Clinical trial NCT02603328
Conditions: Cerebral Cavernous Malformation
Keywords: Cerebral cavernous malformation Statins MRI Permeability Quantitative susceptibility mapping
Sponsor: University of Chicago
Start date: 2018-07-17; Completion date: 2025-03-31
Enrollment: 80 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This phase I/II randomized, placebo-controlled, double-blinded, single-site clinical trial is designed to investigate the effect of a prolonged course of atorvastatin versus placebo on CCM lesional iron deposition assessed by validated quantitative susceptibility mapping (QSM) MRI studies in patients who suffered a symptomatic bleed within the preceding one year.

Detailed description:
This phase I/II randomized, placebo-controlled, double-blinded, single-site clinical trial is designed to investigate the effect of a prolonged course of atorvastatin versus placebo on CCM lesional iron deposition assessed by validated quantitative susceptibility mapping (QSM) MRI studies in patients who suffered a symptomatic bleed within the preceding one year. Subjects will also be assessed by lesional and brain vascular permeability MRI using dynamic contrast enhanced quantitative perfusion (DCEQP) and a number of clinical evaluation tools. Subjects shall be followed for 2 years from randomization, the period of highest likelihood of rebleed after a recent CCM hemorrhage. Subjects will undergo clinical and MRI evaluations at baseline, and at 12 and 24 months during the study period. Enrolled subjects and the treating team will be blinded to treatment group allocation.

Arms: arm 1: Atorvastatin 80mg OD (optimal dose). Treatment dose will be de-escalated to 40mg based on reported adverse events. arm 2: Identically looking capsules containing no active ingredient
Interventions: intervention 1: Atorvastatin intervention 2: Placebo
Intervention descriptions: intervention 1: 40-80 mg OD intervention 2: inactive

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Version 03/28/2023 
 
Atorvastatin Treatment of Cavernous Angiomas with Symptomatic 
Hemorrhage Exploratory Proof of Concept 
(AT CASH EPOC) 
 
 
 
 
 
 
 
 
 
 
NCT02603328 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol 
March 29, 2023 (IRB approved April 18, 2023) 
 
Version 5.0 
 
 
 
 
 
 
 
 
 
 
 
 


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Atorvastatin Treatment of Cavernous Angiomas with 
Symptomatic Hemorrhage Exploratory Proof of Concept 
(AT CASH EPOC)  
Phase I-IIa Randomized, Placebo-Controlled, Double-Blinded, 
Single-Site Clinical Trial 
 
 
Study Co-chairs: 
 
Issam Awad, MD, Professor of Neurosurgery and Neurology (Principal Investigator) 
Neurovascular Surgery Program, University of Chicago Medicine 
Chicago, Illinois 
 
Daniel Hanley MD, Professor of Neurology, Brain Injury Outcomes Unit 
Johns Hopkins University Medical Institutions 
Baltimore, Maryland 
 
 
 
Supported by: 
 
Requested as an R01 Exploratory Clinical Trial from the National Institute of 
Neurological Disorders and Stroke (NINDS) 
[PAR-17-122] 
 
 
 
 
 
 
 
Sponsor of IND Exemption: 
Issam Awad, MD 
 
Registration number (clinicaltrials.gov):  
NCT02603328 
 
 


 
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TABLE OF CONTENTS 
 
    Page 
 
SYNOPSIS  
 
 
 
 
 
 
 
 
         3  
 
 
 
 
          
          
1. STUDY OBJECTIVES  
 
 
 
 
 
 
         4  
2. BACKGROUND                                                                                                                4 
            2.1  
Supporting data  
            2.2        
Rationale 
 
3.   STUDY DESIGN                                                                                                               15 
            3.1   
Patient Population  
      3.2  
Blinding 
      3.3              Randomization  
      3.4              Method of Dosing                                                                                                           
4 
SELECTION AND ENROLLMENT OF SUBJECTS                                                        17 
 
4.1   
Inclusion Criteria 
 
4.2  
Exclusion Criteria 
 
4.3  
Study Enrollment Procedures 
5.   STUDY INTERVENTION                                                                                                  19 
 
 
5.1  
Intervention, Administration, and Duration 
 
 
5.2  
Handling of Study Intervention 
 
 
5.3  
Concomitant Intervention 
 
 
5.4  
Adherence Assessment 
6.   CLINICAL, LABORATORY AND IMAGING EVALUATIONS                                          21 
 
6.1  
Schedule of Evaluations  
 
6.2  
Timing of Evaluations 
 
6.3  
Special Instructions and Definitions of Evaluations 
 
6.4  
ROCK Activity Assays 
 
6.5  
Detailed Imaging Protocols 
  7.   MANAGEMENT OF ADVERSE EXPERIENCES  
 
 
 
        33 
 
 
7.1   
Role of the Trial Nurse (TN) 
 
 
7.2   
Adverse Events Management Protocol 
 
 
7.3   
Common Adverse Events 
8.    CRITERIA FOR INTERVENTION DISCONTINUATION  
 
 
        40 
9.    STATISTICAL CONSIDERATIONS 
 
 
 
 
 
        40  
 9.1  
General Design Issues  
 
 9.2  
Outcomes  
 
 9.3  
Sample Size and Accrual  
 
 
 9.4  
Data Monitoring 
 
 
 9.5  
Data Analyses  
10.   DATA COLLECTION, SITE MONITORING, AND ADVERSE EXPERIENCE              47    
             REPORTING 
 
10.1 
Records to be kept  
 
10.2 
Role of Data Management  
 
10.3 
Quality Assurance  
 
10.4 
Adverse Experience Reporting  
 
11.   HUMAN SUBJECTS                                                                                                      60 
 
11.1 
Institutional Review Board (IRB) Review and Informed Consent 
 
 
11.2 
Subject Confidentiality  
 
 
11.3 
Study Modification/Discontinuation  
12.    PUBLICATION OF RESEARCH FINDINGS 
 
 
 
 
       60 
13.    REFERENCES CITED 
 
 
 
 
 
 
       61 


 
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SYNOPSIS 
 
Study Title 
AT CASH EPOC: Atorvastatin Treatment of Cavernous Angiomas with 
Symptomatic Hemorrhage, Exploratory Proof of Concept (AT CASH EPOC) Trial  
 
Objectives 
 
The Primary Aim of the study is to assess whether the proposed intervention pro-
duces evidence of QSM biomarker activity (indicative of reduced or increased lesional 
bleeding) during 2 years of prospective follow-up of cavernous angioma (CA) after a re-
cent symptomatic hemorrhage (SH).  
 
Secondary Aims shall assess (1) a second biomarker (DCEQP permeability in 
lesion and brain), (2) Rho kinase (ROCK) activity on peripheral blood leukocytes and on 
any excised lesion specimens during the course of the study, (3) clinical event rates, (4) 
adverse events, and (5) functional outcomes in placebo versus treatment; and (6) we 
shall query pre-specified subgroups.   
 
Design and Outcomes  
This phase I/IIa randomized, placebo-controlled, double-blinded, single-site 
clinical trial is designed to investigate a proof of concept effect of atorvastatin versus 
placebo on CA lesional iron deposition assessed by validated quantitative susceptibility 
mapping (QSM) magnetic resonance imaging (MRI) studies in patients who suffered a 
symptomatic bleed within the preceding one year. Subjects will also be assessed by 
lesional and brain vascular permeability MRI using dynamic contrast enhanced 
quantitative perfusion (DCEQP) and a number of laboratory and clinical evaluation tools. 
Subjects shall be followed for 2 years from randomization, the period of highest likelihood 
of rebleed after a recent CA hemorrhage. Subjects shall undergo clinical and MRI 
evaluations at baseline, and at 12 and 24 months during the study period. Enrolled 
subjects and the treating team shall be blinded to treatment allocation. 
 
Interventions and Duration 
Enrolled subjects will be randomized 1-1 to atorvastatin (starting dose 80 mg PO 
daily) or placebo. Dosing shall continue for the 24-month follow-up period or until reaching 
a safety endpoint, whichever comes first. The study shall continue until all enrolled 
subjects, including those reaching safety endpoints, have undergone their 24 month (end 
of study) MRI and clinical assessment. Laboratory studies are also performed at 3 months 
after dose initiation. Dose de-escalation to 40 mg/day or identical placebo capsule shall 
be allowed at any time during the course of the study, in the case of pre-articulated side 
effects or laboratory abnormalities at the initial dose. At the 12 and 24-month follow up 
visits, clinical evaluations, and lesional QSM, brain and lesional DCEQP permeability, and 
peripheral blood leukocyte ROCK activity will be assessed to determine the response to 
atorvastatin or placebo.  


 
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Sample Size and Population  
The study is designed to include 80 subjects, randomized 1:1 to receive either 
atorvastatin or placebo. Randomization is stratified to insure a balanced treatment 
allocation by gender. The sample size was expanded by 37% to accommodate a a highest 
possible estimate of missing data and potential attrition due to compliance, drug 
intolerance and safety endpoints, leaving at least 25 subjects in each of placebo and 
atorvastatin groups, which, per power calculations, are needed to detect a relevant 
difference in primary QSM biomarker. Subjects will be enrolled at the study investigator’s 
institution where trial preparations have been optimized. Case referrals will be 
encouraged through a regional referral Chicago-wide academic and clinical consortium, 
and through the Angioma Alliance.  
 
At midpoint of the trial, futility analysis is planned, and adaptive recalculation 
of sample size based on the actual observed primary outcome and treatment effect.  
 
 
 
1. STUDY OBJECTIVES 
 
The Primary Aim of the study is to assess whether the proposed intervention pro-
duces evidence of QSM biomarker activity (indicative of reduced or increased lesional 
bleeding) during 2 years of prospective follow-up after a recent symptomatic hemorrhage. 
The primary outcome is the mean percent change in QSM (called the change score) 
per year. Reduced CA hemorrhage would be a signal proof of concept of potential ben-
efit, and increased hemorrhage a potential signal of risk. Primary analysis shall be based 
on intention to treat, and secondary analysis shall examine treatment rendered, consid-
ering attrition and compliance. In cases with multiple lesions, QSM measurements in the 
lesion with initial SH (index lesion) shall be considered for the primary outcome assess-
ment.  
Secondary Aims shall assess (1) a second biomarker (DCEQP permeability in 
lesion and brain), (2) ROCK activity on peripheral blood leukocytes and on any excised 
lesion specimens during the course of the study, (3) clinical event rates, (4) adverse 
events, and (5) functional outcomes in placebo versus treatment; and (6) we shall query 
pre-specified subgroups.   
  
 
2. BACKGROUND 
 
2.1 
Supporting data 
A Common Lesion, an Uncommon Disease. Cavernous angiomas (CAs) consist 
of clustered, giant, blood-filled capillary spaces (“caverns”), lined by endothelium, and 
separated by an amorphous matrix lacking mature vessel wall angioarchitecture (1). CAs 
occur in a sporadic form, manifesting a solitary lesion or a cluster of lesions associated 
with a venous developmental anomaly (2). The disease is familial in 20-30% of cases, 


 
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associated with multifocal lesions that develop over time throughout the patient’s brain 
(3). The familial form (OMIM #116860) exhibits a Mendelian autosomal dominant inher-
itance 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 mo-
dality for these lesions, including sequences revealing chronic and acute hemorrhage, 
and tiny occult lesions. 
CAs are often detected incidentally, or in association with seizures or non-specific 
neurologic symptoms (11-13). The prevalence of CA has been estimated at 0.46-0.63% 
of the population based on consecutive imaging studies in the MRI era (14, 15). A 0.5% 
prevalence was confirmed by the detection of 131 CAs among 24,535 consecutive au-
topsies (16). The natural history of such lesions is exceedingly benign, with less than 
<0.5% annual risk of clinically significant hemorrhage, and there is evidence-based con-
sensus about not needing interventions beyond symptomatic management of such cases 
(17). But once a lesion has manifested a symptomatic hemorrhage (SH), its untreated 
clinical course is quite serious, with a 42.4% (CI 26.8-58.0) rate of recurrent bleed or focal 
neurologic deficit within 5 years (17-19). The highest likelihood of rebleeding in CAs with 
SH is in the following 2-3 years, with bleeding risk subsequently regressing to the low rate 
of asymptomatic lesions. CA with SH is hence a singular clinical entity, distinguish-
ing lesions impacting a patient’s life and meriting clinical intervention. The definition 
of SH in CA has been validated and adjudicated (20).   
Based on <10-12% prevalence of SH among all CAs and assuming 0.5% of 325 
million Americans harbor a CA, it is projected that fewer than 162,500 to 195,000 patients 
are living with a cavernoma that has bled at least once. Another recent population-based 
study in Olmsted County, MN identified CAs in 0.41% of adults undergoing MRI for non-
clinical purposes. In that study, the prevalence of symptomatic disease was only 0.037% 
(21). This would translate to an estimated prevalence of 120,000 symptomatic CAs in the 
U.S population. A fraction of these would have had a recent SH. Thus, while overall CAs 
are common, those that are symptomatic and warranting therapeutic targeting, and par-
ticularly the CA with SH meet the rare disease definition of <200,000 affected Amer-
icans, by any estimate. 
An Umet Clinical Need and Consensus Regarding the Therapeutic Target. CAs 
are typically observed expectantly, and surgically excised only after significant clinical 
sequelae (typically one or more SH). Healthcare costs of hemorrhagic stroke can reach 
up to $27,400/case in the first 90 days (2007 dollars), excluding socioeconomic impact of 
lost productivity (22). 
Lesions in the brainstem and deep brain locations are more likely than other CAs 
to bleed (23), rebleed (19), and cause severe disability (18, 24). 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. While brain surgery for excision of CA may benefit some patients, it can be 
associated with significant cost and morbidity. A typical craniotomy costs $37,438 in 2011 
dollars (25), excluding the cost of complications and morbidity. Surgical excision of CAs, 
particularly brainstem lesions, is associated with an alarming rate of surgical adverse 
events (Figure 1) (26). Hence, excision of CA is typically considered per current clinical 


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practice and evidence-based guidelines only after one or more recurrent SHs, partic-
ularly in deep or brainstem locations (17, 27). In a non-randomized population-based 
cohort study, lesion excision was overall associated with significantly worse functional 
outcomes and greater complications compared to conservative management (26). Stere-
otactic radiosurgery has been used to treat CAs but there is controversy about its effec-
tiveness and concern about complications and radiation-induced genesis of new CA le-
sions (28, 29). 
The rates of development of a new CA (in familial cases), and of first SH in asymp-
tomatic CAs, are far too low to allow meaningful testing or to compel primary prevention 
strategies.  CAs 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 guidelines (17), with clinical equipoise for testing novel therapies 
aimed at preventing re-bleeding. It would be desirable to develop a drug that stabi-
lizes the CA after a recent SH, and prevents recurrent bleeding. It would mitigate 
the costs and neurologic sequelae of re-bleeds and surgical resection in many pa-
tients. Based on all natural history studies, the therapeutic benefit for secondary preven-
tion (symptomatic re-bleed) would be greatest within 2-3 years after an SH (17-19). 
 
Figure 1. Incidence of adverse events after surgical treatment for CA. Note particularly high rate of morbidity in 
brainstem CAs, those reported with highest reported rebleed rates, and greatest disability. From Moultrie et al (26). 


