Assessing Benefits of NIRAF Detection for Identifying Parathyroid Glands During Total Thyroidectomy
Phase: NA
Conditions: Postoperative Hypoparathyroidism, Thyroid Disease, Thyroid Neoplasms, Thyroid Cancer
Sponsor: Medical College of Wisconsin

PROTOCOL DATE:  July 31, 2021 
OFFICIAL TITLE:  AŜŜôŜŜĖĲČ ôĲôƱťŜ ĺċ bIRAF DôťôèťĖĺĲ ċĺŘ IîôĲťĖċyĖĲČ PÍŘÍťēyŘĺĖî @lÍĲîŜ DuŘĖĲČ 
TĺťÍl TēyŘĺĖîôèťĺıy 
bCT0͔͔͖͖͗͘2 

 
MCW Protocol No: PRO 40572 
1 
Version No.: 1 
IDE No.: DEN170056  
 
Version Date: 07/31/2021 
 
 
 
 
 
 
Evaluating Impact of Near Infrared Autofluorescence (NIRAF) Detection for 
Identifying Parathyroid Glands during Parathyroidectomy 
 
 
Short Title: 
 
NIRAF Parathyroidectomy 
 
 
Tracy S. Wang, MD, MPH 
 
Carmen C. Solórzano, MD, FACS 
 
Current Version Number and Date 
 
V1 07/31/2021 
 
 
Proprietary and Confidential 
The information in this document is considered privileged and confidential, and may not be disclosed 
to others except to the extent necessary to obtain Institutional Review Board approval and  
informed consent, or as required by federal and state laws. Persons to whom this information is 
disclosed should be informed that this information is privileged and confidential and  
that it should not be further disclosed. 
 
 

 
MCW Protocol No: PRO 40572 
2 
Version No.: 1 
IDE No.: DEN170056  
 
Version Date: 07/31/2021 
 
Title: Evaluating Impact of Near Infrared Autofluorescence (NIRAF) Detection for 
Identifying Parathyroid Glands during Parathyroidectomy 
MCW Protocol No.:  VANDERBILT-NIRAF-
PARATHYROID 
Clinical trials.gov No.:  NCT05579782 
IRB Pro No.:  PRO 40572 
FDA IDE No.:  DEN170056 (Class II) 
Principal Investigator:  
Tracy S. Wang, MD, MPH 
Professor 
Medical College of Wisconsin 
Department of Surgery 
Division of Surgical Oncology 
8701 Watertown Plank Road 
Telephone: 414-955-1459 
Email: tswang@mcw.edu  
Vanderbilt University, Co-Investigator:  
Carmen C. Solórzano, MD, FACS 
Professor of Surgery 
Vanderbilt University Medical Center 
Nashville, TN 37235 
1301 Medical Center Drive 
Nashville, TN 37232 
Email: carmen.solorzano@vumc.org  
Sub-investigator/Responsible Investigator:  
Sophie Dream, MD 
Assistant Professor 
Medical College of Wisconsin 
Department of Surgery 
Division of Surgical Oncology 
8701 Watertown Plank Road 
Telephone: 414-955-1434 
Email: sdream@mcw.edu  
 
 
 

 
MCW Protocol No: PRO 40572 
3 
Version No.: 1 
IDE No.: DEN170056  
 
Version Date: 07/31/2021 
 
VERSION HISTORY 
Version 1, Version Date 07/31/2021 
Initial submission of the protocol.  
Version 
Date 
1 
07/31/2021 
 
 
 
 
 
 
 
 
 
 
 

 
MCW Protocol No: PRO 40572 
4 
Version No.: 1 
IDE No.: DEN170056  
 
Version Date: 07/31/2021 
 
TABLE OF CONTENTS 
VERSION HISTORY ......................................................................................................................................... 3 
TABLE OF CONTENTS .................................................................................................................................... 4 
PROTOCOL SUMMARY ................................................................................................................................... 6 
1 BACKGROUND ............................................................................................................................................. 7 
PARATHYROIDECTOMY SURGERY .............................................................................................. 7 
2 HYPOTHESIS, OBJECTIVES, AND ENDPOINTS ......................................................................................... 8 
2.1 PRIMARY OBJECTIVE ........................................................................................................... 8 
2.2 PRIMARY OUTCOME MEASURES ........................................................................................... 8 
2.3 SECONDARY OUTCOME MEASURES ..................................................................................... 9 
3 STUDY DESIGN ........................................................................................................................................... 10 
3.1 GENERAL DESCRIPTION .................................................................................................... 10 
PRIMARY COMPLETION............................................................................................................ 11 
3.2 STUDY COMPLETION ......................................................................................................... 11 
4 SUBJECT PARTICIPATION, DISCONTINUATION, AND WITHDRAWAL .................................................. 11 
4.1 SUBJECT STATUS .............................................................................................................. 11 
4.2 PRESCREENING AND SCREENING LOG ................................................................................ 11 
4.3 CONSENT ......................................................................................................................... 12 
4.4 ELIGIBILITY CONFIRMATION ................................................................................................ 12 
4.5 ELIGIBILITY CRITERIA ........................................................................................................ 13 
4.6 INCLUSION CRITERIA ......................................................................................................... 13 
4.7 EXCLUSION CRITERIA ........................................................................................................ 13 
4.8 ENROLLMENT .................................................................................................................... 14 
4.9 SCREENING ...................................................................................................................... 14 
4.10  LOST TO FOLLOW-UP ...................................................................................................... 15 
4.11  ACCRUAL SUSPENSION AND CLOSURE............................................................................. 15 
4.12  END OF STUDY DEFINITION ............................................................................................. 16 
4.13  STUDY DISCONTINUATION AND CLOSURE ......................................................................... 16 
5 ADVERSE EVENTS: DEFINITIONS AND REPORTING REQUIREMENTS ................................................ 17 
5.1 DEFINITIONS ..................................................................................................................... 17 
5.2 MONITORING AND RECORDING AN ADVERSE EVENT ............................................................ 19 
6 STATISTICAL CONSIDERATIONS ............................................................................................................. 24 
7 REGULATORY COMPLIANCE, ETHICS AND STUDY MANAGEMENT ..................................................... 24 
7.1 ETHICAL STANDARD .......................................................................................................... 24 
7.2 REGULATORY COMPLIANCE ............................................................................................... 24 
7.3 PRESTUDY DOCUMENTATION ............................................................................................. 24 
7.4  INSTITUTIONAL REVIEW BOARD ......................................................................................... 24 
7.5  SUBJECT CONFIDENTIALITY AND ACCESS TO SOURCE DOCUMENTS/DATA ........................... 25 
7.6  PROTECTION OF HUMAN SUBJECTS ................................................................................... 26 
7.7  CHANGES IN THE PROTOCOL ............................................................................................. 26 
7.8  INVESTIGATOR COMPLIANCE ............................................................................................. 27 

 
MCW Protocol No: PRO 40572 
5 
Version No.: 1 
IDE No.: DEN170056  
 
Version Date: 07/31/2021 
 
8 DATA HANDLING AND RECORD KEEPING .............................................................................................. 27 
8.1 OVERVIEW ........................................................................................................................ 27 
8.2  DATA MANAGEMENT RESPONSIBILITIES ............................................................................. 27 
8.3  HANDLING AND DOCUMENTATION OF CLINICAL SUPPLIES.................................................... 28 
8.4  SOURCE DOCUMENTS ...................................................................................................... 28 
8.5  CASE REPORT FORMS ...................................................................................................... 29 
8.6  STUDY RECORD RETENTION ............................................................................................. 29 
9 REFERENCES ............................................................................................................................................. 31 

 
 
