Study to Calculate the Radiation-Absorbed Dose of Technetium-99m Macroaggregated Albumin (99mTc-MAA) to the Whole Body and Non-Liver Critical Organs
Phase: PHASE4
Conditions: Carcinoma, Carcinoma, Hepatocellular, Liver Neoplasm
Sponsor: Sirtex Medical

Sirtex Medical Inc. 
Document ID: STX2301 
MAApping Clinical Study Protocol 
Revision: A 
99mTc-MAA & SIR-Spheres® Y-90 resin microspheres 
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Study to Calculate the Radiation-Absorbed Dose of Technetium-99m 
Macroaggregated Albumin (99mTc-MAA) to the Whole Body and Non-
Liver Critical Organs (MAApping Study) 
Clinical Study Protocol 
Study Protocol Number: STX2301 
ClinicalTrials.gov Number: NCT05848947
Revision: A, 01Mar2023 
Sirtex Medical Inc. 
300 Unicorn Park Drive 2nd Floor 
Woburn, MA 01801 
Tel: 781-721-3800 
THIS STUDY PROTOCOL CONTAINS CONFIDENTIAL INFORMATION FOR USE BY THE INVESTIGATORS 
AND THEIR DESIGNATED REPRESENTATIVES PARTICIPATING IN THE STUDY. IT SHOULD BE HELD 
CONFIDENTIAL AND MAINTAINED IN A SECURE LOCATION. IT SHOULD NOT BE COPIED OR MADE 
AVAILABLE FOR REVIEW BY ANY UNAUTHORIZED PERSON OR FIRM. 

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CLINICAL STUDY PROTOCOL SYNOPSIS 
Sirtex Medical Study Number: STX2301 
Study Title 
Study to Calculate the Radiation-Absorbed Dose of Technetium-99m 
Macroaggregated Albumin (99mTc-MAA) to the Whole Body and Non-Liver 
Critical Organs (MAApping Study) 
Identifying 
Regulatory Numbers 
Clinicaltrials.gov – NCT05848947 
Study Objective 
To evaluate the dosimetry of 99mTc-MAA after intra-arterial administration to the 
whole body and non-liver critical organs. 
Product Description 
Technetium-99m macroaggregated-albumin consists of macroaggregated-
albumin particles labeled with technetium-99m (99mTc ), with a size between 10 
and 90 microns in diameter. 99mTc is a gamma emitting radioactive isotope 
commonly used for diagnostic localization studies.  
Study Design 
The investigation is a prospective, single center, open label, single-arm study.  
Patients enrolled in the study will have 3 imaging scans taken after 99mTc-MAA 
injection, the final of which will occur between 18 and 24 hours post-injection. 
Number of Sites & 
Subjects 
The study will be conducted at one clinical site in the United States and will 
enroll 5 subjects. 
Study Population 
The intended population for the study is patients who are undergoing evaluation 
for SIR-Spheres administration. All subjects enrolled will already be planned to 
receive 99mTc-MAA per clinical standard of care, and the decision to offer 
enrollment in the study will occur only after the decision to deliver 99mTc-MAA 
for SIRT planning has already been made. 
Endpoints 
1.
Mean absorbed dose (Gy) for the whole body
2.
Mean absorbed dose (Gy) for critical non-liver organs
3.
Mean activity (Bq) for the whole body
4.
Mean activity (Bq) for critical non-liver organs
5.
Effective dose (Gy) for the whole body
Study Eligibility 
Criteria 
Subjects must meet all the following inclusion criteria: 
1.
Willing, able, and mentally competent to provide written informed consent
2.
Age 18 or older at the time of consent
3.
Patients who are being evaluated for SIR-Spheres treatment eligibility
Subjects must not meet any of the following exclusion criteria: 
1.
Patients who are contraindicated for SIR-Spheres treatment
2.
Patients who are contraindicated for 99mTc-MAA per the manufacturer’s
package insert

