A Randomized, Non-Inferiority Study of a Hydrogel Packing System Compared to Standard of Care Packing During Image-Guided High-Dose Rate Brachytherapy Boost for Cervical Cancer
Phase: NA
Conditions: Cervical Cancer
Sponsor: University of Virginia

PROTOCOL COVER PAGE 
 
 
Protocol 
 
A Randomized, Non-Inferiority Study of a Hydrogel Packing System 
Compared to Standard of Care Packing During Image-Guided High-Dose 
Rate Brachytherapy Boost for Cervical Cancer  
 
                                                                     
Version Date:  16 November 2021 
 
NCT04499521 
 

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A Randomized, Non-Inferiority Study of a Hydrogel Packing 
System Compared to Standard of Care Packing During Image-
Guided High-Dose Rate Brachytherapy Boost for Cervical 
Cancer  
Protocol Number: RadOnc 003 
Principal Investigator: Kara Romano, MD 
Funded by: National Cancer Institute 
Version Date:  16 November 2021 
Confidentiality Statement 
The information contained in this document is the property of the University of Virginia Cancer Center 
Office of Clinical Research and the Department of Radiation Oncology.  Distributing, copying, or 
disclosing information contained in this document requires prior authorization from the University of 
Virginia Cancer Center, except that this document may be disclosed to the appropriate institutional 
review boards or other regulatory agencies as required by law.   

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Key Roles and Study Governance 
Overall Principal 
Investigator 
 
Kara Romano, MD 
University of Virginia 
ked7c@virginia.edu 
Sub-Investigators at the 
University of Virginia  
Einsley Janowski, MD 
ej8t@virginia.edu 
 
Christopher McLaughlin, MD 
cm9rs@virginia.edu 
 
Timothy Showalter, MD 
434-924-9412 
tns3b@virginia.edu 
PI at the Allegheny Health 
Network 
Zachary Horne, MD 
Zachary.Horne@AHN.ORG 
Biostatistician
Gina Petroni, PhD 
grp4c@virginia.edu 
Data Coordinating Center
UVA Coordinating Center 
UVA SOM Clinical Trials Office 
434.924.9553 
 gms4x@hscmail.mcc.virginia.edu 
 
 
 

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TABLE OF CONTENTS 
STATEMENT OF COMPLIANCE ................................................................................... 5 
ABBREVIATIONS .......................................................................................................... 6 
 
SYNOPSIS .......................................................................................................... 7 
 
SCHEMA ............................................................................................................ 9 
2 
INTRODUCTION ..................................................................................................... 9 
 
STUDY RATIONALE ............................................................................................. 9 
 
BACKGROUND ...................................................................................................11 
 
RISK/BENEFIT ASSESSMENT ..............................................................................14 
3 
OBJECTIVES AND ENDPOINTS ..........................................................................15 
4 
STUDY DESIGN ....................................................................................................16 
 
OVERALL DESIGN ..............................................................................................16 
 
END OF STUDY DEFINITION ................................................................................16 
5 
STUDY POPULATION ...........................................................................................16 
 
INCLUSION CRITERIA .........................................................................................16 
 
EXCLUSION CRITERIA ........................................................................................17 
 
LIFESTYLE CONSIDERATIONS .............................................................................17 
 
SCREEN FAILURES ............................................................................................17 
6 
STUDY INTERVENTION ........................................................................................18 
 
DESCRIPTION OF STUDY INTERVENTION(S) .........................................................18 
 
DOSING AND ADMINISTRATION ...........................................................................18 
 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY ........................................18 
 
REGISTRATION AND RANDOMIZATION .................................................................19 
 
CONCOMITANT THERAPY ...................................................................................19 
7 
STUDY CLOSURE, STUDY INTERVENTION DISCONTINUATION AND 
PARTICIPANT DISCONTINUATION OR WITHDRAWAL ............................................20 
 
STUDY DISCONTINUATION AND CLOSURE ...........................................................20 
 
PARTICIPANT DISCONTINUATION/WITHDRAWAL ...................................................20 
 
PROCEDURES FOR DISCONTINUATION OF STUDY INTERVENTION ..........................21 
8 
STUDY ASSESSMENTS AND PROCEDURES .....................................................21 
 
CLINICAL ASSESSMENTS ...................................................................................21 
 
PARTICIPANT REPORTED OUTCOMES .................................................................21 
 
PHYSICIST AND PHYSICIAN ASSESSMENTS ..........................................................21 
9 
DATA AND SAFETY MONITORING PLAN ...........................................................22 
 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ............................................22 
 
UNANTICIPATED ADVERSE DEVICE EFFECTS .......................................................26 
 
REPORTING EVENTS TO PARTICIPANTS ..............................................................27 
 
REPORTING OF PREGNANCY ..............................................................................27 
 
UNANTICIPATED PROBLEMS ...............................................................................27 
 
DATA BREACH ..................................................................................................28 
 
PROTOCOL DEVIATION ......................................................................................29 
 
PARTICIPANT WITHDRAWALS/DROPOUTS PRIOR TO STUDY COMPLETION .............30 

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10 
STATISTICAL CONSIDERATIONS ...................................................................30 
10.1 
DESIGN ............................................................................................................30 
 
RANDOMIZATION AND STRATIFICATION ...............................................................31 
 
EVALUATION OF SAMPLE POPULATIONS AND CRITERIA ........................................31 
 
SAMPLE SIZE AND ACCRUAL ..............................................................................31 
 
SAFETY MONITORING ........................................................................................32 
 
ANALYSES ........................................................................................................33 
11 
REGULATORY AND OPERATIONAL CONSIDERATIONS ..............................33 
 
REGULATORY AND ETHICAL CONSIDERATIONS ....................................................33 
 
DATA HANDLING AND RECORD KEEPING .............................................................37 
 
PUBLICATION AND DATA SHARING POLICY ..........................................................37 
 
CONFLICT OF INTEREST POLICY .........................................................................38 
12 
REFERENCES ...................................................................................................39 
13 
APPENDICES ....................................................................................................41 
 
SCHEDULE OF ACTIVITIES (SOA) ........................................................................41 
13.2 
PHYSICIST/DOSIMETRIST CASE REPORT FORM ...................................................42 
 
PARTICIPANT PACKING DISCOMFORT ASSESSMENT / EVALUACIÓN DE LA 
INCOMODIDAD DEL EMPAQUE DE LA PARTICIPANTE ........................................................43 
 
PHYSICIAN CASE REPORT FORM ........................................................................44 
13.5 
PROTOCOL AMENDMENT HISTORY .....................................................................45 
 
 
 

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STATEMENT OF COMPLIANCE 
The trial will be conducted in accordance with International Conference on Harmonisation 
Good Clinical Practice (ICH GCP), applicable United States (US) Code of Federal 
Regulations (CFR), and the NIH/NCI Terms and Conditions of Award. The Principal 
Investigator will assure that no deviation from, or changes to the protocol will take place 
without prior agreement from the overall Principal Investigator, and documented approval 
from the Institutional Review Board (IRB), except where necessary to eliminate an 
immediate hazard(s) to the trial participants. All personnel involved in the conduct of this 
study have completed Human Subjects Protection and GCP Training. 
The protocol, informed consent form(s), recruitment materials, and all participant materials 
will be submitted to the IRB for review and approval.  Approval of both the protocol and 
the consent form must be obtained before any participant is enrolled.  All changes to the 
consent form will be IRB approved; a determination will be made regarding whether a new 
consent needs to be obtained from participants who provided consent, using a previously 
approved consent form. 
 
 
 
 
 
Lead Principal Investigator 
 
 
______________________  
_______________________  
_________ 
Name (print)  
 
 
Signature 
 
 
 
Date 
 
 
Site Principal Investigator 
 
 
_______________________  
_________________________  
_________ 
Name (print)  
 
 
Signature 
 
 
 
Date 

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ABBREVIATIONS 
AE 
Adverse Event 
AHN 
Allegheny Health Network 
aVAE 
Acute Vaginal Adverse Events 
CC DSMC 
Cancer Center Data Safety Monitoring Committee 
CFR 
Code of Federal Regulations 
CET 
California Endocurietherapy 
COC 
Certificate of Confidentiality 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
D2cc 
Dose to the Hottest 2 cc (for each organ) 
EBRT 
External Beam Radiation 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Forms 
EDC 
Electronic Document Capture 
EMBRACE 
Image guided intensity modulated External beam radiochemotherapy and MRI based 
adaptive BRAchytherapy in locally advanced CErvical cancer 
GCP 
Good Clinical Practice 
HDR 
High-Dose Rate  
HIPAA 
Health Insurance Portability and Accountability Act  
HRT 
Hormone Replacement Therapy 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation  
IDE 
Investigational Device Exemption 
IRB-HSR 
Institutional Review Board for Health Sciences Research 
IUD 
Intrauterine Device 
kPA 
Kilopascal 
KPS 
Karnofsky Performance Status 
MRN 
Medical Record Number 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NIH  
National Institutes of Health 
NIH IC 
NIH Institute or Center 
NSR 
Non-Significant Risk 
OHRP 
Office for Human Research Protections 
PEG 
Polyethylene glycol 
PEGDA 
Polyethylene glycol diacrylate 
PRC 
Protocol Review Committee 
PI 
Principal Investigator 
QC 
Quality Control 
RT 
Radiation Therapy 
SAE 
Serious Adverse Event 
SOA 
Schedule of Activities 
SOP 
Standard Operating Procedure 
SPRT 
Sequential Probability Ratio Test 
UADE 
Unanticipated Adverse Device Effect 
UP 
Unanticipated Problem 
US 
United States 
UVA 
University of Virginia 
UVA CC 
University of Virginia Coordinating Center 
VBP 
Vaginal Balloon Packing 
VGP 
Vaginal Gauze Packing 
VHPS 
Vaginal Hydrogel Packing System 
WOCBP 
Women of Childbearing Potential 

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PROTOCOL SUMMARY 
 
Synopsis  
Title: 
A Randomized, Non-Inferiority Study of a Hydrogel Packing System 
Compared to Standard of Care Packing During Image-Guided High-
Dose Rate Brachytherapy Boost for Cervical Cancer 
Study Description:
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Objectives & 
Endpoints: 
 
Brachytherapy is administered in conjunction with external beam 
radiation therapy and concurrent chemotherapy in women with locally 
advanced cervical cancer and is an essential component of curative 
therapy for this disease.1 Contemporary high-dose rate (HDR) 
brachytherapy is commonly delivered in 4-6 separate fractions on an 
outpatient basis with conscious sedation or mild oral sedation. 
Vaginal packing is a mandatory component of cervical cancer 
brachytherapy,1 serving to displace the rectum and bladder from the 
high-dose regions and to stabilize brachytherapy applicators (Figure 
2). Traditional vaginal packing methods include vaginal gauze packing 
(VGP) and rectal retractors (also called posterior vaginal speculum 
blades or rectal blades). VGP has been the preferred packing method 
in most centers due to its availability and low cost, but it causes patient 
discomfort and lacks reproducibility since it is highly dependent upon 
physician placement.2 Rectal retractors provide some displacement of 
the rectum but do not displace the bladder. Additionally, they are 
difficult to place due to device crowding from the vertical column of 
applicators and rectal retractor. Vaginal balloon packing (VBP) 
methods have been developed to provide a more comfortable and 
reproducible method of vaginal packing, but these are expensive.2-7 
The high cost limits uptake of VBP in the US, since hospitals must 
absorb this cost for a treatment that already delivers relatively poor 
reimbursement compared to other radiation modalities.8 Current 
packing options are suboptimal for contemporary image-guided 
brachytherapy delivered on an outpatient basis under mild sedation.  
This study validates the clinical performance of a new hydrogel-based 
packing technique (BrachyGel Vaginal Hydrogel Packing System, 
(BrachyGel VHPS)) in patients with cervical cancer. This approach is 
expected to meet the needs of contemporary, image-guided 
brachytherapy at a low cost and with much less patient discomfort. 
Participants will receive brachytherapy according to standard 
guidelines but packing would alternate between standard and 
BrachyGel. Participants will assess discomfort/pain, and clinicians 
and physicists will assess imaging properties, completeness and 
overall experience.  
BrachyGel VHPS is considered by the FDA to be a non-significant risk 
(NSR) device and therefore this study does not require an 
Investigational Device Exemption (IDE) from the FDA.  
 
