CASH (Cavernous Angiomas With Symptomatic Hemorrhage) Trial Readiness
Conditions: CCM, Cavernoma, Cerebral Cavernous Malformation, Cerebral Cavernous Malformations 1, Cerebral Cavernous Malformations 2, Cerebral Cavernous Malformations 3, Cavernous Angioma
Sponsor: University of Chicago

Trial Readiness in Cavernous Angiomas with Symptomatic Hemorrhage (CASH) 
Protocol 
Version 1.5 
14-October-2020 
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Trial Readiness in Cavernous Angioma with Symptomatic 
Hemorrhage (CASH) 
 
 
 
 
NCT03652181 
 
 
 
 
 
 
 
 
Protocol 
October 14, 2020 (IRB approved November 13, 
2020) 
 
 
 
 
Version 1.5 
 

Trial Readiness in Cavernous Angiomas with Symptomatic Hemorrhage (CASH) 
Protocol 
Version 1.5 
14-October-2020 
NIH-FDA Clinical Trial Protocol Template – v1.0 5 Apr 2017 
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Trial Readiness in Cavernous Angiomas with 
Symptomatic Hemorrhage (CASH) 
Principal Investigator: Dr. Issam Awad, Dr. Kelly Flemming, Dr. Helen Kim 
Funded by: NINDS 
Protocol Version Number: 1.5 
10-October-2020 

Trial Readiness in Cavernous Angiomas with Symptomatic Hemorrhage (CASH) 
Protocol 
Version 1.5 
14-October-2020 
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Table of Contents 
Statement of Compliance .............................................................................................................................................. 3 
1 Protocol Summary .................................................................................................................................................... 4 
1.1 Synopsis ............................................................................................................................................................. 4 
1.2 Schema .............................................................................................................................................................. 5 
1.3 Schedule of Activities (SoA) ............................................................................................................................... 5 
2 Introduction .............................................................................................................................................................. 7 
2.1 Study Rationale ................................................................................................................................................. 7 
2.2 Background ....................................................................................................................................................... 8 
2.3 Risk/Benefit Assessment ................................................................................................................................. 10 
3 Objectives and Endpoints ....................................................................................................................................... 12 
4 Study Design ........................................................................................................................................................... 13 
4.1 Overall Design ................................................................................................................................................. 13 
4.2 Scientific Rationale for Study Design ............................................................................................................... 13 
4.3 End of Study Definition.................................................................................................................................... 16 
5.1 Inclusion Criteria.............................................................................................................................................. 17 
5.2 Exclusion Criteria ............................................................................................................................................. 17 
5.4 Screen Failures ................................................................................................................................................... 17 
6 Study Intervention .................................................................................................................................................. 18 
7 Study Intervention Discontinuation and Participant Discontinuation/Withdrawal ................................................ 19 
7.1 Participant Discontinuation/Withdrawal from the Study ............................................................................... 19 
7.2 Lost to Follow-Up ............................................................................................................................................ 19 
8 Study Assessments and Procedures ....................................................................................................................... 20 
9 Statistical Considerations ........................................................................................................................................ 21 
9.1 Statistical Hypotheses AND PROPOSED ANALYSES ......................................................................................... 21 
9.2 Sample Size Determination ............................................................................................................................. 22 
9.3 Populations for Analyses ................................................................................................................................. 23 
9.4 Statistical Analyses .......................................................................................................................................... 24 
9.4.1 General Approach  ...................................................................................................................................... 24 
9.4.2 Sub-Group Analyses  ................................................................................................................................... 26 
10 Supporting Documentation and Operational Considerations .............................................................................. 27 
10.1 Regulatory, Ethical, and Study Oversight Considerations ............................................................................. 27 
10.1.1 Informed Consent Process  ....................................................................................................................... 27 
10.1.2 Study Discontinuation and Closure  .......................................................................................................... 27 
10.1.3 Confidentiality and Privacy  ....................................................................................................................... 28 
10.1.4 Future Use of Stored Data  ........................................................................................................................ 29 
10.1.5 Key Roles and Study Governance  ............................................................................................................. 30 
10.1.6 Quality Assurance and Quality Control  ..................................................................................................... 31 
10.1.7 Data Handling and Record Keeping  .......................................................................................................... 31 
10.1.8 Protocol Deviations  .................................................................................................................................. 32 
10.1.9 Publication and Data Sharing Policy  ......................................................................................................... 33 
10.2 Abbreviations ................................................................................................................................................ 33 
11 References ............................................................................................................................................................ 35 

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STATEMENT OF COMPLIANCE 
 
 
The trial will be carried out in accordance with the following: 
 
 
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 46, 
21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812) 
 
 
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are responsible for 
the conduct, management, or oversight of NIH-funded clinical trials have completed Human Subjects 
Protection Training. 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the Institutional Review Board (IRB) for review and approval. Approval of both the protocol 
and the consent form must be obtained before any participant is enrolled. Any amendment to the 
protocol will require review and approval by the IRB before the changes are implemented to the study. In 
addition, all changes to the consent form will be IRB-approved; a determination will be made regarding 
whether a new consent needs to be obtained from participants who provided consent, using a previously 
approved consent form. 

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1 PROTOCOL SUMMARY 
 
 
1.1 SYNOPSIS 
 
 
 
Title: 
Trial Readiness in Cavernous Angiomas with Symptomatic Hemorrhage 
Study Description: 
This U01 project will address gaps in knowledge and barriers to clinical trial 
readiness in cerebral cavernous angioma patients with recent symptomatic 
hemorrhage (CASH) 
Objectives: 
Primary Objectives: 
1. To assess enrollment rates, harmonize data and determine baseline 
characteristics of patients with CASH across sites 
2. MRI Biomarker Validations 
3. Rate of recurrent symptomatic hemorrhage over 2 years in patients 
with CASH. 
Secondary Objectives: Functional status of CASH cases at enrollment and 
during follow-up; impact of bleed on functional status 
Endpoints: 
Primary Endpoint (Aim 3): 
• Recurrent bleeding during follow-up, homogeneity in years 1 and 2 
Secondary Endpoints (Aim 3): 
• 
Biomarker changes during follow-up, homogeneity in years 1 and 2 
• 
Functional status and quality of life change in years 1 and 2 compared 
to baseline 
Study Population: 
Adult patients with cerebral cavernous malformations (CCMs) who have 
had a symptomatic hemorrhage within the prior year, where the bleeding 
lesion has not been excised or radiated 
Phase: 
Trial readiness 
Description of 
Sites/Facilities Enrolling 
Participants: 
Seven high volume cavernous angioma clinical centers 
University of Chicago, Mayo Clinic, University of Utah, University of New 
Mexico, Barrow Neurological Institute and University of San Francisco  and 
Johns Hopkins University.  Additional sites may be added as needed to 
reach enrollment goals. 
Description of Study 
Intervention: 
This is an observational cohort study of CASH cases with no intervention. 
Study Duration: 
The study will last 5 years. 
Participant Duration: 
Patients enrolled in the Screening and Clinical Assessment (SCA) arm will 
have a  single,  baseline  visit.   Patients  enrolled  in  the  Follow-up  and 

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Biomarker Validation (FUBV) arm will have a baseline visit, along with two 
yearly follow-up visits, for a total of 3 visits. This is an observational study 
and all study visits can be completed remotely via telephone and/or 
telemedicine platforms.   
In order to minimize the need for research-only in-person visits, 
telemedicine visits may be substituted for in person clinical trial visits or 
portions of clinical trial visits where determined to be appropriate and 
where determined by the investigator not to increase the participants 
risks. Prior to initiating telemedicine for study visits the study team will 
explain to the participant, what a telemedicine visit entails and confirm 
that the study participant is in agreement and able to proceed with this 
method. Telemedicine acknowledgement will be obtained in accordance 
with the Guidance for Use of Telemedicine in Research. In the event 
telemedicine is not deemed feasible, the study visit will proceed as an in-
person visit. Telemedicine visits will be conducted using HIPAA compliant 
method approved by the Health System and within licensing restrictions 
 
 
 
 
1.2 SCHEMA 
 
 
 
Timeline of study visit and procedures 
performed. 
Baseline 
1 year 
(12 months ± 
1 month)* 
2 year 
(24 months ± 
1 month)* 
Type of Visit 
In Person/Remote 
In Person/Remote 
In Person/Remote 
Informed Consent 
X 
Baseline clinical and radiographic data 
X 
Verify clinical features (timing of prior SH, 
X 
X 
X 
mRS score assessment 
X 
X 
X 
EQ-5D questionnaire 
X 
X 
X 
PROMIS29 
X 
X 
X 
NIH stroke scale 
X 
X 
X 
QSM/DCEQP MRI sequences* 
X 
X 
X 
MRI standard sequences* 
X 
X 
X 
(*) to be performed on subset of cases in the FUBV arm 
 
 
 
 
1.3 SCHEDULE OF ACTIVITIES (SOA) 
 
 
 
Procedures 
Screening 
Enrollment/baselin
e 
1 year 
(12 months ± 1 
month)* 
2 year 
(24 months ± 1 
month)* 

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Type of Visit 
In Person/Remote In Person / Remote In Person/Remote In Person/Remote 
Informed consent 
X 
Demographics 
X 
Medical history 
X 
Verify  clinical  and  
radiographic  data 
X 
X 
X 
Physical exam 
X 
X 
X 
Vital signs 
X 
X 
X 
Height 
X 
X 
X 
Weight 
X 
X 
X 
mRS score assessment 
X 
X 
X 

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EQ-5D questionnaire 
X 
X 
X 
PROMIS29 
X 
X 
X 
NIH Stroke Scale 
X 
X 
X 
QSM/DCEQP MRI sequences* 
X 
X 
X 
MRI standard sequences* 
X 
X 
X 
 
(*) to be performed on subset of cases in the FUBV arm 
 
 
For this trial, some sites will recruit subjects for the SCA arm only while other sites recruit subjects for 
the FUBV arm. Subjects who are screened for the FUBV arm and do not qualify, will be screened and 
offered potential enrollment in the SCA study arm, if applicable. 
 