MCW Protocol No: PRO 40572 
6 
Version No.: 1 
IDE No.: DEN170056  
 
Version Date: 07/31/2021 
 
PROTOCOL SUMMARY 
Title 
Evaluating Impact of Near Infrared Autofluorescence (NIRAF) Detection for 
Identifying Parathyroid Glands during Parathyroidectomy 
Principal 
Investigator  
Tracy S. Wang, MD 
Study 
Population 
Parathyroidectomy patients 
Primary 
Objectives 
The specific aim of this study is to determine if PTeye is beneficial or not for 
(i) intraoperative identification of parathyroid tissues, (ii) improving efficiency 
of parathyroid surgeries, and (iii) minimizing risk of postsurgical 
complications. 
Study Design 
Double-arm, open-label 
Study
Intervention 
PTeye 
Number of 
Subjects 
N = 160. Each investigator will enroll 40 subjects to the PTeye group and 40 
subjects to the control group. 
Estimated Time 
to Complete 
Enrollment: 
Approximately 2 years 
 
 

 
 
MCW Protocol No: PRO 40572 
7 
Version No.: 1 
IDE No.: DEN170056  
 
Version Date: 07/31/2021 
 
1 BACKGROUND 
Parathyroid Surgery 
Inability of the surgeon to identify or localize the diseased PG can occur in 5 – 10% of cases 
resulting in failed parathyroidectomies (1, 2). As a result, persistent hyperparathyroidism can 
occur in these patients resulting in unnecessary repeat surgeries that may be associated with 
increased morbidity and costs (3, 4). Ultrasound imaging, 99mTechnetium-sestamibi 
scintigraphy, and computed tomography (CT) have so far demonstrated variable efficacy in 
preoperative localization of diseased PGs (5, 6) and may not always correlate well with the 
surgical field of view as observed intraoperatively. Consequently, most surgeons rely on visual 
identification of PGs during surgery, whereby the accuracy of PG identification is eventually 
determined by her/his surgical skill and experience (7, 8). When in doubt, a surgeon routinely 
confirms the identity of PG tissue intraoperatively by sending the specimen for frozen section 
analysis that typically requires a wait time of 20–30 minutes per sample (9) and has additional 
costs.  
By easily being able to distinguish parathyroid from other tissues intraoperatively, postsurgical 
complications and associated costs may be reduced. The unique discovery of near infrared 
autofluorescence (NIRAF) in parathyroid tissues demonstrated that optical modalities that detect 
NIRAF can be utilized for non-invasive and label-free identification of parathyroid tissues with an 
accuracy as high as 97%.(10, 11) Since then, several research groups have explored the 
feasibility of localizing parathyroid glands using NIRAF detection with reasonable success, 
resulting in FDA approval for this optical technique (12). In this study, we plan to evaluate 
whether an FDA-approved device called ‘PTeye’ (AiBiomed, Santa Barbara, CA) is beneficial or 
not, for the surgeon and patient during parathyroid operations. The results of such a study will 
help us to understand and assess the true impact of optical modalities such as PTeye on (i) 
improving the quality and efficiency of parathyroid surgeries and (ii) minimizing risk of 
postsurgical complications and related expenses.   
Animal Studies and Previous Human Studies 
Modalities that rely on NIRAF detection for label-free parathyroid identification have been 
successfully validated in several studies (13-16). FDA approval for this application was recently 
granted to Fluobeam (a commercially available imaging system) and PTeye (a commercial fiber 
probe-based system) in 2018 (12). Certain outcome studies have reported that imaging-based 
systems for NIRAF detection such as the PDE Neo II system was able to reduce the number of 
frozen sections required during parathyroid procedures (15). However, other studies have 
reported that they observed no benefit from imaging-based systems in parathyroid localization 
(17). In a recent study, Thomas et al. demonstrated that a fiber probe-based system – the 
PTeye – was more sensitive in parathyroid identification compared to the imaging-based system 
by PDE Neo II (18). To date, there has been no studies that determine the impact of a fiber 
probe-based system (i.e. PTeye) during parathyroid surgeries in minimizing a number of frozen 
sections obtained intraoperatively or postsurgical complications. 
Known Risks and Potential Benefits 
The proposed study is designed to collect NIRAF measurements from neck tissues with a 
commercial device called PTeye during a parathyroidectomy. The device that will be used for 
NIRAF measurements is an FDA-approved device.  

 
 
MCW Protocol No: PRO 40572 
8 
Version No.: 1 
IDE No.: DEN170056  
 
Version Date: 07/31/2021 
 
Each PTeye measurement takes less than 2 seconds, with the whole set of measurements not 
adding more than 5 minutes to the surgical procedure. Thus, there is a minimal increase of risk 
of surgery due to the potential five extra minutes of anesthesia time associated with the study. 
In addition, the participating surgeon will evaluate the eligibility of the patient based on his or her 
medical condition. Patients with high anesthetic risks will not be asked to participate in the 
study. 
Since the power of near infrared light from PTeye will be extremely low, no side effects should 
be introduced to the patient. 
There should not be any discomforts, inconveniences, and/or risk resulting from this study. 
The study should not increase the risk of infection as a disposable sterile probe is used for each 
patient.   
The PTeye device used in this study has been FDA-approved. The FDA approval is granted 
based on the caveat that necessary precautionary measures will be taken by the surgeon to 
minimize the probable risks (as listed in the device brochure). The PTeye may be associated 
with unknown/unforeseen risks as with any other FDA-approved medical devices used during 
surgical procedures. 
2 HYPOTHESIS, OBJECTIVES, AND ENDPOINTS 
The goal of this study is to assess whether using PTeye – a NIRAF detection modality – can 
improve patient outcomes and reduce healthcare associated costs after parathyroid surgeries.  
By being able to quickly and definitively locate parathyroid glands while in the operating room, 
the duration of surgical procedure could be further reduced. In addition, the number of frozen 
section biopsy and associated costs can be minimized. Furthermore, repeat surgeries as a 
result of missing a diseased parathyroid gland at the time of the initial parathyroidectomy for 
hyperparathyroidism could potentially be avoided. 
2.1 Primary Objective 
The specific aim of this study is to determine if PTeye is beneficial or not for (i) 
intraoperative identification of parathyroid tissues, (ii) improving efficiency of parathyroid 
surgeries, and (iii) minimizing risk of postsurgical complications. 
2.2 Primary Outcome Measures 
2.2.1 Persistent hyperparathyroidism (Immediate) 
Failure of intra-operative parathyroid hormone (PTH) to normalize (defined as failure of 
PTH to drop > 50% of its baseline value at final intra-operative PTH assay and/or failure 
of PTH to drop < 65 pg/ml or 6.9 pmol/L). [Time Frame: During parathyroidectomy (PTx) 
procedure] 
2.2.2 Persistent hyperparathyroidism or hypercalcemia (transient) 

 
 
MCW Protocol No: PRO 40572 
9 
Version No.: 1 
IDE No.: DEN170056  
 
Version Date: 07/31/2021 
 
Elevated blood calcium levels (total blood calcium level > 10.5 mg/dL or 2.6 mmol/L) 
with/without elevated parathyroid hormone (PTH) (serum intact PTH > 65 pg/ml or 6.9 
pmol/L) at first postoperative visit. [Time Frame: 5-14 days after PTx procedure] 
2.2.3 Persistent hyperparathyroidism or hypercalcemia (failed parathyroidectomy) 
 
If blood calcium with/without parathyroid hormone (PTH) has not normalized at 1st post-
operative visit, calcium and/or PTH is subsequently measured as necessary. Patient is 
defined to have a failed parathyroidectomy if hypercalcemia/hyperparathyroidism 
(defined as total blood calcium level > 10.5 mg/dL or 2.6 mmol/L, with/without elevated 
serum intact PTH > 65 pg/ml or 6.9 pmol/L) persists at or after the 6th postoperative 
month. [Time Frame: 6 months after PTx procedure] 
 
2.3   Secondary Outcome Measures 
2.3.1 Overall number of parathyroid glands identified 
 
Overall number of parathyroid glands identified (Experimental Group: Glands identified 
with naked eye + NIRAF;Control Group: Glands identified with naked eye) [Time Frame: 
Immediate. During PTx procedure.] 
 
