Subarachnoid Hemorrhage and Soluble Epoxide Hydrolase Inhibition Trial
Phase: PHASE1
Conditions: Subarachnoid Hemorrhage, Aneurysmal, Delayed Cerebral Ischemia, Vasospasm, Cerebral, Endothelial Dysfunction
Sponsor: Oregon Health and Science University

Subarachnoid hemorrhage and soluble epoxide hydrolase inhibition: a phase 1b trial 
 
 
Protocol Number: SUSHI-1 
 
 
Principal Investigator: Ross Martini MD 
Co-Investigators: Miriam Treggiari MD PhD, Justin Cetas MD PhD, Nabil Alkayed MD PhD 
Safety Monitor: Peter Schulman MD 
Biostatistician: N. David Yanez PhD 
 
 
IND Sponsor: Oregon Health and Science University 
Funded by: Foundation for Anesthesia Education and Research 
 
 
Version Number:  v.3.0 
29 November 2018 
 
 
 

  
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Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................ 1 
SIGNATURE PAGE ................................................................................................................................ 2 
LIST OF ABBREVIATIONS ..................................................................................................................... 3 
1 
PROTOCOL SUMMARY .............................................................................................................. 4 
1.1 
Synopsis ............................................................................................................................. 4 
1.2 
Schema .............................................................................................................................. 6 
1.3 
Key roles and contact information ....................................................................................... 7 
2 
INTRODUCTION .......................................................................................................................... 8 
2.1 
Study Rationale .................................................................................................................. 8 
2.2 
Background ........................................................................................................................ 8 
2.3 
Risk/Benefit Assessment .................................................................................................. 10 
2.3.1 
Known Potential Risks ..................................................................................... 10 
2.3.2 
Assessment of Potential Risks and Benefits ..................................................... 11 
3 
OBJECTIVES AND ENDPOINTS ............................................................................................... 11 
4 
STUDY DESIGN ........................................................................................................................ 13 
4.1 
Overall Design .................................................................................................................. 13 
4.2 
Scientific Rationale for Study Design ................................................................................. 14 
4.3 
Justification for Dose......................................................................................................... 14 
4.4 
End of Study Definition ..................................................................................................... 14 
5 
STUDY POPULATION ............................................................................................................... 14 
5.1 
Inclusion Criteria ............................................................................................................... 14 
5.2 
Exclusion Criteria .............................................................................................................. 14 
5.3 
Screen Failures ................................................................................................................ 15 
5.4 
Strategies for Recruitment and Retention .......................................................................... 15 
6 
STUDY INTERVENTION ............................................................................................................ 15 
6.1 
Study Intervention(s) Administration .................................................................................. 15 
6.1.1 
Study Intervention Description ......................................................................... 15 
6.1.2 
Dosing and Administration ............................................................................... 16 
6.2 
Preparation/Handling/Storage/Accountability ..................................................................... 16 
6.2.1 
Acquisition and accountability .......................................................................... 16 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ......................................... 16 
6.2.3 
Product Storage and Stability ........................................................................... 16 
6.2.4 
Preparation ...................................................................................................... 16 
6.3 
Measures to Minimize Bias: Randomization and Blinding .................................................. 16 
6.4 
Study Intervention Compliance.......................................................................................... 17 
6.5 
Concomitant Therapy ........................................................................................................ 17 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .................................................................................................... 17 
7.1 
Discontinuation of Study Intervention ................................................................................ 17 
7.2 
Participant Discontinuation/Withdrawal from the Study ...................................................... 17 
7.3 
Lost to Follow-Up .............................................................................................................. 17 
8 
STUDY ASSESSMENTS AND PROCEDURES .......................................................................... 18 
8.1 
Screening, Consent, and Randomization .......................................................................... 18 
8.2 
Baseline Evaluation .......................................................................................................... 18 
8.3 
Study Drug Administration Schedule ................................................................................. 19 
8.4 
Safety Assessments ......................................................................................................... 19 
8.4.1 
Daily Assessments .......................................................................................... 19 
8.4.2 
Disease related and adverse event tracking ..................................................... 19 
8.5 
Pharmacodynamic Effect Assessments ............................................................................. 20 

  
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8.5.1 
Sample Collection ............................................................................................ 20 
8.5.2 
Eicosanoid Profile and SEH Activity Assay ....................................................... 20 
8.5.3 
Inflammatory and Endothelial Injury Sample Processing .................................. 21 
8.5.4 
EPHX2 Polymorphism Analysis Sample Processing......................................... 21 
TERTIARY ENDPOINT ASSESSMENTS........................................................................................... 22 
8.6 
Adverse Events and Serious Adverse Events .................................................................... 22 
8.6.1 
Definition of Adverse Events (AE) .................................................................... 22 
8.6.2 
Definition of Serious Adverse Events (SAE) ..................................................... 23 
8.6.3 
Classification of an Adverse Event ................................................................... 23 
8.6.4 
Time Period and Frequency for Event Assessment and Follow-Up ................... 24 
8.6.5 
Adverse Event Reporting ................................................................................. 25 
8.6.6 
Serious Adverse Event Reporting .................................................................... 25 
8.6.7 
Reporting Events to Participants ...................................................................... 25 
8.7 
Unanticipated Problems .................................................................................................... 25 
8.7.1 
Definition of Unanticipated Problems (UP) ....................................................... 25 
8.7.2 
Unanticipated Problem Reporting .................................................................... 26 
8.7.3 
Reporting Unanticipated Problems to Participants ............................................ 26 
9 
STATISTICAL CONSIDERATIONS ............................................................................................ 26 
9.1 
Statistical Endpoints.......................................................................................................... 26 
9.2 
Sample Size Determination ............................................................................................... 27 
9.3 
Populations for Analyses................................................................................................... 27 
9.4 
Statistical Analyses ........................................................................................................... 27 
9.4.1 
General Approach ........................................................................................... 27 
9.4.2 
Missing Values ................................................................................................ 28 
9.4.3 
Analysis of the Primary Endpoint ..................................................................... 28 
9.4.4 
Analysis of the Secondary and Tertiary Endpoints ............................................ 28 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ......................... 29 
10.1 
Regulatory, Ethical, and Study Oversight Considerations .................................................. 29 
10.1.1 
Informed Consent Process............................................................................... 29 
10.1.2 
Study Discontinuation and Closure .................................................................. 29 
10.1.3 
Confidentiality and Privacy ............................................................................... 30 
10.1.4 
Safety Oversight .............................................................................................. 30 
10.1.5 
Quality Assurance and Quality Control ............................................................. 31 
10.1.6 
Data Handling and Record Keeping ................................................................. 31 
10.1.7 
Protocol Deviations .......................................................................................... 31 
10.1.8 
Conflict of Interest Policy ................................................................................. 32 
10.2 
Protocol Amendment History ............................................................................................. 33 
11 
SCHEDULE OF ACTIVITIES ...................................................................................................... 34 
12 
REFERENCES .......................................................................................................................... 34 

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STATEMENT OF COMPLIANCE 
 
The trial will be conducted in accordance with International Conference on 
Harmonization Good Clinical Practice (ICH GCP) and applicable United States (US) 
Code of Federal Regulations (CFR). The Principal Investigator will assure that no 
deviation from, or changes to the protocol will take place without prior agreement from 
the Investigational New Drug (IND) sponsor, funding agency and documented approval 
from the Institutional Review Board (IRB), except where necessary to eliminate an 
immediate hazard(s) to the trial participants. All personnel involved in the conduct of this 
study have completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent forms, recruitment materials, and all participant materials 
will be submitted to the IRB for review and approval.  Approval of both the protocol and 
the consent form must be obtained before any participant is enrolled.  Any amendment 
to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  All changes to the consent form will be IRB approved; a 
determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 
 
 

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SIGNATURE PAGE 
 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable US federal regulations and ICH guidelines.  
 
 
 
 
Signed: 
 
 
 
 
 
Date:  
 
 
Ross Martini MD, Principal Investigator 
 
 

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LIST OF ABBREVIATIONS 
AE 
 
adverse event 
AST 
 
Aspartate aminotransferase 
ALT 
 
Alanine aminotransferase  
BUN 
 
blood urea nitrogen 
CRF 
 
case report form 
CSF 
 
cerebrospinal fluid 
CT 
 
computed tomography 
DCI 
 
delayed cerebral ischemia 
DDI 
 
drug drug interaction 
DHET  
dihydroxyeicosatrienoic acids 
DPOME 
dihydroxyoctadec-12-enoic acid 
ECG 
 
electrocardiogram 
eCRF   
electronic case report form 
EETs  
epoxyeicosatrienoic acids 
EF 
 
ejection fraction 
EMR  
electronic medical record 
EPOME 
epoxyoctadecenoic acid 
EVD 
 
external ventricular drain 
FDA 
 
food and drug administration 
GCP 
 
good clinical practice 
GLP 
 
good laboratory practice 
GMP  
good manufacturing practice 
GOSE  
Extended Glasgow Outcome Scale  
HDL 
 
high density lipoprotein 
ICH 
 
International Conference on Harmonization 
IND 
 
Investigational New Drug 
IRB 
 
Institutional Review board 
LAR 
 
legally authorized representative 
LDL 
 
low density lipoprotein 
LV 
 
left ventricle 
MCA  
middle cerebral artery 
MOP  
manual of procedures 
MR 
 
magnetic resonance 
mRS  
modified Rankin scale 
NSICU  
Neurosciences Intensive Care Unit 
NSTEMI 
non-ST elevation myocardial infarction 
OHRP  
office for human research protections 
OHSU  
Oregon Health and Science University 
PCP 
 
primary care provider 
PI 
 
principal investigator 
QC 
 
quality control 
SAE 
 
serious adverse event 
SAH 
 
subarachnoid hemorrhage 
sEH 
 
soluble epoxide hydrolase 
SOA 
 
Schedule of activities  
SOP 
 
standard operating procedure 
STEMI  
ST elevation myocardial infarction 
UP 
 
unanticipated problem 
US 
 
United States 

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1 
 
PROTOCOL SUMMARY 
1.1 SYNOPSIS  
Title: 
Subarachnoid hemorrhage and soluble epoxide hydrolase 
inhibition: a phase 1b trial 
 
