Validation Study of Treating Arteriovenous Malformation With Stereotactic Radiosurgery Using CT Angiography for Treatment Planning
Phase: EARLY_PHASE1
Conditions: Arteriovenous Malformations
Sponsor: University of Texas Southwestern Medical Center

 
STU042018-100, Timmerman, FormA-ResearchProtocol, Mod_17, 04-27-21 (1)  
 
 
CONFIDENTIAL 
This material is the property of the UTSW Simmons Comprehensive Cancer Center.  
Do not disclose or use except as authorized in writing by the study sponsor. 
Template Updated: 12/2012; 9/2013; 8/2014; 4/2015; 10/2015; 11/2016; 12/2018; 07/2020 
 
STU 042018-100   
Validation study of treating Arteriovenous Malformation with Stereotactic Radiosurgery using CT 
angiography for treatment planning 
 
 
Principal Investigator:  
Robert Timmerman, M.D. 
 
 
 
University of Texas Southwestern Medical Center 
 
 
 
2280 Inwood Road 
 
 
 
Dallas, Texas  75390-9303 
 
 
 
 
Phone: 214-645-8525  
 
 
 
 
Fax: 214-645-8527 
 
 
 
 
Robert.Timmerman@UTSouthwestrn.edu 
 
Co-Principal Investigator: 
Babu Welch, M.D. 
 
 
 
University of Texas Southwestern Medical Center 
 
 
 
5161 Harry Hines Boulevard, CS5.112  
 
 
 
Dallas, Texas 75390-8855 
 
 
 
 
Phone: 214-648-8779 
 
 
 
 
Fax: 214-648-2265 
 
 
 
 
Babu.Welch@UTSouthwestern.edu  
 
 
 
 
 
 
 
Biostatistician:  
 
Chul Ahn, Ph.D. 
 
 
 
 
Department of Clinical Sciences 
 
Study Drug/Treatment:  
Radiation, Stereotactic Radiosurgery with Gamma Knife  
 
Funding Source:  
Department of Radiation Oncology at UTSW  
 
Initial version: 
Version 1 – 8/16/2017 
 
Amended: 
 
Version 2 – 3/9/2020 
 
 
Version 3 – 4/20/2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
UT Southwestern Medical Center (UTSW) 
Harold C. Simmons Comprehensive Cancer Center 
Attn: Clinical Research Office 
5323 Harry Hines Blvd. MC 9179 
Dallas, Texas 75390-9179 
 

 
STU042018-100, Timmerman, FormA-ResearchProtocol, Mod_17, 04-27-21 (1)  
 
 
CONFIDENTIAL 
This material is the property of the UTSW Simmons Comprehensive Cancer Center.  
Do not disclose or use except as authorized in writing by the study sponsor. 
Template Updated: 12/2012; 9/2013; 8/2014; 4/2015; 10/2015; 11/2016; 12/2018; 07/2020 
 
 
Signature Page 
 
The signature below constitutes the approval of this protocol and the attachments, and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the protocol, including 
all statements regarding confidentiality, and according to local legal and regulatory requirements and 
applicable U.S. federal regulations and ICH guidelines. 
 
Amendment/Version #: Version 3 
 
STU 042018-100: Validation study of treating Arteriovenous Malformation with Stereotactic Radiosurgery 
using CT angiography for treatment planning 
 
Principal Investigator (PI) Name: Robert Timmerman, M.D. 
 
 
PI Signature: _____________________________ 
 
 
Date: ____________________ 
 
 

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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ............................................................................................................. 1 
STUDY SCHEMA ............................................................................................................................. 2 
STUDY SUMMARY .......................................................................................................................... 3 
1.0    BACKGROUND AND RATIONALE ....................................................................................... 4 
1.1 
Disease Background............................................................................................................... 4 
1.2 
Stereotactic Radiosurgery (SRS) ........................................................................................... 4 
1.3 
Rationale ................................................................................................................................. 5 
2.0    STUDY OBJECTIVES ............................................................................................................. 6 
2.1 
Primary Objectives .................................................................................................................. 6 
2.2 
Secondary Objectives ............................................................................................................. 6 
2.3 
Endpoints ................................................................................................................................ 6 
3.0    PATIENT ELIGIBILITY ........................................................................................................... 7 
3.1 
Inclusion Criteria ..................................................................................................................... 7 
3.2 
Exclusion Criteria .................................................................................................................... 7 
4.0    TREATMENT PLAN ................................................................................................................ 8 
4.1 
SRS Dose and Technique ...................................................................................................... 8 
4.2 
Pre-therapy Assessment ........................................................................................................ 8 
4.3 
Toxicities and Dosing Delays/Dose Modifications .................................................................. 8 
4.4 
Post-therapy Assessment ....................................................................................................... 8 
4.5 
Post-therapy Intervention ....................................................................................................... 8 
4.6 
Duration of Therapy ................................................................................................................ 8 
4.7 
Duration of Follow Up ............................................................................................................. 9 
4.8 
Removal of Patients from Protocol Therapy ........................................................................... 9 
5.0    STUDY PROCEDURES .......................................................................................................... 9 

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5.1 
Screening/Baseline Procedures ............................................................................................. 9 
5.2 
Follow-Up Procedures ............................................................................................................ 9 
5.3 
Time and Events Table ......................................................................................................... 10 
5.4 
Removal of Subjects from Study .......................................................................................... 10 
6.0    MEASUREMENT AND EVALUATION OF AVM TAREGTS ................................................ 10 
6.1 
AVM Targets ......................................................................................................................... 10 
6.2 
Safety/Tolerability ................................................................................................................. 11 
7.0    ADVERSE EVENTS .............................................................................................................. 11 
7.1 
Kidney Injury ......................................................................................................................... 11 
7.2 
Contrast Reactions ............................................................................................................... 12 
7.3 
Adverse Event Monitoring .................................................................................................... 12 
7.4 
Steps to Determine If an Adverse Event Requires Expedited Reporting  ............................ 14 
7.5 
Stopping Rules ..................................................................................................................... 17 
8.0    DRUG INFORMATION .......................................................................................................... 17 
9.0    STATISTICAL CONSIDERATIONS ..................................................................................... 17 
9.1 
Study Design/Study Endpoints ............................................................................................. 17 
9.2 
Sample Size Estimate........................................................................................................... 17 
9.2 
Data Analyses ....................................................................................................................... 17 
10.0    STUDY MANAGEMENT ..................................................................................................... 18 
10.1 Conflict of Interest ................................................................................................................. 18 
10.2 Institutional Review Board (IRB) Approval and Consent ...................................................... 18 
10.3 Required Documentation ...................................................................................................... 18 
10.4 Registration Procedures ....................................................................................................... 18 
10.5 Data Management and Monitoring/Auditing ......................................................................... 18 
10.6 Adherence to the Protocol .................................................................................................... 19 
10.7 Amendments to the Protocol ................................................................................................ 20 

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10.8 Record Retention .................................................................................................................. 20 
10.9 Obligations of Investigators .................................................................................................. 20 
11.0  REFERENCES ...................................................................................................................... 22 

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LIST OF ABBREVIATIONS  
 
 
2-D 
Two Dimensional 
3-D 
Three Dimensional  
AE 
Adverse Event 
AVM 
Arteriovenous malformation 
CT 
Computed Tomography 
CTA 
Computed Tomography Angiography 
DC 
Dice Coefficient 
DOT 
Disease Oriented Team 
DSMB 
Data and Safety Monitoring Board 
ECOG 
Eastern Cooperative Oncology Group 
FFE 
Fast Field Echo 
Gy 
Gray 
HD 
Hausdorff distance 
H&P 
History & Physical Exam 
HRPP 
Human Research Protections Program 
HRQOL 
Health-Related Quality of Life 
ICH 
International Conference of Harmonization 
IRB 
Institutional Review Board 
IR 
Interventional Radiology 
IV 
Intravenous 
LINAC 
Linear Accelerator 
PE 
Physical Exam 
PTV 
Planning Target Volume 
Rx 
Prescription 
SAE 
Serious Adverse Event 
SRS 
Stereotactic Radiosurgery 
UTI 
Urinary Tract Infection 
UTSW 
University of Texas Southwestern 
V12 
Volume of the brain that receives at least 12 Gray of radiation. 
 