2.3.2 Number of parathyroid glands identified with NIRAF 
 
Number of parathyroid glands identified with NIRAF, which was not seen with surgeon's 
naked eye [Time Frame: Immediate. During PTx procedure.] 
 
2.3.3 Number of frozen sections sent for analysis 
 
Number of frozen sections sent for analysis during the procedure to confirm potential 
parathyroid tissue [Time Frame: Immediate. During PTx procedure.] 
 
2.3.4 Number of diseased parathyroid glands identified versus preoperatively localized glands 
 
Number of diseased parathyroid glands identified intra-operatively versus glands 
localized preoperatively using sestamibi, CT or ultrasound [Time Frame: Preoperative to 
immediate during PTx procedure.] 
 
2.3.5 Number of intra-operative parathyroid hormone (PTH) assays sent 
 
Number of intra-operative parathyroid hormone assays sent during the procedure [Time 
Frame: Immediate. During PTx procedure.] 
 
2.3.6 Duration taken to identify first parathyroid gland 
 
Duration taken to identify 1st parathyroid gland in PTx procedure – timed from skin 
incision to finding PG. [Time Frame: Immediate. During PTx procedure.] 
 
2.3.7 Duration taken to identify last parathyroid gland 
 
Duration taken to identify last parathyroid gland in PTx procedure – timed from skin 

 
 
MCW Protocol No: PRO 40572 
10 
Version No.: 1 
IDE No.: DEN170056  
 
Version Date: 07/31/2021 
 
incision to finding the last PG.[Time Frame: Immediate. During PTx procedure.] 
 
2.3.8 Duration of parathyroidectomy (PTx) procedure 
 
Duration of PTx procedure – timed from skin incision until the surgeon notifies the 
anesthesia team to awaken the patient [Time Frame: Immediate. During PTx procedure.] 
 
2.3.9 Duration taken for intraoperative parathyroid hormone (PTH) to normalize 
 
Time taken for PTH to attain cure criteria or normalize - timed from skin incision until the 
PTH levels drops > 50% of its baseline value and/or PTH drops < 65 pg/ml or 6.9 
pmol/L. [Time Frame: Immediate. During PTx procedure.] 
 
2.3.10 Number of nights spent in the hospital after parathyroidectomy 
 
Number of nights spent for postoperative recovery in the hospital after the surgical 
procedure. [Time Frame: 0-72 hours after PTx procedure.] 
 
2.3.11 Number of 'false positive' tissues excised by surgeon 
 
Number of tissues that were excised by surgeon assumed to be parathyroid tissue, but 
is later validated as nonparathyroid tissue (false positive) by histology [Time Frame: 
Immediate to 10 days after PTx procedure.] 
 
2.3.12 Number of doctor visits/emergency department visits or hospital admissions 
 
Number of doctor visits/emergency department visits or hospital admissions due to 
persistent hypercalcemia and/or associated symptoms after parathyroidectomy 
procedure [Time Frame: Up to 6 months after PTx procedure.] 
 
2.3.13 Number of patients who have had repeat parathyroidectomy (PTx) procedure 
 
Number of patients with repeat PTx procedure performed after the current procedure 
[Time Frame: 6 - 12 months after PTx procedure.] 
3 STUDY DESIGN 
3.1 General Description 
This study is a diagnostic study. Patients will be randomly allocated the patient to the 
experimental arm (where the surgeon will use PTeye) or a control arm (where the surgeon will 
not use PTeye). Patients will be allocated via ‘Random Allocation Software’ 
(http://mahmoodsaghaei.tripod.com/Softwares/randalloc.html). The primary outcome of the 
protocol is designed to evaluate the efficacy of PTeye. 

 
 
MCW Protocol No: PRO 40572 
11 
Version No.: 1 
IDE No.: DEN170056  
 
Version Date: 07/31/2021 
 
Primary Completion 
The study will reach primary completion (complete enrollment) approximately 12-18 months 
from the time the study opens to accrual. 
3.2 Study Completion 
The duration of the study is expected to be approximately two years from the time the study opens 
to accrual. 
4 SUBJECT PARTICIPATION, DISCONTINUATION, AND 
WITHDRAWAL   
 
MCW must follow all MCW IRB requirements and policies regarding subject participation, found 
here: 
 
https://www.mcw.edu/HRPP/Policies-Procedures.htm 
 
4.1 Subject Status 
 
 
Subject statuses throughout the trial are defined as follows:   
 
x 
Prescreening: preconsent (subject considering trial or study staff considering patient for 
the trial per institutional recruitment methods). 
x 
Screening: period after consent, but prior to eligibility confirmation. 
x 
Consented: consented, prior to eligibility confirmation. 
x 
Eligible: the local investigator confirms all eligibly criteria apply. 
x 
On study/enrolled: date eligibility is confirmed. 
x 
On arm: date of enrollment. 
x 
On treatment: first day treatment was given to the last day treatment was given. 
x 
Off treatment: the last day treatment was given. 
x 
On follow-up: from last day of treatment to the end of follow-up period. 
x 
Off study: follow-up period completed, with no additional data gathered. 
x 
Withdrawn: subject fully withdraws consent (i.e., refuses ALL follow-up, even survival) or 
is taken off study by the local principal investigator. 
 
4.2 Prescreening and Screening Log 
 
The MCW study principal investigator regularly reviews screen failure reasons to understand 
barriers to accrual and consider amending eligibility criteria. Screen failures are defined as 
participants who were considered for the trial to participate in the clinical trial with or without 
consent, but are not subsequently assigned to the study intervention or enrolled in the study. 
MCWCC CTO will follow its SOPs regarding prescreening and screening tracking. 
 

 
 
MCW Protocol No: PRO 40572 
12 
Version No.: 1 
IDE No.: DEN170056  
 
Version Date: 07/31/2021 
 
4.3 Consent  
 
Investigators or their appropriate designees will identify potentially eligible subjects from their 
clinics, subject self-referrals, referrals from other clinicians, and/or other IRB-approved 
recruitment methods. No study conduct, including subject prescreening, can occur until after 
IRB approval. 
 
A written, signed informed consent form (ICF) and a Health Insurance Portability and 
Accountability Act (HIPAA) authorization must be obtained before any study-specific 
assessments are initiated. A signed ICF copy will be given to the subject and a copy will be filed 
in the medical record (per local IRB policies and SOPs). The original will be kept on file with the 
study records.  
 
4.4 Eligibility Confirmation 
 
Study staff must adhere to MCWCC CTO SOPs regarding eligibility review/confirmation.  
 
 

Subject Initials: _____________     Subject Study ID: _______________      
 
 
MCW Protocol No: PRO 40572 
13 
Version No.: 1 
IDE No.: DEN170056  
 
Version Date: 07/31/2021 
 
4.5 Eligibility Criteria 
*No waivers of protocol eligibility will be granted. 
 
All inclusion and exclusion criteria should be explicitly stated as applying to the subject in the 
source material (e.g., “The patient has been postmenopausal since 2010”). 
4.6 Inclusion Criteria 
1. $OODGXOWVLH\HDUVROGSDWLHQWVZLWKSULPDU\K\SHUSDUDWK\URLGLVPZKRZLOOEH
undergoing parathyroid surgery 
 
2. $OODGXOWVLH\HDUVROGSDWLHQWVZLWKSHUVLVWHQWSULPDU\K\SHUSDUDWK\URLGLVPDIWHU
having undergone a failed prior parathyroid surgery who will be undergoing repeat parathyroid 
surgery 
3. Ability to understand a written informed consent document, and the willingness to sign it. 
 
4.7 Exclusion Criteria 
A potential subject who meets any of the following exclusion criteria is ineligible to participate in 
the study. 
1. Children and minors 
 
2. Pregnant women 
 
3. Patients with concurrent parathyroid and thyroid disease that require total thyroidectomy 
 
4. Patients with secondary or tertiary hyperparathyroidism 
 
 
 “I have reviewed all inclusion and exclusion criteria and confirm the subject is eligible.” 
 
