A Trial of Crizanlizumab for the Treatment of Retinal Vasculopathy With Cerebral Leukoencephalopathy (RVCL)
Phase: PHASE2
Conditions: RVCL - Retinal Vasculopathy Cerebral Leukoencephalopathy
Sponsor: Washington University School of Medicine

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A Trial of Crizanlizumab for the Treatment of Retinal Vasculopathy with Cerebral 
Leukoencephalopathy (RVCL) 
 
Washington University School of Medicine 
Department of Medicine 
660 South Euclid Avenue 
St. Louis, MO  63110 
 
Protocol #: 202008079 
Version Date:  4/8/2025 
 
Principal Investigators: 
Andria L. Ford, M.D. (Wash U Neurology) 
 
 
 
 
email: forda@wustl.edu  
 
 
 
 
Phone: (314) 319-9143 
 
Sub-Investigators:  
Jonathan Miner, M.D., Ph.D. (Wash U Infectious Diseases) 
John Atkinson, M.D. (Wash U Rheumatology) 
 
 
 
 
M. Gilbert Grand, M.D. (Wash U Ophthalmology) 
 
 
 
 
Rajendra Apte, M.D. Ph.D. (Wash U Ophthalmology) 
 
 
 
 
Prabakar Rao, M.D., M.B.A. (Wash U Ophthalmology) 
 
 
 
 
Rennie Rhee, M.D. (UPenn Rheumatology) 
 
 
 
 
 
 
 
Clinical Trials.gov#: 
NCT04611880 
 
 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to 
the extent necessary to obtain informed consent, may not be disclosed to another party 
unless law or regulations require such disclosure.  Persons to whom the information is 
disclosed must be informed that the information is confidential and may not be further 
disclosed by them 

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TABLE OF CONTENTS 
1.0 
BACKGROUND AND STUDY RATIONALE ...................................................... 3 
1.1 
Retinal Vasculopathy with Cerebral Leukoencephalopathy (RVCL) ........ 3 
1.2 
TREX1 [Three prime repair exonuclease 1] ...................................................... 3 
1.3 
Crizanlizumab ............................................................................................................ 3 
1.4 
Study Rationale ......................................................................................................... 3 
2.0 
OBJECTIVES AND ENDPOINTS ...................................................................... 4 
2.1 
Primary Endpoint ...................................................................................................... 4 
3.0 
PATIENT POPULATION ..................................................................................... 4 
3.1 
Inclusion Criteria ...................................................................................................... 4 
3.2 
Exclusion Criteria ..................................................................................................... 5 
3.3 
Inclusion of Women and Minorities .................................................................... 5 
4.0 
STUDY DESIGN / DRUG ADMINISTRATION / TREATMENT ..................... 5 
4.1 
Study Design and Overview of Treatment Plan ............................................... 5 
4.2 
Duration of Therapy ................................................................................................. 5 
4.3 
Duration of Follow-up ............................................................................................. 6 
5.0 
DRUG ADMINISTRATION AND DOSING GUIDELINES ................................ 6 
5.1 
Crizanlizumab ............................................................................................................ 6 
5.2 
Dose Modifications ................................................................................................... 6 
5.3 
Concomitant therapy ............................................................................................. 11 
5.4 
Dose Forms, Strengths and Storage ................................................................. 12 
5.5 
Availability ................................................................................................................. 12 
5.6 
Warnings and Precautions ................................................................................... 12 
6.0 
VISIT SCHEDULE AND ASSESSMENTS ...................................................... 14 
7.0 
SAFETY MONITORING AND REPORTING .................................................... 15 
7.1 
Adverse Events (AEs) and Safety Reporting ................................................... 15 
7.2 
Reporting to Novartis ............................................................................................. 16 
7.3 
Unanticipated Problems ........................................................................................ 18 
7.4 
Noncompliance ......................................................................................................... 18 
7.5 
Serious Noncompliance ......................................................................................... 18 
7.6 
Protocol Exceptions ................................................................................................ 18 
7.7 
Reporting to the Human Research Protection Office (HRPO) ................... 18 
7.8 
Reporting to the FDA ............................................................................................. 18 
7.9 
Timeframe for Reporting Required Events ...................................................... 19 
8.0 
DATA SUBMISSION SCHEDULE ................................................................... 20 
10.0 STATISTICAL METHODS AND DATA ANALYSIS ......................................... 21 
 
 
 

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1.0 
BACKGROUND AND STUDY RATIONALE 
1.1 
Retinal Vasculopathy with Cerebral Leukoencephalopathy (RVCL) 
Retinal vasculopathy with cerebral leukoencephalopathy (RVCL) is a very rare and 
uniformly fatal genetic condition that affects the microvasculature especially of the brain 
and eye. Symptoms begin in adulthood (usually in the mid-30s to early 40s) and include 
loss of vision, mini-strokes, and dementia [1]. Other patients have suffered from 
microvascular disease involving the kidneys, osteonecrosis, and gut ischemia.  Some of 
these features of microvascular occlusive disease resemble ischemic events that occur 
during sickle cell disease, although RVCL patients do not experience pain crises.  RVCL 
includes three conditions which were previously thought to be distinct: hereditary 
endotheliopathy, retinopathy, nephropathy, and stroke (HERNS); cerebroretinal 
vasculopathy (CRV); and hereditary vascular retinopathy (HVR) [2]. RVCL is inherited in 
an autosomal dominant manner and is caused by C-terminal heterozygous frameshift 
(fs) mutations in TREX1, a DNase gene [2]. There is no treatment for RVCL, only 
symptomatic management.  
1.2 
TREX1 [Three prime repair exonuclease 1] 
TREX1 is an endoplasmic reticulum (ER)-associated enzyme that, in addition to its DNA 
enzymatic activities, may also regulate sugar metabolism in the ER [3]. TREX1 
mutations have also been associated with several autoimmune and autoinflammatory 
diseases. In RVCL, frameshift (fs) mutations of TREX1 result in C-terminal truncation 
and this dysregulates the oligosaccharyltransferase (OST) complex leading to free 
glycan release from dolichol carriers. Since microvascular ischemia is the major driver of 
disease and organ damage in RVCL, we hypothesize that preventing leukocyte 
adhesion to the vascular endothelium may protect against microvascular occlusive 
disease in RVCL.  Indeed, selectin-mediated leukocyte adhesion plays a major role in 
microvascular occlusion in multiple microvascular diseases including sickle cell disease. 
1.3 
Crizanlizumab 
Crizanlizumab produced by Novartis is the first and only P-selectin antagonist to receive 
the FDA breakthrough designation for prevention of sickle cell pain crisis. Crizanlizumab 
is a humanized monoclonal P-selectin antibody that prevents leukocyte adhesion to the 
vascular endothelium, thereby limiting risk of microvascular occlusion.  Crizanlizumab 
has undergone Phase I and II trials for sickle cell disease at 2.5 mg/kg and 5 mg/kg 
doses. Crizanlizumab resulted in fewer hospitalizations and fewer pain crises in these 
patients, likely as a consequence of its ability to prevent microvascular occlusion. 
 