 
Subjects enrolled in the SCA arm will have one visit only: the baseline visit.  It is anticipated the visit will 
last less than an hour and include consenting, medical and radiographic history review, a physical, vitals 
and neurological assessments. The visit information and neurological assessments will be completed via 
interview with the site coordinator who will enter the data into the electronic case report forms. 
Subjects enrolled in the SCA arm will not have a standard MRI done at the baseline visit. Instead, data 
will be collected from their latest MRI scan, from which the CASH lesion was identified. 
 
 
Subjects enrolled in FUBV arm will have three study visits: Baseline, Year 1 and Year 2.  It is anticipated 
that each visit will last about 2 hours. The visits will include consenting (Baseline only), medical and 
radiographic history review, a physical, vitals and neurological assessments. The visit information and 
neurological assessments will be completed via interview either in person or via telephone with the site 
coordinator who will enter the data into the electronic case report forms.  Subjects will have a standard 
MRI with additional research sequences. M R I  w i t h  t h e  a d d i t i o n a l  r e s e a r c h  
s e q u e n c e s  w i l l  b e  c o m p l e t e d  w h e n  t h e  p a r t i c i p a n t  h a s  a  r e g u l a r l y  
s c h e d u l e d  s t a n d a r d  o f  c a r e  a p p o i n t m e n t . The MRI sequences include T1, T2, 
SWI/VenBold, and post-contrast scans.  The research MRI sequences are QSM and DCEQP sequences. 
No additional gadolinium is required for the additional research sequences. 
 
 
Subjects will not be compensated for their participation. A large percentage of subjects will be coming in as 
part of their clinical care and we do not anticipate special costs for subjects for these visits.  To promote 
retention and follow up visit compliance, subjects enrolling in the FUBV arm will receive travel 
reimbursement for each of the 3 study visits.   
 
 
Data elements to be collected include: the subject’s age, gender, race and disease-related history. We 
will also collect information about their clinical MRI scans, including the number of lesions seen on the 
scan, as well as, (for FUBV subjects,) the MRI QSM and permeability values, calculated during post- 
processing. This data will be shared with the DCC.  Any personal identifiers, including the subject’s 
name, date of birth, and medical record number, will be held locally, separately from the study file, in 
locked cabinets in private offices per institutional guidelines. 

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Trial Readiness in Cavernous Angiomas with Symptomatic Hemorrhage (CASH) 
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2 INTRODUCTION 
 
 
2.1 STUDY RATIONALE 
 
There are fewer than 200,000 cases of brain cavernous angiomas (CA) in North America today 
who have suffered a symptomatic hemorrhage (SH). Cavernous angiomas with symptomatic hemorrhage 
(CASH) are most likely to re-bleed and cause further neurologic sequelae. Among these are smaller 
cohorts of CASH with different genotypes, lesion locations, or other characteristics portending variable 
disease severity or prospective risk. Surgical resection of CASH is associated with substantial morbidity 
and cost, particularly in deep and brainstem lesions, which are also more likely to bleed, and cause serious 
disability. It would be desirable to develop a drug that stabilizes CASH, and prevent recurrent bleeding. 
CASH with recent bleed, where surgical resection is not undertaken, are the most likely cases to be 
followed expectantly per current evidence based guidelines, with clinical equipoise for testing novel 
therapies to prevent re-bleeding. 
 
 
Candidate Therapeutics Under Development. Several candidate therapeutics have emerged in 
recent years, aimed at targeting signaling aberrations related to the loss of CCM gene function, and 
associated vascular permeability, angiogenic activity and inflammatory response. Several drugs have 
already been shown to prevent lesion development or hemorrhage in preclinical experiments meeting 
the most stringent NINDS criteria of rigor and  objectivity.  Novel  agents are being  pursued  by the 
pharmaceutical industry specifically for this disease, and are currently at various stages of development. 
Other drugs in current clinical use for other applications are being explored for proof of concept effect, 
with the aim of potential repurposing. All these candidate drugs will ultimately require dose optimization 
and testing of safety and efficacy in multi-site clinical trials. 
 
 
Opportunities in Clinical Research. Much progress has been made in understanding the 
epidemiology and natural history of CAs, and several outcome assessment tools have been proposed, 
including an adjudicated definition of SH during clinical follow-up. Advanced magnetic resonance imaging 
techniques have applied dynamic contrast enhanced quantitative perfusion (DCEQP) and quantitative 
susceptibility mapping (QSM) to measure vascular leak and lesional iron content in CAs, and these have 
been linked to clinical activity in longitudinal follow-up, holding promise as sensitive biomarkers of lesional 
hemorrhage. There is a strong collaborative culture among major researchers in this disease, catalyzed by 
a very engaged patient advocacy and support group, the Angioma Alliance. 
 
 
Gaps in Trial Readiness. Established CA research databases have not considered CASH specifically. 
The ability to screen and enroll cases with CASH, particularly those whose lesion has not been resected, 
has never been assessed at multiple sites, nor the spectrum of their baseline characteristics, including 
time from SH, hemorrhagic lesion location, disability status, and demographic features such as gender. 
Quality of life (QOL) has never been systematically evaluated in CAs, and it is unclear what functional 
status instruments best capture the clinical impact of CASH. Biomarkers of vascular permeability and iron 
leak in CAs have never been deployed or validated at multiple sites using uniform protocols. These and 

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clinical outcomes instruments have not been harmonized, nor evaluated for their relative sensitivity and 
reliability, yet are essential to the planning of needed clinical trials. Without this information, clinical trials 
could use false assumptions and likely fail. 
 
 
In response to these gaps in trial readiness, we propose Specific Aim 1 to harmonize data entry, 
and to assess detection rates and baseline characteristics of CASH cases at multiple sites with high volume 
and clinical interest in CAs. Specific Aim 2 shall deploy rigorous tests of feasibility, accuracy, precision and 
reproducibility of biomarker measurements at multiple sites, critical to their potential application as 
surrogate outcomes in clinical trials. Specific Aim 3 shall assess rates of clinical events versus changes in 
biomarkers and functional status/QOL measures during prospective follow-up. Leading CA research 
teams have been assembled with expertise in the questions being tackled, including rigorous statistical 
approaches, sample size estimates, and a data coordinating center with a proven record in trial planning 
and execution. An Executive Committee with broad expertise will advise and make suggestions regarding 
trial design, data capture and collection as a collaborative effort with NINDS. They will offer suggestions 
prior to and during the progress of each aim, propose revisions, help us interpret emerging results, and 
ultimately approve and prioritize workable trial models. There is no DSMB for this non-interventional 
trial. 
 
 
Specific milestones are proposed and go/no-go decisions based on interim analyses and results of 
these aims. Data from this project will insure the most stringent rigor in trial assumptions, including 
validated detection rates and baseline features specific to CASH. We will endorse or reject outcome 
instruments or biomarkers based on empiric observations, hypothesizing a clinically meaningful impact of 
putative therapies. And we will determine the sample size, cogent stratification for relevant subgroups, 
length of follow-up, and the number of sites needed to test trial hypotheses. Corollary goals are to ready 
pilot sites with expertise in these facets of disease evaluation and follow-up, to be deployed and emulated 
in prospective clinical trials. Other goals are to complete preparatory and regulatory milestones needed 
before launching actual trials, and to assemble research core teams who would oversee and manage 
prospective trials. Such a comprehensive project has never been undertaken in this disease. The timing 
cannot be more opportune, with therapeutic targets identified, unmatched collaboration among 
stakeholders, and several drugs ready to benefit from the proposed trial readiness. 
 
 
 
 
2.2 BACKGROUND 
 
Cavernous Angioma: A Common Lesion, an Uncommon Disease. Cavernous angioma (CA) of the 
brain is also referred to in the literature as cerebral cavernous malformation (CCM), hemangioma or 
cavernoma. The lesion consists of clustered, giant, blood-filled capillary spaces (“caverns”), lined by 
endothelium, and separated by an amorphous matrix lacking mature vessel wall angioarchitecture1. CA 
occurs in a sporadic form, manifesting a solitary lesion or a cluster of lesions associated with a venous 
developmental anomaly2. The disease is familial in 20-30% of cases, associated with multiple lesions that 
develop over time throughout the patient’s   brain3. The familial form (OMIM #116860; 

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http://omim.org/entry/116860) exhibits a Mendelian autosomal dominant inheritance due to a 
heterozygous loss-of-function mutation in one of 3 genes (CCM1/KRIT1, CCM2/Malcavernin, and 
CCM3/PDCD10)4-10. Multiple cavernomas may also develop after cranial irradiation. Magnetic resonance 
imaging (MRI) is the hallmark diagnostic modality for these lesions, including sequences revealing chronic 
and acute hemorrhage, and tiny occult lesions. CAs are histologically identical in familial and sporadic 
cases, and harbor somatic mutations in the same three genes11-13. 
 
