Clinical trial NCT03787303
Conditions: Metastatic Breast Cancer Thyroid Dysfunction
Sponsor: Aultman Health Foundation
Start date: 2019-03-01; Completion date: 2022-03-09
Enrollment: 7 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Up to one third of breast cancer patients have hypothyroidism or hyperthyroidism. L-thyroxine (T4), or Synthroid, is the most commonly prescribed agent for the management of hypothyroidism in the US. However, there are data suggesting that triiodothyronine (T3) may have benefits in preventing disease progression over l-thyroxine (T4).

Detailed description:
It is estimated that there are approximately 155,000 living with metastatic breast cancer in the US and the number is estimated to increase over the next years (SEER data). Although their median survival has improved over the last 2 decades from 17 months to approximately 24 months attributed to newer treatments, there is an ongoing need for additional strategies and research to improve survival and quality of life.

Many studies have explored the connection between hypothyroidism and hyperthyroidism and breast cancer with varied results ranging up to one third prevalence. Low Triiodothyronine (T3) and elevated Thyroid-Stimulating Hormone (TSH) levels have been detected in newly diagnosed breast cancer patients. Other studies have suggested that some of the common symptoms reported by breast cancer survivors such as fatigue and depression can be attributed to subclinical hypothyroidism.

L-thyroxine (T4) is the most commonly prescribed agent for the management of hypothyroidism in the US. However, there are data suggesting that T4 is a potent pro-oncogenic agent. Proposed mechanisms include stimulation of mitogenesis, angiogenesis and resistance to apoptosis, opposition of anti-PDL-1 and radiation effects. It has been postulated that the avbeta3integrin that is universally expressed on cancer cells harbors a thyroid hormone receptor and T4 interacts with it.

Triiodothyronine (T3) on the other hand, is significantly less oncogenic and less mitogenic and is downstream of T4 which is a T3 pro-hormone. Therefore, exogenous supplementation of T3 would decrease the T4 levels creating the desired state of euthyroid hypothyroxinemia.

The rationale of this study is to replace L-thyroxine (T4) with Triiodothyronine (T3) in hypothyroid patients with metastatic breast carcinoma while they continue to receive standard systemic therapy, titrating the dose to achieve a state of euthyroid hypothyroxinemia which is turn would result in a lower risk of disease progression and improved survival by lowering the concentration of T4.

Arms: arm 1: Following discontinuation of L-thyroxine (T4), triiodothyronine (T3) will be initiated at a 3:1 ratio. The dose will be titrated by the investigator to maintain levels of free T4 \< 50% of normal range while maintaining a euthyroid state. Triiodothyronine (T3) tablets for oral administration will be prescribed once or twice daily depending on the total dose. Treatment duration will be approximately 9 months during which time the subjects will continue to be treated and monitored as usual for their metastatic breast cancer. During the study period and at the conclusion of the study period, there will be continuous evaluations of the disease status and thyroid status with the option of resuming the original thyroid replacement or continuation of the triiodothyronine (T3).
Interventions: intervention 1: Triiodothyronine (T3)
Intervention descriptions: intervention 1: Participants will have their L-thyroxine (T4) discontinued and Triiodothyronine (T3)/liothyronine sodium initiated at 3: 1 and titrated.

Protocol documents:
ICF_002.pdf: 
Page 1 of 10 
_____________________________________ 
Protocol Version Date:  Version 5 [4/8/2020] 
Consent Version Date:  9/30/2020 
Aultman HRRB Review:  10/16/2020 
INFORMED CONSENT DOCUMENT FOR PARTICIPATION 
OF A SUBJECT IN A RESEARCH STUDY 
. 
A Single Arm Phase II Pilot Study of Euthyroid Hypothyroxinemia in 
Metastatic Breast Carcinoma 
Aultman Health Foundation 
 
Principal Investigator 
Shruti Trehan MD 
Your Study Doctor 
Your Study Doctor 
Your Research Coordinator 
Your Research Coordinator 
Aultman Hospital 
Cancer Clinical Trials 
2600 6th St SW 
Canton, OH   44710 
Phone Number: (330) 363-1250 
24 Hour Phone Number: (330) 
438-6333 
  
