Surgical Procedures
Conditions
Keywords
GSK1278863, Thoracic Aortic Aneurysm Repair
Brief summary
This study will test the hypothesis that GSK1278863 will reduce neurologic, renal, and/or cardiac ischemia in patients undergoing elective descending thoracic aorta/thoracoabdominal aortic aneurysm (DTA/TAAA) repair, a population known to be at high risk for ischemic events from their underlying pathology and the surgical complexity required to address their disease. Approximately 160 subjects will be stratified according to intervention type (surgical or endovascular repair, with the latter limited to 50% of the total study population) and randomized in a 1:1 fashion to treatment with GSK1278863 (300 milligrams \[loading dose\] followed by 100 milligrams \[mg\]/day x 4 days) or placebo starting prior to planned repair, through postoperative day 3. The duration of participation in this study is expected to be approximately 4 to 8 weeks from screening to follow-up.
Interventions
DRUGGSK1278863
White, round biconvex, film coated tablet with unit dose strength of 100 mg for oral administration
DRUGPlacebo
White, round biconvex, film coated GSK1278863 matching placebo tablet for oral administration
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adults \>= 18 years of age who require the following types of descending thoracic aorta or thoracoabdominal aorta repair for atherosclerotic aneurysm or chronic dissection (de novo Type B or residual Type B \[following Type A repair\]) via open surgery or endovascular stenting (TEVAR) as per their treating surgeon * Open surgery: Extent I TAAA (+/-distal arch) if it extends to or beyond renal ostia. Extent II TAAA (+/-distal arch). Extent III TAAA (defined as proximal extent or anastamosis superior to inferior pulmonary vein). Extent IV TAAA only with a prior TEVAR or if it is a redo procedure (in this setting a redo is a prior abdominal aortic aneurysm (AAA) open or endovascular aortic repair (EVAR), with either proximal suture line disruption or mesenteric segment aneurysm recurrence requiring redo Extent IV reconstruction). DTA repair with one of the following: Safi extent C coverage. Subclavian to diaphragm disease extent. \>75% of total DTA length. -TEVAR with one of the following: Full DTA coverage with previous abdominal EVAR or open AAA. Full DTA coverage including Zone 2 to celiac (i.e., distal arch plus full coverage DTA). Full DTA coverage with celiac artery coverage with or without left subclavian artery coverage (Zone 2 or Zone 3 proximal landing), or full DTA (either Zone 2 or Zone 3) with extension distal to celiac with visceral debranching (e.g., the abdominal hybrid Extent 2 TAAA). Note: Zone 2 is defined as between the left carotid through coverage of the left subclavian artery and Zone 3 is defined as the first 3cm distal to the left subclavian (e.g., between left subclavian and ligamentum \[isthmus\]). * Completed any staging or bypass procedure that precedes the aortic repair at least 48 hours prior to the repair. * Expect placement of a lumbar CSF catheter during the procedure with plans to maintain it for at least 48 hours per the treating physician. * 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 \[in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) \> 40 milli international unit /mililiter (mL) and estradiol \< 40 picogram/mL (\<147 picomoles/Liter) is confirmatory\]. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the 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 enrollment. For most forms of HRT, at least 2-4 weeks will 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. Child-bearing potential and agrees to use one of the contraception methods from screening until completion of the Follow-up Visit. * Male subjects with female partners of child-bearing potential must agree to use one of the contraception methods. This criterion must be followed from the time of Screening until the completion of the Follow-up Visit.
