Assessing Benefits of Near Infrared Autofluorescence (NIRAF) Detection for Identifying Parathyroid Glands During Total Thyroidectomy
Phase: NA
Conditions: Thyroid Neoplasms, Thyroid Diseases, Hypoparathyroidism, Endocrine System Diseases, Endocrine Gland Neoplasms, Neoplasms by Site, Neoplasms, Head and Neck Neoplasms, Parathyroid Diseases
Sponsor: University of Michigan

Assessing Beneﬁts of Near Infrared 
Autoﬂuorescence (NIRAF) Detection for Identifying 
Parathyroid Glands during Total Thyroidectomy 
 
NCT05022667 
 
Date of IRB Approval: June 24, 2021 

Assessing Benefits of Near Infrared Autofluorescence 
(NIRAF) Detection for Identifying Parathyroid Glands 
during Total Thyroidectomy. 
 Research Protocol 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 
 

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 
clearance for marketing this optical technique (7). 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 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 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 (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 University of Michigan (UM). At UM, the initial 
evaluation will be conducted while the surgeon is evaluating the patients at the Endocrine Surgery 
Clinics. 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 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 after surgery, 5-14 days 
after surgery and 6 months after surgery), (vi) blood parathyroid hormone (PTH) levels (within 24 
hours after surgery, 5-14 days after surgery and 6 months after surgery), (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 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.  
• 
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 market authorization by the 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 UM 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.  
 
 
 
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. In order to detect a difference among individual surgeons, this will require 
recruitment of 40 patients per arm, per surgeon. Therefore, a total of 160 patients (study and 
control arm) should be recruited for this study at this study site. 
 
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 years 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. 
Antakia R, Edafe O, Uttley L, Balasubramanian SP. Effectiveness of Preventative 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. 2014 Mar; 101(4):307-
20. 
3. 
Sosa JA, Bowman HM, Tielsch JM, et al. The Importance of Surgeon Experience for 
Clinical and Economic Outcomes from Thyroidectomy. Annals of Surgery. 1998; 
228(3):320-30. 
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 
autofluorescence spectroscopy for parathyroid detection. Surgery. 2016; 159(1):193-203. 
6. 
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. 

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 autofluorescence 
imaging of parathyroid glands. Surgical Endoscopy. 2016:1-6 
9. 
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. 
10. 
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 
11. 
Benmiloud F, Godiris-Petit G, Gras R, et al. Association of Autofluorescence-Based 
Detection of the Parathyroid Glands During Total Thyroidectomy With Postoperative 
Hypocalcemia Risk: Results of the PARAFLUO Multicenter Randomized Clinical Trial. 
JAMA Surgery. 2019; (in press) 
12. 
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; 
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13. 
DiMarco A, Chotalia R, Bloxham R, et al. Does fluoroscopy prevent inadvertent 
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14. 
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)