 

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Objectives 
Endpoints 
Primary 
 
To determine if BrachyGel 
Vaginal Hydrogel Packing 
System (BrachyGel) is non-
inferior to standard method 
vaginal packing (standard) in 
dose thresholds for the rectum 
and the bladder. 
The dose to the hottest 2 cc 
(D2cc) (in Gy) for the rectum 
and the bladder in periods 1 and 
2 (e.g. fractions 2 and 3).  
Secondary
 
To estimate the difference in 
the safety profile of BrachyGel 
compared to standard vaginal 
packing. 
Frequency, intensity, and 
duration of adverse events in 
periods 1 through 4 (e.g. 
fractions 2 through 5).  
To estimate period effects in 
dosimetry thresholds (D0.1cc, 
D1cc, D2cc) between 
BrachyGel and standard 
vaginal packing for the rectum 
and the bladder. 
The dose to the hottest 0.1 cc 
(D0.1cc), 1 cc (D1cc), and 2 cc 
(D2cc) (in Gy) for the rectum 
and the bladder in periods 1 
through 4 (e.g. fractions 2 
through 5). 
Exploratory 
 
To estimate the difference in 
participant-reported discomfort 
between BrachyGel and 
standard vaginal packing  
Participant-reported discomfort 
from packing scored on a 4 
point scale for periods 1 through 
4 (e.g. fractions 2 through 5). 
To estimate the difference in 
physician/physicist evaluation 
of imaging properties and 
completeness of packing 
between BrachyGel and 
standard vaginal packing. 
Physician/physicist evaluation of 
imaging properties and 
completeness of packing scored 
on a 4 point scale for periods 1 
through 4 (e.g. fractions 2 
through 5). 
To estimate the difference in 
physician-scored use 
experience between 
BrachyGel and standard 
vaginal packing. 
Physician-scored use 
experience scored on a 4-point 
scale for periods 1 through 4 
(e.g. fractions 2 through 5). 
Study Population:
Adult women with locally advanced cervical cancer (FIGO Stages IB1-
IVB) for whom brachytherapy boost is planned using intracavitary 
high-dose rate brachytherapy as part of definitive radiation therapy. 
Description of 
Sites/Facilities 
Enrolling 
Participants: 
Participants will be enrolled at the University of Virginia and at the 
Allegheny Health Network 
Description of Study 
Intervention: 
Participants will receive brachytherapy according to clinical care and 
will alternate between standard packing and BrachyGel packing.  The 
order of alternation will vary between Arms A and B. 
Study Duration: 
Accrual should be completed within 14 months and data collection and 
analysis will take after 12 additional months (total of 26 months).   

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Participant Duration: 
Each participant will receive 5 fractions of brachytherapy, each about 
2-7 days apart, followed by a 30 day safety visit.  
 
 
Schema 
 
  
2 INTRODUCTION 
 
Study Rationale  
Brachytherapy, an essential component of multidisciplinary cancer care, is increasingly 
image-based and focused on a customized, three-dimensional treatment plan.9 For 
women with locally advanced 
cervical 
cancer, 
the 
most 
common cancer among women 
worldwide, brachytherapy is 
administered 
in 
conjunction 
with external beam radiation 
therapy 
and 
concurrent 
chemotherapy.1 and it is an 
essential 
component 
of 
curative therapy in this patient 
population. 
Technological 
advances have ushered in a 
new era of elegant, highly 
conformal, 
image-based 
Figure 1. Study Schema 
Figure 2. Tandem and Ovoid Brachytherapy with Intrauterine
Tandem and Ovoids and Vaginal Gauze Packing 

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treatment with high dose-rate (HDR) intra-cavitary brachytherapy with tandem-based 
applicators. Contemporary HDR tandem-based brachytherapy is commonly delivered in 
4-6 separate fractions on an outpatient basis with conscious sedation or mild oral sedation, 
as opposed to traditional low dose-rate brachytherapy delivered in 1-2 insertions with 
general anesthesia. 
Vaginal packing is a mandatory component of cervical cancer brachytherapy,1 serving to 
displace rectum and bladder from the high-dose regions and to stabilize brachytherapy 
applicators (Figure 2). Traditional vaginal packing methods include vaginal gauze packing 
(VGP) and rectal retractors. These options, however, are suboptimal for contemporary 
image-guided brachytherapy delivered on an outpatient basis under mild sedation. 
Although VGP is the preferred packing method in most centers because of its availability 
and low cost, it causes patient discomfort in the modern era of outpatient, multi-fraction 
HDR brachytherapy courses and lacks reproducibility because it is highly dependent upon 
physician placement.2 Placement of VGP has been cited as the most technique-
dependent part of the entire cervical cancer brachytherapy procedure 7. Rectal retractors, 
also known as posterior vaginal speculum blades or rectal blades, do provide some 
displacement of the rectum, but do not displace the bladder. Additionally, they are difficult 
to place due to device crowding from the vertical column of applicators and rectal retractor. 
Vaginal balloon packing (VBP) methods have been developed to provide a more 
comfortable and reproducible method of vaginal packing.2-7 However, in the US 
commercially available VBP (Alatus, RadiaDyne, LLC, Houston, TX) costs approximately 
$400 per application, totaling $2,000 for a 5-fraction course. High cost limits uptake of 
VBP in the US, since hospitals must absorb this cost for a treatment that already delivers 
relatively poor reimbursement compared to other radiation modalities.8  
Recently, a new hydrogel-based packing system has been developed: BrachyGel Vaginal 
Hydrogel Packing System. On the basis of the results from the pre-clinical testing, the 
BrachyGel Vaginal Hydrogel Packing System should improve comfort for patients and 
should be easier for physicians to utilize during brachytherapy. Additionally, it is expected 
to reduce variation in physician performance, better pack lateral and irregular regions of 
the vagina (Figure 4), image clearly by CT and MRI, minimize air pockets (Figure 3), and 
provide a more affordable option compared to the commercial balloon product. 
 
Figure 4. BrachyGel (right) expands to fill 
irregular cavities within a phantom, in contrast 
to the fixed shape of VBP (left). 
Figure 3. BrachyGel (right) provides uniform filling, in
contrast to gauze (left). Both materials shown in glass
jars of uniform diameter. The blue X represents a dose
point as used in brachytherapy planning software.  

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Background  
 Cervical Cancer and Brachytherapy 
In 2016, there were an estimated 12,990 new diagnoses of cervical cancer and 60,050 
diagnoses of uterine cancer in the United States.10 Brachytherapy is standard of care 
treatment for the majority of these women, approximately 8,000 women with cervical 
cancer and 42,000 women with uterine cancer. Based on the average number of 
procedures per patient (5 for cervical, 3 for uterine), we project over 150,000 individual 
brachytherapy procedures in the US alone. The polymer hydrogel solution (BrachyGel) 
provides a tailored solution that fits ideally within an image-based brachytherapy 
paradigm. The past two decades have seen an overall trend toward increasing 
implementation 
of 
image-based 
brachytherapy 
techniques 
with 
volume-based 
prescriptions and advanced treatment planning using CT and MRI11,12. This product is 
tailored for image-based brachytherapy, providing customized packing that is visualized 
well on CT and MRI. 
 Standard of Care Packing Options 
Table 1. Existing vaginal packing options for use with tandem-based cervical cancer 
brachytherapy. 
Vaginal Packing 
Strategy 
Strengths 
Limitations 
Gauze 
-Inexpensive 
-Amount of gauze and 
specific placement 
controlled by physician 
-Displaces bladder and 
rectum 
-Uncomfortable for patient 
-Limited use for outpatients, was developed 
in era of inpatient brachytherapy 
-Heterogeneous density  
-Prolonged insertion process involving 
manual packing of gauze strip with forceps 
Balloon Packing 
Device (i.e., 
Alatus system by 
Radiadyne in 
Houston, TX) 
-Rapid insertion of 2 balloons 
-Can be inflated with dilute 
contrast, improving image 
and providing attenuation 
-Displaces bladder and 
rectum, may improve 
dosimetry vs gauze5,6 
-Exceedingly expensive (~$400 per fraction 
for a total of $~2000 per 5-fraction course ) 
-Device crowding in vaginal space due to 3 
brachytherapy devices and 2 balloons with 
tubing 
-Heterogeneous density  
-Interference of posterior balloon with 
posterior edge of most common tandem 
applicator (Fletcher-Suit), which curves to 
contact posterior vaginal wall 
Rectal Retractor 
-Provides some displacement 
of rectum 
-Difficult to place due to device crowding 
from vertical column of applicators and 
rectal retractor 
-Heterogeneous density  
-Does not displace the bladder 
 BrachyGel Vaginal Hydrogel Packing System  
The product consists of the hydrogel solution, delivery gun, and a reaction bag. After 
standard brachytherapy applicators are in place, one reaction bag is inserted into the 
anterior vagina and a second bag into the posterior vagina. The hydrogel reagent 
containers are then placed within the delivery gun and connected to the reaction bag tube. 
The hydrogel reagents mix within the reaction bag (including the tubing) and the hydrogel 

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expands within the bag to serve 
as 
vaginal 
packing. 
The 
expansion of the hydrogel serves 
to displace tissue and conform to 
the patient anatomy to fill the 
vaginal space. The posterior and 
anterior reaction bags are filled 
separately. Figure 6 shows the 
anticipated steps involved in 
clinical use of the BrachyGel 
Vaginal 
Hydrogel 
Packing 
System. The series of steps 
shown is similar to those involved 
in VBP, so the time required for 
placement 
of 
the 
BrachyGel 
packing should be similar to the 
time required for placement of the 
Alatus balloon system or the VGP system. However, unlike 
VGP, placement of the BrachyGel packing does not require 
forceps to insert strips of gauze in the vagina.  Thus, the 
Brachygel packing approach should improve comfort for 
patients and be easier for physicians to place. 
With the BrachyGel VHPS, the thiol-Michael addition 
reaction leads to hydrogel formation and expansion in situ 
within the vaginal cavity, providing a ~10 kPa force to 
displace vaginal tissue  (chosen to approximate pressure 
from the Valsalva maneuver13) and conforming to a range of 
cavity shapes and dimensions (Figure 5). The expansion to 
fill the vaginal cavity occurs with minimal air pockets, which 
is an improvement over the other available packing 
methods. The hydrogel surrounds the applicator and 
conforms to the vaginal cavity, allowing for a fixed-
geometry, reusable applicator to serve any size or shape 
cavity. The imaging characteristics (Figure 2) on CT and 
MRI are ideal for use as vaginal packing during pelvic 
brachytherapy, with a homogeneous appearance that helps 
discern packing from adjacent bladder and rectum. This is 
the first use of a hydrogel technology to provide customized 
filling of a body cavity during radiation therapy. Furthermore, 
Figure 7. Hydrogel delivery system design, include injection of hydrogel reagents into
bag for reaction inside the bag, port to introduce saline, and air vent to release air from
the bag during reaction. 
Figure 5. Expansion of
hydrogel to conform to 
shape 
of 
cylindrical 
phantom designed to have 
varied diameter. 
Figure 6. The deployment of the BrachyGel Vaginal Hydrogel
Packing System shown in 8 steps to provide posterior and
anterior packing. Vaginal packing is the last part of the
implant procedure. 

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it meets a need for a customized packing that readily conforms to any anatomical variation. 
This improves upon the VBP method, which offers only a range of filling of a pre-set shape 
and volume. 
The delivery system design also contains innovative characteristics that are not available 
in current packing systems (Figure 7). The BrachyGel system includes a vent tube for air 
to escape from the bag while the hydrogel forms. In addition, there is a tube available for 
the physician to inject saline prior to removing the hydrogel packing in cases where a 
softer hydrogel would help with extraction of the packing. These design characteristics 
optimize the imaging characteristics of the packing (by evacuating air), allow fine-tuning 
by the physician (saline port), and maximize patient comfort. 
 Pre-Clinical Experience 
The BrachyGel Vaginal Hydrogel was formulated on the basis of the attributes of the thiol-
Michael addition reaction (Figure 9), which is unprecedented as a method for customized 
vaginal packing. This approach is based upon its biocompatibility, limited production of 
heat, and favorable imaging and radiation 
attenuation properties of constituent 
materials. The thiol-Michael click reaction 
involves 
the 
base 
or 
nucleophile-
catalyzed addition of a thiolate into an 
electron-deficient alkene. The reaction 
was chosen due to the ability to produce 
a biocompatible gel that forms quickly 
and reliably. Among its many other uses, 
the thiol-Michael addition reaction finds 
significant 
application 
in 
hydrogel 
synthesis 
with 
precursors 
including 
poly(ethylene 
glycol) 
(PEG)-based 
materials, polysaccharides, polypeptides, 
and 
synthetic 
materials. 
Common 
applications include drug-delivery, tissue 
engineering, and tissue repair. The 
development of this hydrogel packing 
strategy is described in a 2017 article in 
Polymer.14 
O
O
O
O
O
SH
O
O
SH
O
O
HS
n
n
n
O
O
O
O
m
+
NaHCO3 (aq.)
37 °C
THIOCURE ETTMP 1300
PEGDA
 
Figure 9. Approach to form hydrogel using an aqueous solution of trifunctional thiol THIOCURE 
ETTMP 1300 and poly(ethylene glycol) diacrylate (PEGDA). 
Figure 8. CT (above) and MRI (below) images of
hydrogel packing applied to cadaver with tandem
and ovoid applicator in place. There is homogenous
hydrogel 
signal 
(black 
arrows) 
with 
rectum
displacement (white arrows). 