 
 
_________________________________________         
 
 
_______________ 
(Local Investigator Signature and Date) 
 
 

 
 
 
MCW Protocol No: PRO 40572 
14 
Version No.: 1 
IDE No.: DEN170056  
 
Version Date: 07/31/2021 
 
4.8 Enrollment 
Subject enrollment logistics are defined as follows: 
 
x 
OnCore® enrollment entry must occur within 24 hours of eligibility confirmation. 
x 
A case/subject/sequence number is assigned in OnCore® from the MCW staff in sequence 
(i.e., inputted from the site staff, not generated by OnCore®). 
o Sites enter the case number according to the following template “XXX-XXX-001” or 
“XXX-001” (unless otherwise specified by MCW OnCore® Staff), where the “XXX” 
sections are abbreviations are determined by MCW OnCore® Staff, and “001” is the 
sequential subjects who consented to the trial at the site (e.g., the first enrolled case 
number would be XXX-XXX-001, but the second would be XXX-XXX-002). 
 
4.9 Screening 
The screening procedures and assessments must be completed on the day of consultation for 
parathyroidectomy.   
 
Patient demographics 
 
Blood chemistry assessment of serum calcium, ionized calcium, parathyroid hormone (PTH) 
levels, and 25-OH vitamin D levels 
 
Day of Parathyroidectomy 
 
To be completed within 30 days of the last dose of the study drug. 
 
 
Patient demographics 
 
Duration of surgery 
 
Number of frozen section analyses performed 
 
Frozen section and permanent histology reports of all excised tissues 
 
Follow-Up Visits 
 
Patients will be followed for six months following parathyroidectomy. The visits will be within 5-
14 days after surgery and at 6 months after surgery.The following procedures will be performed 
at the follow-up visit(s): 
 
 
Physical examination 
 
Vital signs 
 
Blood chemistry assessment of serum calcium, ionized calcium, parathyroid hormone 
(PTH) levels, and 25-OH vitamin D levels 
 
Concomitant medications 
 
History of visits to the Emergency room, hospitalization, or repeat surgery due to high 
calcium levels 

 
 
 
MCW Protocol No: PRO 40572 
15 
Version No.: 1 
IDE No.: DEN170056  
 
Version Date: 07/31/2021 
 
 
Documentation of postsurgical complications 
 
Consent Withdrawal 
 
A subject may decide to withdraw from the study at any time. MCWCC CTO will follow its IRB of 
record’s SOPs regarding consent withdrawal.  
 
If a subject intends on withdrawing consent, staff should confirm which of the following options 
the subject chooses and document the discussion: 
 
-  Full consent withdrawal with no study follow-up. 
 
-  Selective consent withdrawal from interventional portion of the study, but agree to continued 
follow-up of associated clinical outcome information. 
 
Investigator-initiated Withdrawal 
 
The investigator will withdraw a subject whenever continued participation is no longer in the 
subject’s best interests. Reasons for withdrawing a subject include, but are not limited to, 
disease progression, the occurrence of an adverse event or a concurrent illness, a subject’s 
request to end participation, a subject’s noncompliance or simply significant uncertainty on the 
part of the investigator that continued participation is prudent. The reason for study withdrawal 
and the date the subject was removed from the study must be documented. 
 
4.10  Lost to Follow-up 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit and/or is unable to be reached for follow-up: 
 
x 
The investigator or designee must make every effort to regain contact and/or reschedule a 
missed visit with the participant. 
x 
A participant is deemed lost to follow-up if his/her status cannot be obtained after all of the 
following occurs at two consecutive scheduled protocol calendar timepoints: 
o Three telephone calls (at least one day apart) from the study team are unanswered  
AND  
o A letter to the participant’s last known mailing address goes unanswered. 
AND 
o These contact attempts must be documented in the participant’s medical record or 
study file.  
x 
Update OnCore® (follow-up tab and eCRF) when a participant is officially considered lost to 
follow-up. 
x 
If a subject is considered lost to follow-up, but subsequently contacts the participating site 
study team, the subject should be considered in follow-up again. 
 
4.11  Accrual Suspension and Closure 
The MCW PI facilitates the suspension and closing of accrual in the following manner: 
 
x 
OnCore® tracks accrual throughout the study. 

 
 
 
MCW Protocol No: PRO 40572 
16 
Version No.: 1 
IDE No.: DEN170056  
 
Version Date: 07/31/2021 
 
x 
If the study must be suspended, OnCore® is updated to a ‘suspended’ status. 
x 
When the accrual number is reached, OnCore® notifies staff of study closure. 
 
4.12  End of Study Definition 
A participant is considered to have completed the study if he or she has completed all phases of 
the study including the last visit or the last scheduled procedure shown in the calendar of events 
or has been discontinued. 
 
4.13  Study Discontinuation and Closure 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause (as determined by the MCW study principal investigator, DSMC, sponsor, 
and/or IRB). Written notification, documenting the reason for study suspension or termination, 
will be provided by the suspending or terminating party to study participants, investigator, 
funding agency, the Investigational New Drug (IND) sponsor and regulatory authorities. If the 
study is prematurely terminated or suspended, the MCW principal investigator (PI) will promptly 
inform the MCW Institutional Review Board (IRB) and sponsor and will provide the reason(s) for 
the termination or suspension. Study participants will be contacted, as applicable, and be 
informed of changes. 

 
 
 
MCW Protocol No: PRO 40572 
17 
Version No.: 1 
IDE No.: DEN170056  
 
Version Date: 07/31/2021 
 
5 ADVERSE EVENTS: DEFINITIONS AND REPORTING 
REQUIREMENTS 
5.1 Definitions 
5.1.1 Adverse Event (AE) and Serious Adverse Events (SAE) 
The investigator and his or her team will follow the Medical College of Wisconsin policies related 
to adverse event reporting. This information may be found on the Human Research Protection 
Program website.  
Serious AE (SAE) means any untoward medical occurrence that at any dose: 
x 
Death. Results in death. 
x 
Life threatening. Is life threatening (refers to an AE in which the patient was at risk of 
death at the time of the event. It does not refer to an event which hypothetically might 
have caused death if it were more severe). 
x 
Hospitalization. Requires inpatient hospitalization or prolongation of an existing 
hospitalization (see clarification in the paragraph below on planned hospitalizations). 
x 
Disability/incapacity. Results in persistent or significant disability or incapacity. 
(Disability is defined as a substantial disruption of a person’s ability to conduct normal 
life functions). 
x 
Medically important event. This refers to an AE that may not result in death, be 
immediately life threatening, or require hospitalization, but may be considered serious 
when, based on appropriate medical judgment, may jeopardize the patient, require 
medical or surgical intervention to prevent one of the outcomes listed above, or involves 
suspected transmission via a medicinal product of an infectious agent. 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; any 
organism, virus, or infectious particle (e.g., prion protein transmitting transmissible 
spongiform encephalopathy), pathogenic or nonpathogenic, is considered an infectious 
agent.  
Clarification should be made between a serious AE (SAE) and an AE that is considered severe 
in intensity (Grade 3 or 4), because the terms serious and severe are NOT synonymous. The 
general term severe is often used to describe the intensity (severity) of a specific event; the 
event itself, however, may be of relatively minor medical significance (such as a Grade 3 
headache). This is NOT the same as serious, which is based on patient/event outcome or action 
criteria described above, and is usually associated with events that pose a threat to a patient’s 
life or ability to function. A severe AE (Grade 3 or 4) does not necessarily need to be considered 
serious. For example, a white blood cell count of 1000/mm3 to less than 2000 is considered 
Grade 3 (severe) but may not be considered serious. Seriousness (not intensity) serves as a 
guide for defining regulatory reporting obligations. 