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MAApping Clinical Study Protocol 
 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
Sirtex Medical Study Number: STX2301  
Study Duration 
Enrollment is expected to take approximately 2 months. Each study subject will 
actively participate in the study through 24-hour follow-up. The overall study 
duration, from screening the first patient to the final follow-up visit, data 
analysis, and final report, is expected to be approximately 3 months. 
Study Sponsora 
Sirtex Medical Inc. 
300 Unicorn Park Drive, 2nd Floor 
Woburn, MA 01801 
Study Site 
Inland Imaging 
5715 N Lidgerwood 
Spokane, WA 99208 
Contract Research 
Organization (CRO) 
BRIGHT Research Partners 
730 2nd Avenue South, Suite 500 
Minneapolis, MN 55402 
 
 
 
 
 
a Detailed contact information is maintained in a separate Sponsor Contact List managed by the CRO 

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TABLE OF CONTENTS 
1.0 
ABBREVIATIONS ............................................................................................................... 8 
2.0 
CLINICAL BACKGROUND ............................................................................................... 10 
3.0 
REGULATORY CLASSIFICATION .................................................................................. 10 
4.0 
99MTC MAA DESCRIPTION .............................................................................................. 12 
4.1 
Principle of Operation / Mechanism ............................................................................. 12 
5.0 
OBJECTIVE ...................................................................................................................... 13 
6.0 
ENDPOINTS ..................................................................................................................... 13 
6.1 
Primary Endpoints ......................................................................................................... 13 
6.2 
Rationale for Study Endpoints ...................................................................................... 13 
7.0 
STUDY DESIGN ............................................................................................................... 14 
7.1 
Overall Design .............................................................................................................. 14 
7.2 
Number of Sites & Subjects .......................................................................................... 14 
7.3 
Study Population ........................................................................................................... 14 
7.4 
Study Duration .............................................................................................................. 14 
7.5 
Subject Eligibility Criteria .............................................................................................. 14 
7.5.1 
Inclusion Criteria ....................................................................................................... 14 
7.5.2 
Exclusion Criteria ...................................................................................................... 14 
8.0 
STUDY METHODOLOGY ................................................................................................ 14 
8.1 
Screening Visit .............................................................................................................. 16 
8.1.1 
Informed Consent Process ....................................................................................... 16 
8.1.2 
Vulnerable Population ............................................................................................... 17 
8.2 
Point of Enrollment & Numbering of Study Subjects .................................................... 17 
8.3 
Procedure Visit .............................................................................................................. 17 
8.4 
Subject Follow-Up (3 timepoints: 0-2 hours, 6-10 hours & 18-24 hours) .................... 17 
8.4.1 
SPECT/CT Acquisition Protocol ............................................................................... 18 
8.4.2 
Imaging Analysis ....................................................................................................... 18 
8.5 
Early Withdrawal/Premature Discontinuation of Subjects ............................................ 18 
8.5.1 
Subject Replacement ................................................................................................ 19 
9.0 
STATISTICAL METHODS ................................................................................................ 19 
9.1 
Analysis Data Sets ........................................................................................................ 19 

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9.2 
General Principles ......................................................................................................... 19 
9.3 
Analysis of Primary Endpoints ...................................................................................... 19 
9.4 
Safety Analysis ............................................................................................................. 20 
10.0 
MEASURES TO AVOID & MINIMIZE BIAS ..................................................................... 20 
11.0 
BENEFITS & RISK ANALYSIS ......................................................................................... 20 
11.1 
Potential Benefits of Study Participation ...................................................................... 20 
11.2 
Potential Risks Associated with Study Participation .................................................... 20 
11.3 
Methods to Minimize Risks ........................................................................................... 20 
12.0 
ADVERSE EVENTS ......................................................................................................... 21 
12.1 
Adverse Event Definitions............................................................................................. 21 
12.2 
Adverse Event Collection & Documentation ................................................................ 21 
12.3 
Adverse Event Reporting Timeframes ......................................................................... 21 
12.4 
Adverse Event Severity ................................................................................................ 22 
12.5 
Adverse Event Relatedness ......................................................................................... 22 
13.0 
ADMINISTRATIVE PROCEDURES ................................................................................. 23 
13.1 
Records & Reports........................................................................................................ 23 
13.1.1 Case Report Forms................................................................................................... 23 
13.1.2 Sponsor / CRO Study Records ................................................................................. 23 
13.1.3 Investigator Study Records....................................................................................... 23 
13.1.4 Investigator Reporting Requirements ....................................................................... 24 
13.1.5 Record Storage & Retention ..................................................................................... 24 
13.2 
Data Management ........................................................................................................ 24 
13.3 
Product Accountability .................................................................................................. 24 
13.4 
Site Qualification & Selection ....................................................................................... 25 
13.5 
Site Training .................................................................................................................. 25 
13.6 
Site Monitoring .............................................................................................................. 25 
13.7 
Institutional Review Board (IRB)................................................................................... 25 
13.8 
Protocol Deviations ....................................................................................................... 26 
13.9 
Protocol Amendments .................................................................................................. 26 
13.10 
Study Suspension or Termination ................................................................................ 26 
13.11 
Subject Confidentiality .................................................................................................. 27 
13.12 
Audits & Inspections ..................................................................................................... 27 
13.13 
Statements of Compliance............................................................................................ 27 

