Evaluation of Thyroid Stunning From a Diagnostic Dose of I-123
Phase: PHASE1
Conditions: Differentiated Thyroid Cancer
Sponsor: University of Colorado, Denver

Protocol 8.0 v. 3.1.18 
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COMIRB Protocol 
 
PROTOCOL #: 
 
12-0300 
 
COLORADO MULTIPLE INSTITUTIONAL REVIEW BOARD 
CAMPUS BOX F-490    TELEPHONE:  303-724-1055  Fax:  303-724-0990 
 
 
 
Project Title: Evaluation of Thyroid Stunning from a Diagnostic Dose of I-123 
Principal Investigator:  Jennifer Kwak, MD 
Version: 8.0 v. 7/26/2018 
 
I. 
Hypotheses and Specific Aims:  
Specific Aim: In a test-retest protocol, determine whether I-123 causes stunning. 
Hypothesis: Pretreatment dosimetry with I-123 does not cause stunning of thyroid tissue and, 
therefore, does not reduce the benefit of subsequent therapeutic doses of I-131. Before I-123 can 
be used as the standard of comparison for other isotopes of radioiodine such as I-124, it must be 
proven that I-123 causes little or no stunning. We propose to address this question with the first 
prospective randomized intra-patient comparison of I-123 dosimetry by doing a I-123 imaging 
study twice, test-retest, before doing routine I-131 remnant ablation. 
 
II. Background and Significance: The annual incidence of differentiated thyroid cancer in the 
United States is approximately 44,000 cases and the annual death rate is approximately 1,700 
individuals (1). Although many patients do well with conventional therapy of surgery and remnant 
thyroid tissue ablation with I-131, a significant minority of patients develop regional and/or 
distant metastases. Initially, these metastases are differentiated and take up iodine and the 
standard of care is I-131 radioiodine therapy. 
 
Currently, most hospitals treat patients with differentiated thyroid metastases with a 
fixed dose of 100 to 200 mCi of 1-131 while a few university centers use individualized dosimetry 
to determine the maximum safe tolerable dose. The dosimetric approach is based on the 
assumption that a larger dose is more likely to ablate residual functioning thyroid cancer than a 
smaller dose. Although the dosimetric approach was described more than 45 years ago by Benua 
(2), there is still no consensus with respect to the advantage of the dosimetric approach over the 
fixed dose (3-9). 
 
In the case of treatment with a fixed dose, the patient is usually treated with a 
therapeutic dose of I-131 without performing a preliminary biodistribution study. However, in the 
case of treatment with the maximum safe dose of I-131 based on dosimetry, it is necessary to give 
an initial small dose of radioiodine, usually I-131, to measure the biodistribution of radioiodine 
and in turn to calculate the maximum dose that the patient can safely tolerate. The dilemma is 
that there is significant, but controversial, evidence that the initial small dose of I-131 may stun 
the thyroid metastases and decrease the uptake of the subsequent therapeutic dose of I-131, 
thus defeating the purpose of dosimetrically determining the maximum safe dose (4,10-20). 
 
The radioisotope of iodine, I-123, is a pure gamma emitter and is thought to be less likely 
to cause stunning than I-131. However, there are some reports that even I-123 can cause stunning 
(21-24). 
 
If it is demonstrated that I-123 does not cause significant stunning, a follow-up separately 
funded prospective study can be designed to determine whether a dosimetrically determined 
dose of I-131 is superior to a fixed dose. If an individually calculated maximum dose is determined 
to be superior, it would suggest that the dosimetric approach, which is currently used in only a 

Protocol 8.0 v. 3.1.18 
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small minority of patients, should be offered to all patients. This would represent a major advance 
in the treatment of patients with metastatic differentiated thyroid cancer. Alternatively, if a 
dosimetrically determined dose of I-131 is not superior to a fixed dose, all patients can be treated 
with the simpler less costly fixed dose regimen.  
 
III. Preliminary Studies/Progress Report:  N/A 
 
IV. Research Methods 
 
A. Outcome Measure(s):  Difference in uptake of I-123 in the thyroid remnant in the neck in 
the two imaging studies. Greater than a 20% decrease from the first to second study will 
indicate evidence of stunning. 
 
B. Description of Population to be Enrolled:   
 
Inclusion criteria: 
1. Patient must be 21-years-old or greater. 
2. Patient must be status post near total thyroidectomy for differentiated 
thyroid cancer without known distant metastases and who are planning to 
undergo routine remnant thyroid tissue ablation with I-131. 
3. Patients must qualify for thyroid ablation with I-131. 
 
Exclusion criteria: 
1. Women who are pregnant or breastfeeding. 
2. Prior bovine TSH use. 
3. Known metastatic thyroid cancer. 
4. History of cardiovascular disease that may adversely affect patient 
participation at the discretion of the primary investigator. 
5. Patients on hemodialysis. 
6. Patients with acute serious illnesses at the discretion of the primary 
investigator. 
 