 
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2.2. Rationale 
Preliminary Studies: Mechanistic Rationale, Preclinical Studies and Bi-
omarker Validations  
Defective Endothelial Barrier and Chronic Bleeding as Hallmarks of CA Pathology. 
CAs invariably exhibit hemosiderin (and other non-heme iron) deposition indicat-
ing chronic hemorrhage (30, 31). Our group (32) and others (33, 34) documented that 
the endothelial cells (ECs) lining lesional caverns manifest a “leaky” phenotype, with a 
defective EC barrier. Loss of KRIT1 results in disruption of junctional integrity, resulting 
in increased endothelial permeability in vitro (35) and in vivo (36). Loss of Malcavernin 
and PDCD10 has similar effects (36-38). Importantly, although familial CCM patients may 
be heterozygous for CCM1, CCM2 or CCM3 mutations, the ECs within CA lesions show 
loss of the relevant protein (39), due to a somatic mutation of the remaining wild-type 
allele at the respective locus (40, 41). Similar somatic mutations have been described 
in sporadic CA lesions as familial ones (42), indicating that an identical disease 
pathway resulting in lesional loss of CCM protein underlies familial and sporadic 
CAs.  
CCM Gene Loss Results in Endothelial Permeability, Mediated by RhoA/ROCK 
Activation. The loss of any of the 3 disease genes in ECs activates the GTPase protein 
RhoA, and results in increased actin stress fiber, decreased EC lumen formation and 
increased permeability (36, 37, 43, 44). Recent evidence that CAs arise from endo-
thelial gain of MEKK3-KLF2/4 signaling, also showed that this activity is upstream 
of RhoA, and that the causative effect on CA development is mediated via Rho ac-
tivation (45). The activity of Rho kinase (ROCK), an effector of RhoA, is also increased 
in these systems, reflected by phosphorylated myosin light chain (pMLC), a critical target 
of ROCK (36, 43, 44). ROCK activation was demonstrated in surgically excised hu-
man CA lesion specimens from sporadic and all 3 familial genotypes (36, 38, 42). 
ROCK Inhibition Reverses CCM-Related Cellular Phenotypes. Work from our 
group in collaboration with Ginsberg at UCSD demonstrated that ECs from Ccm1+/– or 
Ccm2+/– mice exhibit a generalized vascular leakage in vitro and in vivo that is reversed 
by fasudil, a specific ROCK inhibitor (36). Others have reported that the vascular leakage 
in Ccm2+/– mice can be inhibited by statins which inhibit RhoA prenylation, a critical early 
step in RhoA/ROCK activation (37). Thus inhibition of ROCK is a potential therapeutic 
target, reversing CCM-related junctional instability in sporadic and familial lesions 
which harbor similar somatic mutations and robust ROCK activity (42).  
Animal Models in the Heterozygous State Recapitulate the Human Disease. New 
opportunities to investigate CA pathogenesis arose from our discovery, and confirmation 
by Douglas Marchuk at Duke University and others, of biallelic somatic mutations in CA 
lesions (39-41). Based on the postulated two-hit Knudsonian mechanism, Marchuk and 
our team jointly developed a robust mouse model of CCM, recapitulating the human dis-
ease in the heterozygous state (46-48). When crossed into a background of elevated 
somatic mutation load (Trp53-/- or Msh2-/-), Ccm1, 2 or 3+/- (heterozygous) mice manifest 
a rich repertoire of lesions with histology, phenotypic signatures and ultrastructure identi-
cal to the human lesions. These models helped us characterize the burden of primordial 
and mature CCM lesions, and quantify lesional hemorrhage (integrated density of 


 
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non-heme iron accumulated in lesions). We then hypothesized that in vivo ROCK in-
hibition with Fasudil or statins would inhibit lesion development and hemorrhage.  
Fasudil but not Simvastatin Blunt CA Lesion Development. Both Decrease Hem-
orrhage in Murine Lesions. Our group was first to show that ROCK inhibitor fasudil pre-
vents CA lesion development in murine Ccm1 model (49). Further preclinical studies have 
confirmed these results in a larger cohort of mice using contemporaneous randomized 
treatment assignment versus placebo, and blinded outcome assessment per NINDS 
guidelines (50). Oral fasudil, administered at 100 mg/kg/day from 1-4 months of age sig-
nificantly reduced the development of mature (multicavernous) CA lesions. Oral simvas-
tatin 40 mg/kg/day had no significant effect on lesion development. Both fasudil and 
simvastatin significantly decreased non-heme iron deposits in CA lesions compared to 
placebo, indicating decreased lesional hemorrhage (51). Decreased iron burden by 
fasudil and simvastatin were also noted in the Ccm2 model. ROCK inhibition also signifi-
cantly decreased CCM iron leak after lesion development, when ROCK inhibitor was ad-
ministered for only 1 month, later in the mouse’s life. 
Atorvastatin Recapitulates the Benefits of Fasudil, Better Than Simvastatin. As 
simvastatin dose escalation is currently limited by the U.S. Food and Drug Administration 
(FDA), we sought to test the more potent drug atorvastatin (52) in our models, par-
ticularly since higher doses of atorvastatin have been shown to effect more robust 
ROCK inhibition in humans (53, 54). The same Ccm1+/-Msh2-/- mice were more recently 
treated with oral atorvastatin at 80 mg/kg/day for the same duration as with the prior ex-
periements, and these achieved significant robust inhibition of lesional development and 
hemorrhage, as with fasudil (Figure 2). In these recent experiments, lesion burden was 
assessed by newer demonstrably more rigorous volumetric micro-CT technique (55). We 
then contemporaneously assessed pharmacologic ROCK inhibition in the more aggres-
sive Ccm3+/-Trp53-/-  model (38), with random treatment assignment to placebo, 
fasudil, simvastatin and atorvastatin, at the same doses and for the same duration as 
with the other genotypes. Atorvastatin again showed a significant and robust benefit 
in both lesion development and hemorrhage, similar to fasudil, but better than 
simvastatin (Figure 3). This is the first evidence of therapeutic benefit of ROCK inhibition 
in the most aggressive Ccm3 model. There were significantly fewer pMLC immunoposi-
tive ECs lining CA lesions, and fewer pMLC immunopositive leukocytes within the lesions 
in atorvastatin treated brains, consistent with blunted ROCK activity (Figure 4).  Alto-
gether, these results establish a firm biologic premise of (1) therapeutic benefit by 
atorvastatin similar to specific ROCK inhibitor fasudil, and better than the lower 
potency simvastatin, and (2) effect of atorvastatin is associated with ROCK inhibi-
tion effect.  
There were neither deleterious effects on animal weights nor on the rate of attrition 
with any statin treatment of murine models of all genotypes from weaning to 4 months of 
age. Animals which died before completing statin therapy, had no greater prevalence of 
cerebral hemorrhage than those taking placebo or fasudil. These preclinical results reas-
sure us that chronic statin therapy, including higher potency atorvastatin effecting 
ROCK inhibition, decreases iron leak in murine CA lesions, with no hint of in-
creased hemorrhage or attrition. Interestingly, while the benefit of fasudil was limited 
to male cohorts (51), there was significant benefit of atorvastatin (lesion burden and iron 


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deposit) in both male and female mice in these latest studies.    
 
 
 
  
Quantitative Susceptibility Mapping (QSM) as a Biomarker of CA Lesional Hemorrhage. 
Since iron deposit in lesions is modified by ROCK inhibitor and statins in mice, the Awad group 
has recently applied a novel technique for assessing iron concentration in CA lesions using 
C 
Figure 3. ROCK inhibition in Ccm3+/-Trp53-/- mu-
rine brains. Representative images show de-
creased (A) lesion burden by micro-CT volumet-
rics. (B) non-heme iron deposition by Perls staining 
with atorvastatin treatment, bar=100Pm. (C) 
Fasudil and atorvastatin, but not simvastatin, de-
creased lesion burden (pink bars, left axis) com-
pared with placebo. All 3 drugs decreased non-
heme iron per brain (blue bars, right axis), an effect 
most  robust with atorvastatin. 
 
A 
B
Figure 2. Atorvastatin 80 mg/kg/day 
decreased lesion burden (pink bars, 
left axis) and non-heme iron (blue 
bars, right axis) compared with place-
bos in Ccm1+/-Msh2-/- mice. 
 
Figure 4. Chronic atorvastatin treatment 
significantly reduced the prevalence of 
pMLC (a marker of ROCK activity) im-
munopositive ECs lining CAs, and leuko-
cytes within lesions in brains of Ccm3+/-
Trp53-/- mice. Immunopostivity was as-
sessed by two observers blinded to treat-
ment assignment. 
C


 
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quantitative 
susceptibility 
mapping (QSM) on MRI. We 
published validations of the 
technique including precise 
correlations of QSM with iron 
concentration in ferric, ferrous 
and ferumoxytol phantom so-
lutions, and the exact predic-
tion by QSM of iron content in 
excised CCM lesions assayed 
by mass spectroscopy (56). 
We later showed strong in-
terobserver 
agreement 
in 
QSM measurements in human 
CAs, stability of QSM in clini-
cally stable lesions, reproduci-
bility of QSM across MRI in-
strument platforms at two hos-
pitals, and greater lesional 
QSM in older patients and in 
cases with prior symptomatic 
bleeds (57). 
 
In other pilot work we 
show significant correlation of 
mean lesional QSM in murine 
brains imaged ex vivo in the human 3T MRI magnet, with histologic iron densitometry of Perls 
staining of the same lesions after brain sectioning (Figure 5). This demonstrates that differences 
in QSM may be used to assess the same parameter of treatment effect (lesional non-heme 
iron density) impacted in preclinical studies. The observed 87.8-100% range of artorvastatin 
treatment effect on Perls iron stain intensity in Ccm1 and Ccm3 models (Figures 2-3) would cor-
respond to an effect size of 0.043 to 0.151 ppm difference in mean lesional QSM. 
Linking QSM Change to Clinical Events in Longitudinal Follow-up of Previously 
Stable Human CAs.  
 
Figure 5. Correlation of mean lesional non-heme iron density on coronal 
hostologic images at largest lesion diameter (Y axis, log transformed), 
and mean lesional QSM by volumetric MRI at 3T (X axis, in ppm) in 
murine brains with CA lesions. At left are representative coronal 
histologic slices with H&E and Perls stain, and a matched coronal MRI 
QSM image of the same lesion obtained ex vivo prior to brain sectioning. 
 
Figure 6. QSM changes during person-year epochs in longitudinal follow-up of previously stable CA lesions. (Left) 
Lesions manifesting growth or symptomatic bleeding during follow-up exhibited a significant increase in QSM (+ 
44%, *p=0.01). (Center) Lesions which remained stable had a slight significant decrease in QSM (-3.2%, 
**p=0.003). In cases with multiple lesions, the unstable and stable lesions were analyzed separately. (Right) Re-
ceiver operating curve of sensitivity and specificity of QSM change in association clinical events.  


 
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We recently reported the first prospective assessment of QSM during longitudinal 
follow-up of human CCM subjects, and correlated paired QSM assessments during 1-
year epochs with new clinical events (58). Among cases without recent bleeding or lesion 
growth within a year of the first measurement, CCM lesions that remained stable during 
longitudinal follow-up had a tiny average decrease (-3.2%) in mean lesional QSM. CCMs 
with demonstrated growth or symptomatic bleeding exhibited a significant increase 
(+44%) in mean lesional QSM (Figure 6). Receiver operating curves (ROC) of QSM 
change in individual subjects demonstrated a sensitivity of 82.29% and specificity of 
88.89% at a +5.81% threshold change, highly significant (p = 0.0004), with a mere 
+5.81% QSM change. These results link a robust QSM change directly to clinical 
events, and define a threshold QSM change as a sensitive and specific biomarker 
event.  
QSM change and clinical events in CAs after recent Symptomatic Hemorrhage. In 
further pilot studies, we assessed lesional QSM change during prospective follow-up of 
a pilot cohort of CA patients with a clinical bleed within the prior year (meeting the 
proposed trial criteria) (59). 
  
Sixteen subjects followed for 1 or 2 years (total 22 person-year epochs), underwent 
paired QSM assessments at the beginning and end of each person-year epoch. Mean 
QSM in the index CA hemorrhagic lesion increased by an average of +7.93% per person-
 
Figure 7. (Left) QSM measurements at the beginning and end of 22 person-year epochs of follow-up of cases with CA that 
had bled within 1 year, and followed for 1-2 years. Cases underwent annual QSM, allowing paired measurements at the 
beginning and end of each person-year epoch. In cases with multiple lesions, only QSM measurements in the lesion with 
initial hemorrhage (index lesion) were considered herein. Paired measurements in red identify epochs with a recorded 
threshold QSM increase by >6% in the index lesion. (Right) Number of person-year epochs with and without threshold QSM 
change, and clinical events during these epochs. All clinical events occurred in the setting of > 6% increase in QSM (59). 
 


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year epoch in the full cohort. Closer examination revealed 10/22 epochs with a docu-
mented threshold biomarker event (≥6% QSM increase). This was twice as frequent 
as clinical events. No clinical event occurred without a threshold increase in QSM 
(Figure 7). A primary aim of the proposed trial shall explore whether the change in 
QSM is altered by statin treatment. A secondary aim shall explore the relationship 
of QSM change to clinical events in statin and placebo treated subjects. 
 Quantitative Vascular Permeability in Lesion and Brain as a Potential  Biomarker 
of Statin Therapy. Work by the New Mexico and Chicago groups demonstrated vascular 
hyperpermeability in human CA lesions, using dynamic contrast enhanced quantitative 
perfusion (DCEQP) MRI technique with gadolinium (60, 61). Our group further showed 
that more permeable CA lesions by DCEQP are associated with greater mean QSM (60). 
And we recently demonstrated, as with QSM, that CAs that bleed during longitudinal 
surveillance also manifest significant increases in lesional permeability (mean 
change +85.9%; p = 0.005) (58).   
Our group has also reported greater 
permeability in normal brain white matter far 
(WMF) from lesions in familial cases (con-
sistent with germline hemizygosity of CCM 
genes in those patients), than in sporadic 
cases (whose normal brain is unaffected by 
CCM genes) (62). Nine CA subjects, already 
taking statins for routine cardiovascular in-
dications unrelated to CA (5 familial, 4 spo-
radic), had lower mean WMF permeability 
than 60 cases not taking statins (34 familial, 
26 sporadic) (Figure 8) (62). This effect was 
observed in both sporadic and familial 
cases, and we can postulate that it may reflect 
ROCK inhibition by statin in background brain.  
No differences in lesional permeability 
were noted with statin exposure in this retro-
spective cohort. Neither were consistent effects on lesional permeability noted in the first 
clinical trial of simvastatin (up to 40 mg/day) in familial patients with common Hispanic 
CCM1 mutation (trials.gov# NCT0176445), performed by the New Mexico group (interim 
results, CCM Investigators Workshop, Washington, DC, November 2015). However, it 
remains unclear if there would be an effect of statins on permeability of CA lesions 
after recent SH, where a large increase in mean lesional permeability is demon-
strated (58), or whether higher statin doses would achieve greater permeability re-
ductions consistent with more robust ROCK inhibition (53, 54). These results and 
critical knowledge gaps justify continued exploration of vascular permeability biomarker 
in association with a treatment mechanistically targeting ROCK mediated hyperpermea-
bility. The impact on lesional and brain vascular permeability of statin, at doses 
effecting ROCK inhibition, shall be examined as a secondary aim in the proposed 
trial.  
 
 
Figure 8. The effect of concomitant statin use on 
vascular permeability measured by DCEQP in 
white matter far from lesions (WMF). There was a 
trend towards lower WMF permeability (Ki) in pa-
tients taking statins for cardiovascular disease 
than those not taking statins, in sporadic and fa-
milial CA subjects (P=0.07) (62). 


 
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Translation to Human Therapies and the Choice of Drug and Dose 
Safety Considerations and Potential Translation to Human Therapies. Fasudil is a 
specific ROCK inhibitor (63) approved for human use in Japan with an intravenous dose 
of 90 mg/day, for a period of 2 weeks to prevent cerebral vasospasm after aneurysmal 
subarachnoid hemorrhage (64). Experience with more chronic administration of fasudil in 
man is limited, and serious adverse events have been reported (65). Because of the pau-
city of experience and questionable safety in chronic use, and the expired worldwide pa-
tent on the drug, there is currently no pathway for the approval of fasudil for chronic 
use in man. The pharmaceutical industry is developing a number of potential ROCK1 or 
ROCK2 inhibitors for more specific targeting of peripheral and brain vasculature, respec-
tively. While a ROCK2 inhibitor might enhance therapeutic effects on brain vessels in-
cluding CAs, and minimize peripheral side effects (more likely mediated by ROCK1), such 
drug has not been used in humans and is now undergoing preclinical development 
(R44NS095420 grant with Awad as coPI). A pharma pipeline for safer or more effec-
tive chronic ROCK inhibitors will require several years before potential Investiga-
tional New Drug (IND) and clinical trials in man. 
 
Therapeutic clinical trials with statins have already been advocated in CAs based 
on statin inhibition of RhoA prenylation, a critical early step in RhoA/ROCK path-
way activation (37, 66, 67). A clinical database at University of Chicago includes 24 hu-
man subjects with known CAs enrolled in Institutional Review Board (IRB) approved 
NINDS funded biomarker studies, who are receiving various statins for routine cardiovas-
cular indications unrelated to their CA disease (atorvastatin 10-80 mg; simvastatin 10-60 
mg; lovastatin 80 mg). Among those patients followed for 247 lesion-years (T2-weighted 
lesions > 4 mm counted), there was only 1 documented SH (0.4 SH per 100 lesion-years). 
This rate is substantially lower than 173 bleeds during 1,604 lesion-years  (T2-weighted 
lesions > 4 mm) of follow-up of  statin naïve cases in the same database (10.7 SH per 
100 lesion-years). While this data does not control for treatment assignment or dose ef-
fect, it does not raise any concern about hemorrhage tendency among CA patients 
receiving statins nor in comparison to bleed rates reported in the literature (18). Nor 
have there been any cases in the New Mexico trial (see below, and letter by Leslie Mor-
rison) nor any reported case in the published literature of CA hemorrhage after initiation 
of statin therapy (Search was performed on August 20th 2017 using MEDLINE portal for 
keywords “cerebral cavernous malformation”, “angioma” or “cavernoma” and “statin” or 
“atorvastatin” and “hemorrhage” or “bleeding”).  
Statins have been widely used and well tolerated in neurosurgical patients, includ-
ing (as with fasudil) for the treatment of vasospasm after subarachnoid hemorrhage (68). 
Statins have recently been reported to portend better outcome after intracerebral hemor-
rhage in man (69). In a meta-analysis of clinical trials of stroke prevention, including 
83,205 patients, there was no evidence of increased hemorrhagic risk with long term 
statin use (70). Two clinical trials of stroke prevention (but not all others) did suggest a 
potentially increased hemorrhage risk with statin in secondary analyses (70). In one 
study, preconditioning and possibly the early withdrawal of statin were observed to 
worsen cerebral vasospasm after subarachnoid hemorrhage (71). Two recent reports as-
sociated statin use with cerebral aneurysm rupture (72) and with cerebral microbleeds in 
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Considering all evidence class and level, current American Stroke Association guidelines 
on management and prevention of intracerebral hemorrhage include no restrictions on 
the use of statins in patients with hemorrhagic stroke (74). Altogether there is no hint of 
deleterious effects on statin-treated murine CA models (in fact statins resulted in de-
creased lesional hemorrhage), nor any suspected or reported harmful effects in humans 
with CA to date, These cautious enthusiasm and concerns about other potentially 
harmful pleiotropic effects, create a veritable equipoise, motivating a need for spe-
cific and careful study of statins in hemorrhagic CA (75).  
The Case for Atorvastatin as the Study Drug, at Doses Effecting ROCK Inhibition 
in Humans. A Phase I safety trial with simvastatin at dose up to 40 mg/day (trials.gov# 
NCT0176445) noted no deleterious effects in open label enrollment. At least one patient 
in that trial manifested a dramatic decrease in lesional and brain permeability upon initi-
ating statin therapy (See letter by Leslie Morrison). That trial was limited to familial cases 
with common Hispanic CCM1 mutation, and enrolled cases with largely stable CAs with-
out recent SH. It was not designed to explore higher statin doses effecting maximal 
ROCK inhibition, nor was it designed to include sporadic and familial cases after re-
cent SH. While that trial was underpowered, and a different case selection and enhanced 
biomarkers may have offered better sensitivity, the results argue for dose escalation or 
for testing another statin. Simvastatin limits dose escalation above 40 mg/day per current 
USFDA label. Atorvastatin is approved for higher doses, twice as potent as simvastatin 
in measurable effects (52). Doses of atorvastatin of 40-80 mg/day are needed to 
achieve a robust pleiotropic ROCK inhibition effect, specifically assayed in human 
peripheral blood leukocytes (53, 54). Rosuvastatin, which allows even higher dose es-
calation than atorvastatin has not been used as long or by as many patients as atorvas-
tatin. A systematic review of atorvastatin tolerance and side effects at those doses 
was carefully considered in the design and safety monitoring plan of the proposed 
trial.  
Equivalency of Mouse Versus Human Atorvastatin Dose. In humans the dosage 
of statins varies between approximately 0.1–1 mg/kg  bodyweight, while most studies in 
rodents have used doses of 1–100 or even 500 mg/kg (76). An atorvastatin mouse dose 
of 80 mg/kg/day is equivalent to a calculated “human starting dose” of  44.8 mg/day ac-
cording to USFDA guidelines: Human starting dose = Mouse dose X 0.08 (Scaling factor) 
X 70 kg (Adult weight) (77, 78). A plasma area under curve (0-24 hours) profile for 
atorvastatin indicates that a human dose of 96 mg/day replicates the mouse dose of 80 
mg/kg/day (79). And per empiric evidence, at least 100 mg/kg/day dose is needed to 
decrease disease activity in a collagen induced arthritis murine model (80, 81) while 
atorvastatin at 40 mg/day decreases the disease activity score (DAS28) in arthritis pa-
tients (82, 83). And we noted ROCK inhibition effect in mice with atorvastatin 80 
mg/kg/day, an effect observed in humans at 40-80 mg/day. Hence the atorvastatin dose 
of 80 mg/kg/day in our preclinical experiments corresponds to a human dose range 
of 40-80 mg/day, commonly used in clinical practice and shown to achieve ROCK 
inhibition pleiotropic effect.  We propose to use these same doses in the proof of con-
cept trial. 
 
