18F-Fluorocholine for the Detection of Parathyroid Adenomas
Phase: PHASE2
Conditions: Hyperparathyroidism, Primary
Sponsor: Thomas Hope

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. 
18F-Fluorocholine for the Detection of Parathyroid Adenomas 
Protocol Number:  IRB# 16-19297 
Study Drug:  18F-fluorocholine 
Version Number:  2.1 
Version Date:  3/25/2019 
IND Number:  130342 
Principal Investigator 
Insoo Suh, MD   
University of California San Francisco 
 
 
 
Co-Principal Investigator
Thomas Hope, MD 
Revision History 
Version 1.1 
3/31/2016 
Version 1.2 
Version 1.3 
6/23/2017  
3/8/2018 
Version 2.1 
3/25/2019  
NCT# 03764007

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Phase III – 18F-fluorocholine 
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Protocol Signature Page 
Protocol No.: 16-19297 
Version Date: 25MAR2019 
UCSF Principal Investigator / Study Chair 
Printed Name 
Signature 
Date 
1. I agree to follow this protocol version as approved by the UCSF Institutional Review Board
(IRB).
2. I will conduct the study in accordance with applicable IRB requirements, Federal
regulations, and state and local laws to maintain the protection of the rights and welfare of
study participants.
3. I certify that I, and the study staff, have received the requisite training to conduct this
research protocol.
4. I have read and understand the information in the Investigators’ Brochure (or
Manufacturer’s Brochure) regarding the risks and potential benefits. I agree to conduct the
protocol in accordance with Good Clinical Practices (ICH-GCP), the applicable ethical
principles, the Statement of Investigator (Form FDA 1572), and with local regulatory
requirements. In accordance with the FDA Modernization Act, I will ensure the registration
of the trial on the www.clinicaltrials.gov website.
5. I agree to maintain adequate and accurate records in accordance with IRB policies,
Federal, state and local laws and regulations.

 
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Abstract 
Title 
18F-Fluorocholine for the Detection of Parathyroid Adenomas 
Patient population 
Patients with primary hyperparathyroidism. 
Rationale for 
Study 
Based on the promise shown in the preliminary results of these FCH 
PET pilot studies, we propose to evaluate this modality in a larger, 
appropriately powered prospective study. Specifically, we propose to 
conduct a large prospective study comparing the accuracy of US and 
MIBI with FCH PET (with either low-dose CT or MRI) as first-line 
imaging modalities in patients with HPT.  We believe that this more 
robust study design will provide more rigorous evidence on the true 
accuracy and added value of FCH PET for parathyroid localization. 
Primary Objective 
To investigate the performance (accuracy) of 18F-fluorocholine PET in 
the detection of hyperfunctioning parathyroid glands in surgical patients 
with biochemically proven primary hyperparathyroidism. 
Study Design 
This is a single arm Phase III study evaluating the accuracy of 18F-
fluorocholine for the detection of parathyroid adenomas. 
Number of 
patients 
140 patients. 
Duration of 
Therapy 
Patients will receive a single dose of 18F-Fluorocholine.  
Duration of Follow 
up 
Patients will be followed-up off study to determine if they undergo a 
parathyroidectomy.   
Duration of study 
The study will reach completion five years from the time the study 
opens to accrual. 
Study Drugs 
18F-fluorocholine. 
Safety 
Assessments 
Patient reported adverse events during the day of imaging will be 
recorded.  
Efficacy 
Assessments 
The 18F-fluorocholine PET studies will be interpreted by three blinded 
readers, and the reads will be correlated with pathology at time of 
parathyroidectomy to determine the accuracy of 18F-fluorocholine PET 
to detect the location of an abnormal parathyroid adenoma.  
Additionally, the accuracy of 18F-fluorocholine will be compared to 
sestamibi when available.  
 
 