Exclusion criteria
* The subject has a traumatic aortic dissection. * The subject has a baseline NIHSS \> 1 or modified Rankin Scale \> 1. * The subject has a history of myocardial infarction, stroke, or spinal infarct within the past 3 months. * The subject has active ulcer disease or recent gastrointestinal bleeding within the past 6 months. * The subject has a history of deep venous thrombosis or pulmonary embolism in the past 12 months. * The subject has been treated for a malignancy (excluding non-melanomatous skin cancers) within the past 12 months and is not confirmed to be disease free. * The subject has had treatment for retinal neovascularization (e.g., diabetic proliferative retinopathy or age related macular degeneration) within 3 months of randomization. * The subject is currently receiving dialysis. * The subject is currently receiving or expected to require treatment (within the study period) with erythropoiesis medication such as epoetin alfa (Procrit, Epogen), or darbepoetin alfa (Aranesp). * The subject has any of the following at screening: Hemoglobin \>15.5 gram (g)/decilitre (dL) (male subjects or post-menopausal females) Hemoglobin \>14.5 g/dL (pre-menopausal female subjects) Single QTc \>=480 millisecond (msec); or QTc \>=500 msec in subjects with bundle branch block (these criteria do not apply to subjects with predominately paced rhythms) Aspartate aminotransferase and alanine aminotransferase \>=2xupper limit of normal (ULN); alkaline phosphatase and bilirubin \>=1.5xULN (isolated bilirubin \>=1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%) A positive pre-study drug/alcohol screen Lactation or pregnancy (as determined by positive serum or urine hCG test) * The use of prohibited medications * History of regular alcohol consumption within 6 months of the study defined as: an average weekly intake of \>14 drinks for males or \>7 drinks for females. One drink is equivalent to 12 g of alcohol: 12 ounces (360 mL) of beer, 5 ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits. * The subject has participated in a clinical trial and 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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Peak in Cerebrospinal Fluid (CSF) S100 Beta Within 48 Hours Following Descending Thoracic Aorta/Thoracoabdominal Aortic Aneurysm (DTA/TAAA) Repair | Baseline (Day 0) to 48 hours following DTA/TAAA repair | 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. |
| Change From Baseline to Peak in CSF Glial Fibrillary Acidic Protein (GFAP) Within 48 Hours Following DTA/TAAA Repair | Baseline (Day 0) to 48 hours following DTA/TAAA repair | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Abnormal Electrocardiography (ECG) Parameters | Up to Follow-up (Day 45) | 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. |
| Number of Participants With Clinical Chemistry Parameters of PCI | Up to post-operative Day 7 | 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. |
| Number of Participants With Hematology Parameters of PCI | Up to post-operative Day 7 | 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. |
| Change From Baseline in Area Under Curve (AUC) for CSF S100 Beta to 48 Hours | Baseline(Day 0) to 48 hours following DTA/TAAA repair | 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. |
| Change From Baseline in AUC for CSF GFAP to 48 Hours | Baseline(Day 0) to 48 hours following DTA/TAAA repair | 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. |
| Change From Baseline to Peak in CSF Biomarker Erythropoietin Within 48 Hours Following DTA/TAAA Repair | 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. |
| Change From Baseline to Peak in CSF Biomarker Lactate Dehydrogenase Within 48 Hours Following DTA/TAAA Repair | Baseline (Day 0) to 48 hours following DTA/TAAA repair | 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. |
| Change From Baseline to Peak in CSF Biomarker Tau Protein Within 48 Hours Following DTA/TAAA Repair | 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. |
| Change From Baseline to Peak in CSF Biomarker Neuron-specific Enolase (NSE) Within 48 Hours Following DTA/TAAA Repair | 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. |
| Number of Participants With Neurologic Outcomes Assessed by the National Institutes of Health Stroke Scale (NIHSS) | Surgical Day (Day 0), Post-operative Day 1, 2, 7 and follow-up (Day 45) | 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. |
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Up to Follow-up (Day 45) | 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. |
| Number of Participants With Neurologic Outcomes Assessed by the American Spinal Injury Association (ASIA) Lower Extremity Motor Outcome Scale | Surgical Day (Day 0), Post-operative Day 1, 2, 7 and follow-up (Day 45) | 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). |
| Number of Participants With Clinical Composite of All Cause Mortality, Stroke, Spinal Infarction, MI, Need for Dialysis/Sustained Doubling of Serum Creatinine | Up to Follow-up (Day 45) | 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. |
| Assessment in AUC for Markers of Ischemic Organ Injury Including Tropinin Within 48 Hours | Baseline (Day 0) and 8 to 48 hours following DTA/TAAA repair | 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. |
| PK Parameters in CSF: Cmax of GSK1278863 | Prior to potential neurological ischemia (PNI), 2, 24, 36 and 48 hours post PNI | 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. |
| Number of Participants With Composite Index of All Cause Mortality and Disability (NIHSS>5/ASIA<40) | Up to Follow-up (Day 45) | 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. |
| Pharmacokinetic (PK) Parameters in Blood: AUC(0-t) of GSK1278863 | 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 | 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. |
| PK Parameters in CSF: AUC(0-t) of GSK1278863 | Prior to potential neurological ischemia (PNI), 2, 24, 36 and 48 hours post PNI | 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. |
| PK Parameters in Blood: Maximum Observed Concentration (Cmax) of GSK1278863 | 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 | 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. |
| PK Parameters in Blood: Time of Occurrence of Cmax (Tmax) of GSK1278863 | 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 | 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. |
| PK Parameters in CSF: Tmax of GSK1278863 | Prior to potential neurological ischemia (PNI), 2, 24, 36 and 48 hours post PNI | 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. |
| Number of Participants With Neurologic Outcomes Assessed by Modified Rankin Scale (mRS) | Post-operative Day 7 and follow-up (Day 45) | 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). |
| Number of Participants With Vital Signs of Potential Clinical Importance (PCI) | Up to Follow-up (Day 45) | 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. |
Countries
Canada, United States
Participant flow
Recruitment details
This study was conducted across 10 centers in the United States and 2 centers in Canada from 31 October 2013 to 08 October 2014.