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13.14 
Finance & Agreements ................................................................................................. 27 
13.15 
Publications & Public Disclosure .................................................................................. 27 
13.16 
Study Contacts .............................................................................................................. 28 
14.0 
DEFINITIONS ................................................................................................................... 28 
15.0 
REFERENCES ................................................................................................................. 30 
16.0 
REVISION HISTORY ........................................................................................................ 30 
 
LIST OF FIGURES 
Figure 1: Study Flow Diagram ...................................................................................................... 15 
 
 
LIST OF TABLES 
Table 1: Schedule of Study Activities ........................................................................................... 16 
Table 2: Investigator Reporting Requirements............................................................................. 24 
 
 

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7.0 
STUDY DESIGN 
7.1 
Overall Design 
The investigation is a prospective, single center, open label, single-arm study. Patients enrolled 
in the study will have 3 imaging scans taken after 99mTc-MAA injection, the final of which will 
occur between 18 and 24 hours post-injection. 
7.2 
Number of Sites & Subjects 
The study will be conducted at one clinical site in the United States and will enroll 5 subjects.  
7.3 
Study Population 
The intended population for the study is patients who are undergoing 99mTc-MAA injection as 
evaluation for subsequent SIRT.  All subjects enrolled will already be planned to receive 99mTc-
MAA per clinical standard of care, and the decision to offer enrollment in the study will occur 
only after the decision to deliver 99mTc-MAA for SIRT planning has already been made. 
7.4 
Study Duration 
Enrollment is expected to take approximately 2 months. Each study subject will actively 
participate in the study through 24-hour follow-up. The overall study duration, from screening 
the first patient to the final follow-up visit, data analysis, and final report, is expected to be 
approximately 3 months. 
7.5 
Subject Eligibility Criteria 
7.5.1 Inclusion Criteria 
Subjects must meet all the following inclusion criteria: 
1. Willing, able, and mentally competent to provide written informed consent 
2. Age 18 or older at the time of consent 
3. Patients who are being evaluated for SIR-Spheres treatment eligibility 
7.5.2 Exclusion Criteria 
Subjects must not meet the following exclusion criteria: 
1. Patients who are contraindicated for SIR-Spheres treatment 
2. Patients who are contraindicated for 99mTc-MAA per the manufacturer’s package insert 
8.0 
STUDY METHODOLOGY 
Study assessments and data collection points are visually represented in Figure 1 and Table 1 
and are described below. Study procedures should be followed as they have been designed to 
address any known or foreseeable factors that may compromise the outcome of the clinical 
study or the interpretation of results (e.g., subject baseline characteristics, concomitant 

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medication, the use of medical devices, and subject-related factors such as age, gender, or 
lifestyle) and methods for addressing these factors (e.g., subject selection, statistical analysis). 
Figure 1: Study Flow Diagram 
 