 
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List of Abbreviations 
AE 
adverse event 
CRC 
Clinical Research Coordinator 
CRF 
case report form 
CT 
computerized tomography 
CTCEA 
Common Terminology Criteria for Adverse Events 
CTMS 
Clinical Trial Management System 
DSMP 
Data and Safety Monitoring Plan 
FCH 
18F-fluorocholine 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
IND 
investigational new drug application 
IP 
investigational product 
IRB 
Institutional Review Board 
IV 
intravenous 
MRI 
PET 
magnetic resonance imaging 
positron emission tomography 
PK 
pharmacokinetics 
PTH 
parathyroid 
SD 
standard deviation 
SPECT 
Single photon emission computed tomography 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Table of Contents 
Protocol Signature Page ......................................................................................................... 2 
Abstract .................................................................................................................................. 3 
List of Abbreviations ............................................................................................................... 4 
1 
Introduction .................................................................................................................... 7 
1.1 
Background ......................................................................................................................... 7 
1.2 
18F-fluorocholine for parathyroid adenomas ....................................................................... 7 
1.3 
Preliminary Data .................................................................................................................. 8 
1.4 
Rationale for the Proposed Study ........................................................................................ 8 
2 
Objectives of the Study .................................................................................................... 8 
2.1 
Primary objective ................................................................................................................ 8 
3 
Study Endpoints .............................................................................................................. 9 
3.1 
Primary endpoint 1 .............................................................................................................. 9 
3.2 
Primary endpoint 2 .............................................................................................................. 9 
3.3 
Secondary endpoint ............................................................................................................. 9 
4 
Study Design ................................................................................................................... 9 
4.1 
Characteristics ..................................................................................................................... 9 
4.2 
Number of Subjects ............................................................................................................. 9 
4.3 
Eligibility Criteria ................................................................................................................. 9 
4.3.1 
Inclusion Criteria ................................................................................................................................... 9 
4.3.2 
Exclusion Criteria .................................................................................................................................. 9 
4.4 
Duration of Study .............................................................................................................. 10 
4.5 
Study Timeline ................................................................................................................... 10 
5 
Study Drugs ................................................................................................................... 10 
5.1.1 
Investigational Drug: 18F-fluorocholine ............................................................................................. 10 
6 
Administration Plan ...................................................................................................... 10 
6.1 
Dosage and Administration ............................................................................................... 10 
6.2 
Monitoring and Toxicity Management ............................................................................... 10 
7 
Study Procedures and Observations .............................................................................. 10 
7.1 
Schedule of Procedures and Observations ......................................................................... 10 
7.1.1 
Pre-Imaging Period ............................................................................................................................. 11 
7.1.2 
Imaging Period .................................................................................................................................... 11 
7.1.3 
Long Term Follow-up Procedure ........................................................................................................ 11 
8 
Reporting and Documentation of Results ...................................................................... 11 

 
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8.1 
Evaluation of Safety ........................................................................................................... 11 
8.2 
Definitions of Adverse Events ............................................................................................ 11 
8.2.1 
Adverse Event ..................................................................................................................................... 11 
8.2.2 
Adverse reaction ................................................................................................................................. 12 
8.3 
Recording of an Adverse Event .......................................................................................... 13 
8.4 
Follow-up of Adverse Events .............................................................................................. 14 
8.5 
Adverse Events Monitoring ................................................................................................ 14 
8.6 
Expedited Reporting .......................................................................................................... 14 
9 
Statistical Considerations and Evaluation of Results ...................................................... 15 
9.1 
Statistical Design ............................................................................................................... 15 
9.2 
Analyses Plans ................................................................................................................... 15 
9.2.1 
18F-fluorocholine blinded reads ......................................................................................................... 15 
9.2.2 
Sestamibi evaluation .......................................................................................................................... 16 
9.3 
Evaluation of Safety ........................................................................................................... 17 
10 
Study Management ................................................................................................... 17 
10.1 
Pre-study Documentation .................................................................................................. 17 
10.2 
Institutional Review Board Approval ................................................................................. 17 
10.3 
Informed Consent .............................................................................................................. 17 
10.4 
Changes in the Protocol ..................................................................................................... 18 
10.5 
Handling and Documentation of Clinical Supplies .............................................................. 18 
10.6 
Case Report Forms (CRFs) .................................................................................................. 18 
10.7 
Record Keeping and Record Retention ............................................................................... 18 
References ............................................................................................................................ 20 
Appendix 1 
Schedule of Study Procedures and Assessments .............................................. 22 
Appendix 2 
UCSF Policy/Procedure for Required Regulatory Documents for UCSF 
Investigator-Initiated Clinical Trials with an Investigator held Investigational New Drug (IND)
 
23 
 
 
 
 
 