C. Study Design and Research Methods: The proposed research will be the first study to 
perform test-retest studies in a group of patients to answer the long standing and 
fundamental question of whether diagnostic doses of I-123 cause stunning. Ten patients 
will be studied. If the patient elects to pursue participation in the study, the consent form 
will be explained to the patient 
 
If the patient consents, the patient will undergo two I-123 whole body imaging studies 
prior to the I-131 thyroid remnant ablation.  
 
 
 
 
 
 
 

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Figure 1. General Scheme of Investigational Plan 
The current standard of care is indicated in the solid black boxes and the additional research 
component is the dashed boxes. 
 
 
 
 
Figure 2. Timing of standard of care and research interventions for the study population. 
 
 

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Patient Preparation 
 
 Participants will be placed on a low iodine diet for 1 week before the dosimetry study 
and continue on this diet until 24 hours after the therapeutic dose of 131I.   
Patient is prepared for the study by receiving an intramuscular injection of rhTSH 
(Thyrogen). The patients are prepared for receiving radioiodine by receiving an intramuscular 
injection of rhTSH (Thyrogen) on days 1, 2, 8, 9, 15 and 16 in order to raise the blood level of 
TSH and maximally stimulate the residual thyroid tissue to take up iodine (25-27). The 
Thyrogen received on days 1, 2, 8 and 9 will be provided free of charge by Genzyme. The 
subject’s vital signs will be monitored before and after each Thyrogen injection.  The 
Thyrogen injection will be withheld if vital signs show significant alterations from the patient’s 
baseline. 
Female patients of reproductive age who have not undergone a hysterectomy will 
undergo serum pregnancy tests on days 3 and 17 prior to administration of radioiodine.  
All patients will have blood samples taken on days 3, 10, and 17 in the morning, to 
document that rhTSH was given and that there was a rise in thyroglobulin level (TSH action on 
thyroid cells) prior to administration of radioiodine. 
 
Diagnostic imaging with I-123 
 
On days 3 and 10 the patient is given 3 mCi of 123I orally in the morning.  The participant 
will be asked to fast at least 4 hours before and 1 hour after the I-123 oral dose to control for 
interference with I-123 uptake. 
Imaging with gamma camera from the top of the head to the thighs is performed on days 
4 and 11.  
In each of the I-123 whole body diagnostic imaging studies, one done for research 
purposes and the other as routine care, a region of interest will be placed over the I-123 
uptake in the residual thyroid tissue and the number of counts will be recorded (28). Less 
than a 20% decrease in counts from the first to the second study will be considered no 
significant stunning (29). The Null hypothesis is that there will be less than a 20% decrease in 
I-123 in the thyroid remnant from the first to the second study.  
In order to more accurately measure I-123 uptake in the residual thyroid tissue from the 
I-123 whole body diagnostic image, an I-123 standard will be placed in the field of imaging at 
the time of image acquisition. Use of I-123 standard is common practice for calibrating I-123 
activity in the body. By using an I-123 standard, in addition to recording the number of counts 
in the residual thyroid tissue and comparing the count differences between the first and 
second study, percent uptake of I-123 in the residual thyroid tissue can be calculated for each 
study and compared. Less than a 20% decrease in percent uptake of I-123 in the residual 
thyroid tissue will be considered no significant stunning and provide additional supportive 
data to measuring counts in the residual thyroid tissue. 
 
If thyroid cancer metastases are incidentally discovered in the patient with no known 
metastases, the patient will be removed from the study and referred back to Endocrinology.   
 
Thyroid tissue ablation with I-131 
 
On day 17, the patient is given a fixed therapeutic dose of 131I determined by the 
endocrinologist and nuclear medicine physician (range 30-100 mCi 131I).  

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Post-treatment imaging evaluation 
 
Approximately 7 to 10 days after therapeutic dose of radioiodine (day 23-26), patient 
returns for routine, standard of care post 1131I treatment imaging. 
 
 
D. Description, Risks and Justification of Procedures and Data Collection Tools: A risk of 
participating in this research study is the relatively small additional radiation dose from 
second dosimetric study preceding the standard I-131 therapeutic ablation. Assuming a 
typical 30-100 mCi I-131 ablation dose, the one additional I-123 diagnostic study will 
increase the effective whole body dose by approximately 0.5%-1.6%. The small increase in 
radiation to the remnant thyroid tissue should be of no consequence since it will be 
ablated by the large therapeutic dose of I-131 one week later.  
 
Another possible risk is that the radiation to the thyroid remnant from the initial 
experimental dosimetry studies will stun the remnant to the extent that it may not be 
effectively ablated. This is highly unlikely since the commonly used 30-100 mCi dose of I-
131 is chosen for a significant margin of error so that very few remnants are not 
successfully ablated. 
 
Patient Safety Monitoring Plan: Subject will remain in the clinical area for 20-30 minutes 
after each injection to be assessed for any acute adverse events. Symptoms will be 
recorded before and 20-30 minutes after injections. Subjects will be provided a primary 
phone number and an after-hours phone number to call with any questions or concerning 
symptoms. The most common reported side-effect symptoms are headache observed in 
5% and nausea observed in 5% of patients. I-123 is a well-established FDA approved 
radiopharmaceutical used for diagnostic imaging of thyroid tissue and serious long term 
adverse events have not been reported. As a result, patients will be followed for potential 
adverse events until the completion of the routine standard of care treatment when the 
patient returns on days 23-26 for post-treatment imaging study.  
 