INTRODUCTION 
This is a clinical trial, a type of research study. Your study doctor will explain the clinical trial to you. 
Clinical trials include only people who choose to take part voluntarily. Please take your time to make 
your decisions about taking part. You may discuss and consult with friends, family and your health care 
team. If you have any questions, you can ask your study doctor for more explanation. 
You are being asked to take part in a research study.  The following information is being given to you to 
explain the purpose of the study, what you will be asked to do as a participant, and the potential risk 
and benefits.  It will also explain that you do not have to participate in this study to receive medical care.  
You are encouraged to ask questions before deciding whether you wish to participate, or at any time 
during the course of the study.  You will be told of any new findings that may influence your decision to 
continue to participate. 
We understand that information about you and your health is personal. We are committed to protecting 
the privacy of that information. Because of this commitment, we must obtain your authorization before 
we may use or disclose your protected health information for the purposes of this clinical trial. Another 
form called the “Authorization to Use and/or Disclose (Release) Individually Identifiable Health 
Information for Research Purposes” provides that authorization and helps us make sure that you are 
properly informed of how this information will be used or disclosed.  


Page 2 of 10 
_____________________________________ 
Protocol Version Date:  Version 5 [4/8/2020] 
Consent Version Date:  9/30/2020 
Aultman HRRB Review:  10/16/2020 
In order to participate in this study, you will be required to sign both this consent document and the 
authorization document.  
WHO IS CONDUCTING THIS STUDY? 
This study is being carried out under the sponsorship of Aultman Health Foundation. 
WHAT IS THE USUAL TREATMENT OF HYPOTHYROIDISM IN METASTATIC BREAST CANCER PATIENTS? 
You are being asked to participate in this study because you have metastatic breast cancer. 
Approximately 20 out of every 100 patients with metastatic breast cancer will also have hypothyroidism, 
or low thyroid function, which is most commonly treated with levothyroxine or T4 (SYNTHROID TM), an 
oral thyroid replacement therapy. 
WHAT ARE MY OTHER CHOICES IF I DO NOT TAKE PART IN THIS STUDY? 
If you decide not to take part in this study, you have other choices. For example: 
• 
You may choose to have the usual approach described above. 
• 
You may choose to take part in a different study, if one is available. 
WHY IS THIS STUDY BEING DONE? 
The purpose of this study is to compare any good and bad effects of using triiodothyronine or T3 to 
levothyroxine in patients who are undergoing treatment for metastatic breast cancer and have 
hypothyroidism or low thyroid function. This study will allow researchers to test whether this new 
approach is better, the same, or worse than the usual approach of using levothyroxine.  The study will 
also look at what percentage of women who are undergoing treatment for metastatic breast cancer 
have underactive thyroid function or hypothyroidism. 
Triiodothyronine has been approved by the Food and Drug Administration (FDA) of the United States for 
the treatment of hypothyroidism. Triiodothyronine and levothyroxine both work by providing 
replacement thyroid hormone but are felt to have different effects on cancer cells which is why the 
study is being conducted.  
The study researchers would also like to learn more about fatigue and quality of life. All study 
participants will be asked to complete a standardized questionnaire, commonly referred to as FACT-B. 
WHAT ARE THE STUDY GROUPS? 
This is a Phase II trial so all the study participants will be in one group.  All participants will be prescribed 
triiodothyronine (CYTOMEL/liothyronine sodium).   
Approximately 30 subjects will be enrolled in this study. 
 


Page 3 of 10 
_____________________________________ 
Protocol Version Date:  Version 5 [4/8/2020] 
Consent Version Date:  9/30/2020 
Aultman HRRB Review:  10/16/2020 
STUDY PROCEDURES 
Initial thyroid screening tests will determine if you qualify for the study.   The study will also require an 
electrocardiogram (often called ECG or EKG, a heart tracing device) at baseline.  
Once the baseline screening tests are completed you will meet with the study team and you will be 
switched from levothyroxine (T4) to triiodothyronine (T3) (CYTOMEL/liothyronine sodium).  You will be 
asked to stop taking your levothyroxine (T4) and wait four (4) days before you start taking the study 
medication triiodothyronine (T3).  
You will take your prescribed dose of triiodothyronine (CYTOMEL/liothyronine sodium) tablet(s) every 
day.  Your study doctor will prescribe whether you should take the study medication once per day, or 
twice per day.   It is suggested that you take the study drug each day at the same time.  The tablets 
should NOT be crushed.    
You will be asked to take the study drug, triiodothyronine, for 9 months.    At the end of this period it 
will be up to you and your physician whether you stay on triiodothyronine or switch back to 
levothyroxine.  There is a follow up visit at 12 months.   
There are prescriptions, over the counter medications and dietary supplements (sometimes known as 
alternative or complementary) which may interact with the study drugs and cause side effects.  You 
should provide a complete list of all your medications and supplements at the time of enrollment to the 
study.    
Tell your doctor about all other medicines you use, especially: 
• 
antidepressants; 
• 
birth control pills or hormone replacement therapy; 
• 
blood thinner such as warfarin (Coumadin, Jantoven); 
• 
digoxin (digitalis, Lanoxin); 
• 
epinephrine (EpiPen) or norepinephrine (Levophed); 
• 
insulin or oral diabetes medication; 
• 
medications that contain iodine (such as I-131); 
• 
salicylates such as aspirin, Nuprin Backache Caplet, Kaopectate, Pamprin Cramp Formula, Pepto-
Bismol; or 
• 
steroid medication such as prednisone. 
This list is not complete and other drugs may interact with Cytomel/liothyronine sodium.   Tell your 
doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal 
products. Do not start a new medication without telling your doctor.   