 
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1 Introduction 
There is significant clinical need for new superior imaging techniques to localize parathyroid 
adenomas in patients with primary hyperparathyroidism. Adequate preoperative imaging is vital 
for successful minimal invasive parathyroidectomy, the standard of care for these patients. F18-
Choline PET has shown to accurately localize parathyroid adenomas in selected patients with 
negative conventional imaging. A larger comparative study is now necessary before this scan 
can be introduced in the standard work up of these patients. 
1.1 
Background  
Primary hyperparathyroidism (PHPT) is a common endocrine disorder, with an incidence of 
around 45 per 100,000 person years (1).  PHPT is characterized by autonomous hypersecretion 
of parathyroid hormone (PTH) by one or more parathyroid glands, leading to an elevated serum 
calcium concentration. Hypercalcemia can cause a wide variety of well-described symptoms 
ranging from constipation to osteoporosis and also increases the risk of mortality resulting from 
cardiovascular disease (2).  Diagnosis is typically established biochemically, with the finding of a 
relatively elevated serum calcium level with a concomitant inappropriately-elevated PTH level. 
In over 80% of cases, PHPT is caused by a single parathyroid adenoma.  The remainder of 
other causes includes multigland disease (either multiple adenomas or 4-gland hyperplasia) and 
very rarely parathyroid carcinoma (3).  Surgery is currently the only method of definitive cure as 
well as the most effective treatment modality overall.  Most patients with PHPT are surgical 
candidates, but particularly if they are symptomatic or younger than 50 years of age (4).  In the 
majority of cases, the method of surgical intervention has shifted over the past 2 decades, 
evolving from extensive bilateral neck exploration to a more minimally invasive 
parathyroidectomy (MIP) approach (5).  MIP has been made possible by improvements in 
preoperative imaging studies that are able to accurately identify (localize) the abnormal 
gland(s), which in turn have allowed surgeons to perform limited, targeted explorations, with its 
attendant benefits to shorter operative time, lower complication rate, and smaller incision length 
(2). Most centers including UCSF routinely perform a combination of neck ultrasound and Tc-
99-sestamibi scan (with or without fusion SPECT-CT) for first-time, non-reoperative cases. The 
diagnostic value of single photon emission computed tomography (SPECT/CT) in predicting the 
localization of the adenoma has been proven to be the best imaging modality in comparison to 
normal SPECT, dual-phase planar scintigraphy and subtraction scintigraphy (6-8).  However, 
even SPECT/CT fails to identify the gland in up to 30% of the cases (9).  These cases mandate 
the traditional bilateral neck exploration, with its abovementioned attendant disadvantages 
compared to MIP. 
1.2 
18F-fluorocholine for parathyroid adenomas 
Recently, a case report was published describing a potential new imaging modality for patients 
with pHPT.  Quak et al. reported the incidental finding of a parathyroid adenoma using 18F-
Fluorocholine (FCH) PET-CT in a patient suspected of recurrence of prostate cancer (10).  
Choline is part of the phospholipid layer in the cell membrane; it is hypothesized that 
hyperfunctioning parathyroid cells have an increased activity of the phospholipid/Ca2+-
dependent protein kinase which would lead to increased choline uptake and in turn greater 
imaging accuracy of PET detection with radiolabeled choline such as FC (11).  Since then three 
studies with preliminary results have been published showing a superior detecting rate of FCH 
PET-CT over different types of conventional imaging in both patients with PHPT and secondary 
hyperparathyroidism (12-14).  Although these initial results with FC have been encouraging, the 
total body of evidence is still very small and more research is needed. 

 
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1.3 
Preliminary Data 
At our institution, we are completing a prospective pilot-study in which the feasibility of choline 
PET as a second-line imaging modality is investigated.  Only patients with negative or 
discordant US and MIBI are enrolled.  After FCH PET, patients undergo surgery and have 
biochemical follow up to compare the accuracy of localization.  So far 8 patients have been 
scanned, all of whom have shown a distinctly positive finding on PET scan (Figure 1).   In all 
eight patients who have undergone surgery, the offending parathyroid adenomas were identified 
intraoperative at exactly the location indicated by PET with biochemical cure confirmed at 
follow-up.  
 
Figure 1: T2 image, FCH PET image, and fused FCH PET/MRI image in a patient with pHPT 
and negative MIBI. A clear focus of tracer uptake is noted posterior ot the left thyroid with 
associated T2 hyperintense nodule, consistent with a parathyroid adenoma.  On surgical 
exploration this was found to be a parathyroid adenoma. 
1.4 
Rationale for the Proposed Study 
Based on the promise shown in the preliminary results of these FCH PET pilot studies, we 
propose to evaluate this modality in a larger, appropriately powered prospective study. 
Specifically, we propose to conduct a large prospective study comparing the accuracy of US 
and MIBI with FCH PET (with either low-dose CT or MRI) as first-line imaging modalities in 
patients with HPT.  We believe that this more robust study design will provide more rigorous 
evidence on the true accuracy and added value of FCH PET for parathyroid localization. 
 
2 Objectives of the Study 
2.1 
 Primary objective 
To investigate the performance (accuracy) of 18F-fluorocholine PET in the detection of 
hyperfunctioning parathyroid glands in surgical patients with biochemically proven primary 
hyperparathyroidism. 
 

 
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3 Study Endpoints 
3.1 
Primary endpoint 1 
Sensitivity and specificity of 18F-fluorocholine PET for the detection of abnormal parathyroid 
adenomas confirmed by pathology as compared to sestamibi imaging. 
3.2 
Primary endpoint 2 
Sensitivity and specificity of 18F-fluorocholine PET for the detection of abnormal parathyroid 
adenomas confirmed by pathology as compared to a predefined threshold. 
3.3 
Secondary endpoint 
Detection rate of 18F-fluorocholine PET in patients who have not undergone surgical resection. 
 