 
CAs are often detected incidentally, or in association with seizures or non-specific symptoms14-16. 
The natural history of such lesions is exceedingly benign, with <0.5% annual risk of clinically significant 
hemorrhage, and there is consensus about these cases not needing interventions beyond symptom 
management and surveillance17. But once a lesion has manifested a symptomatic hemorrhage (SH), its 
untreated clinical course is quite serious, with a 42% (CI 27-58) rate of recurrent bleeding or focal 
neurologic deficit within 5 years17-19. CASH is hence a singular clinical entity, distinguishing lesions with a 
unique risk profile, impacting a patient’s life and meriting clinical intervention. The adjudicated definition 
of CASH20 requires diagnostic evidence of new lesional bleeding or hemorrhagic growth, in association 
with directly attributable symptoms. 
 
 
Lesions in the brainstem and deep brain locations are more likely than other CAs to bleed21, 
rebleed18, and cause severe disability19, 22. It is unclear if this greater propensity to SH simply reflects the 
clinical impact of bleeds in those locations, while lesions in less eloquent brain regions may bleed at similar 
rates but more likely without symptoms. Per current clinical practice and evidence-based guidelines, CAs 
are typically observed expectantly, and surgically excised only after significant clinical sequelae (typically 
one or more hemorrhagic strokes) particularly in deep or brainstem locations17, 23. Healthcare costs of 
hemorrhagic stroke can reach up to $27,400/case in the first 90 days (2007 dollars), excluding 
socioeconomic impact of lost productivity24. 
 
 
While brain surgery for lesion excision may benefit some patients, it can be associated with 
significant cost and morbidity. It is expensive, with a typical craniotomy costing $37,438 in 2011 dollars25, 
excluding the cost of complications. More concerning are complications and morbidity with CA surgical 
excision, particularly with brainstem lesions, associated with a particularly alarming rate of surgical 
adverse events23. In a non-randomized population-based cohort study, lesion excision was associated with 
significantly worse functional outcomes and greater complications compared to conservative 
management23. Stereotactic radiosurgery has been proposed but there is controversy about its 
effectiveness and concern about complications and radiation-induced genesis of new CAs26, 27. 
 
 
The rates of development of new lesions, and of first SH in asymptomatic CAs, are far too low to 
allow meaningful testing or to compel primary prevention strategies for CASH. Cases with recent SH, 
where surgical resection is not undertaken (mostly in deep and brainstem locations), are the most likely 
to be followed expectantly per current evidence based guidelines17, with clinical equipoise for testing 
novel therapies aimed at preventing re-bleeding. It would be desirable to develop a drug that stabilizes 
CASH, and prevent recurrent bleeding. It would mitigate neurologic sequelae of re-bleeds and the 
complications of surgical resection in many patients. Based on current knowledge of natural history, the 

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likelihood of therapeutic benefit for secondary prevention (symptomatic re-bleed) would be greatest 
within 2-3 years after a SH17-19. 
 
 
 
 
 
2.3 RISK/BENEFIT ASSESSMENT 
 
This is an observational cohort study with no planned intervention. 
 
 
Risks to participants of this study are minimal and include loss of privacy and confidentiality, and 
risks associated with MRI and intravenous gadolinium administration. To minimize risk to 
participants, follow up visits have the option of being done remotely.  Visits that require 
MRI scans, the scans will be completed during the participants standard of care visit.  
Protection against these minimal risks shall be insured by each site’s PI and the project’s central 
institutional review board (cIRB). 
 
 
Protection against loss of privacy and confidentiality. The main risk to study participants is loss of 
privacy, which is minimized through utilization of sound confidentiality procedures. All study personnel 
will undergo certification on the protection of human subjects, currently through CITI, as well as HIPAA 
certification. All study records will be kept locally in locked files in private offices. Electronic files will be 
kept on secured drives managed at each institution, with access limited to key study personnel. All study 
data will be entered on a secure, password-protected database managed by the Data Coordinating Center 
at Johns Hopkins University. 
Reasons for exclusion for screened patients not enrolled into the trial will be recorded. Each 
participating site will enter screening data into the trial’s EDC system for review of screening and eligibility 
performance. Data to be collected for screen failed patients will include, age (numerical), gender, race, 
type of disease (sporadic or familial), and reason for exclusion from the study. Once all fields are 
completed, or an inclusion/exclusion criterion is failed, the system will either document the subject as a 
screen failure or prompt the coordinator to enroll the eligible subject. Ineligible patients will be assigned 
a unique screening number with no protected health information (e.g., name, medical record number, 
date of birth, etc.) stored in the system. Following written informed consent each enrolled subject is then 
assigned a unique study number, which contains a unique site number, by the EDC for data collection 
purposes. A list of enrolled subjects including identifiable information (name, medical record number, 
contact information, etc.) mapped to unique study number, along with signed consent forms, will be 
maintained in a secure location by local study personnel at the site, outside of the EDC, for local tracking 
purposes. Data analyzed on enrolled cases in Aims 1-3 shall be conducted without any access to any 
information about subject identity. 
Because patients being studied already carry the diagnosis of CA, we do not believe that 
participation in this study will adversely affect the patient’s ability to obtain life or medical insurance or 
employment. Information from this research will remain anonymous and confidential in the research 
database, and security measures will be in place to prevent unauthorized access to the system and data. 
 
 
Protection against risk of gadolinium enhanced MRI. Patients in the follow-up cohort (FUBV) will 

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be  consented  specifically  for  undergoing  three  contrast  enhanced  MRI  scans  over  2  years,  as  a 

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requirement for the study (contrast to be used is called MultiHance). Patients with CASH have likely 
undergone numerous prior MRI studies as part of standard of care diagnosis and management of their 
disease. Those with gadolinium allergy, or who cannot tolerate MRI scans because of claustrophobia will 
be excluded. Patients with retained metal objects are also excluded unless the metal object can be 
positively confirmed to be MRI compatible, as per standard clinical MRI procedures. Per institutional 
policy, every patient will be screened and excluded for pregnancy, where safety of high field MRI and 
gadolinium contrast agents have not been established. 
Gadolinium-based contrast agents have been used for diagnosis and treatment guidance in more 
than 100 million patients worldwide over the past 25 years, with a spectacular safety record, and no 
known untoward clinical effect except in rare instances and only in patients with renal insufficiency. We 
shall use current U.S. FDA guidelines to screen for and exclude patients with renal insufficiency, which 
are at risk of developing rare nephrogenic systemic fibrosis. There is currently no known clinical 
significance, nor any restriction of gadolinium use by the U.S. FDA despite reports of potential 
accumulation of trace gadolinium molecule in the human brain. If evidence emerges during the trial of 
clinical harmful effects of gadolinium or formal U.S. FDA injunction against its use, we would cease its use 
and obtain IRB and NINDS approval to modify the protocol to continue the study without gadolinium 
permeability biomarker. This would not impact the QSM lesional iron concentration biomarker, which 
does not require gadolinium contrast. 
 
 
There will be no direct benefits to patients for participating in this study. However, the 
information gained from this study may lead to successful clinical trials testing novel therapies in patients 
with cerebral cavernous angiomas. 

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3 OBJECTIVES AND ENDPOINTS 
 
Specific Aim 1: To harmonize data entry, and assess prospective enrollment rates and baseline 
characteristics of CASH cases at multiple high volume sites with clinical interest in CAs. 
 
 
Specific Aim 2: To test the feasibility, accuracy, precision and reproducibility of MRI biomarker 
measurements at multiple sites, critical to their potential application as predictive, diagnostic or outcome 
measures. 
 
 
Specific Aim 3: To assess rates of symptomatic hemorrhage and changes in biomarkers and 
functional status/QOL measures during prospective follow-up. 
 
 
Specific milestones are proposed and go/no-go decisions based on interim analyses and results of 
these aims. Data from this project will insure the most stringent rigor in trial assumptions, including 
validated enrollment rates and baseline features specific to CASH. Results will endorse or reject outcome 
instruments or biomarkers based on empiric observations, hypothesizing a clinically meaningful impact of 
putative therapies. 

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4 STUDY DESIGN 
 
 
 
4.1 OVERALL DESIGN 
 
This is an observational cohort study of CASH cases with no intervention. Seven high-volume 
cavernous angioma sites have been identified for this project. We propose to activate sites and prepare 
data structure in year 1, then prospectively screen and enroll 200 CASH cases in years 2-5 at multiple sites. 
We shall collect harmonized baseline data, and enroll a subset of approximately 120 cases into the follow- 
up and imaging biomarker validation (FUBV) arm at 4 or so sites to assess and compare clinical outcomes, 
biomarker outcomes, and functional status and patient-reported quality of life outcomes for potential use 
in future clinical trials. 
 
 
Clinical Coordinating Center (CCC): 
The Clinical Coordinating Center, located at the University of Chicago, will train site coordinators 
on the protocol and data entry, as well as track enrollment rates. The CCC will also be responsible for 
answering site questions about enrollment and subject eligibility. 
 
 
Data Coordinating Center (DCC): 
The Data Coordinating Center, located at Johns Hopkins University, will develop and oversee the 
trial electronic data system to ensure the integrity of data collection, safety and coordination of data 
storage and access. Study site staff will be trained, sites activated and pilot cases completed in year 1 and 
data collection thereafter for years 2-5. The DCC shall performed data monitoring and generate data 
reports for analysis by Investigators as proposed in the respective Specific Aims 1-3.  The DCC will review 
the online case forms for completeness, logic, and consistency, then verify the entered data against the 
uploaded source records/data collection worksheets in a random 5% sample of cases. Routine queries 
identified in this process will be entered into the EDC system (triggering an automated notice to the site). 
The monitors will then work with the site personnel to obtain correction of all data errors and resolution 
of the corresponding queries. 
 