 


 
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3 STUDY DESIGN 
 
3.1 Patient Population 
The study will enroll 80 adult patients 18-80 years of age (inclusive) with untreated 
CAs of all genotypes who suffered an adjudicated symptomatic lesional hemorrhage (20) 
within one year of enrollment. The hemorrhagic lesion would need to have been consid-
ered for surgery, and ultimately not resected. We are hence specifically targeting deep 
and brainstem lesions with greatest risk of rebleeding in the subsequent 2 years, most 
likely to benefit from stabilizing vascular leak. Given identical somatic mutations and 
demonstrated lesional ROCK activity (38, 42), cases with sporadic and familial CAs of all 
genotypes are included (except for post-irradiation cases). Inclusion and exclusion criteria 
are detailed in Protocol Section 4, aiming to exclude cases receiving prior statin therapy 
in any form or for any indication in the prior year, cases at high risk for statin intolerance, 
cases where the hemorrhagic lesion has been treated with surgery or radiation, and other 
customary exclusions in similar trials. Children will not be enrolled, per Investigational 
New Drug (IND) exemption restriction for this trial.  
The Neurovascular Surgery Program at the U Chicago has an international reputa-
tion in CA clinical care and research (www.uchospitals.edu/ccm) and is the first recog-
nized Center of Excellence by the Angioma Alliance (www.angioma.org). During the 
past 2 years (June 2015 - May 2017) the study PI’s clinic evaluated  171 CA patients, and 
149 cases, or 87% were enrolled in IRB approved clinical surveillance and bi-
omarker validation projects. Of these, 37 had suffered a SH during the prior year, 3 of 
whom were on statin therapy and 7 underwent surgery for lesion excision upon SH (in-
cluding a case on statin). Hence, 28 subjects (14/ year) would have met inclusion criteria, 
and at least 12 cases/ year would be enrolled in At CASH EPOC trial from current U 
Chicago case activity, based on our 87% enrollment record in IRB studies even without 
promised intervention. This in in addition to cases (“on the docket”) who bled in the year 
prior to trial launch. 
We plan to boost trial enrollment from Chicago Consortium sites (see letters from 
NU, Rush UIC Neurosurgery Chiefs, and Chicago StrokeNet PI Dr S Prabhakhan) target-
ing >30 CA cases/year with SH for screening, but need only enroll 10 additional 
cases/year though these regional referrals and other healthcare professionals in the 
Chicago Neurological Society (including all practicing neurosurgeons and neurologists 
serving a 9 million regional population within driving distance of our center). The Angioma 
Alliance (see letter)  has identified 48 CA cases throughout the U.S. with SH in the prior 
year, not taking statins, whose lesion was not resected and who expressed willingness to 
travel for a trial. We target screening of 20 such cases but need only enroll 5 additional 
cases/year through this national referral to meet our enrollment trarget.  
Our team has used similar Chicago consortia to recruit cases for the CLEAR and 
MISTIE trials. The Angioma Alliance has had a strong record of referring patients from 
outside Chicago and their enrollment in research studies at our site. We plan a city wide 


 
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seminar upon approval of the trial, and secured its funding from the Kluver Memorial 
fund at U Chicago, to present it to regional clinicians. Trial brochure (attached) and trial 
status updates shall be e-mailed to members of the Chicago Neurological Society, to 
the Society of Neurological Surgeons (including all U.S. neurosurgery academic chairs 
and program directors) and to all registered CA patients in the Angioma Alliance every 6 
months. We intend to facilitate the enrollment and retention of trial subjects from out-
side the region, with stipends covering travel expenses for enrollment and follow-up visits. 
We note that there is no other ongoing clinical trial of a competing therapy.  
Back up no-cost plan of extending enrollments into year 4 can be considered, 
and a last resort option of enlisting another site with accredited biomarker validations, and 
a record of case enrollment through the CASH Trial Readiness network (U01 
NS104157, 2017-2022) also led by the trial PI. Retention is promoted through 
scheduled calls every 3 months, and emails with trial status updates every 6 months to 
enrolled subjects. 
 
 
3.2 Blinding 
 
The study is designed as a double-blind, placebo-controlled clinical trial. Enrolled 
subjects will be blinded to treatment rendered, as will the PIs, outcomes assessors 
processing the radiological biomarkers, the trial staff at the Chicago site and the Data 
Coordinating Center (DCC) staff at the Baltimore site. Atorvastatin and placebo capsules 
will be formulated by a third party pharmacy representing two different doses of 
atorvastatin (40 and 80mg) or placebo.  The Research Pharmacy at the Chicago site shall 
be informed electronically about the treatment allocation (see Section 3.3 
Randomization), and it shall dispense the appropriate drug or placebo in a 6-month 
supply, given at enrollment then mailed by the study team biannually, one month ahead 
of expected date of exhausting the supply. Subjects in the treatment group will receive 
unlabeled color coded capsules containing pulverized atorvastatin tablets in the 
designated doses. Subjects in the control group will receive identical looking color coded 
capsules containing inactive filler. In the case of dose de-escalation, the Research 
Pharmacy shall be instructed about the decision to lower the dose, and it shall dispense 
capsules of different color indicating the lower dose, or identical colored placebo 
capsules, without breaking the blind to the patient or research team.  
The Baltimore statistician shall prepare safety reports including comparison of 
adverse events (AEs) and interim outcome measures by treatment group labeled as A or 
B without identifying either as active treatment (See Sections 9.4 on Data Monitoring and 
10.3 on Quality Assurance and Data and Safety Monitoring). If a concern is raised about 
safety and the need to suspend trial enrollment, the independent medical safety monitor 
(IMSM) may request to identify A or B groups as treatment or placebo. Individual subjects 
will not be identifiable in the safety reports, maintaining the double-blinding if the trial is 
resumed.  
 


 
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3.3 Randomization  
Once a patient is determined to be potentially eligible for participation in the study, 
the site coordinator or a designated member of the study team at the Chicago site will 
enter the Inclusion/Exclusion information about the study subject into the VISION 
(Prelude Dynamics, Austin, Texas) web-based electronic case report form (eCRF) 
system. The VISION system will process these subject variables, determine eligibility and, 
if eligible, assign an identification number and treatment method to the patient. The 
randomization process is handled by an embedded software module designed using SAS 
(v.9.4 or higher). This module is part of the system and is invoked by the coordinator or 
investigator within the eCRF system. Randomization is triggered by the investigator or 
coordinator, via completion of a form in the eCRF, after all eligibility checks are performed. 
If the coordinator/investigator checks the randomize box and saves the form, the system 
will automatically set the enrollment date, assign a study ID and trigger the embedded 
randomization algorithm to determine the randomized treatment (including a final check 
to make sure the subject meets all eligibility criteria).  The site coordinator is provided with 
a unique, blinded electronic treatment assignment number (randomized patient number) 
at the end of this process. 
Enrolled subjects are randomized to the atorvastatin or placebo arm in a 1:1 
ratio. Randomization shall be stratified by sex, with separate permuted blocks for 
each sex. A unique treatment assignment number (randomized subject number) and its 
corresponding treatment group allocation will be generated. This shall be communicated 
electronically through to the Research Pharmacy in Chicago, to appropriately dispense 
the capsules containing active drug or placebo.  
 
3.4 Method of Dosing 
After randomization, enrolled subjects in both groups will be given unlabeled color-
coded capsules to be taken once daily. In the absence of signs or symptoms of statin-
related adverse events (Table 2), subjects will be instructed to continue on the same 
regimen. The dose may be de-escalated based on subject’s tolerance. Subjects reporting 
adverse events per pre-specified criteria (Category B detailed below) will be put onto the 
lower dose (40 mg/day) of atorvastatin, with a different color. Subjects randomized to the 
placebo arm will receive an equivalent supply of identical color unlabeled capsules, 
devoid of the active ingredient, to be administered in the same fashion as the active drug. 
They will undergo the same evaluations, dose adjustments, and follow up visits as the 
treatment cohort. 
 
 
4. SELECTION AND ENROLLMENT OF SUBJECTS 
 
4.1 
 Inclusion Criteria 
 
4.1.1 Age 18-80 (inclusive). 


 
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4.1.2 Asymptomatic, mild or moderate disability requiring some help but 
able to attend own bodily needs without assistance. Defined as 
modified Rankin score (mRS) 0 – 3. 
4.1.3 Diagnosis of CCM of any genotype supported by relevant imaging 
studies, where surgical resection is not performed after due 
consideration per current standard of care..  
4.1.4 Symptomatic CCM bleeding event within 1 year prior to enrollment.  
4.1.5 Must be willing/able to travel to the study site for study visits 
(baseline, 12 and 24 months) over the course of the study. 
 
    
4.2  Exclusion Criteria 
4.2.1 Pre-menopausal women who are breastfeeding, pregnant or likely 
to get pregnant during the study period. 
4.2.2  Prior surgical treatment of the hemorrhagic CCM lesion.  
4.2.3  Failure to pass MRI safety screening (claustrophobic, metal 
implant, etc.). 
4.2.4  Known allergy or intolerance to gadolinium. 
4.2.5  Severely impaired renal function (eGFR < 60ml/min), active renal 
disease or status post-kidney transplants. 
4.2.6  Statin therapy, for any indication, for more than 7 continuous days 
or greater than 14 total days within 12 months preceding 
enrollment.  
4.2.7  Indication to use statin medication for current approved indication, 
unrelated to CCM. 
4.2.8  Known allergy or intolerance to statins. 
4.2.9  Liver dysfunction or active liver disease (including chronic viral 
hepatitis) defined as baseline serum transaminases levels twice the 
upper range of normal. 
4.2.10 Previous diagnosis of skeletal muscle disorders of any cause 
(myopathy), or baseline creatine kinase levels five times the upper 
range of normal. 
4.2.11 Currently treated with or likely to need treatment with one or more 
of prohibited medications listed in section 5.3. 
4.2.12 Active drug or alcohol use or dependence that, in the opinion of the 
site investigator, would interfere with adherence to study 
requirements. 
4.2.13 Serious illness (requiring systemic treatment and/or hospitalization) 
until subject either completes therapy or is clinically stable on 
therapy, in the opinion of the site investigator, for at least 30 days 
prior to study entry. 
4.2.14 Any other condition that the investigator believes would pose a 
significant hazard to the subject if the investigational therapy were 
initiated, including conditions resulting in or precipitating myopathy 
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4.2.15 In the investigator’s opinion, the patient is unstable, and would 
benefit from a specific intervention rather than treatment with 
atorvastatin. 
4.2.16 Inability or unwillingness of subject or legal guardian/representative 
to give written informed consent. 
4.2.17 No documentation of valid healthcare insurance. 
4.2.18 No medical record confirmation of a primary care physician or other 
provider of ongoing medical care.  
4.2.19 Previous cranial irradiation or radiosurgical treatment. 
4.2.20 Use of ritonavir as an oral drug for COVID-19 
 
4.3 
Study Enrollment Procedures  
4.3.1 Pre-screening:   
Local CA Patients: Patients under the care of the study principal investigator 
will be pre-screened for eligibility. Pre-screening will include a review of medical 
records, prior imaging, and laboratory studies. Depending on the date of the last 
clinically symptomatic hemorrhagic event, eligible patients will be contacted and 
briefed about the study and if interested, will be invited to the screening/baseline 
visit. Subjects will be sent a copy of the consent form for their review prior to their 
first study visit. We estimate that at least 50% of subjects will come from this 
source. 
Referred CA patients: patients referred through the Angioma Alliance, other 
healthcare professionals, or self-referred will undergo pre-screening evaluation 
over the phone with the Trial Nurse (TN) or coordinator to determine eligibility for 
the trial. Patients meeting the pre-screening criteria will be sent a copy of the 
consent form and will be asked to send a digital copy of their most recent MRI scan 
to confirm their diagnosis. Once diagnosis is confirmed by the study PI, subjects 
will be invited for the screening/baseline research visit at the University of Chicago 
Medicine.   
4.3.2 Screening and Enrollment:  
All potential subjects will be scheduled to meet with the principal 
investigator. The visit will involve detailed screening, including collection of medical 
history, prior and concomitant medications, and a neurological examination to 
confirm eligibility. Surgical resection will be considered in every case as an 
alternative to medical therapy, per current standard of care. As part of the 
screening, blood tests will be performed, which in the case of successful 
enrollment, will serve as baseline laboratory results (Section 6.3.6). With 
verification of eligibility criteria, informed consent will be finalized. A travel stipend 
for each trial related visit will be provided to subjects from outside the 
Chicago area who are required to travel greater than 200 miles to the study 
center.  
 
 
4.3.3 Baseline Imaging: 


 
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Randomized subjects will undergo a baseline MRI, which will include 
special sequences utilized throughout the trial (DCEQP and QSM). This will be 
pre-scheduled at the same time as the screening visit (particularly for subjects 
traveling from outside the Chicago area), or as soon as practical for local patients. 
 
 
5. STUDY INTERVENTION 
 
5.1 Intervention, Administration, and Duration 
Study drug will be administered orally as a single daily dose in the morning. 
Subjects in the treatment group will be started on their corresponding dose 80mg of 
atorvastatin or placebo. Should the subject report an adverse event meeting pre-
specified criteria (Adverse events Category B below), he/she will be put on the lower 
dose (40 mg) of drug or matched colored placebo capsule. 
Administration of study drug shall continue once daily dose in the morning for 24 
total months with scheduled visits and repeat imaging at 12 and 24 months from 
enrollment, unless the subject reaches attrition or a safety endpoint before then. If 
new symptoms arise at any point after starting the study intervention subjects will be 
contacted by the study-designated TN for further assessment and be provided with 
instructions regarding continuation of study intervention based on the study adverse 
events management protocol (Section 7). 
 
 
5.2 Handling of Study Intervention 
A third party pharmacy will be contracted to formulate and supply atorvastatin and 
placebo capsules for the trial. The Research Pharmacy at the University of Chicago 
will be responsible for storage, packaging and dispensing the study drug in 
conjunction with the research team.  
 