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The site will retain the original signed ICF in the subject’s study records and will provide a copy 
of the ICF to the subject. The site will document the consent process (e.g., that the subject was 
consented, the date on which the consent was obtained, that a copy of the signed ICF was 
given to the subject, and that no study procedures were conducted prior to obtaining consent) in 
the subject’s medical records.  
Subjects will be informed of any new information that may make him/her change their mind 
about staying in the study. Subjects may be asked to sign a new ICF if this occurs. 
8.1.2 Vulnerable Population 
To preserve the ethical integrity of this study, the sponsor does not intend to enroll vulnerable 
subject populations (e.g., incarcerated persons or adults with severe cognitive challenges) in 
this study since such populations may be coerced or compelled to participate in a clinical study 
without a full understanding or against their will these subjects should be excluded (in 
consideration of 21 CFR 56.111(b)).  
8.2 
Point of Enrollment & Numbering of Study Subjects 
A patient will be considered enrolled as a study subject when the investigator deploys any 
release of the 99mTc-MAA into the patient. The lowest available subject number will be assigned, 
progressing sequentially for each enrolled subject thereafter. 
8.3 
Procedure Visit 
The intra-hepatic 99mTc-MAA infusion and scan will be conducted by a trained interventional 
radiologist; steps are briefly outlined below.  
• 
Establish the anticipated treatment volume using angiography assessed by imaging 
(e.g., cone beam CT) 
• 
Select the hepatic artery with a microcatheter corresponding to the anatomical area of 
interest, and in a position that will simulate treatment with SIR-Spheres Y-90 resin 
microspheres 
• 
Attach a syringe containing 150 MBq of 99mTc-MAA and infuse it into the hepatic artery 
via the microcatheter 
• 
Flush and remove the microcatheter  
• 
Transfer the patient to nuclear medicine for SPECT/CT imaging within 2 hours   
An adverse event (AE) assessment will be performed and the results will be recorded on the AE 
case report form (CRF). 
8.4 
Subject Follow-Up (3 timepoints: 0-2 hours, 6-10 hours & 18-24 hours)  
Subjects will be evaluated at the three specified imaging timepoints post- 99mTc-MAA injection. 
The assessments described below will be performed at each timepoint, and results will be 
recorded on the relevant eCRFs. 

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• 
Adverse event 
• 
Investigator decision 
If a subject is withdrawn from the study early, a Study Completion CRF must be completed to 
describe the reason for early withdrawal. In situations where study withdrawal is due to an 
adverse event, subjects will be followed until resolution of the adverse event or determination 
that the subject’s condition is stable. 
If a subject chooses to withdraw from the study and also withdraws consent for disclosure of 
further information, no further study assessments should be performed and no additional data 
collected. The sponsor may retain and continue to use any data collected prior to the withdrawal 
of consent. 
8.5.1 Subject Replacement 
If a subject is withdrawn prior to the 24-hour follow-up, they will be replaced. Subject numbering 
will proceed as described in Section 8.2. 
9.0 
STATISTICAL METHODS 
9.1 
Analysis Data Sets 
The primary analysis will consist of all available data on all subjects enrolled, referred to in 
International Conference on Harmonisation (ICH) E9 Statistical Principles for Clinical Trials as 
the full analysis set. As the study is a treatment-only, single arm design, comparisons between 
treatment and control groups are not pertinent, and summaries of results will principally be 
presented for the entire study population. 
9.2 
General Principles 
Continuous data will be summarized using the following descriptive statistics: mean, standard 
deviation, median, and range or interquartile range. Categorical variables will be summarized 
using frequency counts and percentages. For events that can occur more than once in a single 
subject, such as AEs, the percentage will be based on the number of subjects experiencing the 
event; both subject and event counts will be reported. 
All statistical analyses will be performed using SAS (version 9.4 or higher, SAS Institute Inc. 
Cary, NC), R (version 3.2 or higher, R Foundation for Statistical Computing, Vienna, Austria) or 
other widely accepted statistical or graphical software. 
9.3 
Analysis of Primary Endpoints 
The primary endpoints are defined in Section 6.1 and will be presented descriptively under the 
general principles cited above. Summary statistics for each endpoint will be reported at each of 
the three timepoints at which they are measured, thereby obtaining activity (GBq) and dose (Gy) 
over time related to 99mTc-MAA as part of SIRT planning. As the study is nonrandomized, 
summary statistics of primary interest are those for the enrolled population as a whole and 