4.2 SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
Justification of Rare Disease. Brain CA lesion prevalence has been estimated at 0.46-0.63% of the 
population based on consecutive imaging studies in the MRI era27-29. A 0.5% lesion prevalence was 
confirmed by the detection of 131 CAs among 24,535 consecutive autopsies30. In these consecutive 
imaging or autopsy studies, consistently <10% of lesions had manifested a SH. In the one prospective 
population based study in the MRI era, 12% of detected CAs presented with a SH19.  Based on <10-12% 
CASH prevalence among all cavernomas and assuming 0.5% of 325 million adults of the U.S. population 
harbor a CA, it is projected that fewer than 162,500 to 195,000 adults are living with a cavernoma that 
has bled at least once. Fewer numbers would harbor a CA with a more recent SH, warranting therapeutic 
targeting. Based on an estimated prevalence of 60,000 cavernomas in the U.S. with clinical symptoms 
warranting therapeutic intervention, Recursion Pharmaceuticals received Orphan Drug Designation in 
2010 from the U.S. Food and Drug Administration (FDA) (http://www.pr.com/press-release/640210). 

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Similarly, the European Consortium Orphanet has designated brain CA as a rare disease, Orpha164 
(http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=164). 
 
Knowledge Gaps Regarding the Prevalence of CASH and Baseline Characteristics. For planning and 
executing multi-site clinical trials, it is unclear what fraction of CA patients would meet the likely trial 
eligibility criteria of SH within the prior year with an unresected lesion. That prevalence varied between 
10-25% in the three largest ongoing CA research databases at U.S. institutions, with different referral 
patterns and enrollment criteria. This might vary further at other institutions, and with systematic 
screening. Prospective prevalence of CASH in systematic screening of CAs, and enrollment rates at 
multiple sites are not known. These data are essential for the proper design of clinical trials, including the 
number of prospective sites needed. It is further unclear how CASH cases might vary by age, sex, familial 
versus sporadic, lesion size and location, associated venous anomaly, past bleeds, and baseline disability. 
These features varied or were not assessed consistently in the 3 active prospective CA research databases 
in the U.S. More importantly, the assessment of these features at multiple sites has never been 
harmonized or adjudicated. Further, it is unclear what functional status and Quality of Life (QoL) 
instruments best capture the clinical impact of CASH. Inclusion/exclusion criteria and stratification for 
these characteristics will be important in clinical trials, as they will impact natural risk, and potentially the 
effect of putative therapies. These critical knowledge gaps will be addressed in Specific Aim 1 of this 
proposal. 
 
 Opportunities and Challenges with Novel Biomarkers Linked to Clinical Bleeding in CAs. 
Vascular leak is a fundamental feature of CAs, mediating hemorrhage and the associated accumulation of 
non-heme iron (including hemosiderin). Pre-clinical studies demonstrated rescue of vascular permeability 
and decreased lesional iron deposition with ROCK inhibitors and statins31, and B-cell depletion therapy32 
in murine CA models recapitulating the human disease. Awad’s group in Chicago implemented a novel 
MRI application of assessing iron deposition in human CAs using quantitative susceptibility mapping 
(QSM)33-36. Mean lesional QSM was shown to reflect actual iron concentrations assessed by mass 
spectroscopy in resected human CA specimens35. Researchers in Chicago and New Mexico optimized a 
second technique, dynamic contrast enhanced quantitative perfusion (DCEQP) measure on MRI in human 
subjects, reflecting mechanistically postulated vascular hyper-permeability33, 34, 37-39. The Awad team used 
both QSM and DCEQP successfully in over 200 CA subjects and showed strong inter-observer agreement 
in QSM and DCEQP measurements, stability of both measurements in clinically stable lesions, and 
reproducibility across MRI instrument platforms at the Chicago site36, 38. As predicted by the conservation 
of mass hypothesis, CA lesions with greater permeability (Ki) had higher lesional iron content (QSM)36, and 
lesional iron content was greater in older patients and in CAs with prior SH36. More recent studies 
demonstrated a significant increase of mean lesional QSM and DCEQP Ki in human CA lesions manifesting 
interval SH or growth during longitudinal follow-up, while these did not change in stable lesions33. There 
were tight, sensitive and specific thresholds of QSM and DCEQP increases in association with clinical 
events33. Therefore, it is postulated that the QSM and DCEQP may be used as in vivo measures of 
hemorrhagic activity and vascular leak, respectively, and may reflect sensitive, clinically meaningful 
therapeutic effect in human CAs. No other biomarkers have been as linked mechanistically to CA, nor 
associated as closely with clinical events. 

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However, the QSM validations and clinical correlations in CAs have been conducted at a single 
site to date, and DCEQP was applied to CAs at only two sites using slightly different protocols. FDA 
approved image acquisition sequences of QSM and DCEQP have been implemented on different MRI 
instruments from major manufacturers, but their validation at multiple sites have not been reported, nor 
specifically in CAs. The feasibility, accuracy, precision and reproducibility of biomarker measurements at 
multiple sites are critical to their potential application as outcomes instruments in clinical trials. We 
propose a rigorous approach to address these gaps in Specific Aim 2 of this project. 
 
Knowledge Gaps Regarding Follow- and 
Outcomes Assessment. Reducing the rate of 
recurrent SH as a clinical outcome would 
decrease the burden of disease, since a single SH 
 
 
Table.  Power Calculation Models 
Numbers of patients needed, based on different re-bleed 
rates. Calculated by Parexel, 90% power, 1-sided, Type 1 
error 0.025, treatment allocation 1:1, dropout rate 10%. 
can lead to devastating neurologic sequelae. This 
Annual rate of 
SH in control 
Follow- 
up period 
Reduction in 
SH rate (%) 
Sample 
size/group 
would be an approvable outcome, adjudicated, 
readily defined and easy to measure. Yet there 
are many knowledge gaps  and potential 
obstacles to planning clinical trials based on this 
primary outcome. Attempting to power a study 
6% 
1.5 yrs 
25% 
3341 
1.5 yrs 
50% 
720 
15% 
1.5 yrs 
25% 
1161 
1.5 yrs 
50% 
253 
30% 
1.5 yrs 
25% 
435 
1.5 yrs 
50% 
98 
based on recurrent SH would require at least a 1- to 2-year study and a significant number of patients 
(Table). The relative mix of lesions with different re-bleed rates will greatly influence the sample size 
needed to show treatment effect based on this primary outcome. Limiting trials to brainstem lesions 
would enhance statistical power, but also restrict recruitment and prevent generalizability of a drug’s 
effects to other CASH cases that could benefit. Other studies suggest an equally high rate of SH in deep 
supra-tentorial and possibly cerebellar CAs21. The rates of recurrent SH have never been assessed 
prospectively at multiple sites in CASH trial candidates. 
 
Moderate to severe disability after SH has been reported in 11-22% of patients17, 40-42. A CA re- 
bleed causes significantly greater disability than initial SH22. The proportion of CASH cases with any 
functional disability varied between 26 and 65% at U Chicago, Mayo and BVMC cohorts. Only two studies 
assessed QOL in CAs, and both were limited to surgical patients. One study43 used Karnofsky performance 
scale, Patzold Rating and SF-36, and the second44 used only SF-36. Newer QoL scores (e.g. EQ-5D and 
PROMIS 29) have been validated and are more specific for stroke patients compared to SF-3645-53, and 
easier to obtain than the Patzold Rating54.  No study to date has reported QOL measures or their changes 
over time in CASH patients observed without surgery. It would be useful to assess functional outcome 
and QOL measures at baseline and document their change over time with or without a symptomatic re- 
bleed. One or more may be fit for use as a putative outcome in clinical trials of pharmacotherapies, and 
may even be useful in future surgical trials. As to the QSM and DCEQP biomarkers of lesional hemorrhage 
and permeability, even if they are successfully and reliably deployed at multiple sites, it remains unclear 
how they change during longitudinal follow-up in cases with CASH, and whether their changes are more 
sensitive than clinical events. The gaps of knowledge regarding outcome measures in clinical trials are 
addressed in Specific Aim 3 of this proposal. 

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Urgent Need for Clinical Trial Readiness. Potential drug development for CASH is very promising, 
but also illustrates what past-NINDS Director Story Landis, PhD described as “an embarrassment of 
riches”. As with many rare neurologic diseases, fundamental discoveries have identified cogent 
mechanistic targets for therapies, but their development into viable clinical solutions invariably meets 
obstacles and uncertainties in trial readiness. In this disease, there is a huge opportunity through clinical 
equipoise to target CAs with recent SH, where surgical resection of lesion is not undertaken, with the aim 
of preventing recurrent bleeding within 2-3 years. There are unique collaborations among major experts 
and stakeholders in place, yet a critical “Valley of Death” awaits drug development in the absence of 
readiness for multi-site clinical trials. Obstacles include a lack of harmonization of screening, baseline 
cohort characterization, prevalence rates and screen/enroll ratios, risk stratification and the assessment 
of clinical, functional and biomarker outcomes at multiple sites. Further gaps include the unknown rate 
and sensitivity (fitness for purpose) of outcome parameters during  follow-up, needed to postulate 
treatment effects. These obstacles and gaps are readily addressed by the proposed clinical readiness 
project. The timing cannot be more opportune, with therapeutic targets identified, and several drugs 
ready to benefit from a track to clinical testing in about five years. 
 
 
 
4.3 END OF STUDY DEFINITION 
 
A participant is considered to have completed the study if he or she has completed all phases of 
the study including the last visit or the last scheduled procedure shown in the Schedule of Activities (SoA), 
Section 1.3. 
 
 
Cases whose CASH lesion has been resected will be considered to have reached endpoint, and will 
not be followed further during the study. The indication for surgery shall be noted, including any SH prior 
to CASH lesion resection. 
 