 
 
 
 

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STUDY SCHEMA 
 
 
      Current clinic flow  
 
 
              
 Protocol clinic flow 
 
 
Eligibility 
 Documented AVM with early draining vein 
 Able to undergo cerebral arteriography and/or 
CT angiography 
Eligibility 
 Documented AVM with early draining vein 
 Able to undergo both cerebral arteriography 
and CT angiography 
Planning MRI for SRS 
 T1 weighted post contrast sequence  
 + / - FFE sequence or CT angiogram as 
directed by the treating team 
Planning MRI for SRS 
 T1 weighted post contrast sequence 
 + / - FFE sequence as directed by the treating 
team 
Planning CT for SRS 
 CT Angiogram without exceeding the limits of 
IV contrast 
Planning Cerebral Arteriography for SRS 
2-D (planer) cerebral arteriography with digital 
subtraction - vessels imaged and outlined as 
directed by the Neurointerventional Specialist  
Planning Cerebral Arteriography for SRS 
2-D (planer) cerebral arteriography with digital 
subtraction - vessels imaged and outlined as 
directed by the Neurointerventional Specialist 
Target contouring based on 
CT angiogram and MRI 
alone, by the same 
neurosurgeon that created 
the IR cerebral 
arteriography/MRI based 
target 
SRS treatment planning  
Compare interventional 
cerebral arteriography 
based target used in 
treatment to CT angiogram 
based and MRI alone 
based targets 
Fiducial reference (stereotactic) fusion of IR and 
MRI - target contoured as directed by the treating 
Neurosurgeon 
SRS treatment 
planning  
Fiducial reference (stereotactic) fusion of IR and 
MRI ±CT angiogram based target contoured as 
directed by the treating Neurosurgeon 
at a later date (≥1 month) &  
blinded 
SRS treatment 
SRS treatment 

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STUDY SUMMARY 
 
Title 
Validation study of treating AVM with SRS using CT angiography for 
treatment planning 
Short Title 
 SRS for AVM with CT angiography 
Protocol Number 
STU 042018-100   
Phase 
Feasibility 
Methodology 
Prospective enrollment and conduct open-label, retrospective analysis 
Study Duration 
2 years 
Study Center(s) 
Single-center  
Objectives 
Evaluate whether a treatment plan based on CT angiography can 
accurately and precisely identify the target nidus as compared to 
standard cerebral arteriography fused to MRI.  
Number of Subjects 
14  
Diagnosis and Main 
Inclusion Criteria 
Patients with AVM requiring SRS, age ≥ 10 years.  
Size     <= 3.5cm; <= 12cc 
Study Product(s), Dose, 
Route, Regimen 
Radiation, Stereotactic Radiosurgery with Gamma Knife, using standard 
of care, as directed by the treating Radiation Oncologist and 
Neurosurgeon. 
Duration of administration 
One day procedure 
Reference therapy 
Radiation, Stereotactic Radiosurgery of AVM using standard of care 
approach and MRI 
Statistical Methodology 
The target volume generated by IR angiogram will be compared to the 
target volume generated by CT angiogram using the Sorensen-Dice 
coefficient and surface to surface distance. 
 
 
 

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1.0  
BACKGROUND AND RATIONALE 
1.1 
Disease Background 
Arteriovenous malformation (AVM) is a congenital vascular malformation 
where there is direct arterial to venous connections without an intervening 
capillary network, creating a system of feeding arteries, tangled 
malformation or nidus, and draining veins engorged from the high 
pressure (Figure 1). Acting as a shunt, AVM results in a high pressure 
arteriovenous communication. The average annual risk of bleeding is 2–
3 %1. Abnormal flow and a vascular “steal” phenomenon appear to be 
associated with larger AVMs and have been suggested to underlie some 
clinical symptoms associated with cerebral AVMs2.  
A combination of MRI and interventional cerebral arteriography is often used to assess the likely 
success and risks of surgical, endovascular, or stereotactic radiosurgery (SRS). Surgical resection 
remains the primary treatment modality for patients with AVM as it eliminates the source of 
hemorrhage. However, surgery may be intolerable in cases with AVM in deep locations and / or 
eloquent areas of the brain. Embolization may be used as an independent curative therapy, 
however, it is more commonly utilized prior to surgery as an adjunct (reviewed in 3). SRS is another 
local treatment modality that has been established as an effective treatment for cerebral AVM4. 
Although commonly used, CT angiography for the treatment planning of SRS for AVM has not been 
validated against formal cerebral arteriography. 
1.2 
Stereotactic Radiosurgery (SRS) 
SRS is an effective and minimally invasive approach compared to surgery. Its main drawback is 
the longer duration of time to achieve total obliteration of the AVM, ranging from six months to five 
years after the procedure5.  Although the effect of SRS is not immediate, SRS is a preferable 
treatment option for patients with AVMs that are not surgically accessible or in patients with 
comorbidities that make them poor surgical candidates. In SRS, a potent dose of highly conformal 
radiation is delivered in a single fraction to the target nidus, leading to elimination in blood flow 
through the nidus in 40-80% of patients depending on AVM size6. SRS of AVM leads to the closure 
of the malformed vascular lumen, likely due to endothelial cell proliferation and fibrosis. In many 
centers that perform SRS, patients with AVM only undergo T1-weighted MRI image with gadolinium 
contrast to delineate the target volume. While MRI provide excellent soft tissue information, the 
AVM nidus is often difficult to be distinguished from the draining vein or a hematoma in the case of 
a previous hemorrhage, which leads to a treatment target considerably larger than the nidus itself. 
Other centers use volumetric CT angiograms to define the target.  
At our institution, we routinely perform interventional cerebral arteriography on the day of the SRS 
procedure for improved target delineation. Following image acquisition, an neurointerventional 
specialist manually delineates the AVM nidus on the planar angiogram images; these images are 
stereotactically fused with the MR images. The nidus of the AVM is then contoured by the 
Neurosurgeon using the mutual information, to distinguish the AVM from a draining vein or the 
surrounding hematoma if there was prior hemorrhage. This extra information from the angiography 
allows the target volume to be significantly smaller compared to targets generated solely from MRI 
sequence, allowing us to spare the surrounding normal brain parenchyma. Even though the 
addition of angiography is time consuming and requires multi-modality team care, this approach 
has allowed our institution to treat the smallest possible target, yet achieve excellent obliteration 
rates of AVM with very low toxicity from the procedure. At our institution we also use CT angiogram 
at the treatment team’s discretion to further enhance the accurate delineation of the final treatment 