Study Description: 
Soluble epoxide hydrolase (sEH) is the metabolizing enzyme of 
epoxyeicosatrienoic acids (EETs), which may play a role in reducing 
neuroinflammation and regulating cerebral blood flow after 
subarachnoid hemorrhage (SAH).  We hypothesize that 
pharmacologic inhibition of the sEH enzyme is safe and will result in 
increased EETs availability at the neurovascular unit, and a 
measured increase in the EET/DHET ratio in the serum and 
cerebrospinal fluid.  This study is a double-blind, placebo-controlled, 
phase 1b randomized trial to evaluate the safety and of 
GSK2256294, an inhibitor of soluble epoxide hydrolase, in patients 
with aneurysmal SAH.  
 
Objectives: 
 
Primary Objective:  
Determine the safety of administration of GSK2256294 in patients 
with aneurysmal SAH.  
Secondary Objective:  
Determine the pharmacodynamics effect of administration of 
GSK2256294 in patients with aneurysmal SAH on reducing EETs 
metabolism and biomarkers of cerebrovascular inflammation and 
endothelial injury. 
Tertiary Objective:  
Provide preliminary estimates of clinical endpoints to inform the 
design of a larger trial  
 
Endpoints: 
Primary Endpoints:  
Determination of safety 
Secondary endpoints:  
1. Study days 7 and 10 serum EET/DHET ratios 
2. Study days 7 and 10 cerebrospinal fluid (CSF) EET/DHET 
ratios 
3. Study days 7 and 10 serum EPOME/DPOME ratios 
4. Neuroinflammatory and endothelial injury biomarker levels 
from the blood and CSF at day 7 and day 10. 
Tertiary, exploratory endpoints:  
Clinical outcomes associated with SAH including neurologic 
status, disposition, vital status and incidence of delayed 
cerebral ischemia. 
 
Up to 30 subjects will be randomized.  Patients age 18 or above with 
confirmed ruptured will be approached to provide written informed 
consent. In order to be eligible to participate in this study, an 
individual must meet all of the following criteria: non-contrast CT with 
evidence of subarachnoid hemorrhage, and digital subtraction 
cerebral angiography or CT angiogram documenting the presence of 

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a cerebral aneurysm. An individual who meets any of the following 
criteria will be excluded from participation in this study: evidence of 
prolonged QTc >500 milliseconds, baseline AST and ALT > 2x 
normal reference values, administration of strong inducers/inhibitors 
of CYP3A4, symptom onset compatible with SAH of ≥ 3 days prior to 
admission to Oregon Health and Science University Neurosciences 
Intensive Care Unit (OHSU NSICU), unable to speak or understand 
English or Spanish, current pregnancy based on urine HCG positive 
pregnancy test, preexisting severe neurologic deficit or condition, 
chronic renal failure requiring dialysis, severe terminal disease with 
life expectancy <6 months, or refusal of informed consent. 
 
Phase: 
Phase 1B 
 
Description of 
Sites/Facilities 
Enrolling 
Participants: 
The study will take place at Oregon Health & Science University 
Hospital, with enrollment of patients admitted to the OHSU NSICU, a 
part of a comprehensive stroke center certified by the American 
Heart Association and Joint Commission for Accreditation of 
Healthcare Organizations, with a catchment area including the state 
of Oregon, Southwest Washington and Northern California. 
Approximately 80-100 patients with aneurysmal SAH are admitted 
each year. 
 
Description of Study 
Intervention: 
Up to 30 patients will be equally randomized to receive once daily 
either 10 mg dose of GSK2256294 or placebo enterally for a 
duration of 10 days.  
 
Study Duration: 
24 months 
 
Participant Duration: 
90 days 
 
 

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1.2 SCHEMA 
Prior to  
Enrollment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Days 2-10 
 
 
 
 
 
 
 
Hospital 
Discharge 
 
 
 
 
 
90 day 
Follow-up 
 
 
Screen potential participants by inclusion and exclusion criteria; obtain history, document. 
Obtain informed consent. 
Perform baseline assessment of characteristics of present illness, physiologic data and 
demographics, and baseline sample collection as detailed in Section 11, Schedule of 
Activities 
Administer first dose of study drug or placebo 
Adverse event review, disease related events review and outcomes assessment, as 
detailed in Section 11, Schedule of Activities 
Adverse event review and 
outcomes assessment, as detailed in 
Section 11, Schedule of Activities 
 
Placebo 
N=10 
GSK2256294 
N=10 
Daily administration of study drug or placebo 
Adverse event, disease related event review and daily clinical assessments 
On days 7 and 10: Sample collection from blood and cerebrospinal fluid (CSF) as detailed 
in Section 11, Schedule of Activities 
Randomization 

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1.3 KEY ROLES AND CONTACT INFORMATION 
 
 
Principal Investigator: 
Ross Martini MD 
Oregon Health & Science University 
Department of Anesthesiology and 
Perioperative Medicine 
(503) 494-5067 
martinir@ohsu.edu 
Co-Investigators: 
Miriam Treggiari MD PhD MPH 
Oregon Health & Science University 
Department of Anesthesiology and 
Perioperative Medicine 
(503) 494-5735 
treggiar@ohsu.edu 
 
Justin Cetas MD PhD 
Oregon Health & Science University 
Department of Neurological Surgery 
(503) 494-5863 
cetasj@ohsu.edu 
 
Nabil Alkayed MD PhD 
Oregon Health & Science University 
Department of Anesthesiology and 
Perioperative Medicine 
Knight Cardiovascular Institute 
(503) 494-7641 
alkayedn@ohsu.edu 
Safety Monitor: 
Peter Schulman, MD 
Oregon Health & Science University 
Department of Anesthesiology and 
Perioperative Medicine 
(503) 494-7641 
schulman@ohsu.edu 
Project Biostatistician: 
N. David Yanez, PhD 
Oregon Health & Science University 
School of Public Health 
(503) 494-5354 
yanezn@ohsu.edu 
 
 
 

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2 
 
INTRODUCTION 
 
2.1 STUDY RATIONALE  
 
SAH due to the rupture of an intracranial aneurysm is a life threatening medical emergency with 
a mortality of 25-40%.  In survivors of the initial bleeding, endothelial injury and blood in the 
subarachnoid space induce an intense inflammatory response, leading to vessel wall thickening 
and caliber reduction over the first 10-14 days following the bleed. This inflammatory process 
may cause delayed cerebral ischemia (DCI).   DCI is the clinical result of a complex 
neurovascular inflammatory response characterized by blood brain barrier breakdown, impaired 
blood vessel autoregulation, direct inflammatory injury, thrombosis, and cerebral edema. The 
ultimate result is decreased cerebral blood flow and altered neurovascular communications.  
The inflammatory and ischemic injury associated with DCI may result in long-term cognitive 
dysfunction and functional disability in >50% of survivors. 
  
In an effort to prevent and treat DCI, patients with SAH require intensive care unit monitoring of 
hemodynamics and neurologic function for 10-14 days after the primary hemorrhage. Monitoring 
of the tone of intracranial blood vessels is routinely carried out daily with transcranial Doppler 
flow velocities, and cerebral angiography when indicated.  Clinical deteriorations that are 
accompanied by signs of decreased cerebral blood flow are treated with blood pressure 
augmentation and/or intra-arterial vasodilators, with limited therapeutic effectiveness. The only 
recommended pharmacological therapy is the prophylactic administration of a 21-day course of 
the calcium channel blocker nimodipine.[1]] There are currently no other effective therapies to 
directly target microvascular blood vessel dysregulation or neuroinflammation. 
 
2.2 BACKGROUND  
 
Epoxyeicosatrienoic acids (EETs) are arachidonic acid metabolites that are emerging as 
important regulators of cerebral blood flow and neuroinflammation after brain injury, including 
SAH.[2, 3] EETs are synthesized by cytochrome P450 epoxygenases in response to cellular 
insults including ischemia. The beneficial properties of EETs, which have been demonstrated in 
vitro and in vivo, include: vasodilation, promotion of angiogenesis, reduced microvascular 
thrombosis, inhibition of platelet aggregation, decreased apoptosis, and decreased 
inflammation. All these processes are disturbed following SAH.  EETs have multiple sites of 
action: on the endothelium where they likely regulate inflammatory response, on vascular 
smooth muscle where they are involved in regulating vasomotor tone, and more broadly 
throughout the neurovascular units regulating neurovascular communication.  
Multiple biomarkers have been identified that characterize neuroinflammation after SAH, and 
many have been associated with EETs signaling (Table 1). EETs are primarily metabolized to 
inactive dihydroxyeicosatrienoic acids (DHETs) by the enzyme soluble epoxide hydrolase 
(sEH), which is expressed in cerebral endothelial and smooth muscle cells as well as astrocyte 
cell bodies and foot processes.[4]  
Several polymorphisms in the gene responsible for sEH transcription, designated EPHX2, alter 
the structure and function of the enzyme.[5, 6] One variant conferring increased sEH activity 
and inactivation of EETs, known as K55R, has been linked to hypertension, ischemic stroke and 
coronary artery disease.[7-9] In patients with SAH, K55R genotype sEH is associated with 

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increased mortality and incidence of stroke.[10] Conversely, pharmacologic inhibition of sEH 
reduces infarct size after transient cerebral ischemia in animal models.[11]  
 
Inhibition of sEH in humans has recently become feasible due to the availability of a drug under 
development by GlaxoSmithKline, GSK2256294. 
 