1.4 
Study Rationale 
Mutations in TREX1 cause RVCL. The disease-causing mutation was discovered at 
Washington University in Saint Louis. P-selectin is mobilized to the surface of activated 
vascular endothelial cells and promotes leukocyte adhesion to the blood vessel wall.  Dr. 
Miner did his PhD training in the McEver laboratory, where crizanlizumab was first 
generated, and therefore has significant expertise in P-selectin, crizanlizumab, and 
related pathophysiology. Now, Dr. Miner cares for the largest cohort of RVCL patients in 
the world, and leads a research laboratory that has a major focus on rare vasculopathies 
including RVCL.  The Miner laboratory has preliminarily observed a correlation with 
levels of soluble P-selectin and the number of brain lesions in patients with RVCL.  Since 
microvascular occlusive disease can result from leukocyte adhesion to the vascular 
endothelium, we hypothesize that crizanlizumab will help to limit ischemia and brain 
lesions in patients with RVCL. This may lead to the development of fewer ischemic brain 
and eye lesions.  

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There is no approved or effective therapy for RVCL, which is 100% penetrant and 
causes blindness and early-onset dementia in 100% of patients.  In some patients with 
RVCL, anti-inflammatory treatment (e.g., prednisone) has reduced the size of 
edematous brain lesions. Unfortunately, prednisone is too toxic for long-term 
continuous therapy, and we do not treat these patients with maintenance steroids. 
Furthermore, other immunosuppressive medications have not been effective, and 
cytokine levels are not elevated in RVCL. Collectively, our findings indicate that 
RVCL is not an autoinflammatory or autoimmune disease.  Instead, our 
histological analysis and cytokine assays suggest that RVCL is a disease of 
endothelial dysfunction, leading to microvascular occlusion and ischemia.  Since 
crizanlizumab has less toxicity than prednisone and can prevent vasoocclusion, we 
expect that crizanlizumab will limit the progression of brain and eye lesions in patients 
with RVCL. 
RVCL typically results in new brain and eye lesions that are readily apparent on imaging 
at 6- or 12-month intervals.  Numbers and the size of new ischemic brain and eye 
lesions will be monitored at visits to assess disease progression while on crizanlizumab.   
2.0 
OBJECTIVES AND ENDPOINTS 
2.1 
Primary Endpoint 
The primary endpoint is rate of progression in cerebral lesions in the year after initiation 
of crizanlizumab compared to the year before initiation. 
2.2 
Secondary endpoints include: 
1) Rate of progression in white matter atrophy one year after initiation of crizanlizumab 
compared to one year prior to initiation. 
2) Rate of progression in retinal lesions development one year after initiation of 
crizanlizumab compared to one year prior to initiation.  
3) Rate of progression in cognitive decline one year after initiation of crizanlizumab 
compared to one year prior to initiation. 
4) Safety of crizanlizumab will be measured by serious and non-serious adverse events 
deemed by the study PI to be related to crizanlizumab treatment in any participants  
5) Tolerability of crizanlizumab measured by doses held and/or discontinuation of 
crizanlizumab for each participant throughout the duration of the study. 
6) Quality of life while receiving crizanlizumab will be assessed by SF-36 score. 
3.0 
PATIENT POPULATION 
3.1 
Inclusion Criteria 
1. A diagnosis of RVCL with confirmation by genetic test 
2. At least 25 years of age with imaging evidence of RVCL brain or eye disease at the 
time of study registration 
3. Normal hematologic function defined as: WBC > 4x109/L, ANC > 1.5x109/L and 
Platelets > 100x109/L 
4. Females of childbearing potential (FCBP) must agree to refrain from becoming 
pregnant while on study drug and for 3 months after discontinuation from study drug, 
and must agree to use adequate contraception including hormonal contraception, 
(i.e. birth control pills, etc.), barrier method contraception (i.e. condoms), or 
abstinence during that time-frame 
5. Able to understand and willing to sign an IRB-approved written informed consent 
document (or that of legally authorized representative, if applicable) 
 

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3.2 
Exclusion Criteria 
1. Acute bacterial, fungal, or viral infection 
2. Known HIV, untreated latent tuberculosis (TB), or active hepatitis B or C infection or 
zoster 
3. Pregnant and/or breastfeeding.  Negative serum pregnancy test required prior to 
starting study treatment.  For FCBP, a negative urine pregnancy test is required 
before each infusion. 
4. Known hypersensitivity to one or more of the study agents 
5. Currently receiving or has received any investigational drugs within the 14 days prior 
to the first dose of study drug 
6. Liver function tests (LFTs) higher than 3x the upper limit of normal within last 30 days 
7. Treatment with other monoclonal antibody medications within last 30 days 
8. Treatment with various forms of anticoagulation within last 30 days, including but not 
limited to clopidogrel or coumadin or direct thrombin inhibitors 
3.3 
Inclusion of Women and Minorities 
Both men and women and members of all races and ethnic groups are eligible for this 
trial.   
4.0 
STUDY DESIGN / DRUG ADMINISTRATION / TREATMENT 
4.1 
Study Design and Overview of Treatment Plan 
Up to 20 RVCL patients will receive crizanlizumab 5 mg/kg at weeks 1 and 3, and then 5 mg/kg 
beginning week 7 and every month thereafter for 24 total months. Patients living in the northeast 
may choose to have their monthly infusions administered at University of Pennsylvania except 
for month 1, 6, 12, 18 and 24, where they must return to Washington University for follow-up 
monitoring and infusion. Other than adverse event recording and documentation of infusions, no 
data collection will occur at the University of Pennsylvania. The University of Pennsylvania will 
maintain documentation of all infusions, and all adverse events occurring at University of 
Pennsylvania will be directly communicated to the primary investigator at Washington University 
in Saint Louis within 24 hours. Monitoring and all other data collection will occur at Washington 
University in St. Louis, and will include standard-of-care serial MRI as well as standard-of-care 
eye disease monitoring at pre-defined intervals (see Section 6.0).   
4.2 
Duration of Therapy 
If at any time the constraints of this protocol are considered to be detrimental to the 
patient’s health and/or the patient no longer wishes to continue protocol therapy, the 
protocol therapy will be discontinued and the reason(s) documented in the case report 
forms.  
Patients will be removed from the study for any of the following reasons: 
• 
Death 
• 
Adverse event(s) that, in the judgment of the investigator, may cause severe or 
permanent harm or which rule out continuation of the study drug 
• 
General or specific changes in the patient’s condition that render the patient 
unacceptable for further treatment in the judgment of the investigator 
• 
Suspected pregnancy, confirmed by pregnancy test 
• 
Serious noncompliance with the study protocol 