Pre-assignment details
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).
Participants by arm
| Arm | Count |
|---|---|
| GSK1278863 300 mg Loading + 100 mg QD 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). | 27 |
| 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). | 28 |
| Total | 55 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 2 |
| Overall Study | Investigator discretion | 0 | 1 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Recovery | 2 | 0 |
Baseline characteristics
| Characteristic | Placebo | Total | GSK1278863 300 mg Loading + 100 mg QD |
|---|---|---|---|
| Age, Customized 21 to 88 years | 28 Participants | 55 Participants | 27 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 9 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 19 Participants | 43 Participants | 24 Participants |
| Sex: Female, Male Female | 10 Participants | 19 Participants | 9 Participants |
| Sex: Female, Male Male | 18 Participants | 36 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 6 / 27 | 2 / 28 |
| other Total, other adverse events | 20 / 27 | 19 / 28 |
| serious Total, serious adverse events | 20 / 27 | 14 / 28 |
Outcome results
Primary
Change From Baseline to Peak in Cerebrospinal Fluid (CSF) S100 Beta Within 48 Hours Following Descending Thoracic Aorta/Thoracoabdominal Aortic Aneurysm (DTA/TAAA) Repair
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GSK1278863 300 mg Loading + 100 mg QD | 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 |
| Placebo | Change From Baseline to Peak in Cerebrospinal Fluid (CSF) S100 Beta Within 48 Hours Following Descending Thoracic Aorta/Thoracoabdominal Aortic Aneurysm (DTA/TAAA) Repair | 566.78 Nanograms per liter (ng/L) | Standard Deviation 1897.172 |
p-value: 0.08295% CI: [-292.84, 4749.11]ANCOVA
Primary
Change From Baseline to Peak in CSF Glial Fibrillary Acidic Protein (GFAP) Within 48 Hours Following DTA/TAAA Repair
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GSK1278863 300 mg Loading + 100 mg QD | 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 |
| Placebo | Change From Baseline to Peak in CSF Glial Fibrillary Acidic Protein (GFAP) Within 48 Hours Following DTA/TAAA Repair | 283.03 Microgram per liter (µg/L) | Standard Deviation 1092.448 |
p-value: 0.199795% CI: [-424.04, 1979.94]ANCOVA
Secondary
Assessment in AUC for Markers of Ischemic Organ Injury Including Tropinin Within 48 Hours
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.
Time frame: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| GSK1278863 300 mg Loading + 100 mg QD | 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 |
| GSK1278863 300 mg Loading + 100 mg QD | 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 |
| Placebo | Assessment in AUC for Markers of Ischemic Organ Injury Including Tropinin Within 48 Hours | Troponin I | 7.23 µg*hour/L | Geometric Coefficient of Variation 0.65 |
| Placebo | Assessment in AUC for Markers of Ischemic Organ Injury Including Tropinin Within 48 Hours | Troponin T | 4.19 µg*hour/L | Geometric Coefficient of Variation 0.75 |
Comparison: For Troponin Ip-value: 0.501295% CI: [0.3, 11.32]ANOVA
Comparison: For Troponin Tp-value: 0.805395% CI: [0.07, 8.57]ANOVA
Secondary
Change From Baseline in Area Under Curve (AUC) for CSF S100 Beta to 48 Hours
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.
Time frame: Baseline(Day 0) to 48 hours following DTA/TAAA repair
Population: PD Population.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| GSK1278863 300 mg Loading + 100 mg QD | Change From Baseline in Area Under Curve (AUC) for CSF S100 Beta to 48 Hours | 17263.25 Hour*nanogram per liter (hour*ng/L) | Geometric Coefficient of Variation 316.4 |
| Placebo | Change From Baseline in Area Under Curve (AUC) for CSF S100 Beta to 48 Hours | 9758.27 Hour*nanogram per liter (hour*ng/L) | Geometric Coefficient of Variation 221.85 |
p-value: 0.15395% CI: [0.8, 3.9]ANOVA
Secondary
Change From Baseline in AUC for CSF GFAP to 48 Hours
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.