4 Study Design 
4.1 
Characteristics 
This is a prospective single arm single center Phase III study evaluating the ability of 18F-
fluorocholine to detect the location of parathyroid adenomas. 
4.2 
 Number of Subjects 
A total of 140 patients will be enrolled in this study. 
4.3 
 Eligibility Criteria 
Patients must have baseline evaluations performed prior to the first dose of study drug and must 
meet all inclusion and exclusion criteria.  In addition, the patient must be thoroughly informed 
about all aspects of the study, including the study visit schedule and required evaluations and all 
regulatory requirements for informed consent.  The written informed consent must be obtained 
from the patient prior to enrollment.  The following criteria apply to all patients enrolled onto the 
study unless otherwise specified. 
4.3.1 Inclusion Criteria 
1. Age ≥ 13 years. 
2. Biochemically proven hyperparathyroidism and an indication for surgery. 
3. Ability to understand a written informed consent document, and the willingness to sign it. 
4.3.2 Exclusion Criteria 
1. Pregnancy. 
2. Patients unlikely to comply with study procedures, restrictions and requirements and 
judged by the Investigator to be unsuitable for study participation. 

 
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4.4 
Duration of Study 
Patients will undergo a single imaging study using 18F-fluorocholine.  Study related procedures 
will end after the study visit.  Patients who undergo subsequent parathyroidectomy, will have 
their results reviewed and compared to the results from the imaging study.  
4.5 
Study Timeline 
140 patients over five years are expected to enroll, with an expected enrollment of 28 patients 
per year. 
 
5 Study Drugs 
5.1.1 Investigational Drug: 18F-fluorocholine 
18F-fluorocholine will be synthesized by the UCSF cyclotron facility under GMP conditions.  
 
6 Administration Plan 
6.1 
Dosage and Administration 
All patients will receive a one-time injection of 18F-fluorocholine of 4-7 mCi.  
6.2 
Monitoring and Toxicity Management 
Each patient receiving 18F-fluorocholine will be evaluable for safety.  The safety parameters 
include spontaneous reports of adverse events reported to the investigator by patients. 
Each patient will be assessed after the administration of 18F-fluorocholine for the development 
of any toxicity. Toxicity will be assessed according to the NCI CTCAE v4.0.  
 
7 Study Procedures and Observations 
7.1 
Schedule of Procedures and Observations 
The study-specific assessments are detailed in this section and outlined in Section 6 Schedule 
of Study Procedures and Assessments.  Screening assessments must be performed within 60 
days prior to the first dose of investigational product.  Any results falling outside of the reference 
ranges may be repeated at the discretion of the investigator. All on-study visit procedures are 
allowed a window of ± 5 days unless otherwise noted.  Treatment or visit delays for public 
holidays or weather conditions do not constitute a protocol violation. 
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 copy of the signed ICF will be given to the subject and a copy will 
be filed in the medical record.  The original will be kept on file with the study records.   

 
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7.1.1 Pre-Imaging Period 
7.1.1.1 Screening Assessments (Day -60 to Day 1) 
The Screening assessments must be completed within 60 days of the Day 1 Visit.  Patients will 
not be required to have undergone US or sestamibi imaging prior to FCH PET. 
• 
Written informed consent will be obtained prior to performing any study related activities. 
• 
Inclusion/exclusion criteria will be checked. 
7.1.2 Imaging Period 
7.1.2.1 Study Procedures (Day 1) 
• 
Administration of 18F-fluorocholine 
o The one-time nominal injected dose will be 4 to 7 mCi containing FCH.  Patient 
shall begin imaging between 20 and 60 minutes after the injection of the 
radiopharmaceutical.   
• 
Imaging using either PET/CT or PET/MRI 
o Coverage for the scan will extend from the base of the skull to the pulmonary 
artery.  PET acquisition will be for a minimum of 10 minutes per bed position. 
o A dictated report will be made of the imaging findings and be provided to the 
endocrine surgeons.  FCH PET imaging results will be used in conjunction with 
other imaging modalities, including available ultrasound and sestamibi studies, to 
direct surgical intervention. 
7.1.3 Long Term Follow-up Procedure 
Patients will be followed-up off protocol for up to one year.  For patients who subsequently 
undergo parathyroidectomy, the determination of biochemical cure will proceed per the usual 
standard of care, including the use of intraoperative PTH (IOPTH) measurements, and calcium 
and PTH measurements in the postoperative setting at standardized intervals.  Biochemical 
cure will be documented if the 2-4 week postoperative serum calcium and PTH levels drop both 
in comparison to preoperative values as well as to normal ranges. In addition, the final 
pathological diagnosis will be recorded for comparison purposes. 
 
8  Reporting and Documentation of Results 
8.1 
Evaluation of Safety 
Analyses will be performed for all patients having received at least one dose of study drug.  The 
study will use the CTCAE v4.0 for reporting of non-hematologic adverse events and modified 
criteria for hematologic adverse events. 
8.2 
Definitions of Adverse Events 
8.2.1 Adverse Event 
An adverse event (also known as an adverse experience) is defined as any untoward medical 
occurrence associated with the use of a drug in humans, whether or not considered drug 
related.  More specifically, an adverse event (can be any unfavorable and unintended sign (e.g., 