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The suitability of a PEG-based hydrogel for the intended use as vaginal packing has been 
demonstrated. A mild base (NaHCO3) rapidly formed a hydrogel in vitro using this reaction. 
Characteristics included rapid hydrogel-formation in less than 2 minutes, a hydrogel 
modulus capable of displacing vaginal tissue (~10 kPa) with a lack of appreciable soluble 
species after the reaction, and the ability to absorb additional water after hydrogel 
formation. Measuring the effect of formulation variables such as PEGDA molecular weight, 
initial polymer concentration, and base concentration on the hydrogel-formation rate and 
modulus demonstrated hydrogel properties well suited for brachytherapy packing 
materials.  The water absorption of the hydrogel revealed its ability to absorb water in 
order to fine-tune tissue displacement. CT and MRI imaging studies displayed favorable 
radiation attenuation, demonstrating clear hydrogel distinguishability from native tissue 
and the metal applicator, vital for image-guided treatment planning (Figure 8). Biological 
evaluation against human vaginal epithelial cells verified hydrogel cytocompatibility. 
Based on available public information, this constitutes the first use of a water-absorbing 
hydrogel designed as a packing solution for pelvic brachytherapy applications. 
 Relevant Clinical Experience 
The investigational product has been used in cadavers, but not in living humans. Data 
related to cadaver studies, biocompatibility and leakage studies may be found in the 
investigator’s brochure.  
 
Risk/Benefit Assessment   
 Known Potential Risks  
Vaginal brachytherapy is associated with the following acute side effects according to the 
EMBRACE study (Image guided intensity modulated External beam radiochemotherapy 
and MRI based adaptive BRAchytherapy in locally advanced CErvical cancer).  
In a study of over 1000 patients receiving brachytherapy, urinary morbidity, in particular 
urinary frequency, urgency, incontinence and cystitis, was seen in up to 24.5% of patients 
at all grades following brachytherapy15. At grades 2-4, prevalence rates were significantly 
lower at up to 5.0%. Most grade 3 and 4 urinary morbidity was urinary frequency, 
incontinence, and ureteral strictures, with grade 3-4 fistula, bleeding, spasm, and cystitis 
much lower at <1.0% and actuarial 3-year incidence of all grade 3 and 4 urinary morbidity 
events was 5.3%15.  
In a study of 960 patients, rectal bleeding was seen in 20.1% of patients at grade 1, 6% 
at grade 2, 1.6% at grade 3, and 0.1% at grade 416. This effect was dose dependent, with 
patients receiving ≤ 65 Gy having only minor and less frequent adverse events (risk of 
fistula was 0-2.7%), while patients receiving ≥ 75 Gy had more major and frequent events 
(12.5% risk of fistula). Overall rectal morbidity ≥ grade 2 was 10% at 69.5 Gy.  
In a study of 1176 patients receiving brachytherapy for cervical cancer, grade 3-4 bowel 
morbidity frequency was 5% at grade 3 and 5.9% at grade 417. Stenosis/stricture/fistula 
frequency was 2% at grade 3 and 2.6% at grade 4. Less severe events (grade 1 and 2) 
were more common, with 28-33% experiencing short term diarrhea, flatulence, 
incontinence, difficulty in controlling bowels, constipation, and abdominal cramps.  
 
Vaginal morbidity with brachytherapy for cervical cancer occurred relatively frequently in 
the EMBRACE study. In a group of 630 patients, frequency of vaginal stenosis overall was 

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21%, but the effect was dose-dependent with 20%, 27%, and 34% of patients experiencing 
grade ≥ 2 events following 65 Gy, 75 Gy, and 85 Gy, respectively18. 
Additionally, patients may experience localized pain during the procedure due to the 
packing material. It is hypothesized that this will be short term (will resolve within 1 day) 
and will be significantly decreased during/following treatments with BrachyGel packing. 
 Known Potential Benefits  
Participants may experience less pain and/or side effects of vaginal packing during and 
following fractions delivered with the BrachyGel Vaginal Hydrogel Packing System than 
fractions delivered with standard of care packing systems. There should be no difference 
in experience between arms, as both Arms A and B will undergo two fractions with the 
Brachygel system and two fractions with the standard of care system. 
 Assessment of Potential Risks and Benefits  
It is expected that brachytherapy fractions delivered with BrachyGel as the packing system 
will be at least as comfortable and as safe as standard of care. Similarly, the quality of 
image guidance during fractions delivered with BrachyGel as the packing system should 
be at least as good as with standard of care packing systems. If BrachyGel is determined 
to be non-inferior to standard of care options, BrachyGel may present a less expensive, 
more comfortable, and highly effective option for delivery of brachytherapy for cervical 
cancer. The risks of participation for individual participants should not be greater than with 
standard brachytherapy and this study may identify an additional effective, low-cost, 
comfortable packing system option for future cervical cancer patients requiring 
brachytherapy.     
3 OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
 
To determine if BrachyGel Vaginal Hydrogel 
Packing System (BrachyGel) is non-inferior to 
standard method vaginal packing (standard) in 
dose thresholds for the rectum and the bladder. 
The dose to the hottest 2 cc (D2cc) (in Gy) 
for the rectum and the bladder in periods 1 
and 2 (e.g. fractions 2 and 3).  
Secondary 
 
To estimate the difference in the safety profile of 
BrachyGel compared to standard vaginal 
packing. 
Frequency, intensity, and duration of 
adverse events in periods 1 to 4 (e.g. 
fractions 2 through 5).  
To estimate period effects in dosimetry 
thresholds (D0.1cc, D1cc, D2cc) between 
BrachyGel and standard vaginal packing for the 
rectum and the bladder. 
The dose to the hottest 0.1 cc (D0.1cc), 1 
cc (D1cc), and 2 cc (D2cc) (in Gy) for the 
rectum and the bladder in periods 1 
through 4 (e.g. fractions 2 through 5). 
Exploratory
 
To estimate the difference in participant-
reported discomfort between BrachyGel and 
standard vaginal packing. 
Participant-reported discomfort from 
packing scored on a 4-point scale for 
periods 1 through 4 (e.g. fractions 2 
through 5). 

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To estimate the difference in physician/physicist 
evaluation of imaging properties and 
completeness of packing between BrachyGel 
and standard vaginal packing. 
Physician/physicist evaluation of imaging 
properties and completeness of packing 
scored on a 4-point scale for periods 1 
through 4 (e.g. fractions 2 through 5). 
To estimate the difference in physician-scored 
use experience between BrachyGel and 
standard vaginal packing. 
Physician-scored use experience scored on 
a 4-point scale for periods 1 through 4 (e.g. 
fractions 2 through 5). 
 
4 STUDY DESIGN  
 
Overall Design 
This is a two-center, stratified and randomized, four period, two arm crossover, non-
inferiority trial to demonstrate that BrachyGel Vaginal Hydrogel Packing System is non- 
inferior to standard method vaginal packing (standard).  
Two sites are included in the trial design in order to reflect the most common applicators 
used in intracavitary cervical cancer brachytherapy: 
 
Tandem and ovoid brachytherapy+/- interstitial needles (UVA cohort) 
 
Tandem and ring-based brachytherapy +/- interstitial needles (AHN cohort) 
The BrachyGel Hydrogel Vaginal Packing System will be compared to gauze packing 
and/or rectal retractor packing per the institution’s standard of care packing practice. 
Participants will be stratified by site (UVA/AHN) and randomized to either Arm A or Arm 
B. Fraction 1 for all participants (both Arms) will be according to standard of care packing 
and fractions 2-5 (periods 1-4) will alternate between standard of care and BrachyGel 
packing, as shown in Figure 1. 
 
 
End of Study Definition 
Primary completion date is the date that the final participant was examined or received an 
intervention for the purposes of final collection of data for the primary outcome, whether 
the clinical study concluded according to the pre-specified protocol or was terminated.  
 
Study completion date is the date the final participant was examined or received an 
intervention for purposes of final collection of data for the primary and secondary outcome 
measures and adverse events (for example, last participant’s last visit), whether the 
clinical study concluded according to the pre-specified protocol or was terminated.  
 
5 STUDY POPULATION 
 
Inclusion Criteria 
In order to be eligible to participate in this study, an individual must meet all of the following 
criteria: 
1. Biopsy showing cancer of the cervix (squamous cell carcinoma, adenocarcinoma, 
adenosquamous, neuroendocrine, etc) 

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2. FIGO IB1 – IVB Staging according to FIGO and TNM guidelines 
3. Planning to receive brachytherapy as a part of the definitive treatment for cervical 
cancer 
4. Karnofsky performance status (KPS) ≥ 70 or ECOG status ≤1 
5. Stated willingness to comply with all study procedures and availability for the 
duration of the study  
6. Age ≥ 18 years 
7. Agreement to adhere to Lifestyle Considerations (see section 5.3) throughout 
study duration 
 
 
Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in 
this study: 
1. History of pelvis or abdominal radiation therapy (RT) that is not a part of the 
definitive treatment plan for the cancer  of interest”  
2. History of total or partial hysterectomy 
3. Plan to receive external beam RT (EBRT) alone as the definitive treatment plan 
for the cancer of interest 
4. Known pregnancy or lactation (no pregnancy test required prior to participation) 
5. Known contraindications to brachytherapy 
 
Lifestyle Considerations 
During this study, women of childbearing potential are required to use highly effective 
contraception methods following study entry and through the last fraction of 
brachytherapy. 
Women of childbearing potential (WOCBP) includes any female who has experienced 
menarche and who has not undergone successful surgical sterilization (hysterectomy, 
bilateral tubal ligation or bilateral oophorectomy) or is not postmenopausal (defined as 
amenorrhea ≥ 12 consecutive months; or women on hormone replacement therapy (HRT) 
with documented serum follicle stimulating hormone level > 35 mIU/mL). 
The following birth control methods are allowed during the study: 
1. Barrier methods 
a. Diaphragm with spermicide 
b. Cervical cap with spermicide 
c. Condom with spermicide 
 
2.  Hormonal methods 
a. Hormonal contraceptives (such as the birth control pill) 
b. Intra-uterine device (IUD) 
 
3. Abstinence (no heterosexual activity) 
 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical trial 
but are not subsequently randomly assigned to the study intervention or entered in the 
study. A minimal set of screen failure information is required to ensure transparent 

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reporting of screen failure participants, to meet the Consolidated Standards of Reporting 
Trials (CONSORT) publishing requirements (for NIH studies) and to respond to queries 
from regulatory authorities. Minimal information includes demography and any serious 
adverse event (SAE). 
Individuals who do not meet the criteria for participation in this trial because of a modifiable 
factor may be rescreened. 
6 STUDY INTERVENTION 
 
Description of Study Intervention(s)  
Participants will be assigned to Arm A or Arm B, as described in section 4.1 and Figure 1. 
Fraction 1 for all participants (both Arms) will receiving standard of care packing. During 
fractions 2-5 of brachytherapy, participants will have vaginal packing alternating between 
the BrachyGel Vaginal Hydrogel Packing System and standard of care vaginal packing, 
strategy which will include gauze vaginal packing or rectal retractor. 
For Arm A of the study, the BrachyGel Packing System will be used during fractions 3 
and 5. Standard packing will be used for fractions 1, 2 and 4. 
For Arm B of the study, the BrachyGel Packing System will be used during fractions 2 
and 4.  Standard packing will be used for fractions 1, 3 and 5. 
 
Dosing and Administration 
 Dose Delays 
Delays in brachytherapy fractions will be according to institutional guidelines. 
 