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target volume. However, it had not been routinely done due to uncertain benefit in treatment 
planning and a concern for renal burden from additional intravenous (IV) contrast usage. 
1.3 
Rationale for the Protocol 
While interventional cerebral arteriography is the gold standard for the diagnosis, treatment 
planning and follow up of AVM, it is an invasive procedure that comes with the risk of stroke (< 1 
%), arterial dissection (< 0.5%), transient ischemia (< 3 %) and bleeding at the puncture site7-11. 
The risk of developing neurologic complications after the procedure appears to be elevated in 
patients with atherosclerotic cerebrovascular disease or cardiovascular disease, patients older than 
55 years of age, and with fluoroscopic time beyond 10 minutes11,12. Interventional cerebral 
arteriography is also the gold standard in the diagnosis of acute ischemic stroke. Nevertheless, it 
is rarely performed nowadays as the primary diagnostic test in the acute setting. The main reason 
for the change in practice pattern is the advent of the noninvasive techniques such as CT and MR 
angiography and duplex and transcranial Doppler ultrasound that can rapidly visualize intracranial 
arterial disease. While SRS of AVM is not performed in the acute setting, performing a noninvasive 
angiogram instead of interventional arteriography will reduce the total treatment time by three to 
four hours. Such reduction in the procedure time will likely improve patient comfort and satisfaction 
as it will reduce the time these patient would need to wear the uncomfortable stereotactic 
headframe.  
While noninvasive imaging with CT and MR angiography have still not replaced interventional 
cerebral arteriography, technical advances are allowing these modalities to serve as powerful 
adjuncts (reviewed in 
13). 
In 
fact, 
interventional cerebral 
arteriography 
only 
provides 
two-
dimensional 
(2D) 
spatial 
information 
when combined with 
the 
gamma 
knife 
treatment 
planning 
system and requires 
an MRI of the brain for 
the 
3D 
information 
(Figure 2) while CT or 
MR 
angiography 
provide 3D information 
that could be used in 
the treatment planning 
of SRS. However, the 
use 
of 
these 
reconstructed 
angiographic images 
for treatment planning 
of SRS has not been 
validated 
against 
interventional cerebral 
arteriography.  
 
Major risk factor for 
contrast 
agent-
induced nephropathy 
is 
underlying 
renal 
dysfunction14. 
If 
a 
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is truly normal, then a high volume of contrast will not lead to nephropathy. In practice, however, 
the dose of contrast is a concern in patients undergoing catheter angiography and CT on the same 
day because certain doses are associated with adverse contrast reactions and nephropathy, 
although the data on this issue are limited15. Iopamidol (ISOVUE®) is the main intravascular 
contrast agent used at our institution. For multiple procedures on same day, the maximum 
recommended dose is 225 mL of ISOVUE-370 for adults and 125 mL for children between the ages 
of 10 to 18 (ISOVUE package insert, Bracco Diagnostic Inc, Cranbury, NJ). In these circumstances, 
due regard should be given to the clinical need for an optimal study with an adherence to the 
maximum recommended dose. In the vast majority of cases, contrast agent–induced nephropathy 
will be manifest by a transient increase in serum creatinine level, which usually peaks at 4–7 days 
and gradually returns to baseline14. A persistent elevation of serum creatinine level is 
unusual.  Typically, both CTA and conventional angiography can be performed with less than 100cc 
of IV or IA contrast administration. 
Finally, interventional cerebral arteriography adds an extra few hours to the overall clinic stay with 
an extra hour for the actual procedure, use of interventional radiology and recovery facility, and 
requires the patient to lay flat for several hours after the procedure due to the access of femoral 
artery. CT angiogram is expected to increase the procedure duration by another 15-30 minutes for 
transfer, set up and image acquisition. Although the patients enrolled on this study will endure 
approximately 30 minutes longer stay at the clinic, replacing the interventional cerebral 
arteriography with CT angiography in the treatment planning of SRS may ultimately reduce the total 
hospital stay by approximately three hours.  
In summary, we propose to evaluate whether a target volume based on CT angiography can serve 
as a reliable substitute for a target based on interventional cerebral arteriography. Patients on this 
protocol will still get treated based on target generated by interventional cerebral arteriography but 
also receive CT angiography. If the target volume based on CT angiography are adequate 
compared to their invasive counterpart, future investigators may selectively omit performing 
interventional cerebral arteriography in the treatment planning for SRS of AVM. Use of CT 
angiography may lead to reduction in the risk from the procedure and cost, improve the efficiency 
of the treatment process ideally without compromising the success of the procedure, with greater 
patient comfort and satisfaction.  
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objective 
To evaluate whether target(s) based on CT angiogram can accurately and precisely identify 
the target nidus as well as an interventional cerebral arteriogram.  
2.2 
Secondary Objectives 
2.2.1 
To analyze and compare dosimetric parameters, including planning target volume 
(PTV) and V12, of an SRS treatment plan based on MRI alone, with interventional 
cerebral arteriography, and CT angiograms. 
2.2.2 
To evaluate the total time it takes to perform the additional CT angiograms and 
compare it to the duration of the interventional procedure. 
2.3 
Endpoints 
 
The primary endpoint of this study is to compare the target generated from interventional 
cerebral arteriography (reference) to targets generated from CT angiogram and MRI 
alone, to assess whether noninvasive imaging approaches are non-inferior to the UTSW 
standard. 

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3.0 
PATIENT ELIGIBILITY 
Eligibility waivers are not permitted. Subjects must meet all of the inclusion and exclusion criteria 
to be registered to the study. Study treatment may not begin until a subject is registered. 
3.1 
Inclusion Criteria 
3.1.1 
Documented AVM with draining vein(s). 
 
3.1.2 
Adequate renal function (serum Creatinine < 1.5 mg/dl within 30 days of SRS) to 
undergo contrast CT and interventional cerebral arteriography on the same day, 
as determined by treating physicians. 
 
3.1.3 
AVM must be physically separated from the optic pathway, brainstem or spinal 
cord. 
 
3.1.4 
The maximum diameter of AVM nidus must be less than 3.5 cm and/or less than 
12 cc.  
 
3.1.5 
Age ≥ 10 years. 
 
 
3.1.6 
All men, as well as women of child-bearing potential must agree to use adequate 
contraception (hormonal or barrier method of birth control; abstinence) prior to 
study entry and for the duration of study participation. Should a woman become 
pregnant or suspect she is pregnant while participating in this study, she should 
inform her treating physician immediately 
 
3.1.6.1 A female of child-bearing potential is any woman (regardless of sexual   
orientation, marital status, having undergone a tubal ligation, or remaining 
celibate by choice) who meets the following criteria: 
 
 
Has not undergone a hysterectomy or bilateral oophorectomy; or 
 
Has not been naturally postmenopausal for at least 12 consecutive 
months (i.e., has had menses at any time in the preceding 12 
consecutive months). 
 
3.1.7 
Ability to understand and the willingness to sign a written informed consent. 
3.2 
Exclusion Criteria 
 
3.2.1 
Patients without a documented AVM. 
 
3.2.2 
Patients with a contraindication to CT such as contrast allergy, kidney failure or 
implanted metal devices or foreign bodies or severe claustrophobia. 
 
3.2.3 
Use of Nephrotoxic drugs, such as gentamycin, high-dose nonsteroidal anti-
inflammatory drugs, or certain chemotherapeutic drugs within 10 days of the 
procedure.  
 
