Clinical trial NCT04573777
Conditions: Ischemic Stroke
Keywords: Intracranial Atherosclerosis
Sponsor: University of California, Los Angeles
Start date: 2021-04-23; Completion date: 2021-12-16
Enrollment: 10 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study will be to understand the underlying mechanism by which PCSK9 inhibition reduces the rate of ischemic stroke seen in the pivotal studies that led to its FDA approval for ASCVD such as ischemic stroke. Those trials (FOURIER and ODYSSEY) enrolled almost 50,000 patients and showed that PCSK9 inhibition therapy is safe and effective. The investigators hypothesize that PCSK9 inhibition lowers the rate of stroke by reducing atherosclerotic plaque, which would be particularly beneficial for patients with intracranial atherosclerosis, who have the highest rate of recurrent stroke of any stroke mechanism.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Repatha
Intervention descriptions: intervention 1: 140 MG in 1 ML Prefilled Syringe PCSK9 Inhibitor

Protocol documents:
Prot_SAP_001.pdf: 
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Reducing Intracranial atheroSclErosiS with Repatha (RISER) 
 
Principal Investigators 
 
David Liebeskind, MD 
University of California Los Angeles  
 
Adam de Havenon, MD  
University of Utah 
 
 
Sponsor  
University of California, Los Angeles 
 
 
Identifying Numbers 
ClinicalTrials.gov: NCT04573010 
 
 
 
 
 
Protocol Version 1.8 
 
 
 
April 2021 
 
 
 
 
 
 
Confidentiality Statement 
 
This document is confidential and is to be distributed for review only to investigators, potential investigators, consultants, 
study staff, and applicable independent ethics committees or institutional review boards. The contents of this document shall 
not be disclosed to others without written authorization unless it is necessary to obtain informed consent from potential 
study participants. 
 
 


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A. Background and Significance 
A.1. Intracranial Atherosclerotic Disease 
Intracranial atherosclerotic disease (ICAD) is the cause of ischemic stroke in 40% of Asians, 29% of 
African-Americans, and 10% of Caucasians. These demographics make it the most common cause of 
stroke in the world.1–5 A primary goal of stroke treatment is to prevent recurrence.6,7 From 2000-2010, 
the average annual rate of recurrence for all causes of stroke was 5%.8 For patients with treated 
carotid atherosclerosis, who have excellent medical and surgical options, the rate is below 5%.9–12 In 
striking contrast, the WASID study (2005) reported that ICAD patients had a 22.9% annual 
recurrence. This was improved upon in the SAMMPRIS trial (2011), where aggressive medical 
management and a personal wellness coach achieved a 12.2% annual recurrence and surgical 
stenting led to a higher rate (20%).13,14 Although the medical treatment that is effective for carotid 
stenosis reduces stroke risk for ICAD patients, there is significant opportunity for improvement.15–18 
Furthermore, many ICAD patients with stroke have minimal stenosis, yet large outwardly remodeling 
plaques.19–21 This has led ICAD researchers to expand their focus beyond stenosis alone. High-
resolution vessel wall MRI (vwMRI) is a powerful tool to study ICAD. Compared to luminal 
angiography (CTA, MRA, etc.), vwMRI protocols include imaging of both the lumen and, by 
suppressing blood on MRI, the vessel wall itself. vwMRI has unique potential to identify validated 
biomarkers of stroke risk that could be used for preliminary trials of novel therapeutic agents to 
reduce ICAD stroke risk.  
A.2. PCSK9 Inhibition for Patients with ICAD  
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, by modifying LDL receptors, have 
been shown to dramatically lower LDL. There is robust evidence that lowering LDL cholesterol is 
beneficial in atherosclerotic disease, due to plaque-stabilizing effects. The FOURIER and ODYSSEY 
studies showed that patients randomized to PCSK9 inhibition had dramatic LDL reduction and a 
lower overall incidence of stroke (1.2 versus 1.6% of patients over three years). The GLAGOV study 
showed that, compared to placebo, evolocumab (Repatha) decreased coronary artery plaque volume. 
GLAGOV also demonstrated a linear relationship between LDL cholesterol reduction and plaque 
volume regression. However, these findings do not provide adequate evidence that Repatha reduces 
the risk of ICAD stroke. FOURIER and ODYSSEY did not adjudicate the etiology of stroke and, for 
the stroke outcome, they included cardioembolic and lacunar strokes, which typically account for up 
to 50% strokes. The risk reduction from a PCSK9 inhibitor like Repatha would primarily be for patients 
with large artery atherosclerosis, such as ICAD. As a result, the absolute risk reduction seen in those 
studies does not represent the potential of Repatha in a patient population at risk for stroke. 
A.3. Repatha  
Repatha is an FDA-approved PCSK9 inhibitor shown to reduce the risk of cardiovascular events, 
including myocardial infarction, stroke, and coronary revascularization. Repatha is a patient-
administered subcutaneous injection that is well tolerated. Common side effects include flu-like 
symptoms, cough, back pain, and dizziness. Further information can be obtained at: 
(https://www.pi.amgen.com/~/media/amgen/repositorysites/pi-amgen-com/repatha/repatha_pi_hcp_english.pdf). 
A.4. Stenosis and Plaque Atheroma Volume Measured on vwMRI 
We will measure both stenosis and atheroma volume to have two primary outcomes with validated 
biomarker potential. Stenosis is measured using WASID criteria.13 Atheroma volume is either directly 
measured or inferred by measuring the area of entire vessel (the outer wall boundary area) on an 
axial slice and subtracting the lumen area. In a study of middle cerebral artery ICAD, the atheroma 
volume on vwMRI was larger in the 26 symptomatic patients compared to the 35 asymptomatic 
patients (12.9±3.1 mm2 vs. 8.2±3.6 mm2, p<0.001). A second study enrolled 139 patients with 
moderate to severe middle cerebral artery atherosclerosis, who contributed 112 culprit and 53 non-


