Evaluating Impact of Near Infrared Autofluorescence (NIRAF) Detection for Identifying Parathyroid Glands During Parathyroidectomy
Phase: NA
Conditions: Parathyroid Adenoma, Parathyroid Neoplasms, Parathyroid Hyperplasia, Parathyroid Cancer, Hypercalcemia, Primary Hyperparathyroidism
Sponsor: Vanderbilt-Ingram Cancer Center

 
 
Study Protocol and Statistical Analysis Plan  
Brief Title: Evaluating Impact of NIRAF Detection for Identifying Parathyroid Glands 
During Parathyroidectomy 
 
Official Title: Evaluating Impact of Near Infrared Autofluorescence (NIRAF) Detection 
for Identifying Parathyroid Glands During Parathyroidectomy 
 
ClinicalTrials.gov ID: NCT04299425 
 
Release Date: December 08, 2020 
 
 

 
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Evaluating Impact of Near Infrared Autofluorescence 
(NIRAF) Detection for Identifying Parathyroid Glands 
during Parathyroidectomy 
 Research Protocol 
 
 
 
 
 
 
Carmen C. Solórzano, MD, FACS 
Professor of Surgery 
Chair, Department of Surgery 
Director, Vanderbilt Endocrine Surgery 
Vanderbilt University Medical Center 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Table of Contents: 
 
Study Schema 
1.0 
Background 
2.0 
Rationale and Specific Aims 
3.0 
Animal Studies and Previous Human Studies 
4.0 
Inclusion/Exclusion Criteria 
5.0 
Enrollment/Randomization 
6.0 
Study Procedures 
7.0 
Risks of Investigational Agents/Devices (side effects) 
8.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk 
to Participants or Others 
9.0 
Study Withdrawal/Discontinuation 
10.0 Statistical Considerations 
11.0 Privacy/Confidentiality Issues 
12.0 Follow-up and Record Retention 
 

 
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1.0 
Background 
 
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 clearance for marketing this optical 
technique (12). In this study, we plan to evaluate whether an FDA-cleared 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.   
 
2.0 
Rationale and Specific Aims 
 
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. The specific aims 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. 
 
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.   
   
3.0 
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 clearance for marketing 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 

 
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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. 
 
4.0 
Inclusion/Exclusion Criteria 
 
Inclusions:  
• 
All adults (i.e., ≥ 18 years old) patients with primary hyperparathyroidism who 
will be undergoing parathyroid surgery 
• 
All adults (i.e., ≥ 18 years old) patients with persistent primary 
hyperparathyroidism after having undergone a failed prior parathyroid surgery 
who will be undergoing repeat parathyroid surgery 
 
Exclusion: 
• 
Children and minors 
• 
Pregnant women 
• 
Patients with concurrent parathyroid and thyroid disease that require total 
thyroidectomy 
• 
Patients with secondary or tertiary hyperparathyroidism 
 
5.0 
Enrollment/Randomization 
 
The research will be designed as a single center study, where patient recruitment will be 
conducted by the participating surgeons at Vanderbilt University Medical Center (VUMC). 
At VUMC, the initial evaluation will be conducted while the surgeon is evaluating the 
patients at the Endocrine Surgery Clinics at the Vanderbilt Eskind Diabetes Center, 
Vanderbilt Ingram Cancer Center or the Odess clinic (for ENT patients). The final eligibility 
of each patient for participating in this study will be determined by the participating surgeon 
in accordance of his/her medical conditions. Following the exclusion criteria, the study will 
aim to accrue all eligible patients who are going to the OR as part of their standard surgical 
procedure: 
 
1.  
On the date of procedure consent at clinic or the date of surgery, patients will be 
given a paper consent form detailing about the outcome study with PTeye in 
addition to the consent for the surgical procedure that will be performed.  
2.  
The key study personnel will briefly describe the PTeye and its application to the 
patient. 
3.  
If the patient is interested in participating, the key study personnel will provide the 
patient with a paper-based consent form.  
4. 
The key study personnel or the surgeon assigned to the patient will be available to 
discuss the protocol with the patient (including, risks, benefits, alternatives, etc.).  
The patient will also be provided with the contact information of the principal 
investigator should they have any questions. 
5. 
If the patient consents to be part of the study, a scan of their signed consent form 
will be stored digitally in the patient’s medical record.  

 
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Prior to surgery, the patient will be assigned a unique ID (e.g. Para_001). The unique ID 
will be utilized for randomly allocating the patient to the experimental arm (where the 
surgeon will use PTeye) or a control arm (where the surgeon will not use PTeye). The 
allocation will be conducted by the study coordinator using ‘Random Allocation Software’ 
(http://mahmoodsaghaei.tripod.com/Softwares/randalloc.html). 
 