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evaluation of subgroups is not planned a priori and no hypothesis testing against predefined null 
hypotheses or between subgroups is expected. 
9.4 
Safety Analysis 
An overall summary of severe adverse events (AEs, grade ≥3) that occur over the 24-hour 
period of the study will be presented. The summary will include the number and percentage of 
subjects with at least one AE and the total number of AEs. Complete subject listings of all site-
reported AEs will be provided. 
AEs will additionally be classified according to Common Terminology Criteria for Adverse 
Events (CTCAE) v5.0 terms, summarized by severity, relationship to the m99Tc-MAA study, 
outcome, and seriousness. Serious adverse events (SAEs) will be summarized according to 
severity and relationship. Multiple occurrences of the same AE are counted once at the 
maximum grade. 
10.0 MEASURES TO AVOID & MINIMIZE BIAS 
The study has several measures that have been implemented to avoid and minimize bias, 
including use of an independent CRO for study operations management, monitoring, and data 
management. 
11.0 BENEFITS & RISK ANALYSIS 
11.1 
Potential Benefits of Study Participation 
There are no guaranteed benefits from participation in this study. There is no obligation for a 
patient to take part in this study. As an alternative to participation, patients may choose to 
receive standard of care mapping procedures while being evaluated for SIR-Spheres eligibility. 
11.2 
Potential Risks Associated with Study Participation 
Risks associated with 99mTc-MAA mapping procedure will be listed in the site’s procedure 
consent form used per their standard of care.  
Two non-standard of care SPECT/CT scans will be conducted for this study, which involves 
additional exposure to ionizing radiation. Ionizing radiation exposure risks include a very small 
increase in the likelihood that a person exposed to radiation will develop cancer later in life. 
However, the doses used in CT examinations are 10 to 100 times lower than the dose levels 
that have been reported to increase the risk of cancer (McCollough). 
11.3 
Methods to Minimize Risks 
99mTc-MAA is a well-known and well characterized radiopharmaceutical. Only authorized users 
with training and licensure per 10 CFR 35.290 can order 99mTc as a radioisotope to be used for 
imaging and localization.  

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In addition, risks will be further minimized through careful subject screening and selection, 
training of investigators and study staff, adherence to the scheduled assessments, and regular 
monitoring visits.  
12.0 ADVERSE EVENTS 
12.1 
Adverse Event Definitions 
Adverse events (AEs) will be adjudicated for severity, seriousness, and for relatedness to the 
m99Tc-MAA drug and m99Tc-MAA procedure. Refer to Section 14.0 for AE definitions. 
12.2 
Adverse Event Collection & Documentation 
Collection of AEs will start on the day of the procedure for enrolled subjects and will be 
assessed and reported throughout the study. Investigators must obtain all information available 
to determine the seriousness, relatedness, and outcome of the adverse event. All AEs will be 
followed until resolution or investigator determination that the subject’s condition is stable. 
All reported AEs will be documented on the AE eCRF. Copies of de-identified source 
documentation that contain significant information related to the event (e.g., progress notes, 
consultations, nurse’s notes, operative reports, subject summaries) may be requested by the 
sponsor and CRO as needed for evaluation. 
The following are not considered AEs for this study: 
• 
Any condition that is recorded as pre-existing on the Baseline eCRF, unless there is a 
worsening of that condition in terms of nature, severity, or degree of incidence. 
• 
Planned hospitalization for pre-existing conditions or a procedure required by the 
protocol, without serious deterioration in health.  
• 
AEs arising from vascular access (e.g., hematoma, pseudoaneurysm, etc.), catheter 
selection (e.g., rupture, dissection, thrombosis). 
12.3 
Adverse Event Reporting Timeframes 
The investigator is responsible for reporting SAEs to the IRB in accordance with the IRB’s 
procedures. 
• 
Investigator Report: If a subject experiences a reportable AE the investigator must 
notify the sponsor/CRO and the reviewing IRB immediately. 
• 
Postmarketing safety reports: Applicants (individual or corporate entity that holds an 
NDA) are required to submit post-marketing safety reports to the FDA for human drug 
products with approved NDAs (§ 314.80). 