 
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an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
drug, without any judgment about causality.  An adverse event can arise from any use of the 
drug (e.g., off-label use, use in combination with another drug) and from any route of 
administration, formulation, or dose, including an overdose.  
8.2.2 Adverse reaction 
An adverse reaction is defined as any adverse event caused by the use of a drug.  Adverse 
reactions are a subset of all suspected adverse reactions for which there is reason to conclude 
that the drug caused the event. 
8.2.2.1 Suspected  
A suspected adverse reaction is defined as any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety reporting, 
“reasonable possibility” indicates that there is evidence to suggest a causal relationship 
between the drug and the adverse event.  A suspected adverse reaction implies a lesser degree 
of certainty about causality than an adverse reaction. 
8.2.2.2 Unexpected  
An adverse event or suspected adverse reaction is considered unexpected if it is not listed in 
the investigator brochure or package insert(s), or is not listed at the specificity or severity that 
has been observed, or, if an investigator brochure is not required or available, is not consistent 
with the risk information described in the general investigational plan or elsewhere in the current 
application.  
“Unexpected,” as used in this definition, also refers to adverse events or suspected adverse 
reactions that are mentioned in the investigator brochure as occurring with a class of drugs or 
as anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the particular drug under investigation. 
Adverse events that would be anticipated to occur as part of the disease process are 
considered unexpected for the purposes of reporting because they would not be listed in the 
investigator brochure.  For example, a certain number of non-acute deaths in a cancer trial 
would be anticipated as an outcome of the underlying disease, but such deaths would generally 
not be listed as a suspected adverse reaction in the investigator brochure. 
Some adverse events are listed in the Investigator Brochure as occurring with the same class of 
drugs, or as anticipated from the pharmacological properties of the drug, even though they have 
not been observed with the drug under investigation.  Such events would be considered 
unexpected until they have been observed with the drug under investigation. For example, 
although angioedema is anticipated to occur in some patients exposed to drugs in the ACE 
inhibitor class and angioedema would be described in the investigator brochure as a class 
effect, the first case of angioedema observed with the drug under investigation should be 
considered unexpected for reporting purposes. 
8.2.2.3 Serious 
An adverse event or suspected adverse reaction is considered serious if, in the view of either 
the investigator or sponsor, it results in any of the following outcomes:  
• 
Death 
• 
Life-threatening adverse event 

 
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• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life function 
• 
Congenital anomaly/birth defect 
Important medical events that may not result in death, are life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition.  Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
8.2.2.4 Life-threatening 
An adverse event or suspected adverse reaction is considered life-threatening if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk 
of death. It does not include an adverse event or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death.  
8.3 
Recording of an Adverse Event 
Data about these events and their severity will be recorded using the NCI CTCAE v4.0.  The 
Investigator will assign attribution of the possible association of the event with use of the 
investigational drug:  
Relationship  
Attribution  
Description  
Unrelated to investigational 
drug/intervention 
Unrelated 
The AE is clearly NOT related to the 
intervention  
Unlikely 
The AE is doubtfully related to the 
intervention  
Related to investigational 
drug/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  
 
Signs or symptoms reported as adverse events will be graded and recorded by the Investigator 
according to the CTCAE.  When specific adverse events are not listed in the CTCAE they will be 
graded by the Investigator as none, mild, moderate or severe according to the following grades 
and definitions: 

 
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Grade 0 
No AE (or within normal limits) 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
Grade 2 
Moderate; minimal, local, or noninvasive intervention (e.g., packing, cautery) 
indicated; limiting age-appropriate instrumental activities of daily living (ADL) 
Grade 
3: 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL 
Grade 
4: 
Life-threatening consequences; urgent intervention indicated 
Grade 
5: 
Death related to AE 
8.4 
Follow-up of Adverse Events 
All adverse events will be followed with appropriate medical management until resolved.  
Patients removed from study for unacceptable adverse events will be followed until resolution or 
stabilization of the adverse event.  For selected adverse events for which administration of the 
investigational drug was stopped, a re-challenge of the subject with the investigational drug may 
be conducted if considered both safe and ethical by the Investigator. 
8.5 
Adverse Events Monitoring  
The Investigator will assess all adverse events and determine reportability requirements to the 
UCSF Institutional Review Board (IRB); 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. 
8.6 
Expedited Reporting  
Reporting to UCSF Institutional Review Board 
The Principal Investigator must report events meeting the UCSF IRB definition of “Unanticipated 
Problem” (UP) within 5 business days of his/her awareness of the event.  
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).  
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. 

 
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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 7 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)).  
 