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culprit lesions.22 The combination of stenosis + atheroma burden + luminal area produced an odds 
ratio of 3.99 (95% CI: 1.74-9.13, p=0.001) for culprit plaque. The GLAGOV study showed that PCKS9 
inhibition reduced the percent atheroma volume of coronary arteries over a 78 week treatment 
period.23 With atheroma volume now established as a viable biomarker, vwMRI is the optimal test to 
monitor it and stenosis, both for ICAD and in other locations of the cerebrovasculature, such as the 
carotid arteries, cervical vertebral arteries, and aortic arch.  
A.5. Impact 
The result of this study will be a dataset that lays the foundation for a randomized controlled trial of 
Repatha in ICAD patients. The data collected in this study will allow us to optimize a future clinical 
trial designed to demonstrate a reduction in stroke risk, ultimately making more efficient and 
economical progress towards our ultimate research goal of preventing stroke with Repatha. While we 
are proposing future studies to reduce ICAD stroke risk, it should be noted that our study will also 
evaluate the potential for Repatha to decrease cerebrovasculature stenosis and plaque burden, which 
would be a compelling primary prevention indication.  
B. Approach  
B.1. Study Hypothesis 
We hypothesize that inhibition of PCSK9 with Repatha in patients with moderate to severe 
intracranial atherosclerosis will reduce validated biomarkers of stroke risk (stenosis and percent 
atheroma volume). To answer our hypothesis, we propose a single arm study of Repatha in 150 
patients with a prior history of ischemic stroke and ICAD causing at least 50% stenosis of a major 
intracranial artery in the Circle of Willis (“index artery”).  
B.2. Study Design 
We will enroll 150 ICAD patients with a prior history of ischemic stroke. Patients will be enrolled at up 
to 8 medical centers in North America. All patients will receive Repatha for 78 weeks and will have an 
MRI before beginning study medication and a comparison MRI immediately after completing study 
medication.  
B.3. Investigational Treatment 
The investigational treatment is Repatha 140 mg administered subcutaneously with a single-dose 
pre-filled pen syringe every 2 weeks for a total of 39 treatments. Dose modification is not allowed.  
B.3.a. Inclusion Criteria 
• 
Adult patients, ≥ 18 years of age 
• 
History of ischemic stroke, defined as an episode of neurological dysfunction caused by focal 
cerebral, spinal, or retinal infarction (American Heart Association definition).  
• 
Large vessel atherosclerosis of an intracranial artery in the circle of Willis with 50-99% stenosis 
by WASID criteria (percent stenosis = (1-[diameter stenosis/diameter normal]) x 100%) on MRA, 
CTA or DSA 
▪ Eligible arteries: vertebral (V4), basilar, PCA (P1, P2), MCA (M1, M2), tICA, ACA (A1)  
• 
Current statin use or contraindication to statin  
• 
Fasting LDL-C ≥ 70 mg/dL or LDL-C ≥ 60 mg/dL if lipoprotein (a) > 30 mg/dL; within a year of 
randomization and on the current statin medication/dose 
B.3.b. Exclusion Criteria 
• 
Gadolinium or PCSK9 inhibitor allergy 
• 
Acute or chronic kidney disease with eGFR<30 ml/min/1.73m2 
• 
Pacemaker or other MRI contraindications per American College of Radiology guidelines24  
• 
Inability to return for 78 week follow-up clinic visit and vwMRI 


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• 
Pregnant at time of enrollment 
B.4. Investigational New Drug Status 
We will not require an IND. Repatha is indicated to reduce the risk of myocardial infarction, stroke, 
and coronary revascularization in adults with established cardiovascular disease; and as an adjunct 
to diet, alone or in combination with other lipid-lowering therapies (e.g., statins, ezetimibe), for 
treatment of adults with primary hyperlipidemia to reduce low-density lipoprotein cholesterol (LDL-C). 
Our patient population meets these criteria given 1) history of ischemic stroke and 2) presence of 
moderate to severe ICAD.  
B.5. Patient Recruitment 
Patients will be approached first by a member of their clinical care team in order to gain permission 
for a study member to approach to discuss the study in detail. Only co-investigators or study 
coordinators on this study will consent patients. Standard consenting procedures will be followed, 
including giving patients and family members adequate time to discuss the study with the study team 
and amongst themselves prior to consenting. A full, written, IRB- approved Informed Consent 
document will be provided to the patient (or representative) for signature after the patient or patient’s 
representative has had time to read it and ask questions. A copy will be given to the patient for his/her 
records. Proxy consent by legally authorized representatives will be allowed in the case of post-stroke 
aphasia or other cognitive disability, in order to not bias study entry by stroke severity.  
B.6. Patient Withdrawal 
A patient has the right to withdraw from the study at any time, for any reason, and without 
repercussion. The investigator has the right to withdraw a patient from the study in the event of an 
intercurrent illness, adverse event, treatment failure, protocol violation, cure, and for administrative or 
other reasons. An excessive rate of withdrawals would render the study uninterpretable; therefore, 
unnecessary withdrawal of patients will be avoided. Should a patient (or a patient's legally authorized 
guardian or representative) decide to withdraw, all efforts will be made to complete and report 
observations as thoroughly as possible. Early termination procedures will be followed. 
B.7. Patient Replacement 
Patients prematurely withdrawn from the study can be replaced, if needed, to ensure an adequate 
number of evaluable patients. The investigator, (in cooperation with the study statistician, if 
applicable) will decide whether or not to replace withdrawn patients. 
B.8. Investigation Drug Management 
At each study site, the drug management will be performed by their respective Investigational Drug 
Services (IDS). Study drug will be refrigerated at the site at a temperature of 2 to 8ºC; refrigerator 
temperature will be logged daily. At no time, will product be left unattended or outside the control of 
an individual knowledgeable with regard to product temperature requirements. Moreover, no one will 
administer product that has not been maintained according to temperature requirements. Study drug 
will be shipped at a temperature of 2 to 8°C to the investigator or designee at regular intervals or as 
needed during the study. During site close-out, and following drug reconciliation and documentation, 
all opened and unopened vials of study drug will be destroyed -or- returned to Amgen Inc. or 
designee. All drug accountability records will be kept current. The primary investigator will account for 
all opened and unopened vials of study drug. These records will contain the dates, quantity, and 
study medication: 
a) dispensed to each patient, 
b) returned from each patient (if applicable), and 
c) disposed of at the site or returned to Amgen Inc. or designee 
All accountability records will be made available for inspection by regulatory agency inspectors. 


