Assessing Benefits of Near Infrared Autofluorescence (NIRAF) Detection for Identifying Parathyroid Glands During Total Thyroidectomy.
Phase: NA
Conditions: Postoperative Hypoparathyroidism, Thyroid Neoplasms, Thyroid Cancer
Sponsor: Vanderbilt-Ingram Cancer Center

 
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Assessing Benefits of Near Infrared Autofluorescence 
(NIRAF) Detection for Identifying Parathyroid Glands 
during Total Thyroidectomy. 
 Research Protocol 
 
 
NCT: NCT04281875 
 
 
 
 
 
Carmen C. Solórzano, MD, FACS 
Professor of Surgery 
Chair, Department of Surgery 
Director, Vanderbilt Endocrine Surgery 
Vanderbilt University Medical Center 
 
 
Colleen M. Kiernan, MD, MPH, FACS 
Assistant Professor of Surgery 
Department of Surgery 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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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 
 
Inadvertent damage to or excision of a healthy parathyroid gland (PG) following a total 
thyroidectomy could result in transient hypocalcemia (< 6 months) in 5 – 35% of cases or 
permanent hypocalcemia (> 6 months) in up to 7% of the patients (1, 2). Patient that 
develop hypocalcemia will thus need to take high doses of oral calcium and vitamin D 
levels every 4–8 hours temporarily if it is a case of transient hypocalcemia or for the rest 
of their life if is a case of permanent hypocalcemia. Preoperative modalities such as 
ultrasound imaging, 99mTechnetium-sestamibi scintigraphy, and computed tomography 
(CT) are not as effective in localizing healthy parathyroid glands 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 (3). 
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 (4), is costly and has risk of possible injury to a healthy PG.  
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% (5, 6). Since then, several research 
groups have explored the feasibility of localizing parathyroid glands using NIRAF detection 
with reasonable success, resulting in FDA permitting marketing for this optical technique 
(7). In this study, we plan to evaluate whether the device called ‘PTeye’ (AiBiomed, Santa 
Barbara, CA) is beneficial or not, for the surgeon and patient during total thyroidectomies. 
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 total 
thyroidectomies 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 total 
thyroidectomy procedures. 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 total thyroidectomies, 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, accidental 
excision or damage to healthy parathyroid glands during total thyroidectomy procedures 
can be decreased, thus minimizing the risk for postoperative hypocalcemia and 
hypoparathyroidism. 
   
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 (8-11). FDA recently allowed marketing to 
Fluobeam (a commercially available imaging system) and PTeye (a commercial fiber 

 
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probe-based system) in 2018 (7). Certain outcome studies have reported that imaging-
based systems for NIRAF detection such as Fluobeam was able to reduce the incidence 
of postsurgical transient hypocalcemia after total thyroidectomy (10, 11). However, other 
studies have reported that they observed no benefit from imaging-based systems in 
minimizing postsurgical hypocalcemia (13). In a recent study, Thomas et al. demonstrated 
that a fiber probe-based system – the PTeye – was more sensitive in parathyroid 
identification compared to an imaging-based system for NIRAF detection (14). To date, 
there has been no studies that determine the impact of a fiber probe-based system (i.e. 
PTeye) during total thyroidectomy operations 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 thyroid disease who will be 
undergoing total thyroidectomy (includes patients who have undergone a prior 
neck exploration for parathyroid disease or other but have an intact thyroid 
gland). 
• 
All adults (i.e., ≥ 18 years old) patients with persisting thyroid disease and will be 
undergoing re-operative or completion thyroidectomy. 
 
Exclusion: 
• 
Children and minors 
• 
Pregnant women 
• 
Patients with concurrent parathyroid and thyroid disease  
• 
Patients with incidental enlarged parathyroid discovered during thyroidectomy 
procedure. 
• 
Patients undergoing thyroid lobectomy or partial thyroidectomy 
 
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.).  

 
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The patient will also be provided with the contact information of the principle 
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.  
Prior to surgery, the patient will be assigned a unique ID (e.g. TThy_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 total thyroidectomy 
procedure. 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 total thyroidectomy 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, within 24 hours 

 
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after surgery, 1st postoperative visit after surgery and 6 months after surgery (if followed 
up)), (vi) blood parathyroid hormone (PTH) levels (within 24 hours after surgery, 1st 
postoperative visit after surgery and 6 months after surgery (if followed up), (vii) history 
and duration of calcium and/or Vitamin D supplementation before and after surgery and 
(viii) postsurgical complications, if any and history of ER visits or hospitalization due to low 
blood 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 total 
thyroidectomies. 
 
7.0 
Risks 
 
• 
The proposed study is designed to collect NIRAF measurements from neck tissues 
with a commercial device called PTeye during a total thyroidectomy. The device 
that will be used for NIRAF measurements has been permitted for marketing by 
the FDA.  
• 
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 permitted by the FDA for marketing. 
The FDA permit for marketing 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 cleared for marketing 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.  
 
 

 
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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.  
 
9.0 
Statistical Considerations 
 
Benmiloud et al. studied the impact of NIRAF-based identification of parathyroid glands 
during total thyroidectomies, 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 (10). 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 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. 
 
10.0 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 a HIPPA-compliant data spread-
sheet with access limited solely to the investigators listed on the study. 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.  
  
11.0 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.  
 
12.0 References 

 
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1. 
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and Other Surgical Measures on Hypocalcemia Following Bilateral Thyroid 
Surgery: A Systematic Review and Meta-Analysis. Thyroid. 2014; 25:95-106. 
2. 
Edafe O, Antakia R, Laskar N, et al. Systematic review and meta-analysis of 
predictors of post-thyroidectomy hypocalcaemia. The British journal of surgery. 
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3. 
Sosa JA, Bowman HM, Tielsch JM, et al. The Importance of Surgeon Experience 
for Clinical and Economic Outcomes from Thyroidectomy. Annals of Surgery. 
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4. 
Novis DA, Zarbo RJ. Interinstitutional comparison of frozen section turnaround 
time. Archives of pathology & laboratory medicine. 1997; 121(6):559. 
5. 
McWade MA, Sanders ME, Broome JT, et al. Establishing the clinical utility of 
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6. 
McWade MA, Paras C, White LM, et al. A novel optical approach to intraoperative 
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7. 
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. 
8. 
Ladurner R, Sommerey S, Arabi NA, et al. Intraoperative near-infrared 
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9. 
Falco J, Dip F, Quadri P, et al. Increased identification of parathyroid glands using 
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10. 
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11. 
Benmiloud F, Godiris-Petit G, Gras R, et al. Association of Autofluorescence-
Based Detection of the Parathyroid Glands During Total Thyroidectomy With 
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Randomized Clinical Trial. JAMA Surgery. 2019; (in press) 
12. 
Thomas G, McWade MA, Paras C, et al. Developing a clinical prototype to guide 
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13. 
DiMarco A, Chotalia R, Bloxham R, et al. Does fluoroscopy prevent inadvertent 
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