Pharmacokinetics and product metabolism 
In human and animal studies, the oral bioavailability of GSK2256294 was generally high, 
indicating good absorption, low plasma clearance and a half-life of 20-30 hours. Steady state 
was achieved within 6-8 days after daily repeat dosing in humans.[12] GSK2256294 has low to 
moderate protein binding, high passive permeability, and a moderate volume of distribution. 
Structural information on GSK2256294 metabolism in humans following both single and repeat 
oral doses in both healthy volunteers and obese smokers indicated GSK2256294 was the major 
drug related component in human plasma with biliary and urinary metabolites being formed by 
either oxidation with or without subsequent glucuronidation and N-demethylation. Similar 
metabolites were detected in human and nonclinical hepatocytes.  
 
In vitro data indicated limited potential for GSK2256294 to be a perpetrator of cytochrome P450 
-mediated drug interactions. Population-based physiologically based pharmacokinetics model 
simulations, evaluating the risk of an interaction between GSK2256294 and a strong CYP3A4 
inhibitor, predicted a moderate increase (3.2 fold) to the mean systemic exposure of 
GSK2256294 when administered together. Co-administration of strong inhibitors and inducers 
of CYP3A4 has been recommended to be prohibited.  
  
GSK2256294 inhibited the human breast cancer resistance protein and organic anion 
transporting polypeptide 1B1 in vitro, suggesting the potential for drug interactions with statins 
that have their disposition modulated by these transporters. However, a physiologically based 
pharmacokinetic population based drug-drug interaction modelling simulation between 
GSK2256294 and sensitive substrates (including rosuvastatin) has predicted the clinical 
interaction risk to be negligible (<1.05 fold). Hence monitoring of adverse events is 
recommended with the concomitant use of GSK2256294 with statins. 
 
Toxicology 
Administration of GSK2256294 was well tolerated at doses up to 600 mg/kg/day in the rat and 
1000 mg/kg/day in the monkey. A dose of 1000 mg/kg/day in the rat was generally less 
tolerated, with adverse clinical signs of reduced food consumption and body weight loss along 
with macroscopic and microscopic gastric and renal changes and urinalysis effects. In addition, 
increased liver weight and hepatocyte hypertrophy at 1000 mg/kg/day were noted in rats, along 
with associated thyroid follicular cell hypertrophy, effects which are often secondary to drug 
metabolizing enzyme induction in rats (systemic exposure was also reduced at Days 14 and 28 
in rat as compared to Day 1). Minimal to mild atrophy of mammary glands was also seen in 
male rats at 1000 mg/kg/day. At >100 mg/kg/day in rats, there were increased serum 
cholesterol concentrations along with elevated high-density lipoprotein (HDL) and low-density 
lipoprotein (LDL) fractions. These were considered non-adverse. GSK2256294 was negative in 
a battery of genotoxicity assays. 
 
In reproductive and developmental toxicity studies to date, assessment of male rat fertility in 13 
week studies has identified no test article-related effects on male mating, fertility or male 
mediated fetal developmental toxicity after 2 and 11 weeks of dosing at up to 1000 mg/kg/day. 
 
Human Studies 

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The pharmacokinetics, pharmacodynamics and safety of GSK2256294 has been evaluated in 
three Phase I studies: an ascending single and repeat dose study of GSK2256294 in healthy 
male volunteers and otherwise healthy adult male overweight and moderately obese smokers, a 
single dose study in healthy young and elderly subjects, and a repeat dose study in healthy 
volunteers. When administered with food (high fat meal), there was, on average, a 22% 
increase in AUC of GSK2256294 with similar maximum plasma concentration. The median time 
to peak concentration was delayed by approximately 2 hours when GSK2256294 was 
administered with food (3.0 hrs versus 1.0 hr). These differences were not deemed to be 
clinically significant and GSK2256294 can be administered without any meal restrictions in 
future clinical studies. 
 
GSK2256294 was eliminated mainly by direct biliary secretion and metabolism with metabolites 
being excreted in both urine and bile. Renal elimination of unchanged parent represented <5% 
of the dose. In the single dose cohorts AE reporting was higher following GSK2256294 than 
placebo, but there was no evidence of increased reporting with increased dose.  
 
Pharmacodynamics and Dose Finding 
The inhibitory effect of GSK2256294 on exogenous deuterium-labeled EETs was estimated in 
an ex vivo assay in healthy volunteers and otherwise healthy overweight to moderately obese 
smokers following single doses of 2-20mg, and following 14 days of once daily repeat dosing at 
6mg and 18mg.[12]  The sEH activity was evaluated by the formation of 14,15 dDHET, 
corrected for non-sEH mediated hydrolysis and subsequently the % inhibition of sEH activity 
was defined.  >95% enzyme inhibition was observed for up to 48 hours following a single 10mg 
dose.  >98% enzyme inhibition was observed to be sustained for up to 48 hours following 14 
days of daily administration. 
 
 
2.3 RISK/BENEFIT ASSESSMENT   
 
2.3.1 KNOWN POTENTIAL RISKS  
 
GSK2256294 has been studied in several clinical cohorts. The most commonly reported AEs in 
healthy volunteers were contact dermatitis and headache, and in healthy adult male overweight 
and moderately obese smokers were headache and fatigue. Most AEs were of mild or moderate 
intensity. In the repeat dose cohorts of healthy adult male overweight and moderately obese 
smokers, AE reporting was similar in frequency overall following repeat administration of 
GSK2256294 compared with placebo. The most frequently reported AEs were headache and 
nasopharyngitis. All AEs were considered to be of mild or moderate severity. There was one AE 
leading to withdrawal (presyncope) reported in heathy volunteers and one SAE in healthy adult 
male overweight and moderately obese smokers (nephrolithiasis) reported. Neither of these 
events were deemed likely to be related to the study drug. 
 
Clinically significant abnormalities in clinical chemistry and hematology parameters were 
infrequent and most were present at baseline. Following repeat dosing with GSK2256294, there 
was a statistically significant decrease in HDL compared to baseline. The ratio to placebo of 
change from baseline in HDL was not statistically significant, though there was a trend for a 
dose-dependent difference. There were no changes in vital signs of clinical importance. A 
clinically significant abnormality (nodal rhythm) was reported for one subject with presyncope. 
 

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There were no fatal or non-fatal SAEs and no adverse event leading to the withdrawal. 
Treatment with GSK2256294 did not increase the room air pulmonary artery systolic pressure 
and did not augment the normal hypoxic pulmonary vasoconstrictive response in healthy 
subjects. No clinically significant changes in any of the clinical laboratory parameters, 
electrocardiograms (ECGs) and vital signs were observed.   
 
GSK2256294 has been generally well tolerated in the clinic, although most studies with 
GSK2256294 have been of relatively short duration and the safety database is not extensive. 
Due to limited experience in human subjects, there is currently not enough information available 
about the relationship between administration of GSK2256294 and adverse events to assign 
causality. It is possible that there are other long-range risk associated with drug administration 
that have not been identified in previous trials.  
 
No efficacy studies have been conducted to date. There is a potential that administration of the 
study drug will improve EETs signaling and reduce neuroinflammation and endothelial injury.  
Patients in the treatment group may experience less vasoconstriction, fewer delayed ischemic 
complications after SAH, and improved neurologic outcomes. 
 
This study will also involve sample collection from the blood and CSF.  Blood samples will be 
collected whenever possible from indwelling venous or arterial access. In the absence of an 
available access site, venipuncture will be performed by the bedside RN.  CSF samples will be 
collected by accessing the EVD, which will have been placed as part of the patient’s routine 
medical care for SAH.  The EVD will be accessed in the same fashion as for routine, clinically-
directed sampling, and wherever possible at the same time.  EVD access may very slightly 
increase the risk of introduction of bacteria and the development of ventriculitis.  
 
2.3.2 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
 
Based on previous phase 1 trials, the adverse event profile and pharmacologic interactions of 
GSK2256294 are minimal.[12]  There is a lack of detailed, long-term event tracking, and this will 
be the first study of GSK2256294 in a critically ill patient population, so it is possible that there 
will be unanticipated adverse events.  The drug exposure period will be relatively short, in line 
with previous phase 1 trials, and the monitoring will be significantly more intensive, which limits 
the additional risk.  
 
In addition, patients admitted to the intensive care unit for the treatment of SAH will routinely 
undergo numerous blood draws, sampling of CSF and diagnostic procedures as part of the 
accepted standard of care.  Our proposed study will not change the risks inherent to specimen 
sampling. Blood and CSF samples will be obtained at the same time (whenever feasible) and in 
the same fashion as routine and standard of care samples are obtained. 
 