Time frame: Baseline(Day 0) to 48 hours following DTA/TAAA repair
Population: PD Population.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| GSK1278863 300 mg Loading + 100 mg QD | Change From Baseline in AUC for CSF GFAP to 48 Hours | 182.35 Hour*microgram per liter (hour*µg/L) | Geometric Coefficient of Variation 15899.84 |
| Placebo | Change From Baseline in AUC for CSF GFAP to 48 Hours | 58.32 Hour*microgram per liter (hour*µg/L) | Geometric Coefficient of Variation 1413.66 |
p-value: 0.137795% CI: [0.69, 14.26]ANOVA
Secondary
Change From Baseline to Peak in CSF Biomarker Erythropoietin Within 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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GSK1278863 300 mg Loading + 100 mg QD | 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 |
| Placebo | Change From Baseline to Peak in CSF Biomarker Erythropoietin Within 48 Hours Following DTA/TAAA Repair | 0.61 International units per liter (IU/L) | Standard Deviation 1.582 |
p-value: <0.000195% CI: [21.95, 47.17]ANCOVA
Secondary
Change From Baseline to Peak in CSF Biomarker Lactate Dehydrogenase Within 48 Hours Following DTA/TAAA Repair
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GSK1278863 300 mg Loading + 100 mg QD | 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 |
| Placebo | Change From Baseline to Peak in CSF Biomarker Lactate Dehydrogenase Within 48 Hours Following DTA/TAAA Repair | 1.28 Millimoles per liter (mmol/L) | Standard Deviation 1.16 |
p-value: 0.240495% CI: [-0.37, 1.45]ANCOVA
Secondary
Change From Baseline to Peak in CSF Biomarker Neuron-specific Enolase (NSE) Within 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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GSK1278863 300 mg Loading + 100 mg QD | 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 |
| Placebo | Change From Baseline to Peak in CSF Biomarker Neuron-specific Enolase (NSE) Within 48 Hours Following DTA/TAAA Repair | 5.65 µg/L | Standard Deviation 7.214 |
p-value: 0.089395% CI: [-0.65, 8.87]ANCOVA
Secondary
Change From Baseline to Peak in CSF Biomarker Tau Protein Within 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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GSK1278863 300 mg Loading + 100 mg QD | 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 |
| Placebo | Change From Baseline to Peak in CSF Biomarker Tau Protein Within 48 Hours Following DTA/TAAA Repair | 751.21 ng/L | Standard Deviation 1053.951 |
p-value: 0.052695% CI: [-10.73, 1862.49]ANCOVA
Secondary
Number of Participants With Abnormal Electrocardiography (ECG) Parameters
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.
Time frame: Up to Follow-up (Day 45)
Population: All Subjects Population.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| GSK1278863 300 mg Loading + 100 mg QD | Number of Participants With Abnormal Electrocardiography (ECG) Parameters | Post-operative Day 2, Abnormal-NCS | 18 Participants |
| GSK1278863 300 mg Loading + 100 mg QD | Number of Participants With Abnormal Electrocardiography (ECG) Parameters | Post-operative Day 5, Abnormal-NCS | 14 Participants |
| GSK1278863 300 mg Loading + 100 mg QD | Number of Participants With Abnormal Electrocardiography (ECG) Parameters | Post-operative Day 3, Abnormal-CS | 1 Participants |
| GSK1278863 300 mg Loading + 100 mg QD | Number of Participants With Abnormal Electrocardiography (ECG) Parameters | Post-operative Day 6, Abnormal-NCS | 14 Participants |
| GSK1278863 300 mg Loading + 100 mg QD | Number of Participants With Abnormal Electrocardiography (ECG) Parameters | Post-operative Day 3, Abnormal-NCS | 17 Participants |
| GSK1278863 300 mg Loading + 100 mg QD | Number of Participants With Abnormal Electrocardiography (ECG) Parameters | Post-operative Day 7, Abnormal-NCS | 15 Participants |
| GSK1278863 300 mg Loading + 100 mg QD | Number of Participants With Abnormal Electrocardiography (ECG) Parameters | Post-operative Day 4, Abnormal-NCS | 13 Participants |
| GSK1278863 300 mg Loading + 100 mg QD | Number of Participants With Abnormal Electrocardiography (ECG) Parameters | Follow-up, Abnormal-NCS | 11 Participants |
| GSK1278863 300 mg Loading + 100 mg QD | Number of Participants With Abnormal Electrocardiography (ECG) Parameters | Post-operative Day 1, Abnormal-NCS | 18 Participants |
| Placebo | Number of Participants With Abnormal Electrocardiography (ECG) Parameters | Follow-up, Abnormal-NCS | 13 Participants |
| Placebo | Number of Participants With Abnormal Electrocardiography (ECG) Parameters | Post-operative Day 1, Abnormal-NCS | 18 Participants |
| Placebo | Number of Participants With Abnormal Electrocardiography (ECG) Parameters | Post-operative Day 2, Abnormal-NCS | 17 Participants |
| Placebo | Number of Participants With Abnormal Electrocardiography (ECG) Parameters | Post-operative Day 3, Abnormal-NCS | 16 Participants |
| Placebo | Number of Participants With Abnormal Electrocardiography (ECG) Parameters | Post-operative Day 3, Abnormal-CS | 1 Participants |
| Placebo | Number of Participants With Abnormal Electrocardiography (ECG) Parameters | Post-operative Day 4, Abnormal-NCS | 18 Participants |
| Placebo | Number of Participants With Abnormal Electrocardiography (ECG) Parameters | Post-operative Day 5, Abnormal-NCS | 17 Participants |
| Placebo | Number of Participants With Abnormal Electrocardiography (ECG) Parameters | Post-operative Day 6, Abnormal-NCS | 10 Participants |
| Placebo | Number of Participants With Abnormal Electrocardiography (ECG) Parameters | Post-operative Day 7, Abnormal-NCS | 15 Participants |
Secondary
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
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.