5.3 Concomitant Interventions 
5.3.1 Required Interventions 
• Daily oral administration of the study drug.  
• Laboratory blood testing at screening, 3, 12 and 24 months. Tests will 
include liver enzymes and creatinine kinase (to be repeated if clinically 
indicated).  
• A total of three MRI scans involving special sequences for QSM and IV 
contrast material for DCEQP acquisition. IV contrast administration will be 
preceded by a blood test to check renal function as indicated per hospital 
policy. 
5.3.2 Prohibited Interventions 
The following drugs are contraindicated throughout the trial as they are 
associated with increased risk of rhabdomyolysis when combined with 
statins. If clinically indicated the decision whether or not these medications 
can be taken should be discussed with the study PI who will weigh the 
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• Cyclosporine  
• Fibrates 
• Niacin 
• Azol antifungals  
• HIV/HCV protease inhibitors  
• Macrolide antibiotics 
• Colchicine 
            5.3.3 Precautionary Interventions 
The following drugs interact with Atorvastatin. If unavoidable, extra 
measures should be put in place for closer monitoring. 
• OCP1 
• Antacids2 
• Digoxin3 
• Lipid lowering resins2 
• Rifampicin4  
• Grapefruit juice5 
• Calcium channel blockers6 
 
1 Values for norethindrone and ethinyl estradiol may be increased, co-administration of statins and an oral 
contraceptive increased serum levels for norethindrone and ethinyl estradiol. These increases should be 
considered when selecting an oral contraceptive for a woman taking atorvastatin. 
2Interfere with absorption of atorvastatin from GI tract 
3When multiple doses of atorvastatin and digoxin were co-administered, steady state plasma digoxin 
concentrations increased by approximately 20%. Patients taking digoxin should be monitored appropriately. 
4As well as other known activators of the Cyt-P450(3A4) isoform which metabolizes most statins in the liver. 
Interaction affects the pharmacokinetic properties of the drug leading to changes in serum concentration. 
5Contains one or more components that inhibit Cyt-P450(3a4) and can increase plasma concentrations of 
atorvastatin, especially with excessive grapefruit juice consumption (>1.2 liters per day). 
6Weak inhibitors of Cyt-p(3a4) system 
 
5.4 Adherence Assessments 
 The team is in the process of evaluating potential electronic monitoring devices, 
an eDiary and a smart bottle. Both devices are equipped with a SIM card and programmed 
to wirelessly transmit compliance data to the study database in real time. Both devices 
are linked to a closed loop electronic feedback system that is programmed to set off 
reminders in escalating manner and ultimately notify the study team. In addition to 
compliance, these innovative monitoring systems will also allow subjects to notify the 
team early on of any adverse events or change in concomitant medications. All 
compliance data will be continuously recorded in the study database and will be used to 
guide decision-making. In addition, members of the research team in liaison with the local 
pharmacy will perform pill counts to confirm adherence at the time of follow up visits. 
In addition, the TN or research coordinagtor shall contact each subject for 
scheduled phone calls every three months (to be completed every 10-14 weeks), with a 
structured questionnaire about compliance and tolerance. 
 
 


 
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6. CLINICAL, LABORATORY AND IMAGING EVALUATIONS 
 
All enrolled subjects will go through the same schedule of investigations and follow 
up visits throughout the study period (Table 1). 
 
 
 
6.1 Schedule of evaluations 
Evaluation 
 V1  
Screening 
(0) 
V2 
Safety 
labs, 
Phone 
call 
(3m) 
V3,4 
Phone 
call 
(6, 9m) 
V5 
Follow up  
(12m) 
V6-8 
Phone 
call 
(15,18,21
m) 
V9 
End of 
Study  
(24m) 
Informed consent 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Inclusion/Exclusion 
criteria  
X 
 
 
 
 
 
CCM History 
X 
 
 
 
 
 
Statin History 
X 
 
 
 
 
 
Medical/Surgical History 
X 
 
 
X 
 
X 
Prior and concomitant 
medications 
X 
X 
X 
X 
X 
X 
Physical and Neurological 
Examination 
X 
 
 
X 
 
X 
MMSE  
X 
 
 
X 
 
X 
mRS 
X 
X 
X 
X 
X 
X 
Euro-QoL-5D Scale 
X 
 
 
X 
 
X 
Euro-QoL VAS 
X 
 
 
X 
 
X 
Neuro-QoL 
X 
 
 
X 
 
X 
Intervention adherence/  
Adverse Events* 
 
X 
X 
X 
X 
X 
MRI 
X 
 
 
X 
 
X 
Laboratory investigations 
 
 
 
 
 
 
• 
CBC 
X 
 
 
 
 
 
• 
Renal functions 
X 
X 
 
X 
 
X 
• 
LFTs 
X 
X 
 
X 
 
 
• 
TFTs 
X 
 
 
 
 
 
• 
CK 
X 
X 
 
X 
 
 
• 
Lipid profile 
X 
 
 
X 
 
X 
• 
Hepatitis viral profile 
X 
 
 
 
 
 
• 
HIV 
X 
 
 
 
 
 
• 
Pregnancy test 
X 
 
 
 
 
 
Study intervention 
initiation/continuation 
assessment 
X 
X 
X 
X 
X 
 
Randomization 
X 
 
 
 
 
 
 


 
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Table 1: AT CASH EPOC trial, schedule of evaluations. 
*These are assessed at each follow-up, by automated weekly follow-up messages 
circulated by the electronic monitoring system, and in scheduled calls with each enrolled 
subject every three months (1-0-14 weeks), as described in section 5.4


 
 
 
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6.2 Timing of Evaluations 
 
 
6.2.1 Initial screening visit (V0) – up to 30 days prior to enrollment 
This visit may occur on the same day as the baseline visit (V2) at the discretion of 
the investigator. Subjects will undergo the following assessments and sign an 
informed consent form in order to be randomized into this study: 
• 
Informed consent 
• 
Obtain subject demographics 
• 
Eligibility criteria (inclusion/exclusion criteria) 
• 
Neurosurgical review (confirmation of diagnosis, date of last symptomatic 
hemorrhage, statin use, past medical and surgical history) 
• 
Laboratory blood tests (CBC, renal functions, LFT, CK, lipid profile, HIV, 
hepatitis viral profile and  pregnancy test) 
• 
Blood sample processed for ROCK activity assay on peripheral leukocytes, 
and plasma stored in biobank for future/ancillary biomarker studies.  
• 
Characterization of genotype in cases with multiple lesions, or referral to 
Angioma Alliance for genotyping through the Alliance’s program 
(www.angioma.org).  
6.2.2 Second screening visit (V1) – Baseline 
The screening visit (V0) and the baseline visit (V1) could occur on the same day at 
the investigator’s discretion. The following will be performed at the baseline visit prior 
to each subject receiving study treatment: 
• 
Eligibility criteria (inclusion/exclusion criteria) 
• 
Physical, neurological and mini-mental state examination (MMSE) 
• 
Modified Rankin score (mRS) 
• 
Euro-QoL 5D, Euro-QoL VAS, Neuro-QoL SF Cog evaluations 
• 
MRI 
• 
Discuss results of MRI 
• 
Meeting with Trial Nurse  
• 
Evaluation for suitability of atorvastatin therapy 
• 
Randomization 
• 
Providing study monitoring device (eDiary/smart bottle)  
6.2.3 Three month phone call and safety labs (V2) 
The 3 month visit (V2) will consist of a phone call from the Trial Nurse or coordinator 
as well as laboratory tests.  During the phone call, the TN or coordinator will collect 
information about the patient’s current mRS, concomitant medications, and any 
adverse events.  The following laboratory tests need to be completed as part of 
standard care at 3 months: 
• 
Renal function 
• 
LFT 
• 
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6.2.4 Six and 9 month follow-up phonce call (V3 and V4) 
The 6 and 9 month visits will consist of a phone call from the Trial Nurse or 
coordinator to collect the following information: 
• Modified Rankin score (mRS) 
• Concomitant medications 
• Adverse events 
 
6.2.5 Twelve month follow-up visit (V5) – 12m +/- 4wks  
The following assessments will be performed on all subjects at 12 months from 
enrollment:  
• 
Laboratory blood tests (Renal functions, LFT, CK and lipid profile) 
• 
MRI with DCEQP and QSM 
• 
mRS 
• 
Euro-QoL 5D, Euro-QoL VAS, Neuro-QoL SF Cog evaluations 
• 
Intervention adherence/ adverse events review: review results of laboratory 
investigations, review study monitoring device (eDiary/smart bottle), manual 
pill count, elicit drug-related adverse events, full medical examination, MMSE, 
assess suitability for continuation of statin therapy. 
• 
Neurosurgical review: neurological examination, MMSE, discuss results of 
MRI, dose modification if necessary. 
• 
Blood sample processed for ROCK activity assay on peripheral leukocytes, 
and plasma stored in biobank for future/ancillary biomarker studies.  
 
6.2.6 Fifteen, 18, and 21 month follow-up phonce call (V6, V7, and V8) 
The 15, 18, and 21 month visits will consist of a phone call from the Trial Nurse or 
coordinator to collect the following information: 
• Modified Rankin score (mRS) 
• Concomitant medications 
• Adverse events 
 
6.2.7 End of study visit (V9) – 24m +/- 4wks  
The following interventions will be performed on all subjects at 24 months from 
enrollment:  
• 
Laboratory blood tests (renal functions, LFT, CK and lipid profile) 
• 
Intervention adherence/ adverse events review: review results of laboratory 
investigations, review study monitoring device (eDiary/smart bottle), manual 
pill count, elicit drug-related adverse events, full medical examination, MMSE, 
assess suitability for continuation of statin therapy 
• 
MRI with DCEQP and QSM 
• 
mRS 
• 
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• 
Neurosurgical review: neurological examination, MMSE and discuss results 
of MRI 
• 
Blood sample processed for ROCK activity assay on peripheral leukocytes, 
and plasma stored in biobank for future/ancillary biomarker studies.  
 
6.3 Special Instructions and Definitions of Evaluations 
 
6.3.1 Neurosurgical Evaluation 
Subjects will undergo a comprehensive neurological examination at every visit 
beginning with the screening visit (minus the 3-month lab test as that is done with their 
own PCP). Serial neurological examinations will objectively document subject’s 
neurological status and monitor for any new deficits or changes from baseline 
neurological status. The comprehensive neurological evaluation will include the Mini-
mental state examination (MMSE) and documentation of Modified Rankin Score (mRS), 
and a baseline quality of life assessments (Euro Quol 5D and Visual Analog Scale, and 
Neuro QOL Communications Short Form).  
 
6.3.2 Confirmation of diagnosis and recent history  
Diagnosis of cerebral cavernous malformation is based on radiological imaging, 
which utilizes high-resolution MRI sequences. Conventional sequences [T1-weighted, 
T2-weighted, FLAIR and susceptibility weighted imaging (SWI) sequences] are helpful in 
diagnosing clinically significant CCM lesions. Inactive lesions are depicted by regular to 
ovoid area >10 mm of homogenous signal loss surrounded by a hyperintense 
hemosiderin (iron) ring. Active lesions show evidence of blood at different ages within 
the lesion and are best seen on T1-weighted images, to be correlated with clinical 
symptoms (18) 
 
6.3.3 Informed Consent 
The informed consent process can begin at any time during screening but must be 
obtained prior to randomization. A signature on the consent form does not translate into 
enrollment in the study. The study center will document the informed consent process 
and the signing of the consent form in a written progress note, place a signed copy of 
the consent form in the hospital medical records, and keep the signed original consent 
form in the subject study binder (paper or electronic). A signed copy must be given to 
the subject as well. Informed consent will include specific consideration of the alternative 
option of surgical lesion excision. 
 
6.3.4 Evaluating suitability for statin therapy 
This evaluation will be performed at screening, 3 and 12 months. These visits will 
include an evaluation of subjects’ tolerance to study drug, a review of any new 
symptoms, a complete physical examination, and an evaluation of lab results. Subjects 
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6.3.5 MRI 
A magnetic resonance imaging protocol that includes DCEQP and QSM 
sequences will be performed at baseline, 12 and 24 months from enrollment. The 
imaging protocol will be performed using the 3T instrument, and involves intravenous 
contrast injection and utilizes special FDA approved sequences directed at assessing 
lesional/brain white matter permeability and iron deposition as detailed in Section 6.5. 
Prior to every MRI scan, subjects will have their renal functions checked if needed 
according to the local protocol.  
 
6.3.6 Laboratory tests 
These assessments will be performed at the baseline, 12 and 24 month follow up 
visits prior to every MRI scan according to the study schedule (Table 1) (84, 85). 
Assessments marked with an asterisk (*) will also be performed at the 3 month follow up 
visit as part of the subject’s local, routine care to assess statin tolerance:  
• Complete blood count (CBC): performed as part of baseline blood tests and 
repeated only if clinically indicated  
• Renal functions*: Renal functions and electrolytes, performed at screening to 
determine subjects baseline renal function and safety of IV contrast material. 
Repeated prior to every scheduled MRI scan and as clinically indicated. Could be 
substituted with pin-prick tests prior to IV contrast administration according to local 
protocol.  
• Liver function tests (LFTs)*: liver transaminases, alkaline phosphatase and 
bilirubin performed at baseline and at 6 months from enrollment on all subjects.  
• Thyroid function tests (TFTs): performed at screening and when investigating 
adverse events.  
• Serum creatine kinase (CK)*: performed at baseline and at 6 months from 
enrollment on all subjects.  
• Lipid profile: Total cholesterol, HDL and LDL. 
• Hepatitis viral profile 
• HIV (Known cause of myopathy, which is one of the most common side effects of 
statins resulting in cessation of treatment). 
• Pregnancy test 
• Blood sample shall also be drawn for ROCK activity assay on peripheral 
leukocytes as detailed in 6.4 below, and plasma freeze-stored for future or ancillary 
biomarker studies.   
6.3.7 Unscheduled Evaluations 
The electronic feedback system will allow for the exchange of notifications between 
the subject and study team. Unscheduled evaluations could be in the form of a telephone 
call or an actual visit to the study center. Evaluations could be triggered by the subject 
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any concerns about compliance or prohibited concomitant interventions. In the event of 
a possible drug-related adverse event an unscheduled visit will be arranged wherein a 
clinical evaluation and/or other relevant investigations will be performed.  
 
6.3.8 Pregnancy  
Because of the unknown teratogenicity profile of the study drug, women of 
childbearing age are excluded from the trial unless they are surgically sterilized or using 
a reliable method of contraception. In addition to formal laboratory testing at screening, 
negative pregnancy status will be confirmed for all women of childbearing potential prior 
to each MRI evaluation per local institutional policy. Pregnancy during the trial will be 
considered a safety endpoint; drug administration shall cease but patient will be followed 
for the duration of the study. 
 
6.4 ROCK Activity Assays 
 
6.4.1 ROCK Activity on Peripheral Leukocytes  
 
Our collaborator James Liao has shown that ROCK activity may be quantified in 
human leukocytes isolated from peripheral blood [by assessing the ratio of pMBS/glycer-
aldehyde-3-phosphate dehydrogenase (GAPDH) protein], and that this activity is inhibited 
by statins (54, 86, 87). It is our intention to investigate whether ROCK activity in peripheral 
blood leukocytes is impacted by the treatment intervention at the proposed doses in CA 
subjects with recent hemorrhage. We have already performed these analyses in correla-
tion with brain permeability measurements and disease severity in CAs, in conjunction 
with prior exploratory developmental project (R21NS087328), and data from those stud-
ies has been published (88).  
In addition clinical laboratory tests to be performed at baseline, and at 12 and 24 
months follow-up visits (V1, V3 and V4), 5-10 ml of blood are collected into heparinized 
vacutainer tubes. Leukocytes are isolated from the blood and frozen at -86°C after fixing 
in 50% trichloroacetic acid/50 mM dithiothreitol. Cells are thawed and relative ROCK ac-
tivity in leukocytes is assessed by Western transfers as described by our collaborator 
James Liao (54, 86, 87, 89). Since ROCK phosphorylates MBS (MYPT1), relative ROCK 
activity will be assessed by the ratio of the intensity of pMBS staining/GAPDH staining. 
GADPH is chosen as reference since it was shown to be a more reliable internal control 
in Western blot analysis of leukocytes than other housekeeping proteins (90). For these 
quantitative assays, we shall use the pMBS antibody developed by our collaborator Liao, 
targeting the Thr853 of MBS site, known to be specific for only ROCK and not other ser-
ine/threonine kinases (91, 92). Lysophosphatidic acid-stimulated NIH3T3 fibroblast ly-
sates will be run on all gels as a positive control to standardize results between experi-
ments (89). We shall enter the pMBS/GADPH ratio in immunoblots for each subject/visit 
as “ROCK Activity on Peripheral Leukocytes” for subsequent secondary analyses as pro-
posed in the SAP, comparing placebo and intervention groups at baseline, and at 1 and 
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6.4.2 Ancillary Biomarker and Lesional Studies  
Plasma Samples for Ancillary Studies. The plasma from the blood samples shall 
be stored at -86°C for subsequent/ancillary biomarker studies (88, 93). Subjects enrolled 
in this trial will be consented for plasma biomarker studies under separately approved 
IRB protocol.  
ROCK Activity in Excised Lesions. Additional assessment of lesional ROCK ac-
tivity shall be performed on any excised lesion specimens during the course of the 
study, as per current aim of ongoing program project studying signaling aberrations in CA 
(P01NS092521), and techniques published by our laboratory (36, 38, 42, 46, 49, 51, 94). 
Subjects enrolled in this trial who ultimately undergo lesion resection will be consented 
for these lesional studies under separately approved IRB protocol.  
.  
6.5 Detailed Imaging Protocols 
 
6.5.1  MRI Sequences for Characterizing the CA Lesion  
The following standard clinical shall be conducted on a 3T instrument for compa-
rability of sequences, consistent with evidence-based consensus recommendations for 
optimal imaging of cavernous angiomas (CA) (17).  
Those shown below in BOLD are specifically relevant to biomarker measurements 
of iron content by quantitative susceptibility mapping (QSM), and permeability by dynamic 
contrast enhanced quantitative perfusion (DCEQP). Note that the proposed DCEQP scan 
will image the first pass of the contrast agent normally injected for the clinically indicated 
purpose of post-gadolinium (Gd) anatomic imaging. It does not require additional contrast 
burden (in fact it uses a lower contrast dose than for routine clinical indications). We will 
require that all imaging be performed on a 3T MRI scanner and an 8-channel head coil to 
allow for parallel imaging.  
• Sagittal T1-weighted sequence 
• Coronal T2-weighted sequence 
• Axial VenBOLD 
• Axial diffusion-weighted sequence 
• Axial T2-weighted sequence 
• FLAIR long TR 
• Axial T1 -weighted sequence pre-Gd contrast 
• CCM Axial T2*-weighted sequence 
• AIF Localizer 3D TOF-MRA  
• T1–weighted mapping SR-SPGR 
• DCE Multi-phase SR-SPGR +C 
 
The index CA with SH shall be characterized by the PI as to location (lobe, su-
perficial/deep based on distance of lesion epicenter < or > along a line between cortical 
surface and ventricle, basal ganglia, thalamus, cerebellum, brainstem), and size (maximal 
diameter in mm on axial T2- and T1-weighted images). This information shall be entered 
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intra-lesional hemorrhage, the full lesion diameter shall be sized (including the “hemo-
siderin ring” on T2–weighed sequences). In cases of extra-lesional hemorrhage, the max-
imum diameter of the CA and the hematoma shall be separately noted. These character-
izations of lesion size and location are well standardized clinically, with the prescribed 
sequences at 3T field strength (17). Lesion size will not be considered on gradient echo 
or susceptibility sequences where blooming effects may introduce errors.  
 