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• 
Lost to follow-up 
• 
Patient withdraws consent 
• 
Investigator removes the patient from study 
• 
Investigator decides to close the study 
 
4.3 
Duration of Follow-up 
Following completion of protocol treatment patients will be followed for up to 2 years with 
standard-of-care imaging and examinations as detailed in section 6.0. 
5.0 
DRUG ADMINISTRATION AND DOSING GUIDELINES 
5.1 
Crizanlizumab 
Crizanlizumab will be supplied in single use vials containing 10 mL at a concentration of 
10 mg/mL for administration by IV infusion. Each patient will receive one dose of crizanlizumab 
on day 1 of Week 1, day 1 of Week 3, day 1 of Week 7, and then day 1 of every 4-week cycle. 
On infusion day, the pharmacist or designated personnel will prepare individual doses of 
crizanlizumab for subjects on a milligram per kilogram basis in a 100 mL infusion bag in 
accordance with the Pharmacy Manual. Crizanlizumab will be administered over 30 minutes by 
IV infusion.  
 
Treatments 
Pharmaceutical 
form and route of 
administration 
Dose 
Frequency and/or 
Regimen 
SEG101 
 Intravenous infusion 
5.0 mg/kg 
Dosing on day 1 of 
weeks 1, week 3, 
and week 7, and then 
every 4 weeks 
 
Vital signs will be taken before and after each infusion.  Patients will be monitored for 30 
minutes post infusion. Temperature above 100 degrees F at time of infusion will be documented 
and may delay treatment at the discretion of the PI.  
COVID-19 screening questions will be performed prior to the baseline visit and at each 
subsequent visit during the COVID-19 pandemic. If a patient fails the screening process or has 
symptoms of upper respiratory infection, loss of taste or loss of smell, then a COVID-19 test will 
be performed. Treatment will be held until results are confirmed to be negative, and once the 
patient is no longer having symptoms of infection. If COVID-19 test results are positive, the 
quarantine period to return for treatments will be at least 21 days, with days 19, 20, and 21 
being symptom-free. After that time, if the patient remains symptom-free, crizanlizumab 
treatments may resume. 
5.2 
Dose Modifications  
If a subject does not tolerate the protocol-specified dosing schedule, dose interruptions will be 
strongly considered by the PI based on the clinical situation. Dose reductions are not allowed.  
If a subject experiences drug-induced toxicity, the subject will be closely monitored and a 
decision to continue or discontinue the subject from the study will be made at the next dose 
scheduled. Missing two consecutive doses for suspected drug-related AEs (drug toxicity) will be 
considered criteria for permanently discontinuing the patient from treatment. 

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Dose interruptions and discontinuation protocol are summarized in the below Table.  
 
 
 
Dose interruption and re-initiation of investigational treatment 
Worst toxicity 
CTCAEa Grade (CTCAE version 5) during a 
cycle of therapy 
  
Investigations (Hematologic) 
Neutropenia (ANC) 
Grade 1 (ANC < LLN - 1.5 x 109/L) and 
Grade 2 (ANC < 1.5 x 109/L – 1.0 x 109/L ) 
Maintain dose level. 
Grade 3 (ANC < 1.0 x 109/L – 0.5 x 109/L) 
Mandatory: Interrupt dose until resolved to ≤ 
Grade 2 or next dose scheduled. If abnormality 
persists, permanently discontinue the subject 
from the study. 
Grade 4 (ANC < 0.5 x 109/L) 
Mandatory: 
Permanently 
discontinue 
the 
subject from the study.  
Febrile neutropenia (ANC < 1.0 x 109/L, 
fever ≥ 38.3°C) 
Mandatory: Interrupt dose until resolved or 
next dose schedule. If abnormality persists, 
permanently discontinue the subject from the 
study. 
Thrombocytopenia 
Grade 1 (LPT < LLN - 75,000/mm3) and 
Grade 2 (LPT < 75,000 - 50,000/mm3) 
Maintain dose level. 
Grade 3 (LPT < 50,000 - 25,000/mm3) 
Interrupt dose until resolved to ≤ Grade 2 or 
next dose scheduled. If abnormality persists, 
permanently discontinue the subject from the 
study. 
Grade 4 (LPT < 25,000/mm3) 
Mandatory: 
Permanently 
discontinue 
the 
subject from the study. 
Investigations (Hepatic) 
Isolated Direct Bilirubin 
Grade 1  
>ULN - 1.5 x ULN if baseline was normal; > 
1.0 - 1.5 x baseline if baseline was 
abnormal  
 
Continue study treatment. 

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Grade 2 and 3  
(>1.5 - 10.0 x ULN if baseline was normal; 
>1.5 - 10.0 x baseline if baseline was 
abnormal)  
 
Interrupt 
study 
treatment. 
Monitor 
LFTsb weekly, or more frequently if clinically 
indicated, until resolved to ≤ 1.5 x ULN or 
baseline. Monitor for hemolysis. If resolved to 
≤ Grade 1 or baseline, then continue study 
treatment. 
Grade 4 (>10.0 x ULN if baseline was 
normal; >10.0 x baseline if baseline was 
abnormal)  
 