6.0 
Study Procedures 
 
For patients assigned to the study arm, the surgeon will use the PTeye as an intraoperative 
tool to identify if a suspect tissue is a parathyroid or not, during the parathyroid surgery. 
The surgeon will first take 5 baseline NIRAF measurements on the thyroid gland (or neck 
muscle, if thyroid is absent) using the disposable sterile fiber probe that is connected to 
the PTeye console (see Figure 1), as per device functionality requirements. The 
subsequent step would involve touching the target tissue in the neck with the fiber optic 
probe, following which the PTeye will indicate to the surgeon if the tissue is parathyroid or 
not. Parameters which are displayed on the PTeye console – Baseline values, Detection 
Intensity, Parathyroid Detection Ratio – will be recorded for each patient enrolled in the 
study arm. PTeye indicates that a tissue is parathyroid if it displays the ‘Parathyroid 
Detection Ratio’ is greater than 1.2. The rest of the surgical procedure will follow according 
to standard protocol.  
 
For patients assigned to the control arm, the surgeon will not use the PTeye and will 
proceed with the parathyroid surgery as usual, while relying solely on her/his surgical 
experience in identifying the parathyroid glands during the operations. 
 
 
 
Figure 1. A commercial fiber probe-based system (PTeye, AiBiomed) for detecting near infrared 
autofluorescence (NIRAF) utilized for intraoperative parathyroid gland identification. PTeye 
consists of 1) the console that has a display and indicates to the surgeon if a tissue is parathyroid 
or not, 2) a detachable fiber optic probe, and 3) a foot-pedal which is activated by the surgeon for 
tissue NIRAF measurements. 
 
 
De-identified information regarding (i) patient demographics, (ii) duration of surgery, (iii) 
number of frozen section analysis performed, (iv) frozen section and permanent histology 
reports of all excised tissues, (v) blood calcium levels (before surgery, 1st postoperative 

 
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visit after surgery and 6 months after surgery (if followed up)), (vi) parathyroid hormone 
(PTH) levels (1st postoperative visit after surgery and 6 months after surgery (if followed 
up)) and (vii) postsurgical complications, if any and history of ER visits or hospitalization 
or repeat surgeries due to high calcium, will be compiled for all enrolled patients. These 
preoperative, intraoperative and postoperative investigations are to be performed at the 
surgeon’s discretion as necessary for the patient. These parameters would then be 
compared between the study arm and the control arm to truly gauge the impact or value 
of a device like PTeye for parathyroid surgeries. 
 
7.0 
Risks 
 
• 
The proposed study is designed to collect NIRAF measurements from neck tissues 
with a commercial device called PTeye during a parathyroidectomy..  
• 
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 granted clearance for marketing by 
the FDA. The marketing authorization by FDA has been 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-cleared medical 
devices used during surgical procedures. 
 
8.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk 
to Participants or Others 
 
Upon identification, adverse events resulting from this in vivo data acquisition procedure 
will be reported to the PI as well as the Vanderbilt IRB immediately. The study will be 
immediately terminated and not resumed until the sources leading to the adverse events 
are identified.  
 
9.0 
Study Withdrawal/Discontinuation 
 
The data acquisition procedure will be terminated if the medical conditions of the 
participant show some unexpected and adverse changes.  The decision of terminating the 
study will be determined by the participating surgeon.  
 

 
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10.0 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. To assess the influence of impact for surgeons 
based on her/his surgical experience, one senior surgeon (>10 years of experience) and 
one junior surgeon (<5 years of experience) will participate in study. Overall, 160 patients 
need to be enrolled to assess the impact of this technology. 
 
11.0 Privacy/Confidentiality Issues 
 
All study staff are required to complete the CITI Protection of Human Subjects Training 
Program.  All data pertaining to this study will be stored in the HIPPA compliant REDcap 
data management program.  Access to study data will be limited to the investigators listed 
on the study only. Only indirect identifiers such as medical record number (MRN) will be 
used. Participants’ information, including his or her name and medical record number, will 
be available only to the PI and key study personnel. It will be stored in a password-
protected computer and a locked file cabinet in the study coordinator’s office where we 
also will store the consent forms. All records will only be available to the PI and key study 
personnel. All information potentially identifying the participant will not be included in the 
data analysis or reporting of results therein.  
  
12.0 Follow-up and 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.  
 
13.0 References 
 
1. 
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North America. 2008 2008/12/01/;41(6):1269-74. 

 
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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 
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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 
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6. 
Ahuja AT, Wong KT, Ching ASC, et al. Imaging for primary hyperparathyroidism 
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Sosa JA, Powe NR, Levine MA, et al. Thresholds for Surgery and Surgical 
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8. 
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9. 
Novis DA, Zarbo RJ. Interinstitutional comparison of frozen section turnaround 
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11. 
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12. 
The United States Food and Drug Administration. FDA permits marketing of two 
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13. 
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19. 
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