Variation 129.26	—
Pharmacokinetic (PK) Parameters in Blood: AUC(0-t) of GSK1278863 Blood, Post-operative Day 3	3710.790 Hour*ng/mL Geometric Coefficient of Variation 115.20	—

SECONDARY outcome

Timeframe: Prior to potential neurological ischemia (PNI), 2, 24, 36 and 48 hours post PNI

Population: PK Population. Only those participants available at the indicated time points were analyzed.

CSF samples were collected immediately after the lumbar drain was placed, just prior to PNI, and 2, 24, 36 and 48 hours post PNI. In participants that developed spinal ischemia, the CSF drain was potentially maintained for longer than 48 hours. In that instance, daily CSF samples for PK were collected until the drain was removed. AUC (0-t) was determined using the linear trapezoidal rule for increasing concentrations and the logarithmic trapezoidal rule for decreasing concentrations.

Outcome measures

Outcome measures
Measure	GSK1278863 300 mg Loading + 100 mg QD n=26 Participants Eligible participants received GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).	Placebo Eligible participants received Placebo matching GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by Placebo matching GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).
PK Parameters in CSF: AUC(0-t) of GSK1278863	37.340 Hour*ng/mL Geometric Coefficient of Variation 156.10	—

SECONDARY outcome

Timeframe: Pre-dose, 1 to 3 hours post-dose, every 5 hours for 24 hours, 1, 3, 8 and 24 hours post-dose on Day 1 and 3

Population: PK population. Only those participants available at the indicated time points were analyzed.

Outcome measures

Outcome measures
Measure	GSK1278863 300 mg Loading + 100 mg QD n=27 Participants Eligible participants received GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).	Placebo Eligible participants received Placebo matching GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by Placebo matching GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).
PK Parameters in Blood: Maximum Observed Concentration (Cmax) of GSK1278863 Blood, Surgical Day	705.701 Ng/mL Geometric Coefficient of Variation 83.43	—
PK Parameters in Blood: Maximum Observed Concentration (Cmax) of GSK1278863 Blood, Post-operative Day 1	358.518 Ng/mL Geometric Coefficient of Variation 192.32	—
PK Parameters in Blood: Maximum Observed Concentration (Cmax) of GSK1278863 Blood, Post-operative Day 3	779.801 Ng/mL Geometric Coefficient of Variation 110.20	—

SECONDARY outcome

Timeframe: Prior to potential neurological ischemia (PNI), 2, 24, 36 and 48 hours post PNI

Population: PK Population. Only those participants available at the indicated time points were analyzed.

Outcome measures

Outcome measures
Measure	GSK1278863 300 mg Loading + 100 mg QD n=26 Participants Eligible participants received GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).	Placebo Eligible participants received Placebo matching GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by Placebo matching GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).
PK Parameters in CSF: Cmax of GSK1278863	2.364 Ng/L Geometric Coefficient of Variation 105.24	—

SECONDARY outcome

Timeframe: Pre-dose, 1 to 3 hours post-dose, every 5 hours for 24 hours, 1, 3, 8 and 24 hours post-dose on Day 1 and 3

Population: PK Population. Only those participants available at the indicated time points were analyzed.

Outcome measures

Outcome measures
Measure	GSK1278863 300 mg Loading + 100 mg QD n=27 Participants Eligible participants received GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).	Placebo Eligible participants received Placebo matching GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by Placebo matching GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).
PK Parameters in Blood: Time of Occurrence of Cmax (Tmax) of GSK1278863 Blood, Surgical day	1.725 Hours Interval 0.0 to 16.38	—
PK Parameters in Blood: Time of Occurrence of Cmax (Tmax) of GSK1278863 Blood, Post-operative Day 1	3.017 Hours Interval 0.02 to 24.43	—
PK Parameters in Blood: Time of Occurrence of Cmax (Tmax) of GSK1278863 Blood, Post-operative Day 3	3.017 Hours Interval 0.77 to 8.18	—

SECONDARY outcome

Timeframe: Prior to potential neurological ischemia (PNI), 2, 24, 36 and 48 hours post PNI

Population: PK Population. Only those participants available at the indicated time points were analyzed.