 
Cases who develop a recurrent SH during follow-up, and their CASH lesion has not been excised, 
will remain in the study until they complete follow- up, and will undergo all scheduled assessments. 
 
 
If an enrolled subject decides to discontinue the study, fails follow-up, or develops an exclusion 
criterion after enrollment in the study (becomes pregnant, undergoes CASH lesion excision, etc.), he/she 
will be considered an attrition after recording the causative event. Data collected prior to the attrition 
shall still be included in the study and no further patient follow-up will take place. An allowance in sample 
size calculation is made for up to 30% attrition or missing data from any cause. 
 
 
5 Study Population 

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5.1 INCLUSION CRITERIA 
 
(1) 18 years of age and older. 
(2) diagnosed with a brain CA (single or multiple). 
(3) had a SH within the past year (with demonstrated new lesional bleeding or hemorrhagic growth >3mm 
on diagnostic studies AND attributable new symptoms). 
(4) no prior treatment of the symptomatic lesion (after neurosurgical consultation). Subject is able to 
provide informed consent. 
 
 
 
 
5.2 EXCLUSION CRITERIA 
 
(1) have symptomatic spinal CA’s 
(2) have received prior brain irradiation. 
(3) cases where verification of SH with clinical and imaging review cannot be accomplished. 
(4) No prior or planned treatment of the symptomatic lesion (after neurosurgical consultation) 
 
 
Subjects meeting these eligibility criteria are considered eligible for the SCA arm. 
 
Additional FUBV Arm Exclusion Criteria. To be eligible for Aims 2 and 3, CASH cases enrolled in Aim 1 will 
be further excluded from FUBV arm inclusion for the following reasons: 
(1) unable to undergo MRI with contrast and/or because of contraindications (e.g. pacemaker, metallic 
foreign body, pregnancy) or other reasons (severe claustrophobia, too large or too heavy for MRI scanner). 
(2) pregnant or breastfeeding women due to unknown harm to fetus/child from MRI. 
(3) Subject will be unable/unlikely to return for follow-up visit 
 
5.4 SCREEN FAILURES 
 
Sites will enter all patients with CCM disease seen at their institution. The study database 
(VISION-EDC) will include a list of possible exclusions from which the study team will choose for all patients 
found to be not eligible for the trial. The most common reason for exclusion is likely to be a lack of 
ymptomatic hemorrhage within the last year. 

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6 STUDY INTERVENTION 
 
 
 
This a non-interventional study. 

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7 
STUDY 
INTERVENTION 
DISCONTINUATION 
AND 
PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
 
 
 
7.1 PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
Cases whose CASH lesion has been resected will be considered to have reached endpoint, and will 
not be followed further during the study. The indication for surgery shall be noted, including any SH prior 
to CASH lesion resection. 
 
 
Cases who develop a recurrent SH during follow-up, and their CASH lesion has not been excised, 
will remain in the study until they complete follow-up. They will undergo the scheduled follow-up 
assessments at Years 1 and 2. 
 
 
Participants are free to withdraw from participation in the study at any time upon request. 
 
7.2 LOST TO FOLLOW-UP 
 
If an enrolled subject decides to discontinue the study, fails follow-up, or develops an exclusion 
criterion after enrollment in the study (becomes pregnant, undergoes CASH lesion excision, etc.), he/she 
will be considered an attrition after recording the causative event. Data collected prior to the attrition 
shall still be included in the study. An allowance in sample size calculation is made for up to 30% attrition 
or missing data from any cause. 
 
 
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
 
• 
The site will attempt to contact the participant and reschedule the missed visit [within 2 months 
of the study window] and counsel the participant on the importance of maintaining the assigned 
visit schedule and ascertain if the participant wishes to and/or should continue in the study. 
 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, 
a certified letter to the participant’s last known mailing address or local equivalent methods). 
These contact attempts should be documented in the participant’s medical record or study file. 
 
• 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 

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8 STUDY ASSESSMENTS AND PROCEDURES 
 
All eligible subjects will be identified by the study team at each site. Based on clinic schedules and 
current patient databases, all CCM patients with a symptomatic hemorrhage within the last 12 months 
(of screening) are eligible for the trial. Sites will screen neurology, neurosurgery, and neurointerventional 
radiology clinic schedules, MRI schedules, and attend Neurovascular rounds to help identify potential 
subjects. Additionally, study sites will rely on referrals from the various services listed above, or self- 
referrals via web searches and through the Angioma Alliance, a patient support group. Once identified, 
the study coordinator at each site, along with the site PI, will screen the subject for basic eligibility. 
Screened subjects not scheduled to come in for a clinical visit within their eligibility window will be 
contacted by the study coordinator or PI to explain the study and determine if the subject is interested. 
When the subject comes in, either for a standard clinic visit or for a study visit, the study team will 
review the subject's medical history to ensure the subject meets the inclusion criteria. The trial will be 
explained and informed consent obtained. After consent is obtained a physical exam (height, weight, 
vital signs) will be completed, a baseline modified Rankin Score obtained, and EQ-5D, PROMIS 29, and NIH 
stroke scale assessments completed. The study team will also collect information about the subject's 
history, pertinent to the disease (history of seizure, resection of other lesions, etc.). All subjects at the 
FUBV sites (enrolled to the FUBV arm) will have a MRI scan including the additional sequences for research 
as specified in Specific Aim 2 (QSM/DCEQP). All women of childbearing age will undergo a urine or serum 
beta-HCG pregnancy test prior to MRI to confirm no pregnancy, per local institutional guidelines. 
 
 
 Subjects enrolled in the FUBV arm will return for 2 follow up visits: one at 12 months and the other at 
24 months. Excluding the informed consent process, all baseline procedures will be repeated. Subjects 
will have completed their participation upon completion of the baseline visit procedures (SCA arm) or 
the year 2 visit (FUBV arm). All subjects enrolled in the SCA arm will have one study visit only. 
 
 
FUBV subjects will receive travel stipends  for each of the 3 study visits.  Those subjects traveling less than 
200 miles to the enrolling site will receive $50 per visit (baseline, Year 1, Year 2).  Those traveling more than 
200 miles to the enrolling site will receive $500 per visit (baseline, Year 1, Year 2). 

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9.1 STATISTICAL HYPOTHESES AND PROPOSED ANALYSES 
 
 
Specific Aim 1. Descriptive statistics (frequencies, min, max, mean, standard deviation) and 
contingency table analysis will be performed to identify any possible coding errors. Data inconsistencies 
identified will be sent back to sites for correction. We will calculate the proportion and exact 95% 
confidence interval (CI) of CASH cases among all CA cases at each SCA site and overall. Baseline 
characteristics will be summarized using chi-square tests for categorical variables and t-tests for 
continuous variables. EQ-5D measures are scored on the T-score metric, with a mean of 50 and standard 
deviation (SD) of 10 in a referent population (mild, moderate, and severe impairment is defined as 0.5- 
1.0 SD, 1.0-2.0 SD, or 2.0+ worse than the mean, respectively). Spearman correlation coefficients will be 
calculated between mRS and Euro-QoL and PROMIS29 scales, and mean scores of Euro-QoL and 
PROMIS29 will be stratified by mRS levels. This analysis will allow us to determine ceiling effects of scores 
and how well the Euro-QoL and PROMIS29 data are distributed in CASH cases. Functional and QOL scores 
shall also be analyzed by pre-defined subgroups (sex, genotype and lesion location), to inform 
stratification or the need for adaptive randomization in clinical trials. 
 
Specific Aim 2. This will follow the same design for QSM and DCEQP data acquired using these 
phantoms. A p<0.05 will be considered a failure, or significant non-zero difference. The accuracy of QSM 
and DCEQP values will be assessed at each of the sites participating in the FUBV arm by estimating the 
coefficient of determination r2 between the observed and known phantom values, with r2 ≥ 0.95 needed 
to validate accuracy of each technique35. The Pearson’s correlation coefficients r of the FUBV subjects will 
also be compared using Fisher transformation. The precision of QSM and DCEQP measurements will be 
tested by comparing two separate measurements acquired at each site, using a paired t-test (7 
ferumoxytol concentrations acquired twice by QSM, and 7 permeability values simulated  with  the 
phantom twice by DCEQP). The reproducibility of phantom measurements will be evaluated by comparing 
the QSM and DCEQP simulation values acquired at New Mexico and Mayo Rochester against the values 
obtained at Chicago, and one another, using a two-sample t-test. 
 