 
 
 
MCW Protocol No: PRO 40572 
18 
Version No.: 1 
IDE No.: DEN170056  
 
Version Date: 07/31/2021 
 
5.1.2 Unanticipated Problem Involving Risk to Subject or Other (UPIRSO) 
The investigator and his or her team will follow the Medical College of Wisconsin policies related 
to unanticipated problems involving risks to subjects or others. This information may be found 
on the Human Research Protection Program website.  
5.1.3 AE Attribution and Grading 
Adverse Event Grading 
Grade 
Description 
0 
No AE (or within normal limits). 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
2 
Moderate; minimal, local or noninvasive intervention (e.g., 
packing cautery) indicated; limiting age-appropriate 
instrumental activities of daily living (ADL). 
3 
Severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of hospitalization 
indicated; disabling; limiting self-care ADL. 
4 
Life-threatening consequences; urgent intervention indicated. 
5 
Death related to AE. 
 
Adverse Event Attribution 
Attribution is an assessment of the relationship between the AE and the medical intervention. 
 
Relationship 
Attribution 
Description 
Unrelated to investigational 
agent/intervention 
Unrelated 
The AE is clearly NOT related to the 
intervention 
Unlikely 
The AE is doubtfully related to the 
intervention 
Related to investigational 
agent/intervention 
Possible 
The AE may be related to the 
intervention 
Probable 
The AE is likely related to the 
intervention 
Definite 
The AE is clearly related to the 
intervention 
 

 
 
 
MCW Protocol No: PRO 40572 
19 
Version No.: 1 
IDE No.: DEN170056  
 
Version Date: 07/31/2021 
 
Relationship Assessment:  In-Depth Definitions 
For all collected AEs, the clinician who examines and evaluates the subject will determine the 
adverse event’s causality based on temporal relationship and his/her clinical judgment. The 
degree of certainty about causality will be graded using the categories below: 
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 drug administration and cannot be explained by 
concurrent disease or other drugs or chemicals. The response to withdrawal of the drug 
(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 sequence to administration of the drug, 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, the 
influence of other factors may have contributed to the event (e.g., the subject’s clinical condition, 
other concomitant events). Although an adverse drug event 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: A clinical event, including an abnormal laboratory test result, whose temporal 
relationship to drug administration makes a causal relationship improbable (e.g., the event did 
not occur within a reasonable time after administration of the trial medication) and in which other 
drugs or chemicals or underlying disease provides plausible explanations (e.g., the subject’s 
clinical condition, other concomitant treatments).  
Unrelated: The AE is completely independent of study drug administration, and/or evidence 
exists that the event is definitely related to another etiology. There must be an alternative, 
definitive etiology documented by the clinician.  
5.2 Monitoring and Recording an Adverse Event  
Definition. Any clinically relevant deterioration in laboratory assessments or other clinical 
finding is considered an AE.  
Reporting source. AEs may be spontaneously reported by the patient and/or in response to an 
open question from study personnel or revealed by observation, physical examination or other 
diagnostic procedures.  
Prior to the trial. Planned hospital admissions or surgical procedures for an illness or disease 
that existed before the patient was enrolled in the trial are not to be considered AEs unless the 
condition deteriorated in an unexpected manner during the trial (e.g., surgery was performed 
earlier or later than planned).  

 
 
 
MCW Protocol No: PRO 40572 
20 
Version No.: 1 
IDE No.: DEN170056  
 
Version Date: 07/31/2021 
 
Pretreatment events following signed informed consent. For serious pretreatment events, 
the investigator must determine both the intensity of the event and the relationship of the event 
to study procedures.  
Treatment events. For serious AEs, the investigator must determine both the intensity of the 
event and the relationship of the event to study drug administration.  
Not serious AEs. For non-serious AEs, the investigator must determine both the intensity of the 
event and the relationship of the event to study drug administration. 
Follow-up of Adverse Events 
All adverse events will be followed with appropriate medical management 30 days following the 
last dose of the study drug or treatment or until they are resolved, if they are related to the study 
treatment. 
5.2.1 Procedure for Reporting Drug Exposure during Pregnancy and Birth Events 
If a woman becomes pregnant, or suspects that she is pregnant, while participating in this study, 
she must inform the investigator immediately and permanently discontinue the study drug. The 
sponsor-investigator must notify the DSMC by email. The pregnancy must be followed for the 
final pregnancy outcome. 
If a female partner of a male patient becomes pregnant during the male patient’s participation in 
this study, the sponsor-investigator must also immediately notify the DSMC by email. Every 
effort should be made to follow the pregnancy for the final pregnancy outcome. 
Suggested Pregnancy Reporting Form: 
• 
Pregnancy Report Form (a sample is provided in the appendices)   
5.2.2 Subject Complaints 
If a complaint is received by anyone on the study staff, it will be discussed with the study staff 
and will be addressed on a case-by-case basis. The PI will be notified of any complaints. 
Complaints will be reported to the IRB if indicated.  
If the subject has questions about his or her rights as a study subject, wants to report any 
problems or complaints, obtain information about the study or offer input, the subject can call 
the Medical College of Wisconsin/Froedtert Hospital research subject advocate at 414-955-
8844. This information is provided to the subject in their consent.  
A product complaint is a verbal, written or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality or stability of a drug product. Individuals who 
identify a potential product complaint situation should immediately contact the sponsor and 
report the event. Whenever possible, the associated product should be maintained in 
accordance with the label instructions pending further guidance from a sponsor representative. 
Product complaints in and of themselves are not reportable events. If a product complaint 
results in an SAE, an SAE form should be completed.  

 
 
 
MCW Protocol No: PRO 40572 
21 
Version No.: 1 
IDE No.: DEN170056  
 
Version Date: 07/31/2021 
 
5.2.3 Routine Reporting Procedures for AEs 
Expedited Reporting Procedures for SAEs, SARs, UPIRSOs and DLTs. 
 
Since this is an investigator-initiated study, the principal investigator, also referred to as the 
sponsor-investigator, is responsible for reporting serious adverse events (SAEs) to any 
regulatory agency and to the sponsor-investigator’s IRB. Regardless of expectedness or 
causality, all SAEs (including serious pretreatment events) must also be reported to the DSMC 
as soon as possible, but no later than five calendar days of the sponsor-investigator’s 
observation or awareness of the event.  
 
Signs or symptoms reported as adverse events will be graded and recorded by the investigator, 
according to the CTCAE. When possible, signs and symptoms indicating a common underlying 
pathology should be noted as one comprehensive event.  
 
The investigator will assess all adverse events and determine reporting requirements to the 
MCWCC Data and Safety Monitoring Committee (DSMC) and MCW’s Institutional Review 
Board, and, when the study is conducted under an Investigational New Drug Application (IND), 
to the Food and Drug Administration (FDA), if it meets the FDA reporting criteria. The 
investigator will report SAEs to any regulatory agency and to the sponsor-investigator’s IRB. 
 
All adverse events, whether or not unexpected, and whether or not considered to be associated 
with the use of the study drug, will be entered into OnCore®. 
 
Reporting to the Data and Safety Monitoring Committee 
Regardless of expectedness or causality, all SAEs (including serious pretreatment events) must 
also be reported to the DSMC as soon as possible, but no later than five calendar days of the 
sponsor-investigator’s observation or awareness of the event.  
Report Method:  The investigator will use email to report SAEs to the DSMC. The SAE report 
must include event term(s), serious criteria and the sponsor-investigator’s or sub-investigator’s 
determination of both the intensity of the event(s) and the relationship of the event(s) to study 
drug administration. Intensity for each SAE, including any lab abnormalities, will be determined 
by using the NCI CTCAE as a guideline whenever possible.  
The criteria are available online at http://ctep.cancer.gov/reporting/ctc.html. 
Reporting to MCW Committee Institutional Review Board 
The principal investigator must report events to the MCW IRB within five business days of 
his/her awareness of the event.  
[Guidance on Adverse Event Reporting to the IRB is available online at MCW IRB Policies and 
Procedures.] 
Expedited Reporting to the Food and Drug Administration 
If the study is being conducted under an IND, the sponsor-investigator is responsible for 
determining whether or not the suspected adverse reaction meets the criteria for expedited 
reporting in accordance with Federal Regulations (21 CFR §312.32).  