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12.4 
Adverse Event Severity 
The severity of an AE is a qualitative judgment of the degree of intensity, as determined by the 
investigator. The severity of the AE should be evaluated according to CTCAE v5.0. In the event 
a new version is released, this study will continue to use CTCAE v5.0. Refer to the severity of 
the AE – CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for 
each AE based on this general guideline. 
• 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
• 
Grade 2: Moderate; minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental Activities of Daily Living (ADL) 
o Instrumental ADL: Preparing meals, shopping for groceries and clothes, using 
the telephone, managing money, etc. 
• 
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL 
o Self-Care ADL: Bathing, dressing and undressing, feeding self, using the 
toilet, taking medications, and not bedridden 
• 
Grade 4: Life-threatening consequences; urgent intervention indicated 
• 
Grade 5: Death related to AE 
The assessment of severity should be made independent of the relatedness to the device and 
procedure or the seriousness of the event. CTCAE grading information is available at 
https://ctep.cancer.gov/protocoldevelopment/electronic applications/docs/CTCAE v5 Quick R
eference 5x7.pdf  
12.5 
Adverse Event Relatedness 
The investigator will assess the relatedness of the AE to 99mTc-MAA drug and the 99mTc-MAA 
mapping procedure using the categories listed below (see Section 14.0 for definitions): 
• 
Definitely 
• 
Probably 
• 
Possibly 
• 
Unlikely 
• 
Not Related 

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13.0 ADMINISTRATIVE PROCEDURES 
13.1 
Records & Reports 
13.1.1 Case Report Forms 
Worksheets will be used to collect subject data that is not readily available from the source 
documentation. An electronic data capture (EDC) system will be used to collect study-required 
data on eCRFs. The principal investigator (PI) at the site is responsible for ensuring eCRFs are 
accurate and completed in a reasonable timeframe. The PI is required to review and approve 
the eCRF on the appropriate page(s) to verify the completeness, accuracy, and authenticity of 
the recorded data.  
13.1.2 Sponsor / CRO Study Records 
The sponsor and CRO are responsible for maintaining study records and reports per applicable 
ICH Good Clinical Practices (GCP), FDA regulations, and applicable standard operating 
procedures and study-specific plans (e.g., Monitoring Plan, Data Management Plan, Training 
Plan, and Statistical Analysis Plan). 
13.1.3 Investigator Study Records 
The investigator will securely maintain the following accurate, complete, and current records 
relating to their participation in the study as follows: 
• 
All essential correspondence that pertains to the investigation. 
• 
Records of each subject’s case history and exposure to 99mTc-MAA during the study. 
Case histories include the CRFs and supporting data including, for example, signed and 
dated ICFs and medical records including, for example, progress notes of the physician, 
the individual’s hospital chart(s), and the nurses’ notes. Such records will include: 
o Documents evidencing the informed consent process. The case history of each 
subject will document that informed consent was obtained at the appropriate time. 
o All relevant observations, including records concerning AEs (whether anticipated or 
unanticipated), information and data on the condition of each subject upon entering, 
and during the course of, the investigation, including information about relevant 
previous medical history and the results of all diagnostic tests. 
o A record of the exposure of each subject to the 99mTc-MAA, including the date and 
time of use.   
• 
The protocol, with documents showing the dates and reasons for each deviation from 
the protocol.  
• 
Signed investigator agreements, financial disclosure agreements, investigator protocol 
signature pages, and curriculum vitae. 
• 
IRB approval documents including approval of the protocol, protocol amendments, and 
ICF. 