9 Statistical Considerations and Evaluation of Results 
9.1 
Statistical Design 
We will enroll a total of 140 patients (65 in our initial cohort, on which the sample size estimate 
is based).  The sample size will be based upon comparison to setamibi SPECT (MIBI).  Multiple 
meta-analysis of MIBI SPECT have been performed and demonstrate a sensitivity ranging 79 to 
84% for MIBI SPECT  (15,16).  This detection rate is higher than we see at our institution since 
we are a referral center for patients who have previously failed parathyroidectomy, where the 
study has a lower sensitivity.  For the purpose of our analysis we will do our sample size 
assuming a sensitivity of 70%, which mirrors our practice.  At an 87% power with an alpha level 
of 0.05, we estimate that a sample size of 65 patients would be needed, assuming 100% 
disease prevalence, 70% accuracy of MIBI (sestamibi), an estimated 85% accuracy of FCH 
PET, and 10% dropout rate. 
9.2 
Analyses Plans 
At the time of the imaging study, each scan will be interpreted by a nuclear medicine physician, 
who will be fully cognizant of the clinical, imaging and laboratory data.  Focal uptake on choline 
PET will be reported by location (left/right, location with respect to the thyroid, or description of 
location if atypical), along with measured SUVmax.  These reads will not be used for evaluation 
of the primary endpoint. 
9.2.1 18F-fluorocholine blinded reads 
All 18F-fluorocholine imaging data will be anonymized and collected. PET data will be 
interpreted by three different board certified nuclear medicine readers in a random order at 
separate reading sessions.  Prior to interpretation a training data set using choline PET studies 
not included in the study will be used to train the readers.  Clinical information will not be 
available to the readers at time of interpretation.  Cross sectional imaging from the PET will be 
available for anatomic correlate, but no other imaging study will be available. Each study will be 
characterized by location (left/right, location with respect to the thyroid, or description of location 
if atypical).  “Atypical” refers to adenomas that are not in the thyroid bed and would include the 
mediastinum.  All suspected lesions as well as the single most suspicious lesion will be 
recorded.  For example, in the setting of multiple parathyroid adenomas, one lesion will be 
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The location of each adenoma that is surgically confirmed will be marked in the identical fashion 
(left/right, location with respect to the thyroid [ie inferior or superior], or description of location if 
atypical).  For each reader, lesions will be characterized as follows: 
1. True positive: Location of the suspected adenoma on FCH PET correlates with location 
of an abnormal parathyroid at time of surgery.   For a patient with multiple hyperplastic 
glands, only one gland needs to correlate for the patient to count as a true positive. 
a. For analysis, adenomas described as arising in the mid thyroid bed will 
considered correct if located in either the inferior or superior bed.  
2. False positive: Location of the suspected adenoma on FCH PET does not agree with 
location of an abnormal parathyroid at time of surgery.   
3. True negative: There are no true negatives as patients with primary hyperparathyroidism 
have near 100% incidence of hyperplastic adenomas. 
4. False negative: No evidence of parathyroid adenoma on FCH PET independent of 
findings at time of surgery. 
9.2.2 Sestamibi evaluation 
In patients who had a sestamibi study performed prior to the fluorocholine imaging study, we will 
use the original dictated report from the sestamibi.  This will be done as there may be significant 
bias in the interpretation of the sestamibi studies if re-interpreted.  Identical to the PET data, the 
study reports, will be used to characterized location (left/right, location with respect to the 
thyroid, or description of location if atypical).  All suspected lesions as well as the single most 
suspicious lesion will be recorded. The sensitivity from this analysis will be used as our 
comparator for the FCH PET. For each reader, lesions will be characterized as follows: 
1. True positive: Location of the suspected adenoma on sestamibi correlates with location 
of an abnormal parathyroid at time of surgery.   For a patient with multiple hyperplastic 
glands, only one gland needs to correlate for the patient to count as a true positive. 
a. For analysis, adenomas described as arising in the mid thyroid bed will 
considered correct if located in either the inferior or superior bed.  
2. False positive: Location of the suspected adenoma on sestamibi does not agree with 
location of an abnormal parathyroid at time of surgery.   
3. True negative: There are no true negatives as patients with primary hyperparathyroidism 
have near 100% incidence of hyperplastic adenomas. 
4. False negative: No evidence of parathyroid adenoma on sestamibi independent of 
findings at time of surgery. 
 
The performance of the imaging modalities will be quantified by sensitivity, specificity, positive 
predictive value and negative predictive value.  
Performance will be assessed using surgery as the gold standard with postoperative 
normalization of calcium as the study endpoint as described above.  For this study to have a 
positive outcome, two of the three FCH PET readers have to have a sensitivity that is 10% 
greater than that of sestamibi imaging.   For statistical analysis we will use the McNemars’s test 
with a p-value of 0.05 for significance.  We will also compare the sensitivity of 18F-fluorocholine 
to the predetermined detection sensitivity of 70%.  Again, two of the three FCH PET readers 
have to have a sensitivity that is 10% greater than 70% (ie 80%).  We will also report an 
interreader variability for the FCH PET reads using a Fleiss’s Kappa.  The baseline 
characteristics will be reported as follows: continuous parametric data will be reported as mean 

 
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+/- standard deviation, continuous non-parametric data as medians with interquartile range.  
Dichotomous data will be reported as proportions.  Patients with missing imaging results or 
missing data on the primary endpoint will be excluded from the study.   
In patients who do not subsequently undergo parathyroidectomy, we will use the dictated 
reports to determine the detection sensitive for parathyroid adenomas.  
 