Page 4 of 10 
_____________________________________ 
Protocol Version Date:  Version 5 [4/8/2020] 
Consent Version Date:  9/30/2020 
Aultman HRRB Review:  10/16/2020 
You will undergo periodic blood testing to determine and adjust your dose as needed to maintain a 
satisfactory thyroid level. Your oncologist will continue your cancer treatment such as chemotherapy or 
hormonal therapy.   
You will also have blood work and scans per treating physician’s discretion to monitor the status of your 
cancer.  
You will complete the quality of life survey at time of enrollment and then every 12 weeks for the 
duration of the study.  The questionnaire will take approximately 10-15 minutes to complete. 
HOW LONG WILL I BE IN THIS STUDY? 
You will be followed for approximately 1 year.  The clinical trial team will work closely with you and your 
other health care providers.   
WHAT EXTRA TESTS AND PROCEDURES WILL I HAVE IF I TAKE PART IN THIS STUDY? 
Most of the exams, tests, and procedures you will have are part of the usual approach for your cancer 
care. However, there are some extra tests and procedures that will need to be completed. Baseline 
blood work and electrocardiogram (heart tracing) will be completed.  In the beginning of the study you 
will see the clinical trial team every 4 weeks for the first 12 weeks.  At these visits you will have blood 
work drawn to monitor your thyroid status.  After 12 weeks, blood work will be ordered every 12 weeks, 
or more often if the study doctor feels it is necessary.  You will be required to attend clinic visits with the 
study doctor every 12 weeks throughout the duration of the study.  Scans will be ordered by your 
treating oncologist. You will be requested to complete a questionnaire at the time of enrollment and at 
each clinic visit. 
WHAT POSSIBLE RISKS CAN I EXPECT FROM TAKING PART IN THIS STUDY? 
If you choose to take part in this study, the following is a list risks that you may experience: 
-Lose time at work or home and spend more time in the hospital or doctor’s office then usual. 
-Be asked sensitive or private questions which you normally do not discuss.  You have the right not to 
answer any questions you are not comfortable with. 
-The drug used in this study may affect how different parts of your body work, especially your thyroid 
levels. The study doctor will be testing your blood and will let you know if changes occur that may affect 
your health.  
-There is also a risk that you may have side effects from the study drug.  
Here are important points about side effects: 
• 
The study doctors do not know who will or will not have side effects. 
• 
Some side effects may go away, some may last a long time, or some may never go away. 
• 
Some side effects may be serious and may even result in death.  


Page 5 of 10 
_____________________________________ 
Protocol Version Date:  Version 5 [4/8/2020] 
Consent Version Date:  9/30/2020 
Aultman HRRB Review:  10/16/2020 
Here are important points about how you and the study doctor can make side effects less of a 
problem: 
• 
Tell the study doctor if you notice or feel anything different, so they can determine if you 
are having a side effect. 
• 
The study doctor may be able to treat some side effects. 
• 
The study doctor may adjust the study drug to try and reduce side effects.  
 