Time frame: 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).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| GSK1278863 300 mg Loading + 100 mg QD | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any AEs | 26 Participants |
| GSK1278863 300 mg Loading + 100 mg QD | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any SAEs | 20 Participants |
| Placebo | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any AEs | 23 Participants |
| Placebo | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any SAEs | 14 Participants |
Secondary
Number of Participants With Clinical Chemistry Parameters of PCI
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.
Time frame: Up to post-operative Day 7
Population: All Subjects Population.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| GSK1278863 300 mg Loading + 100 mg QD | Number of Participants With Clinical Chemistry Parameters of PCI | 19 Participants |
| Placebo | Number of Participants With Clinical Chemistry Parameters of PCI | 18 Participants |
Secondary
Number of Participants With Clinical Composite of All Cause Mortality, Stroke, Spinal Infarction, MI, Need for Dialysis/Sustained Doubling of Serum Creatinine
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.
Time frame: Up to Follow-up (Day 45)
Population: All Subjects Population.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| GSK1278863 300 mg Loading + 100 mg QD | 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 |
| GSK1278863 300 mg Loading + 100 mg QD | 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 |
| GSK1278863 300 mg Loading + 100 mg QD | 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 |
| GSK1278863 300 mg Loading + 100 mg QD | 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 |
| GSK1278863 300 mg Loading + 100 mg QD | 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 |
| GSK1278863 300 mg Loading + 100 mg QD | 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 |
| Placebo | Number of Participants With Clinical Composite of All Cause Mortality, Stroke, Spinal Infarction, MI, Need for Dialysis/Sustained Doubling of Serum Creatinine | Death | 2 Participants |
| Placebo | 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 | 10 Participants |
| Placebo | Number of Participants With Clinical Composite of All Cause Mortality, Stroke, Spinal Infarction, MI, Need for Dialysis/Sustained Doubling of Serum Creatinine | Stroke | 2 Participants |
| Placebo | Number of Participants With Clinical Composite of All Cause Mortality, Stroke, Spinal Infarction, MI, Need for Dialysis/Sustained Doubling of Serum Creatinine | Myocardial Infarction | 0 Participants |
| Placebo | Number of Participants With Clinical Composite of All Cause Mortality, Stroke, Spinal Infarction, MI, Need for Dialysis/Sustained Doubling of Serum Creatinine | Composite Above | 12 Participants |
| Placebo | Number of Participants With Clinical Composite of All Cause Mortality, Stroke, Spinal Infarction, MI, Need for Dialysis/Sustained Doubling of Serum Creatinine | Paraplegia | 4 Participants |
Secondary
Number of Participants With Composite Index of All Cause Mortality and Disability (NIHSS>5/ASIA<40)
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.
Time frame: Up to Follow-up (Day 45)
Population: PD Population.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| GSK1278863 300 mg Loading + 100 mg QD | Number of Participants With Composite Index of All Cause Mortality and Disability (NIHSS>5/ASIA<40) | ASIA <40 | 4 Participants |
| GSK1278863 300 mg Loading + 100 mg QD | Number of Participants With Composite Index of All Cause Mortality and Disability (NIHSS>5/ASIA<40) | NIHSS >5 | 4 Participants |
| GSK1278863 300 mg Loading + 100 mg QD | Number of Participants With Composite Index of All Cause Mortality and Disability (NIHSS>5/ASIA<40) | Death | 6 Participants |
| GSK1278863 300 mg Loading + 100 mg QD | Number of Participants With Composite Index of All Cause Mortality and Disability (NIHSS>5/ASIA<40) | Composite Above | 11 Participants |
| Placebo | Number of Participants With Composite Index of All Cause Mortality and Disability (NIHSS>5/ASIA<40) | Composite Above | 4 Participants |
| Placebo | Number of Participants With Composite Index of All Cause Mortality and Disability (NIHSS>5/ASIA<40) | ASIA <40 | 1 Participants |
| Placebo | Number of Participants With Composite Index of All Cause Mortality and Disability (NIHSS>5/ASIA<40) | Death | 2 Participants |
| Placebo | Number of Participants With Composite Index of All Cause Mortality and Disability (NIHSS>5/ASIA<40) | NIHSS >5 | 2 Participants |
Secondary
Number of Participants With Hematology Parameters of PCI
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.