Study participation will not influence the clinical care of patients other than as defined in Section 
11 within the Schedule of Activities. The potential benefit of reduced neuroinflammation and 
improved outcome in patients with an otherwise highly morbid, high mortality disease process 
outweighs these potential risks. Future patients with SAH may be benefited by the knowledge 
gained.   
 
3 
OBJECTIVES AND ENDPOINTS 
 

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• 
Primary Objective: Determine the safety of administration of GSK2256294 in patients 
with aneurysmal SAH.  
 
Frequencies of AEs and SAEs: We will compare AEs and SAEs between the drug and 
placebo groups.  We will also compare daily safety labs (serum sodium, blood glucose, 
blood urea nitrogen (BUN), creatinine, hematocrit, peripheral white blood cell count) 
between the groups. Specific to this patient population, we will also specifically screen 
for disease related events including seizure, new onset cardiomyopathy, 
NSTEMI/STEMI, hyponatremia, hospital acquired infection, mechanical ventilation, and 
thromboembolic events. We will describe the severity of headache (on a daily scale of 0-
10. 
 
Justification: Prior phase 1 studies of GSK2256294 have been in healthy volunteers 
with limited physiologic monitoring. The most common adverse event was headache. 
We will assess safety in this critically ill patient population with special focus on common 
sequelae of subarachnoid hemorrhage.   
 
• 
Secondary Objective: Determine the pharmacodynamic effects of administration of 
GSK2256294 in patients with aneurysmal SAH.  
 
To evaluate the effect of enzymatic inhibition on circulating EETs levels, we will measure 
day 7 and day 10 serum EET/DHET ratios. EETs levels will be measured using liquid 
chromatography and mass spectroscopy. 
 
To evaluate the possible effect of enzymatic inhibition on CSF EETs levels we will 
measure day 7 and day 10 CSF EET/DHET ratios, and compare the drug and placebo 
groups. We will also measure other lipid metabolic substrates of sEH at days 7 and day 
10, specifically serum epoxyoctadecenoic acid (EPOME) and dihydroxyoctadec-12-enoic 
acid (DPOME), to assess sEH enzyme activity.  
 
To evaluate more downstream effects on measures of endothelial injury and 
neuroinflammation, we will measure multiple biomarkers in the blood and CSF at day 7 
and day 10 (Table 1). The biomarkers chosen are surrogate endpoints representing 
pathways of the inflammatory cascade associated with clinical endpoints in SAH. 
 
Justification: EETs are degraded to inactive byproducts DHETs by the enzyme sEH.  
sEH activity has previously been measured after exposure to the study drug, and found 
to reach steady state level of >95% drug inhibition at 7 days. Prior evaluations of drug 
efficacy have used indirect means to measure drug effectiveness in inhibiting exogenous 
EETs degradation. We will directly measure in vivo EETs levels after drug administration 
to determine the degree by which sEH inhibition results in measurable increases in 
systemic EETs.  Endogenous EETs have a very short half-life and require rapid sample 
processing and meticulous storage conditions.   
 
We have chosen to measure the EET/DHET ratio due to the normal fluctuations of EETs 
levels in the post-bleed period after SAH.  The drug will be deemed effective if we 
measure higher EET/DHET ratio in the treatment group compared to placebo, i.e. higher 
EETs suggests decreased metabolism by sEH. It is possible that serum EET/DHET ratio 
will not be measurably increased. EETs have a very short serum half-life (minutes), and 
the most plausible site of action is at the neurovascular unit. 
 

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To more precisely estimate sEH enzyme activity in plasma, we will also measure the 
metabolism of more stable lipid substrates of sEH: EPOME, and the metabolic byproduct 
DPOME. Serum EPOME and DPOME levels have previously been used to measure the 
hydrolase activity of sEH.[13] 
 
We will also determine whether there are CNS effects of the drug, either via direct 
measurement of increased EET/DHET ratio in the CSF, or via downstream effects on 
the inflammatory profile in the CSF and on the markers of endothelial dysfunction. This 
is particularly important because in healthy subjects and animals, the drug does not 
cross the blood brain barrier. It is possible that EETs have a localized action on the 
endothelium and vascular smooth muscle, without crossing the blood brain barrier. sEH 
inhibition may exert anti-inflammatory and vasodilatory effects at this site without 
changing measurable CSF EETs levels. If this is the case, we expect to detect 
differences in CSF inflammatory markers. 
 
We anticipate a possible effect of the study drug in CSF for the following reasons: 1) 
There is breakdown of the blood brain barrier following SAH and both lipid and non-lipid 
soluble molecules may be able cross the neurovascular unit due to increased 
permeability; and 2) Endothelial-derived cytokines and mediators may be transported 
across compartments, including blood, perivascular space, and CSF.  It will be important 
to confirm the site of action of the study drug is only at the endothelium level or if its 
effects on the central nervous system 
 
We will collect biomarkers at multiple time points because eicosanoid levels, endothelial 
dysfunction, and the inflammatory response vary significantly over the natural course of 
subarachnoid hemorrhage.  We may control for significant variations at baseline when 
interpreting the results. 
 
• 
Tertiary Objective:  Provide preliminary estimates of clinically relevant endpoints to 
inform the design of a larger trial. 
 
We will collect clinical measurements on outcomes throughout the treatment course, at 
hospital discharge and at 90-day follow-up. To assess DCI directly, we will measure 
daily middle cerebral artery (MCA) transcranial Doppler flow velocities and the degree of 
angiographic vasospasm.  We will also measure acute changes in neurologic exam, the 
need for therapeutic interventions for DCI, and new stroke on imaging at discharge.   We 
will also measure more objective surrogate outcomes at hospital discharge and 90-day 
follow-up including: hospital length of stay, discharge disposition, modified Rankin Scale 
(mRS), and the extended Glasgow Outcome Scale (GOSE). 
 
Justification: This study is not powered to detect an effect of drug administration on 
these endpoints, but these data will provide information for sample size calculations in 
larger subsequent studies. 
 
4 
STUDY DESIGN  
 
4.1 OVERALL DESIGN 
 
The study is a single site double-blind, placebo-controlled, phase 1b randomized trial to 
evaluate the safety and preliminary pharmacologic activity of GSK2256294 in patients with 

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aneurysmal SAH. We hypothesize that inhibition of the sEH enzyme will be safe in patients with 
SAH, and result in increased EETs availability at the neuroendothelium, eventually leading to 
reduced neuroinflammation. Up to 30 patients will be equally randomized to receive once daily 
enteral administration of either 10 mg dose of GSK2256294 or placebo for a duration of 10 
days.  
 
4.2 SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
This is a safety and proof of concept study. A randomized trial is needed to determine the effect 
of GSK2256294 on EETs metabolism, because EETs levels vary over the natural course of 
recover after SAH, and a placebo group is needed for comparison.  Randomization and double 
blinding additionally limit the influence of potential confounders and selection bias.  
 
4.3 JUSTIFICATION FOR DOSE 
 
GSK2256294 exposures are approximately dose proportional over the range of 6 mg to 20 mg. 
High levels of enzyme inhibition was observed with single doses of 6 to 20 mg, and sustained at 
greater than 95% for 24 hours at a dose of 10 mg in repeat dosing trials. A 10-day 
administration schedule was chosen because this represents the highest risk time period for 
development of neuroinflammatory changes related to delayed cerebral ischemia.  
 
4.4 END OF STUDY DEFINITION 
 
A participant is considered to have completed the study if he or she has completed all phases of 
the study including the last visit shown in the SoA, Section 11. 
 
The end of the study is defined as completion of the last visit or procedure shown in the SoA in 
the trial globally.  
 
5 
STUDY POPULATION 
 
5.1 INCLUSION CRITERIA 
 
In order to be eligible to participate in this study, an individual must meet all of the following 
criteria: 
 
Age > 18 
Head CT evidence of subarachnoid hemorrhageDigital subtraction cerebral angiography 
or CT angiogram documenting the 
presence of a cerebral aneurysm. 
 
 
5.2 EXCLUSION CRITERIA 
 
An individual who meets any of the following criteria will be excluded from participation in this 
study: 
 
Symptom onset compatible with SAH of > 3 days prior to admission to OHSU 

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Evidence of QTc prolongation > 500ms on admission 
Baseline AST and ALT > 2x normal reference range  
Administration of any of the following inducers/inhibitors of CYP3A4: ritonavir, indinavir, 
nelfinavir, saquinavir, clarithromycin, telithromycin, chloramphenicol, ketoconazole, 
itraconazole, nefazodone, cobicistat or enzalutamide. 
Current pregnancy, based on urine HCG positive pregnancy test 
Preexisting severe neurologic deficit or condition 
Chronic renal failure requiring dialysis 
Severe terminal disease with life expectancy <6 months 
Unable to read or understand written or spoken English or SpanishRefusal of informed 
consent 
 
5.3 SCREEN FAILURES 
 
Screen failures are defined as participants who are eligible to participate based on inclusion 
criteria, but meet any of the exclusion criteria.  A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants, to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes screen failure details, eligibility criteria 
and reason for patient exclusion. 
 
 
5.4 STRATEGIES FOR RECRUITMENT AND RETENTION 
 
The study population will draw from all adult patients admitted to the OHSU NSICU, part of a 
comprehensive stroke center certified by the American Heart Association and Joint Commission 
for Accreditation of Healthcare Organizations, with a catchment area including the state of 
Oregon, Southwest Washington and Northern California. Approximately 80-100 patients with 
aneurysmal SAH are admitted each year. All patients admitted with SAH have cerebral 
angiography or CT angiogram early after admission. Research personnel will review patients 
from the ICU census for eligibility on a daily basis.  
 