Possible side effects of Triiodothyronine/liothyronine sodium 
Per product labeling adverse reactions, other than those indicative of hyperthyroidism because of 
overdose are rare.  In rare instances, allergic skin reactions have been reported. 
Signs and symptoms of overdose include: Headache, irritability, nervousness, sweating, arrhythmia 
(including tachycardia), increased bowel motility and menstrual irregularities. Chest pain or heart failure 
may be induced or aggravated. Shock may also develop. Massive overdosage may result in symptoms 
resembling thyroid storm.  
Other side effects include: 
• 
Fatigue 
• 
Temporary hair loss/thinning of hair 
Unanticipated side effects may occur which have not been reported. If you have any unusual 
symptoms, report them immediately to your doctor.  
WHAT POSSIBLE BENEFITS CAN I EXPECT FROM TAKING PART IN THIS STUDY? 
It is not possible to know at this time if the study drug, triiodothyronine is better than the usual 
approach, so this study may or may not help you. This study will help researchers learn things that will 
help people in the future. 
CAN I STOP TAKING PART IN THIS STUDY? 
Yes. You can decide to stop at any time. If you decide to stop for any reason, it is important to let the 
study doctor know as soon as possible so that you can stop safely. If you stop, you can decide whether 
or not to let the study doctor continue to provide your medical information to the research team.  
The study doctor will tell you about new information or changes in the study that may affect your health 
or your willingness to continue in the study.  


Page 6 of 10 
_____________________________________ 
Protocol Version Date:  Version 5 [4/8/2020] 
Consent Version Date:  9/30/2020 
Aultman HRRB Review:  10/16/2020 
The study doctor may take you out of the study: 
• 
If your health changes and the study is no longer in your best interest 
• 
If new information becomes available 
• 
If you do not follow the study rules 
• 
If the study is stopped by the sponsor, IRB or FDA.  
 
WHAT ARE MY RIGHTS IN THIS STUDY? 
Taking part in this study is your choice. No matter what decision you make, and even if your decision 
changes, there will be no penalty to you. You will not lose medical care or any legal rights. 
If you have any questions about YOUR RIGHTS AS A RESEARCH SUBJECT, contact the Aultman Health 
Foundation Human Research Review Board in the Office of Research, 2600 Sixth Street SW, Canton, 
Ohio 44710 (330-323-6793) (email HumanResearch.ReviewBoard@aultman.com) You may contact them 
if you feel under any pressure to enroll or continue to participate in this study.  
WHAT ARE THE COSTS OF TAKING PART IN THIS STUDY? 
The triiodothyronine/liothyronine sodium will be prescribed by the study doctor.  You have the option 
to have the prescription filled at Aultman Hospital, or you may have it filled at a pharmacy of your 
choice.   The cost of the medication will be charged to you or your insurance company.  The cost of 
triiodothyronine/liothyronine sodium may be higher depending upon your prescription coverage plan.   
There is limited funding available to help cover the medication costs for patients that qualify for 
Aultman’s financial assistance programs (application for eligibility required).   The blood work and 
electrocardiogram required as part of this study will be provided to you free of charge.  Costs of clinic 
visits and disease monitoring are considered routine care and therefore will be billed to you or your 
insurance company. 
You and/or your health plan/insurance company will need to pay for all the other costs of treating your 
cancer while in this study, including the cost of tests, procedures, or medicines to manage any side 
effects, unless you are told that certain tests are supplied at no charge. Before you decide to be in the 
study, you should check with your health plan or insurance company to find out exactly what they will 
pay for. 
You will not be paid for taking part in this study. 
WHAT HAPPENS IF I AM INJURED OR HURT BECAUSE I TOOK PART IN THIS STUDY? 
If you are injured or hurt as a result of taking part in this study and need medical treatment, please tell 
your study doctor.  
Aultman will provide necessary medical treatment but they have not arranged to provide compensation 
for any injury you may suffer as a direct consequence of the non-negligent performance of the 