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All drug compliance records will be kept current and will be made available for inspection by 
regulatory agency inspectors. Study drug will be given to patient at the baseline visit, and preferably 
at 6 month intervals thereafter. Instructions for shipping study drug to patients are provided in the 
appendix.  
 
B.9. Study Timeline  
There are two in-person study visits (baseline and 78 week follow-up) when patients will undergo 
vwMRI, approximately 60 minutes long, with a simultaneous clinical evaluation by a study investigator 
physician and blood draw. Every 2-4 months, the study coordinator will determine medication 
adherence, adverse events, or patient-reported recurrent stroke (see Figure 1).  
Figure 1: Schedule of Activities 
 
Screen/ 
Baseline 
Day  
1 
Day  
60 
Day  
120 
Day  
180 
Day  
240 
Day 
320 
Day 
480 
Day  
546 
Informed Consent  
X 
 
 
 
 
 
 
 
 
Medical 
History/Current 
medications 
X 
 
X 
X 
X 
X 
X 
X 
X 
Vitals 
X 
 
 
 
 
 
 
 
X 
Review CTA or 
MRA1 
X 
 
 
 
 
 
 
 
 
Vessel wall MRI 
 
X 
 
 
 
 
 
 
X 
Pregnancy test 
X 
 
 
 
 
 
 
 
 
Creatinine 
X 
 
 
 
 
 
 
 
X 
Lipid panel 
X 
 
 
 
 
 
 
 
X 
Lipoprotein (a) 
X 
 
 
 
 
 
 
 
X 
Apolipoprotein B 
X 
 
 
 
 
 
 
 
X 
Physical exam 
X 
 
 
 
 
 
 
 
X 
Neurological 
exam 
X 
 
 
 
 
 
 
 
X 
NIHSS 
X 
 
 
 
 
 
 
 
X 
Modified Rankin 
Scale 
X 
 
 
 
 
 
 
 
X 
Stroke 
adjudication 
 
 
X 
X 
X 
X 
X 
X 
X 
Adverse event 
determination 
 
 
X 
X 
X 
X 
X 
X 
X 
Serious adverse 
events  
 
 
X 
X 
X 
X 
X 
X 
X 
1. To confirm ICAD of a major intracranial artery 
B.10.  Study Duration 
• Estimated duration of research (study start to final study deliverable): 2 Years  /  6 Months 
• Estimated duration of first patient enrolled to last patient out: 2 Year  /  0 Months 
• Estimated duration for Amgen to supply study drug: 2 Year  /  0 Months 
C. Study Endpoints 


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C.1. Primary Endpoints 
The primary endpoints are nominal change in the stenosis and percent atheroma volume (PAV) of 
cerebrovasculture arteries from baseline to week 78. We will use measure stenosis and PAV on 
vessel wall MRI (vwMRI), which evaluates all arteries from the aortic arch to the distal intracranial 
vasculature in a single scan. The primary endpoints will be analyzed for both: 1) all intra- or 
extracranial arteries that have at least 25% stenosis, and 2) seperately for the intracranial arteries. 
Stenosis and PAV will be measured using standard methodology. 
C.1.a. Primary endpoint measurement: All vwMRIs are on a 3T scanner with a 20- or 32-channel 
head coil and gadolinium. The field of view is from the aorta to the top of the skull. Sequences include 
the following for Siemens scanners and equivalents for Phillips and GE:  
At the completion of patient enrollment, two neuroradiologists will examine all vwMRIs in three 
separate viewing sessions to prevent viewer fatigue. They will be given a rater sheet directing them to 
record findings in the brain and all major vessels of the cerebrovasculature, including: 
a) Stenosis: will be identified by the luminal imaging component of the vwMRI protocol (MR 
angiography of the head and neck). Stenosis will documented on the NIH Stroke CDE “Vessel 
Imaging Angiography”25 for all cerebrovasculature vessels from the aorta to distal intracranial 
vessels. Any vessel with >25% stenosis qualifies for computation of this composite outcome.  
b) Percent atheroma volume (PAV): We will use MRI-PlaqueView (VPDiagnostics, Seattle, WA) to 
measure PAV in the aortic arch, cervical carotid, cervical vertebral and all major intracranial 
arteries. MRI-PlaqueView is a powerful application that allows identification of (a) vessel lumen 
and outer wall (OW), (b) atheroma (both calcified and lipid rich). PAV is measured on the cross- 
sectional slice with the highest % stenosis. PAV = Σ(OWarea − Lumenarea)/ΣOWarea × 1   
C.2. Secondary endpoint 1 
Secondary endpoint 1 is post-contrast plaque enhancement for intracranial arteries and intraplaque 
hemorrhage for the cartotid artery, which are determined by two experienced neuroradiologist raters. 
If there is disagreement, then a third rater serves as a tie-breaker. The signal intensity characteristics 
of both endpoints have been standardized in prior literature. 
 
C.2.a. Secondary endpoint 1 measurement:  
a) ICAD post-contrast plaque enhancement (PPE): is a dichotomous variable evaluated on the T1 
pre- and post-gadolinium sequences, with multiplanar reconstruction so the ICAD can be seen 
in cross section.26 PPE is defined by placing a region-of-interest over areas of gadolinium 
enhancement in ICAD to evaluate if it is equal to or exceeds the signal intensity of the pituitary 
infundibulum, as previously described.27  
Sequence 
3D ToF 
DWI 
3D FLAIR 
3D 
MPRAGE 
PD 
SPACE 
DANTE 
3D SWI 
T1 
SPACE 
DANTE 
T2 
SPACE 
DANTE 
Contrast 
(gadolinium) 
Pre 
Pre 
Pre 
Pre 
Pre 
Pre 
Pre/Post 
Post 
DANTE = Delay Alternating with Nutation for Tailored Excitation (for blood suppression); DWI = Diffusion Weighted Imaging (Tensor 
technique); GRE = Gradient Recalled Echo; MPRAGE = Magnetization Prepared Rapid Acquisition Gradient recalled Echo; PD = 
proton density; SPACE = Sampling Perfection with Application optimized Contrasts using different flip angle Evolution; SWI = 
susceptibility weighted imaging (with quantitative susceptibility mapping); ToF = Time-of-Flight 