3.2.4 
Psychiatric illness/social situations that would limit compliance with study 
requirements. 
 
3.2.5 
Patients must not be pregnant at the time of SRS treatment. 
 
 
 

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4.0 
TREATMENT PLAN 
This is not a therapeutic study, but rather a prospective imaging correlate study. 
4.1 
SRS Dose and Technique 
CT angiogram and interventional cerebral arteriography will be obtained. CT angiogram 
may or may not be used for treatment planning as directed by the treating team. CT 
angiograms will be obtained in all patients to be potentially used in treatment and for 
protocol assessments.  
4.2 
Pre-therapy Assessment 
Pre-therapy assessments will be performed as follows: 
 
Verify the patient has a documented AVM requiring radiation therapy. 
 
Verify age ≥ 10 years. 
 
Verify serum creatinine is age-appropriate with adequate renal function for various 
contrast reagents, within 30 days of SRS.  
 
Verify patient is not pregnant.  
 
Verify women of child-bearing potential and men agree to use adequate contraception 
 
Verify patient is able to understand and the willingness to sign a written informed 
consent. 
 
If any of the above criteria does not meet inclusion criteria, postpone SRS as 
appropriate. 
4.3 
Toxicities and Dosing Delays/Dose Modifications 
The generally accepted safe upper limit total dose of iodinated contrast in one day is 225 
mL of ISOVUE-370 for adults and 125 mL for children between the ages of 10 to 18. The 
amount of the administered contrast may be exceeded at the knowledgeable direction of 
the treating radiologists. All patients enrolled on the study will be assessed for the 
development of toxicity according to the Time and Events table (5.3) should the subject 
receive more than the recommended dose of contrast. Toxicity will be assessed according 
to the NCI Common Toxicity Criteria for Adverse Events (CTCAE), version 5.0. Contrast 
related allergic reactions will also be monitored per CTCAE criteria. Only AEs reported to 
Radiation Oncology discipline per study calendar will be captured and assessed.   
4.4 
Post therapy Assessment 
This is not a therapeutic study, but rather a prospective imaging correlate study. 
4.5 
Post therapy Intervention 
 
Serum creatinine will be checked 1 week (-3 days/+7 days) after the procedure and 
again at 1 month (+/- 10 days) after procedure. 
4.6 
Duration of Therapy 
CT Angiogram will be obtain without exceeding the limits of IV contrast before SRS 
administration (SRS is not a part of this protocol), which typically be completed in one day. 
CT Angiogram will proceed unless: 
 
 
Subject  decides to withdraw from the study, OR 
 
General or specific changes in the patient’s condition render the subject unacceptable 
for further treatment in the judgment of the stereotactic team. 
4.7 
Duration of Follow Up 
Nearly all the information needed for the protocol will be collected on the day of the 
procedure. Only AEs reported to Radiation Oncology discipline per study calendar will be 
captured and assessed. No follow up of AVM outcome is assessed as part of this protocol. 

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4.8 
Removal of Subjects from Protocol Therapy 
Subjects will be removed from therapy when any of the criteria listed in Section 5.5 apply. 
Notify the Principal Investigator, and document the reason for study removal and the date 
the subject was removed in the Case Report Form.  
5.0 
STUDY PROCEDURES 
5.1 
Screening/Baseline Procedures 
Assessments performed exclusively to determine eligibility for this study will be done only 
after obtaining informed consent. Assessments performed for clinical indications (not 
exclusively to determine study eligibility) may be used for baseline values even if the 
studies were done before informed consent was obtained. 
 
All screening procedures must be performed within 90 days prior to registration unless 
otherwise stated. The screening procedures include: 
5.1.1 
Informed Consent 
5.1.2 
Medical history 
Complete medical and surgical history 
5.1.3 
Review subject eligibility criteria 
5.1.4 
Review previous and concomitant medications 
5.1.5 
Physical exam  
Vital signs (temperature, pulse, respirations, blood pressure), height, weight, and        
neurological exam 
5.1.6 
Adverse event assessment 
See section 7 for Adverse Event monitoring and reporting. 
5.1.7 
Serum Creatinine 
5.1.8     Pregnancy test (for females of child bearing potential) 
See section 3.1.6.1 for definition.  
5.2 
Follow-up Procedures 
This is not a treatment study, and the subject will not be followed for AVM outcome for the 
purpose of this study. Serum creatinine value will be checked 1 week (-3 days/+7 days) 
after the procedure and 1 month (+/- 10 days) after the procedure. 
5.3 
Time and Events Table  
 
 
Pre-study1 
Day 0 
1 Week 
(-3 days, +7 days) 
1 Month 
(+/- 10 days) 
Informed Consent 
X 
 
 
 
History and PE  
X 
 
 
 
Serum Creatinine2 
X 
 
X 
X 
Interventional Cerebral 
Arteriography 
 
X 
 
 
CT Angiogram 
 
X 
 
 
Adverse Event Assessment 
 
X3 
X3 
X3 
1 – All screening procedures must be performed within 90 days prior to registration unless otherwise stated 
2 – Within 30 days of SRS procedure 
3 – Only if subject receives more than the recommended dose of contrast 

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5.4 
Removal of Subjects from Study 
Subjects can be taken off the study treatment and/or study at any time at their own request, 
or they may be withdrawn at the discretion of the investigator for safety, behavioral or 
administrative reasons. The reason(s) for discontinuation will be documented and may 
include: 
5.4.1 
Subject voluntarily withdraws from treatment (follow-up permitted); 
5.4.2 
Subject withdraws consent (termination of treatment and follow-up); 
5.4.3 
Subject is unable to comply with protocol requirements; 
5.4.4 
Subject demonstrates disease progression (unless continued treatment with 
study drug/treatment is deemed appropriate at the discretion of the investigator); 
5.4.5 
Subject experiences toxicity that makes continuation in the protocol unsafe; 
5.4.6 
Treating physician judges continuation on the study would not be in the subject’s 
best interest; 
5.4.7 
Subject becomes pregnant (pregnancy to be reported along same timelines as a 
serious adverse event); 
5.4.8 
Development of second malignancy (except for basal cell carcinoma or 
squamous cell carcinoma of the skin) that requires treatment, which would 
interfere with this study; 
5.4.9 
Lost to follow-up. If a research subject cannot be located to document survival 
after a period of 2 years, the subject may be considered “lost to follow-up.” All 
attempts to contact the subject during the two years must be documented  
6.0 
Measurement and evaluation of AVM targets 
6.1 
AVM Target 
Quantitative analysis of the accuracy of the experimentally generated targets will be 
performed in this study based on two established methods of segmentation geometric 
accuracy evaluation (see section 6.1.2).  
6.1.1 
Definitions 
Target: Target is the AVM nidus (figure 1) excluding the feeding artery and draining 
vein or hemangioma, if present.  
 
Reference Target lesion: AVM nidus identified using interventional cerebral 
arteriography superimposed to MRI of brain +/- CT angiography (CTA), per 
treatment team discretion that is used in the actual SRS treatment.  
 
CTA Target lesion: AVM nidus identified using CT angiogram of the brain alone, 
at a later date (greater than one month later) in a blinded manner, by the 
Neurosurgeon who contoured the reference target lesion. 
 
MRI Target lesion: AVM nidus identified using MRI of the brain alone, at a later 
date (greater than one month later) in a blinded manner, by the Neurosurgeon who 
contoured the reference target lesion. 
6.1.2 
Evaluation and comparison of targets 
Two methods of segmentation geometric accuracy evaluation, Dice coefficients 
and Hausdorff distance analysis, will be utilized to compare the reference target 
generated from interventional cerebral arteriography to targets generated from CT 
angiograms.  