 
 
 
MCW Protocol No: PRO 40572 
22 
Version No.: 1 
IDE No.: DEN170056  
 
Version Date: 07/31/2021 
 
The investigator must report in an IND safety report any suspected adverse reaction that is both 
serious and unexpected. The sponsor-investigator needs to ensure that the event meets all 
three definitions:  
 
Suspected adverse reaction  
 
Unexpected  
 
Serious  
 
If the adverse event does not meet all three of the definitions, it should not be submitted as an 
expedited IND safety report. 
The timeline for submitting an IND safety report to FDA is no later than 15 calendar days after 
the investigator determines that the suspected adverse reaction qualifies for reporting (21 CFR 
312.32(c)(1)).  
Any unexpected fatal or life-threatening suspected adverse reaction will be reported to FDA no 
later than seven calendar days after the investigator’s initial receipt of the information (21 CFR 
312.32(c)(2)).  
Any relevant additional information that pertains to a previously submitted IND safety report will 
be submitted to FDA as a Follow-up IND Safety Report without delay, as soon as the 
information is available (21 CFR 312.32(d)(2)).  
Suggested Reporting Form: 
 
US FDA MedWatch 3500A:  
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm 
Any other form deemed appropriate by the sponsor-investigator. 

 
 
 
MCW Protocol No: PRO 40572 
23 
Version No.: 1 
IDE No.: DEN170056  
 
Version Date: 07/31/2021 
 
 
Event Type 
Report Recipients  
PI/Study Chair/ 
Coordinating 
Center 
Institutional 
Review  
Board 
DSM
C 
 
 
FDA 
CTO  
Regulator
y 
Office  
Othe
r 
Serious Adverse Event 
ASAP 
5 days (or annual 
CPR)1 
5 
days 
7 or 15 
days2 
ASAP 
 
Unanticipated Problems Involving Risks to 
Subjects of Others 
ASAP 
5 days (or annual 
CPR)1 
5 
days 
7 or 15 
days2 
ASAP 
 
Evidence of Causal Relationship between Drug 
and AE 
ASAP 
5 days (or annual 
CPR)1 
5 
days 
7 or 15 
days2 
ASAP 
 
Dose-Limiting Toxicity 
ASAP 
5 days (or annual 
CPR)1 
5 
days 
7 or 15 
days2 
ASAP 
 
 
 
 
 
 
 
 
 
Contacts 
Role 
Name 
Entity/Department 
Institution 
Telephone 
Email 
Sponsor-Investigator  
 
MCW 
414- 
 
Research 
Coordinator 
 
 
MCW 
414- 
 
IRB Representative 
 
 
MCW 
414- 
 
DSMC 
 
 
MCW 
414- 
 
Regulatory Contact 
 
 
MCW 
414- 
 
FDA 
 
 
FDA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Footnotes 
1 Consult MCW IRB Policies (contact your regulatory representative) 
2  FDA guidelines:  Suspected adverse reaction, Unexpected and Serious = 7 Days; If not = 15 days 

 
 
 
MCW Protocol No: PRO 40572 
24 
Version No.: 1 
IDE No.: DEN170056  
 
Version Date: 07/31/2021 
 
6 STATISTICAL CONSIDERATIONS 
Benmiloud et al. studied the impact of NIRAF-based identification of parathyroid glands which comprised of a 
group of 93 patients where NIRAF was used by a surgeon for parathyroid identification and a control group of 
153 patients where NIRAF was not used (19). Their study reported that mean parathyroid glands identified by 
surgeon with NIRAF imaging was significantly higher at 3.1±0.9, while that of same surgeon without NIRAF 
imaging was 2.6±0.1 (p=0.0001). Based on this data (mean difference: 0.5 and standard deviation: 1.0), it was 
determined that in order to observe a statistically significant difference (i.e. for an expected mean difference: 
0.7 and expected standard deviation:1.0), 33 patients would be required per group (for a 95% powered study). 
Since this study may involve patient follow-up for data up to 6 months after surgery, we will thus assume an 
approximate data attrition rate of 20%, thus requiring a recruitment of 40 patients per group. Therefore, a total 
of 80 patients (study and control arm) should be recruited per surgeon for this study at this study site. 
7 REGULATORY COMPLIANCE, ETHICS AND STUDY MANAGEMENT 
7.1 Ethical Standard 
This study will be conducted in accordance with the ethical principles that have their origin in the Declaration 
of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with GCP and all applicable regulatory 
requirements. 
7.2 Regulatory Compliance 
This study will be conducted in compliance with: 
 
The protocol 
 
Federal regulations, as applicable, including: 21 CFR 50 (Protection of Human Subjects/Informed 
Consent); 21 CFR 56 (Institutional Review Boards) and §312 (Investigational New Drug Application; 
and 45 CFR 46 Subparts A (Common Rule), B (Pregnant Women, Human Fetuses and Neonates), C 
(Prisoners), and D (Children), GCP/ICH guidelines, and all applicable regulatory requirements. The 
IRB must comply with the regulations in 21 CFR §56 and applicable regulatory requirements. 
7.3 Prestudy Documentation  
Prior to implementing this protocol at MCWCC, the protocol, informed consent form, HIPAA authorization and 
any other information pertaining to participants must be approved by the MCW IRB.  
7.4  Institutional Review Board 
The protocol, the proposed informed consent form and all forms of participant information related to the study 
(e.g., advertisements used to recruit participants) will be reviewed and approved by the MCW Institutional 
Review Board. Prior to obtaining MCW approval, the protocol must be approved by the Medical College of 
Wisconsin Cancer Center Scientific Review Committee. The initial protocol and all protocol amendments must 
be approved by the IRB prior to implementation.  
 
 

 
 
 
MCW Protocol No: PRO 40572 
25 
Version No.: 1 
IDE No.: DEN170056  
 
Version Date: 07/31/2021 
 
Informed Consent Process 
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. Extensive discussion of risks and possible benefits of 
this therapy will be provided to the subjects and their families. Consent forms describing in detail the study 
interventions/products, study procedures and risks are given to the subject and written documentation of 
informed consent is required prior to starting intervention/administering study product. 
Consent forms will be IRB-approved and the subject (and legally authorized representative, if necessary) will 
be asked to read and review the document. Upon reviewing the document, the investigator will explain the 
research study to the subject and answer any questions that may arise. In accordance with 46 CR 46.111, the 
subject will sign and date the informed consent document prior to any procedures being done specifically for 
the study.  
A witness should only sign when required, per FH/MCW IRB policy. If a witness signs the document when not 
required, the study staff should document in the legal medical record (or note to file) the relationship to the 
patient and why a witness signed. (i.e., “Although not required, the subject’s spouse was present during the 
consenting process and signed as the witness.” Or “Although not required, hospital staff was present for 
consenting process and signed as a witness.”) 
The subjects will have the opportunity to discuss the study with their surrogates or think about it prior to 
agreeing to participate. The subjects may withdraw consent at any time throughout the course of the trial.  
A copy of the informed consent document will be given to the subjects for their records. The rights and welfare 
of the subjects 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. If there are changes to the consent form, all 
revisions will be reviewed with study subject at the next appropriate opportunity. Patients who require 
reconsenting will be defined in the IRB approved amendment submission. The process for obtaining informed 
consent will again be performed. Study subjects will not be reconsented for continuing reviews. The MCWCC 
CTO will follow the MCW/FH IRB’s policy for subjects who demonstrate limited English proficiency or limited 
literacy.  
After the subject’s visit in which the consent is signed, it is documented in the clinic chart that the consent has 
been signed and that all questions have been answered to the subject’s satisfaction after adequate time for 
review of the consent. It is also documented that a copy of the consent is given to the subject. The original 
consent is kept with the subject’s study file, and a copy of the consent is sent to the OCRICC office, which will 
then submit to HIM a copy of the signed consent to be scanned into EPIC, the legal medical record. 
7.5  Subject Confidentiality and Access to Source Documents/Data 
Subject confidentiality is strictly held in trust by the sponsor-investigator, participating investigators, and any 
staff. This confidentiality includes the clinical information relating to participating subjects, as well as any 
genetic or biological testing. 
The study protocol, documentation, data and all other information generated will be held in strict confidence. 
No information concerning the study or the data will be released to any unauthorized third party without prior 
written approval of the sponsor-investigator. 
The conditions for maintaining confidentiality of the subjects’ records are required for the life of the data. 
These rules apply equally to any and all MCWCC projects.  
One risk of taking part in a research study is that more people will handle the personal health information 
collected for this study. The study team will make every effort to protect the information and keep it 