Page 7 of 10 
_____________________________________ 
Protocol Version Date:  Version 5 [4/8/2020] 
Consent Version Date:  9/30/2020 
Aultman HRRB Review:  10/16/2020 
procedures described above. However, by signing this form, you do not give up your right to seek 
payment for harm you receive while participating in this study.  The costs for treatment will be billed to 
your insurance company.  If you have no insurance, you would be responsible for any costs. You should 
check with your insurance company to see what they will cover.   
WHO WILL SEE MY MEDICAL INFORMATION? 
Your privacy is very important to us and the researchers will make every effort to protect it. Your 
information may be given out if required by law. For example, certain states require doctors to report to 
health boards if they find a disease such as tuberculosis. However, the researchers will do their best to 
make sure that any information that is released will not identify you. Some of your health information 
will be kept in a central database for research. Your name or contact information will not be put in the 
database. 
There are organizations that may inspect your records. These organizations are required to make sure 
your information is kept private, unless required by law to provide information. Some of these 
organizations are: 
• 
Aultman Health Foundation Human Research Review Board, a group of people who review 
research with the goal of protecting those who take part in the study. 
• 
Aultman Cancer Center 
• 
The Food and Drug Administration  
• 
National Cancer Institute in the United States of America. 
WHERE CAN I GET MORE INFORMATION? 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by US 
Law. This website will not include information that can identify you. At most, the website will include a 
summary of the results. You can search the website at any time.  
WHO CAN ANSWER QUESTIONS ABOUT THIS STUDY? 
You can talk to your study doctor or your research coordinator about any questions or concerns you 
have about this study or to report side effects or injuries. Contact your study doctor or your research 
coordinator at the telephone number and address listed on the first page.  
If you have any questions about COMPENSATION OR MEDICAL TREATMENT FOR RESEARCH-RELATED 
INJURIES contact the Aultman Health Foundation Human Research Review Board in the Office of 
Research, 2600 Sixth St SW, Canton, Ohio 44710 (330-363-6793) (email: 
HumanResearch.ReviewBoard@aultman.com) 


Page 8 of 10 
_____________________________________ 
Protocol Version Date:  Version 5 [4/8/2020] 
Consent Version Date:  9/30/2020 
Aultman HRRB Review:  10/16/2020 
If you have any question about YOUR RIGHTS AS A RESEARCH SUBJECT, contact the Aultman Health 
Foundation Human Research Review Board in the Office of Research, 2600 Sixth St SW, Canton Ohio 
44710 (330-363-6793) (email: HumanResearch.ReviewBoard@aultman.com) 
You may also contact them if you feel under any pressure to enroll or continue to participate in this 
study.  
 
OPTIONAL SUBSTUDY:  RECORDS FOLLOW-UP FOR PARTICIPANTS WHO DO NOT MEET 
ELIGIBILITY FOR TREATMENT STUDY 
If you do not meet eligibility for participation in the treatment portion of this study, the investigators of 
this study would like to follow your health through medical records review.  Your treatment plan and 
monitoring are at the discretion of your treating physician, not this study plan.  We are only asking to 
collect information on the care that you receive as part of standard practice.  Please indicate your 
willingness to participate in this optional follow-up sub-study.   
___ I agree to medical records follow-up if I do not qualify for the treatment portion of this study. 
___ I DO NOT agree to medical records follow-up if I do not qualify for the treatment portion of this 
study.   
 
 
 
 
 
 
 
 
 
 
 
 


Page 9 of 10 
_____________________________________ 
Protocol Version Date:  Version 5 [4/8/2020] 
Consent Version Date:  9/30/2020 
Aultman HRRB Review:  10/16/2020 
CONSENT TO PARTICIPATION IN STUDY 
By signing my name below, I confirm the following: 
• 
I have read (or had read to me) this entire consent document.  All of my questions have 
been answered to my satisfaction. 
• 
The study’s purpose, procedures, risks and possible benefits have been explained to me.   
• 
I agree to let the study team use and share the health information and other information 
gathered for this study. 
• 
I voluntarily agree to participate in this research study.  I agree to follow the study 
procedures as directed.  I have been told that I can stop at any time. 
IMPORTANT:  You will be given a copy of this signed document for your records.  A second copy will be 
kept together with the Investigator’s research records on this study.  A third copy will be placed in your 
Aultman Hospital medical record. 
Please keep it where you can find it easily.  It will help you remember what we discussed today. 
Research Participant’s Name [PRINT]: 
Research Participant’s Signature: 
Date/Time 


Page 10 of 10 
_____________________________________ 
Protocol Version Date:  Version 5 [4/8/2020] 
Consent Version Date:  9/30/2020 
Aultman HRRB Review:  10/16/2020 
INVESTIGATORS CONFIRMING STATEMENT 
I have given this research subject information on the study, which in my opinion is accurate and 
sufficient for the subject to understand fully the nature, risks and benefits of the study, and the rights of 
a research subject.  There has been no coercion or undue influence.   
INVESTIGATOR/INDIVIDUAL OBTAINING CONSENT 
Date 
I have explained the purpose of the research, the study procedures, identifying those that are investigational, the 
possible risks and discomforts and potential benefits.  I have answered any questions regarding the research study 
to the best of my ability. 
SIGNATURE OF TREATING PHYSICIAN 
Date 
My signature certifies I am the physician medically responsible for the subject enrolled in this research study. 
 