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6.1.2.1 Dice Coefficients (DCs = 2(A∩B)/(A+B) ), where A and B are the ground-
truth and evaluated as segmented volumes, respectively. Dice coefficient 
is a simple spatial overlap index and a reproducibility validation metric16 
and a reproducibility validation metric, which has been adopted to 
validate the segmentation of white matter lesions in MRI17 and brain 
tumors18. The value of a Dice Coefficients ranges from 0, indicating no 
spatial overlap between two sets of images, to 1, indicating complete 
overlap.  
 
6.1.2.2  Hausdorff distance (HD) between two finite point sets A and B is defined 
by HD(A, B) = max (h(A, B), h(B, A)), where h(A, B) =maxaϵAminbϵBIIa-bII 
Spatial distance based metric, such as HD, is widely used in the evaluation 
of image segmentation when the segmentation overall accuracy, such as 
the boundary delineation (contour), of the segmentation is of importance19.   
6.2 
Safety/Tolerability 
IV hydration will be initiated prior to all radiosurgery procedures and continued as needed 
until discharge. Patients will be instructed to increase hydration after the procedure and 
report to the treating physician in the event of developing decrease in urine output, new or 
worsening of swelling in extremities or around the eyes, fatigue, shortness of breath, chest 
pain or pressure, confusion or seizure to prevent kidney injury. 
 
 
Serum creatinine will be checked 1 week (-3 days/+7 days) after the procedure and 
again at 1 month (+/- 10 days) after the procedure. 
7.0 
ADVERSE EVENTS 
7.1 
Kidney Injury 
7.1.1 
Contraindications: Contrast allergy, underlying significant renal dysfunction or 
renal failure. 
7.1.2 
Special Warnings and Precautions for Use: The generally accepted safe upper 
limit total dose of iodinated contrast in one day is 225 mL of ISOVUE-370 for 
adults and 125 mL for children between the ages of 10 to 18. The amount of the 
administered contrast may be exceeded at the knowledgeable direction of the 
treating radiologists. 
7.1.3 
Interaction with other medications: Nephrotoxic drugs, such as gentamycin, high-
dose nonsteroidal anti-inflammatory drugs, or certain chemotherapeutic drugs.  
7.1.4 
Adverse Reactions: Sites-specific. Please see section 7.2. 
7.2 
Contrast Reactions 
Acute contrast reactions occur within minutes of administration of iodinated contrast. An 
estimated 3% of patient will experience mild contrast reaction that requires no treatment. 
However, moderate reactions such as bronchospasm or hypotension can occur in about 
1 in 250 patients (0.4%) and about 1 in 1600 to 2500 (0.04-0.06%) of patients could 
experience a severe reaction 20.Treatment consist of administering medications directed 
at the specific cause of symptoms, such as bronchospasm with beta-2 agonist inhaler, 
while an airway or laryngeal edema should be treated with epinephrine. Antihistamine 
and/or corticosteroids could be administered if necessary. Delayed adverse reactions 
develop more than one hour after the procedure but within 7 days of IV contrast 
administration. It is mild in majority of cases and resolve without intervention. Non-
specific symptoms range from Flu-like illness, arthralgia, aches and pains, parotitis, fever, 

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abdominal pain and headache. Treatment consists of antihistamine and/or 
corticosteroids. Severe cases may require a referral to a dermatologist.  
7.3 
Adverse Event Monitoring 
             Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of subjects enrolled in the studies as well as those 
who will enroll in future studies using similar agents. Adverse events are assessed in a 
routine manner at scheduled times during a trial. Additionally, certain adverse events 
must be reported in an expedited manner to allow for optimal monitoring of subject safety 
and care. 
 
All subjects experiencing an adverse event that is reported to Radiation Oncology 
discipline per study calendar, regardless of its relationship to study therapy, will be 
monitored until:  
 
The adverse event resolves or the symptoms or signs that constitute the adverse 
event return to baseline or is stable in the opinion of the investigator;  
 
There is a satisfactory explanation other than the study treatment for the changes 
observed; or 
 
Death. 
 
7.3.1 
Definitions  
An adverse event is defined as any untoward or unfavorable medical occurrence 
in a human research study participant, including any abnormal sign (for example, 
abnormal physical exam, imaging finding or clinically significant laboratory finding), 
symptom, clinical event, or disease, temporally associated with the subject’s 
participation in the research, whether or not it is considered related to the subject’s 
participation in the research. 
 
Adverse events encompass clinical, physical and psychological harms. Adverse 
events occur most commonly in the context of biomedical research, although on 
occasion, they can occur in the context of social and behavioral research. Adverse 
events may be expected or unexpected. 
Acute Adverse Events  
Adverse events occurring in the time period from the signing of the informed 
consent, through 1 month (+/- 10 days) post treatment planning procedure (CT 
angiogram) will be considered acute adverse events. Only kidney-specific adverse 
events will be followed should the subject receive more than the recommended 
dose of contrast, according to good medical practices. Acute adverse events, that 
are collected as specified within the protocol, will be assessed and reported as per 
below. 
Late Adverse Events 
Adverse effects occurring in the time period after the end of acute monitoring will 
be defined as late adverse events. Late adverse events will not be captured, 
assessed, graded or reported. 
Severity  
Adverse events will be graded by a numerical score according to the defined NCI 
Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0. 
Adverse events not specifically defined in the NCI CTCAE will be scored on the 
Adverse Event log according to the general guidelines provided by the NCI CTCAE 
and as outlined below.     
 
Grade 1: Mild 

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 
Grade 2: Moderate 
 
Grade 3: Severe or medically significant but not immediately life 
threatening 
 
Grade 4: Life threatening consequences 
 
Grade 5: Death related to the adverse event 
Serious Adverse Events  
OHRP and UTSW HRPP define serious adverse events as those events, 
occurring at any dose, which meets any of the following criteria:  
 
Results in death   
 
Is life-threatening (places the subject at immediate risk of death from the 
event as it occurred) 
 
Results in inpatient hospitalization1, 2 or prolongation of existing 
hospitalization  
 
Results in persistent or significant disability/incapacity  
 
Results in a congenital anomaly/birth defect  
 
Based upon appropriate medical judgment, may jeopardize the subject’s 
health and may require medical or surgical intervention to prevent one of 
the other outcomes listed in this definition. 
Note: A “Serious adverse event” is by definition an event that meets any of the 
above criteria. Serious adverse events may or may not be related to the research 
project. A serious adverse event determination does not require the event to be 
related to the research. That is, both events completely unrelated to the condition 
under study and events that are expected in the context of the condition under 
study may be serious adverse events, independent of relatedness to the study 
itself. As examples, a car accident requiring >24 hour inpatient admission to the 
hospital would be a serious adverse event for any research participant; likewise, 
in a study investigating end-stage cancer care, any hospitalization or death which 
occurs during the protocol-specified period of monitoring for adverse and serious 
adverse events would be a serious adverse event, even if the event observed is 
a primary clinical endpoint of the study. 
1Pre-planned hospitalizations or elective surgeries are not considered SAEs. 
Note: If events occur during a pre-planned hospitalization or surgery, that 
prolongs the existing hospitalization, those events should be evaluated and/or 
reported as SAEs.   
2 NCI defines hospitalization for expedited AE reporting purposes as an inpatient 
hospital stay equal to or greater than 24 hours. Hospitalization is used as an 
indicator of the seriousness of the adverse event and should only be used for 
situations where the AE truly fits this definition and NOT for hospitalizations 
associated with less serious events. For example: a hospital visit where a patient 
is admitted for observation or minor treatment (e.g. hydration) and released in 
less than 24 hours. Furthermore, hospitalization for pharmacokinetic sampling is 
not an AE and therefore is not to be reported either as a routine AE or in an 
expedited report. 
 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRSOs): 
The phrase “unanticipated problems involving risks to subjects or others” is 
found, but not defined in the HHS regulations at 45 CFR 46, and the FDA 
regulations at 21 CFR 56.108(b)(1) and 21 CFR 312.66. For device studies, part 
812 uses the term unanticipated adverse device effect, which is defined in 21 

