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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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).

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).

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.

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.

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.

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.

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.

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.

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.

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.

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.