 
 
 
 
 
 

SAP_003.pdf: 
B-TREUH 
NCT03787303 
Study of Euthyroid Hypothyroxinemia in Metastatic Breast Carcinoma 
Shruti Trehan, MD 
April 14, 2022 


STATISTICAL ANALYSIS  
Statistical Methods  
 Compared mean scores over time to identify whether there were differences over time periods.  
 Repeated measures analysis of variance (ANOVA) over 4 time periods to see if there was a statistical 
significance. 

Prot_000.pdf: 
Page 1 of 11 
 
A Single Arm Phase II Pilot Study of Euthyroid Hypothyroxinemia in Metastatic Breast 
Carcinoma 
 
*Principal Investigator: Shruti Trehan, MD 
**Co-Investigators: Suzanne Cheng, MD 
Sponsor:  Aultman Health Foundation 
Protocol ID:  2018.08.ST 
ClinicalTrials.gov Identifier:  NCT03787303 
Version:  5.0 [April 8, 2020] 
*, ** This is the intellectual property of the above mentioned and may not be reproduced, used, claimed 
ownership, republished, reprinted, created and/or generated regarding its content without our written and 
legal consent. 
 
1.0 
Background and Rationale: 
It is estimated that there are approximately 155,000 living with metastatic breast cancer in the 
US and the number is estimated to increase over the next years (SEER data).  Although their 
median survival has improved over the last 2 decades from 17 months to approximately 24 
months attributed to newer treatments, there is an ongoing need for additional strategies and 
research to improve survival and quality of life. (2,3,4) 
Many studies have explored the connection between hypothyroidism and hyperthyroidism and 
breast cancer with varied results ranging up to one third prevalence.  Low T3 and elevated TSH 
levels have been detected in newly diagnosed breast cancer patients. Other studies have 
suggested that some of the common symptoms reported by breast cancer survivors such as 
fatigue and depression can be attributed to subclinical hypothyroidism. (2,3,4) 
L-thyroxine (T4) is the most commonly prescribed agent for the management of hypothyroidism 
in the US. However, there are data suggesting that T4 is a potent pro-oncogenic agent. Proposed 
mechanisms include stimulation of mitogenesis, angiogenesis and resistance to apoptosis, 
opposition of anti-PDL-1 and radiation effects.  It has been postulated that the avbeta3integrin 
that is universally expressed on cancer cells harbors a thyroid hormone receptor and T4 
interacts with it. (2,3,4) 
Triiodothyronine (T3) on the other hand, is significantly less oncogenic and less mitogenic and is 
downstream of T4 which is a t3 pro-hormone. Therefore, exogenous supplementation of T3 
would decrease the T4 levels creating the desired state of euthyroid hypothyroxiemia. (2,3,4) 


Page 2 of 11 
 
Previous Data 
Phase 2 clinical trial of recurrent GBM (Hercbergs et. al) demonstrated that this strategy was 
feasible and tolerable however due to small numbers and heavily pretreated population with 
high (expected) mortality, conclusive results are pending. (2,3) 
Cross sectional retrospective compassionate use study inducing euthyroid hypothyroxinemia 
successfully reported improved progression free and overall survival in patients with high grade 
synovial sarcoma and brain stem glioma 8 and 7 years. (2,3) 
Rationale and Hypothesis 
The rationale of this study is to replace L-thyroxine (T4) with Triiodothyronine (T3) in 
hypothyroid patients with metastatic breast carcinoma while they continue to receive standard 
systemic therapy, titrating the dose to achieve a state of euthyroid hypothyroxinemia which in 
turn would result in a lower risk of disease progression and improved survival by lowering the 
concentration of T4.  
2.0 
Primary Objective 
1. To prospectively evaluate the progression-free survival in hypothyroid patients with 
metastatic breast carcinoma who are rendered euthyroid and hypothyroxinemic. 
Secondary Objectives 
1. To quantitate the prevalence of hypothyroidism in metastatic breast cancer patients. 
2. To monitor QOL at baseline, 3, 6, 9 and 12 months.  
3. To prospectively study the feasibility and average time required to achieve the euthyroid                     
hypothyroxinemia state in qualifying patients.  
 