 
Specific Aim 3. Time to recurrent SH will be analyzed using Kaplan Meier method and Cox 
proportional hazards regression approach. Rates of recurrent SH/patient/year from initial SH qualifying 
event, and SH/patient/year from enrollment (potentially more relevant for trial modeling) will be 
estimated along with 95% CIs. Changes in mean lesional QSM and Ki during 1 and 2-year epochs will be 
compared using paired t-test or Wilcoxon signed rank test to assess changes within patients over time, 
including 95% CIs. To test predictive, monitoring or surrogate outcome hypotheses, two sample t-test or 
Wilcoxon rank sum test will be used to compare such changes between patients with and without 
recurrent SH. Categorical variables such as proportions of patients with a drop in mRS score ≥ 1 point, 
difference in EQ-5D and PROMIS 29 scores, NIHSS scores, between patients with and without recurrent 
SH will be compared using Chi-square or Fisher’s exact test. Associations of baseline characteristics (sex, 
lesion locations, familial/sporadic) and recurrent SH as a binary outcome (yes/no) will be assessed using 

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univariable and multivariable logistic regression and reported as odds ratios and 95% CIs. Depending on 
the number of recurrent SH over the 2-year period, we may analyze re-bleeds as a continuous outcome 
and the associations of baseline features or biomarkers assessed using linear regression. Performance of 
final model(s) will be assessed using r2  in the case of linear regression, area under the curve (AUC) and 
Hosmer Lemeshow goodness of-fit test55  in the case of logistic regression, or concordance index in the 
case of Cox proportional hazards regression. AUCs between various models (univariable) will be compared 
using the method proposed by DeLong et al56. For biomarkers, we will create a binary variable (yes/no) 
depending on whether the % change in mean lesional QSM or Ki during 1-year epochs exceed previously 
defined respective thresholds (+ 5.8% QSM and +39.6% for Ki)33 that were significantly associated with 
new clinical events at high sensitivity and specificity in previously stable lesions. We will then assess the 
association of this newly created variable (“biomarker event”) with SH rate treated as continuous (using 
two sample t-test or Wilcoxon rank sum test) and binary (using Chi-square or Fisher’s exact test) outcomes 
of interest. Finally, we shall compare the sensitivity/specificity of changes in mRS, QOL, and NIHSS scores, 
and lesional QSM and Ki in relation to SH during the same epochs, using McNemar’s test with SH (yes/no 
binary) as the reference standard. All tests will be 2-sided and p-values <0.05 considered statistically 
significant. 
 
 
 
 
9.2 SAMPLE SIZE DETERMINATION 
 
Screening and Clinical Assessment (SCA) Arm: We calculated the width of the exact 95% CI for 
detecting CASH cases, varying the prevalence from 10% to 25% based on the range in preliminary data, 
and total sample sizes screened from 500 to 1,500. Based on these sample size models, we propose 
recruiting 200 CASH cases for the SCA arm of this project, to be enrolled during years 2-5, an average of 
50 cases/year at all sites, and less than one case/site/month. Assuming a 15% prevalence of CASH cases 
(the average in three ongoing registries), a screening sample size of 1,333 would be required over a 4-year 
period (333 cases to be screened/year) to detect 200 CASH cases ± 2% (i.e., 13% to 17%). Even if the true 
prevalence is lower (e.g. 10%) or higher (25%), we will have excellent precision to within ± 1.5% to 2.5%, 
respectively, corresponding to 134 - 334 CASH cases for the same screening sample size. These CASH 
sample sizes will also allow flexibility in describing the proportion of important subgroups (i.e. sex, lesion 
location, genotype), and provide realistic estimates of recruitment at SCA sites (screened/enrolled ratio). 
 
 
The 7 main sites are all high-volume CA clinical centers, with demonstrated ability to screen the 
requisite number of cases. Their recent clinical activity is demonstrated by the number of CA cases (n) 
seen over a 12-month period with diagnosis ICD9 228.02 on initial or follow-up visits at each of the 
institutions: 1) University of Chicago (n=106), 2) Mayo Clinic-Rochester (n=70), 3) University of New 
Mexico (n=80), 4) University of Utah (n=40), and 5) Barrow Neurological Institute, Phoenix (n=200); TOTAL 
(n=496). We would need to screen 1,333 CA cases over a 4-year period at the 5 sites (333 CAs screened 
each year), in order to identify and enroll 200 CASH cases, based on the estimated prevalence of 15% 
CASH cases among overall CA cases. This is a very realistic target, with 496 CAs actually evaluated per year 
at the 5 sites for the SCA arm.    To help meet the target enrollment, The University of California- San 

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Francisco (n=70) was added as a recruitment site in February 2019 and Johns Hopkins University (n=150) 
will be added in 2020. If we do not meet our target enrollment of CASH cases, we may add additional, 
yet to be decided on, sites. 
 
 
Follow-up and Biomarker Validation (FUBV) Sites: University of Chicago, University of New Mexico, 
Mayo, University of California San Francisco, and Johns Hopkins were chosen because of additional 
established infrastructure for advanced imaging, including identified MRI physicists, neuroradiologists and 
site engineers who will work with the Biomarker Imaging Core (BIC) on implementing QSM and DCEQP 
protocols. A subset of approximately 120 CASH cases will be enrolled at FUBV sites to perform imaging 
biomarker validation studies (Specific Aim 2) and follow-up of CASH cases annually for up to two years 
(Specific Aim 3) to evaluate changes in outcomes. This subset of CASH cases will undergo a research MRI 
scan at baseline and at 1 and 2-year follow-up visits and undergo modified Rankin Scale (mRS) score 
and EQ-5D, PROMIS 29, and NIHSS assessments. A target recruitment of 120 CASH cases over 3-4 years 
at the sites conducting the FUBV arm is amply justified, with demonstrated 256 CA cases recently evaluated 
per year at those sites, expecting to identify 38 CASH cases each year (15% prevalence). Utah and Barrow 
may also serve as alternate FUBV arm sites if needed, with large demonstrated CA clinical activity. The 
University of California San Francisco  and Johns Hopkins are now   part of the FUBV arm . 
 
 
Assuming a sample size of 120 CASH cases, and allowing 30% dropouts or missing biomarker or 
other data, we would have 84 evaluable patients (168 patient-years). We project 10%-20% re-bleed 
rate/year, supported by population studies and meta-analyses of CASH18, 19, with the higher estimate 
particularly applying to brainstem cases. We would hence expect 17-34 SHs. Based on this, for continuous 
outcomes we will have 80% power at an alpha level of 0.05, to detect a difference between the means of 
patients with and without re-bleeding of at least 0.63-0.77 standard deviation. For categorical outcomes 
(i.e. presence or absence of a risk factor) we will be able to detect a difference of 32-40% between these 
two groups. This allows testing of questions regarding the rate of SH, and the prevalence of other 
outcomes in relation to SH during follow-up (Specific Aim 3). 
 
 
 
9.3 POPULATIONS FOR ANALYSES 
Cavernous angiomas with symptomatic hemorrhage (CASH) are most likely to re-bleed and cause 
further neurologic sequelae. It would be desirable to develop a drug that stabilizes CASH, and prevent 
recurrent bleeding. CASH with recent bleed, where surgical resection is not undertaken, are the most 
likely cases to be followed expectantly per current evidence based guidelines, with clinical equipoise for 
testing novel therapies to prevent re-bleeding. They are the most likely cases to be targeted for clinical 
trials. 
 
 
Appropriate and complete statistical modeling of data collected by the sites for both SCA/FUBV 
arms are imperative to the planning, development, and completion of a successful Phase III interventional 
trial. The most critical component is the accurate assessment of the enrollment rates of CASH across 
several sites, as well as the between-site variability in these estimates. Both within and between sites 
variability will be used to adequately power a Phase III trial, will be calculated by developing random- 
effect models along with using appropriate link functions quantifying the rates of CASH in these models. 

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As a follow-up step, in-depth data analyses will be performed using the demographic, imaging, 
clinical and biomarker data collected. These are applied to develop models assessing how predictive each 
of these factors is to the development of recurrent SH. Understanding which factors are most predictive 
of SH will be crucial in developing a covariate adaptive randomization scheme for the Phase III trial that 
insures proper balance in these prognostic factors between treatment arms. Finally, statistical 
assessments of changes in lesional iron content and permeability biomarkers, QOL, mRS, and NIHSS during 
follow-up of CASH patients will be performed. Understanding how these measures change over time will 
be an important step in the process of developing hypotheses on the effect of treatment on these as 
putative secondary or surrogate outcomes, or as potential composite outcomes. 
 
 
 
 
9.4 STATISTICAL ANALYSES 
 
 
9.4.1 GENERAL APPROACH 
Data collection. Key variables to be collected in this study will be decided on by all stakeholders 
in Year 1. At a minimum, these will include patient demographics, genotype, baseline MRI lesion features 
of the hemorrhagic CA (size, location), time from SH, prior bleeds/dates, and diagnosis date. Functional 
status will be measured using the modified Rankin Scale (mRS) score57, Euro-QoL53, PROMIS2952, and NIH 
Stroke Scale. PROMIS 29 short forms are an assessment of anxiety, depression, and fatigue, and have been 
validated for use in several common neurological disorders. Presence of obstructive sleep apnea. Recent 
findings suggest that sleep apnea results in decreased blood flow to the brain. This transient ischemia 
may be implicated in CA hemorrhage. Sleep apnea questions will be included in the dataset and response 
analyses as described under the topic Predictors of SH. 
 
 
Data harmonization. Common data elements from each site will be reviewed, updated, and 
harmonized using an iterative, stepwise process based on DataSHaPER (DataSchema and Harmonization 
Platform for Epidemiologic Research) recommendations58-60. Questionnaires, codebooks, and protocols, 
etc. at the 3 established CA databases (Table 2) will be compiled and distributed for review. A series of 
Executive Committee teleconference calls will be held in Year 1 to decide on a set of ‘target’ data elements 
for potential clinical trials, as has been similarly done with the consensus process for developing clinical 
guidelines paper17. The EDHC and DCC will then develop standardized electronic data entry forms and 
codebooks for data collection. Each site shall be trained in abstracting and entering data for their cases 
online. Data will be collected prospectively in Years 2-5. Analysis datasets will be generated quarterly by 
the DCC for quality control analysis by EDHC. 
 
 
Event  Rate: Time to recurrent SH will be analyzed using Kaplan Meier method and Cox 
proportional hazards regression approach. Rates of recurrent SH/patient/year from initial SH qualifying 
event, and SH/patient/year from enrollment (potentially more relevant for trial modeling) will be 
estimated along with 95% CIs. 