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b) Carotid intraplaque hemorrhage (IPH): MPRAGE positive plaque is defined as voxels with at 
least 2-fold signal intensity compared to sternocleidomastoid muscle as previously described. 
MPRAGE positive plaques can be reliably identified. Kappa values for inter- and intra-rater 
reliability for detection of MPRAGE positive plaque were 0.806 and 0.818 respectively (very 
good agreement).28,29  
c) MRA Flow Dynamics (MFD): We will measure MFD using accepted quantitative MRA 
methodology. The VERiTAS study provided prospective confirmation of the importance of MFD 
as a biomarker of stroke risk for patients with ICAD. Given that MFD can easily be measured in 
our vwMRI protocol, we will acquire the data required for its quantification.  
C.3. Secondary endpoint 2 
To better understand the mechanism of Repatha’s effect on intra- and extracranial atherosclerosis, 
we will measure the endpoint of change in cholesterol markers [LDL-C, HDL-C, lipoprotein (a), 
apolipoprotein B, and triglyceride level]. The change in cholesterol markers will be correlated with the 
primary and secondary study endpoints on vwMRI. Cholesterol values will be measured at the 
baseline and comparison MRIs, which are 78 weeks apart. If standard of care lab values are available 
within 30 days of the study visit, they can be used in place of the study lab value. An additional 
exploratory outcome that we will measure is the composite endpoint of "recurrent stroke," which 
encompasses new patient-reported symptomatic ischemic stroke, transient ischemic attack, or 
asymptomatic strokes that emerge between MRIs.  
C.3.a. Secondary endpoint 2 measurement:  
a) At both study MRIs, the study coordinator may collect two blood samples. Standard of care lab 
values can be used in place of these tests, if the values are from within 30 days of the study 
visit. If standard of care labs are not available, then the following samples will be tested. One 
sample may be tested with an i-STAT for creatinine levels prior to the MRI and, in women of 
child-bearing age who are not on birth control, a bHCG should be tested. The second sample 
may be sent for testing of LDL-C, HDL-C, triglycerides, apolipoprotein B, and lipoprotein (a), 
biomarkers of cardiovascular disease risk. 
b) At both study visits (baseline vwMRI and follow-up vwMRI), a physician will assess patients 
and their medical records for stroke. The physician will also have access to the data from the 
neuroradiologist raters. The endpoint of stroke is defined for all arterial distributions in the 
cerebrovasculature.  
C.4. Data Collection and Management 
Baseline and follow-up patient data are written on a case report form and then entered into a 
REDCap case report form (eCRF) based on the NIH Stroke Common Data Elements (CDE). We will 
also complete CRFs based on the “Demographics,” “Health History,” “Prior Health Status,” and 
“Drugs” forms,25 and utilize the SNOMED coding system for comorbidities.30 All data analysis is 
conducted with Stata. 
D. Methodology 
D.1. Statistical methods 
We will fit a mixed effects linear regression model, specifically a LOESS smoothing curve, to change 
in stenosis/PAV and on-treatment LDL-C, HDL-C, and lipoprotein(a). We will also use a multivariable 
linear regression model with the outcome of the primary endpoints, adjusted for covariates that could 
be confounders such as age, gender, smoking, statin use/dose and relevant medical comorbidities. 
The primary endpoints will also be compared to an assumed value of 0% change in stenosis and PAV 
that would correspond to optimal medical management without a PCSK9 inhibitor. Although, some 
studies have suggested statin therapy can reduce carotid atherosclerosis, no such effect is known for 


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ICAD. For this analysis, we will use linear mixed effects model to detect differences in the stenosis 
and PAV endpoints between patients taking Repatha or the presumed historical control values of 0% 
change. For the secondary endpoints, we will use logistic and linear regression depending on the 
nature of the variable and use the primary predictors of on-treatment LDL-C, HDL-C, and 
lipoprotein(a). For the exploratory endpoint of recurrent stroke, we will use the above mentioned 
methods as well as a Cox proportional hazards model for the endpoint of recurrent stroke with the 
observed rate in this study compared to controls matched according to degree to stenosis of the 
index artery. Due to differences in arterial structure and flow dynamics, there may be a more 
significant plaque reduction in certain intracranial vessels. We anticipate subgroup analyses, for 
example comparing change in stenosis or PAV in the middle cerebral artery versus the vertebral 
artery.  
D.2. Power Analysis 
We power our study on the primary endpoint of change in stenosis and PAV. The GLAGOV trial 
showed 0.95% reduction in PAV for patients randomized to Repatha versus a 0.05% increase in PAV 
for patients in the placebo arm and was 78 weeks in length. Because the major intracranial arteries 
have a similar luminal diameter to coronary arteries, we may reasonably expect a 1% reduction in 
PAV for our 78 week study as documented in previous literature. Patients with intracranial 
atherosclerosis can be expected to have at least 3 additional sites of atherosclerosis, including 
extracranial arteries, that will be included in the series of PAV outcomes. Each subject will provide 
four sites of atherosclerosis and therefore, 4 PAV measurements. This cluster designed study will be 
modeled by a mixed effects linear regression to account for the cluster of arteries per patient. We 
obtain >80% power for our sample size of 150 patients, two-sided significance level 0.05, and a 
conservative assumed standard deviation of 4% from previous studies for the assumed 1% reduction 
in PAV against the documented control PAV of 0%.23 With 150 patients, the minimum effect size 
possible to detect with 80% power is a 0.51% reduction. A 0.50% difference has been reported to be 
the cutoff to distinguish individuals that experience cardiovascular events versus those who do not.23 
Assuming a withdrawal rate of 25-30%, we would still reach >90% power for a 1% reduction with the 
above-listed conditions. We do not expect to show a significant reduction in recurrent stroke, but 
anticipate seeing a trend towards that outcome. This data could be used to accurately construct and 
power a subsequent trial with the primary outcome of recurrent stroke. Finally, in GLAGOV the linear 
relationship between change in stenosis, PAV and on-treatment LDL-C was very robust. We will be 
replicate this finding through means of a generalized linear mixed effects model. Our effective sample 
size may be sufficiently large enough to match the GLAGOV trial as each patient will be able to 
contribute an average of 4 arteries giving us an expected sample size between 800 and 1200 
dependent on a conservative prediction of intra-class correlation. All reported p-values will be two-
sided and deemed significant at the 0.05 level.  
D.3. Loss to Follow-up  
Based on the SPRINT MIND trial, we anticipate that up to 25-30% will not complete the follow-up 
clinic visit or vwMRI, and have accounted for this in our sample size calculation.31 If less patients than 
expected return for yearly follow-up MRI scans, we can enroll additional patients as needed, but do 
not expect this to be necessary or costly if necessary. If we have difficulty finding enough patients to 
enroll in the study, we will expand enrollment to the VA hospitals at our study sites, which would 
significantly increase potential patients.  
E. Safety Definitions, Reporting, and Monitoring 
E.1. Adverse Event (AE) 
An AE is any untoward medical occurrence in a patient administered the study drug which may or 
may not have a causal relationship with the study drug. Therefore, an AE is any unfavorable and 