Time frame: Up to post-operative Day 7
Population: All Subjects Population.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| GSK1278863 300 mg Loading + 100 mg QD | Number of Participants With Hematology Parameters of PCI | 25 Participants |
| Placebo | Number of Participants With Hematology Parameters of PCI | 16 Participants |
Secondary
Number of Participants With Neurologic Outcomes Assessed by Modified Rankin Scale (mRS)
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).
Time frame: Post-operative Day 7 and follow-up (Day 45)
Population: PD population. Only those participants available at the indicated time points were analyzed.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| GSK1278863 300 mg Loading + 100 mg QD | Number of Participants With Neurologic Outcomes Assessed by Modified Rankin Scale (mRS) | Post-operative Day 7, Mild (Score 0-1) | 9 Participants |
| GSK1278863 300 mg Loading + 100 mg QD | Number of Participants With Neurologic Outcomes Assessed by Modified Rankin Scale (mRS) | Post-operative Day 7, Moderate (Score 2-3) | 1 Participants |
| GSK1278863 300 mg Loading + 100 mg QD | Number of Participants With Neurologic Outcomes Assessed by Modified Rankin Scale (mRS) | Post-operative Day 7, Severe (Score >=4) | 10 Participants |
| GSK1278863 300 mg Loading + 100 mg QD | Number of Participants With Neurologic Outcomes Assessed by Modified Rankin Scale (mRS) | Follow-up, Mild (Score 0-1) | 8 Participants |
| GSK1278863 300 mg Loading + 100 mg QD | Number of Participants With Neurologic Outcomes Assessed by Modified Rankin Scale (mRS) | Follow-up, Moderate (Score 2-3) | 4 Participants |
| GSK1278863 300 mg Loading + 100 mg QD | Number of Participants With Neurologic Outcomes Assessed by Modified Rankin Scale (mRS) | Follow-up, Severe (Score >=4) | 6 Participants |
| Placebo | Number of Participants With Neurologic Outcomes Assessed by Modified Rankin Scale (mRS) | Follow-up, Moderate (Score 2-3) | 7 Participants |
| Placebo | Number of Participants With Neurologic Outcomes Assessed by Modified Rankin Scale (mRS) | Post-operative Day 7, Mild (Score 0-1) | 11 Participants |
| Placebo | Number of Participants With Neurologic Outcomes Assessed by Modified Rankin Scale (mRS) | Follow-up, Mild (Score 0-1) | 14 Participants |
| Placebo | Number of Participants With Neurologic Outcomes Assessed by Modified Rankin Scale (mRS) | Post-operative Day 7, Moderate (Score 2-3) | 8 Participants |
| Placebo | Number of Participants With Neurologic Outcomes Assessed by Modified Rankin Scale (mRS) | Follow-up, Severe (Score >=4) | 4 Participants |
| Placebo | Number of Participants With Neurologic Outcomes Assessed by Modified Rankin Scale (mRS) | Post-operative Day 7, Severe (Score >=4) | 5 Participants |
Secondary
Number of Participants With Neurologic Outcomes Assessed by the American Spinal Injury Association (ASIA) Lower Extremity Motor Outcome Scale
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).
Time frame: 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.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| GSK1278863 300 mg Loading + 100 mg QD | 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 |
| GSK1278863 300 mg Loading + 100 mg QD | 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 |
| GSK1278863 300 mg Loading + 100 mg QD | 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 |
| GSK1278863 300 mg Loading + 100 mg QD | 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 |
| GSK1278863 300 mg Loading + 100 mg QD | 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 |
| GSK1278863 300 mg Loading + 100 mg QD | 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 |
| GSK1278863 300 mg Loading + 100 mg QD | 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 |
| GSK1278863 300 mg Loading + 100 mg QD | 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 |
| GSK1278863 300 mg Loading + 100 mg QD | 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 |
| GSK1278863 300 mg Loading + 100 mg QD | 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 |
| GSK1278863 300 mg Loading + 100 mg QD | 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 |
| GSK1278863 300 mg Loading + 100 mg QD | 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 |
| GSK1278863 300 mg Loading + 100 mg QD | 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 |
| GSK1278863 300 mg Loading + 100 mg QD | 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 |
| Placebo | 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) | 1 Participants |
| Placebo | 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 |
| Placebo | 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) | 1 Participants |
| Placebo | 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) | 0 Participants |
| Placebo | 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) | 0 Participants |
| Placebo | 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) | 19 Participants |
| Placebo | 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) | 22 Participants |
| Placebo | 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 |
| Placebo | 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) | 24 Participants |
| Placebo | 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) | 2 Participants |
| Placebo | 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 |
| Placebo | 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) | 21 Participants |
| Placebo | Number of Participants With Neurologic Outcomes Assessed by the American Spinal Injury Association (ASIA) Lower Extremity Motor Outcome Scale | Follow-up, Severe (Score <=25) | 1 Participants |
| Placebo | 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) | 0 Participants |
Secondary
Number of Participants With Neurologic Outcomes Assessed by the National Institutes of Health Stroke Scale (NIHSS)
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.