6.5.2  MRI Sequences for QSM and DCEQP Biomarker Measurements 
In addition to the standard clinical scans (i.e. those un-bolded above), research 
scans will involve 1 additional image acquisition for QSM and 3 acquisitions for DCEQP 
(those in bold under MRI sequences above).  These are performed at baseline and at 
two follow-up scans. These protocols are adapted from protocols previously published by 
many investigators, and they have been used and vetted extensively at The University of 
Chicago, included validations specifically in CA patients. The same protocols are undet-
going multi-site validation in conjunction with parallel CASH Trial Readiness Project 
(U01NS104157).  
 
Quantitative Susceptibility Map-
ping (QSM)  
A 
single 
three-dimen-
sional, multi-echo, T2*-weighted, 
spoiled gradient echo sequence 
will be used for data collection and 
create of the QSM images (Figure 
9). The imaging parameters are: 
3D, axial, FOV/matrix = 240 
mm/256x256; 
repetition 
time 
(TR)= 55 ms/5 echos times uni-
form spacing, flip angle = 15°; par-
titions = 120,1.0 mm.  
The stack will be oriented 
parallel to the corpus callosum 
before being repositioned in the 
S/I direction over the area of inter-
est. The protocol design allows 
coverage of most if not all of the 
brain; ensure the area of interest 
is covered.  
QSM images will be de-identified, extracted in DICOM format and post-processed 
at University of Chicago. The QSM images will be reconstructed using a morphology-
enabled dipole inversion (MEDI) algorithm (95, 96), as previously reported (60). Inspec-
tion of image quality is performed immediately by the technician, and this non-contrast 
acquisition may be repeated in the unlikely event that motion artifacts are identified.  
 
Dynamic Contrast-Enhanced Quantitative Perfusion (DCEQP)  
Localization for Whole Head Coverage for  
Quantitative Susceptibility Mapping 
 
 
 
Figure 9: Multi-echo T2*-weighted images cover the whole brain 
and are used to quantify magnetic susceptibility in cavernous an-
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The DCEQP protocol consists of 
3 components that are run in se-
quence: (1) Arterial Input Func-
tion (AIF) Localizer (2) T1-
weighted map and (3) Contrast 
Enhanced DCE dynamic scan.  
Arterial 
Input 
Function 
(AIF) Localizer:  A 3D Time-of-
Flight acquired at the level of the 
lower brainstem and pons to 
cover the internal carotid arteries 
(Figure 10, yellow box). The re-
constructed maximum intensity 
projection (MIP) images in both 
the coronal and sagittal views will 
be used to prescribe the slice to 
locating the artery for the AIF.  
After the AIF localizer is 
acquired to image the position 
and angulation of the internal carotid arteries, a saturation recovery gradient recalled se-
quence (SPGR) will be acquired both for an initial T1-weighted measurement and for the 
subsequent dynamic imaging (Figure 11). The prototypical acquisition parameters will be: 
echo time TE = 1.9 ms, repetition time TR = 3.9 ms, flip angle = 30°, field of view = 230 x 
182 mm2, slice thickness = 8 mm, matrix size = 96×61, SENSE factor = 2, centric order 
phase encoding. The same base sequence is used for both the T1-weighted mapping 
and the dynamic series part. The base sequence consists of two imaging slabs (stacks):  
Arterial Input Function Localizer with Time-of-
Flight Magnetic Resonance Angiogram 
 
 
 
Figure 10: A Time-of-Flight magnetic resonance angiogram 
should cover the distal internal carotid artery and serves to aid in 
the prescription of the slices needed of proper acquisition of the 
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Slab A - contains a single 
slice, used for locating the In-
ternal Carotid Artery (ICA) used 
for determining the AIF (arterial 
input function). 
Slab B - contains 4 slices 
covering the areas of interest in 
the brain. One of those slices 
should include coverage of the 
CASH lesion, and another the 
choroid plexus, to be used as 
an internal reference.  
Important: 
The 
Slab 
A 
should be perpendicular (so the 
flow is perpendicular to the 
Slab A imaging plane) to the 
particular internal carotid artery 
(left or right) you wish to use for 
AIF. Please make a note during 
the data acquisition. Also, cau-
tion should be taken to avoid 
clinoid (c5) or petrous (c2) seg-
ments of the ICA.  
T1-weighted 
mapping: 
For 
the 
purposes 
of 
T1-
weighted mapping, SPGR im-
ages should be acquired with 
the following inversion times 
Seven Time Delays (TD) val-
ues (120 ms, 300 ms, 600 ms, 
1000 ms, 2000 ms, 4000 ms and 10,000 ms). A single image stack shall be acquired for 
each TD.   
Dynamic Contrast-Enhanced (DCE) Scan: The passage of the bolus of the con-
trast agent will be imaged using a saturation TD of 120 ms to minimize the effect of water 
exchange in such measurements (97). A multi-phase, saturation recovery SPGR with 
identical coverage, localization and spatial resolution as the T1-weighted mapping acqui-
sition should be acquired next. This multi-phase acquisition should fix the delay time (TD 
= 120 ms) and acquire 250 phases (i.e. time points) in conjunction with an injection of a 
T1-weighted shorting, Gd-based contrast agent.  Co-localization is critical in order to spa-
tially register the T1-weighted map to the dynamic contrast kinetic scans.  
Contrast Injection: MRI-based contrast kinetic will be mapped with a dynamic T1-
weighted scan acquired during the injection of the contrast agent which is normally used 
for post-Gd T1-weighted imaging. Specifics are: 
OMNISCAN (gadodiamide) will be administered http://www.rxlist.com/omniscan-
drug.htm. Dosage will be based on the patient’s weight (see chart included at 
Separate Slice Locations Prescribed for the  
Permeability Data and Arterial Input Function 
 
 
 
Figure 11: Top: Use a sagittal localizer to cover the relevant anatomy 
containing the cavernous angioma and choroid plexus (Slab A: top 
slices). Angulate the lower slice (Slab B), used for the arterial input 
function based on the 3D time of flight from both sagittal (lower left) 
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http://www.rxlist.com/omniscan-drug/indications-dosage.htm, use chart for 0.1 mMol/kg). 
The injection rate is performed using a computer controlled power injector through an 18 
gauge catheter placed in the antecubital vein. Injection and saline flush (15 ml) should 
both be at 4.0 ml/sec and initiated after the 9th measurement (12 seconds after scan 
initiation) of the dynamic sequence (250 total,5:32 of total scan time). Since the scan will 
be performed as a part of routine clinical care with and without contrast, one half of the 
contrast agent for the permeability scan. After the permeability scan is complete, we inject 
the remaining half-dose (i.e. an additional 0.1 mmol/kg by body weight, for a total dose of 
0.2 mml/kg) and perform routine post-contrast clinical MRIs. If the scan is to be performed 
only for research purposes, the remaining contrast need not be injected, and post-con-
trast sequences may be foregone. 
Notes: 
● The slice positions of the T1-weighted mapping and the dynamic series need to be 
identical since a per-pixel based fit is performed during reconstruction 
● Try to the tell subject to remain as still as possible to eliminate motion artifacts during 
this long scan - no additional motion correction post-processing is currently performed.  
 
6.5.3 Data Export and Image Post-Processing 
The raw data (images) relevant to biomarker postprocessing will be de-identified and ex-
tracted in the classical (not Philips “enhanced”) DICOM format. The needed sequences 
are: 
  
• Axial VenBOLD,  
• Axial T2-weighted TSE matrix  
• Axial T2*-weighted 
• AIF TOF localizer (called fast inflow angio) 
• MIP fast inflow angio 
• All images from the T1-weighted mapping scans for each inversion [i.e. delay time, 
TI (TI_00120 to TI_10000)] 
• Dynamic DCE images (called hperf120) 
 
Additionally, the single QSM sequence will be extracted in DICOM format. The de-identi-
fied images shall be locally archived and uploaded into a secured shared server at the 
Magnetic Resonance Imaging Center (MRIC), traceable only to the assigned trial subject 
number and date of the scan. The University of Chicago Research Computer Center Mid-
way computer shall be used for the storage and back up of raw imaging data, while 
deidentified calculated dynamic contrast enhanced quantitative perfusion (DCEQP) and 
quantitative susceptibility mapping (QSM) values are linked to enrolled subject number 
and submitted through the trial’s electronic case report forms (eCRP) to the Data Coordi-
nating Center.  
 
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All post-imaging processing will be completed locally at the MRIC using an existing 
image reconstruction pipeline on a computer running MATLAB software (Mathworks, Na-
tick, MA). QSM images will be reconstructed by using a morphology-enabled dipole in-
version algorithm (98), which generates the local susceptibility distribution by inverting 
the estimated tissue field map with prior information from the magnitude images. The 
tissue field map will be obtained by removing the background field induced by large sus-
ceptibility sources (i.e. air/tissue interface) from the field map derived from the gradient-
echo phase images (60). Mean lesional susceptibility values will be generated by drawing 
a region of interest (ROI) around the lesion on the resulting QSM image in ImageJ for 
each slice in which the lesion is visible, then averaging all pixels within the ROIs for a 
lesion. 
Final permeability values will be calculated in MATLAB by applying the Patlak 
method voxel-wise, represented by the following equation: 
𝐶𝑡(𝑡)
𝐶𝑎(𝑡) = 𝐾𝑖
∫𝐶𝑎(𝜏)𝑑𝜏
𝑡
0
𝐶𝑎(𝑡)
+ 𝑉𝑏, where 
each Ct(t) is the concentration time-course of each voxel of tissue. The unidirectional in-
flux constant, Ki, is estimated as the slope of the Patlak plot created by the above equa-
tion. This equation becomes valid after some time as the vascular phase vanishes, and 
data points from the first third of each time course are not included for this estimation. 
More detailed discussions of the methodology have been published (60).  
Lesional permeability values will be generated similarly to QSM. For DCEQP stud-
ies, in addition to the lesion of interest, ROIs will be taken for either the choroid plexus (if 
covered by the imaging stack) or normal-appearing white matter far (> 5 mm) from the 
lesion, to be used as an internal reference value at follow up. Permeability values for 
White Matter Far (WMF) shall be generated in regions of interest (ROI) covering 3.6 X 
3.6 mm (16 pixels or approximately 12.9 mm2/ROI based on 256-256 matrix for axial brain 
MR slices). WMF regions are chosen in brain devoid of CA lesions on any MR sequence, 
as far as possible from and always >16 mm from the border of a visualized lesion, includ-
ing the tiny SWI lesions. 
 
 
7. MANAGEMENT OF ADVERSE EXPERIENCES 
 
           In the event of an adverse event (Table 2), the first concern will be for the safety 
of the subject. Subjects will be closely monitored and are required to notify the trial PI or 
designated TN of any new symptoms that occur following treatment onset. Managed 
adverse events include all new symptoms, whether expected or unexpected, which are 
assessed by the TN, in consultation with the on-site statin expert physician, to be 
reasonably or possibly related to the study intervention. All adverse events that the study 
team is notified about will trigger at least an unscheduled telephone evaluation. During 
the evaluation, a member of the study team will assess the seriousness of the reported 
event, its attributability to the study intervention and advise the subject regarding the 
treatment plan, including whether to continue on the study drug (99, 100). Serious criteria, 
definitions, and guidance for reporting follow in section 10.4: Adverse Experience 
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Historically, very low levels of low-density lipoproteins (LDL) have been 
sporadically associated with some detrimental effects. However, clinical trials on statin 
therapy have not demonstrated any substantial correlation between lower LDL levels and 
safety. There is no evidence that lowering low-density lipoprotein levels in people with 
normal cholesterol profile is inherently unsafe (101).  
7.1 Role of Trial Nurse (TN) and Study Coordinator 
A trial nurse (TN) working closely with the PI (backed up and sharing call with a 
trained clinical research coordinator) will be available 24 hours a day, 7 days per week 
on a special pager and cell phone, and shall be the first portal of contact for study 
subjects. The TN will also be responsible for following up with subjects in between 
scheduled visits (in response ot calls by the subjects or at regular scheduled phone calls 
every three months). H/she will help assess attributability of any new symptoms to the 
study intervention (section 10.5) and instructing subjects when it is necessary to seek 
medical attention. The TN and study coordinator shall be blinded to the study group 
allocation. They will be supplied with management algorithms detailing the standards of 
care in dealing with the most recognized side effects of the study intervention (25, 102, 
103). The TN and coordinator will be able to access subjects’ electronic case report form 
(eCRF) to track their course throughout the study and document any events. The TN and 
study coordinator shall be overseen by and have unfettered access to the study PI 
regarding any trial related clinical questions. They shall have direct access to the External 
Medical Safety Monitor (see below) in the absence of the PI. 
 
7.2 Adverse Event Management Protocol  
Mild adverse events (Table 2, Category A) encountered by any subject regardless 
of assigned treatment will be recorded, relayed to the safety monitoring team and closely 
followed by the TN.  More concerning adverse events (Category B) will be managed by 
withholding the study intervention for 2-4 weeks pending resolution of symptoms or 
biochemical abnormalities. Subjects will then be restarted on the lower dose (40 mg/day) 
of the study intervention (atorvastatin or placebo). Depending on the dose at which 
adverse events occurred, the process can be repeated, tapering the dose down to attrition 
as deemed appropriate by the PI in consultation with the external medical safety monitor 
(MSM). Intolerable or potentially serious adverse events that recur or persist in spite of 
dose reduction, along with other serious adverse events listed in Section 8 will lead to 
unblinding and determination of endpoint for that subject in the trial. A statin expert 
physician consultant is available at the Chicago site to advise regarding adverse event 
management in individual cases. 
 
7.3 Common Adverse Events 
 
7.3.1 CA hemorrhage   
Best care criteria defined by the American Heart Association (AHA) guidelines for 
management of ICH will be the standards of care for all general medical care in this 
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guidelines for the management of ICH (74), (ii) European Stroke Initiative (EUSI) 
Guidelines for the management of intracranial hemorrhage (104), and (iii) the AANS 
guidelines for management of elevated intracranial pressure (105). Management may 
include blood pressure reduction, use of platelets and prothrombotic agents, and use of 
a surgical procedure. The care team is required to preserve life and functional outcomes 
in these instances. The management of each adverse event will be recorded and will be 
reviewed by the safety monitoring team.  
 
If a CA symptomatic bleed is verified as per adjudicated criteria (20), including a 
rebleed of prior lesion or new bleed from another lesion, then a safety endpoint will have 
been reached, and the subject will be notified, and decision is made to cease the study 
intervention. Patients will remain in the study for the remaining scheduled follow-ups. 
The lesion that has hemorrhaged shall be considered for treatment as per current 
guidelines and standards of care.  
 
7.3.2 Myositis/Rhabdomyolysis.   
Skeletal muscle inflammation is a rare but well recognized adverse event in statin 
therapy. The severity of this inflammation ranges from mild myalgia to multi-organ 
system failure secondary to myoglobinuria (Table 2). Management should follow 
standard of care and is to be dictated by the PI based on symptom severity/degree of 
lab value elevation, in consultation with the on-site statin consultant. Management may 
include vigorous hydration, alkalinization of urine, correcting electrolytes, and in extreme 
cases hemodiafiltration. The decision to declare a safety endpoint in the case of myositis, 
versus the decision to decrease the dose of drug will depend on severity of the myositis 
as per established guidelines.  
 