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unintended sign (including abnormal laboratory finding), symptom, or disease which is temporally 
associated with the use of a study drug, whether or not considered related to the study drug. An AE 
also includes any worsening (i.e. any clinically significant change in frequency and/or intensity) of a 
pre-existing condition that is temporally associated with the use of the study drug. The most 
commonly occurring adverse reactions reported from clinical studies with Repatha were injection site 
reactions (including erythema/redness, itching, swelling, pain, tenderness), upper respiratory tract 
signs and symptoms (mainly nasopharyngitis, sinusitis, influenza, and upper respiratory tract 
infection), back pain, urinary tract infection, and cough. For this study, investigators will record all 
potential AEs, but the following are always considered as AEs: 
a) Increase in ALT: ALT >3  x ULN 
b) Allergic events: allergic drug reactions and/or local injection site reactions deemed to be 
allergic by the Investigator (or have an allergic component), that require consultation with 
another physician for further evaluation of hypersensitivity/allergy as per the Investigator’s 
medical judgment should be reported as an AE. 
c) Overdose with Repatha: An overdose (accidental or intentional) is an event suspected by the 
Investigator or spontaneously notified by the patient (not based on systematic injection counts) 
and defined as at least five times the intended dose within the intended therapeutic interval (ie, 
5 or more injections are administered in <14 calendar days), to be reported using the Term 
“OVERDOSE (accidental or intentional), indicating the circumstance in parentheses (eg, 
“overdose [accidental]” or “overdose [intentional]”). The patient should be monitored and 
appropriate treatment instituted. The circumstances of the overdose should be clearly specified 
in the verbatim and symptoms, if any, entered on separate AE/SAE forms.  
d) Neurologic events: Neurologic events that require additional examinations/procedures and/or 
referral to a specialist should be reported as an AE. If the event does not require additional 
examinations/procedures and/or referral to a specialist, it should be reported as a standard AE. 
e) Neurocognitive events: Neurocognitive events will be considered as AE. 
E.2. Serious Adverse Event (SAE) 
A SAE is any untoward medical occurrence that at any dose:  
a) Results in death, 
b) Is life threatening, (Note: the term “life-threatening” refers to an event/reaction in which the 
patient was at risk of death at the time of the event/reaction; it does not refer to an event/ 
reaction which hypothetically might have caused death if it were more severe), 
c) Requires inpatient hospitalization or results in prolongation of existing hospitalization, 
d) Results in persistent or significant disability/incapacity, 
e) Is a congenital anomaly/birth defect, or 
f) Is a medically important event or reaction. Medical and scientific judgment should be exercised 
in deciding whether other situations should be considered serious, such as important medical 
events that might not be immediately life-threatening or result in death or hospitalization, but 
might jeopardize the patient or might require intervention to prevent one of the other outcomes 
listed in the definition above. 
E.3. Recording and Reporting AEs and SAEs 
All AEs and SAEs will be recorded on the REDCap electronic CRF (“eCRF”) and in the patient’s 
source documents. Laboratory, vital signs or ECG abnormalities will be recorded as AEs only if they 
are medically relevant. Unexpected and study drug-related SAEs will also be reported promptly to 
Amgen Inc. and the FDA under the voluntary MedWatch reporting system. The investigator will 
promptly report to the IRB all unanticipated problems involving risks to patients. This includes death 
and all SAEs related to the use of the study drug. To report an SAE, the FDA will be contacted within 
24 hours and Amgen Inc. within 7 calendar days. 