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CFR 812.3(s). Guidance from the regulatory agencies considers unanticipated 
problems to include any incident, experience, or outcome that meets ALL three 
(3) of the following criteria: 
• 
Unexpected in terms of nature, severity or frequency given (a) the 
research procedures that are described in the protocol-related 
documents, such as the IRB-approved research protocol and informed 
consent document; and (b) the characteristics of the subject population 
being studied;  
 
 
 
 
AND 
• 
Related or possibly related to participation in the research (possibly 
related means there is a reasonable possibility that the incident, 
experience, or outcome may have been caused by the procedures 
involved in the research); 
 
AND  
• 
Suggests that the research places subjects or others at greater risk of 
harm (including physical, psychological, economic, or social harm) than 
was previously known or recognized. Note: According to OHRP, if the 
adverse event is serious, it would always suggest a greater risk of harm. 
 
Follow-up  
All adverse events, as specified in section 7.3, will be followed up according to 
good medical practices.  
Kidney-specific adverse events will be followed up should the subject receive 
more than the recommended dose of contrast, according to good medical 
practices.  
7.4 
Steps to Determine If a Serious Adverse Event Requires Expedited Reporting to 
the SCCC DSMC 
Step 1: Identify the type of adverse event using the NCI Common Terminology Criteria 
for Adverse Events (CTCAE v5).  
 
Step 2: Grade the adverse event using the NCI CTCAE v5. 
 
Step 3: Determine whether the adverse event is related to the protocol therapy.  
Attribution categories are as follows: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE may NOT be related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
Note: This includes all events that occur within the acute adverse events reporting period 
as defined in section 7.3 and is attributed (possibly, probably, or definitely) to the 
treatment planning procedure (CT angiogram). 
 
Step 4: Determine the prior experience of the adverse event. Expected events are those 
that have been previously identified as resulting from administration of the treatment. An 
adverse event is considered unexpected, for expedited reporting purposes only, when 
either the type of event or the severity of the event is not listed in: 
 
the current known adverse events listed in the Agent Information Section of this 
protocol (if applicable); 
 
the drug package insert (if applicable); 
 
the current Investigator’s Brochure (if applicable) 

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 
the Study Agent(s)/Therapy(ies) Background and Associated Known Toxicities 
section of this protocol 
7.4.1 
Reporting SAEs and UPIRSOs to the Simmons Comprehensive Cancer 
Center (SCCC) Data Safety Monitoring Committee (DSMC) 
 
SAEs and UPIRSOs at all sites, which occur in research subjects on protocols for 
which the SCCC is the DSMC of record require reporting to the DSMC 
regardless of whether IRB reporting is required. All SAEs occurring during the 
protocol-specified monitoring period and all UPIRSOs should be submitted to the 
SCCC DSMC within 5 business days of the study team members’ awareness of 
the event(s). In addition, for participating centers other than UTSW, local IRB 
guidance should be followed for local reporting of serious adverse events or 
unanticipated problems. 
 
The UTSW study PI is responsible for ensuring SAEs/UPIRSOs are submitted to 
the SCCC DSMC Coordinator. This may be facilitated by the IIT project manager, 
study team, sub-site or other designee. Hardcopies or electronic versions of the 
eIRB Reportable Event report; FDA Form #3500A forms, or other sponsor forms, 
if applicable; and/or any other supporting documentation available should be 
submitted to the DSMC Coordinator.  The DSMC Coordinator forwards the 
information onto the DSMC Chairman who determines if immediate action is 
required. Follow-up eIRB reports, and all subsequent SAE or UPIRSO 
documentation that is available are also submitted to the DSMC Chair who 
determines if further action is required. (See Appendix III of the SCCC DSMC Plan 
for a template Serious Adverse Event Form which may be utilized). 
  
 
If the event occurs on a multi-institutional clinical trial coordinated by the UTSW 
Simmons Comprehensive Cancer Center, the IIT Project Manager or designee 
ensures that all participating sites are notified of the event and resulting action, 
according to FDA guidance for expedited reporting. DSMC Chairperson reviews 
all SAEs and UPIRSOs upon receipt from the DSMC Coordinator.  The DSMC 
Chairperson determines whether action is required and either takes action 
immediately, convenes a special DSMC session (physical or electronic), or 
defers the action until a regularly scheduled DSMC meeting.  
 
 
Telephone reports to: 
 
Sarah Neufeld, Management Analyst 
214-648-1836 
Written reports to: 
 
Department of Radiation Oncology 
Clinical Research Office 
The University of Texas Southwestern Medical Center 
Attention: Sarah Neufeld, Project Manager 
2201 Inwood Road 
Dallas, Texas  75390-9303 
FAX #: 214-648-5923 
 
UTSW SCC Data Safety Monitoring Committee Coordinator 
Email: SCCDSMC@utsouthwestern.edu 
Fax: 214-648-5949 or deliver to BLB.306 
 
 

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UTSW Institutional Review Board (IRB) 
Submit via eIRB with a copy of the final sponsor report as attached supporting 
documentation 
 
7.4.2 
Reporting Unanticipated Problems Involving Risks to Subjects or Others 
(UPIRSOs) to the UTSW HRPP 
 
UTSW reportable event guidance applies to all research conducted by or on 
behalf of UT Southwestern, its affiliates, and investigators, sites, or institutions 
relying on the UT Southwestern IRB. Additional reporting requirements apply for 
research relying on a non-UT Southwestern IRB. 
 
According to UTSW HRPP policy, UPIRSOs are incidents, experiences, 
outcomes, etc. that meet ALL three (3) of the following criteria: 
1. Unexpected in nature, frequency, or severity (i.e., generally not expected in a 
subject’s underlying condition or not expected as a risk of the study; 
therefore, not included in the investigator’s brochure, protocol, or informed 
consent document),AND 
2. Probably or definitely related to participation in the research, AND 
3. Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized.  Note: According to OHRP, if the adverse 
event is serious, it would always suggest a greater risk of harm. 
 
For purposes of this policy, UPIRSOs include unanticipated adverse device 
effects (UADEs) and death or serious injury related to a humanitarian use device 
(HUD).  
 
UPIRSOs must be promptly reported to the UTSW HRPP within 5 working days 
of study team awareness. 
 
For research relying on a non-UT Southwestern IRB (external, central, or single 
IRB): 
 
Investigators relying on an external IRB who are conducting research on behalf 
of UT Southwestern or its affiliates are responsible for submitting LOCAL 
UPIRSOs to the UT Southwestern IRB within 5 working days of study team 
awareness. Investigators must report to their relying IRB according to the relying 
IRB’s policy. In addition, the external IRB’s responses or determinations on these 
local events must be submitted to the UT Southwestern IRB within 10 working 
days of receipt. 
 
Events NOT meeting UPIRSO criteria: 
 
Events that do NOT meet UPIRSO criteria should be tracked, evaluated, 
summarized, and submitted to the UTSW HRPP/IRB at continuing review. 
 