Preparation/Handling/Storage/Accountability 
 Acquisition and Accountability 
The investigational devices will be stored in a secure area. Each package of the Brachygel 
Vaginal Hydrogel Packing System will be single-use specific to a particular participant and 
any remaining packs will be destroyed in accordance with institutional policies, as directed 
by Brachyfoam. 
 Appearance, Packaging, and Labeling 
Details on the appearance, packaging and labeling may be found in the clinical use 
instructions provided. The device will be labeled in accordance with 21 CFR 812.5 and will 
include the following information: lot number, quantity of contents, name and place of 
business of the manufacturer, packer or distributor, and the required investigational device 
statement (“CAUTION: --Investigational device. Limited by Federal (or United States) law 
to investigational use”). The labeling will also include relevant contraindications, hazards, 
adverse effects, interfering substances or devices, warnings or precautions. 
 Product Storage and Stability 

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The device will be stored by the study team at a temperature between 35 and 72 degrees 
Fahrenheit (2 and 22 degrees Celsius). The product is stable with these conditions for at 
least 6 months after manufacture. 
 Preparation 
Please see the clinical use instructions provided for this information. 
 
Registration and Randomization 
All participants must sign the consent form prior to determination of eligibility for this study.    
 
When a site is ready to enroll a patient, the following documentation must be scanned and 
emailed to the UVA Coordinating Center:  
 
Patient and staff signed signature page of the current informed consent form 
(ICF)  
 
Completed Inclusion/Exclusion checklist demonstrating subject eligibility  
 
Supporting documentation needed to confirm eligibility (lab results, scan 
results etc.)  
Consult the Study Reference Manual for instructions on sending this information. The 
Coordinating Center will consult with the Overall Study PI if questions arise in confirming 
eligibility. The UVA Coordinating Center will communicate the subject number and arm 
assignment to the enrolling site. 
Registration will occur following verification of eligibility by the treating physician. Eligibility 
confirmation and registration can occur after the 1st brachytherapy fraction but must occur 
before the 2nd brachytherapy fraction. 
Participants who are consented and accrued to the study should be registered in the 
designated EDC System in accordance with the Clinical Trial Management System Policy. 
General guidelines are available in the User Manual and Data Entry Guide.  
Participants should receive their first fraction of brachytherapy within 14 days of 
registration. 
Randomization will be discussed with participants during the process of informed consent, 
and informed consent must be documented prior to randomization. Randomization will be 
stratified by institution, and will be based on equal allocation between arms. The 
randomization sequences will be generated by the study statisticians and loaded into 
RAND and accessed in  the designated EDC System. Randomization will occur no sooner 
than 10 days prior to the second fraction of brachytherapy. 
This study does not involve any blinding or masking procedures.  Participants will be told 
which arm they are assigned to. 
 
 
Concomitant Therapy 
For this protocol, a prescription medication is defined as a medication that can be 
prescribed only by a properly authorized/licensed clinician. Medications to be reported in 

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the Case Report Form (CRF) are medications used for pain control for each brachytherapy 
procedure. 
 Rescue Medicine/Supportive Care 
Supportive care should be according to institutional guidelines. 
7 STUDY CLOSURE, STUDY INTERVENTION DISCONTINUATION AND 
PARTICIPANT DISCONTINUATION OR WITHDRAWAL 
 
Study Discontinuation and Closure 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause.  Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to the investigator, 
funding agency, and regulatory authorities.  If the study is prematurely terminated or 
suspended, the Principal Investigator (PI) will promptly inform the Institutional Review 
Board (IRB) and will provide the reason(s) for the termination or suspension.  Study 
participants will be contacted, as applicable, and be informed of changes to study visit 
schedule. 
  
Circumstances that would warrant termination or suspension include, but are not limited 
to: 
 
Determination of unexpected, significant, or unacceptable risk to participants  
 
Insufficient compliance to protocol requirements 
 
Data that are not sufficiently complete and/or evaluable 
 
Determination that the primary endpoint has been met 
 
Change in funding status 
 
If the study is halted due to safety concerns, protocol compliance and/or data quality, the 
study may resume once these concerns are addressed and satisfy the IRB and Data and 
Safety Monitoring Committee. 
 
Participants receiving the study intervention at the time of study discontinuation should 
complete procedures described in section 7.3. 
 
 
Participant Discontinuation/Withdrawal  
Participants are free to withdraw from participation in the study at any time upon request. 
A participant’s study treatment would be discontinued for the following reasons: 
 
Pregnancy 
 
Significant study intervention non-compliance  
 
Severe, CTCAE Grade ≥ 4 adverse event considered at least possibly related to 
the packing procedure 
 
Participant is unable to receive further brachytherapy due to an adverse event or 
a change in status (e.g. decline due to disease, change in goals of care, 
development of metastases). 
 
Participant decision to withdraw from study treatment and/or the study 

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The reason for participant discontinuation or withdrawal from study treatment will be 
recorded on the case report form. Participants that withdraw from study treatment only, 
will continue with study follow-up. Participants that withdraw from study treatment and 
study follow-up will not be contacted for any further study visits. 
 
 
Procedures for Discontinuation of Study Intervention 
Discontinuation from brachytherapy according to the study does not mean discontinuation 
from the study, and remaining study procedures should be completed as indicated by the 
study protocol.  If a clinically significant finding is identified (including, but not limited to 
changes from baseline) after enrollment, the investigator or qualified designee will 
determine if any change in participant management is needed. Any new clinically relevant 
finding will be reported as an adverse event (AE). 
The data to be collected and procedures to be completed at the time of study intervention 
discontinuation are included in the schedule of assessments in section 13.1.  
8 STUDY ASSESSMENTS AND PROCEDURES 
 
Clinical Assessments  
 Physical Exam  
A complete physical exam will be completed at screening. Karnofsky performance status 
(KPS) or ECOG status will be collected at the time of each physical exam. 
 Assessment of Adverse Events 
Each participant will be evaluated by a licensed clinician at each study visit.  The NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 5 will be used for the 
characterization and grading of adverse events.  
 
Participant Reported Outcomes 
Participant-reported discomfort during 
both standard and BrachyGel packing 
placement/removal will be assessed following fractions 2-5 of brachytherapy. See section 
13.3 for the questions included. The participant will either be given a paper survey of the 
questions to complete or a member of the clinical or study team will read the questions 
and possible responses to the participant and the responses will be recorded at that time. 
The questions must be answered directly following the completion of brachytherapy within 
1 hour of removal of packing.   
If the participant is sedated for a particular brachytherapy fraction, the participant will not 
complete the participant discomfort survey questions for that fraction.  
 
Physicist and Physician Assessments 
Physician & physicists will evaluate imaging properties, completeness of packing and 
general experience of using each packing systems (both standard of care and Brachygel)  

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following fractions 2-5 for each participant. Only the dosimetry measurements will be 
collected for the first fraction. See sections 13.2 and 13.4 for the instruments. 
 
 
 
9 DATA AND SAFETY MONITORING PLAN  
 
Adverse Events and Serious Adverse Events 
 Definition of Adverse Events (AE) 
For the purposes of this protocol, we define an adverse event to be any untoward medical 
occurrence associated (at least possibly related) with the use of the study intervention(s)  
 Definition of Serious Adverse Events (SAE) 
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the 
view of either the investigator or sponsor, it results in any of the following outcomes:  
 
death,  
 
a life-threatening adverse event,  
 
inpatient hospitalization or prolongation of existing hospitalization,  
 
a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions, or  
 
a congenital anomaly/birth defect.  
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the participant and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. A planned medical 
or surgical procedure is not, in itself, an SAE. 
 Classification of an Adverse Event 
9.1.3.1 Severity of Event 
For adverse events (AEs) not included in CTCAE version 5.0, the following guidelines will 
be used to describe severity.  
• 
Mild – Events require minimal or no treatment and do not interfere with the 
participant’s daily activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with 
functioning. 

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• 
Severe – Events interrupt a participant’s usual daily activity and may require 
systemic drug therapy or other treatment. Severe events are usually potentially 
life-threatening or incapacitating.  Of note, the term “severe” does not necessarily 
equate to “serious”. 
 
 
 
9.1.3.2 Relationship to Study Intervention 
All adverse events (AEs) must have their relationship to study intervention assessed by 
the clinician who examines and evaluates the participant based on temporal relationship 
and his/her clinical judgment. The degree of certainty about causality will be graded using 
the categories below. Relationship of the adverse event to brachytherapy and packing 
system will be assessed separately. In a clinical trial, the study product must always be 
suspect.  
 
Definitely Related – There is clear evidence to suggest a causal relationship, and 
other possible contributing factors can be ruled out. The clinical event, including 
an abnormal laboratory test result, occurs in a plausible time relationship to study 
intervention administration and cannot be explained by concurrent disease or other 
drugs or chemicals. The response to withdrawal of the study intervention 
(dechallenge) should be clinically plausible. The event must be pharmacologically 
or phenomenologically definitive, with use of a satisfactory rechallenge procedure 
if necessary. 
 
 
Probably Related – There is evidence to suggest a causal relationship, and the 
influence of other factors is unlikely. The clinical event, including an abnormal 
laboratory test result, occurs within a reasonable time after administration of the 
study intervention, is unlikely to be attributed to concurrent disease or other drugs 
or chemicals, and follows a clinically reasonable response on withdrawal 
(dechallenge). Rechallenge information is not required to fulfill this definition. 
 
 
Possibly Related – There is some evidence to suggest a causal relationship (e.g., 
the event occurred within a reasonable time after administration of the trial 
medication). However, other factors may have contributed to the event (e.g., the 
participant’s clinical condition, other concomitant events). Although an AE may rate 
only as “possibly related” soon after discovery, it can be flagged as requiring more 
information and later be upgraded to “probably related” or “definitely related”, as 
appropriate. 
 
Unlikely to be related – A clinical event, including an abnormal laboratory test 
result, whose temporal relationship to study intervention administration makes a 
causal relationship improbable (e.g., the event did not occur within a reasonable 
time after administration of the study intervention) and in which other drugs or 
chemicals or underlying disease provides plausible explanations (e.g., the 
participant’s clinical condition, other concomitant treatments). 
 
 
Not Related – The AE is completely independent of study intervention 
administration, and/or evidence exists that the event is definitely related to another 

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etiology. There must be an alternative, definitive etiology documented by the 
clinician. 
9.1.3.3 Expectedness 
The treating investigator will be responsible for determining whether an adverse event 
(AE) is expected or unexpected. An AE will be considered unexpected if the nature, 
severity, or frequency of the event is not consistent with the risk information previously 
described for the study intervention and/or this population. Expected AEs are described in 
Table 2. 
Table 2 
Adverse event
Maximum grade expected
Diarrhea  
3 
Cystitis 
2 
Rectal perforation  
3 
Rectal fistula  
3 
Proctitis  
3 
Rectal pain  
2 
Rectal hemorrhage 
3 
Bowel perforation  
3 
Bladder perforation  
2 
Hematuria  
2 
Urinary frequency  
2 
Urinary incontinence 
2 
Urinary urgency 
2 
Pelvic pain 
2 
Vaginal perforation  
3 
Vaginal hemorrhage 
2 
 Abnormal Laboratory Values 
Laboratory values will not be collected or assessed for this study. Abnormal laboratory 
values will not be recorded or reported in this study.  
 Time Period and Frequency for Event Assessment and Follow-Up 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to 
the attention of study personnel during study visits and interviews of a study participant 
presenting for medical care, or upon review by a study monitor. 
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be 
captured on the appropriate case report form (CRF). Information to be collected includes 
event description, time of onset, clinician’s assessment of severity, relationship to study 
product (assessed only by those with the training and authority to make a diagnosis), and 
time of resolution/stabilization of the event. All AEs occurring while on study must be 
documented appropriately regardless of relationship. All AEs will be followed to adequate 
resolution. 
 
Any medical condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. However, if the study participant’s 
condition deteriorates at any time during the study, it will be recorded as an AE.  

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Changes in the severity of an AE will be documented to allow an assessment of the 
duration of the event at each level of severity to be performed. AEs characterized as 
intermittent require documentation of onset and duration of each episode. 
Study staff will record all reportable events with start dates occurring any time after 
brachytherapy fraction 2 is completed until 30 days (for non-serious AEs) or anytime (for 
SAEs considered related to the study intervention) after the last day of study treatment.  
At each study visit, the investigator will inquire about the occurrence of AE/SAEs since the 
last visit.  Events will be followed for outcome information until resolution or stabilization. 
 Adverse Event Reporting 
AEs must be recorded into the EDC system designated by the University of Virginia 
database, per the following guidelines. 
Table 3 
Table 3: High Risk Studies  
Reporting requirements for AEs that occur within 30 days of the last dose of protocol specified treatment
Grade 1 
Grade 2 
Grade 3 
Grade  
4 & 5 
Expected 
and 
Unexpected 
 
Expected 
 
Unexpected 
Expected
 
Unexpected
Expected 
and 
Unexpected 
Without
hospitalization 
With
hospitalization 
Without
hospitalization 
With
hospitalization 
Unrelated
Unlikely 
30 days
30 days
30 days
30 days
15 days
30 days
15 days
7 days
Possible
Probable 
Definite 
30 days 
30 days 
15 days 
30 days 
15 days 
7 days 
7 days 
(24-hrs)*
7 days 
*Enter into Cancer Center database within 24 hours if unexpected and definitely related to protocol specified treatment 
Hospitalization defined as an inpatient hospital stay or prolongation of a hospital stay equal to or greater than 24 hours 
 Serious Adverse Event Reporting 
The study clinician will report to the overall study PI any serious adverse event, whether 
or not considered study intervention related, including those listed in the protocol or clinical 
use instructions, and must include an assessment of whether there is a reasonable 
possibility that the study intervention caused the event. See Study Reference Manual for 
contact information and instructions for reporting. 
 