To ensure completeness of follow up procedures, we will collect contact information from the 
patient, the patients legally authorized representative (LAR), the primary care provider (PCP), 
and the disposition location (facility) contact information at hospital discharge.   The 
CareEverywhere electronic medical record network and obituary screening will be used to 
identify deaths. 
 
6 
STUDY INTERVENTION 
 
6.1 STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION DESCRIPTION 
 
GSK2256294, a potent and selective inhibitor of soluble epoxide hydrolase, will be administered 
to the treatment group, and a matched placebo will be administered to the placebo group for a 
total treatment course of 10 days.  

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6.1.2 DOSING AND ADMINISTRATION 
 
Subjects will receive either 10mg of GSK256294 or matched placebo. The first dose of drug or 
placebo will be administered after informed consent, randomization and collection of baseline 
laboratory samples.  Subsequent doses will be administered daily for a total treatment course of 
10 days. Subjects who are able to swallow will receive the capsule formulation orally.  Subjects 
not able to swallow will receive the contents of the capsule suspended in normal saline, 
administered via orogastric or nasogastric enteral access by the bedside nurse. Missed doses 
will be administered as soon as feasible. No restriction to food intake is necessary. 
 
6.2 PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
GlaxoSmithKline will supply the drug capsule and matched placebo to the OHSU investigational 
pharmacy.  At the end of the trial, unused product will be returned to GlaxoSmithKline or 
destroyed. 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
GSK2256294 is available in capsule form. The capsules are opaque Swedish orange hard 
gelatin, containing a white powder. Matched placebo capsules which are also opaque Swedish 
orange containing white powder will be administered to the placebo group. The capsules are 
packaged into white, opaque, high density polyethylene bottles with child-resistant closures. The 
label for the clinician administering the drug will identify the medication as the “Study Drug”.  
The label will contain the study number, subject number, quantity of product, and directions for 
use. 
 
6.2.3 PRODUCT STORAGE AND STABILITY 
 
The capsule will be stored at room temperature, and the drug is stable up to 30oC. 
 
6.2.4 PREPARATION 
 
Capsule packaging will be labeled as described above and dispensed from the OHSU 
investigational pharmacy to the OHSU NSICU on a daily basis.  At the time of administration, 
the bedside nurse will administer the capsule formulation orally in patients able to swallow.  If 
patients are unable to swallow, the bedside nurse will open the capsule and suspend the 
contents in 10mL of 0.9% normal saline, and administered immediately after suspension via 
orogastric or nasogastric tube. 
 
6.3 MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 
Participants who meet all eligibility criteria and consented for study participation will be 
randomized by notifying the research pharmacy service. A randomization list will be generated 
by computer generated sequence and will determine whether the subject receives active drug or 
matched placebo. The randomization procedure will require confirmation of the eligibility criteria 
to ensure that the integrity of the randomization is maintained. Subjects will be randomized to 
one of the two treatment arms based on an unrestricted or “fair-coin” randomization procedure. 

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Randomization will be carried out in STATA using a uniform distribution with a specific random 
number seed so that the results are reproducible. The research pharmacy service will maintain 
the randomization list and provide the study drug as appropriate. All participants who complete 
the informed consent process will be assigned a study identification number. Numbers will be 
assigned in consecutive order starting with the number 100. This number will be followed with 
another two-digit number representing the randomization sequence starting at 01. Participants 
will be referenced by the study identification number. 
 
6.4 STUDY INTERVENTION COMPLIANCE 
 
Study drug administration will be recorded in the electronic medical record (EMR), which will be 
used as source documentation, and administration verified daily.  Missed doses and reason will 
be recorded on a study log. The drug accountability record will be maintained by the 
investigational pharmacy.   
 
6.5 CONCOMITANT THERAPY 
 
Relevant concomitant medications prescribed during the study drug administration period will be 
recorded from the EMR in the following classes: vasopressors, antihypertensives, hyperosmolar 
therapy, nimodipine, insulin, statins and antibiotics. 
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 DISCONTINUATION OF STUDY INTERVENTION 
 
Discontinuation from drug or placebo administration does not mean discontinuation from the 
study, and remaining study procedures should be completed as indicated by the study protocol. 
All patients are expected to complete the treatment course unless they experience an SAE that 
is thought to be related to the study drug, die, are discharged early, or withdraw early from the 
study. 
 
7.2 PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue or withdraw a participant from the study if any clinical AE, 
laboratory abnormality, or other medical condition or situation occurs such that continued 
participation in the study would not be in the best interest of the participant 
The reason for participant discontinuation or withdrawal from the study will be recorded on the 
Case Report Form (CRF). Subjects who sign the informed consent form and are randomized 
but do not receive the study intervention may be replaced. 
7.3 LOST TO FOLLOW-UP 
 
A participant will be considered lost to follow-up if he or she is unable to be contacted by the 
study site staff within 2 weeks of the 90-day follow-up visit. 
 

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The following actions must be taken if study personnel are unable to contact participant for 
follow-up: 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, contact with PCP. We will also screen obituaries and check the EMR for 
potential deaths.  
• 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 SCREENING, CONSENT, AND RANDOMIZATION 
 
Screening: Research coordinators will survey the NSICU census on a daily basis to determine 
which patients are potentially eligible for enrollment. Patients who have cerebral angiography 
demonstrating ruptured intracranial aneurysm who satisfy the inclusion/exclusion criteria will be 
approached to provide informed consent. For women of childbearing potential, baseline urine 
pregnancy test will be performed at admission as part of the standard of care. If not already 
performed as part of standard medical care, liver function tests will be sent to determine 
subjects’ baseline liver function. 
 
Consent: We have developed a written consent to be reviewed and signed by the study 
participant or surrogate decision making. The recruitment process may take place in-person or 
by phone. A phone script is attached with this submission. Either the PI, coinvestigators or 
research staff will explain the objectives, risks and benefits of the study to the patient. We will 
allow adequate time to answer questions and address concerns.  
 
Some patients will not be able to provide informed consent due to incapacity. Legally authorized 
surrogate decision makers will be approached to provide consent in these scenarios. There will 
be no financial compensation or incentive provided to study participants. Study candidates must 
sign the informed consent form before any study-specific tests or procedures are performed. 
 
Enrollment/randomization: Eligible patients are defined as participants meeting all inclusion 
criteria and none of the exclusions and who have provided a written informed consent. 
Participants must be screened, consented, and enrolled in the study within 48 hours of 
admission to the OHSU NSICU.  Participants will be randomized as described above. All 
participants who complete the informed consent process will be assigned a study identification 
number. Numbers will be assigned in consecutive order starting with the number 100. This 
number will be followed with another two-digit number representing the randomization sequence 
starting at 01. Participants will be referenced by the study identification number. 
 
8.2 BASELINE EVALUATION 
 
Baseline subject evaluation and testing will be performed in conjunction with routine intensive 
care unit treatment and monitoring.  Data will be collected from the medical record or 
patient/surrogate interview. 
• 
Patient Demographics: Ethnographic characteristics (age, sex, race/ethnicity, weight, 
height, BMI), level of education, and detailed contact information for follow-up 

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• 
Characteristics of present illness: Hunt and Hess Score, Fisher grade, location of 
aneurysm, surgical vs interventional treatment (completed or planned) and Glasgow 
Coma Scale (GCS) will be collected at the time of randomization. 
• 
Baseline Physiologic Data: The first laboratory results and vital signs obtained at the 
time of ICU admission will be recorded, and detailed in the variable list in section 12. We 
will also collect details about history of preexisting medical comorbidities using the 
Charlson Comorbidity Index Score, screening for tobacco use, and targeted questions 
about neurologic history. A baseline EKG will be performed as part of the standard of 
care, and reviewed for evidence of conduction abnormalities or acute myocardial 
ischemia. 
• 
Admission medications: Selected classes of medications administered from the time 
of ICU admission to randomization will be recorded. We will also record selected classes 
of home medications the patient may have been taking prior to hospitalization. 
 
8.3 STUDY DRUG ADMINISTRATION SCHEDULE 
 
The investigational pharmacy will maintain blinding, labeling and dispensing to healthcare 
providers of the study drug as described above.  The first dose of study drug will be 
administered immediately after randomization.  Subsequent doses will be administered daily in 
the morning for a total of 10 days. The preferred route of administration is orally, but patients 
with SAH are often neurologically compromised and unable to safely swallow.  A suspended 
formulation will be administered via the orogastric or nasogastric route for patients deemed 
unsafe to swallow. 
 
8.4 SAFETY ASSESSMENTS 
 
8.4.1 DAILY ASSESSMENTS 
 
Daily assessments will be performed beginning on the randomization day (day=1), and on 
subsequent study days that subjects receive study drug (days 2-10). The randomization day will 
be defined as the time from randomization to the next 6:59 AM. All subsequent study days will 
be defined as a 24-hour window between 7:00AM and 6:59 AM the following day.  Study staff 
will perform daily assessments from data collected from the medical record as part of patients’ 
routine intensive care unit treatment and monitoring, or by patient interview. These include: 
• 
Vital Signs: every four hour vital signs including blood pressure from noninvasive and 
arterial sources, heart rate, body temperature, and the presence of absence of 
mechanical ventilation; 
• 
Cardiac Monitoring: daily QTc interval, and the presence of cardiac arrhythmias on 
continuous EKG monitoring. 
• 
Intake and Output: total fluids administered and total drain and urine output; 
• 
Laboratory Assessments: serum sodium, blood glucose, BUN, creatinine, hematocrit, 
peripheral white blood cell count; 
• 
Neurologic Assessments: GCS, MCA transcranial Doppler velocities and Lindegaard 
ratios, and headache severity; 
• 
Concomitant medications:  Daily administration of selected classes of hospital 
administered concomitant medications will be reviewed for all study subjects during the 
first 10 days. 
 