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E.4. Reporting AEs and SAEs Leading to Withdrawal from the Study 
All SAEs and AEs that lead to a patient’s withdrawal from the study will be reported to the IRB and to 
Amgen Inc. within 7 calendar days.  
E.5. Abnormal Laboratory, Vital Signs, or Other Results 
The criteria for determining whether an abnormal objective test finding will be reported as an AE are 
as follows: 
a) the test result is associated with accompanying symptoms, and/or 
b) the test result requires additional diagnostic testing or medical/surgical intervention, and/or 
c) the test result leads to a change in dosing (outside of protocol-stipulated dose adjustments), 
discontinuation from the study, significant additional concomitant drug treatment, or other 
therapy. 
Repeating an abnormal test, in the absence of any of the above conditions, does not constitute an 
AE. Any abnormal test result that is determined to be an error does not require reporting as an AE.  
Pregnancy occurring in a female patient during the study or within 14 days following the last dose of 
study drug will be reported to Amgen Inc. within 10 calendar days. After confirmation of pregnancy, 
patients will no longer be given study drug and will be instructed to refrain from taking additional 
doses. Follow-up of pregnancy outcomes will be mandatory during the study. 
E.6. Evaluation of Severity 
The severity of an AE will be graded by the investigator using a 3–point scale (mild, moderate, or 
severe) and reported in detail as indicated on the CRF/eCRF and/or SAE form, as appropriate. 
a) Mild: Does not interfere in a significant manner with the patient’s normal functioning level. It 
may be an annoyance. Prescription drugs are not ordinarily needed for relief of symptoms, but 
may be given because of personality of the patient. 
b) Moderate: Produces some impairment of functioning but is not hazardous to health. It is 
uncomfortable or an embarrassment. Treatment for symptom may be needed. 
c) Severe: Produces significant impairment of functioning or incapacitation and is a definite 
hazard to the patient’s health. Treatment for symptom may be given and/or patient 
hospitalized. 
If a laboratory value is considered an AE, its severity will be based on the degree of physiological 
impairment the value indicates. 
E.7. Evaluation of Causality 
The relationship to treatment will be determined by the investigator and reported on the CRF/eCRF 
and/or SAE form, as appropriate. Events related to atherosclerosis such as primary atherosclerosis 
complications, will be considered anticipated unless they are fatal or present with unusual features in 
the context of the underlying condition. When determining causality of such events, the sponsor will 
consider them in the context of that individual patient’s condition. Events that may be considered 
anticipated in a patient with advanced disease may not be considered anticipated in a patient with 
milder disease.  
The following terms will be used: 
a) Not Related: likely or clearly due to causes other than the study drug. 
b) Related: possibly, probably, or definitely related to the study drug. 
E.8. Reasons for Permanent Discontinuation of Study Drug  
When attributed to Repatha administration: hypersensitivity or angioedema reactions requiring 
hospitalization.  
E.9. Investigator Alert notification 


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UCLA or its designee will inform all investigators participating in this clinical trial, as well as any other 
clinical trial using the same investigational drug, of any SAE that meets the relevant requirements for 
expedited reporting (an AE that is serious, unexpected based on the Investigator’s Brochure, and has 
a reasonable suspected causal relationship to the study drug). 
E.10. Premature Termination 
The investigator will notify UCLA of a desire to close-out a site in writing, providing at least 30 days’ 
notice. The final decision will be made by the investigator after consultation with UCLA. In all cases, 
the appropriate IRB and Health Authorities will be informed according to applicable regulatory 
requirements, and adequate consideration will be given to the protection of the patients’ interests. 
E.11. Monitoring of Study Site 
The study monitor and/or designee (e.g. contract research organization (“CRO”) monitor) will visit the 
study site prior to enrollment of the first patient, and periodically during the study. In accordance with 
International Conference on Harmonisation (“ICH”) guidelines, the monitor will compare the eCRF 
entries with the appropriate source documents. Additional review may include, but is not limited to, 
patient ICFs, documentation of patient recruitment and follow-up, AEs, SAEs, and concomitant 
therapy; as well as records of study drug dispensing, compliance, and accountability. A copy of the 
drug dispensing log will be provided to the study monitor upon request. 
E.11.a. Source Document Requirements 
Investigator will prepare and maintain adequate and accurate patient records (source documents). 
The investigator will keep all source documents on file with the CRF. Case report forms and source 
documents will be available at all times for inspection by authorized representatives of the regulatory 
authorities. 
E.11.b. Case Report Form Requirements 
Study data obtained in the course of the clinical study will be recorded on REDCap eCRFs by trained 
site personnel. An eCRF will be completed for each and every patient enrolled in the study. After 
review of the clinical data for each patient, the investigator will provide an electronic signature. A copy 
of each eCRF page will be retained by the investigator as part of the study record and will be 
available at all times for inspection by authorized representatives of the regulatory authorities. 
Corrections to the eCRF will be entered in the eCRF by the investigator or an authorized designee. 
All changes, including date and person performing corrections, will be available via the audit trail, 
which is part of the system. For corrections made via data queries, a reason for any alteration will be 
provided. 
E.12. Audits and Inspections 
This study may be subject to a quality assurance audit or inspection by the regulatory authorities. 
Should this occur, the investigator will be responsible for: 
a) Informing UCLA of a planned inspection by the authorities as soon as notification is received 
b) Providing access to all necessary facilities, study data, and documents for the inspection or 
audit 
c) Communicating any information arising from inspection by the regulatory authorities to UCLA 
immediately 
d) Taking all appropriate measures requested by the regulatory authorities to resolve the 
problems found during the audit or inspection 
Documents subject to audit or inspection include but are not limited to all source documents, 
CRFs/eCRFs, medical records, correspondence, ICFs, IRB files, documentation of certification and 
quality control of supporting laboratories, and records relevant to the study maintained in any 
supporting pharmacy facilities. Conditions of study material storage are also subject to inspection. In 
all instances, the confidentiality of the data will be respected. 