Mandatory: Permanently discontinue study 
treatment.  
Isolated ALT elevation 
Grade 1 (> ULN - 3.0 x ULN) 
Maintain dose level. 
Grade 2 (> 3.0 - 5.0 x ULN) 
Maintain dose level. Repeat LFTsb as soon as 
possible, preferably within 48-72 hours from 
awareness of the abnormal results; if abnormal 
lab values are confirmed upon the repeat test, 
then monitor LFTsb weekly, or more frequently 
if clinically indicated, until resolved to ≤ 3.0 x 
ULN. If resolved, then continue with next dose 
scheduled. 
Grade 3 (> 5.0 - 20.0 x ULN) 
Interrupt dose. Repeat LFTsb as soon as 
possible, preferably within 48-72 hours from 
awareness of the abnormal results; monitor 
LFTsb weekly, or more frequently if clinically 
indicated, until resolved to ≤ 3.0 x ULN. If 
resolved, 
then 
continue 
with 
next 
dose 
scheduled. 
Grade 4 (> 20.0 x ULN) 
Mandatory: 
Permanently 
discontinue 
the 
subject from the study.  
Combined elevations of ALT and bilirubin (direct (conjugated)) 
• For subjects with normal baseline 
ALT and direct bilirubin value: ALT >3.0 
x ULN combined with direct bilirubin 
>2.0 x ULN without evidence of 
cholestasisc OR 
• 
For subjects with elevated baseline ALT 
or direct bilirubin value: ALT>2x baseline 
AND > 2.0 x baseline direct bilirubin 
Mandatory: in the absence of cholestasis 
(ALP< ULN), subject will be immediately 
discontinued from study treatment. Repeat 
LFTs as soon as possible, preferably within 48 
hours from awareness of the abnormal results, 
then with weekly monitoring of LFTsb), or more 
frequently if clinically indicated, until ALT, or 
bilirubin 
have 
resolved 
to 
baseline 
or 
stabilization over 4 weeks.  
Infections 
Grade 1 and 2 
Maintain dose level. 
Grade 3 
Mandatory: Interrupt dose until resolved. If 
resolved, 
then 
continue 
with 
next 
dose 
scheduled. 

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Grade 4 
Mandatory: 
Permanently 
discontinue 
the 
subject from the study. 
Infusion-related reactions 
Grade 1 
Mild 
transient 
reaction; 
infusion 
interruption not indicated; intervention not 
indicated 
Continue 
study 
treatment 
and 
increase 
monitoring of vital signs as medically indicated 
until the participant is deemed medically stable 
in the opinion of the investigator.  
• Consider slowing infusion rate. 
 
Grade 2 Therapy or infusion interruption 
indicated 
but 
responds 
promptly 
to 
symptomatic 
treatment 
(e.g., 
antihistamines, 
NSAIDS, 
narcotics, 
IV 
fluids); prophylactic medications indicated 
for <=24 hrs. 
• Interrupt infusion and increase monitoring 
of vital signs as medically indicated until 
the participant is deemed medically stable 
in the opinion of the investigator.  
• Administer appropriate medical therapy (e.g. 
analgesics such as paracetamol 
/acetaminophen or NSAIDs and anti-
histamines), as per local institutional 
guidelines and clinical presentation. 
o Steroids will be used with caution 
unless clinically indicated (e.g. 
management of 
hypersensitivity/anaphylaxis). 
• If symptoms resolve, restart infusion per 
investigator discretion at a slower rate 
under (e.g. 50%) continuous observation. 
Ensure a minimum of 1-hour observation 
period prior to restarting the infusion. 
o Before restarting, administer 
premedication (e.g. analgesics such 
as paracetamol/acetaminophen or 
NSAIDs and anti-histamines within 1 
hour prior to dosing) as per local 
institutional guidelines for 
prophylaxis of infusion related 
reactions, including subsequent 
infusions. 
• In case of recurring infusion reactions 
despite premedication and prolonged 
infusion, consider discontinuation of study 
treatment.  
 
Grade 3 and 4 
Prolonged (e.g., not rapidly responsive to 
symptomatic 
medication 
and/or 
brief 
interruption of infusion); recurrence of 
symptoms following initial improvement; 
Mandatory: Permanently discontinue study 
treatment. 
If considered helpful, collect blood sample 
immediately after onset of the AE for further 
characterization of the IRR according with the  

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hospitalization 
indicated 
for 
clinical 
sequelae 
Life-threatening 
consequences; 
urgent 
intervention indicated 
local 
institutional 
guidelines, 
clinical 
presentation and  the responsible physician 
assessment 
General Note: Decision for dosing is made on prior lab results, not those from labs performed 
on the day of infusion. If lab results found to be abnormal, repeat (unscheduled) labs will be 
performed at least 1 week prior to scheduled dose in order to have results to show resolution of 
the abnormality before the scheduled dose is given 
a Common Toxicity Criteria for Adverse Events (CTCAE Version 5) 
b Core LFTs consist of ALT, AST, GGT, total bilirubin (fractionated [direct and indirect], LDH, 
albumin, creatinine kinase and ALP. 
c “Cholestasis” defined as ALP elevation (> 2.0 x ULN and R value < 2). Note: The R value is 
calculated by dividing the ALT by the ALP, using multiples of the ULN for both values. It denotes 
whether the relative pattern of ALT and/or ALP elevation is due to cholestasis(R ≤ 2), 
hepatocellular ( R ≥ 5), or mixed (R >2 and < 5) liver injury 
5.2.1 Follow-up for toxicities 
Subjects whose investigational treatment is interrupted or permanently discontinued due to an 
adverse event must be followed up at least once a week (or more frequently if required by 
institutional practices, or if clinically indicated) for 4 weeks, and subsequently at approximately 
4-week intervals, until resolution or stabilization of the event, whichever comes first. Appropriate 
clinical experts (e.g. ophthalmologist, endocrinologist, dermatologist, psychiatrists) will be 
consulted as deemed necessary. All subjects must be followed up for adverse events and 
serious adverse events for 105 days following the last doses of investigational treatment. 
Follow up on potential drug-induced liver injury (DILI) cases 
Subjects with an elevation of transaminases  in combination with an increase of  total bilirubin 
(TBIL) and a normal ALP  may be indicative of potential DILI, and will be considered as clinically 
important events. 
Subjects meeting the following criteria will require further follow-up as outlined below: 
• 
For subjects with normal ALT and Direct BIL value at baseline: ALT > 3.0 x ULN 
combined with Direct BIL > 2.0 x ULN without evidence of cholestasis 
• 
For subjects with elevated ALT or Direct BIL value at baseline: ALT > 2.0 x baseline 
AND Direct BIL > 2.0 x baseline 
• 
For subjects with normal ALT at baseline: ALT > 5.0 x ULN for more than 2 weeks 
• 
For subjects with elevated ALT at baseline: ALT >3.0 x baseline for more than 2 weeks 
For these patients, repeat LFTs as soon as possible, preferably within 48-72 hours. Patients will 
be closely monitored and workup for competing etiologies initiated, including hemolysis or 
cholestasis, defined as ALP elevation > 2.0 x ULN with R value < 2. 
Note: (The R value is calculated by dividing the ALT by the ALP (alkaline phosphatase), using 
multiples of the ULN for both values. It denotes whether the relative pattern of ALT and/or ALP 
elevation is due to cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R >2 and < 5) liver 
injury). 
In the absence of cholestasis or an alternative explanation, these subjects will be immediately 
discontinued from study treatment. The evaluation will include laboratory tests, detailed history, 
physical assessment and the possibility of liver metastasis or new liver lesions, 
obstructions/compressions as described below: 