8.4.2 DISEASE RELATED AND ADVERSE EVENT TRACKING 

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Daily disease related event log and adverse event log forms will be completed.  Specific 
complications common in patients with SAH will be abstracted from the medical record with the 
date and time of onset and resolution. These include: 
 
• 
Seizure: Electrographic or generalized tonic clonic seizure activity; 
• 
Cerebral angiography results and interventions, including the distribution and severity 
of cerebral vasospasm; 
• 
Neurologic deteriorations attributable to DCI: Defined as the development of new 
focal neurological signs or decreased level of consciousness that resulted in a decrease 
in the Glasgow Coma Scale (GCS) score of 2 points, lasting at least 1 hour, and not 
attributable to infection, changes in sedation, or non-ischemic cerebral pathology such 
as acute hydrocephalus); 
• 
The need for intervention to manage DCI: Defined as use of augmented blood 
pressure goals, cardiac index monitoring, or intra-arterial vasodilator therapy; 
• 
New onset or previously undocumented myocardial dysfunction: left ventricular 
ejection fraction (LVEF) < 45%, or a > 10% change from baseline LVEF, LV contractile 
pattern consistent with neurogenic cardiomyopathy at any measured LVEF, or new wall 
motion abnormalities; 
• 
NSTEMI/STEMI: ST segment changes on 12 lead ECG suspicious for myocardial 
ischemia, or any elevation of serum troponin above reference range; 
• 
Hospital acquired infection: Culture data resulting in the use of antibiotics for > 72 
hours; 
• 
Liver dysfunction: Liver function tests will be assessed on study day 7. AST or ALT > 
3x above baseline values will be identified as an adverse event 
• 
Thromboembolic events: Imaging-documented presence of extracranial venous or 
arterial thrombus. 
 
8.5 PHARMACODYNAMIC EFFECT ASSESSMENTS 
 
8.5.1 SAMPLE COLLECTION 
 
 
Blood samples will be collected from study participants after randomization but prior to 
administration of the first dose of study drug or placebo, and again on study day 7 and study 
day 10. For patients with an external ventricular drain (EVD), cerebrospinal fluid (CSF) will be 
collected at each timepoint as well. 
 
10 mL of blood and 5 mL of CSF will be collected at each time point. If the indwelling external 
ventricular drain is removed prior to study day 10, CSF samples will be collected on the day of 
planned removal. In the event of inability to collect CSF due to obstructed catheter, or low 
intracranial CSF volume, one additional attempt will be allowed within a period of 24 hours.   
 
Blood samples will be collected by the bedside nurse and processed for storage by study 
personnel.  CSF samples will be collected by physician medical staff, from external ventricular 
drainage access, and then processed for storage by study personnel.  
 
 
8.5.2 EICOSANOID PROFILE AND SEH ACTIVITY ASSAY 

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Samples will be spun down to remove cellular components, and 1mL of the resulting plasma 
and 2 mL of CSF will be reserved for eicosanoid profile determination.  An antioxidant will be 
added to the plasma and CSF, and these aliquots will be frozen at -80oC in opaque glass vials. 
Vials will be labeled with the participant ID, type of sample, and date and time of collection. At 
the end of the enrollment period after the last sample collection, liquid chromatography and 
mass spectroscopy will be used to determine EET and DHET levels and EPOME and DPOME 
levels. All samples will be batch processed based on protocols developed and validated by the 
OHSU Bioanalytical Core Lab.  
 
8.5.3 INFLAMMATORY AND ENDOTHELIAL INJURY SAMPLE PROCESSING 
 
The remaining plasma and CSF obtained at each sample collection time point will be frozen at -
80oC and reserved for batch processing of the following biomarkers below.  Luminex assays for 
the biomarkers will processed in the OHSU Anesthesiology Core Lab at the end of the 
enrollment period after the last sample collection. 
 
TABLE 1: Neuroinflammatory and endothelial injury biomarkers associated with EETs signaling 
Biomarker 
Role 
Blood 
CSF 
Drug Action 
Eicosanoid Profile (EETs and 
DHETs) 
Drug effect marker[12] 
X 
X 
Inflammatory Biomarkers 
Tumor necrosis factor alpha 
(TNF-α) 
Neuroinflammatory marker, 
apoptosis, decreased in EETs 
knockouts[4] 
 
X 
Interleukin 1β (IL-1β) 
Neuroinflammatory marker[14] 
 
X 
Interferon gamma (IFN-γ) 
Neuroinflammatory marker, 
decreased in sEH knockouts[4] 
 
X 
Interleukin 6 (IL-6) 
Neuroinflammatory marker, 
associated with vasospasm,[14] 
decreased in sEH knockouts[4] 
 
X 
Interleukin 8 (IL-8) 
Neuroinflammatory marker, 
associated with vasospasm[14] 
 
X 
Monocyte chemoattractant 
protein 1 (MCP-1) 
Neuroinflammatory marker, 
associated with vasospasm[14] 
 
X 
Endothelial Injury 
e-selectin 
Leukocyte adhesion marker[15] 
X 
 
p-selectin 
Platelet adhesion marker[16] 
X 
 
Vascular cell adhesion marker 
(VCAM-1) 
Vascular inflammation, blood brain 
barrier breakdown, hydrocephalus[17] 
X 
 
Platelet endothelial cell 
adhesion marker (PECAM-1, 
CD31) 
Leukocyte, platelet, monocyte 
adhesion, angiogenesis[16] 
X 
 
Intercellular adhesion 
molecule (ICAM-1) 
Endothelial surface marker for 
inflammation [16] 
X 
 
 
 
8.5.4 EPHX2 POLYMORPHISM ANALYSIS SAMPLE PROCESSING 
 
sEH activity variation as a result of genetic polymorphisms of EPHX2 have the potential to exist 
in the study population and act as confounders.  We will determine sEH EPHX2 genotype at the 
end of the enrollment period after the last sample collection. DNA will be extracted and purified 
from peripheral leukocytes isolated from collected blood samples.  Allelic discrimination of 

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EPHX2 will be performed by TaqMan amplification and quantitative PCR (qPCR). We will use 
probes for 2 of the most common EPHX2 genotypes, K55R and R287Q, as these are the most 
common and demonstrated to have a clinical effect in patients with SAH. We have previously 
validated this method with DNA sequencing.  
 
TERTIARY ENDPOINT ASSESSMENTS 
 
Discharge and Follow-up Assessments: 
At hospital discharge and 90-day follow-up, we will also measure objective clinical surrogate 
endpoints. The hospital discharge assessment will be abstracted from the patient medical 
record and obtained from patient interview. The 90-day follow-up assessment will be obtained 
from phone interview with the patient or their surrogate. We will collect the following information: 
 
• 
At Hospital Discharge:  
o Hospital length of stay, in days 
o New stroke on imaging: We will review the last head CT or other brain imaging 
to detect the presence of a new area of cerebral infarction. We will define a 
cerebral infarction identified on hospital discharge that was not present on 
imaging between 24–48 hours after aneurysm occlusion, and not attributable to 
other causes such as surgical clipping or endovascular treatment. Hypodensities 
resulting from extraventricular drains or residual intraparencyhmal hematomas 
will not be considered new strokes. 
o Discharge disposition: We will record the disposition from the hospital in one 
of the following categories: home, home with services, rehab, LTAC, SNF, 
hospice, death 
o Modified Rankin Scale: We will determine and record the mRS score from 
where 0 – no symptoms, 1 – no significant disability, able to carry out all usual 
activities despite some symptoms, 2 – slight disability. Able to look after own 
affairs without assistance, but unable to carry out all previous activities, 3 – 
moderate disability, requires some help, but able to walk unassisted, 4 – 
moderately severe disability, unable to attend to own bodily needs without 
assistance, and unable to walk unassisted, 5 – severe disability, requires 
constant nursing care and attention, bedridden, incontinent, 6 – deceased. 
• 
At 90-day follow up 
o Modified Rankin Scale 
o Extended Glasgow Outcome Scale (GOSE): At 90 day follow up, we will 
determine the GOSE based on a structured interview of 19 questions detailed in 
the variable list and assessment tools. We will record the GOSE on a scale of 1-
8 where 1 – deceased, 2 – vegetative state, 3 – low severe disability, 4 – upper 
severe disability, 5 – low moderate disability, 6 –upper moderate disability, 7 – 
low good recovery, 8 – upper good recovery.  
 
8.6 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.6.1 DEFINITION OF ADVERSE EVENTS (AE) 
 
Adverse event means any untoward medical occurrence associated with the use of an 
intervention in humans, whether or not considered intervention-related (21 CFR 312.32 (a)). 
 

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8.6.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of 
either the investigator or sponsor, it results in any of the following outcomes: death, a life-
threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a 
persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions, or a congenital anomaly/birth defect. Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered serious when, based 
upon appropriate medical judgment, they may jeopardize the participant and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition.  
 
8.6.3 CLASSIFICATION OF AN ADVERSE EVENT 
8.6.3.1 SEVERITY OF EVENT 
 
For adverse events (AEs) not included in the protocol defined grading system, the following 
guidelines will be used to describe severity.  
 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s 
daily activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic 
drug therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”. 
 