7.3.3 Hepatotoxicity 
Drug-induced liver insult runs a spectrum from asymptomatic elevation of liver 
enzymes to acute fulminant hepatitis. However, it is now well recognized that statin-
related hepatic adverse events are exceptionally rare and unpredictable. Analysis of 
safety data pooled from 49 clinical trials of atorvastatin in 14,236 patients showed that 
persistent elevation in hepatic transaminases does not exceed 0.6% (106). Statin-
induced liver insult almost invariably occurs in cases with pre-existing chronic liver 
disease (e.g. viral/ alcoholic hepatitis, etc.) or concomitant ingestion of hepatotoxic drugs 
(25, 102, 103). All subjects in this study will be screened for risk of hepatic toxicity prior 
to enrollment, as per current recommendations by both the American College of 
Cardiology/American Heart Association (ACC/AHA) and FDA (107). The FDA has 
recently revised safety guidelines to remove the need for routine monitoring of liver 
enzymes in patients taking statins. To detect asymptomatic elevation of liver enzymes, 
enrolled subjects will also have their liver enzymes checked at 3 months and at each 
follow up visit. Additionally, subjects exhibiting any evidence of liver dysfunction at any 
point throughout the trial will undergo extensive hepatitis workup and further 
management in accordance with the trial adverse events management algorithms. 
(Table 2) 
 


 
 
 
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7.3.4 Other adverse events. 
Other commonly reported adverse reactions (incidence ≥ 2% and greater than 
placebo) regardless of causality, reported in patients treated with atorvastatin in previous 
placebo-controlled trials, such as nasopharyngitis, diarrhea and urinary tract infection, will 
be individually reported and managed as elaborated in section 7.2.  
Table 2 below summarizes potential adverse events by body systems that have 
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Adverse Event 
Category 
Mild AE 
(Category A) 
Moderate AE 
(Category B) 
Serious AE 
(Category C) 
General/Constitutional  
• 
Malaise / Fatigue 
Tolerable/self-limited 
Intolerable/persistent 
Recurrence after dose reduction 
• 
Pyrexia 
38.0 - 39.0 degrees C (100.4 - 
102.2 degrees F). self-limited 
Intolerable/persistent 
Recurrence after dose reduction 
• 
Allergic reactions 
Erythema multiform 
Mild self-limited classic allergic 
responses such as pruritis, 
hives or urticaria, cutaneous 
vasodilation (“flushing”), 
development of edema 
(peripheral or airway), 
peripheral vasodilation 
(hypotension), bronchospasm, 
and/or tachycardia. 
Recurrence after dose 
reduction/Anaphylactic 
reaction/Steven-Johnson 
syndrome / Toxic epidermal 
necrolysis 
Muscular 
• 
Musculoskeletal pain 
(3.5%), muscle spasm 
(3.6%), arthralgia (6.9%) 
Tolerable/self-limited 
Intolerable/persistent 
Recurrence after dose reduction 
• 
Joint swelling 
Asymptomatic; clinical or 
diagnostic observations only. 
Intolerable/persistent 
Recurrence after dose reduction 
• 
Incipient Myositis 
CK < 3 x ULN, no relevant 
clinical symptoms. 
CK >3 x ULN Plus new 
elevation of ALT, irrespective of 
musculoskeletal symptoms. 
Recurrence after dose reduction 
• 
Definite Myositis (0.08%) 
 
 
Myalgia Plus markedly 
elevated serum creatine kinase 
>10 x ULN 
Recurrence after dose reduction 
• 
Rhabdomyolysis 
 
 
Myositis Plus evidence of new 
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Adverse Event 
Category 
Mild AE 
(Category A) 
Moderate AE 
(Category B) 
Serious AE 
(Category C) 
• 
Tendon Rupture 
 
 
Tendon Rupture 
GI/Hepatobiliary 
• 
Pharyngeal pain (2.3%) , 
dyspepsia (4.7%), nausea 
(4%), bloating, eructation, 
flatulence or diarrhea 
(6.8%) 
Tolerable, self-limited  
Intolerable/persistent 
Recurrence after dose reduction 
• 
Hepatitis (0.6%) 
Elevated Transaminases (ALT, 
AST):  <ULN - 3.0 x ULN, no 
relevant clinical symptoms. 
Elevated Transaminases (ALT, 
AST):  >ULN - 3.0 x ULN, no 
relevant clinical symptoms. 
Recurrence after dose reduction / 
ALT >3.0 ULN; >3 x ULN with the 
appearance or worsening of 
fatigue, nausea, vomiting, right 
upper quadrant pain or 
tenderness, fever, rash, or 
eosinophilia 
• 
Acute Liver failure  
 
 
Hepatitis plus abnormal plasma 
levels of ammonia, bilirubin, lactic 
dehydrogenase, and alkaline 
phosphatase 
• 
Cholestasis 
 
Serum conjugated bilirubin >1.5 
x ULN; clinical jaundice. 
Recurrence after dose reduction 
• 
Pancreatitis 
 
 
Severe abdominal pain; vomiting 
plus enzyme elevation (amylase 
200 above ULN with elevated 
lipase levels) or radiologic findings 
Nervous System 
• 
Dizziness, insomnia (3%), 
Depression, nightmares 
Tolerable, self-limited  
Intolerable/persistent 
Recurrence after dose reduction 


 
 
 
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Adverse Event 
Category 
Mild AE 
(Category A) 
Moderate AE 
(Category B) 
Serious AE 
(Category C) 
• 
Cognitive impairment 
1 points drop in MMSE; not 
interfering with work/school/life 
performance; specialized 
educational services/devices not 
indicated 
>1 points drop in MMSE; 
interfering with work/school/life 
performance; specialized 
educational services/devices not 
indicated 
Persistence after dose reduction 
• 
Symptomatic Intracerebral 
Hemorrhage 
 
 
New onset neurological symptoms 
Plus intraparenchymal or 
intralesional hemorrhage 
confirmed on imaging studies  
Endocrine system 
• 
Hyperglycemia 
 
New impaired glucose 
tolerance/glycemic control 
Persistence after dose reduction 
Respiratory  
• 
Nasopharyngitis (8.3%) 
Tolerable, self-limited 
Intolerable/recurrent 
Recurrence after dose reduction 
• 
Epistaxis  
Mild episode, self-limited 
Requiring medical attention, 
Recurrent episodes  
Recurrence after dose reduction 
Genitourinary  
• 
Urinary tract infection 
(5.7%) 
Simple cystitis 
Recurrent cystitis 
/pyelonephritis 
Recurrence after dose reduction 
 
Table 2: Statin-related adverse events.  
AEs are classified based on body system, severity and reported incidences (102, 103, 106-108) 
 
 
 


 
 
 
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8. CRITERIA FOR INTERVENTION DISCONTINUATION 
 
Atorvastatin/Placebo administration will be discontinued for any of the following 
reasons (designated as serious AEs or Category C in the preceding Table 2):  
 
• 
Symptomatic intracerebral hemorrhage (ICH) whether primary, arising from 
index cavernous malformation that previously bled, or in other lesion, or other 
ICH of any kind  
• 
Severe allergic reaction  
• 
Rhabdomyolysis  
• 
Markedly elevated liver enzymes  
• 
Liver failure 
• 
Pancreatitis 
• 
Pregnancy 
• 
Intolerable adverse events that persist or recur after serial dose reduction. 
• 
In the investigator’s judgment, withdrawal from the trial would be in the 
subject’s best interest (Drug interaction/glycemic control).  
• 
The subject or legal representative withdraws consent, or patient undergoes 
surgical resection or irradiation of CCM lesion, other brain surgery or 
irradiation for any cause.  
• 
Patient develops clinical indications for statin use for cholesterol or 
cardiovascular indications unrelated to CCM.   
If one or more of these events occur after commencing the study drug, the subject 
will be considered to have reached a safety endpoint. Study drug or placebo shall be 
discontinued. All subjects reaching safety endpoints will be followed through the 24-month 
follow up visit as a part of the outcome assessment for the study. An attempt will be made 
to contact subjects who withdraw from the study or who are lost to follow up for safety 
evaluation. If these subjects wish not to cooperate there will be no additional follow up.    
 
 
9. STATISTICAL CONSIDERATIONS 
9.1 General Design Issues 
This shall be a double-blinded randomized, placebo-controlled, exploratory phase I-
IIa proof of concept clinical trial. It shall include adults aged 18-80 years with untreated 
CA of any genotype, who suffered a symptomatic lesional hemorrhage within the preced-
ing year. We plan to enroll 80 subjects during years 1-3, specifically targeting cases 
whose hemorrhagic lesion was not resected, with greatest risk of rebleeding in subse-
quent 2 years. Inclusion and exclusion criteria aim to exclude cases receiving prior statin 
therapy in any form or for any indication in the past year, cases at high risk for statin 
intolerance, and other customary exclusions in similar trials. Children will not be enrolled, 
per IND Exemption restriction for this trial. 
Enrolled subjects will be blinded to treatment rendered, as will the investigators con-
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and PIs, the clinical personnel caring for the patient, and DCC staff. The safety monitoring 
team will have access to A/B treatment designations but will be blinded to which group A 
and B are assigned, unless a concern is raised and consideration to suspend enrollment 
in the trial. Atorvastatin and placebo capsules will be formulated by a third party pharmacy 
in two color coded tiers (green and blue) representing different doses of atorvastatin (40 
and 80 mg) or placebo. The 40 mg dose (or color matched placebo capsule) will be used 
in subjects who develop mild side effects on the initial dose target of 80 mg/day.  
After satisfying the screening criteria, patients will be assigned a subject number 
and randomized to the atorvastatin or placebo arm in a 1:1 ratio (See section 3.3 Ran-
domization). This will be implemented upon subject enrollment, and communicated to the 
Research Pharmacy at the Chicago site via the web-based Electronic Data Capture 
(EDC) system. Administration of study drug shall continue thereafter, at once daily oral 
dose for 24 months, with scheduled visits and repeat imaging at 12 and 24 months 
from enrollment, and follow-up calls quarterly, and weekly feed back on compli-
ance by electronic monitoring device. Safety endpoints include a symptomatic intra-
cranial hemorrhage, from the index CA lesion or another source, or a serious adverse 
event (SAE) necessitating drug discontinuation (Protocol Section 8). If new symptoms 
arise at any point after starting the study or relevant laboratory test abnormalities, subjects 
will be contacted by the TN for further assessment and instructions regarding continuation 
of study intervention, dose de-escalation or discontinuation, based on the study adverse 
events management protocol (See Protocol Section 7). This approach is similar to that 
used in other statin trials (84, 85, 99, 100, 102, 106, 107, 109). 
 
9.2 Outcomes 
 
The primary outcome is the mean percent change in lesional QSM per year (called 
the change score). Each patient contributes two outcome measurements (at year 1 and 
year 2) based on intention-to-treat.  Evaluation of the intervention on this outcome will be 
performed as a time-averaged difference between two arms using a repeated measures 
analysis implemented as a linear mixed model, adjusted for gender (110). Patients with 
outcome measurements in both periods will be included in the initial intention-to-treat 
analysis. In cases with multiple lesions, only QSM measurements in the lesion with initial 
hemorrhage (index lesion) shall be considered for the primary outcome assessment. A 
secondary analysis of the percent QSM change per year shall be conducted per treatment 
rendered for all patients with at least one annual epoch of measurements. 
 
Secondary outcomes shall include: 
• Changes in DCEQP vascular permeability measurements in the index le-
sion and in brain (white matter far from lesion),  
• Rates of QSM and DCEQP biomarker events, representing increases in in-
dex lesional QSM or DCEQP above previously articulated “biomarker 
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adjudicated criteria; and rates of lesional expansion, defined as an increase 
in maximum lesion diameter on T2-weighted sequences by 2 mm or more. 
• Adverse event rates and serious adverse event rates, and drug compliance 
• Changes in functional outcome (mRS, MMSE, Euro-QoL 5D, Euro-QoL 
VAS, Neuro-QoL evaluations) 
• ROCK Activity Assay on Peripheral leukocytes (pMBS/GADPH ratio in im-
munoblots for each subject/visit)   
• Impact of sex, genotype and lesion location on primary and secondary out-
comes (pre specified subgroup analyses) 
 
9.3 Sample Size and Accrual 
 
9.3.1 Sample size and Treatment Effect Estimation 
Sample size calculations were based on providing sufficient power to test the pri-
mary hypothesis, that the proposed intervention impacts QSM biomarker activity (indica-
tive of reduced or increased lesional bleeding) during 2 years of prospective follow-up 
after a recent CA SH. The primary outcome is the mean % change in lesional QSM 
per year (called the change score). Each patient contributes two outcome measure-
ments (at year 1 and year 2, i.e. epochs). Evaluation of the intervention on this outcome 
will be performed as a time-averaged difference between two arms using a repeated 
measures analysis implemented as a linear mixed model and intention-to-treat principle 
(110).  
Estimating a “First-in-Man” treatment effect on a biomarker can be difficult 
when such effect is demonstrated mechanistically but the translation to a human effect 
size remains unknown (111). Based on pilot data linking QSM change to clinical events, 
we propose a minimum, clinically meaningful and mechanistically plausible treat-
ment effect to be a 20% absolute difference in the mean change score. It would be 
“a minimum expected effect”,  <1/2 the mean 44% QSM increase observed with CA bleed 
or growth during longitudinal 1-year follow-up of previously stable lesions; and “clinically 
meaningful”, > 3X the threshold of QSM change associated with maximum sensitivity-
specificity on ROC analyses (58). The absolute QSM effect size postulated herein is 
“plausible mechanistically”. It would be 0.0068 ppm [20% of 0.0340 ppm mean QSM 
change observed during follow-up of CA with SH (59)], 6-22 folds lower than the observed 
range of artorvastatin treatment effect on Perls stain intensity in Ccm1 and Ccm3 murine 
models (Figures 2, 3, 5).  
One-year %QSM change in 16 pilot study patients (Figure 7), followed for either 1 
or 2 years (22 patient-year epochs), was used to estimate the 1-year/patient standard 
deviation and within-patient correlation of the primary outcome in trial candidates.  A sam-
ple size calculation was performed using a repeated measures analysis of two annual 
percent QSM change scores, assuming a two-tailed test, power = 0.9 and alpha = 0.05 
(112). The actual within person correction from the pilot data was estimated at approxi-
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worth of data, we chose the more conservative within person correlation of 0 for our sam-
ple size estimates. In addition, we assumed a common standard deviation of 30 for the 
mean percent change score, which to be conservative is about 20% larger than the stand-
ard deviation in our pilot data. To detect a 20% absolute difference between the mean 
change score in each arm, based on two annual change scores measured per pa-
tient (at years 1 and 2), 25 patients per arm would be required. To detect a smaller or 
larger effect size, an absolute difference of 15% or 25%, 44 or 17 patients per arm would 
be required, respectively (Hintze 2014, PASS v13, NCSS, Kaysville, Utah, USA 
www.ncss.com). The sample size was further expanded by 37.5% to accommodate the 
highest estimate of missing data from all causes as discussed below. Hence we shall aim 
to enroll 40 patients/arm, 80 total subjects. 
 
9.3.2  Potential Missing Data, Attrition and Premature Trial Endpoint 
We considered all potential causes of missing data and we developed strategies 
to minimize and mitigate them. In initial pilot studies, 34 of 177 (19%) QSM assessments 
in CA patients were unusable due to technical reasons (mostly patient movement during 
image acquisition). We eliminated this problem in the most recent 25 consecutive cases 
with specific patient instructions. We now implement a further step of reviewing the QSM 
acquisition, and rapidly processing it (10 minutes on local Matlab computer terminals in 
our laboratory). This allows us to repeat the QSM acquisition if needed, before proceeding 
with contrast injection for DCEQP measurements. This “chaperoned biomarker acquisi-
tion” reduces to virtually zero the rate of missing QSM measures (See letter by Dr Chris-
toforidis and Protocol Section 6.5). We nevertheless project up to 10% missing biomarker 
data related to imaging (claustrophobia, etc.). We further project an additional 10% miss-
ing data due to imperfect follow-up, higher than that recorded in recent trials conducted 
by our teams (113, 114).  
Up to 20% of subjects randomized to atorvastatin (10% of trial subjects) might not 
tolerate the 80 mg/day dose. Many will continue the drug at the lower dose. In fact, seri-
ous side effects or intolerance of the lower dose are expected to result in attrition 
in less than 5% of cases, per extensive meta-analyses of trial experience with the study 
drug (See Protection of Human Subjects; and Protocol section 7.3). Another 20-30% of 
cases might reach a prespecified study endpoint because of SH, and they would also 
stop the drug before the end of the 2-years follow-up. All subjects who stop the drug, and 
those with non-compliance as defined, will still be followed for the full 2 years with sched-
uled clinical and imaging assessments, and will be included in the primary analysis per 
intention-to-treat.  
To permit secondary analysis per treatment rendered, at the power and Type I 
error described above, we decided to expand the sample size by an ample 37.5%, 
factoring the highest combined estimates of missing data and attrition. 
 
9.3.3 Futility Analysis 
Due to concerns that the treatment may not be effective in reducing QSM meas-
urements, we will perform a futility analyses once satisfactory primary outcome data 
(paired QSM assessment) has been logged on 50 of the planned 100 person-year epochs 
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with two-year and one-year will be included in the data. Therefore, within person correla-
tions between year 1 and year 2 will be controlled for in the futility assessment. As we 
have powered the study to see a 20% difference in percent QSM change values between 
treatment arms, we will call the trial intervention futile if we see a difference in QSM 
change scores of 10% or less between treatment. The futility analysis will be performed 
using a linear mixed-effects model adjusted for gender, and a one-sided confidence in-
terval will be created around estimated regression coefficient from this model, which rep-
resents the mean group difference in the percentage change of QSM scores between 
treatment arms. In general, the futility analyses should not be too strict so as not to over-
look a non-trivial effect size. Based on recommendations by Freidlin and Korn (115), we 
will consider a 99% one-side confidence on the difference in change scores between 
treatment groups. Under the futility analyses, three possible outcomes are possible: 1) 
the estimated group difference in change scores will be greater than 10%, 2) the estimate 
difference will be less than 10%, but the 99% one-sided confidence interval will include 
7.5%, and 3) the estimate group difference will be less than 10% and the upper 99% 
confidence interval will exclude 10%. A recommendation to stop the trial would be 
made under scenario 3, since this situation would indicate a 99% confidence that 
the true effect size is in fact less than 10%, and is therefore futile.  
 