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1. Laboratory tests will include ALT, AST, albumin, creatine kinase, total bilirubin, direct and 
indirect bilirubin, GGT, LDH, prothrombin time (PT)/INR and alkaline phosphatase. 
2. A detailed history, including relevant information, such as review of ethanol, concomitant 
medications, herbal remedies, supplement consumption, and history of any pre-existing liver 
conditions or risk factors, will be collected. 
3. Further local testing for acute hepatitis A, B, C or E infection and liver imaging (e.g. biliary 
tract) may be warranted. 
4. Obtain PK sample, as close as possible to last dose of study drug. 
5. Additional local testing for other hepatotropic viral infection (CMV, EBV or HSV), 
autoimmune hepatitis or liver biopsy may be considered as clinically indicated or after 
consultation with specialist/hepatologist. 
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified will be considered as “medically 
significant”, and thus, meet the definition of SAE and will be reported as SAE using the term 
“potential drug-induced liver injury." All events will be followed up with the outcome clearly 
documented. 
5.3 
Concomitant therapy 
 
All medications (other than crizanlizumab) and significant non-drug therapies (including physical 
therapy, and herbal/natural medications) administered during treatment will be noted in the 
patient’s medical record. 
Please refer to the below sections for information on permitted and prohibited medications and 
non-drug therapies. 
5.3.1 Permitted concomitant therapy  
 
Please refer to the IB.  
Aspirin, NSAIDs and prophylactic doses of anticoagulants are permitted, while other anti-
platelets agents or anticoagulants at doses targeting therapeutic levels are prohibited. 
Other approved medications for supportive care (antiemetics, anxiolytics, hypnotics, 
antihistamines) are permitted, including marinol. 
Infusion-related reactions have been reported in patients treated with crizanlizumab. 
Prophylactic pre-medication is permitted, and sites will follow local practice and guidelines for 
administration of monoclonal antibodies; pre-medications may be adjusted based on clinical 
presentation as deemed appropriate (e.g. for pain management). 
There is no existing clinical data on concomitant use of crizanlizumab and corticosteroids. For 
patients presenting for acute pain related to sickle cell disease, the 2020 guideline from 
American Society of Hematology suggests against corticosteroids for acute pain management.1 
If a participant experiences a grade 3 or grade 4 infusion related reaction, study drug will be 
discontinued. 
Vitamin and mineral supplements (e.g. fish oil, folic acid, L-arginine, L-citrulline, magnesium, 
riboflavin, vitamin C, vitamin D, vitamin E, and Zinc) are also permitted, though caution is 
advised when taking amounts exceeding 100% of the recommended daily allowance. 
5.3.2 Prohibited Medications 
 

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Participants should not take tocilizumab (Actemra®), etanercept (Enbrel®), adalimumab 
(Humira®), infliximab (Remicade®), rituximab (Rituxan®), abatacept (Orencia®), anakinra 
(Kineret®), certolizumab pegol (Cimzia®), golimumab (Simponi®), cyclosporine, tofacitinib 
(Xeljanz®), baricitinib (Olumiant®) or other immunosuppressive drugs while taking crizanlizumab. 
Taking crizanlizumab with these medicines may increase risk of infection. 
 
Please refer to the IB. 
As far as possible avoid co-administering drugs with a “Known”, “Possible”, or “Conditional” risk 
of Torsades de Pointes as per www.qtdrugs.org during the course of treatment: 
• If concomitant administration of drugs with a “Known risk of Torsades de Pointes” is required 
and cannot be avoided, crizanlizumab will be interrupted.  Treatment may only be resumed after 
5 half-lives (of the QT-prolonging drug) from last dose of the QT prolonging drug, and close 
ECG monitoring is advised. 
• If during the course of treatment, concomitant administration of a drug with ¨Possible risk¨ or 
¨Conditional risk of Torsades de Pointes¨ is required, based on the Treating Physician 
assessment and clinical need, treatment may be continued under close ECG monitoring to 
ensure patient safety. 
A list of drugs associated with QT prolongation and/or TdP is available online at 
www.qtdrugs.org 
The use of other investigational agents is prohibited during treatment of crizanlizumab. In 
addition, the administration of monoclonal antibodies other than crizanlizumab is prohibited, due 
to the theoretical potential for cross-reactivity and/or overlapping toxicities with other monoclonal 
antibodies. If investigational agents or other monoclonal antibodies have been used in the past, 
they must have been discontinued at least 30 days (or 5 half-lives of that agent, whichever is 
greater) prior to starting crizanlizumab treatment. 
Infusion-type reactions were rarely reported in prior studies with crizanlizumab, so prophylaxis 
for such reactions is not recommended. If a patient experiences severe infusion- related 
reaction, crizanlizumab will be discontinued and appropriate treatment provided. 
5.4 
Dose Forms, Strengths and Storage 
Crizanlizumab 10 mg/ml vials (100 mg per vial).  Drug will be stored in the appropriate 
conditions, similar to other biologic drugs administered to our patients.  
5.5 
Availability 
Crizanlizumab will be provided by Novartis.  
5.6 
Warnings and Precautions 
Crizanlizumab is not recommended for use during pregnancy or lactation and will not be given 
to pregnant or breastfeeding mothers, neonates, or children. Crizanlizumab administration will 
be avoided, where possible, to patients with acute infection  
5.6.1 Pregnancy Risks – Precautions and Restrictions 
It is not known conclusively what effects crizanlizumab has on human pregnancy or 
development of the embryo or fetus.  Therefore, female patients participating in this study 
should avoid becoming pregnant, and male patients should avoid impregnating a female 
partner.  Non-sterilized female patients of a reproductive age group should use effective 
methods of contraception through defined periods during and after study treatment as specified 
below: 
• 
Female patients must meet one of the following: postmenopausal or surgically 
sterile for at least 1 year before the screening visit, agree to practice two effective 
methods of contraception from the time of signing of the informed consent form through 

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90 days after the last dose of the study drug, or agree to practice true abstinence, when 
this is in line with the preferred and usual lifestyle of the subject.  (Periodic abstinence 
[e.g., calendar ovulation, symptothermal, post-ovulation methods] and withdrawal are not 
acceptable methods of contraception.) 
• 
If a patient is suspected to be pregnant, the study drug will be immediately 
discontinued.  In addition, a positive urine test must be confirmed by a serum pregnancy 
test.  If it is confirmed that the patient is not pregnant, the patient may resume dosing. 
 