 
 
 
MCW Protocol No: PRO 40572 
26 
Version No.: 1 
IDE No.: DEN170056  
 
Version Date: 07/31/2021 
 
confidential, but it is possible that an unauthorized person might see it. Depending on the kind of information 
being collected, it might be used in a way that could embarrass the subject or affect his/her ability to get 
insurance. 
While data are being collected and after all data have been collected but are still in the process of being 
analyzed, the subject’s data/PHI are stored in the locked Clinical Research Office in the Clinical Trials Office. 
Databases in which the study subject information is stored and accessed are password protected, allowing for 
limited access by authorized personnel only. Data/PHI kept in the case report forms contain the study 
identifiers, subject initials, date of birth and date of service.  
After all study queries and analyses are completed, the data/PHI will not be destroyed but will be archived  in 
a secure long-term storage site in order to keep an accurate record of screened and enrolled subjects for the 
sponsor and potential audit purposes only specific for this study. Data/PHI would not be destroyed until 
permission is granted by the sponsor to destroy the records.  
The sponsor-investigator will allow access to all source data and documents for the purposes of monitoring, 
audits, IRB review and regulatory inspections.  
The study monitor or other authorized representatives of the sponsor-investigator 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 subjects in this study. The clinical study site will permit 
access to such records. 
7.6  Protection of Human Subjects 
7.6.1  Protection from Unnecessary Harm 
Each clinical site is responsible for protecting all subjects involved in human experimentation. This is 
accomplished through the IRB mechanism and the informed consent process. The IRB reviews all proposed 
studies involving human experimentation and ensures that the subject’s rights and welfare are protected and 
that the potential benefits and/or the importance of the knowledge to be gained outweigh the risks to the 
individual. The IRB also reviews the informed consent document associated with each study in order to 
ensure that the consent document accurately and clearly communicates the nature of the research to be done 
and its associated risks and benefits. 
7.6.2  Protection of Privacy 
As noted, patients will be informed of the extent to which their confidential health information generated from 
this study may be used for research purposes. Following this discussion, they will be asked to sign informed 
consent documents. The original signed document will become part of the patient’s medical records, and each 
patient will receive a copy of the signed document.  
7.7  Changes in the Protocol 
Once the protocol has been approved by the MCW IRB, any changes to the protocol must be documented in 
the form of an amendment. The amendment must be signed by the investigator and approved by IRB prior to 
implementation.  
If it becomes necessary to alter the protocol to eliminate an immediate hazard to patients, an amendment may 
be implemented prior to IRB approval. In this circumstance, however, the investigator must then notify the IRB 
in writing within five working days after implementation.  
The IRB may provide, if applicable regulatory authority(ies) permit, expedited review and approval/favorable 
opinion for minor change(s) in ongoing studies that have the approval /favorable opinion of the IRB. The 
investigator will submit all protocol modifications to the sponsor and the regulatory authority(ies) in 
accordance with the governing regulations. 

 
 
 
MCW Protocol No: PRO 40572 
27 
Version No.: 1 
IDE No.: DEN170056  
 
Version Date: 07/31/2021 
 
Changes to the protocol may require approval from the sponsor. 
Any departures from the protocol must be fully documented in the source documents. 
7.8  Investigator Compliance  
The investigator will conduct the study in compliance with the protocol given approval/favorable opinion by the 
IRB and the appropriate regulatory authority(ies).  
Onsite Audits 
Auditing is essential to ensure that research conducted at the Medical College of Wisconsin (MCW) Cancer 
Center is of the highest quality and meets MCW and regulatory agency standards.  
Regulatory authorities, the IRB and/or sponsor may request access to all source documents, data capture 
records and other study documentation for on-site audit or inspection. Direct access to these documents must 
be guaranteed by the investigator, who must provide support at all times for these activities. 
8 DATA HANDLING AND RECORD KEEPING 
8.1 Overview 
Every effort is made to uphold the integrity of the project, the research, the institution and the researchers 
involved. Data collection guidelines and methodologies are carefully developed before the research begins. 
Investigators focus on the following to ensure data integrity:  well-trained data collectors/recorders to ensure 
consistency and quality, well-designed data collection protocols and ongoing monitoring. In this way, study 
rigor and validity are maintained. Data is protected from physical damage as well as from tampering, loss or 
theft. This project’s data management is a multidisciplinary activity that includes investigators, research 
coordinators and nurses, data mangers, support personnel, biostatisticians and database programmers. 
Quality control will be applied to each stage of data handling to ensure that all data are reliable and have been 
processed correctly.  
8.2  Data Management Responsibilities 
8.2.1  Principal Investigator 
The principal investigator oversees the management of patient records/case report forms and ensures that a) 
complete and accurate data will be obtained and provided to the sponsor; b) patient records are maintained to 
include history, prescribed medication and investigational product(s), measurements, exams, evaluations and 
adverse events; c) corrections are applied to clinical research data according to principles of good research 
practice (i.e., single-line delete, date and initial). He or she will ensure that there is correlation between the 
case report forms and the source documents.  
8.2.2  Research Coordinator  
A research coordinator creates, collects and organizes clinical trial documentation. He or she ensures that 
source documentation and data abstraction and entry are being done at protocol specified time points. 
 
8.2.3  Research Nurse/Medical Staff 
The research nurse and medical staff document protocol-required care or assessment of the subject’s 
outcomes, adverse events and compliance to study procedures. 
 

 
 
 
MCW Protocol No: PRO 40572 
28 
Version No.: 1 
IDE No.: DEN170056  
 
Version Date: 07/31/2021 
 
8.2.4  Biostatistician 
The biostatistician may assist in CRF development (content and design), dataset specifications (annotation of 
CRFs and record layout) and validation. 
8.3  Handling and Documentation of Clinical Supplies 
The MCWCC principal investigator will maintain complete records showing the receipt, dispensation, return or 
other disposition of all investigational drugs. The date, quantity and batch or code number of the drug, and the 
identification of patients to whom study drug has been dispensed by patient number and initials will be 
included. The sponsor-investigator will maintain written records of any disposition of the study drug. 
The principal investigator shall not make the investigational drug available to any individuals other than to 
qualified study patients. Furthermore, the principal investigator will not allow the investigational drug to be 
used in any manner other than that specified in this protocol. 
8.4  Source Documents 
Source documents for clinical information (patient history, diagnosis, clinical and diagnostic test reports, etc.) 
are maintained in the patient’s clinical file.  
The source documents for this protocol are as follows:   
Original documents, data and records (e.g., hospital records, clinical and office charts, laboratory notes, 
memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing records, recorded data from 
automated instruments, copies or transcriptions certified after verification as being accurate copies, 
microfiches, photographic negatives, microfilm or magnetic media, X-rays, subject files and records kept at 
the pharmacy, at the laboratories and at medico-technical departments involved in the clinical trial). 
All source documents will be written following ALCOA standards:  
ALCOA Attribute 
Definition 
Attributable 
Clear who has documented the data. 
Legible 
Readable and signatures identifiable. 
Contemporaneous 
Documented in the correct time frame along with the flow of events. 
If a clinical observation cannot be entered when made, chronology 
should be recorded. Acceptable amount of delay should be defined 
and justified. 
Original  
Original, if not original should be exact copy; the first record made 
by the appropriate person. The investigator should have the original 
source document. 
Accurate 
Accurate, consistent and real representation of facts. 
Enduring 
Long-lasting and durable. 
Available and 
accessible 
Easily available for review by treating physicians and during 
audits/inspections. The documents should be retrievable in 
reasonable time. 
Complete 
Complete until that point in time. 
Consistent 
Demonstrate the required attributes consistently. 
Credible 
Based on real and reliable facts. 
Corroborated 
Data should be backed up by evidence. 
 