Outcome measures

Outcome measures
Measure	GSK1278863 300 mg Loading + 100 mg QD n=26 Participants Eligible participants received GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).	Placebo Eligible participants received Placebo matching GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by Placebo matching GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).
PK Parameters in CSF: Tmax of GSK1278863	15.326 Hours Interval 8.097 to 22.554	—

Adverse Events

GSK1278863 300 mg Loading + 100 mg QD

Serious events: 20 serious events

Other events: 20 other events

Deaths: 6 deaths

Placebo

Serious events: 14 serious events

Other events: 19 other events

Deaths: 2 deaths

Serious adverse events

Other adverse events

Additional Information

GSK Response Center

GlaxoSmithKline

Phone: 866-435-7343

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER

Measure	GSK1278863 300 mg Loading + 100 mg QD n=27 participants at risk Eligible participants received GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).	Placebo n=28 participants at risk Eligible participants received Placebo matching GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by Placebo matching GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).
Respiratory, thoracic and mediastinal disorders Respiratory failure	11.1% 3/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	3.6% 1/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Respiratory, thoracic and mediastinal disorders Acute respiratory distress syndrome	3.7% 1/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	0.00% 0/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	3.7% 1/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	0.00% 0/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Respiratory, thoracic and mediastinal disorders Chronic respiratory failure	0.00% 0/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	3.6% 1/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Respiratory, thoracic and mediastinal disorders Haemothorax	3.7% 1/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	0.00% 0/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Respiratory, thoracic and mediastinal disorders Hypoxia	3.7% 1/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	0.00% 0/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Respiratory, thoracic and mediastinal disorders Pneumonia aspiration	3.7% 1/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	0.00% 0/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Respiratory, thoracic and mediastinal disorders Pneumothorax	3.7% 1/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	0.00% 0/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	3.7% 1/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	0.00% 0/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Respiratory, thoracic and mediastinal disorders Pulmonary haemorrhage	3.7% 1/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	0.00% 0/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Respiratory, thoracic and mediastinal disorders Pulmonary oedema	0.00% 0/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	3.6% 1/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Nervous system disorders Spinal cord ischaemia	7.4% 2/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	3.6% 1/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Nervous system disorders Cerebrospinal fluid leakage	0.00% 0/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	3.6% 1/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Nervous system disorders Cerebrovascular accident	3.7% 1/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	0.00% 0/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Nervous system disorders Monoplegia	3.7% 1/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	0.00% 0/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Nervous system disorders Neurological decompensation	3.7% 1/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	0.00% 0/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Nervous system disorders Paraparesis	0.00% 0/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	3.6% 1/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Nervous system disorders Paraplegia	3.7% 1/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	0.00% 0/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Nervous system disorders Subarachnoid haemorrhage	0.00% 0/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	3.6% 1/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Vascular disorders Peripheral ischaemia	14.8% 4/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	0.00% 0/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Vascular disorders Aortic aneurysm rupture	3.7% 1/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	0.00% 0/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Vascular disorders Arterial haemorrhage	3.7% 1/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	0.00% 0/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Vascular disorders Deep vein thrombosis	3.7% 1/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	0.00% 0/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Vascular disorders Embolism	3.7% 1/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	0.00% 0/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Vascular disorders Haemodynamic instability	3.7% 1/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	0.00% 0/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Vascular disorders Peripheral artery thrombosis	3.7% 1/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	0.00% 0/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Renal and urinary disorders Renal failure acute	18.5% 5/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	0.00% 0/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Renal and urinary disorders Renal failure	7.4% 2/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	0.00% 0/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Renal and urinary disorders Renal artery thrombosis	3.7% 1/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	0.00% 0/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Blood and lymphatic system disorders Thrombocytopenia	14.8% 4/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	0.00% 0/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Blood and lymphatic system disorders Disseminated intravascular coagulation	3.7% 1/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	3.6% 1/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Blood and lymphatic system disorders Heparin-induced thrombocytopenia	3.7% 1/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	0.00% 0/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Blood and lymphatic system disorders Leukocytosis	0.00% 0/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	3.6% 1/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Injury, poisoning and procedural complications Post procedural haemorrhage	3.7% 1/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	3.6% 1/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Injury, poisoning and procedural complications Postoperative respiratory failure	7.4% 2/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	0.00% 0/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Injury, poisoning and procedural complications Internal injury	3.7% 1/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	0.00% 0/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Injury, poisoning and procedural complications Postoperative thoracic procedure complication	0.00% 0/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	3.6% 1/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Injury, poisoning and procedural complications Spinal cord injury	3.7% 1/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	0.00% 0/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Injury, poisoning and procedural complications Subdural haematoma	0.00% 0/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	3.6% 1/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Cardiac disorders Cardio-respiratory arrest	3.7% 1/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	3.6% 1/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Cardiac disorders Ventricular fibrillation	7.4% 2/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	0.00% 0/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Cardiac disorders Cardiogenic shock	0.00% 0/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	3.6% 1/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Cardiac disorders Sinus tachycardia	0.00% 0/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	3.6% 1/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Gastrointestinal disorders Gastrointestinal haemorrhage	7.4% 2/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	0.00% 0/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Gastrointestinal disorders Ileus	3.7% 1/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	0.00% 0/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Gastrointestinal disorders Retroperitoneal haematoma	0.00% 0/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	3.6% 1/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Gastrointestinal disorders Upper gastrointestinal haemorrhage	0.00% 0/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	3.6% 1/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Gastrointestinal disorders Volvulus	3.7% 1/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	0.00% 0/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Infections and infestations Septic shock	3.7% 1/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	3.6% 1/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Infections and infestations Cystitis klebsiella	3.7% 1/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	0.00% 0/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Infections and infestations Incision site infection	0.00% 0/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	3.6% 1/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Infections and infestations Pneumonia klebsiella	3.7% 1/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	0.00% 0/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Infections and infestations Wound infection staphylococcal	3.7% 1/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	0.00% 0/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
General disorders Multi-organ failure	14.8% 4/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	0.00% 0/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
General disorders Ischaemic ulcer	3.7% 1/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	0.00% 0/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Investigations Pulse absent	3.7% 1/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	0.00% 0/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Investigations Red blood cells CSF positive	0.00% 0/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	3.6% 1/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Investigations Transaminases increased	3.7% 1/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	0.00% 0/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Hepatobiliary disorders Hepatic failure	3.7% 1/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	0.00% 0/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Metabolism and nutrition disorders Lactic acidosis	3.7% 1/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	0.00% 0/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.