 
 

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6.0 
VISIT SCHEDULE AND ASSESSMENTS 
 
Baseline1 
Week 1 
Week 3 
Week 5 
Week 7 and every 4 
weeks for up to 2 
years  
(7, 11, 15, etc.) 
Study  
Discontinuation 
Follow-up2 
Informed Consent 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Physical Exam3 
X 
 
 
 
X 
X 
X 
Retinal Exam4 
X 
 
 
 
X10 
X 
X 
SF-36 survey 
X 
 
 
 
X10 
X 
X 
Brain Magnetic Resonance 
Imaging (MRI)5 
X 
 
 
 
X10 
X 
X 
Cognitive Testing6 
X 
 
 
 
X10 
X 
X 
Complete Blood Count 
(CBC)7 
X 
 
 
X 
X11 
X 
 
Comprehensive Metabolic 
Panel (CMP)8 
X 
 
 
X 
X11 
X 
 
Infection Screening9 
X 
 
 
 
 
 
 
Crizanlizumab Administration 
 
X 
X 
- 
X 
 
 
Note: Crizanlizumab administration and all assessments allowed +/- 1-week window for scheduling issues.  
1. Within 30 days prior to initiating crizanlizumab 
2. Every 6 months following end of study visit for up to 2 years 
3. Including vital signs (BP, HR and temperature)  
4. Performed by Drs. M. Gilbert Grand, Rajendra Apte or P. Kumar Rao (See Appendix B) 
5. Performed by Dr. Andria Ford on HRPO 201509147 via Fluid-attenuated inversion recovery (FLAIR) MRI. MRI scans not dependent on participation in Dr. 
Ford’s study 
6. See Appendix A for list of assessments 
7. Including differential 
8. Sodium, potassium, chloride, bicarbonate, glucose, BUN, creatinine, calcium, total protein, albumin, total bilirubin, alkaline phosphatase, AST [SGOT], and 
ALT [SGPT] 
9. All patients will receive pre-screening to rule out infections (e.g., hepatitis B / C, HIV, tuberculosis, etc.) according to package insert for crizanlizumab 
10. Weeks 27, 51, and 75, and 999 only. Assessments may be +/- 2 weeks.  
11. Weeks 15, 27, 39. 51, 637, 759, 87, and 995 only. Assessments may be +/- 2 weeks.  

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7.0 
SAFETY MONITORING AND REPORTING 
In compliance with the University Institutional Data and Safety Monitoring Plan, the Principal 
Investigator will complete a Data and Safety Monitoring (DSM) report semi-annually beginning 
six months after accrual has opened (if at least five patients have been enrolled) or one year 
after accrual has opened (if fewer than five patients have been enrolled at the six-month mark). 
The Principal Investigator will review all patient data at least every six months, and complete a 
semi-annual report. This report will include: 
• 
HRPO protocol number, protocol title, Principal Investigator name, data coordinator 
name, regulatory coordinator name, and statistician 
• 
Date of initial HRPO approval, date of most recent consent HRPO approval/revision, 
date of HRPO expiration, date of most recent QA audit, study status, and phase of 
study 
• 
History of study including summary of substantive amendments; summary of accrual 
suspensions including start/stop dates and reason; and summary of protocol 
exceptions, error, or breach of confidentiality including start/stop dates and reason 
• 
Study-wide target accrual and study-wide actual accrual 
• 
Protocol activation date  
• 
Average rate of accrual observed in year 1, year 2, and subsequent years  
• 
Expected accrual end date and accrual by cohort 
• 
Objectives of protocol with supporting data and list the number of participants who 
have met each objective 
• 
Measures of efficacy  
• 
Early stopping rules with supporting data and list the number of participants who 
have met the early stopping rules 
• 
Summary of toxicities with the number of dose-limiting toxicities indicated 
• 
Abstract submissions/publications 
• 
Summary of any recent literature that may affect the safety or ethics of the study 
The study Principal Investigator and Research Patient Coordinator will monitor for serious 
toxicities on an ongoing basis. Once the Principal Investigator or Research Patient Coordinator 
becomes aware of an adverse event, the AE will be reported to the HRPO according to 
institutional guidelines. 
7.1 
Adverse Events (AEs) and Safety Reporting 
Definition: any unfavorable medical occurrence in a human subject including any 
abnormal sign, symptom, or disease. 
Grading: the descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for all 
toxicity reporting.  A copy of the CTCAE version 5.0 can be downloaded from the CTEP 
website: http://evs.nci.nih.gov/ftp1/CTCAE/About.html 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for the 
terms listed that should be used are those provided by the Department of Health and 
Human Services’ Office for Human Research Protections (OHRP).  A copy of this 
guidance can be found on OHRP’s website: 
http://www.hhs.gov/ohrp/policy/advevntguid.html 

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7.2 
Reporting to Novartis 
The following safety information must be reported to Novartis: 
7.2.1 Serious Adverse Events 
Any serious Adverse Events (SAEs), including the transmission of an infectious agent via a 
medicinal product, or reports of drug exposure during pregnancy or lactation (including initial 
and follow up reports) in patients exposed to the “Product” within 24 hours of becoming aware of 
it, including those which may have been the reason for the patient to discontinue treatment, 
Serious adverse event (SAE) is defined as one of the following: 
• Is fatal or life-threatening 
• Results in persistent or significant disability/incapacity 
• Constitutes a congenital anomaly/birth defect 
• Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
• Requires inpatient hospitalization or prolongation of existing hospitalization, 
• Note that hospitalizations for the following reasons will NOT be reported as serious 
adverse events: 
• Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes) 
• Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• Treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
Note that treatment on an emergency outpatient basis that does not result in hospital admission 
and involves an event not fulfilling any of the definitions of a SAE given above is not a serious 
adverse event 
To ensure patient safety, every SAE, regardless of causality assessment, occurring after the 
patient has provided informed consent and until 105 days after the patient has stopped 
participation to the MAP must be reported to Novartis within 24 hours of learning of its 
occurrence.  
Any SAEs experienced after this 105-day period will only be reported to Novartis if the Treating 
Physician or other involved health care professional suspects a causal relationship to the 
treatment with Crizanlizumab.  
Recurrent episodes, complications, or progression of the initial SAE must be reported as follow-
up to the original episode, regardless of when the event occurs. This report must be submitted 
within 24 hours of the Treating Physician or other involved health care professional receiving the 
follow-up information. An SAE that is considered completely unrelated to a previously reported 
one will be reported separately as a new event. 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form. The Treating Physician or other involved health care professional must assess the 
relationship to the treatment with crizanlizumab, complete the SAE Report Form and send the 
completed, signed form by fax within 24 hours. 