All serious adverse events (SAEs) will be followed until satisfactory resolution or until the 
site investigator deems the event to be chronic or the participant is stable. Other 
supporting documentation of the event may be requested by the UVA Coordinating Center 
(UVA CC) and should be provided as soon as possible. 
 
Site Reporting Requirements 
 
Any Event Resulting in death that is deemed DEFINITELY related to (caused by) 
study participation  
 
OR 

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Any event deemed serious   
 
 
Report to the UVA CC within 24 hours from the time the study team received 
knowledge of the event according to UVA CC requirements.  
 
Non relying sites: report to your IRB in accordance with your IRB guidelines.   
 
Relying sites (use the UVA IRB-HSR as the IRB of record):  the UVA CC will 
report to the UVA IRB-HSR in accordance with the guidelines. 
 
UVA site: report to the UVA IRB-HSR in accordance with the guidelines. 
 
UVA Reporting Guidelines 
 
 
Notify the UVA IRB-HSR of any event resulting in death that is deemed 
DEFINITELY related to (caused by) study within 24 hours from the time the study 
team received knowledge of the event.  Report using IRB Online and by telephone. 
 
Notify the UVA IRB-HSR of any serious, unexpected and related adverse event 
within 7 calendar days from the time the study team receives knowledge of the 
event.  Timeline includes submission of signed hardcopy of AE form.  Report using 
IRB online.  
 
For events considered at least possibly related to BrachyGel, notify Brachyfoam 
within 72 hours of UVA CC’s awareness of the event. To do so, email 
tshowalter.brachyfoam@gmail.com.   
 
Unanticipated Adverse Device Effects 
 Definition of Unanticipated Adverse Device Effect (UADE) 
Unanticipated adverse device effect is any serious adverse effect on health or safety or 
any life-threatening problem or death caused by, or associated with a device, if that effect, 
problem, or death was not previously identified in nature, severity, or degree of incidence 
in the investigational plan or application (including a supplementary plan or application), 
or any other unanticipated serious problem associated with a device that relates to the 
rights, safety, or welfare of subjects (21 CFR 812.3(s)). 
 Reporting of UADE 
Site Reporting Requirements 
 
The study investigator shall complete an Unanticipated Adverse Device Effect 
Form and submit to the UVA CC and to the reviewing Institutional Review Board 
(IRB) according to the IRB’s guidelines, but in no event later than 10 working days 
after the investigator first learns of the effect.   
 
Non relying sites: report to your IRB in accordance with your IRB guidelines.   
 
Relying sites (use the UVA IRB-HSR as the IRB of record): report to the UVA CC 
within 5 calendar days so that the UVA CC can report to the reviewing IRB within 
10 calendar days.  
 
UVA site: report to the UVA CC within 5 calendar days so that the UVA CC can 
report to the reviewing IRB within 10 calendar days.  

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UVA Reporting Guidelines 
 
The UVA CC is responsible for conducting an evaluation of an unanticipated 
adverse device effect and shall report the results of such evaluation to all reviewing 
IRBs and participating investigators within 10 working days after the UVA CC first 
receives notice of the effect. Thereafter, the UVA CC shall submit such additional 
reports concerning the effect as the IRBs/participating investigator requests. 
 
If the PI or UVA DSMC determine that an unanticipated adverse device effect 
presents an unreasonable risk to subjects shall terminate all investigations or 
parts of investigations presenting the risk as soon as possible.  Termination shall 
occur not later than 5 working days after the sponsor makes this determination 
and not later than 15 working days after the UVA CC first received notice of the 
effect. 
 
For events considered at least possibly related to BrachyGel, notify Brachyfoam 
within 72 hours of UVA CC’s awareness of the event. To do so, email 
tshowalter.brachyfoam@gmail.com. 
 
Reporting Events to Participants 
If there is any new information relevant to the participant’s willingness to continue to 
participate in the study, such as if there are new risks of the study treatment identified that 
were not included on the consent form that the participant signed, the study team will 
contact the participant to discuss this information. If the participant is still receiving study 
treatment, the study team will present the participant with an updated consent and confirm 
that he or she wants to continue receiving study treatment. Each site PI will determine 
whether new risks are applicable to participants who are in follow-up, whether participants 
need to be notified, and whether re-consenting is required. 
 
Reporting of Pregnancy 
Pregnancy does not need to be reported to UVA IRB-HSR. Women found to be pregnant 
should not receive any further brachytherapy. While the study intervention (packing 
system type) should not affect pregnant women or the unborn child, pregnant women 
should not receive radiation in this area.  
 
Unanticipated Problems 
 Definition of Unanticipated Problems (UP) 
The Office for Human Research Protections (OHRP) considers unanticipated problems 
(UPs)(may include a data breach) involving risks to participants or others to include, in 
general, any incident, experience, or outcome that meets all 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 
Institutional Review Board (IRB)-approved research protocol and informed 
consent document; and (b) the characteristics of the participant population being 
studied; 
• 
Related or possibly related to participation in the research (“possibly related” 
means there is a reasonable possibility that the incident, experience, or outcome 
may have been caused by the procedures involved in the research); and 

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• 
Suggests that the research places participants or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized. 
• 
This definition could include an unanticipated adverse device effect.  Please refer 
to section 9.2.1 for the definition of an unanticipated adverse device effect. 
 
 Unanticipated Problem Reporting 
Site Reporting Requirements 
 
UPs that are SAEs will be reported in accordance with the guidelines for SAE 
reporting. 
 
 
UPs that are not adverse events, protocol deviations or data breaches (see section 
9.6 for reporting for data breaches)  
o Report to the UVA CC within 2 calendar days from the time the study team 
receives knowledge of the event.  
o Non- relying sites: Report to your IRB of record in accordance with your 
IRB guidelines.   
o Relying sites (use the UVA IRB-HSR as the IRB of record): the UVA CC 
will report to the UVA IRB-HSR in accordance with the guidelines. 
o UVA Site: report to the UVA IRB-HSR in accordance with the guidelines—
see sponsor reporting requirements. 
 
UVA Reporting Guidelines 
 
Report UPs that are not adverse events or protocol deviations to the UVA IRB-
HSR within 7 calendar days from the time the study team receives knowledge of 
the event.  Report using the Unanticipated Problem Report form. 
 
Report to Brachyfoam within 48 hours of UVA CC’s awareness of the event. To 
do so, email tshowalter.brachyfoam@gmail.com. 
 
All UPs will be reported to appropriate institutional officials (as required by an 
institution’s written reporting procedures), the supporting agency head (or 
designee), and the Office for Human Research Protections (OHRP) in accordance 
with institutional policies. 
 
An unanticipated device effect may also qualify as an unanticipated problem.  Please 
follow the guidelines for reporting UADEs in section 9.2.2. 
 Reporting Unanticipated Problems to Participants 
If during the course of the study there is an unanticipated problem that affects current or 
past participants, affected participants will be contacted if needed. 
 
Data Breach 
 Definition of Data Breach 
An unauthorized acquisition, access, or use of protected health information (PHI) that 
compromises the security or privacy of such information. 

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 Reporting a Data Breach 
Site Reporting Requirements 
 
Report to the UVA CC within 24 hours from the time the study team receives 
knowledge of the event.  
 
Non- relying sites: Report to your IRB of record in accordance with your IRB 
guidelines.   
 
Relying sites (use the UVA IRB-HSR as the IRB of record): the UVA CC will report 
to the UVA IRB-HSR in accordance with the guidelines. 
 
UVA Site: report to the UVA IRB-HSR in accordance with the guidelines. 
 
 
UVA Reporting Guidelines 
 
Report to the UVA Corporate Compliance and Privacy Office as soon as possible 
and no later than 24 hours from the time the incident is identified.  Report by 
telephone. 
 
Report to ITC if the breach involves electronic data.  Report as soon as possible 
and no later than 24 hours from the time the incident is identified.  Refer to the 
following for details:  http://security.virginia.edu/report-information-security-
incident. 
 
Report to UVA police if the breach includes such things as stolen computers.  
Report by telephone. 
 
Report to Brachyfoam within 48 hours of UVA CC’s awareness of the event. To 
do so, email tshowalter.brachyfoam@gmail.com. 
 
 
Protocol Deviation 
 Definition of Protocol Deviation 
A protocol deviation is defined as any change, deviation, or departure from the study 
design or procedures of a research project that is NOT approved by the institution’s IRB 
prior to its initiation or implementation, OR deviation from standard operating procedures, 
Good Clinical Practices (GCPs), federal, state or local regulations. Protocol violations may 
or may not be under the control of the study team or UVA staff. These protocol violations 
may be major or minor violations. 
 Protocol Exception 
Protocol exceptions are circumstances in which the investigator wishes to deviate from 
eligibility criteria or one or more of the specific procedures called for in a research plan. 
Unlike modifications that apply to all subsequent subjects in the research, a 
protocol/research plan exception only applies to a specific subject or group of subjects. 
Exceptions are planned, and the investigator gets approval from the lead site ahead of 
time. Such a request should be rare and justified in terms of serving the best interests of 
the potential study participant. The Lead site will receive permission from the DSMB for 
any exceptions at the Lead site.  
 Reporting of a Protocol Deviation or Exception 

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It is the responsibility of the site investigator to use continuous vigilance to identify and 
report deviations. All deviations must be addressed in study source documents.  
Site Reporting Requirements: Major Deviations Only 
 
Report to the UVA CC within 4 calendar days from the time the study team receives 
knowledge of the event.  
 
Non- relying sites: Report to your IRB of record in accordance with your IRB 
guidelines.   
 
Relying sites (use the UVA IRB-HSR as the IRB of record): the UVA CC will report 
to the UVA IRB-HSR in accordance with the guidelines—see sponsor reporting 
requirements. 
 
UVA Site: report to the UVA IRB-HSR in accordance with the guidelines—see 
sponsor reporting requirements. 
  
 
UVA Reporting Guidelines 
 
Report to the UVA IRB-HSR major deviations within 7 calendar days from the time 
the study team received knowledge of the event.  Report using the Protocol 
Deviation and Protocol Exception Reporting Form. 
 
Report major deviations to Brachyfoam within 7 calendar days of UVA CC’s 
awareness of the event.   
 
Minor deviations do not need to be reported to the UVA IRB-HSR.  Refer to the 
Study Reference Manual for instructions on recording minor deviations. 
 
 
Participant Withdrawals/Dropouts Prior to Study Completion 
Participants who withdraw consent and those dropping out of the study secondary to an 
AE will be reported to the UVA IRB yearly on the IRB continuation form. 
10 STATISTICAL CONSIDERATIONS  
10.1 Design 
This is a two-center, stratified and randomized, four period, two arm crossover, non-
inferiority trial to demonstrate that BrachyGel Vaginal Hydrogel Packing System (hydrogel) 
is non- inferior to standard method vaginal packing (standard) in dose thresholds for D2cc 
(in Gy) for rectum and bladder by more than a non-inferiority margin of δ=1 Gy. Outcomes 
will be measured after each of 5 treatment fractions with results from the 1st fraction 
serving as the baseline measurement for each participant. D2cc measurements within 
organs varies between fractions as well as by participants, thus, each participant will 
receive both types of vaginal packing with order of packing type being chosen at random. 
Specifically, all participants will receive the standard method during the 1st fraction and 
then either sequence A (standard-hydrogel-standard-hydrogel) or sequence B (hydrogel-
standard-hydrogel-standard) chosen at random, for the remaining four fractions. It is 
possible for participants to require less therapy during the final fraction (ie maximum 
therapy has been applied to the tumor), thus, the choice of ordering is limited to these two 
orderings to ensure that both packing types are administered to each participant with the 
primary assessment based upon fraction 2 and 3 data (ie, a two period, two treatment 
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Randomization and Stratification 
Participants will be stratified by site (UVA, AHN). Randomization will occur with equal 
allocation to each ordering (Arm A or Arm B) using a stratified block randomization scheme 
with varying block sizes (of 2-4). Randomization will occur prior to the 2nd fraction of 
brachytherapy. 
 