For more information on UTSW HRPP/IRB reportable event policy, see 
https://www.utsouthwestern.edu/research/hrpp/quality-assurance/ 
7.5 
Stopping Rules 
The study is designed to end if the rate of kidney injury from multiple contrast usage is 
higher than expected despite meeting the maximum recommended dose of contrast or an 
inability to consistently meet the recommended dose of contrast. 

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8.0 
DRUG INFORMATION 
ISOVUE 300 and 370 ® are products of Bracco Diagnostics, Inc, Cranbury, NJ. Per the ISOVUE 
package insert, the maximum recommended dose of ISOVUE-370 for multiple procedures is 225 
mL for adults and 125 mL for children between the ages of 10 to 18. ISOVUE is the brand 
currently used by UTSW hospitals. There are other vendors of iodinated contrast and UTSW’s 
utilization may change.  
9.0 
STATISTICAL CONSIDERATIONS 
9.1 
Study Design/Study Endpoints 
The primary endpoint of this study is to compare the target generated from interventional 
cerebral arteriography (reference) to targets generated from CT angiogram and MRI alone, 
to assess whether noninvasive imaging approaches are non-inferior to the UTSW 
standard.  
9.2 
Sample Size estimate 
Each patient will have measurements of Dice similarity coefficients for both invasive and 
noninvasive approaches.  A previous study21 showed that the mean for Dice similarity 
coefficient of the AVM nidus between CTA and MRI was 0.765 and the standard deviation 
was 0.0894. A sample size of 14 patients achieves 92% power to detect non-inferiority 
using a one-sided t-test with a significance level of 0.05 when the margin of non-inferiority 
is -0.077 (10% margin) and the true difference between the mean of invasive approach 
and non-invasive approach is 0.0. Sample size was estimated using a non-inferiority test 
for one mean in PASS 14 software.  
9.3 
Data Analysis Plans 
Interim reports will be prepared every six months until 35 days after the last patient is 
enrolled. In general, the interim reports will contain information about patient accrual rate 
with projected completion dates of the trial, status of and compliance rate of target 
generation from CT angiogram and MRI alone per protocol, and the frequencies and 
severity of renal toxicity of the subjects.  
10.0 
STUDY MANAGEMENT 
10.1 
Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, 
or financial gain greater than the minimum allowable by their institution, etc.) must have 
the conflict reviewed by the UTSW COI Committee and IRB according to UTSW Policy on 
Conflicts of Interest.  All investigators will follow the University conflict of interest policy. 
10.2 
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in accordance 
with federally mandated regulations. The IRB must approve the consent form and protocol. 
 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) 
and to ethical principles that have their origin in the Declaration of Helsinki. 
 
 
Before recruitment and enrollment onto this study, the subject will be given a full 
explanation of the study and will be given the opportunity to review the consent form. Each 
consent form must include all the relevant elements currently required by the FDA 
Regulations and local or state regulations. Once this essential information has been 
provided to the subject and the investigator is assured that the subject understands the 

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implications of participating in the study, the subject will be asked to give consent to 
participate in the study by signing an IRB-approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the subject and by the person who conducted the informed 
consent discussion. 
10.3 
Required Documentation (for multi-site studies) 
Not applicable for this protocol. 
10.4 
Registration Procedures 
All subjects must be registered in Velos before enrollment to the study. Prior to 
enrollment, eligibility criteria must be confirmed with the study coordinator. 
 
The first subject enrolled at UTSW will receive a number beginning with 101 and each 
patient enrolled thereafter will have a sequential ID number (i.e. 102, 103, 104). 
 
Each newly consented subject should be numbered using the schema provided above. 
Upon registration, the registrar will assign the additional registration/randomization code 
according to the numbering schema outlined above, which should then be entered as the 
patient study ID in Velos upon updating the status to “enrolled”. 
10.5 
Data Management and Monitoring/Auditing 
REDCap is the UTSW SCCC institutional choice for the electronic data capture of case 
report forms for SCCC Investigator Initiated Trials. REDCap will be used for electronic 
case report forms in accordance with Simmons Comprehensive Cancer Center 
requirements, as appropriate for the project 
 
Trial monitoring will be conducted no less than annually and refers to a regular interval 
review of trial related activity and documentation performed by the DOT and/or the CRO 
Multi-Center IIT Monitor. This review includes but is not limited to accuracy of case report 
forms, protocol compliance, timeless and accuracy of Velos entries and AE/SAE 
management and reporting. Documentation of trial monitoring will be maintained along 
with other protocol related documents and will be reviewed during internal audit.   
 
Toxicity reviews will be performed, via the interim reports, every 6 months until 35 days 
after the last patient is enrolled. These reviews will be documented by the study team 
and/or the UTSW Simmons Comprehensive Cancer Center (SCCC) Data Safety 
Monitoring Committee (DSMC). 
 
The UTSW Simmons Comprehensive Cancer Center (SCCC) Data Safety Monitoring 
Committee (DSMC) is responsible for monitoring data quality and patient safety for all 
UTSW SCCC clinical trials.  As part of that responsibility, the DSMC reviews all serious 
adverse events and UPIRSOs in real time as they are reported and reviews adverse 
events on a quarterly basis.  The quality assurance activity for the Clinical Research 
Office provides for periodic auditing of clinical research documents to ensure data 
integrity and regulatory compliance.  A copy of the DSMC plan is available upon request. 
 
The SCCC DSMC meets quarterly and conducts annual comprehensive reviews of 
ongoing clinical trials, for which it serves as the DSMC of record. The Quality Assurance 
Coordinator (QAC) works as part of the DSMC to conduct regular audits based on the 
level of risk. Audit findings are reviewed at the next available DSMC meeting.  In this 
way, frequency of DSMC monitoring is dependent upon the level of risk.  Risk level is 
determined by the DSMC Chairman and a number of factors such as the phase of the 

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study; the type of investigational agent, device or intervention being studied; and 
monitoring required to ensure the safety of study subjects based on the associated risks 
of the study. Protocol-specific DSMC plans must be consistent with these principles. 
10.6 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, and well-
being of the study subject requires alternative treatment, the study shall be conducted 
exactly as described in the approved protocol.  
10.6.1 Exceptions (also called single-subject exceptions or single-subject waivers): 
include any departure from IRB-approved research that is not due to an 
emergency and is: 
 intentional on part of the investigator; or 
 in the investigator’s control; or 
 not intended as a systemic change (e.g., single-subject exceptions to eligibility 
[inclusion/exclusion] criteria) 
Reporting requirement*: Exceptions are non-emergency deviations that 
require prospective IRB approval before being implemented. Call the IRB if 
your request is urgent. If IRB approval is not obtained beforehand, this 
constitutes a major deviation. For eligibility waivers, studies which utilize the 
SCCC-DSMC as the DSMC of record must also obtain approval from the 
DSMC prior to submitting to IRB for approval. 
10.6.2 Emergency Deviations: include any departure from IRB-approved research that 
is necessary to:  
 Avoid immediate apparent harm, or 
 Protect the life or physical well-being of subjects or others 
Reporting requirement: Emergency deviations must be promptly reported 
   to the IRB within 5 working days of occurrence. 
10.6.3 Serious Noncompliance (formerly called major deviations or violations): 
include any departure from IRB-approved research that: 
 
Increase risk of harm to subjects; and/or 
 
Adversely affects the rights, safety, or welfare of subjects (any of which may 
also be an unanticipated problem); and/or 
 
Adversely affects the integrity of the data and research (i.e. substantially 
compromises the integrity, reliability, or validity of the research) 
Reporting requirement*: Serious Noncompliance must be promptly 
reported to the IRB within 5 working days of discovery. 
 