3.0 
Investigational Plan / Schema 
This is a single site Phase 2 interventional pilot study of euthyroid hypothyroxinemia in 
patients diagnosed with metastatic breast carcinoma.  The study will enroll 
approximately 30 participants.  It is anticipated that recruitment will take up to four (4) 
years.  End of the study is the date of the last visit or last scheduled procedure for the 
last patient. An Intent-to Treat (ITT) population with a priori planned subgroup analysis 
will be used for analysis purposes.   
Study Design:  All enrolled participants will undergo baseline screening lab work (TSH, 
FreeT3, FreeT4, CBC, CMP), EKG and physical examination.   Once it is determined that they 
meet eligibility criteria they will have their L-thyroxine (T4) discontinued and 
Triiodothyronine (T3) initiated.  The Triiodothyronine (T3) will be titrated by the investigator to 


Page 3 of 11 
 
maintain levels of free T4 < 50% normal range.  Treatment duration will be 9 months.  Disease 
status will be assessed at 3, 6, 9, and 12 months. 
Eligibility Criteria 
• 
Age greater than or equal to 18 
• 
Male or female with diagnosis of metastatic breast carcinoma and documented history 
of hypothyroidism .   
• 
TSH level within normal range at baseline  
• 
Life expectancy estimated > 3 months 
• 
Ability and willingness to provide informed consent 
Exclusion Criteria 
• 
Life expectancy estimated to be less than 3 months  
• 
Is currently pregnant or intends to become pregnant during the duration of the study 
• 
Active angina, NYHA advanced [Class III/IV] CHF, or uncontrolled cardiac arrhythmia 
within 6 months of enrollment 
• 
History of thyrotoxicosis or adrenal insufficiency unless previously treated > 5 years ago 
and resolved without active replacement hormonal therapy as per Principal 
Investigator discretion. 
• 
Hypersensitivity to any active or extraneous constituents in Cytomel/liothyronine 
sodium 
4.0 
Study Procedures 
It is anticipated that 20% of the patients with metastatic breast cancer will qualify for 
participation in this study.  Patients who screen fail after meeting initial eligibility will be asked 
to allow record follow-up so the data can be used for the initial endpoint of prevalence. 
Rescreening will not be permitted.   
Following consent and confirmation of eligibility participants will have their L-thyroxine (T4) 
discontinued and Triiodothyronine (T3)/liothyronine sodium initiated at 3: 1 mcg respectively.  
Study will allow use of Triiodothyronine (cytomel/liothyronine) and all available generic 
liothyronine sodium compounds. Triiodothyronine dosing will be rounded up to the closest 
commercial dose available.  For patients on L-thyroxine there will be a washout period of four 
(4) days between discontinuation and the initiation of triiodothyroinine.    Day 0 will be the day 
of enrollment.  Day 1, or day 5 (if washout required) will be the day of the first dose of 
Triiodothyronine  treatment.   Triiodothyronine tablets are administered orally as a once a day 
dosing, or split dosing at the Investigators discretion.  Usual maintenance dose is 25 to75mcg 
daily.   It will be recommended that the drug be taken at the same time each day, but this is not 
mandatory.  


Page 4 of 11 
 
Drug titration will be in accordance with thyroid function testing to maintain levels of free T4 at 
<50% normal range.  The treatment period will continue for 9 months (270 days).  In the event 
of loco/regional recurrence or progression there is no need to discontinue study treatment 
because this is not one of the endpoints.   
During the treatment period participants will have lab testing every 4 weeks for the first 12 
weeks and then every 12 weeks until study drug is discontinued.  Participants will be scheduled 
for a clinic visit every 12 weeks.  Compliance with Triiodothyronine (T3) and adverse events will 
be assessed at each clinic visit.  Disease state will be assessed at 3, 6, 9, and 12 months via 
clinical examination, laboratory results and radiographic findings performed as part of routine 
care.  Participants will also be asked to complete a Quality of Life survey (FACT-B) at each clinic 
visit.   
Unscheduled visits and management for metastatic breast cancer are at the discretion of the 
investigator. Unscheduled visits may include physical examinations, vital signs, ECOG 
performance status, concomitant medication, adverse event collection, disease symptoms 
assessment, laboratory testing, Triiodothyronine (T3) dose adjustments, or to resumed dosing, if 
previously interrupted. 
Discontinuation of Study Treatment:  At the end of the treatment period, the investigator will 
have the discretion to resume thyroxine or continue Triiodothyronine (T3); however, if it is not 
covered by insurance the patient will be responsible.      
If subjects discontinue study treatment prematurely for any reason they will be asked to 
continue follow-up until study completion. 
All patients will be scheduled for a 12-month safety follow-up visit. 
 