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The telephone and telefax number of the contact persons in the local Novartis Patient Safety, 
specific to the site, are listed in the Treating Physician or other involved health care health care 
professional folder provided to the site. The original copy of the SAE Report Form and the fax 
confirmation sheet must be kept with the case report form documentation at the site 
participating in this MAP. 
Follow-up information is sent to the same person to whom the original SAE Report Form was 
sent, using a new SAE Report Form stating that this is a follow-up to the previously reported 
SAE and giving the date of the original report. The follow-up information will describe whether 
the event has resolved or continues, if and how it was treated, whether the patient continued or 
withdrew from participation to this MAP. 
If the SAE is not previously documented in the Investigator’s Brochure a local Patient Safety 
Department associate or representative may urgently require further information from the 
Treating Physician or other involved health care professional for Health Authority reporting. 
7.2.2 Pregnancies 
 
To ensure patient safety, any occurrence of a pregnancy in a patient on treatment with 
Crizanlizumab must be reported to Novartis within 24 hours of learning of its occurrence. Any 
SAE experienced during pregnancy must be reported on the SAE Report Form. The pregnancy 
will be followed up to determine outcome, including spontaneous or voluntary termination, 
details of the birth, and the presence or absence of any birth defects, congenital abnormalities, 
or maternal and/or newborn complications. 
Pregnancy will be recorded on a Pregnancy Form and reported by the Treating Physician or 
other involved health care professional to the local Novartis Patient Safety Department. In case 
of any congenital abnormality, birth defect or maternal and newborn complications, the possible 
relationship to Crizanlizumab will be reported. 
Pregnancy outcomes must be collected for the female partners of any males who were treated 
with Crizanlizumab. Consent to report information regarding these pregnancy outcomes will be 
obtained from the mother. 
7.2.3 Non-Serious Adverse Events 
 
Any non-serious Adverse Events (AEs) (including initial and follow up reports) in patients 
exposed to the “Product” twice annually through AE reconciliations, including those which may 
have been the reason for the patient to discontinue treatment. 
7.2.4 Other Relevant Safety Information 
 
Any other relevant safety information on the list below, in patients exposed to the “Product”, 
including initial and follow up reports twice annually: 
• lack of efficacy (with or without clinical symptoms), 
• overdose (with or without clinical symptoms), 
• withdrawal reactions and rebound effects (with or without clinical symptoms), 
• intentional drug misuse/ abuse (with or without clinical symptoms), 
• drug dependence/addiction (with or without clinical symptoms), 
• medication errors (including maladministration, dispensing or prescribing errors) (with 
or without clinical symptoms),  
• drug-drug or drug-food interaction (with or without clinical symptoms), 

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• disease progression and aggravation (with or without clinical symptoms),  
• unexpected beneficial effects and 
• treatment non-compliance with clinical symptoms. 
7.3 
Unanticipated Problems 
Definition: 
• 
Unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the subject 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 subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized. 
7.4 
Noncompliance 
Definition: failure to follow any applicable regulation or institutional policies that govern 
human subjects research or failure to follow the determinations of the IRB.  
Noncompliance may occur due to lack of knowledge or due to deliberate choice to 
ignore regulations, institutional policies, or determinations of the IRB. 
7.5 
Serious Noncompliance 
Definition: noncompliance that materially increases risks, that results in substantial 
harm to subjects or others, or that materially compromises the rights or welfare of 
participants. 
7.6 
Protocol Exceptions 
Definition: A planned deviation from the approved protocol that are under the research 
team’s control. Exceptions apply only to a single participant or a singular situation. 
Pre-approval of all protocol exceptions must be obtained prior to the event.  
7.7 
Reporting to the Human Research Protection Office (HRPO)  
The PI is required to promptly notify the IRB of the following events: 
• 
Any unanticipated problems involving risks to participants or others which 
occur at any WU, BJH or SLCH institution, or that impacts participants or the 
conduct of the study. 
• 
Noncompliance 
with 
federal 
regulations 
or 
the 
requirements 
or 
determinations of the IRB. 
• 
Receipt of new information that may impact the willingness of participants to 
participate or continue participation in the research study. 
These events must be reported to the IRB within 10 working days of the occurrence of 
the event or notification to the PI of the event.  The death of a research participant that 
qualifies as a reportable event will be reported within 1 working day of the occurrence 
of the event or notification to the PI of the event. 
7.8 
Reporting to the FDA 
The conduct of the study will comply with all FDA safety reporting requirements.  

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PLEASE NOTE THAT REPORTING REQUIREMENTS FOR THE FDA DIFFER FROM 
REPORTING REQUIREMENTS FOR HRPO.  It is the responsibility of the investigator to 
report any unanticipated problem to the FDA as follows: 
• 
Report any unexpected fatal or life-threatening adverse experiences associated 
with use of the drug (i.e., there is a reasonable possibility that the experience 
may have been caused by the drug) by telephone or fax no later than 7 calendar 
days after initial receipt of the information.  A life-threatening adverse experience 
is defined as any adverse drug experience that places the subject (in the view of 
the investigator) at immediate risk of death from the reaction as it occurred, i.e., it 
does not include a reaction that, had it occurred in a more severe form, might 
have caused death. 
• 
Report any serious, unexpected adverse experiences, as well as results from 
animal studies that suggest significant clinical risk within 15 calendar days after 
initial receipt of this information.  A serious adverse drug experience is defined as 
any adverse drug experience occurring at any dose that results in any of the 
following outcomes: 
o Death 
o A life-threatening adverse drug experience 
o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant disability/incapacity (i.e., a substantial 
disruption of a person’s ability to conduct normal life functions) 
o Any other experience which, based upon appropriate medical judgment, 
may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above 
An unexpected adverse drug experience is defined as any adverse drug 
experience, the specificity or severity of which is not consistent with the current 
investigator brochure (or risk information, if an IB is not required or available). 
All MedWatch forms will be sent by the investigator or investigator’s team to the FDA at 
the following address or by fax:  
Food and Drug Administration 
Center for Drug Evaluation and Research 
Division of Pulmonary, Allergy and Rheumatology Products 
5901-B Ammendale Rd. 
Beltsville, MD 20705-1266 
FAX: 301-796-9728 
7.9 
Timeframe for Reporting Required Events  
Reportable adverse events will be collected from first dose of study treatment through 28 
days following the last study treatment. 
 