Evaluation of Sample Populations and Criteria  
 Study Population 
Safety: All randomized participants receiving at any protocol treatment will be evaluated 
for safety outcomes.  
Evaluable: All randomized eligible participants receiving at least 3 fractions of treatment 
will be evaluated for study outcomes. 
 Study Outcomes & Endpoints 
Study measurements will be captured post each fraction of treatment. Assessments may 
include: 
 
Adverse events 
 
Dosimetry 
 
Physicist evaluation of imaging/packing 
 
Physician evaluation of imaging/packing 
 
Participant discomfort survey 
There are two primary endpoints based upon dosimetry measurements in the bladder 
and the rectum. Each endpoint is the difference between D2cc dosimetry measurements 
obtained during periods 1 and 2 (fractions 2 and 3 under the 2x2 crossover structure). 
Additional assessments include data from periods 3 and 4 (fractions 4 and 5).  
Additional endpoints include measurements over all periods for: 
 
Bladder and rectal dosimetry as measured by D0.1 cc and D1 cc. 
 
Participant reported discomfort  
 
Physicist evaluated imaging properties  
 
Physician evaluated imaging properties  
 
Physician evaluated use experience  
 
Sample Size and Accrual 
For this crossover study the primary comparison is based upon the 2x2 initial crossover 
portion. The primary endpoint is the difference of D2cc dosimetry measurements between 
periods 1 and 2 (fractions 2 and 3) for sequence arm A and sequence arm B based upon 
a two-sample comparison of the mean difference to the non-inferiority margin. Data from 
51 patients treated at UVA with fraction 2 and 3 information, reported overall in Romano 
et al 201819, with standard packing resulted in a mean (standard deviation) of 0.12 (1.56) 
and 0.10 (0.92) D2cc for the difference for bladder and rectal dosimetry, respectively. The 

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width of the 95% CI for the mean difference was 0.9 and 0.5 for bladder and rectal 
dosimetry, respectively. Based upon these measurements and clinical judgement, a non-
inferiority margin of δ=(0.12+1.56=1.68) was chosen for this study. 
Justification for the sample size is based upon obtaining sufficient accrual to test the 
primary hypothesis that use of the hydrogel vaginal packing is non-inferior to standard 
packing methods in 1) bladder and 2) rectal dosimetry by more than a non-inferiority 
margin. Let diffA and diffB denote the differences between fractions. 
The primary hypothesis to be tested is Ho: µdiffA - µdiffB ≥ δ versus Ha: µdiffA - µdiffB < δ, where 
the non-inferiority margin, δ=1.68, each for bladder and rectal, with a one-sided 2.5% level 
t-test. A sample size of 20 evaluable cervical cancer participants per arm achieves 94% 
power to detect non-inferiority using a one-sided t-test when the margin of non-inferiority 
is 1.68, the true difference between the means and the reference (standard) value is 0.12, 
and the assume population standard deviation is 1.56. Power is 96% if one uses the 
estimates for rectal dosimetry. 
Adjusting for participants not satisfying the evaluable criteria (section 10.3.1), it is 
estimated that approximately 57 cervical cancer participants will need to be accrued to the 
study in order to test the primary study hypothesis. Each site may allow up to 10 oncologist 
and 4 physicists/dosimetrist to participate in completing the Physician and Physicist 
Assessments.  
 
Safety Monitoring 
All study participants who receive treatment will be assessed for the occurrence of 
treatment related adverse events. Adverse events of potential concern related to the 
vaginal packing, are acute vaginal adverse events (aVAE) which: i) is determined to be at 
least possibly related to BrachyGel; ii) occurs within the first 30 days from 1st 
Brachytherapy treatment utilizing BrachyGel (ie. Period 2 or 3 depending on the 
randomization arm); and iii) meets the criterion below: 
Has any of the following vaginal toxicities grade >=3 according to CTCAE: 
 
Vaginal pain 
 
Vaginal perforation 
 
Vaginal hemorrhage 
 
Vaginal inflammation 
 
Vaginal infection 
 
Dyspareunia 
Safety will be assessed by monitoring the number of participants who experience an 
aVAE. Results reported in Romano et al 2017 on high-dose brachytherapy experience at 
UVA noted that 0/74 = 0% (upper limit of 95% CI of 4.9%) patients experienced grade ≥3 
aVAE.20 Others have reported similarly low rates with at most 2% for late vaginal 
toxicity.21,22 For this study the upper boundary of a sequential probability ratio test (SPRT) 
based upon a binomial test of proportions for aVAE will be used for monitoring, to protect 
against excessive aVAE rates.  The stopping boundary is for a SPRT contrasting a null 
4% versus an unacceptable 9% aVAE rate, with nominal type I and II errors of 10% and 
10%, respectively. The slope of the parallel line for monitoring is 2.54 and the intercept is 
0.062. 

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Safety stopping guidelines for the occurrence of aVAEs are detailed in the following table. 
If a stopping bound is crossed then accrual to the study will be suspended until the study 
PI, co-investigators and the DSMC can review the data, and determine if the study should  
continue, be amended or be closed to further accrual. 
Number of participants who received BrachyGel Number with grade ≥ 3 aVAE
3-7 
≥ 3 
8-23 
≥ 4 
24-39 
≥ 5 
40-45 
≥ 6 
 
 
Analyses 
Two main sets of analyses for all endpoints are proposed. The first limits assessment to 
data from periods 1 and 2, and the second uses data from all periods. The first set will 
summarize data based upon differences between period endpoints, with comparisons by 
arm. The second will employ repeated measure models to estimate period effects.  
For fractions 2-5, adverse events will be summarized by frequency and severity and 
packing type. For the ordinal measures, mean differences and 95% confidence intervals 
for the difference will be calculated by packing type. Repeated measure models will be 
used to describe treatment’ effects over time and F-tests will be used to assess period 
affects. Graphical methods will aid in assessing model assumptions. 
 
 
 
 
 
11 REGULATORY AND OPERATIONAL CONSIDERATIONS 
 Regulatory and Ethical Considerations 
 Informed Consent Document  
Consent forms will be written in accord with federal regulations and will be reviewed and 
approved by the UVA IRB-HSR prior to use. Signed consent forms and other research 
records will be retained in a confidential manner. 
 Consent Procedures and Documentation 
Informed consent is a process that is initiated prior to the individual’s agreeing to 
participate in the study and continues throughout the individual’s study participation. 
Consent forms will be Institutional Review Board (IRB)-approved and the participant will 
be asked to read and review the document. A member of the study team will explain the 
research study to the participant and answer any questions that may arise. A verbal 
explanation will be provided in terms suited to the participant’s comprehension of the 
purposes, procedures, and potential risks of the study and of their rights as research 
participants.  Participants will have the opportunity to carefully review the written consent 
form and ask questions prior to signing. The participants should have the opportunity to 

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discuss the study with their family or surrogates or think about it prior to agreeing to 
participate. The participant will sign the informed consent document prior to any 
procedures being done specifically for the study. Results from procedures completed prior 
to consent for standard of care purposes may be used for research purposes. Participants 
must be informed that participation is voluntary and that they may withdraw from the study 
at any time, without prejudice. A copy of the informed consent document will be given to 
the participants for their records. The informed consent process will be conducted and 
documented in the source document (including the date), and the form signed, before the 
participant undergoes any study-specific procedures. The rights and welfare of the 
participants will be protected by emphasizing to them that the quality of their medical care 
will not be adversely affected if they decline to participate in this study. 
Doctors and physicists who plan to complete the Physician and Physicist Assessment 
Surveys are considered participants. A member of the study team will explain the research 
study and allow the individual to review the protocol. Doctor and physicist participants 
must be informed that participation is voluntary and that they may withdraw from the study 
at any time, without prejudice. Doctors and physicists will give verbal consent to 
participate.  
 Confidentiality and Privacy  
Participant confidentiality and privacy is strictly held in trust by the participating 
investigators, their staff, and the sponsor(s) and their interventions. This confidentiality is 
extended to cover testing of biological samples and genetic tests in addition to the clinical 
information relating to participants. Therefore, the study protocol, documentation, data, 
and all other information generated will be held in strict confidence. Consents will be 
maintained in a confidential manner in accordance with the code of federal regulations 
and HIPAA. When possible, specimens will be coded with IDs (not MRN or name). No 
information concerning the study or the data will be released to any unauthorized third 
party without prior written approval of the sponsor.  
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), regulatory agencies or pharmaceutical company 
supplying study product may inspect all documents and records required to be maintained 
by the investigator, including but not limited to, medical records (office, clinic, or hospital) 
and pharmacy records for the participants in this study. The clinical study site will permit 
access to such records. 
The study participant’s contact information will be securely stored at each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept 
in a secure location for as long a period as dictated by the reviewing IRB, Institutional 
policies, or sponsor requirements. 
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be entered and stored in the designated EDC System. This will include 
limited participant identifying information, including participants’ initials and dates of birth. 
Individual participants and their research data will be identified by a unique study 
identification number. The study data entry and study management systems used by 
clinical sites and UVA CC research staff will be secured and password protected.  

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Certificate of Confidentiality 
To further protect the privacy of study participants, a site may apply for a Certificate of 
Confidentiality. For NIH studies, this will automatically be issued by the National Institutes 
of Health (NIH) and an application is not necessary.  This certificate protects identifiable 
research information from forced disclosure. It allows the investigator and others who have 
access to research records to refuse to disclose identifying information on research 
participation in any civil, criminal, administrative, legislative, or other proceeding, whether 
at the federal, state, or local level. By protecting researchers and institutions from being 
compelled to disclose information that would identify research participants, Certificates of 
Confidentiality help achieve the research objectives and promote participation in studies 
by helping assure confidentiality and privacy to participants. 
 Safety Oversight 
The University of Virginia Cancer Center Data and Safety Monitoring Committee (CC 
DSMC) will provide oversight of the conduct of this study.  The CC DSMC will report to the 
UVA Protocol Review Committee (PRC). 
The UVA CC DSMC will review the following: 
 
All adverse events 
 
Audit results 
 
Application of study designed stopping/decision rules 
 
Whether the study accrual pattern warrants continuation/action 
 
Protocol violations 
The UVA CC DSMC will meet every month for aggregate review of data.  Tracking reports 
of the meetings are available to the PI for review.  Issues of immediate concern by the 
DSMC are brought to the attention of the sponsor (and if appropriate to the PRC and IRB) 
and a formal response from the sponsor is requested.  Per the UVA Cancer Center NIH 
approved institutional plan, this study will be audited approximately every 6 months.  The 
audit may include direct access to source data/documents. 
Any study under the purview of the University of Virginia IRB-HSR is subject to review of 
files at the University of Virginia. Studies are chosen for Post-approval Monitoring either 
a) at random or b) requested by a study team member or any member of the IRB-HSR.   
 
The purpose of Post-approval Monitoring audits is to ensure that documentation of clinical 
research studies is of the highest quality, verify protocol adherence, and ensure that all 
Federal and local rules concerning clinical research are being fulfilled.  Post-approval 
monitoring is done by staff within the office of the Vice President for Research (VPR) in 
accordance with their Standard Operating Procedures. The conduct of an on-site review 
may include but is not limited to: 
 
requests for progress reports from investigators, 
 
examinations of research records, including signed informed consent documents, 
protocol modifications, and unexpected, serious, and/or related adverse 
experience reports, 
 
contacts with research subjects, or 
 
observation of the consent process and/or research procedures. Examples of 
when observation of the consent process could occur are: 

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 
Full board IRB determines during review of a project that a conflict of 
interest exists such that the informed consent process should be observed 
by a neutral party; 
 
IRB is made aware of a complaint or concern with regard to the informed 
consent process; or 
 
IRB determines as a result of the monitoring process that the consent 
process is insufficient and education/training is required for conduct of 
consent. 
 