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13.4 
Site Qualification & Selection 
The sponsor and/or CRO will assess the potential site to ensure the investigators and his/her 
staff meet the following criteria at minimum: 
• 
The site has an interventional radiologist that can act as a principal investigator. 
• 
The investigators are qualified by experience and training. 
• 
The site has the appropriate 99mTc-MAA SPECT/CT imaging equipment. 
• 
The site has adequate research support staff with the availability to fulfill the clinical 
study requirements specified in the protocol.  
• 
The investigators are not on the FDA disqualified or debarred list. 
13.5 
Site Training 
Training of the clinical site personnel will be the responsibility of the study sponsor and the 
CRO. Site personnel will be trained per the study-specific Training Plan. All site personnel will 
undergo training prior to performing any study-related procedures. All training will be 
documented. Existing site personnel who have been delegated new tasks and new site 
personnel will undergo training as designated in the Training Plan.  
13.6 
Site Monitoring 
This clinical study will be monitored according to a study-specific Monitoring Plan that complies 
with GCP. Monitors will assess for appropriate study conduct and data integrity, including review 
of eCRFs and parity checks with the source documentation, worksheets, and hospital charts. 
Periodic site visits will be conducted (either on-site or remotely), including a site initiation visit, 
routine monitoring visits, and a study closeout visit upon completion of the study. At a minimum, 
the ICF and the ICF process, imaging timepoint data, and AE data will be 100% monitored and 
compared to source documentation. Monitoring will include comparison of eCRFs to source 
documentation for accuracy and appropriateness, and review for unreported AEs.  
13.7 
Institutional Review Board (IRB) 
The CRO must have documented IRB approval for the protocol and the site-specific ICF prior to 
site activation to enroll subjects. The IRB approval documentation should be signed by the IRB 
chairperson and clearly identify the study (i.e., study number, protocol title, and version), the 
documents that were approved (e.g., protocol, ICF), and the date of IRB approval. The site will 
not be activated until a copy of written and dated IRB approval has been received by the CRO 
and other applicable study activation requirements are complete. 
The site must submit any protocol or ICF amendments to the IRB and is required to forward a 
copy of the written approval to the CRO. An IRB approval of the amended document(s) must be 
obtained before implementation and before new subjects are consented to participate in the 
study using the amended ICF, if applicable. The IRB should also be informed of any event likely 

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to affect the safety of subjects or the conduct of the study. Any additional requirements imposed 
by the IRB or regulatory authority shall be followed, if appropriate. 
The ICF must be reviewed by the CRO before it is submitted to the IRB for approval. 
13.8 
Protocol Deviations 
A protocol deviation is defined as a circumstance in which the investigator or other site 
personnel did not conduct the trial according to the protocol, applicable laws/regulations, or any 
study agreements (e.g., Clinical Trial Agreement or Investigator Agreement).  
Every attempt will be made to adhere to the protocol. However, should an investigator be 
required to deviate from the protocol to protect the life or physical well-being of a study subject 
in an emergent circumstance, such notice will be given to the sponsor or CRO and IRB as soon 
as possible, but no more than 5 working days from the date the emergency occurred. Except for 
an emergent circumstance, prior approval from the sponsor, the IRB, and the FDA (when 
required) is required for any change in, or deviation from, the protocol, as such changes may 
affect the scientific soundness of the protocol or the rights, safety, and welfare of study subjects.  
Protocol deviations will be documented on the Protocol Deviation eCRF. Deviations are 
reportable to the IRB during the annual reporting process, unless otherwise directed by the 
governing IRB requirements.   
Repeated protocol deviations will be closely monitored by the CRO/sponsor. If excessive 
deviations or a failure to reduce deviations is noted, the sponsor reserves the right to suspend 
study enrollment or terminate the site from the study until a sufficient system is in place at the 
site to reduce further deviations (21 CFR 812.46(a)).   
13.9 
Protocol Amendments 
Changes to the protocol must be documented in a formal protocol amendment prior to 
implementation in the study. Amendments to the protocol will be initiated by the sponsor or CRO 
and must be approved by the IRB prior to implementation at the site. 
13.10 Study Suspension or Termination 
No formal statistical rule for early termination of this study for insufficient effectiveness of the 
study drug is defined. 
The sponsor reserves the right to terminate or suspend the study for valid scientific reasons or 
reasons related to the protection of subjects (e.g., the discovery of an unexpected, significant, or 
unacceptable risk to the subjects). The sponsor also reserves the right to terminate the study for 
business reasons. Refer to the Clinical Trial Agreement for specific information regarding study 
termination (by IRB withdrawal of approval, by principal investigator (PI), or by sponsor).   
If the study is terminated prematurely or suspended, the sponsor will promptly inform the 
Investigator of the termination or suspension and the reason(s). The IRB will also be informed, 