 
 
 
 

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8.0 
DATA SUBMISSION SCHEDULE 
Case report forms with appropriate source documentation will be completed according to the 
schedule listed in this section. 
Case Report Form 
Submission Schedule 
Original Consent Form 
Prior to Registration 
Registration Form 
Eligibility Form 
On-Study Form 
Medical History Form 
Baseline 
Safety Labs Form (CBC & CMP) 
Baseline 
Within 30 days of initiating   
crizanlizumab 
Every 3 months, with labs 
reviewed prior to infusions  
End of Study 
SF-36 Survey 
Baseline 
Every 6 months 
End of Study 
Each Follow-Up 
Response Assessment Form 
(Imaging, Clinical, & Retinal)  
Baseline 
Every 6 months 
End of Study 
Each Follow-Up 
Adverse Events Form 
Ongoing 
 
 
 
 
 

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10.0 
STATISTICAL METHODS AND DATA ANALYSIS 
This is a Phase II trial evaluating the safety, tolerability, and efficacy of crizanlizumab for the 
treatment of RVCL. A maximum of 20 patients will be enrolled.  
Primary Endpoint Statistical analysis: The primary endpoint is rate of progression in cerebral 
lesions as assessed by FLAIR MRI. The rate of progression (calculated in percentage) can be 
variable across patients but we estimate it to be ~15% per year on average. The analysis will be 
a pre-post intervention comparison of the rate (number of new or worsened lesions) measured 
the year after initiation of crizanlizumab compared to the year (+/- 3 months) prior to initiation. A 
Wilcoxon signed rank test will test the hypothesis that rate of progression is decreased post 
crizanlizumab intervention. For those who the pre- evaluation is not within +/- 4 weeks of the 
one-year mark, the actual rate in the pre-treatment period will be used to estimate the one-year 
rate assuming that progression occurs in a linear fashion. Only patients with pre- and post- 
evaluations available will be considered evaluable for the primary endpoint. Those not evaluable 
for the primary analysis will still be enrolled and followed on protocol for all other analyses.  
Primary Endpoint Power analysis:  Based on the uncertainty of the proportion of patients 
enrolled who will be evaluable, definitive power analyses are not feasible. Therefore, sample 
power calculations were performed a range of possibilities. Assuming the average rate of 
progression in the year prior to initiation of crizanlizumab is ~15%, we estimate that the effect 
size the corresponds with a 50% rate reduction (from 15% to 7.5%, for example) is ~0.5 - ~1 
based on interpatient variation. A sample size of 20 patients evaluable for the primary endpoint 
will allow us to detect an effect size of >0.6 with 80% power at one-sided 0.05 alpha. A sample 
size of 10 evaluable patients will allow us to detect an effect size >0.9. This study is designed to 
generate preliminary data rather than confirm hypotheses and, thus, not definitively powering 
the study is acceptable.  
 

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Secondary endpoint analyses include: 
1) Rate of progression in white matter atrophy two years after initiation of crizanlizumab 
compared to one year prior to initiation of crizanlizumab.  Statistical analysis: a Wilcoxon 
signed rank test (matched pairs pre-post intervention) will test the hypothesis that rate of 
progression is decreased two years post crizanlizumab initiation compared to one-year 
pre crizanlizumab initiation. 
2) Rate of progression in retinal lesions development two years after initiation of 
crizanlizumab compared to one year prior to initiation of crizanlizumab.  Statistical 
analysis: a Wilcoxon signed rank test (matched pairs pre-post intervention) will test the 
hypothesis that rate of progression is decreased two years post crizanlizumab initiation 
compared to one-year pre crizanlizumab initiation. 
3) Rate of progression in cognitive decline two years after initiation of crizanlizumab 
compared to one-year prior to initiation of crizanlizumab. Statistical analysis: a Wilcoxon 
signed rank test (matched pairs pre-post intervention) will test the hypothesis that rate of 
progression is decreased two years post crizanlizumab initiation compared to one-year 
pre crizanlizumab initiation. 
4) Safety of crizanlizumab will be measured by serious and non-serious adverse events 
deemed by the study PI to be related to crizanlizumab treatment in any participants. 
Statistical analysis: Descriptive  
5) Tolerability of crizanlizumab measured by dose-lowering and/or discontinuation of 
crizanlizumab for each participant throughout the duration of the study. Statistical 
analysis: Descriptive 
6) Quality of life while receiving crizanlizumab will be assessed by SF-36 score. Statistical 
analysis: Descriptive 
 
 

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12.0    REFERENCES 
1. Retinal Vasculopathy with Cerebral Leukoencephalopathy (RVCL). (2013). NIMBL. 
http://www.nimbl.eu/ni/Home. Accessed 10/9/2013. 
2. Kavanagh, D., et al. (2008) New roles for the major human 3'–5' exonuclease TREX1 in 
human disease. Cell Cycle; 7(12):1718-1725.  
3. Hassan, M, et al. (2015). Cytosolic nuclease TREX1 regulates oligosaccharyltransferase 
activity independent of nuclease activity to suppress Immune activation.  Immunity; 43: 
463-474. 
4. Wood KC, Hebbel RP, Granger DN. Endothelial cell P-selectin mediates a 
proinflammatory and prothrombogenic phenotype in cerebral venules of sickle cell 
transgenic mice. American journal of physiology Heart and circulatory physiology 2004; 
286:H1608-14. 
5. McEver RP, Cummings RD. Role of PSGL-1 binding to selectins in leukocyte 
recruitment. The Journal of Clinical Investigation 1997;100:S97-103. 
 
 

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Appendix A: Cognitive Testing   
The following assessments will be performed: 
• 
Montreal Cognitive Assessment Test (MoCA) score 
• 
Free and Cued Selective Reminding (FCSRT) memory test 
• 
Coding Symbol Test 
• 
Verbal fluency 
• 
Gait speed 
• 
Neurological exam 
• 
Barthel Index of Activities of Daily Living (ADLs) 
• 
Geriatric depression scale 
• 
State-Trait Anxiety scale 
 
 

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Appendix B: Retinal Exam 
Specific retinal findings typical of RVCL include microaneurysms, cotton wool spots, capillary 
drop out, proliferative retinopathy and pre-retinal hemorrhage. The tests below will be done at 
baseline, and every sixth months of treatment to assess RCVL.  
 
• 
Examination including: Snellen, acuity, slit lamp, fundus biomicroscopy, and indirect 
ophthalmoscopy of the fundus 
• 
Standard Digital Retinal photographs of both eyes as per the ETDRS protocol or Wide-
field color photographs with corresponding angiographic image protocol 
• 
Fluorescein angiography of the retinal circulation including wide-field angiography 
• 
High Resolution OCT scans of the macula