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Biomarker changes over 2 years: Changes in mRS, EQ-5D, PROMIS 29, and NIHSS scores, mean 
lesional QSM and Ki during 1 and 2-year epochs will be compared using paired t-test or Wilcoxon signed 
rank test to assess changes within patients over time, including 95% CIs. 
 
 
Predictors of SH: Two sample t-test or Wilcoxon rank sum test will be used to compare such 
changes between patients with and without recurrent SH. Categorical variables such as proportions of 
patients with a drop in mRS score ≥ 1 point, between patients with and without recurrent SH will be 
compared using Chi-square or Fisher’s exact test. Associations of baseline characteristics (sex, lesion 
locations, familial/sporadic) and recurrent SH as a binary outcome (yes/no) will  be assessed  using 
univariable and multivariable logistic regression and reported as odds ratios and 95% CIs. Depending on 
the number of recurrent SH over the 2-year period, we may analyze re-bleeds as a continuous outcome 
and the associations of baseline features or biomarkers assessed using linear regression. Performance of 
final model(s) will be assessed using r2  in the case of linear regression, area under the curve (AUC) and 
Hosmer Lemeshow goodness of-fit test55  in the case of logistic regression, or concordance index in the 
case of Cox proportional hazards regression. AUCs between various models (univariable) will be compared 
using the method proposed by DeLong et al56. For biomarkers, we will create a binary variable (yes/no) 
depending on whether the % change in mean lesional QSM or Ki during 1-year epochs exceed previously 
defined respective thresholds (+ 5.8% QSM and +39.6% for Ki) that were significantly associated with new 
clinical events at high sensitivity and specificity in previously stable lesions33. We will then assess the 
association of this newly created variable (“biomarker event”) with SH rate treated as both continuous 
(using two sample t-test or Wilcoxon rank sum test) and binary (using Chi-square or Fisher’s exact test) 
outcomes of interest. Finally, we shall compare the sensitivity/specificity of changes in mRS, QOL, and 
NIHSS scores, and lesional QSM and Ki  in relation to SH during the same epochs, using McNemar’s test 
with SH (yes/no binary) as the reference standard. All tests will be two-sided and p-values <0.05 
considered statistically significant. 
 
 
We will calculate the proportion and exact 95% confidence interval (CI) of CASH cases among all 
CA cases at each SCA site and overall. Baseline characteristics will be summarized using chi-square tests 
for categorical variables and t-tests for continuous variables. Baseline Euro-QoL and PROMIS29 measures 
will be validated for use in CAs. Euro-QoL and PROMIS29 measures are scored on the T-score metric, with 
a mean of 50 and standard deviation (SD) of 10 in a referent population (mild, moderate, and severe 
impairment is defined as 0.5-1.0 SD, 1.0-2.0 SD, or 2.0+ worse than the mean, respectively). Spearman 
correlation coefficients will be calculated between mRS and Euro-QoL and PROMIS29 scales, and mean 
scores of Euro-QoL and PROMIS29 will be stratified by mRS levels. This analysis will allow us to determine 
ceiling effects of scores and how well the Euro-QoL and PROMIS29 data are distributed in CASH cases. 
 
 
Homogeneity of event rates, biomarker changes, and other endpoints in years 1 and 2. This will be 
assessed, as it impacts (1) sample size calculations for time averaged assessments of the impact therapies, 
and (2) whether future trials should be conducted for 1 or 2 years. 

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9.4.2 SUB-GROUP ANALYSES 
All endpoints (rebleed rates, biomarker changes, functional status and QOL changes) shall be 
analyzed by pre-defined subgroups (sex, genotype and lesion location), information which may influence 
stratification or the need for adaptive randomization in clinical trials. 

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10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
 
10.1.1 INFORMED CONSENT PROCESS 
 
 
 
10.1.1.1 CONSENT/ASSENT 
AND OTHER INFORMATIONAL 
DOCUMENTS PROVIDED TO 
PARTICIPANTS 
Consent forms describing in detail the study procedures and risks are given to the participant and 
written documentation of informed consent is required prior to starting intervention/administering study 
intervention. 
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Consent forms will be Institutional 
Review Board (IRB)-approved and the participant will be asked to read and review the document.  The 
investigator or study team member will explain the research study to the participant and answer any 
questions that may arise. A verbal explanation will be provided in terms suited to the participant’s 
comprehension of the purposes, procedures, and potential risks of the study and of their rights as 
research participants. Participants will have the opportunity to carefully review the written consent  
form and ask questions prior to signing. The participants will have the opportunity to discuss the study 
with their family or surrogates or think about it prior to agreeing to participate. The participant will sign 
the informed consent document prior to any procedures being done specifically for the study. 
Participants will be informed that participation is voluntary and that they may withdraw from the study 
at any time, without prejudice. A copy of the signed, informed consent document will be given to the 
participants for their records. The informed consent process will be conducted and documented in the 
study files (including the date), and the form signed, before the participant undergoes any study-specific 
procedures. The rights and welfare of the participants will be protected by emphasizing to them that the 
quality of their medical care will not be adversely affected if they decline to participate in this study. 
Non-English speaking participants will not be targeted for enrollment. In the event of a participant who  
is eligible for enrollment but does not speak English, the institution’s“short form” consent document 
may be given to the participant in their respective language. A “short form” consent document is 
defined as a document stating that the elements of the informed consent have been fully presented 
orally to the participant in the participants native language through the use of an interpreter. 
 
 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
 
The study may be modified or discontinued at any time by the IRB, the NINDS, the PI, the OHRP, or other 
government agencies as part of their duties to ensure that research subjects are protected. Additionally, 
yearly go/no-go decision points have been built into the study, as described below. 

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Participant confidentiality and privacy is strictly held in trust by the participating investigators and 
their staff. No information concerning the study or the data will be released to any unauthorized third 
party without prior written approval of the sponsor. 

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All research activities will be conducted in as private a setting as possible. 
 
 
The study monitor, the Clinical Coordinating Center (CCC), the Data Coordinating Center (DCC), 
other authorized representatives of the sponsor, representatives of the Institutional Review Board (IRB) 
or regulatory agencies may inspect all documents and records required to be maintained by the 
investigator, including but not limited to medical records (office, clinic, or hospital) for the participants in 
this study. The clinical study site will permit access to such records. 
 
 
The study participant’s contact information will be securely stored at each clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure location for 
as long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 
 
 
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored by Prelude Dynamics. Research data will be synchronized to 
our internet-accessible clinical trials management software platform (VISION™ by Prelude Dynamics, 
Austin, TX). This system is used by the Data Coordinating Center (BIOS) for rapid and efficient protocol 
management in large, multicenter, acute stroke trials. Prelude Dynamics and Johns Hopkins Health 
Systems Corporation and The Johns Hopkins University have an executed Business Associate Agreement 
in place. Study participant data will not include the participant’s contact or identifying information. 
Rather, individual participants and their research data will be identified by a unique study identification 
number. The study data entry and study management systems used by clinical sites and by Prelude 
Dynamics research staff will be secured and password protected. At the end of the study, all study 
databases will be de-identified and archived by Prelude Dynamics with BIOS at Johns Hopkins. 
 
10.1.4 FUTURE USE OF STORED DATA 
 
Firsts in this Disease: Harmonization of Baseline Characteristics and Outcomes Assessments. We 
propose for the first time a harmonized multi-site assessment of enrollment rates of CASH, baseline 
features relevant to stratification in clinical trials, and follow-up assessments of functional outcomes and 
QOL in relation to clinical bleeds. Without this information, clinical trials could use false assumptions and 
likely fail. We introduce novel biomarkers of vascular leak and hemorrhage, with firm mechanistic 
foundations, that have been linked to clinical disease activity. We shall test their reliability and validity at 
multiple sites, and assess their changes over time, with and without clinical re-bleeds, hence their fitness 
as outcomes instruments in clinical trials. Such a comprehensive project has never been undertaken 
previously in this disease. The recent James Lind Alliance priority setting partnership conducted by 
Cavernoma Alliance U.K. identified among the top priorities for research several aims of this trial readiness 
proposal (http://www.jla.nihr.ac.uk/priority-settingpartnerships/cavernoma/). 
 
Scientific Rigor and Translation to Trial Modeling. Teams at UCSF and Mayo Clinic include 
investigators and statisticians, with respective experience in disease characteristics and data 
harmonization, and in prospective follow-up and natural history. The Chicago team contributes engineers 

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and physicists with demonstrated expertise with the proposed biomarkers, and a statistician with the 
greatest experience in the analysis of QSM and DCEQP data. The team at Johns Hopkins contributes a solid 
record in data structure, safety and integrity, trial modeling (including highly successful CLEAR and MISTIE 
trials, and recent planning of AT-CCM POC), and a longstanding proven collaboration with Awad’s Chicago 
team. The senior statistician at Johns Hopkins and statisticians from the various Cores will cross-critique 
statistical plans proposed in each of the aims, and refine them during year 1, adding another level of peer- 
input and diversity of opinions, and optimizing data format for future analyses. Later in the project, they 
will construct workable models for multi-site trials based on emerging results. This will insure the most 
stringent rigor in trial assumptions, including validated estimates and confidence intervals of detection 
rates and baseline features of eligible subjects. They will endorse or reject outcome instruments or 
biomarkers based on empiric observations, hypothesizing a clinically meaningful impact of putative 
therapies. And they will propose the most optimal sample size, length of follow-up, and number of sites 
needed to test trial hypotheses. Our Advisory Committee will provide guidance and prioritization of 
workable trials to be conducted by industry or academia. 
 
 
Ultimately, the data collected in this trial will help shape future trials in this disease by informing 
enrollment possibilities, disease progression, numbers of subjects available, feasibility of enrolling at 
multiple centers, etc. The data collected during this study will be analyzed to better understand this 
population and will be used to prepare grants for future trials, including drug treatment trials. 
 