 
8.6.3.2 RELATIONSHIP TO STUDY INTERVENTION 
 
All adverse events (AEs) must have their relationship to study intervention assessed by the 
clinician who examines and evaluates the participant based on temporal relationship and his/her 
clinical judgment. The degree of certainty about causality will be graded using the categories 
below. In a clinical trial, the study product must always be suspect.  
 
• 
Related – The AE is known to occur with the study intervention, there is a reasonable 
possibility that the study intervention caused the AE, or there is a temporal relationship 
between the study intervention and event. Reasonable possibility means that there is 
evidence to suggest a causal relationship between the study intervention and the AE. 
• 
Not Related – There is not a reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study 
intervention and event onset, or an alternate etiology has been established. 
 
OR 
 
• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out. The clinical event, including an abnormal 
laboratory test result, occurs in a plausible time relationship to study intervention 
administration and cannot be explained by concurrent disease or other drugs or 
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clinically plausible. The event must be pharmacologically or phenomenologically 
definitive, with use of a satisfactory rechallenge procedure if necessary. 
• 
Probably Related – There is evidence to suggest a causal relationship, and the 
influence of other factors is unlikely. The clinical event, including an abnormal laboratory 
test result, occurs within a reasonable time after administration of the study intervention, 
is unlikely to be attributed to concurrent disease or other drugs or chemicals, and follows 
a clinically reasonable response on withdrawal (dechallenge). Rechallenge information is 
not required to fulfill this definition. 
• 
Potentially Related – There is some evidence to suggest a causal relationship (e.g., the 
event occurred within a reasonable time after administration of the trial medication). 
However, other factors may have contributed to the event (e.g., the participant’s clinical 
condition, other concomitant events). Although an AE may rate only as “possibly related” 
soon after discovery, it can be flagged as requiring more information and later be 
upgraded to “probably related” or “definitely related”, as appropriate. 
• 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, 
whose temporal relationship to study intervention administration makes a causal 
relationship improbable (e.g., the event did not occur within a reasonable time after 
administration of the study intervention) and in which other drugs or chemicals or 
underlying disease provides plausible explanations (e.g., the participant’s clinical 
condition, other concomitant treatments). 
• 
Not Related – The AE is completely independent of study intervention administration, 
and/or evidence exists that the event is definitely related to another etiology. There must 
be an alternative, definitive etiology documented by the clinician. 
 
8.6.3.3 EXPECTEDNESS  
 
The principal investigator and independent safety monitor will be responsible for determining 
whether an adverse event (AE) is expected or unexpected.  An AE will be considered 
unexpected if the nature, severity, or frequency of the event is not consistent with the risk 
information previously described for the study intervention or reported in the investigator 
brochure 
8.6.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND 
FOLLOW-UP 
 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the 
attention of study personnel during study visits and interviews of a study participant presenting 
for medical care, or upon review by a study monitor. 
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured 
on the appropriate case report form (CRF). Information to be collected includes event 
description, time of onset, clinician’s assessment of severity, relationship to study drug 
(assessed only by those with the training and authority to make a diagnosis), and time of 
resolution/stabilization of the event. All AEs occurring while on study must be documented 
appropriately regardless of relationship. All AEs will be followed to adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. However, if the study participant’s condition 
deteriorates at any time during the study, it will be recorded as an AE.  
 

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Changes in the severity of an AE will be documented to allow an assessment of the duration of 
the event at each level of severity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode. 
 
Research staff will record all reportable events with start dates occurring any time after informed 
consent is obtained until 28 days post randomization or hospital discharge, whichever comes 
sooner.  At each study visit, the investigator will inquire about the occurrence of AE/SAEs since 
the last visit.  Events will be followed until resolution or stabilization. 
 
8.6.5 
ADVERSE EVENT REPORTING  
 
Summaries of adverse events will be recorded for each study visit, and reported to the 
independent safety monitor, the institutional review board, and the study sponsor annually, in 
accordance with regulatory requirements.  Expected disease-related events common in the 
study population which will not be reported per the standard process for reporting include: 
seizure, need for intervention to manage DCI, new onset cardiomyopathy, hypotension, 
hypertension, NSTEMI/STEMI, hyponatremia, hospital acquired infection, respiratory failure 
requiring mechanical ventilation, therapeutic antimicrobial use and indication, thromboembolic 
events, and disease related death. 
 
8.6.6 SERIOUS ADVERSE EVENT REPORTING  
 
The investigators will report within 72 hours of knowledge to the independent safety monitor, 
any unexpected serious adverse event, whether or not considered study intervention related, 
including those listed in the protocol or investigator brochure and must include an assessment 
of whether there is a reasonable possibility that the study intervention caused the event. Study 
endpoints that are serious adverse events (e.g., all-cause mortality) must be reported in 
accordance with the protocol unless there is evidence suggesting a causal relationship between 
the study intervention and the event (e.g., death from anaphylaxis). In that case, the investigator 
must immediately report the event to the independent safety monitor and to the IRB 
 
All serious adverse events (SAEs) will be followed until satisfactory resolution or until the site 
investigator deems the event to be chronic or the participant is stable.  
 
The investigators will be responsible for notifying the Food and Drug Administration (FDA) and 
GlaxoSmithKline of any unexpected fatal or life-threatening suspected adverse reaction as soon 
as possible, but in no case later than 7 calendar days after the sponsor's initial receipt of the 
information.  
 
8.6.7 REPORTING EVENTS TO PARTICIPANTS  
 
Participants who experience adverse events will be followed until resolution, and will be referred 
for consultation as needed. 
 
8.7 UNANTICIPATED PROBLEMS 
 
8.7.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
 

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The Office for Human Research Protections (OHRP) considers unanticipated problems 
involving risks to participants or others to include, in general, any incident, experience, or 
outcome that meets all of the following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the Institutional Review 
Board (IRB)-approved research protocol and informed consent document; and (b) the 
characteristics of the participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means 
there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously known 
or recognized. 
 
 
8.7.2  UNANTICIPATED PROBLEM REPORTING  
 
The investigator will report unanticipated problems (UPs) to the Institutional Review Board 
(IRB). The UP report will include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB 
project number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or 
outcome represents an UP;  
• 
A description of any changes to the protocol or other corrective actions that have been 
taken or are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following 
timeline:   
 
• 
UPs that are serious adverse events (SAEs) will be reported to the IRB and to the study 
sponsor within 72 hours of the investigator becoming aware of the event.  
• 
Any other UP will be reported to the IRB and to the study sponsor within 7 days the 
investigator becoming aware of the problem.  
• 
All UPs should be reported to appropriate institutional officials (as required by an 
institution’s written reporting procedures), the supporting agency head (or designee), 
and the Office for Human Research Protections (OHRP) within of the IRB’s receipt of the 
report of the problem from the investigator. 
 
8.7.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
 
Participants who experience adverse events related to unanticipated problems will be followed 
until resolution, and will be referred for consultation as needed. 
 
9 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL ENDPOINTS 
 

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Primary Endpoint: Safety 
• 
Determination of safety 
 
Secondary Endpoints: Blood and CSF biomarkers of drug pharmacodynamic effect 
• 
Day 7 serum EET/DHET ratio 
• 
Day 7 CSF EET/DHET ratio 
• 
Day 7 CSF inflammatory cytokines 
• 
Day 7 serum endothelial injury biomarkers 
• 
Day 7 serum EPOME/DPOME ratio 
• 
Day 10 serum EET/DHET ratio 
• 
Day 10 CSF EET/DHET ratio 
• 
Day 10 CSF inflammatory cytokines 
• 
Day 10 serum endothelial injury biomarkers 
• 
Day 10 serum EPOME/DPOME ratio 
 
Tertiary Endpoints: Clinical endpoints 
• 
Incidence of neurologic changes attributable to DCI 
• 
Incidence of angiographic vasospasm 
• 
Incidence of new stroke at hospital discharge 
• 
Hospital length of stay 
• 
Hospital discharge Modified Rankin Scale score 
• 
Hospital discharge disposition 
• 
90-day follow-up Modified Rankin Scale score 
• 
90-day follow-up Glasgow Outcome Scale Extended score 
 
 
9.2 SAMPLE SIZE DETERMINATION 
 
The total sample size was selected a priori based on the need to evaluate and describe the 
safety profile of the study drug in this patient population.  
 
9.3 POPULATIONS FOR ANALYSES 
 
Any patient who receives a single dose of study drug will be included in safety analyses as part 
of the safety population.  Only patients who compete 10 days of study drug administration will 
be included in the secondary analyses as part of the per-protocol population. 
 
9.4 STATISTICAL ANALYSES 
 
9.4.1 GENERAL APPROACH 
 
The statistical analysis performed for this study will be presented for all patients who receive at 
least 1 dose of the study drug.  There will be no a priori stopping rules, since the entire sample 
is required to evaluate safety.  However, the study can be stopped at any time for reasons 
related to safety concerns. The statistical analyses will be performed using STATA® version 13 
or later (STATACorp, College Station TX).  
 

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The number of participants included in each analysis set will be summarized, along with the 
reason for any exclusions. Participants discontinuing from study treatment and/or withdrawing 
from study participation the primary reason for discontinuation will be summarized.  
 
Descriptive summaries of demographic and baseline characteristics will be tabulated for all 
participants. 
 