 
9.3.4 Adaptive Adjustments to Sample size 
In addition to looking at the futility of the treatment effect, we will also assess the 
actual within person correlation in the year 1 and year 2 outcome measures, and the 
variance in the change scores within each arm. Since the sample size is strongly related 
to these two statistics, estimating the true correlation and variances will allow us to pro-
pose adjustments to the sample size at the midpoint of the trial. A larger than expected 
correlation and/or a smaller than expected variance of the change scores will allow 
us to reduce the final sample size but still retain the same estimated power. We do 
not anticipate projecting a higher sample size than initially proposed, given our conserva-
tive assumptions regarding the within person correlation in the year 1 and year 2 outcome 
measures and variance in the change scores. 
 
9.4 Data Monitoring 
 
Data safety and monitoring procedures will be in place before enrollment begins 
and monitoring will be performed on a regular basis throughout the subject accrual and 
treatment periods. 
 
9.4.1  Data and Safety Monitoring Team 
The data and safety monitoring team was discussed and approved by the NINDS 
staff. It will comprise the local IRB, the trial’s safety compliance officer (SCO) (Section 
10.3.2), and an IMSM from outside the study and data management institutions, assisted 
by two external medical safety consultants with expertise in CCM disease and in statin 
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of the research, adjudicating adverse events, performing interim safety and efficacy anal-
yses, and assessing progress towards achieving the goals of the study. 
Safety assessment will take place at the end of the first year, after 30 participants 
have completed 12 months of follow-up and again after 60 subjects have completed 12 
months of follow-up. Additional reviews will be decided on an ad hoc basis based on the 
frequency of safety endpoints encountered during the trial. The Brain Injury Outcomes 
(BIOS) statistician will provide the IMSM and the PI relevant tables including information 
regarding demographics, rebleeding rates, AEs, SAEs, and radiological and laboratory 
abnormalities (CT scans, liver function, etc.), per treatment assignments labeled A and B 
without unblinding. In addition, the IMSM will be provided with a copy of the SAE forms 
received. Further information will be given to the IMSM upon his/her request. The IMSM 
will provide written recommendation as to whether the study may continue, possible 
amendment(s) to the protocol, or whether the study should be stopped. The final decision 
will rest with the study PI, guided by protocol mandated safety thresholds to suspend and 
potentially revise or stop the trial (see below). Any protocol revision would require 
approval by the IRB, and shall be discussed with NINDS staff and external consultants 
prior to implementation. 
 
9.4.2  Safety Threshold 
While the proposed trial is underpowered to detect a significant difference in symp-
tomatic clinical rebleeding rates between groups, differential and absolute rates of 
hemorrhage in the placebo and treatment cohorts will be critically analyzed 
throughout the trial. Continuous monitoring will be initiated with the enrollment of the 
tenth subject in the study. A symptomatic brain hemorrhage from the index hemorrhagic 
CA lesion or another source will be considered a safety endpoint for the respective sub-
ject. The natural history of untreated brainstem CA demonstrates a 32.1% (CI 1-59%) 
bleeding risk within two years after prior hemorrhage (18), and our own pilot data of 14 
trial candidates undergoing biomarker studies showed 4 symptomatic rebleeds (28%) 
during 21 patient-years of follow-up (Figure 7). We will hence decide to implement a run-
ning safety threshold to preemptively suspend trial enrollment for a full safety review if at 
any time, >40% of subjects in the treatment group suffer a symptomatic brain hem-
orrhage from the index CCM lesion or another source. Subclinical bleeding is likely 
more common, and the proposed trial is designed and powered to identify increased sub-
clinical iron leak in CCM lesions using our validated QSM biomarker, in addition to careful 
monitoring of clinically overt hemorrhages.  
9.5 Data analysis  
Exploratory analyses for quality assurance and understanding of missing data pat-
terns and distributions will be performed on the outcomes and all measurements to be 
used in the primary and secondary analyses. For the primary aim, a linear mixed model 
will be used that adjusts for gender to evaluate the difference between the two arms in 
the QSM change of the index hemorrhagic lesion per patient. Adjustment for gender is 
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ling for stratification variables can lead to upwardly biased standard errors and a de-
creased power (116). The model accounts for within-patient correlation between the 
measurements (117, 118). Patients with outcome measurements in both periods will be 
included in the initial intention-to-treat analysis. A secondary analysis of the percent QSM 
change per year shall be conducted per treatment rendered for all patients with at least 
one annual epoch of measurements. Significance levels are assumed as per sample size 
calculations. 
To address secondary aims, each of the other outcomes will be analyzed with a 
similar approach, first per intention-to-treat sample in patients receiving two annual 
epochs of follow-up, and second by treatment-rendered in all patients with at least one 
annual epoch of measurements. To assess the difference in level of DCEQP permeability 
in lesion and brain between the two arms, a linear mixed model adjusted for gender as 
described for QSM will be used to evaluate the difference in percent change per year in 
lesional and WMF permeability. A similar adjusted linear logistic mixed model for the bi-
nary outcomes will be used to evaluate the difference between the two arms in the rates 
of symptomatic hemorrhage (per adjudicated definition), lesion expansion, and “bi-
omarker event” (increase in QSM during an epoch above the pre-defined 6% threshold). 
To assess the difference of event rates for adverse events (AEs) per patient, an adjusted 
Poisson linear mixed model controlling for gender will be used to regress count outcomes 
in order to evaluate the difference in AE event rates between the two treatment arms. The 
AEs will be assigned preferred terms per body systems according to the Medical Diction-
ary for Drug Regulatory Affairs (MEDDRA) classification of the WHO terminology. AEs 
(categorized by body system) and abnormal laboratory data will be summarized and com-
pared by treatment group. The compliance rate, general attrition rate and the attrition rate 
due to adverse events between the two groups shall also be compared. For analysis of 
leukocyte ROCK activity and functional outcomes (mRS, Euro QOL 5D and VAS, Neuro 
QOL Communication, and mini-MS score), an adjusted linear mixed model will be used 
to evaluate the difference in respective outcome score change per year between the two 
arms. We will report point-estimates, confidence intervals, and p-values for each analysis.  
Demographic and baseline data, including age, gender, ethnicity, age at symptom 
onset, number of prior hemorrhagic events, number of T2-weighted lesions, number of 
susceptibility weighted imaging (SWI) lesions, etc., will be summarized. As a secondary 
model, a linear mixed model that adjusts for those baseline factors shown to associated 
with the outcome will be created, and will consider the constraints of a small numbers in 
the respective sub-cohorts. Presenting the mean, standard deviation, median, minimum 
and maximum with the total number of patients contributing values, will summarize con-
tinuous endpoints. Presenting the frequency or proportion of patients in each category 
will summarize categorical endpoints. For all analyses, biased effects in three prespeci-
fied subgroups shall be queried (male/female, sporadic/familial genotype, and brain-
stem/other lesion location). If the numbers of genotyped subjects allow, we will also com-
pare treatment effect in different genotypes among familial cases. Similar analyses were 
recently performed by our team in the MISTIE II and CLEAR III trials (113, 114). 
 
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As mentioned above, every effort will be made to minimize the number of patients 
will missing outcome measures. However, despite these best efforts, it is likely that some 
missing outcome data will be present in this data set. In order to account for these missing 
outcome values, we will perform a sensitivity analyses that uses a Markov chain Monte 
Carlo (MCMC) model to impute several possible measures for patients missing the pri-
mary outcome.  
With multiple imputation (MI), we assume that the missing data points are missing 
at random (MAR) (119). We will use those baseline demographic variables, which are 
strongly associated with clinical outcome, to improve the missing outcome imputations. 
We will then generate an iteration series plot and autocorrelation function (ACF) plot for 
MCMC simulation. We shall plan 20 imputations with a 98% relative efficiency to accom-
modate a worst-case scenario, where 37.5% of the outcomes data points are missing 
(120). To verify if the missing data points occur at random we will utilize a tipping-point 
approach (121) that will follow MI procedure for sensitivity analysis and estimation of the 
MI departure from the MAR assumption. We shall use the sensitivity analysis to recalcu-
late efficacy estimates from regression models described in the data analysis of the pri-
mary and secondary outcomes. This will help determine how sensitive efficacy estimates 
are under different assumed distributions for missing outcomes data. In other words, the 
results obtained by imputing missing data with several plausible outcomes will give a 
range of possible treatment effects under different assumptions of missingness.  
We will have greater confidence in efficacy estimates if we obtain clinically and 
statistically significant results under the worst-case scenarios from the sensitivity anal-
yses (e.g. imputing no improvement in the QSM change scores for all patients with miss-
ing data in the active treatment arm).  In contrast, greater caution should be given to es-
timates of efficacy if results obtained from regression analyses are no longer clinically 
and statistically significant under extreme scenarios for the missing data. SAS 9.4 (SAS 
Institute Inc., Cary, NC, USA) will be used for MI and sensitivity analysis.  
Analysis of Treatment Compliance 
Treatment compliance is crucial to validate the study objectives. A compliance 
threshold of 90% will be implemented for proposed analyses per treatment rendered. 
Drug adherence will be rigorously monitored through an innovative electronic system that 
will provide continuously streamed real time data in addition to confirmatory manual pill 
count at each follow up call and scheduled visits. Assessment of compliance is an integral 
component at every scheduled or unscheduled evaluation and will be based on the 
electronically acquired data as well as the missed doses log in the case report form 
(CRF). A subject will be deemed noncompliant with the study intervention if he/she misses 
more than 21 consecutive doses at any point, or accumulate a log of 75 missed doses 
throughout the study. Treatment compliance shall be compared in atorvastatin versus 
placebo cases as one of the secondary aims of the study. 
 


 
 
 
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10. DATA COLLECTION, SITE MONITORING, AND ADVERSE 
EXPERIENCE REPORTING 
 
10.1 Records to Be Kept 
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]). 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 
10.2 Role of Data Management 
The trial investigator will permit trial related monitoring, audits, IRB review, and 
regulatory inspections by providing direct access to source data and documents. Data for 
each subject will be reported and recorded on electronic case report forms. Electronic 
case report forms (eCRF) must be completed for every randomized subject.  
 
10.3 Quality Assurance 
AT CASH EPOC will have a robust safety and data monitoring program in full 
compliance with NIH policy of 10-Jun-1998 as expanded by NINDS guidelines published 
14-Sep- 2011 in addition to compliance with all applicable U.S. and international GCP 
regulations. This program, designed to safeguard the well-being of study participants and 
to ensure scientific integrity, will include the following components:   
• 
Oversight by the DCC, Clinical Coordinating Center (CCC), and IRB 
• 
A dedicated independent medical safety monitor (IMSM) and safety compliance 
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• 
Automated data quality checks at the time of eCRF completion by the 
investigational site;  
• 
Dedicated independent data monitoring and quality assurance (QA) teams 
(Emissary International);  
The components of this multifaceted approach, including each dedicated team’s 
specific responsibilities, are discussed below.  
10.3.1. Data Coordinating Center (DCC)  
The DCC will provide an independent review of the research, interim safety and 
efficacy data, and progress towards achieving the goals of the study. To enable the CCC 
to properly manage the trial, the project leadership, and key personnel will jointly work on 
a data monitoring plan early in the process. After the award but before the project begins, 
the CCC will work with the DCC to develop a detailed monitoring plan. The monitoring 
plan will describe the process for reporting adverse events to the IRB, IMSM, and NIH.  
 
Interim safety analyses will be prepared for the DCC on a pre-arranged schedule 
to evaluate efficacy and safety. Safety events will trigger a “suspend recruitment and 
review” by the DCC. Prior to IMSM report generation, the case report forms will be 
finalized, data compiled, all requested analyses conducted, and suitable reports, tables 
and graphs prepared. All deaths will be reviewed.  
10.3.2. Data and safety monitoring  
The study is designed as a single-site trial investigating one minimal-risk 
intervention. Per approval by NINDS, subjects’ safety will be monitored by the PI and 
safety monitoring team as described above. The PI will be actively involved in reviewing 
the progress of each subject and will notify the IRB as well as the external IMSM and the 
NINDS program official about adverse events and unexpected problems that may 
influence their decision to allow the trial to continue.   
Independent Medical Safety Monitor (IMSM):  The study PI will nominate an 
independent experienced physician with relevant expertise who is not in affiliation with 
the study site at University of Chicago Medicine or the data coordinating center at Johns 
Hopkins University and has no conflict of interest. The IMSM will oversee ongoing 
monitoring of reports of SAEs in real time to ensure GCP and to identify safety concerns 
quickly. The IMSM will also serve as a resource to the principal investigator to provide 
advice about management of AEs/SAEs but will not be involved in other aspects of the 
trial. The IMSM may suggest protocol modifications to prevent the occurrence of particular 
AEs. To maximize safety considerations, the IMSM will evaluate SAEs per treatment 
assignments labeled A or B. In the event of unexpected SAEs or an unduly high rate of 
SAEs, the IMSM may request identification of A or B as treatment versus placebo. And 
he/she will promptly contact the PI and the NINDS program officials. The IMSM will be 
assisted by two designated external safety consultants, with expertise in CCM disease 
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Safety Compliance Officer (SCO): The study PI and IRB require a process for 
timely communication of adverse events and complication rates to regulatory agencies. 
Thus, an essential component of this process is the safety compliance officer (SCO). The 
SCO will have the day-to-day responsibility of ensuring that adverse events are promptly 
collected, medically reviewed by the PI or IMSM and appropriately reported to regulatory 
agencies in compliance with GCP standards. The SCO and the statistician at the 
Baltimore site shall be responsible for preparing and communicating incoming documents 
and reports to the PI and IMSM. Inclusion/exclusion criteria, review-of-system reports, 
medical history, medical events, and radiographic imaging entries will be cross-checked 
and reviewed by applying real- time database algorithms, crosschecking sentinel dates 
and times, procedures, AEs, SAEs, and protocol timelines. As aggregate data reports 
and quarterly and annual progress reports are prepared, the SCO will query the TN and 
study coordinator as needed and follow the data entry tasks to completion. The SCO will 
serve as the liaison between the IMSM and the PI and CCC personnel to garner additional 
information as needed and to elicit agreement or disagreement of the CCC with the 
IMSM’s assessment. The SCO will manage the development and revision of trial 
protocols, Manual of Operations and Procedures (MOP), standard operating procedure 
(SOP), and protocol working guidelines with the trial leadership.  
Reporting Dictionary and Data Standards: The SCO will work closely with the 
trial vendors to develop the EDC systems and the corresponding paper CRFs, used for 
all safety-related events. The Common Terminology Criteria for Adverse Events (CTCAE) 
dictionary has been adapted to allow for trial-specific reporting using standardized 
Medical Dictionary for Regulatory Activities (MedDRA) coding.  
10.3.3 Automated Data Quality Checks in the EDC System  
VISION® EDC System: The EDC system has a robust set of data quality checks 
that will be executed at the time of data entry at the investigational site. This includes the 
standard validations available with most EDC systems such as range checks (e.g., to flag 
a high liver function test as incompatible with inclusion criteria, or to ensure a temperature 
is not an impossible value) and data format checks (to flag an invalid date). Additionally, 
our VISION platform will perform very sophisticated cross-form computed calculations 
that would not be available in lesser EDC systems. For example, VISION will conduct a 
series of verifications looking at lab values, demographics, etc. and give the site guidance 
regarding the eligibility of the patient for randomization using complex cross-page 
computations. It will also detect when the CCC has made a protocol variance and present 
a list of such issues to the investigator and the monitoring team for evaluation and follow-
up. Consequently, our EDC system will handle much of the consistency, completeness, 
and logic checks immediately at the time of data collection that normally would have to 
be done by the monitoring team and/or offline using statistical analysis that do not typically 
occur until weeks or months after the patient visit. This capability therefore will result in 
cleaner data that will be more likely to distinguish a treatment effect and significantly 
reduce the cost of, and delays for, monitoring and data cleaning activities.  
10.3.4 Independent Data Monitoring and Quality Assurance Team  


 
 