 
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
 
Scientific Cores: There are three scientific cores that include Epidemiology and Data Core (EDHC), 
Biomarker Imaging Core (BIC) and Follow-up and Clinical Hypotheses Core (FCHC). 
 
 
Executive Committee (EC): Project PI, co-chairs, Core leaders and other site PIs shall form the project’s 
Executive Committee. The EC shall teleconference monthly regarding trial progress and review interim 
analyses yearly and at midterm in each specific aim. The NINDS Program Officer shall attend all EC 
meetings and teleconferences. 
 
 
Advisory Committee (AC): will meet with the EC each fall in conjunction with the Angioma Alliance 
Investigators Workshop and by teleconference each spring. A progress report shall be presented by the 
EC and the AC shall help resolve emerging problems, propose alternative approaches, or identify unique 
opportunities. The AC will make specific suggestions about each aim, propose revisions, and ultimately 
approve the emerging study protocols.  In years 2-4, the AC shall review project progress, and in Years 3- 
5 emerging data (interim reports) and all go/no-go decisions. In Years 4-5, the AC shall be expanded to 
include representative of StrokeNet and NCASTS, agencies who might sponsor Phase III trials. The AC may 
also be called upon for ad hoc advice regarding problems and opportunities as they arise. 
 
 
Central Institutional Review Board (cIRB): The Johns Hopkins University School of Medicine will be utilized 
for this trial readiness project. 

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10.1.6 QUALITY ASSURANCE AND QUALITY CONTROL 
Quality control. After agreement on key variables to be collected in this study, we will generate 
10 case summaries for training, meant to illustrate the variability in identifying CASH cases and will 
discover any uncertainties in target variable definitions that require clarification before sites commence 
data collection. For outcome measures that are more subjective (e.g. verification of SH, mRS, lesion 
size/location), a second clinical assessor with CA experience (Awad, Flemming or Morrison) will review 
the anonymized raw data on the case and assess the parameters independently. We will calculate the 
interrater reliability for the 10 training cases to determine the percent agreement (kappa). 
 
The DCC will review the online case forms for completeness, logic, and consistency, then verify 
the entered data against the uploaded source records/data collection worksheets in a random 5% sample 
of cases. Routine queries identified in this process will be entered into the EDC system (triggering an 
automated notice to the site). The monitors will then work with the site personnel to obtain correction 
of all data errors and resolution of the corresponding queries. 
 
 
 
10.1.7 DATA HANDLING AND RECORD KEEPING 
 
10.1.7.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES 
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
investigator. The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. 
 
 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation 
of data. 
 
 
Hardcopies of the study visit worksheets will be provided for use as source document worksheets for 
recording data for each participant enrolled in the study.  Data recorded in the electronic case report 
form (eCRF) derived from source documents should be consistent with the data recorded on the source 
documents. 
 
 
Clinical data will be entered into the Vision database, a 21 CFR Part 11-compliant data capture system 
provided by Prelude Dynamics. The data system includes password protection and internal quality 
checks, such as automatic range checks, to identify data that appear inconsistent, incomplete, or 
inaccurate. Clinical data will be entered directly from the source documents. 
 
 
10.1.7.2 STUDY RECORDS RETENTION 
Participation in this study requires that original study documents be retained for a minimum of 2 
years following the end of the trial. This standard complies with U.S. FDA regulations (21 cfr §312.62[c]). 

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Records must not be destroyed without first contacting the study investigator to ensure that the time 
limits defined in the regulations have been met. 
 
 
For the purposes of this section, “original study documents” are defined as: 
Subject records created at or available to the study center during the subject’s participation in 
the trial, or any other document that supports entries in the EDC system and represents the 
original source of that information, including but not limited to applicable sections of medical 
charts, patient correspondence, laboratory data, pharmacy logs and drug accountability forms, 
as well as any forms or documents used to compile or maintain original subject data or study 
procedural information. 
 
 
All Essential Regulatory Documents [as defined under Good Clinical Practice (GCP) Regulations] 
including: all material communications with the IRB; all communications that are related to study 
subjects or which otherwise document material study-related procedures or safety issues. All study 
documents should be uploaded to the source documents section of the database. The database will be 
used as the master repository for all site and Sponsor regulatory documents. 
 
 
 
10.1.8 PROTOCOL DEVIATIONS 
 
Protocol Compliance: Procedures will be implemented to maximize adherence to the protocol. 
Early review of data is made possible by real-time entry of data into a database with validations and real- 
time monitoring. Minor or administrative deviations will be reported to the JH IRB at the time of 
continuing review. Examples of minor administrative deviations include: follow up visits and/or study 
tasks occurring outside the protocol required time frame because of the subject’s schedule. 
 
 
 
FDA Guidance for Electronic Data Entry Compliance: The design and development of the 
electronic database system will reflect the FDA Guidance for Industry for Computerized Systems Used in 
Clinical Trials (April 1999) as well as the Electronic Records/Electronic Signatures rule (21 CFR part 11). A 
secure, computer generated, time- stamped electronic record will allow reconstruction of the course of 
events relating to the creation, modification, and deletion of an electronic record. Source documents will 
be retained to enable a reconstruction and evaluation of the trial. The system will ensure that all 
applicable regulatory requirements for record keeping and record retention in clinical trials are met with 
the same degree of confidence as are provided with paper systems. Clinical investigators will retain the 
original copy of all source documents uploaded onto the eCRF. Query resolution correspondence will be 
maintained and eCRF edits will be tracked by the system. Changes to a required record will not obscure 
the original information. The record will clearly indicate the time a change was made and clearly provide 
a means to locate and read the prior information through the audit trail. This audit trail will be in 
compliance with the 21 CFR 11.10(e). The record, along with supporting documentation, will also indicate 
who made the changes and when changes were made. 

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Security measures will be in place to prevent unauthorized access to the system and data. To 
ensure that individuals have the authority to proceed with data entry, the system will be designed to 
verify the electronic signature (user id and password) at the start of a user session. Each entry to an 
electronic record, including any change, will be made under the electronic signature of the individual 
making that entry. A separate electronic signature will not be required for each entry or change; a single 
electronic signature will cover multiple entries or changes. Individuals who maintain the electronic 
record systems as well as the audit trail will carry the responsibilities to protect authenticity, integrity, 
and confidentiality of electronic records. Audit trails will be available at the study site or any other 
location where associated electronic study records are maintained. The system will be designed to 
contain the prompts, lookup values, cross-field validations, flags, and on-line help to encourage 
consistent use of clinical terminology and to alert the user in case that data entered are out of 
acceptable range. External safeguards will be in place to ensure that access to the computerized system 
and to the data is restricted to authorize personnel. Servers will be stored in a physically secured, 
guarded data center. 
 
10.1.9 PUBLICATION AND DATA SHARING POLICY 
 
 
Trial readiness updates shall be presented annually at the Angioma Alliance Investigators 
Workshop. Relevant results shall be presented at a major scientific meeting and submitted for publication 
within one year of the respective interim or final analyses, including a guidelines paper on reporting 
terminology. A complete de-identified dataset containing all variables collected and a data dictionary will 
be submitted to NINDS for data sharing within a timeframe to be agreed upon with NINDS Program 
Officer. We shall discuss with NINDS the application of our data structure to vet and approve as “common 
data 
elements” 
to 
be 
applied 
in 
future 
research 
with 
this 
disease 
(www.commondataelements.ninds.nih.gov). 
 
 
 
 
10.2 ABBREVIATIONS 
AT-CCM POC Atorvastatin in CCM Proof of Concept study 
AUC 
Area Under the Curve 
BIC 
Biomarker Imaging Core 
BIOS 
Brain Injury Outcomes 
BVMC 
Brain Vascular Malformation Consortium 
CA 
Cavernous Angioma 
CASH 
Cavernous Angioma with Symptomatic Hemorrhage 
CCC 
Clinical Coordinating Center 
CCM 
Cerebral Cavernous Malformations 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CITI 
Collaborative Institutional Training Initiative 

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CLEAR 
Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage 
CRF 
Case Report Form 
DataSHaPER 
DataSchema and Harmonization Platform for Epidemiologic Research 
DCC 
Data Coordinating Center 
DCEQP 
Dynamic Contrast Enhanced Quantitative Perfusion 
eCRF 
Electronic Case Report Forms 
EDC 
Electronic Data Capture 
EDHC 
Epidemiology and Data Harmonization Core 
EQ-5D 
Euroquol-5D 
FDA 
Food and Drug Administration 
FUBV 
Follow-up and Biomarker Validation 
GCP 
Good Clinical Practice 
IRB 
Institutional Review Board 
Ki 
Permeability 
MISTIE 
Minimally Invasive Surgery Plus Rt-PA for Intracerebral Hemorrhage Evacuation 
MOP 
Manual of Procedures 
MRI 
Magnetic Resonance Imaging 
mRS 
modified Rankin Score 
NIH 
National Institutes of Health 
NIHSS 
NIH Stroke Scale 
NINDS 
National Institute of Neurological Disorders and Stroke 
PI 
Principal Investigator 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
ROCK 
Rho kinase 
QA 
Quality Assurance 
QC 
Quality Control 
QSM 
Quantitative Susceptibility Mapping 
SAP 
Statistical Analysis Plan 
SCA 
Screening and Clinical Assessment 
SD 
Standard Deviation 
SH 
Symptomatic Hemorrhage 
SOA 
Schedule of Activities 
SOP 
Standard Operating Procedure 
US 
United States 

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