The study Principle investigator, co-investigators and study coordinator will meet monthly 
to review preliminary data and discuss any safety related issues that may arise. The PI will 
be responsible for reporting any serious adverse events that are identified. 
 
E. Potential Scientific Problems: None. 
 
F. Data Analysis Plan: The primary endpoint will be measurement of thyroid remnant 
activity at 24 hours. We predict there will be less than a 20% reduction in the amount of I-
123 in the thyroid remnant when the results of the second administered dose of I-123 is 
compared to the results from the first dose of I-123. The data will be analyzed statistically 
by the t-test and by the sign test. While we plan to study only 10 participants, this should 
be a sufficient number to determine whether there is any evidence of stunning by the 
sign test and, if there is stunning, whether there is more than a 20% stunning effect by 
the t-test. This is a pilot study, but it is likely to give results that are sufficiently definitive 
that it will not need to be repeated with larger numbers of participants. In addition, this is 
an internally funded research project that is intended to generate preliminary data to be 

Protocol 8.0 v. 3.1.18 
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used in a larger NIH grant proposal that will compare fixed versus dosimetrically 
determined I-131 doses for treatment of patients with differentiated thyroid cancer with 
distant metastases. 
 
G. Monitoring and Oversight 
The sponsor investigator will be responsible for monitoring the trial per the trial 
monitoring plan, in addition to overseeing the safety and efficacy of the trial including any 
specimens collected, executing the data and safety monitoring (DSM) plan, and complying 
with all reporting requirements to local and federal authorities. This oversight will be 
accomplished through additional oversight from the Data and Safety Monitoring 
Committee (DSMC) at the University of Colorado Cancer Center (CU Cancer Center).  The 
DSMC is responsible for ensuring data quality and study participant safety for all clinical 
studies at the CU Cancer Center, which is the coordinating institution of this trial.   A 
summary of the DSMC’s activities is as follows: 
 
• Conduct of internal audits 
• Ongoing review of all serious adverse events (SAEs), unanticipated problems (UAPs) and 
reportable adverse events (AEs) 
• Has the authority to close and/or suspend trials for safety or trial conduct issues 
• May submit recommendations for corrective actions to the CU Cancer Center’s 
Executive Committee 
 
Per the CU Cancer Center Institutional DSM Plan, SAEs, UAPs and reportable AEs are 
reported to the DSMC, IRB and the sponsor investigator per protocol.  All SAEs, UAPs and 
reportable AEs are to be reported to the DSMC within 5 business days of the sponsor 
investigator receiving notification of the occurrence. 
 
Each subject’s treatment outcomes will be discussed by the site PI and appropriate staff 
at regularly scheduled meetings.  Data regarding number of subjects, significant toxicities, 
dose modifications, and treatment responses will be discussed and documented in the 
meeting’s minutes. 
 
The sponsor investigator will provide a DSM report to the CU Cancer Center DSMC on a 
six month basis. The DSM report will include a protocol summary; current enrollment 
numbers; summary of toxicity data to include specific SAEs, UAPs and AEs; any dose 
modifications; all protocol deviations; and protocol amendments. The DSM report 
submitted to the DSMC will also include, if applicable, the results of any efficacy data 
analysis conducted.  Results and recommendations from the review of this six month 
report by the DSMC will then be provided to the sponsor investigator in a DSMC review 
letter.  The sponsor investigator is then responsible for ensuring this letter is submitted to 
the site’s IRB of record at the time of IRB continuing review. 
 
Quality Control and Quality Assurance 
 
Site monitoring visits will be performed by the sponsor investigator’s authorized 
representative on a regular basis, pursuant to the Monitoring Plan. During these visits, 
information recorded on the CRFs will be verified against source documents.  Additional 

Protocol 8.0 v. 3.1.18 
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computer programs that identify selected protocol deviations, out-of-range data, and 
other data errors within the electronic data entry may also be used to help monitor the 
study.  As necessary, requests for data clarification or correction will be sent to the 
appropriate site PI. 
 
Independent auditors from the sponsor investigator’s authorized representative will be 
allowed by the site’s PI to audit.  In addition, audits may be conducted at any time by 
appropriate regulatory authorities and/or the IRB. 
 
 
H. Summarize Knowledge to be Gained: There will be no benefits to the human subjects in 
this research project. However, there is likely to be significant benefit to future patients 
with differentiated thyroid cancer. 
 
If it is demonstrated that I-123 does not cause significant stunning, a follow up separately 
funded prospective study can be designed to determine whether a dosimetrically 
determined dose of I-131 is superior to a fixed dose. If an individually calculated 
maximum dose is determined to be superior, it would suggest that the dosimetric 
approach which is currently used in only a small minority of patients should be offered to 
all patients. This would represent a major advance in the treatment of patients with 
metastatic differentiated thyroid cancer. Alternatively, if a dosimetrically determined 
dose of I-131 is not superior to a fixed dose, all patients can be treated with the simpler 
less costly fixed dose regimen. 
 
I. 
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