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E.13. Ethical and Regulatory Considerations 
E.13.a. Good Clinical Practice Statement 
The investigator(s) will conduct the study in accordance with the ethical principles that have their 
origin in the Declaration of Helsinki, and that are consistent with the ICH guidelines for Good Clinical 
Practice (GCP) and applicable regulatory requirements. 
E.13.b. Informed Consent 
The principles of informed consent are described in ICH Guidelines for GCP. UCLA shall have the 
right to review and comment on the informed consent form. It is the responsibility of the investigator 
or designee (if acceptable by local regulations) to obtain written informed consent from each subject 
in accordance with 21 Code of Federal Regulations Part 50 (unless an exemption under such part 
has been approved by the IRB and documentation of same can be provided), prior to his/her 
participation in the study and after the aims, methods, objectives, and potential hazards of the study 
have been explained to the subject in language that he/she can understand. The ICF will be signed 
and dated by the subject and by the investigator or authorized designee who reviewed the ICF with 
the subject. Patients who can write but cannot read will have the ICF read to them before signing and 
dating the ICF. Patients who can understand but who can neither write nor read will have the ICF 
read to them in presence of an impartial witness, who will sign and date the ICF to confirm that 
informed consent was given. The original ICF will be retained by the investigator as part of the 
patient's study record, and a copy of the signed ICF will be given to the patient. If new safety 
information results in significant changes in the risk/benefit assessment, the ICF will be reviewed and 
updated appropriately. All study patients will be informed of the new information and provide their 
written consent if they wish to continue in the study. The original signed revised ICF will be 
maintained in the patient’s study record and a copy will be given to the patient. 
E.13.c. Patients Confidentiality and Data Protection 
The investigator will take all appropriate measures to ensure that the anonymity of each study patient 
will be maintained. The patient's and investigator's personal data will be treated in compliance with all 
applicable laws and regulations. 
E.13.d. Institutional Review Board /Ethics Committee 
An appropriately constituted IRB, as described in ICH Guidelines for GCP, will review and approve: 
a) The protocol, ICF, and any other materials to be provided to the patients (e.g. advertising) 
before any patient may be enrolled in the study 
b) Any amendment or modification to the study protocol or ICF before implementation, unless the 
change is necessary to eliminate an immediate hazard to the patients, in which case the IRB 
will be informed as soon as possible 
Ongoing studies will be reviewed by the IRB on an annual basis or at intervals appropriate to the 
degree of risk. In addition, the IRB will be informed of any event likely to affect the safety of patients 
or the continued conduct of the clinical study. A copy of the IRB approval letter will be sent to UCLA 
prior to shipment of drug supplies to the investigator.  The approval letter will include the study 
number and title, the documents reviewed, and the date of the review. Records of the IRB review and 
approval of all study documents (including approval of ongoing studies) will be kept on file by the 
investigator. 
E.14. Certification of Accuracy of Data 
A declaration assuring the accuracy and content of the data recorded on the CRFs will be signed by 
the investigator. This certification form accompanies each set of CRFs. 
E.15. Retention of Records 
The investigator will retain all essential study documents, including ICFs, source documents, CRFs, 
and drug accountability records for at least 15 years following the completion or discontinuation of the 


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study, or longer if a longer period is required by relevant regulatory authorities. Records will be 
destroyed in a manner that ensures confidentiality. 
E.16. Publication Plan 
Within 6 months of study termination, the primary investigator will submit an article detailing the study 
results for publication in the following medical journals, in order of submission: New England Journal 
of Medicine, Stroke, Neurology, JAMA Neurology, Lancet Neurology. 
References 
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Neuroimaging. 2009;19 Suppl 1:11S–6S.  
2.  Holmstedt CA, Turan TN, Chimowitz MI. Atherosclerotic intracranial arterial stenosis: risk factors, 
diagnosis, and treatment. Lancet Neurol. 2013;12:1106–1114.  
3.  Arenillas JF. Intracranial atherosclerosis: current concepts. Stroke. 2011;42:S20-23.  
4.  Bang OY. Intracranial Atherosclerosis: Current Understanding and Perspectives. J. Stroke. 
2014;16:27–35.  
5.  Koo J. The Latest Information on Intracranial Atherosclerosis: Diagnosis and Treatment. Interv. 
Neurol. 2015;4:48–50.  
6.  Wang Y-L, Pan Y-S, Zhao X-Q, Wang D, Johnston SC, Liu L-P, et al. Recurrent stroke was 
associated with poor quality of life in patients with transient ischemic attack or minor stroke: 
finding from the CHANCE trial. CNS Neurosci. Ther. 2014;20:1029–1035.  
7.  Wang A, Wu L, Wang X, Zhao X, Wang C, Liu L, et al. Effect of recurrent stroke on poor 
functional outcome in transient ischemic attack or minor stroke. Int. J. Stroke Off. J. Int. Stroke 
Soc. 2016;11:NP80.  
8.  Hong K-S, Yegiaian S, Lee M, Lee J, Saver JL. Declining stroke and vascular event recurrence 
rates in secondary prevention trials over the past 50 years and consequences for current trial 
design. Circulation. 2011;123:2111–2119.  
9.  Chaturvedi S, Sacco RL. How Recent Data Have Impacted the Treatment of Internal Carotid 
Artery Stenosis. J. Am. Coll. Cardiol. 2015;65:1134–1143.  
10.  Bonati LH, Dobson J, Featherstone RL, Ederle J, van der Worp HB, de Borst GJ, et al. Long-
term outcomes after stenting versus endarterectomy for treatment of symptomatic carotid 
stenosis: the International Carotid Stenting Study (ICSS) randomised trial. The Lancet. 
2015;385:529–538.  
11.  Brott TG, Howard G, Roubin GS, Meschia JF, Mackey A, Brooks W, et al. Long-Term Results of 
Stenting versus Endarterectomy for Carotid-Artery Stenosis. N. Engl. J. Med. 2016;374:1021–
1031.  
12.  Paraskevas KI, Mikhailidis DP, Veith FJ, Paraskevas KI, Mikhailidis DP, Veith FJ, et al. Definition 
of Best Medical Treatment in Asymptomatic and Symptomatic Carotid Artery Stenosis. 
Angiology. 2016;67:411–419.  
13.  Chimowitz MI, Lynn MJ, Howlett-Smith H, Stern BJ, Hertzberg VS, Frankel MR, et al. 
Comparison of Warfarin and Aspirin for Symptomatic Intracranial Arterial Stenosis. N. Engl. J. 
Med. 2005;352:1305–1316.  
14.  Chimowitz MI, Lynn MJ, Derdeyn CP, Turan TN, Fiorella D, Lane BF, et al. Stenting versus 
aggressive medical therapy for intracranial arterial stenosis. N. Engl. J. Med. 2011;365:993–
1003.  
15.  den Hartog AG, Achterberg S, Moll FL, Kappelle LJ, Visseren FLJ, van der Graaf Y, et al. 
Asymptomatic carotid artery stenosis and the risk of ischemic stroke according to subtype in 
patients with clinical manifest arterial disease. Stroke J. Cereb. Circ. 2013;44:1002–1007.  
16.  Brott TG, Halperin JL, Abbara S, Bacharach JM, Barr JD, Bush RL, et al. 2011 
ASA/ACCF/AHA/AANN/AANS/ACR/ASNR/CNS/SAIP/SCAI/SIR/SNIS/SVM/SVS Guideline on 