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either by the sponsor or investigator, and provided with the reasons(s) for the termination or 
suspension. Regulatory authorities will be informed, as required.  
The IRB may choose to discontinue the study for which they granted approval if the research 
study is not conducted in accordance with the IRB’s requirements or the research study 
indicates unexpected serious harm to subjects.    
13.11 Subject Confidentiality 
All information and data sent to the CRO concerning a subject or their participation in this study 
will be considered confidential. The sponsor, CRO, monitors, IRB, and regulatory 
representatives will have access to these confidential files and have the right to inspect and 
copy all records pertinent to this study for data verification. All data used in the analysis and 
reporting of this study will be without identifiable references to a subject. Subject names and 
contact information will be available to the sponsor, CRO, and monitors during review of medical 
records. Subject names may be available as required for review of study-related radiographic 
images and source documentation. This information will be treated with adherence to 
professional standards of confidentiality. In addition, upon regulatory request, subject records 
shall be provided to regulatory agencies. Efforts will be made to de-identify information 
whenever possible. 
13.12 Audits & Inspections 
Investigators and study sites are required to permit study-related monitoring, audits, IRB review, 
and regulatory inspection(s) and provide direct access to source data/documents. 
13.13 Statements of Compliance 
This study is to be conducted in compliance with the study protocol and in accordance with 
ethical principles that have their origin in the Declaration of Helsinki, as defined in the following 
U.S. and international standards for good clinical practice: 
• 
ICH Guideline for Good Clinical Practice E6 (R2) (2016) 
• 
U.S. Code of Federal Regulations (CFR) regarding clinical studies (21 CFR including 
parts 11, 50, 54 and 56 and 812) and HIPAA (45 CFR 164.508) 
13.14 Finance & Agreements 
Refer to the Clinical Trial Agreement for a description of how the clinical investigation is 
financed and the agreement between the sponsor and the site. 
13.15 Publications & Public Disclosure 
Refer to the Clinical Trial Agreement for publications and public disclosure requirements and 
conditions.  

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13.16 Study Contacts 
Refer to the Study Contact List for detailed contact information, including names, telephone 
numbers, and email addresses. 
14.0 DEFINITIONS 
Adverse drug reaction (ADR): In the pre-approval clinical experience with a new medicinal 
product or its new usages, particularly as the therapeutic dose(s) may not be established, all 
noxious and unintended responses to a medicinal product related to any dose should be 
considered adverse drug reactions. The phrase “responses to a medicinal product” means that 
a causal relationship between a medicinal product and an adverse event is at least a 
reasonable possibility (i.e., the relationship cannot be ruled out). (ICH E6 (R2), 1.1) 
• 
Note regarding marketed medicinal products: A response to a drug which is noxious and 
unintended, and which occurs at doses normally used in man for prophylaxis, diagnosis, 
or therapy of diseases or for modification of physiological function.  
Adverse event (AE):  Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product. (ICH E6 (R2), 1.2) 
Serious adverse event (SAE) or serious suspected adverse reaction: An 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. (U.S. FDA 21 CFR 312.32(a)) 
Suspected adverse reaction (SAR): Any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety reporting, 

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"reasonable possibility" means there is evidence to suggest a causal relationship between the 
drug and the adverse event. Suspected adverse reaction implies a lesser degree of certainty 
about causality than adverse reaction, which means any adverse event caused by a drug. (U.S. 
FDA 21 CFR 312.32(a)) 
Unexpected: An adverse event or adverse drug reaction is considered “unexpected” if the 
nature or severity of the event is not consistent with the applicable product information (e.g., 
Investigator’s Brochure for an unapproved investigational drug or package insert/summary of 
product characteristics for an approved drug). (U.S. FDA 21 CFR 312.32(a)) 
• 
Note: A suspected unexpected serious adverse reaction may be referred to as a 
SUSAR.