Time frame: 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.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| GSK1278863 300 mg Loading + 100 mg QD | Number of Participants With Neurologic Outcomes Assessed by the National Institutes of Health Stroke Scale (NIHSS) | Surgical Day, Mild (Score 1-4) | 0 Participants |
| GSK1278863 300 mg Loading + 100 mg QD | 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 |
| GSK1278863 300 mg Loading + 100 mg QD | 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 |
| GSK1278863 300 mg Loading + 100 mg QD | 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 |
| GSK1278863 300 mg Loading + 100 mg QD | 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 |
| GSK1278863 300 mg Loading + 100 mg QD | 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 |
| GSK1278863 300 mg Loading + 100 mg QD | 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 |
| GSK1278863 300 mg Loading + 100 mg QD | 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 |
| GSK1278863 300 mg Loading + 100 mg QD | 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 |
| GSK1278863 300 mg Loading + 100 mg QD | 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 |
| GSK1278863 300 mg Loading + 100 mg QD | 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 |
| GSK1278863 300 mg Loading + 100 mg QD | Number of Participants With Neurologic Outcomes Assessed by the National Institutes of Health Stroke Scale (NIHSS) | Follow-up, No event (Score=0) | 13 Participants |
| GSK1278863 300 mg Loading + 100 mg QD | 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 |
| GSK1278863 300 mg Loading + 100 mg QD | Number of Participants With Neurologic Outcomes Assessed by the National Institutes of Health Stroke Scale (NIHSS) | Follow-up, Mild (Score 1-4) | 1 Participants |
| GSK1278863 300 mg Loading + 100 mg QD | 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 |
| GSK1278863 300 mg Loading + 100 mg QD | Number of Participants With Neurologic Outcomes Assessed by the National Institutes of Health Stroke Scale (NIHSS) | Follow-up, Moderate (Score 5-15) | 4 Participants |
| GSK1278863 300 mg Loading + 100 mg QD | Number of Participants With Neurologic Outcomes Assessed by the National Institutes of Health Stroke Scale (NIHSS) | Surgical Day, No event (Score=0) | 27 Participants |
| Placebo | Number of Participants With Neurologic Outcomes Assessed by the National Institutes of Health Stroke Scale (NIHSS) | Follow-up, Moderate (Score 5-15) | 2 Participants |
| Placebo | Number of Participants With Neurologic Outcomes Assessed by the National Institutes of Health Stroke Scale (NIHSS) | Surgical Day, No event (Score=0) | 23 Participants |
| Placebo | Number of Participants With Neurologic Outcomes Assessed by the National Institutes of Health Stroke Scale (NIHSS) | Surgical Day, Mild (Score 1-4) | 3 Participants |
| Placebo | Number of Participants With Neurologic Outcomes Assessed by the National Institutes of Health Stroke Scale (NIHSS) | Post-operative Day 1, No event (Score=0) | 14 Participants |
| Placebo | Number of Participants With Neurologic Outcomes Assessed by the National Institutes of Health Stroke Scale (NIHSS) | Post-operative Day 1, Mild (Score 1-4) | 7 Participants |
| Placebo | Number of Participants With Neurologic Outcomes Assessed by the National Institutes of Health Stroke Scale (NIHSS) | Post-operative Day 1, Moderate (Score 5-15) | 1 Participants |
| Placebo | Number of Participants With Neurologic Outcomes Assessed by the National Institutes of Health Stroke Scale (NIHSS) | Post-operative Day 1, Severe (Score >15) | 1 Participants |
| Placebo | Number of Participants With Neurologic Outcomes Assessed by the National Institutes of Health Stroke Scale (NIHSS) | Post-operative Day 2, No event (Score=0) | 15 Participants |
| Placebo | Number of Participants With Neurologic Outcomes Assessed by the National Institutes of Health Stroke Scale (NIHSS) | Post-operative Day 2, Mild (Score 1-4) | 3 Participants |
| Placebo | 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 |
| Placebo | Number of Participants With Neurologic Outcomes Assessed by the National Institutes of Health Stroke Scale (NIHSS) | Post-operative Day 2, Severe (Score >15) | 1 Participants |
| Placebo | Number of Participants With Neurologic Outcomes Assessed by the National Institutes of Health Stroke Scale (NIHSS) | Post-operative Day 7, No event (Score=0) | 16 Participants |
| Placebo | Number of Participants With Neurologic Outcomes Assessed by the National Institutes of Health Stroke Scale (NIHSS) | Post-operative Day 7, Mild (Score 1-4) | 7 Participants |
| Placebo | Number of Participants With Neurologic Outcomes Assessed by the National Institutes of Health Stroke Scale (NIHSS) | Post-operative Day 7, Moderate (Score 5-15) | 1 Participants |
| Placebo | Number of Participants With Neurologic Outcomes Assessed by the National Institutes of Health Stroke Scale (NIHSS) | Post-operative Day 7, Severe (Score >15) | 0 Participants |
| Placebo | Number of Participants With Neurologic Outcomes Assessed by the National Institutes of Health Stroke Scale (NIHSS) | Follow-up, No event (Score=0) | 17 Participants |
| Placebo | Number of Participants With Neurologic Outcomes Assessed by the National Institutes of Health Stroke Scale (NIHSS) | Follow-up, Mild (Score 1-4) | 6 Participants |
Secondary
Number of Participants With Vital Signs of Potential Clinical Importance (PCI)
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.