 
 
 
MCW Protocol No: PRO 40572 
29 
Version No.: 1 
IDE No.: DEN170056  
 
Version Date: 07/31/2021 
 
8.5  Case Report Forms  
The principal investigator and/or his/her designee will prepare and maintain adequate and accurate participant 
case histories with observations and data pertinent to the study. Study-specific case report forms (CRFs) will 
document safety and treatment outcomes for safety monitoring and data analysis. All study data will be 
entered into OnCore® via standardized CRFs, in accordance with the study calendar, using single data entry 
with a secure access account. The clinical research coordinator will complete the CRFs as soon as possible 
upon completion of the study visit; the investigator will review and approve the completed CRFs.  
The information collected on CRFs shall be identical to that appearing in original source documents. Source 
documents will be found in the patient’s medical records maintained by MCWCC personnel. All source 
documentation should be kept in separate research folders for each patient. 
In accordance with federal regulations, the investigator is responsible for the accuracy and authenticity of all 
clinical and laboratory data entered in CRFs. The principal investigator will approve all completed CRFs to 
attest that the information contained on the CRFs is true and accurate.  
All source documentation and data will be available for review/monitoring by the MCWCC DSMC and 
regulatory agencies. 
8.6  Study Record Retention 
The duration of the study is expected to be approximately two year and will depend on patient availability.  
The data acquired from this study will be preserved indefinitely, as it may influence the future development of 
the entire research project.  However, the data will not be accessible to anyone other than the participants of 
this study.  All original paper records, record sheets, preoperative and postoperative lab investigations, 
drug/medication history, post-surgical medical history, histopathological diagnoses of the investigated tissue 
samples, will be collectively retained by the PI or Key Study Personnel.  The data of this study will be stored in 
a password protected computer, and only users with permission from the PI can access the data base.  
The PI at each participating site is required to prepare and maintain adequate records of the disposition of 
study materials and case histories that record all observations and other data pertinent to the investigation on 
each individual administered the materials in the investigation. Case histories include the case report forms 
and supporting data including, for example, signed and dated consent forms. The case history for each 
individual shall document that informed consent was obtained prior to participation in the study. 
Study documentation includes all data entry forms, data correction forms or queries, source documents, 
Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., protocol and 
amendments, IRB correspondence and approval, signed participant consent forms).  
Source documents include all recordings of observations or notations and all reports and records necessary 
for the evaluation and reconstruction of the clinical research study. 
The principal investigator is required to prepare and maintain adequate and accurate case histories that 
record all observations and other data pertinent to the investigation on each individual administered the 
investigational drug or employed as a control in the investigation. Case histories include the case report forms 
and supporting data including, for example, signed and dated consent forms and medical records including, 
for example, progress notes of the physician, the individual's hospital chart(s), and the nurses' notes. The 
case history for each individual shall document that informed consent was obtained prior to participation in the 
study. 
Study documentation includes all CRFs, data correction forms or queries, source documents, sponsor-
investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., protocol and 
amendments, IRB correspondence and approval, signed patient consent forms). 

 
 
 
MCW Protocol No: PRO 40572 
30 
Version No.: 1 
IDE No.: DEN170056  
 
Version Date: 07/31/2021 
 
Source documents include all recordings of observations or notations of clinical activities and all reports and 
records necessary for the evaluation and reconstruction of the clinical research study. 
 

 
 
 
MCW Protocol No: PRO 40572 
31 
Version No.: 1 
IDE No.: DEN170056  
 
Version Date: 07/31/2021 
 
9 REFERENCES 
1. 
Simental A, Ferris RL. Reoperative Parathyroidectomy. Otolaryngologic Clinics of North America. 2008 
2008/12/01/;41(6):1269-74. 
2. 
Cron DC, Kapeles SR, Andraska EA, et al. Predictors of operative failure in parathyroidectomy for 
primary hyperparathyroidism. The American Journal of Surgery. 2017;214:509-14. 
3. 
Doherty GM, Weber B, Norton JA. Cost of unsuccessful surgery for primary hyperparathyroidism. 
Surgery. 1994;116(6):954-8. 
4. 
Wachtel H, Cerullo I, Bartlett EK, et al. What Can We Learn from Intraoperative Parathyroid Hormone 
Levels that Do Not Drop Appropriately? Annals of Surgical Oncology. 2015 June 01;22(6):1781-8. 
5. 
Mohebati A, Shaha AR. Imaging techniques in parathyroid surgery for primary hyperparathyroidism. 
American Journal of Otolaryngology. 2012 12/07;33(4):457-68. 
6. 
Ahuja AT, Wong KT, Ching ASC, et al. Imaging for primary hyperparathyroidism — what beginners 
should know. Clinical Radiology. 2004 11//;59(11):967-76. 
7. 
Sosa JA, Powe NR, Levine MA, et al. Thresholds for Surgery and Surgical Outcomes for Patients with 
Primary Hyperparathyroidism: A National Survey of Endocrine Surgeons. The Journal of Clinical 
Endocrinology & Metabolism. 1998;83(8):2658-65. 
8. 
Chen H, Wang TS, Yen TWF, et al. Operative Failures after Parathyroidectomy for Hyperparathyroidism: 
The Influence of Surgical Volume. Annals of Surgery. 2010;252(4):691-5. 
9. 
Novis DA, Zarbo RJ. Interinstitutional comparison of frozen section turnaround time. Archives of 
pathology & laboratory medicine. 1997;121(6):559. 
10. 
McWade MA, Sanders ME, Broome JT, et al. Establishing the clinical utility of autofluorescence 
spectroscopy for parathyroid detection. Surgery. 2016 1//;159(1):193-203. 
11. 
McWade MA, Paras C, White LM, et al. A novel optical approach to intraoperative detection of 
parathyroid glands. Surgery. 2013 12//;154(6):1371-7. 
12. 
The United States Food and Drug Administration. FDA permits marketing of two devices that detect 
parathyroid 
tissue 
in 
real-time 
during 
surgery. 
Available 
at: 
https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm624982.htm. 
Accessed 
November 3, 2018. 
13. 
Ladurner R, Sommerey S, Arabi NA, et al. Intraoperative near-infrared autofluorescence imaging of 
parathyroid glands. Surgical Endoscopy. 2016:1-6 
14. 
Falco J, Dip F, Quadri P, et al. Increased identification of parathyroid glands using near infrared light 
during thyroid and parathyroid surgery. Surgical Endoscopy. 2017 September 01;31(9):3737-42. 
15. 
Squires MH, Jarvis R, Shirley LA, Phay JE. Intraoperative Parathyroid Autofluorescence Detection in 
Patients with Primary Hyperparathyroidism. Annals of Surgical Oncology. 2019;26:1142-8. 
16. 
Thomas G, McWade MA, Paras C, et al. Developing a clinical prototype to guide surgeons for 
intraoperative label-free identification of parathyroid glands in real time. Thyroid. 2018;28(11):1517-31 
17. 
DiMarco A, Chotalia R, Bloxham R, et al. Autofluorescence in Parathyroidectomy: Signal Intensity 
Correlates with Serum Calcium and Parathyroid Hormone but Routine Clinical Use is Not Justified. 
World journal of surgery. 2019 Jun 15;43(6):1532-7. 
18. 
Thomas G, Squires MH, Metcalf, T., et al. Imaging or a Fiber Probe-based Approach? Assessing 
Different Methods to Detect Near Infrared Autofluorescence for Intraoperative Parathyroid Identification. 
Journal of the American College of Surgeons. 2019; (in press) 
19. 
Benmiloud F, Rebaudet S, Varoquaux A, et al. Impact of autofluorescence-based identification of 
parathyroids during total thyroidectomy on postoperative hypocalcemia: a before and after controlled 
study. Surgery. 2018; 163(1):23-30