9.3 
Evaluation of Safety 
Analyses will be performed for all patients having received at 18F-fluorocholine.  The study will 
use the NCI CTCAE v4.0. 
 
10 Study Management 
10.1 Pre-study Documentation 
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. 
Before initiating this trial, the Investigator will have written and dated approval from the 
Institutional Review Board for the protocol, written informed consent form, subject recruitment 
materials, and any other written information to be provided to subjects before any protocol 
related procedures are performed on any subjects.   
The clinical investigation will not begin until either FDA has determined that the study under the 
Investigational Drug Application (IND) is allowed to proceed or the Investigator has received a 
letter from FDA stating that the study is exempt from IND requirements.  
The Investigator must comply with the applicable regulations in Title 21 of the Code of Federal 
Regulations (21 CFR §50, §54, and §312), GCP/ICH guidelines, and all applicable regulatory 
requirements.  The IRB must comply with the regulations in 21 CFR §56 and applicable 
regulatory requirements. 
10.2 Institutional Review Board Approval 
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 UCSF Institutional Review Board. The initial protocol and all protocol 
amendments must be approved by the IRB prior to implementation.   
10.3 Informed Consent 
All participants must be provided a consent form describing the study with sufficient information 
for each participant to make an informed decision regarding their participation.  Participants 
must sign the IRB-approved informed consent form prior to participation in any study specific 
procedure.  The participant must receive a copy of the signed and dated consent document.  
The original signed copy of the consent document must be retained in the medical record or 
research file.  

 
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10.4 Changes in the Protocol 
Once the protocol has been approved by the UCSF 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 the 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 (5) working days after implementation.  
The Study Chair and the UCSF study team will be responsible for updating any participating 
sites. 
10.5 Handling and Documentation of Clinical Supplies 
The UCSF Principal Investigator and each participating site 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. 
10.6 Case Report Forms (CRFs) 
The Principal Investigator and/or their 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. The Clinical Research Coordinator (CRC) 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 
UCSF 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 onto CRFs.  The PI will approve all 
completed CRFs to attest that the information contained on the CRFs is true and accurate.  
The Principal Investigator will be responsible for ensuring the accurate capture of study data.  At 
study completion, when the CRFs have been declared to be complete and accurate, the 
database will be locked.  Any changes to the data entered into the CRFs after that time can only 
be made by joint written agreement among the Study Chair, the Trial Statistician, and the 
Protocol Project Manager. 
10.7 Record Keeping and Record Retention 
The Principal Investigator is required to maintain adequate records of the disposition of the 
drug, including dates, quantity, and use by subjects, as well as written records of the disposition 
of the drug when the study ends.   

 
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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 (e.g., signed and dated 
consent forms and medical records, such as 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). 
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. 
In accordance with FDA regulations, the investigator shall retain records for a period of 2 years 
following the date a marketing application is approved for the drug for the indication for which it 
is being investigated; or, if no application is to be filed or if the application is not approved for 
such indication, until 2 years after the investigation is discontinued and FDA is notified. 

 
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References 
1. 
Yeh MW, Ituarte PHG, Zhou HC, et al. Incidence and prevalence of primary 
hyperparathyroidism in a racially mixed population. J Clin Endocrinol Metab. 
2013;98:1122–1129. 
2. 
Alex G, Morris L, Pasieka J, Perrier N. Nonclassical symptoms of primary 
hyperparathyroidism and their response to parathyroidectomy. Am Surg. 2013;79:337–
343. 
3. 
Ruda JM, Hollenbeak CS, Stack BC. A systematic review of the diagnosis and treatment 
of primary hyperparathyroidism from 1995 to 2003. Otolaryngol Head Neck Surg. 
2005;132:359–372. 
4. 
Bilezikian JP, Khan AA, Potts JT, Third International Workshop on the Management of 
Asymptomatic Primary Hyperthyroidism. Guidelines for the management of asymptomatic 
primary hyperparathyroidism: summary statement from the third international workshop. J 
Clin Endocrinol Metab. 2009. pp. 335–339. 
5. 
Sackett WR, Barraclough B, Reeve TS, Delbridge LW. Worldwide trends in the surgical 
treatment of primary hyperparathyroidism in the era of minimally invasive 
parathyroidectomy. Arch Surg. 2002;137:1055–1059. 
6. 
Subesinghe M, Scarsbrook A, Lansdown M, Patel C. Efficacy of upfront sestamibi 
SPECT-CT for localisation of parathyroid adenomas prior to minimally invasive 
parathyroidectomy (MIP). Clinical Radiology. 2013;68. 
7. 
Prommegger R, Wimmer G, Profanter C, et al. Virtual neck exploration: a new method for 
localizing abnormal parathyroid glands. Ann Surg. 2009;250:761–765. 
8. 
Lavely WC, Goetze S, Friedman KP, et al. Comparison of SPECT/CT, SPECT, and 
planar imaging with single- and dual-phase (99m)Tc-sestamibi parathyroid scintigraphy. 
Journal of Nuclear Medicine. 2007;48:1084–1089. 
9. 
Ciappuccini R, Morera J, Pascal P, et al. Dual-phase 99mTc sestamibi scintigraphy with 
neck and thorax SPECT/CT in primary hyperparathyroidism: a single-institution 
experience. Clin Nucl Med. 2012;37:223–228. 
10. 
Quak E, Lheureux S, Reznik Y, Bardet S, Aide N. F18-choline, a novel PET tracer for 
parathyroid adenoma? J Clin Endocrinol Metab. 2013;98:3111–3112. 
11. 
Ishizuka T, Kajita K, Kamikubo K, et al. Phospholipid/Ca2+-dependent protein kinase 
activity in human parathyroid adenoma. Endocrinol Jpn. 1987;34:965–968. 
12. 
Kluijfhout WP, Vriens MR, Valk GD, Barth RE, Borel Rinkes IHM, de Keizer B. (18)F-
Fluorocholine PET-CT enables minimal invasive parathyroidectomy in patients with 
negative sestamibi SPECT-CT and ultrasound: A case report. Int J Surg Case Rep. 
2015;13:73–75. 
13. 
Kluijfhout WP, Vorselaars WMCM, Vriens MR, Borel Rinkes IHM, Valk GD, de Keizer B. 
Enabling minimal invasive parathyroidectomy for patients with primary 