Time frame: Up to Follow-up (Day 45)
Population: All Subjects Population.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| GSK1278863 300 mg Loading + 100 mg QD | Number of Participants With Vital Signs of Potential Clinical Importance (PCI) | SBP | 2 Participants |
| GSK1278863 300 mg Loading + 100 mg QD | Number of Participants With Vital Signs of Potential Clinical Importance (PCI) | DBP | 0 Participants |
| Placebo | Number of Participants With Vital Signs of Potential Clinical Importance (PCI) | DBP | 0 Participants |
| Placebo | Number of Participants With Vital Signs of Potential Clinical Importance (PCI) | SBP | 1 Participants |
Secondary
Pharmacokinetic (PK) Parameters in Blood: AUC(0-t) of GSK1278863
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.
Time frame: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| GSK1278863 300 mg Loading + 100 mg QD | Pharmacokinetic (PK) Parameters in Blood: AUC(0-t) of GSK1278863 | Blood, Surgical Day | 3591.449 Hour*ng/mL | Geometric Coefficient of Variation 50.23 |
| GSK1278863 300 mg Loading + 100 mg QD | 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 |
| GSK1278863 300 mg Loading + 100 mg QD | Pharmacokinetic (PK) Parameters in Blood: AUC(0-t) of GSK1278863 | Blood, Post-operative Day 3 | 3710.790 Hour*ng/mL | Geometric Coefficient of Variation 115.2 |
Secondary
PK Parameters in Blood: Maximum Observed Concentration (Cmax) of GSK1278863
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.
Time frame: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| GSK1278863 300 mg Loading + 100 mg QD | PK Parameters in Blood: Maximum Observed Concentration (Cmax) of GSK1278863 | Blood, Surgical Day | 705.701 Ng/mL | Geometric Coefficient of Variation 83.43 |
| GSK1278863 300 mg Loading + 100 mg QD | 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 |
| GSK1278863 300 mg Loading + 100 mg QD | PK Parameters in Blood: Maximum Observed Concentration (Cmax) of GSK1278863 | Blood, Post-operative Day 3 | 779.801 Ng/mL | Geometric Coefficient of Variation 110.2 |
Secondary
PK Parameters in Blood: Time of Occurrence of Cmax (Tmax) of GSK1278863
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| GSK1278863 300 mg Loading + 100 mg QD | PK Parameters in Blood: Time of Occurrence of Cmax (Tmax) of GSK1278863 | Blood, Surgical day | 1.725 Hours |
| GSK1278863 300 mg Loading + 100 mg QD | PK Parameters in Blood: Time of Occurrence of Cmax (Tmax) of GSK1278863 | Blood, Post-operative Day 1 | 3.017 Hours |
| GSK1278863 300 mg Loading + 100 mg QD | PK Parameters in Blood: Time of Occurrence of Cmax (Tmax) of GSK1278863 | Blood, Post-operative Day 3 | 3.017 Hours |
Secondary
PK Parameters in CSF: AUC(0-t) of GSK1278863
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.
Time frame: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| GSK1278863 300 mg Loading + 100 mg QD | PK Parameters in CSF: AUC(0-t) of GSK1278863 | 37.340 Hour*ng/mL | Geometric Coefficient of Variation 156.1 |
Secondary
PK Parameters in CSF: Cmax of GSK1278863
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.
Time frame: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| GSK1278863 300 mg Loading + 100 mg QD | PK Parameters in CSF: Cmax of GSK1278863 | 2.364 Ng/L | Geometric Coefficient of Variation 105.24 |
Secondary
PK Parameters in CSF: Tmax of GSK1278863
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| GSK1278863 300 mg Loading + 100 mg QD | PK Parameters in CSF: Tmax of GSK1278863 | 15.326 Hours |