Measure	GSK1278863 300 mg Loading + 100 mg QD n=27 participants at risk Eligible participants received GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).	Placebo n=28 participants at risk Eligible participants received Placebo matching GSK1278863 300 mg on Day -1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by Placebo matching GSK1278863 100 mg QD for 4 days starting from Day 0 (surgical day).
Vascular disorders Hypertension	11.1% 3/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	21.4% 6/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Vascular disorders Hypotension	14.8% 4/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	17.9% 5/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Vascular disorders Ischaemia	7.4% 2/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	0.00% 0/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Blood and lymphatic system disorders Anaemia	0.00% 0/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	14.3% 4/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Blood and lymphatic system disorders Haemorrhagic anaemia	11.1% 3/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	3.6% 1/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Blood and lymphatic system disorders Leukocytosis	7.4% 2/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	7.1% 2/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Blood and lymphatic system disorders Thrombocytopenia	7.4% 2/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	3.6% 1/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Blood and lymphatic system disorders Coagulopathy	7.4% 2/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	0.00% 0/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Cardiac disorders Atrial fibrillation	14.8% 4/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	10.7% 3/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Cardiac disorders Bradycardia	0.00% 0/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	7.1% 2/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Cardiac disorders Sinus tachycardia	0.00% 0/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	7.1% 2/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Cardiac disorders Supraventricular tachycardia	0.00% 0/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	7.1% 2/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Metabolism and nutrition disorders Hypokalaemia	7.4% 2/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	10.7% 3/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Metabolism and nutrition disorders Hypophosphataemia	11.1% 3/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	7.1% 2/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Metabolism and nutrition disorders Fluid overload	3.7% 1/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	7.1% 2/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Metabolism and nutrition disorders Hypocalcaemia	3.7% 1/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	7.1% 2/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Metabolism and nutrition disorders Hyperglycaemia	0.00% 0/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	7.1% 2/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Metabolism and nutrition disorders Hypernatraemia	7.4% 2/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	0.00% 0/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Gastrointestinal disorders Nausea	18.5% 5/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	17.9% 5/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Gastrointestinal disorders Vomiting	3.7% 1/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	14.3% 4/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Gastrointestinal disorders Constipation	7.4% 2/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	7.1% 2/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Renal and urinary disorders Renal failure acute	14.8% 4/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	25.0% 7/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Respiratory, thoracic and mediastinal disorders Pleural effusion	7.4% 2/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	14.3% 4/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Respiratory, thoracic and mediastinal disorders Atelectasis	3.7% 1/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	10.7% 3/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Respiratory, thoracic and mediastinal disorders Hypoxia	7.4% 2/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	7.1% 2/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Injury, poisoning and procedural complications Procedural pain	7.4% 2/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	10.7% 3/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Injury, poisoning and procedural complications Post lumbar puncture syndrome	3.7% 1/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	10.7% 3/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Injury, poisoning and procedural complications Wound complication	7.4% 2/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	7.1% 2/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Nervous system disorders Headache	11.1% 3/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	14.3% 4/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Nervous system disorders Vocal cord paralysis	3.7% 1/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	7.1% 2/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
General disorders Pain	7.4% 2/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	7.1% 2/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
General disorders Pyrexia	7.4% 2/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	3.6% 1/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
General disorders Catheter site pain	0.00% 0/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	7.1% 2/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Infections and infestations Urinary tract infection	11.1% 3/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	10.7% 3/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Infections and infestations Respiratory tract infection	7.4% 2/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	0.00% 0/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Musculoskeletal and connective tissue disorders Back pain	3.7% 1/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	17.9% 5/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Psychiatric disorders Anxiety	3.7% 1/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	7.1% 2/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Psychiatric disorders Confusional state	0.00% 0/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	7.1% 2/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.
Investigations Troponin increased	11.1% 3/27 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.	0.00% 0/28 • AEs were collected up to Follow-up (Day 45). All Subjects Population was used.