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the Management of Patients With Extracranial Carotid and Vertebral Artery DiseaseA Report of 
the American College of Cardiology Foundation/American Heart Association Task Force on 
Practice Guidelines, and the American Stroke Association, American Association of 
Neuroscience Nurses, American Association of Neurological Surgeons, American College of 
Radiology, American Society of Neuroradiology, Congress of Neurological Surgeons, Society of 
Atherosclerosis Imaging and Prevention, Society for Cardiovascular Angiography and 
Interventions, Society of Interventional Radiology, Society of NeuroInterventional Surgery, 
Society for Vascular Medicine, and Society for Vascular Surgery Developed in Collaboration 
With the American Academy of Neurology and Society of Cardiovascular Computed 
Tomography. J. Am. Coll. Cardiol. 2011;57:e16–e94.  
17.  Windecker S, Stortecky S, Stefanini GG, daCosta BR, Rutjes AW, Nisio MD, et al. 
Revascularisation versus medical treatment in patients with stable coronary artery disease: 
network meta-analysis. BMJ. 2014;348:g3859.  
18.  Pursnani S, Korley F, Gopaul R, Kanade P, Chandra N, Shaw RE, et al. Percutaneous Coronary 
Intervention Versus Optimal Medical Therapy in Stable Coronary Artery Disease. Circ. 
Cardiovasc. Interv. 2012;5:476–490.  
19.  de Havenon A, Yuan C, Tirschwell D, Hatsukami T, Anzai Y, Becker K, et al. Nonstenotic Culprit 
Plaque: The Utility of High-Resolution Vessel Wall MRI of Intracranial Vessels after Ischemic 
Stroke. Case Rep. Radiol. 2015;2015:e356582.  
20.  Kim J-M, Jung K-H, Sohn C-H, Moon J, Shin J-H, Park J, et al. Intracranial plaque enhancement 
from high resolution vessel wall magnetic resonance imaging predicts stroke recurrence. Int. J. 
Stroke. 2016;11:171–179.  
21.  Gutierrez J, Elkind MSV, Virmani R, Goldman J, Honig L, Morgello S, et al. A pathological 
perspective on the natural history of cerebral atherosclerosis. Int. J. Stroke Off. J. Int. Stroke 
Soc. 2015;10:1074–1080.  
22.  Teng Z, Peng W, Zhan Q, Zhang X, Liu Q, Chen S, et al. An assessment on the incremental 
value of high-resolution magnetic resonance imaging to identify culprit plaques in atherosclerotic 
disease of the middle cerebral artery. Eur. Radiol. 2016;26:2206–2214.  
23.  Nicholls SJ, Puri R, Anderson T, Ballantyne CM, Cho L, Kastelein JJP, et al. Effect of 
Evolocumab on Progression of Coronary Disease in Statin-Treated Patients: The GLAGOV 
Randomized Clinical Trial. JAMA. 2016;316:2373–2384.  
24.  Diagnostic Radiology: Magnetic Resonance Imaging (MRI) Practice Parameters and Technical 
Standards - American College of Radiology [Internet]. [cited 2015 Jan 30];Available from: 
http://www.acr.org/Quality-Safety/Standards-Guidelines/Practice-Guidelines-by-Modality/MRI 
25.  Stroke Standards - NINDS Common Data Elements [Internet]. [cited 2015 Jan 3];Available from: 
http://www.commondataelements.ninds.nih.gov/stroke.aspx#tab=Data_Standards 
26.  Mandell DM, Mossa-Basha M, Qiao Y, Hess CP, Hui F, Matouk C, et al. Intracranial Vessel Wall 
MRI: Principles and Expert Consensus Recommendations of the American Society of 
Neuroradiology. Am. J. Neuroradiol. [Internet]. 2016 [cited 2016 Aug 7];Available from: 
http://www.ajnr.org/content/early/2016/07/28/ajnr.A4893 
27.  Gupta A, Baradaran H, Al‐Dasuqi K, Knight‐Greenfield A, Giambrone AE, Delgado D, et al. 
Gadolinium Enhancement in Intracranial Atherosclerotic Plaque and Ischemic Stroke: A 
Systematic Review and Meta‐Analysis. J. Am. Heart Assoc. 2016;5:e003816.  
28.  McNally JS, Kim S-E, Mendes J, Hadley JR, Sakata A, De Havenon AH, et al. Magnetic 
Resonance Imaging Detection of Intraplaque Hemorrhage. Magn. Reson. Insights. 2017;10:1–8.  
29.  Scott McNally J, Yoon H-C, Kim S-E, Narra KK, McLaughlin MS, Parker DL, et al. Carotid MRI 
Detection of Intraplaque Hemorrhage at 3T and 1.5T. J. Neuroimaging. 2015;25:390–396.  
30.  SNOMED Clinical Terms® (SNOMED CT®) [Internet]. [cited 2015 Jan 3];Available from: 
http://www.nlm.nih.gov/research/umls/Snomed/snomed_main.html 


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31.  SPRINT MIND Investigators for the SPRINT Research Group, Williamson JD, Pajewski NM, 
Auchus AP, Bryan RN, Chelune G, et al. Effect of Intensive vs Standard Blood Pressure Control 
on Probable Dementia: A Randomized Clinical Trial. JAMA. 2019;321:553–561.  
 
 
 


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APPENDIX: Drug Shipment to Patients 
 
 
1. When study medication is given to the coordinator, the hand packaging and labeling process 
will begin. 
2. Study drugs need to be kept in a temperature range of 68°F to 77°F at all times, so to ship 
study medications we must prepare them with adequate ice packs and a Styrofoam box. 
3. You can purchase the Styrofoam box and Ice Gel Pack on Amazon, which have the picture 
below and are very inexpensive. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4. Please ensure you keep the ice pack in a 68°F to 77°F temperature location at least 24 hours 
prior to shipment of drug.  
5. Once the packaging is completed, prior to sending it to Fedex or UPS please ensure "UN3373 
Biological Substance Category B" Labels/Stickers are attached on the box. 
6. Once shipment is ready, you may contact UPS or Fedex via the internal mail office within 
institute. Please be sure that your shipment is by over-night shipping.  
7. Once the study drugs are delivered to the participant, the study coordinator is required to 
contact participants to ensure study drugs were received and are not damaged.