10.6.4 
Continuing Noncompliance: includes a pattern of repeated noncompliance 
(in one or more protocols simultaneously, or over a period of time) which 
continues after initial discovery, including inadequate efforts to take or 
implement corrective or preventive action within a reasonable time frame. 
 Reporting requirement*: Continuing Noncompliance must be promptly 
reported to the IRB within 5 working days of discovery. 
 

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10.6.5 
Noncompliance (that is neither serious nor continuing; formerly called 
minor deviations) any departure from IRB-approved research that: 
 
Does not meet the definition of serious noncompliance or continuing 
noncompliance 
 Reporting requirement*: Noncompliance that is neither serious nor 
continuing  should be tracked and summarized the next IRB continuing 
review, or the notice of study closure- whichever comes first. 

*Reporting Requirements reflect UTSW HRPP/IRB guidelines; participating sites should follow 
the reporting guidelines for their IRB of record 
10.7 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Principal Investigator.  A summary of changes document outlining 
proposed changes as well as rationale for changes, when appropriate, is highly 
recommended.  When an amendment to the protocol substantially alters the study design 
or the potential risk to the patient, a revised consent form might be required.  
 
The written amendment, and if required the amended consent form, must be sent to the 
IRB for approval prior to implementation.  
10.8 
Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, 
source documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 
regulatory documents (e.g., protocol and amendments, IRB correspondence and approval, 
signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities 
and all reports and records necessary for the evaluation and reconstruction of the clinical 
research study. 
 
Government agency regulations and directives require that the study investigator retain all 
study documentation pertaining to the conduct of a clinical trial. In the case of a study with 
a drug seeking regulatory approval and marketing, these documents shall be retained for 
at least two years after the last approval of marketing application in an International 
Conference on Harmonization (ICH) region. In all other cases, study documents should be 
kept on file until three years after the completion and final study report of this investigational 
study. 
10.9 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki. The Principal Investigator is responsible for personally overseeing the treatment 
of all study patients. The Principal Investigator must assure that all study site personnel, 
including sub-investigators and other study staff members, adhere to the study protocol 
and all FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and 
after study completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring that all 
the required data will be collected and entered onto the Case Report Forms. Periodically, 
monitoring visits may be conducted and the Principal Investigator will provide access to 
his/her original records to permit verification of proper entry of data. At the completion of 
the study, all case report forms will be reviewed by the Principal Investigator and will require 
his/her final signature to verify the accuracy of the data. 

STU 042018-100, Version 3 
________________________________________________________________________ 
STU042018-100, Timmerman, FormA-ResearchProtocol, Mod_17, 04-27-21 (1) 
 
21 
11.0 
REFERENCES 
 
1 
Pollock, B. E., Flickinger, J. C., Lunsford, L. D., Bissonette, D. J. & Kondziolka, D. Factors that 
predict the bleeding risk of cerebral arteriovenous malformations. Stroke 27, 1-6 (1996). 
2 
Moftakhar, P., Hauptman, J. S., Malkasian, D. & Martin, N. A. Cerebral arteriovenous 
malformations. Part 2: physiology. Neurosurg Focus 26, E11, doi:10.3171/2009.2.FOCUS09317 
(2009). 
3 
Lunsford, L. D., Niranjan, A., Kondziolka, D., Sirin, S. & Flickinger, J. C. Arteriovenous malformation 
radiosurgery: a twenty year perspective. Clin Neurosurg 55, 108-119 (2008). 
4 
Flickinger, J. C., Kondziolka, D., Maitz, A. H. & Lunsford, L. D. An analysis of the dose-response 
for arteriovenous malformation radiosurgery and other factors affecting obliteration. Radiother 
Oncol 63, 347-354 (2002). 
5 
Friedman, W. A. & Bova, F. J. Radiosurgery for arteriovenous malformations. Neurol Res 33, 803-
819, doi:10.1179/1743132811Y.0000000043 (2011). 
6 
Hasegawa, T. et al. Long-term results after stereotactic radiosurgery for patients with cavernous 
malformations. Neurosurgery 50, 1190-1197; discussion 1197-1198 (2002). 
7 
Dion, J. E., Gates, P. C., Fox, A. J., Barnett, H. J. & Blom, R. J. Clinical events following 
neuroangiography: a prospective study. Stroke 18, 997-1004 (1987). 
8 
Heiserman, J. E. et al. Neurologic complications of cerebral angiography. AJNR Am J Neuroradiol 
15, 1401-1407; discussion 1408-1411 (1994). 
9 
Johnston, D. C., Chapman, K. M. & Goldstein, L. B. Low rate of complications of cerebral 
angiography in routine clinical practice. Neurology 57, 2012-2014 (2001). 
10 
Waugh, J. R. & Sacharias, N. Arteriographic complications in the DSA era. Radiology 182, 243-
246, doi:10.1148/radiology.182.1.1727290 (1992). 
11 
Willinsky, R. A. et al. Neurologic complications of cerebral angiography: prospective analysis of 
2,899 
procedures 
and 
review 
of 
the 
literature. 
Radiology 
227, 
522-528, 
doi:10.1148/radiol.2272012071 (2003). 
12 
Kaufmann, T. J. et al. Complications of diagnostic cerebral angiography: evaluation of 19,826 
consecutive patients. Radiology 243, 812-819, doi:10.1148/radiol.2433060536 (2007). 
13 
Tranvinh, E., Heit, J. J., Hacein-Bey, L., Provenzale, J. & Wintermark, M. Contemporary Imaging 
of Cerebral Arteriovenous Malformations. AJR Am J Roentgenol, 1-11, doi:10.2214/AJR.16.17306 
(2017). 
14 
Bettmann, M. A. Frequently asked questions: iodinated contrast agents. Radiographics 24 Suppl 
1, S3-10, doi:10.1148/rg.24si045519 (2004). 
15 
Lasser, E. C., Lyon, S. G. & Berry, C. C. Reports on contrast media reactions: analysis of data from 
reports 
to 
the 
U.S. 
Food 
and 
Drug 
Administration. 
Radiology 
203, 
605-610, 
doi:10.1148/radiology.203.3.9169676 (1997). 
16 
LR, D. Measures of the amount of ecologic association between species. . Ecology 26, 297-302 
(1945). 
17 
Zijdenbos, A. P., Dawant, B. M., Margolin, R. A. & Palmer, A. C. Morphometric analysis of white 
matter lesions in MR images: method and validation. IEEE Trans Med Imaging 13, 716-724, 
doi:10.1109/42.363096 (1994). 
18 
Zou, K. H. et al. Statistical validation of image segmentation quality based on a spatial overlap 
index. Acad Radiol 11, 178-189 (2004). 
19 
Fenster, A. & Chiu, B. Evaluation of Segmentation algorithms for Medical Imaging. Conf Proc IEEE 
Eng Med Biol Soc 7, 7186-7189, doi:10.1109/IEMBS.2005.1616166 (2005). 
20 
Bush, W. H. & Swanson, D. P. Acute reactions to intravascular contrast media: types, risk factors, 
recognition, 
and 
specific 
treatment. 
AJR 
Am 
J 
Roentgenol 
157, 
1153-1161, 
doi:10.2214/ajr.157.6.1950858 (1991). 
21 
Chen, K. K. et al. Application of Time-Resolved 3D Digital Subtraction Angiography to Plan 
Cerebral Arteriovenous Malformation Radiosurgery. AJNR Am J Neuroradiol 38, 740-746, 
doi:10.3174/ajnr.A5074 (2017).