Limited monitoring will be conducted by a quality assurance team at the Allegheny Health 
Network. This includes the following patient related data such as eligibility review and data 
source verification. SAEs will also be reviewed by a safety team at the Allegheny Health 
Network. 
The quality assurance team does not review: 
        contacts with research subjects, or 
        observation of the consent process and/or research procedures. Examples of 
when observation of the consent process could occur are: 
        Full board IRB determines during review of a project that a conflict of 
interest exists such that the informed consent process should be observed 
by a neutral party; 
        IRB is made aware of a complaint or concern with regard to the informed 
consent process; or 
        IRB determines as a result of the monitoring process that the consent 
process is insufficient and education/training is required for conduct of 
consent. 
 Site Monitoring 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial 
participants are protected, that the reported trial data are accurate, complete, and 
verifiable, and that the conduct of the trial is in compliance with the currently approved 
protocol/amendment(s), with International Conference on Harmonisation Good Clinical 
Practice (ICH GCP), and with applicable regulatory requirement(s).  
 
The UVA Coordinating Center will implement ongoing monitoring activities 
for this study to ensure that Participating Institutions are complying with 
regulatory and protocol requirements, data quality, and subject safety. 
Monitoring will occur before the clinical phase of the protocol begins, 
continue during protocol performance and through study completion. 
 
• 
Monitoring may be conducted either remotely or on-site.  For remote visits, 
each institution will be required to provide redacted source documents for 
review or appropriate access to the EMR. The UVA CC will provide the 
Participating Institution with a follow-up letter following completion of the 
monitoring visit which should be maintained in the site regulatory files.  The 
schedule for monitoring may be adjusted according to subject accrual and 
data quality.  The Investigator will be notified in advance of each visit. 
 
•        Independent audits may be conducted by each institution according to 
institutional guidelines. Results of these audits may be requested by the 
UVA Coordinating Center. 

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 Quality Assurance and Quality Control 
Each clinical site will perform internal quality management of study conduct, data and 
biological specimen collection, documentation and completion according to institutional 
policies. 
 
Quality control (QC) procedures will be implemented beginning with the data entry system 
and data QC checks that will be run on the database will be generated. Any missing data 
or data anomalies will be communicated to the site(s) for clarification/resolution. 
 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the 
clinical trial is conducted and data are generated and biological specimens are collected, 
documented (recorded), and reported in compliance with the protocol, International 
Conference on Harmonisation Good Clinical Practice (ICH GCP), and applicable 
regulatory requirements.  
 
The investigational site will provide direct access to all trial related sites, source 
data/documents, and reports for the purpose of monitoring and auditing by the sponsor, 
and inspection by local and regulatory authorities. 
 Data Handling and Record Keeping  
 Data Collection and Management Responsibilities  
Data collection is the responsibility of the clinical trial staff at the site under the supervision 
of the site investigator. The investigator is responsible for ensuring the accuracy, 
completeness, legibility, and timeliness of the data reported.  
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data.   
Data will be collected using a password-protected, centralized electronic case report form 
system. Data recorded in the electronic case report form (eCRF) derived from source 
documents should be consistent with the data recorded on the source documents.  
 Study Records Retention  
Study documents should be retained for a minimum of 2 years after the date of the release 
for commercial distribution by the manufacturer or until at least 2 years have elapsed since 
the formal discontinuation of clinical development of the study intervention. These 
documents should be retained for a longer period, however, if required by local 
regulations. No records will be destroyed without the written consent of the sponsor, if 
applicable. It is the responsibility of the sponsor to inform the investigator when these 
documents no longer need to be retained. Record retention will be in accord with 21 CFR 
62 and HIPAA regulations. 
 Publication and Data Sharing Policy 
This study will be conducted in accordance with the following publication and data sharing 
policies and regulations: 
 

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National Institutes of Health (NIH) Public Access Policy, which ensures that the public has 
access to the published results of NIH funded research. It requires scientists to submit 
final peer-reviewed journal manuscripts that arise from NIH funds to the digital archive 
PubMed Central upon acceptance for publication. 
 Conflict of Interest Policy 
The independence of this study from any actual or perceived influence, such as by 
industry, is critical.  Therefore, any actual conflict of interest of persons who have a role in 
the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and 
managed. Furthermore, persons who have a perceived conflict of interest will be required 
to have such conflicts managed in a way that is appropriate to their participation in the 
design and conduct of this trial.  The study leadership in conjunction with the institution 
has established policies and procedures for all study group members to disclose all 
conflicts of interest and will establish a mechanism for the management of all reported 
dualities of interest. 
 
Dr. Timothy Showalter, an investigator for this study, is also the chief medical officer and 
founder of Brachyfoam, the manufacturer of the BrachyGel Vaginal Hydrogel Packing 
System used in this study. He will serve as a resource for study design and planning, but 
will not enroll patients, or supervise any students or trainees involved in research on this 
project as pertains to the data collection and analysis of results. He will administer 
brachytherapy during about half of the fractions administered at UVA. When he 
administers brachytherapy, he will not complete the physician questionnaire. In these 
instances, Dr. Romano will complete the part of the questionnaire related to completeness 
and imaging clarity of packing and the question related to ease of use will be left blank.  
 
 
 
 

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12 REFERENCES  
1 
Viswanathan, A. N., Thomadsen, B. & American Brachytherapy Soceity Cervical 
Cancer 
Recommendations 
Committee. 
American 
Brachytherapy Society 
consensus guidelines for locally advanced carcinoma of the cervix. Part I: General 
principles. Brachytherapy 11, 33-46 (2012). 
2 
Rai, B. et al. Bladder-rectum spacer balloon in high-dose-rate brachytherapy in 
cervix carcinoma. Int J Radiat Oncol Biol Phys 85, e217-e222 (2013). 
3 
Rai, B. et al. Bladder-rectum spacer balloon versus vaginal gauze packing in high 
dose rate brachytherapy in cervical cancer: A randomized study (Part II). Clinical 
Oncology 27, 713-719 (2015). 
4 
Eng, T. Y., Patel, A. J. & Ha, C. S. Rectal and bladder dose reduction with the 
addition of intravaginal balloons to vaginal packing in intracavitary brachytherapy 
for cervical cancer. Brachytherapy 15, 312-318 (2016). 
5 
Xu-Welliver, M. & Lin, L. L. Evaluation of a balloon-based vaginal packing system 
and patient-controlled analgesia for patients with cervical cancer undergoing high-
dose-rate intracavitary brachytherapy. Practical Radiat Oncol 3, 263-268 (2013). 
6 
Rockey, W. M., Bhatia, S. K., Jacobson, G. M. & Kim, Y. The dosimetric impact of 
vaginal balloon-packing on intracavitary high-dose-rate brachytherapy for 
gynecological cancer. J Contemp Brachytherapy 5, 17-22 (2013). 
7 
Bannerjee, R. & Kamrava, M. Brachytherapy in the treatment of cervical cancer: a 
review. Int J Womens Health 6, 555-564 (2014). 
8 
Bauer-Nilsen, K. et al. Evaluation of delivery costs for external beam radiation 
therapy and brachytherapy for locally advanced cervical cancer using time-driven 
activity-based costing. Int J Radiat Oncol Biol Phys 100, 88-94 (2018). 
9 
Lee, C. D. Recent developments and best practice in brachytherapy treatment 
planning. Br J Radiol 87, 20140146 (2014). 
10 
Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics. 2018. CA Cancer J Clin 
68, 7-30 (2018). 
11 
Trifiletti, D. M. et al. Implementing MRI-based target delineation for cervical cancer 
treatment within a rapid workflow environment for image-guided brachytherapy: A 
practical approach for centers without in-room MRI. Brachytherapy 14, 905-909, 
doi:10.1016/j.brachy.2015.07.005 (2015). 
12 
Trifiletti, D. M. & Showalter, T. N. Image-guided brachytherapy in cervical cancer: 
past, present and future. Future Oncol 11, 2629-2632, doi:10.2217/fon.15.196 
(2015). 
13 
Noakes, K. F., Pullan, A. J., Bissett, I. P. & Cheng, L. K. Subject specific finite 
elasticity simulations of the pelvic floor. J Biomech 41, 3060-3065 (2008). 

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14 
Moon, N. G., Pekkanen, A. M., Long, T. E., Showalter, T. N. & Libby, B. Thiol-
Michael ‘click’ hydrogels as an imageable packing material for cancer therapy. 
Polymer 125, 66-75 (2017). 
15 
Fokdal, L. et al. Physician assessed and patient reported urinary morbidity after 
radio-chemotherapy and image guided adaptive brachytherapy for locally 
advanced 
cervical 
cancer. 
Radiother 
Oncol 
127, 
423-430, 
doi:10.1016/j.radonc.2018.05.002 (2018). 
16 
Mazeron, R. et al. Dose-volume effect relationships for late rectal morbidity in 
patients treated with chemoradiation and MRI-guided adaptive brachytherapy for 
locally advanced cervical cancer: Results from the prospective multicenter 
EMBRACE 
study. 
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412-419, 
doi:10.1016/j.radonc.2016.06.006 (2016). 
17 
Jensen, N. B. K. et al. Bowel morbidity following radiochemotherapy and image-
guided adaptive brachytherapy for cervical cancer: Physician- and patient reported 
outcome from the EMBRACE study. Radiother Oncol 127, 431-439, 
doi:10.1016/j.radonc.2018.05.016 (2018). 
18 
Kirchheiner, K. et al. Dose-effect relationship and risk factors for vaginal stenosis 
after definitive radio(chemo)therapy with image-guided brachytherapy for locally 
advanced cervical cancer in the EMBRACE study. Radiother Oncol 118, 160-166, 
doi:10.1016/j.radonc.2015.12.025 (2016). 
19 
Romano, K. D. et al. High dose-rate tandem and ovoid brachytherapy in cervical 
cancer: dosimetric predictors of adverse events. Radiat Oncol 13, 129, 
doi:10.1186/s13014-018-1074-2 (2018). 
20 
Romano, K. D., Pugh, K. J., Trifiletti, D. M., Libby, B. & Showalter, T. N. Transition 
from LDR to HDR brachytherapy for cervical cancer: Evaluation of tumor control, 
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doi:10.1016/j.brachy.2016.12.005 (2017). 
21 
Delishaj, D. et al. Vaginal toxicity after high-dose-rate endovaginal brachytherapy: 
20 
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doi:10.5114/jcb.2018.79713 (2018). 
22 
Laliscia, C. et al. Acute and late vaginal toxicity after adjuvant high-dose-rate 
vaginal brachytherapy in patients with intermediate risk endometrial cancer: is local 
therapy with hyaluronic acid of clinical benefit? J Contemp Brachytherapy 8, 512-
517, doi:10.5114/jcb.2016.64511 (2016). 
 
 
 

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13 APPENDICES 
 Schedule of Activities (SoA) 
Procedures 
Screening 
(within 6 weeks of 
Brachytherapy 1) 
Brachytherapy 1 
Brachytherapy 2 
Brachytherapy 3 
Brachytherapy 4 
Brachytherapy 5 
30 Day  +/- 2 
weeks Safety 
Follow-up 
Informed consent 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Baseline conditions/assessment 
X2 
 
 
 
 
 
 
Randomization 
 
 
X5 
 
 
 
 
Brachytherapy1 
 
X4 
X 
X 
X 
X 
 
Physical exam  
X2 
 
 
 
 
 
X 
Performance status 
X2 
 
 
 
 
 
X 
Concomitant medications related to 
pain control during procedure7 
 
 
X 
X 
X 
X 
 
Physician Assessments of 
imaging/packing experience 
 
 
X 
X 
X 
X 
 
Physicist Assessments of 
imaging/packing experience 
 
X6 
X 
X 
X 
X 
 
Participant survey3 
 
 
X 
X 
X 
X 
 
Adverse event review and evaluation 
 
 
X---------------------------X 
X 
 
1 Alternations will be based on Arm Assignment according to Figure 1. 
 
2 Must occur within 30 days of Brachytherapy 1. The assessments can be collected on the same day 
as Brachytherapy 1.  
 
3 Participant survey should be completed without 1 hour following removal of packing after 
completion of brachytherapy. Not collected if participant was sedated. 
 
4 Brachytherapy 1 is considered to be a part of the screening visit. Brachytherapy 2 is considered 
to be the “start of treatment.” Brachytherapy 1 must occur within 14 days of registration.  
 