 
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hyperparathyroidism using Tc-99m-sestamibi SPECT-CT, ultrasound and first results of 
(18)F-fluorocholine PET-CT. Eur J Radiol. 2015;84:1745–1751. 
14. 
Lezaic L, Rep S, Sever MJ, Kocjan T, Hocevar M, Fettich J. ¹⁸F-Fluorocholine PET/CT for 
localization of hyperfunctioning parathyroid tissue in primary hyperparathyroidism: a pilot 
study. Eur J Nucl Med Mol Imaging. 2014;41:2083–2089. 
 
 
 

 
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Appendix 1 Schedule of Study Procedures and Assessments 
 
Screening 
(Day -60 to Day 1) 
Imaging 
(Day 1) 
Follow-up (off study) 
(Day 2 to Day 365) 
Informed Consent 
X 
 
 
Inclusion & Exclusion Criteria 
Reviewed 
X 
 
 
Injection of 18F-fluorocholine 
 
X 
 
PET imaging 
- 
PET/MRI or PET/CT 
 
X 
 
Adverse event reporting 
 
X 
 
Clinical follow-up for 
parathyroidectomy results 
 
 
X 
 

 
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Appendix 2 UCSF Policy/Procedure for Required Regulatory Documents for 
UCSF Investigator-Initiated Clinical Trials with an Investigator held Investigational 
New Drug (IND) 
Purpose 
This policy defines the required Regulatory Documents for Single Site and Multicenter 
Investigator Initiated Clinical Trials where the Principal Investigator (PI) holds the IND. 
Background 
The International Conference on Harmonization (ICH) Good Clinical Practices (GCP) Guidelines 
define Essential Regulatory Documents as those documents which individually and collectively 
permit evaluation of the conduct of a trial and the quality of data produced. These documents 
serve to demonstrate compliance with standards of GCP and with all applicable regulatory 
requirements. Filing essential documents in a timely manner can greatly assist in the successful 
management of a clinical trial. 
The Regulatory Documents will consist of electronic files in both iRIS. 
Procedures 
1. Essential Regulatory Documents 
Documents Filed in iRIS: 
• 
IRB approvals for initial submission of application, all modifications, and continuing 
annual renewals 
• 
Current and prior approved protocol versions with signed protocol signature page(s) 
• 
IRB approval letters and Informed Consent Form(s) (ICF) 
• 
Current and prior versions of the Investigator Brochure (IB). 
• 
Serious Adverse Event Reporting 
• 
Protocol Violations and Single Patient Exception (SPE) Reports to IRB with supporting 
fax documentation 
Documents Filed in Regulatory Binder: 
• 
Completed Food and Drug Administration (FDA) 1572 document with Principal 
Investigator’s signature 
• 
For all Principal Investigators and Sub-Investigators listed on the FDA 1572, will need 
Financial Disclosure Forms, CVs, MD Licenses, Drug Enforcement Agency (DEA) 
Licenses, and Staff Training Documents (i.e. Collaborative Institute Training Initiative 
(CITI), etc.) 
• 
Site Initiation Visit (SIV) minutes and correspondence with participating site(s). 
• 
As applicable, approvals for Biosafety Committee, Radiation Committee, and Infusion 
Center 
• 
Serious Adverse Event (SAE) reports to IRB and sponsor. 
• 
MedWatch reporting to FDA and sponsor 
• 
Delegation of Authority Form 
• 
Drug Destruction Standard Operating Procedure (SOP) 
• 
For all laboratories listed on the FDA 1572, will need CLIA certifications, CAP 
certifications, lab licenses, CVs of Lab Directors, and laboratory reference ranges