9.4.2 MISSING VALUES 
Study investigators will monitor the study to maximize completion of data collection and 
samples.  Every effort will be made to retain subjects to follow up.  Patterns of missing data will 
be evaluated for the presence of informative missingness or if missing data are missing 
completely at random or at random. 
9.4.3 ANALYSIS OF THE PRIMARY ENDPOINT 
 
Safety will be assessed by clinical review of all relevant parameters including vital signs, 
laboratory values, adverse events, serious adverse events, disease related events, and 
mortality. Unless specified otherwise, the safety analyses will be conducted for the safety 
population.  
 
Summary tables and listings will be provided for all reported adverse events, defined as adverse 
events that start on or after the first administration of study drug. The reported adverse event 
term will be assigned a standardized preferred term. 
 
Adverse events will be summarized based on the number and percentage of patients 
experiencing the event. In the event a patient experiences repeat episodes of the same adverse 
event, then the event with the highest severity grade and strongest causal relationship to study 
treatment will be used for purposes of incidence tabulations. Tabular summaries will be 
provided for all adverse events, the relationship to study drug treatment the maximum severity 
grade, action taken, and whether the event qualified as SAE or not.  
 
Daily safety laboratory test results will be summarized in a descriptive manner by calculating the 
mean, standard deviation, median, and range.  Directional shifts (comparing baseline grade with 
worst post-baseline grade) will be analyzed using standard shift tables.  The shift table will 
present directional shifts from baseline to above or below the laboratory standard normal range 
using the maximum increase and/or decrease observed throughout the course of 
treatment/observation.  
 
Vital signs will be summarized in a descriptive manner by calculating the mean, standard 
deviation, median, and range in the same manner described for laboratory values.  
 
All deaths will be reported in a patient listing, which will include the primary cause of death and 
the number of days between the date of the last dose of study drug and death.  
 
9.4.4 ANALYSIS OF THE SECONDARY AND TERTIARY ENDPOINTS 
 
Secondary endpoints will be compared between the study drug and placebo groups using the 
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the mean and standard deviation, and differences evaluated with two sample Student’s t-test 
with a two-sided type 1 error rate of 0.05%.  
Tertiary endpoints will be compared descriptively between the groups based on the mean, 
median, standard deviation and range.  
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
10.1.1 INFORMED CONSENT PROCESS 
 
10.1.1.1 
CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS 
PROVIDED TO PARTICIPANTS 
 
Consent forms describing in detail the study intervention, study procedures, and risks are given 
to the participant and written documentation of informed consent is required prior to starting 
intervention/administering study intervention.  The following consent materials are submitted 
with this protocol: Informed consent form and complete variable list. 
 
10.1.1.2 
CONSENT PROCEDURES AND DOCUMENTATION 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continues throughout the individual’s study participation. Consent forms will be 
IRB-approved and the participant will be asked to read and review the document. The 
investigator will explain the research study to the participant and answer any questions that may 
arise. A verbal explanation will be provided in terms suited to the participant’s comprehension of 
the purposes, procedures, and potential risks of the study and of their rights as research 
participants.  Participants will have the opportunity to carefully review the written consent form 
and ask questions prior to signing. The participants should have the opportunity to discuss the 
study with their family or surrogates or think about it prior to agreeing to participate. The 
participant will sign the informed consent document prior to any procedures being done 
specifically for the study. Participants must be informed that participation is voluntary and that 
they may withdraw from the study at any time, without prejudice. A copy of the informed consent 
document will be given to the participants for their records. The informed consent process will 
be conducted and documented in the source document (including the date), and the form 
signed, before the participant undergoes any study-specific procedures. The rights and welfare 
of the participants will be protected by emphasizing to them that the quality of their medical care 
will not be adversely affected if they decline to participate in this study. 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause.  Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to <study participants, 
investigator, funding agency, the Investigational New Drug (IND) sponsor and regulatory 
authorities.  If the study is prematurely terminated or suspended, the Principal Investigator (PI) 
will promptly inform study participants, the Institutional Review Board (IRB), and sponsor and 

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will provide the reason(s) for the termination or suspension.  Study participants will be 
contacted, as applicable, and be informed of changes to study visit schedule. 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping    
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination that the primary endpoint has been met 
• 
Determination of futility 
 
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB and/or Food and Drug Administration (FDA).] 
 
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s) and their interventions. This confidentiality is extended to cover 
testing of biological samples and genetic tests in addition to the clinical information relating to 
participants. Therefore, the study protocol, documentation, data, and all other information 
generated will be held in strict confidence. No information concerning the study or the data will 
be released to any unauthorized third party without prior written approval of the sponsor.  
 
All research activities will be conducted in as private a setting as possible. 
 
The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), regulatory agencies or pharmaceutical company supplying 
study product may inspect all documents and records required to be maintained by the 
investigator, including but not limited to, medical records (office, clinic, or hospital) and 
pharmacy records for the participants in this study. The clinical study site will permit access to 
such records. 
 
The study participant’s contact information will be securely stored at each clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by the reviewing IRB, Institutional policies, or sponsor 
requirements. 
 
10.1.4 SAFETY OVERSIGHT 
 
Safety oversight will be under the direction of an independent safety monitor. The ISM will be 
independent from the study conduct and free of conflict of interest, or measures should be in 
place to minimize perceived conflict of interest. Unless requested by the safety monitor for the 
evaluation of the event and in order to ensure an objective evaluation, the safety monitor will be 
blinded to group assignment. The safety monitor will not be involved in the analysis of data. The 
safety monitor will not have financial, proprietary, professional, or other interests that may affect 
impartial, independent decision-making. All SAEs, AEs, and unanticipated problems related to 
the study will be monitored by the study investigators on an ongoing basis and AEs will be 
summarized annually after enrollment is complete. 
 

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10.1.5 QUALITY ASSURANCE AND QUALITY CONTROL 
 
Quality management of study conduct, data and biological specimen collection, documentation 
and completion will be performed by the PI. 
 
10.1.6 DATA HANDLING AND RECORD KEEPING  
 
10.1.6.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site investigator. The investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported. 
 
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data.   
 
Data recorded in the electronic case report form (eCRF) derived from source documents should 
be consistent with the data recorded on the source documents.  
 
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse 
reactions data) and clinical laboratory data will be entered into the case report forms, consisting 
of an electronic data capture system APOM OCEAN, a 21 CFR Part 11-compliant data capture 
system. The data system includes password protection and internal quality checks, such as 
automatic range checks, to identify data that appear inconsistent, incomplete, or inaccurate. 
Clinical data will be entered directly from the source documents. 
 
10.1.6.2 
STUDY RECORDS RETENTION  
 
Study documents should be retained for a minimum of 2 years after the last approval of a 
marketing application in an International Conference on Harmonization (ICH) region and until 
there are no pending or contemplated marketing applications in an ICH region or until at least 2 
years have elapsed since the formal discontinuation of clinical development of the study 
intervention. These documents should be retained for a longer period, however, if required by 
local regulations. No records will be destroyed without the written consent of the sponsor, if 
applicable. It is the responsibility of the sponsor to inform the investigator when these 
documents no longer need to be retained. 
 
10.1.7 PROTOCOL DEVIATIONS  
 
A protocol deviation is any noncompliance with the clinical trial protocol, International 
Conference on Harmonization Good Clinical Practice (ICH GCP), or Manual of Procedures 
(MOP) requirements. The noncompliance may be either on the part of the participant, the 
investigator, or the study site staff. As a result of deviations, corrective actions are to be 
developed by the site and implemented promptly.  
 
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  

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It is the responsibility of the principal investigator to use continuous vigilance to identify and 
report deviations within 14 working days of identification of the protocol deviation.  Protocol 
deviations must be sent to the reviewing Institutional Review Board (IRB) per their policies. The 
investigator is responsible for knowing and adhering to the reviewing IRB requirements. Further 
details about the handling of protocol deviations will be included in the MOP.  
 
10.1.8 CONFLICT OF INTEREST POLICY 
 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of persons who 
have a role in the design, conduct, analysis, publication, or any aspect of this trial will be 
disclosed and managed. Furthermore, persons who have a perceived conflict of interest will be 
required to have such conflicts managed in a way that is appropriate to their participation in the 
design and conduct of this trial.  The study leadership has established policies and procedures 
for all study group members to disclose all conflicts of interest and will establish a mechanism 
for the management of all reported dualities of interest. 
 
 

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10.2 PROTOCOL AMENDMENT HISTORY 
The table below is intended to capture changes of IRB-approved versions of the protocol, 
including a description of the change and rationale. A Summary of Changes table for the current 
amendment is located in the Protocol Title Page.  
 
Version 
Date 
Description of Change  
Brief Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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11 SCHEDULE OF ACTIVITIES 
See attached 
12 REFERENCES  
 
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Davis, C.M., X. Liu, and N.J. Alkayed, Cytochrome P450 eicosanoids in cerebrovascular function 
and disease. Pharmacol Ther, 2017. 
4. 
Koerner, I.P., et al., Soluble epoxide hydrolase: regulation by estrogen and role in the 
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Sandberg, M., et al., Identification and functional characterization of human soluble epoxide 
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Srivastava, P.K., et al., Polymorphisms in human soluble epoxide hydrolase: effects on enzyme 
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Lee, C.R., et al., Genetic variation in soluble epoxide hydrolase (EPHX2) and risk of coronary 
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Fava, C., et al., Homozygosity for the EPHX2 K55R polymorphism increases the long-term risk of 
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Lazaar, A.L., et al., Pharmacokinetics, pharmacodynamics and adverse event profile of 
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