5 No sooner than 10 days before Brachytherapy 2.  
 
6 Only the dosimetry measurements need to be collected for Brachytherapy 1. 
 
7 Not collected if participant was sedated.  
 
 
 
 
 
 

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13.2 Physicist/Dosimetrist Case Report Form 
Date: ___________________ 
Subject ID: ___________________ 
Fraction: _____ of 5 
Packing Method: ___________________ 
Applicator: ___________________ 
 
 
Prescription dose: ______ Gy 
 
HR-CTV D90:    ______ Gy  
 
Bladder:  
 
 
 
 
Rectum:  
D0.1 cc: ______ Gy  
 
 
 
D0.1 cc: ______ Gy  
 
D1 cc:  ______ Gy  
 
 
 
D1 cc:  ______ Gy 
 
D2cc: ______ Gy   
 
 
 
D2cc:  ______ Gy  
 
 
 
1. Please rate the completeness of the packing by clearly selecting  the most 
appropriate response below: 
 
⃝ N/A (1st Brachytherapy Fraction) 
⃝ Excellent filling of space 
⃝ Good filling of space 
⃝ Fair filling of space 
⃝ Poor filling of space 
 
2. Please rate the imaging clarity of the packing (i.e. ability to discern packing from pelvic 
organs) by clearly selecting  the most appropriate response below: 
 
⃝ N/A (1st Brachytherapy Fraction) 
⃝ Very clear distinction between packing and OARs (organs at risk) 
⃝ Clear distinction between packing and OARs (organs at risk) 
⃝ Poor distinction between packing and OARs (organs at risk) 
⃝ No distinction between packing and OARs (organs at risk) 
 
 
_________________________ 
_________________________ 
___________ 
Print Name 
 
 
 
Signature 
 
 
 
Date 
SIGN

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 Participant Packing Discomfort Assessment / Evaluación de la Incomodidad 
del Empaque de la Participante 
Date/Fecha: ___________________ 
Subject ID/ ID del Sujeto: ___________________ 
Fraction/ Fracción: _____ of 5 
Packing Method/ Método de Empaque: ___________________ 
Applicator/ Aplicador: ___________________ 
 
1. 
Please rate your discomfort during the entire brachytherapy treatment. / Califique 
su malestar durante todo el tratamiento de braquiterapia 
 
⃝ No discomfort/ Sin molestias 
⃝ Mild discomfort/ Molestias leves 
⃝ Moderate discomfort/ Molestias moderadas 
⃝ Severe discomfort/ Molestias severas 
 
 
2. 
Please rate your discomfort during the vaginal packing placement and removal. /  
Califique su molestia durante la colocación y extracción del empaque vaginal.  
 
⃝ No discomfort/ Sin molestias 
⃝ Mild discomfort/ Molestias leves 
⃝ Moderate discomfort/ Molestias moderadas 
⃝ Severe discomfort/ Molestias severas 
 
 
Questionnaire Completed by/ Cuestionario completado por:    
 ⃝ Participant/ Participante  
⃝ Administrator/ Administrador 
 
 
____________________________  
_________________________ 
___________ 
Print Name/ Escriba su Nombre 
  
Signature/ Firma 
 
 
Date/Fecha 
 
 
SIGN

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 Physician Case Report Form 
Date: ___________________ 
Subject ID: ___________________ 
Fraction: _____ of 5 
Packing Method: ___________________ 
Applicator: ___________________ 
 
1. Please rate the completeness of the packing by clearly selecting the most 
appropriate response below: 
 
⃝ Excellent filling of space 
⃝ Good filling of space 
⃝ Fair filling of space 
⃝ Poor filling of space 
 
2. Please rate the imaging clarity of the packing (i.e. ability to discern packing from pelvic 
organs) by clearly selecting  the most appropriate response below: 
 
⃝ Very clear distinction between packing and OARs (organs at risk) 
⃝ Clear distinction between packing and OARs (organs at risk) 
⃝ Poor distinction between packing and OARs (organs at risk) 
⃝ No distinction between packing and OARs (organs at risk) 
 
3. Please rate the ease of packing placement and removal by clearly selecting the most 
appropriate response below: 
 
⃝ Extremely easy 
⃝ Somewhat easy 
⃝ Somewhat difficult 
⃝ Extremely difficult 
⃝ Unable to rate 
 
 
_________________________ 
_________________________ 
___________ 
Print Name 
 
 
 
Signature 
 
 
 
Date
SIGN

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13.5 Protocol Amendment History 
Version Date: from 3/31/2021 to 11/16/2021 
Section(s)
Description of Change 
Title Page, Key Roles and Study 
Governance, ABBREVIATIONS,  
1.1 Synopsis,  
4.1 Overall Study Design,  
10.2 Randomization and 
Stratification,  
11.1.4 Safety Oversight 
Updated site contact information and changed UPMC to AHN. 
Rationale: UPMC has not/will not be participating as an additional site for the trial. The additional 
site has been changed to AHN. 
8.2 Participant reported 
outcomes 
Reworded to include the options for completing the participant 
surveys. Participants can either complete a paper survey of the 
questions or a team member can read the questions/answers 
and record the participant’s selections.  
Rationale: For flexibility, there is no impact in having participants answer the questions on paper 
independently.
9.1.1 Definition of Adverse 
Events (AE) 
Redefined AEs to be any untoward medical occurrence 
associated (at least possibly related) with the use of the study 
intervention(s) 
Rationale:  The new definition streamlines the capture of AEs without underreporting. This 
definition captures pertinent standard clinical care and intervention related AEs of any category.
9.1.7 Serious Adverse Event 
Reporting,  
9.2.2 Reporting of UADE, 9.5.2 
Unanticipated Problem Reporting,  
9.6.2 Reporting a Data Breach,  
9.7.3 Reporting of a Protocol 
Deviation or Exception
Restructured the reporting guidelines to specify which entities 
perform which requirements based on site type. 
Rationale: For clarity on which requirements are performed by the UVA Coordinating Center and 
which are performed by the UVA site study team.  
10.4 Sample Size and Accrual 
Changed the total maximum enrollment goal from 70 to 57 
Rationale: To better align with the study budget.  
13.1 Schedule of Activities 
(SoA) 
Updated calendar footnotes and increased timeframe for the 
collection of baseline physical exam, performance evaluation 
and conditions from within 3 days of Brachytherapy 1 to 
30days. 
Rationale:  For clarity and to align with SOC practice.  
13.2 Physicist/Dosimetrist Case 
Report Form,  
13.3 Participant Packing 
Discomfort Assessment, 13.4 
Physician Case Report Form 
Updated formatting of Questionnaires and added Spanish 
translation to the participant discomfort survey. 
Rationale:  For functionality and to allow Spanish speaking participants the option to complete the 
survey questions on paper independently.
 
Version Date: from 6/25/2020 to 3/31/2021 
Section(s)
Description of Change 
1.2 Schema 
5.8 Registration and 
Randomization 
Removed “after 1st fraction of brachytherapy” from the 
randomization time limit. The randomization timeframe  is “10 days 
prior to 2nd fraction” 

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9.2 Randomization and 
stratification 
Rationale: For flexibility as there is no statistical reason to limit randomization to after the 
first brachytherapy. 
5.1 Inclusion Criteria 
5.2 Exclusion Criteria 
 
Updated Inclusion criteria 2 and exclusion criteria 1 & 3 to clarify 
that radiation therapy that is a part of the patient’s current definitive 
treatment plan for the cancer of interest is acceptable 
Rationale: It is common for the study’s patient population to receive a combination of EBRT, 
brachytherapy and chemotherapy as definitive treatment. The intent is to not exclude individuals 
receiving other therapies that are a part of their current treatment plan for cervical cancer.
Abbreviations 
5.1 Inclusion Criteria 
8.1.1 Physical Exam 
Changed KPS to KPS or ECOG 
Rationale: For flexibility based on standard practice 
5.5 Description of Study 
intervention 
Added a description of the Arm assignments and details about 
fraction 1. 
Rationale: To provide additional clarity on the assignments and to align this section with section 
4.1 
6.3 Product Storage and 
Stability 
Added “after manufacture” 
Rationale: For additional clarity on the expiration of the device. 
5.8 Registration and 
Randomization 
Added statement “eligibility and registration can occur after 1st 
fraction but before 2nd fraction” 
Rationale: The first fraction is considered a “screening procedure” and the second is considered 
the start of treatment. Eligibility confirmation and registration do not need to occur before the first 
fraction.
7.2 Participant reported 
outcomes 
7.3 Physicist and Physician 
reported outcomes 
9.3.2 Study Outcomes & 
Endpoints 
Added “both standard and BrachyGel” 
Reworded “period” to “fraction 2-5” 
Added statement about only dosimetry measurements data will be 
collected from Fraction 1 
Added statement that sedated patients will not be asked the patient 
survey questions 
Rationale: Patient and doctor/physicist surveys only need to be completed starting at fraction 2 
since fraction 2 is considered the start of treatment.  Fraction 1 is considered a part of “screening” 
and the dosimetry values collected will be used as baseline values per section 9.1. Since the 
participant reported outcomes are exploratory, sedated patients can still be enrolled as data for the 
primary endpoints can still be collected.
8.1.4 Abnormal Laboratory 
Values 
8.1.5 
Time 
Period 
& 
Frequency 
 
for 
Event 
Assessment & Follow up 
Reworded to state that Abnormal laboratory values will not be 
considered AEs and will not be recorded or reported 
Rationale: Lab values are not being collected or assessed for the study. Lab values are typically 
not collected for brachytherapy as SOC.  
10.1.2 Consent Procedures 
and Documentation 
Added verbal consenting information for doctors and physicists 
Rationale: Doctors and physicists who plan to complete the Physician and Physicist Assessment 
Surveys are considered participants. Verbal informed consent needs to be obtained 
11.2.1 Data Collection and 
Management 
Responsibilities 
Removed references to Oncore as the eCRF system 
Rationale: Oncore is no longer the primary system being used for IIT eCRFs 

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11.4 Conflict of Interest 
Policy 
Dr. Showalter was shifted from Medical Monitor to Sub-Investigator 
Rationale: Consistency with his corrected role  
12.1 Schedule of Events 
Footnotes 4-6 were added and Footnote 3 updated to account for 
sedated patients 
Rationale: To align with the changes made throughout the document 
12.1 Schedule of Events 
Concomitant  medication review removed from Brachytherapy 1 
Rationale:  Patients are always sedated for Brachytherapy 1 therefore not pain control medications 
would be administered during the procedure.
12.1 Schedule of Events 
Added a +/- 2 week window to the 30 day safety follow up 
Rationale: For flexibility and clarity to account for changes in patient scheduling. 
12.2 
Physicist/Dosimetrist 
CRF 
12.4 Physician CRF 
Reworded “circling” to “clearly selecting” in all of the survey 
questions 
Rationale: To allow electronic completion of CRFs
Abbreviation Table 
5.8 Registration and 
Randomization 
8.1.6 AE Reporting 
10.1.3 Confidentially & 
Privacy 
Reworded “Oncore” references to “ designated EDC system” 
Rationale: Oncore is no longer the exclusive data entry system for the study.  
8.1.5 Time Period & 
Frequency  for Event 
Assessment & Follow up 
12.1 Schedule of Events 
Updated start of AE recording and reporting from time “informed 
consent  was obtained” to “after the completion of the brachytherapy 
fraction 2” 
Rationale: Brachytherapy 2 is considered the start of treatment. The time in between informed 
consent and Brachytherapy 2 is considered screening. All abnormalities occurring during that 
timeframe are considered baseline conditions. 
9.4 Sample size and 
Accrual 
Updated the patient and oncologist/physicist accrual goals.  
Rationale: Added for clarity 
5.1 Inclusion Criteria 
Removed  Inclusion criteria #4 “ ability to read and write English or 
Spanish”  
Rationale: Patient participants do not need to read or write for the study since the patient comfort 
survey is verbally presented to the patient. Any non-English speaking patient can enroll as long as 
the patient can be properly consented and there is an acceptable interpreter for the subject’s native 
language.  
9.7.2 Protocol Exceptions 
Added section and definition 
Rationale: Inadvertently omitted from previous versions. This section is applicable since this is a 
multisite study.
 
 
 
Version Date: 25 June 2020 
Section(s)
Description of Change 

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Key 
Roles 
and 
Study 
Governance 
Dr. Showalter was shifted from Medical Monitor to Sub-Investigator 
Rationale: Dr. Showalter needs to be able to participate as a sub-investigator in order to perform 
brachytherapy and cannot serve as both the medical monitor AND a co-investigator. 
1.1 Synopsis 
5.1 Inclusion Criteria 
Expanded the range of stages to include IB1 and IVB 
Rationale: While uncommon, patients with these stages of disease may receive brachytherapy as 
definitive treatment for cervical cancer and there is no reason to exclude them from participation 
6.5 Concomitant Therapy 
Changed “during the procedure” to “for the procedure” 
Rationale: In some cases pain medication for the procedure may be given prior to the procedure 
or just following, and this should also be captured. 
13.1 Schedule of Activities 
(SOA) 
“Medical History” was updated to “Baseline conditions/assessment” 
Rationale: A true history is not necessary, but an assessment of baseline conditions is required in 
order to assess adverse events