 
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It is important to use an independent Contract Research Organization (CRO) for 
monitoring and quality assurance, to provide the highest level of integrity, industry- proven 
best practices, and professionally trained monitors. Our CRO, Emissary International, 
maintains a team of high-caliber, fully qualified monitors in the U.S. This team will be 
responsible for near real-time review of the clinical data entered into our EDC system 
against source medical records (i.e., Source Document Verification or SDV) as well as 
generation and resolution of the associated data queries.  
QA Monitoring Plan: In accordance with recently drafted FDA recommendation for risk-
based monitoring approaches, this trial will employ centralized monitoring and an EDC 
system to:  
• 
Replace on-site monitoring for activities that can be done better using centralized 
reviewers;  
• 
Verify source medical records remotely to ensure data integrity, reduce 
transcription errors, and identify any undocumented safety events;  
• 
Utilize EDC real-time data quality checks to assess range, consistency, and 
completeness of data at the time of entry; and  
• 
Employ frequent statistical analyses of study data to evaluate individual subject 
data for plausibility and protocol compliance.  
10.3.5 Data Flow for the Data Coordinating Center  
Correction of Automated Errors and Warnings: As data are entered, the EDC 
system will immediately generate automated warnings (yellow highlights) and errors (red 
highlights). Warnings will represent data that is outside expected limits, or where required 
data are missing. Errors will indicate conditions that are intolerable (such as an impossibly 
high body temperature) or that are unrealistic (such as an invalid date format).  
In keeping with FDA requirements for electronic systems, the EDC system will not 
force the investigator/coordinator to immediately change the entered data (as that could 
be misconstrued as encouraging data falsification) but instead simply provide feedback 
via on-screen messages and red/yellow field highlighting. Warnings may be unavoidable, 
due to patient-specific issues, but are documented nonetheless so that they can be 
discussed with the monitoring team. Conversely, red errors must be resolved before the 
case form page can be advanced in the workflow (i.e., signed by the coordinator) so the 
data will be “clean” before it is exported for analysis.  
Additionally, the EDC system will generate external email notifications in response 
to specific entries, such as immediately alerting the CCC of a possible dose/color-code 
error or notifying the safety officer of a new adverse event. The EDC system also 
produces various instantaneous reports that are useful for data quality and safety 
monitoring purposes by both the site staff and the CCC.  
Monitoring Team Source Document Verification and Data Integrity Review: 
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and consistency, then verify the entered data against the uploaded source medical 
records and data collection worksheets. Routine queries identified in this process will be 
entered into the EDC system (triggering an automated notice to the site). The monitors, 
working in conjunction with the DCC, will then work with the CCC personnel to obtain 
correction of all data errors and resolution of the corresponding queries.  
Reviews will include data from the entire course of each patient’s participation in the 
study. In accordance with a formal monitoring plan, this activity will include a review of all 
uploaded source documentation and will entail a 100% source verification of the primary 
safety and efficacy measures. Random sampling will be used to select secondary data 
for similar 100% source verification. Should the data accuracy for a patient exceed certain 
minimum expectations in this step, or if any material data integrity or regulatory 
compliance issues are identified, additional data from a patient will undergo intensive 
monitoring.  
10.3.6 Other Components of Data Management Plan  
Randomization and Data Collection: Each subject is assigned a unique study 
number by the EDC after randomization. Data collection of compliance, concomitant 
medications, and adverse events will assess the subject’s clinical response to treatment 
as part of the clinical trial. This data will be used to assess compliance with the study 
protocol and intervention stopping rules.  
Protocol Compliance: Procedures will be implemented to maximize adherence 
to the protocol (smart bottles). Early review of data is made possible by real- time entry 
of data into a database with validations and real-time monitoring. The study center is 
required to report a protocol deviation within 24 hours of occurrence or as soon as it is 
discovered. If the QA monitor discovers an undocumented major deviation during a 
monitoring activity, the monitor will notify the CCC immediately. A CCC personnel will 
report deviations as they are discovered to the local IRB in accordance with local 
requirements. Routine reporting of protocol deviations will be made to the NINDS and 
other regulatory agencies as required. 
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 
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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.  
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.  
Security Measures: Users at both centers will be aware of system security 
measures and the importance of limiting access to authorized personnel. SOPs will be in 
place for handling and accessing the system to prevent unauthorized access. Access to 
the data at a clinical site will be restricted and monitored by the system through required 
log- on, security verification procedures, and audit trail. The data cannot be altered, 
browsed, queried, or reported via external software applications without entering through 
the protective software. Because the system will be largely through remote access, all 
data and applications used for the study will be logically and physically isolated in the 
servers in order to preclude unintended interaction with non-study use software. These 
servers will be strictly monitored and maintained by designated administrators at an 
independent third party (e.g., only Prelude Dynamics, the contracted EDC vender, has 
password access to the database and only its contracted commercial data center, On- 
Ramp Systems both of Austin, Texas, has access to the physical hardware); neither 
remote sites nor any member of the project team will have the ability to change such 
logical security of the system. Written procedures describing contingency plans for 
continuing the study by alternate means in the event of hardware or facilities failures with 
alternate hardware or at an alternate site will be provided to each site. It should be noted 
that the data management procedures will reflect the advanced use of computer and 
software technology; include database technology, and electronic file management 
principles; and therefore be of the highest possible standards achievable for data security 
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HIPAA-audited and certified for maintenance of banking, credit card, and protected health 
information (PHI).  
Backup Recovery: Records will be backed up daily to prevent a catastrophic loss 
compromising the quality and integrity of the data. Data will be backed up onto digital 
media which will be stored at an offsite location. Backup and recovery logs will be 
maintained to facilitate an assessment of the nature and scope of data loss in the event 
of a system failure.  
Limited Access: Each user will be assigned an individual account with a unique 
username and password. Any user will be locked out after 10 consecutive attempts, with 
any unauthorized access attempt recorded in a log file. Users will be required to exit the 
system upon leaving a workstation. The computer will automatically log off the current 
session when an idle period reaches 30 minutes. For short periods of inactivity, the 
automatic screensaver will be password protected to prevent unauthorized access to the 
system.  
Audit Trails: All changes made to data in the electronic record are tracked and 
recorded in the audit trail. This audit trail will capture the date/time, the contents of the 
changes made, and the login id used to make the change. The audit trails will be created 
incrementally in chronological order, with prevention of overwrite, as such data 
overwriting is in violation of §11.10(e). Audit trail information will be reviewed by pre- 
authorized personnel if the need arises to verify the quality and integrity of the data.  
Date and Time Stamps: All data will be saved on a central server carrying a time 
stamp, which will be documented in the audit trail. The EDC software will display the 
participating site's time zone. Individual users will be unable to change the time on the 
server. 
 
10.4 Adverse Experience Reporting  
 
10.4.1 Specification of Safety Variables: Safety assessments will consist of 
monitoring and reporting adverse events (AEs) and serious adverse events (SAEs), all 
events of death, and any study specific issue of concern. 
  
10.4.1.1 Adverse Events (AEs): 
Definition of AEs: An adverse event is any untoward medical occurrence in a 
patient entered into the study that does not necessarily have a causal 
relationship with the study intervention. An adverse event can be any 
unfavorable and unintended sign (including an abnormal lab finding), symptom, 
or disease temporally associated with the use of the study drug, whether or not 
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initially at the level of the TN. The investigator must follow adverse events to 
resolution whenever possible. 
AEs include the following: 
• AEs not previously observed in the subject that emerge during the protocol-
specified AE reporting period, including signs or symptoms associated with 
intracerebral hemorrhage, myositis, or organ dysfunction that were not 
present prior to the AE reporting period. 
•  Complications that occur as a result of protocol-mandated interventions 
(e.g., contrast nephropathy). 
•  Preexisting medical conditions (other than the condition being studied) 
judged by the investigator to have worsened in severity or frequency or 
changed in character during the protocol-specified AE reporting period. 
 
10.4.1.2 Serious Adverse Events (SAEs) 
Definition of SAEs: A serious adverse event is an adverse event that results in 
any of the outcomes listed below. They generally correspond to Categories B and 
C adverse events in Table. 2. 
• 
 Results in death (i.e., the AE actually causes or leads to death). Study 
investigator agrees to adhere to FDA-defined guidelines and submit an 
expedited report of any death that is related (even remotely) to study drug. 
• 
 Life threatening (i.e., the AE, in the view of the investigator, places the 
subject at immediate risk of death. It does not include an AE that, had it 
occurred in a more severe form, might have caused death.). 
• 
 Requires inpatient hospitalization or prolongs inpatient hospitalization. 
• 
 Persistent or significant disability or incapacity: a substantial disruption of 
a person’s ability to conduct normal life functions. 
• 
 Considered a significant medical event by the investigator based on 
medical judgment (e.g., may jeopardize the subject or may require 
medical/surgical intervention to prevent one of the outcomes listed above). 
Compulsory SAE: Certain AEs in the coding guide are defined as potentially 
serious SAEs if there is a medically qualifying factor. All AEs coded as a grade 4 or 5 will 
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10.4.1.3 Medical events of interest (MEOI)  
Definition of MEOIs: MEOIs must be reported to the PI for safety monitoring team 
review. The AE dictionary, which drives the drop down lists on the AE screen in 
the EDC system, pre-specifies which events are defined as MEOIs. A MEOI may 
or may not satisfy the definition of a SAE but will be reported using the same SAE 
reporting screen in the EDC system and will undergo the same review as a SAE. 
In summary, the MEOIs for the trial are as follows:  
• Myositis/ Rhabdomyolysis 
• Symptomatic Cerebral bleeding events  
• Liver dysfunction. 
• Pancreatitis. 
• Any AE deemed by the site PI or safety monitoring team as possibly, 
probably, or related to the statin therapy. 
• Any AE requiring discontinuation of study intervention or withdrawal from 
follow-up  
 
10.4.2 Assessment of Adverse Events 
All AEs and SAEs whether reported by the subject, elicited by study personnel 
during questioning, or detected through physical examination, laboratory test, or other 
means will be recorded appropriately. Each reported AE or SAE will be described by its 
duration (i.e., start and end dates), regulatory seriousness criteria if applicable, suspected 
relationship to study drug administration, and actions taken. 
 
10.4.2.1 Attributability of AEs to the study drug: The investigator in consultation 
with the MSM will define whether the event is best described as UNRELATED, 
POSSIBLY related, PROBABLY related, or DEFINITELY related to the study drug 
according to the following definitions. To ensure consistency of AE and SAE causality 
assessments, investigators will apply the following general guideline: 
Yes 
There is a plausible temporal relationship between the onset of the AE and the 
administration of the study drug, and the AE cannot be readily explained by the subject’s 
clinical state, concomitant illness or therapies; and/or the AE follows a known pattern of 
response to the study drug; and/or the AE abates or resolves upon discontinuation of the 
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• Possibly Related: The adverse event has a temporal relationship to the study 
drug. However, an alternative etiology may be responsible for the adverse event. 
Information on drug withdrawal may be lacking or unclear. 
• Probably Related: The adverse event has a temporal relationship to the study 
drug. The event is unlikely to be related to an alternative etiology. There is a 
reasonable response on withdrawal (de-challenge). Re-challenge information is 
not required. 
• Definitely Related: The adverse event has a temporal relationship to the study 
drug and resolves when the study drug is discontinued. An alternative etiology is 
not apparent.  
 
No 
Evidence exists that the AE has an etiology other than the study drug (e.g., preexisting 
medical condition, underlying disease, concomitant illness or medication); and/or the AE 
has no plausible temporal relationship to the study drug administration  
• Unrelated: There is evidence that the adverse event definitely has an etiology 
other than the study drug 
10.4.2.2 Unexpected AE definition: Unexpected events are any adverse events 
in which the specificity or severity is not consistent with the natural history of CCM without 
the test intervention. Unexpected will be defined as the specificity or severity of an event 
that is not consistent with the risk information described in this protocol. 
 
10.4.2.3 Adverse Event Reporting Period: The timeframe of reporting adverse 
events extends throughout the study period from randomization until the end of the study 
follow-up period for each enrolled subject. Adverse events must be recorded in the 
medical chart and in the EDC system. 
 
10.4.2.4 Documentation: Documentation must include the event duration 
(start/stop). If a subject is discontinued early from study drug for any reason, CCC 
personnel must clearly report and document the circumstances and data leading to any 
discontinuation using the electronic case report forms. It must be determined if the reason 
for stopping study drug administration is an adverse event. 
 


 
 
 
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10.4.2.5 Follow up of ongoing AEs: For any untoward event(s) the subject 
should be followed until the event resolves or is explained with the frequency of follow up 
designated by the investigator. 
10.4.2.6 Eliciting AEs during follow up visits: At each follow up visit, the subject 
will be asked about the occurrence of AEs since the last contact. AEs that were ongoing 
at the last contact will be updated with a stop date or confirmed as ongoing. This will 
continue until the end of study visit.  
A consistent methodology for eliciting AEs at all subject evaluation time points will be 
adopted. This questionnaire will also be adopted for the automated weekly follow up 
messages circulated by the electronic monitoring system. Examples of non-directive 
questions include: 
• Have you been well since your last clinical visit? 
• Have you had any new health problems since you were last seen? 
• Have you had any recent weakness or altered sensation affecting your 
arms or legs?  
• Have you experienced any recent onset muscle or joint pain?  
• Have you noticed any changes in urine or stool color? 
• Have you had any unusual or unexpected worsening of your underlying 
medical condition? 
10.4.3 Specific Instructions for Recording Adverse Events: 
Investigators should use correct medical terminology/concepts when reporting AEs 
or SAEs. Avoid colloquialisms and abbreviations.  
 
Diagnosis vs. Signs and Symptoms  
If known at the time of reporting, a diagnosis should be reported rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases). However, if a constellation of 
signs and/or symptoms cannot be medically characterized as a single diagnosis or 
syndrome at the time of reporting, it is ok to report the information that is currently 
available. If a diagnosis is subsequently established, it should be reported as 
follow-up information.  
 
Deaths  
All deaths that occur during the protocol-specified AE reporting period, regardless 
of attribution, will be reported to the safety officer. When reporting a death, the 
event or condition that caused or contributed to the fatal outcome should be 
reported as the single medical concept. If the cause of death is unknown and 
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Preexisting Medical Conditions  
A preexisting medical condition is one that is present at the start of the study. Such 
conditions should be reported as medical and surgical history. A preexisting 
medical condition should be re-assessed throughout the trial and reported as an 
AE or SAE only if the frequency, severity, or character of the condition worsens 
during the study. When reporting such events, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., “more frequent headaches”). 
 
Hospitalizations for Medical or Surgical Procedures  
Any AE that results in hospitalizations or prolonged hospitalization should be 
documented and reported as an SAE. If a subject is hospitalized to undergo a 
medical or surgical procedure as a result of an AE, the event responsible for the 
procedure, not the procedure itself, should be reported as the SAE. For example, 
if a subject is hospitalized to undergo coronary bypass surgery, record the heart 
condition that necessitated the bypass as the SAE.  
 
10.4.4 SAE Reporting  
Any alarming, serious, or unexpected adverse event, including death due to any 
cause, which occurs during this study, inclusive of the follow up period, and whether or 
not thought to be related to the test article, must be reported immediately (within 24 hours 
of learning of the event) to the trial PI, the IMSM and to the local IRB as required. 
Completion of an SAE form for each SAE that occurs is required to formerly report the 
event to the trial PI. An expedited safety report will be used by the SCO to notify the PI 
and IMSM of each serious unexpected suspected adverse reaction, and a running total 
thereof. This protocol has a pre-specified monitoring plan for determining if subjects 
receiving the test article are at higher risk for mortality and will only report a death as an 
expedited safety report if there is evidence of a causal relationship between the test article 
and the event resulting in death. In addition, an expedited safety report will be used to 
notify the PI and IMSM if there is an imbalance between the arms suggesting there is a 
reasonable possibility that the test article caused any of the safety endpoints. Otherwise, 
the occurrence of these safety endpoints will be reported on an annual basis. The study 
leadership will submit events meeting the following criteria as expedited Safety Reports 
according to the guidance and timelines below. The completed case report will be emailed 
immediately upon completion to the PI and IMSM. 
 
Calendar Day Telephone or FAX Report:  
The study leadership will notify the IMSM and the IRB for review of any fatal or 
life-threatening adverse event that is unexpected (as defined above) and assessed by 
the PI (in consultation with the IMSM) to be possibly, probably, or definitely related to 
the test article. Such reports will be emailed or faxed within 7 calendar days of the study 
leadership first learning of the event. Relevant follow-up information will be submitted to 
all parties as soon as it becomes available. 
 


 
 
 
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Calendar Day Written Report:  
The study PI will notify the IMSM and the IRB, in a written Safety Report, of any 
serious, unexpected AE (as defined above) that is considered possibly, probably, or 
definitely related to the test article. Such reports will be emailed or faxed within 15 
calendar days of the study leadership first learning of the event. Relevant follow-up 
information will be submitted to all parties as soon as it becomes available. 
 
Annual Written Report:  
The study leadership will notify the IMSM and his designated consultants with a 
listing of all suspected serious adverse reactions which have occurred over this period 
and a report of the subjects’ safety. Written Safety Reports will include an Analysis of 
Similar Events in accordance with 21 CFR §312.32. All safety reports previously filed 
concerning similar events will be analyzed and the significance of the new report in light 
of previous, similar reports commented on. Written safety reports with Analysis of Similar 
Events will be submitted to the IMSM within 15 calendar days of the study leadership first 
learning of the event. 
 
 
11. HUMAN SUBJECTS 
11.1 Institutional Review Board (IRB) Review and Informed 
Consent 
This protocol and the sample informed consent document, and any subsequent 
modifications will be reviewed and approved by the University of Chicago Medicine IRB, 
responsible for oversight of the study.  A signed consent form will be obtained from the 
subject. The consent form will describe the purpose of the study, the procedures to be 
followed, and the risks and benefits of participation.  A copy of the consent form will be 
given to the subject, parent, or legal guardian, and this process will be documented in the 
subject’s record. 
11.2 Subject Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records that leave 
the site will be identified only by the Study Identification Number (SID) to maintain subject 
confidentiality.  All records will be kept in a locked file cabinet.  All computer entry and 
networking programs will be done using SIDs only.  Clinical information will not be 
released without written permission of the subject, except as necessary for monitoring by 
IRB, the NINDS, or the Office for Human Research Protections (OHRP). 
11.3 Study Modification/Discontinuation 
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. 
 


 
 
 
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12. PUBLICATION OF RESEARCH FINDINGS 
 
Publication of the results of this trial will be governed by the policies and 
procedures developed by the study leadership.  Any presentation, abstract, or manuscript 
will be made available for review by the study leadership and the funding agency prior to 
submission. 
 
The results of the trial will be published regardless of its outcome. Publication 
regarding further analyses performed on the data will be by mutual agreement between 
the study leadership and the study investigators. 
 
The investigators may publish or present at scientific meetings the results of this 
study, provided that confidential information is not disclosed, and only after obtaining 
advance written consent from the study leadership. Consent may be withheld at the sole 
discretion of study leadership. 
 
In this regard, a copy of all public disclosures, including but not limited to 
publication manuscripts, abstracts, and seminar presentations by any member of the 
investigative team, should be provided to the study leadership, at least 30 days before 
the manuscript is submitted to the publisher or a presentation is made.  
 
 
 
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