Page 5 of 11 
 
TABLE 1: SCHEDULE OF STUDY PROCEDURES  
Study Phase 
Screening 
Study Visits 
Follow Up Visit 
Visit  
 
3mo 
(+/- 14 
days) 
6mo 
(+/- 14 
days) 
9mo 
(+/- 14 
days) 
12mo 
(+/- 14 days) 
ECOG PS 
X 
X 
X 
X 
X 
Informed Consent 
X 
 
 
 
 
Review Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
Demographics/Medical History 
X 
 
 
 
 
Physical Examination 
X 
X 
X 
X 
X 
Vital Signs: BP, HR, RR 
X 
X 
X 
X 
X 
EKG 
X 
 
 
 
 
Disease assessment 
X 
X 
X 
X 
X 
FACT-B QOL questionnaire 
X 
X 
X 
X 
X 
Prior/Concomitant Medications 
X 
X 
X 
X 
X 
Clinical Laboratory 
Evaluation* 
X 
X 
X 
X 
X 
Pregnancy Test (women of 
childbearing potential only) 
X 
 
 
 
 
Adverse Event Assessment 
X 
X 
X 
X 
X 
• 
*TSH, FreeT3, FreeT4, CBC, CMP every 4 weeks for the first 12 weeks and then every 12 weeks 
until end of study.  
• 
Additional lab work at physician’s discretion. 
Study Drug 
Cytomel (liothyronine sodium) is a commercially available compound which is a synthetic 
formulation of triiodothyronine.  Study drug may be obtained from the Aultman Hospital Retail 
Pharmacy or the pharmacy of the participants choice.  The cost will be charged to the 
participant/insurance company unless they meet the hospital’s indigent policy, in which case study 
drug will be provided free of charge. 
Cytomel capsules should not be opened, crushed, or chewed. Patients should store the Cytomel 
capsules in the original package provided and be instructed to keep all medication out of reach of 
children.   Further details obtained from accessdata.fda.gov. can be found in appendix D.   
 
HOW SUPPLIED 
Cytomel (liothyronine sodium) Tablets: 5 mcg in bottles of 100; 
25 mcg in bottles of 100; and 50 mcg in bottles of 100. 
5 mcg 100’s: NDC 52604-3414-1 
25 mcg 100’s: NDC 52604-3416-1 
50 mcg 100’s: NDC 52604-3417-1 
Store between 15° and 30°C (59° and 86°F). 


Page 6 of 11 
 
 
The Investigator is submitting this study as IND exempt.  Cytomel or liothyronine sodium are being 
used in this study in accordance with approved indications. 
 
5.0 STUDY ADMINISTRATION 
Data Collection and Management 
• 
Data collection for this study will be recorded on paper case report forms.  A compilation 
of the data will be stored in password-protected excel files and follow HIPPA guidelines 
• 
Access to study data will limited to investigator and delegates who have an active role in 
the study. 
• 
The identifiers will be destroyed after publication.  The other data will be retained for 
three years.   
• 
Data sources (if applicable, for existing records) include office and hospital records. 
 
Confidentiality 
All data and records generated during this study will be kept confidential in accordance with 
Institutional policies and HIPAA on subject privacy and that the Investigator and other site 
personnel will not use such data and records for any purpose other than conducting the study.  
No identifiable data will be used for future studies without first obtaining IRB approval. The 
investigator will obtain a data use agreement between provider (the PI) and any recipient 
researchers (before sharing a limited dataset (dates and zip codes)).  
Risk Assessment 
Per Cytomel/liothyronine sodium product labeling adverse reactions, other than those indicative 
of hyperthyroidism because of therapeutic overdose are rare.  In rare instances, allergic skin 
reactions have been reported. 
Signs and symptoms of overdose include: Headache, irritability, nervousness, sweating, 
arrhythmia (including tachycardia), increased bowel motility and menstrual irregularities. Angina 
pectoris or congestive heart failure may be induced or aggravated. Shock may also develop. 
Massive overdosage may result in symptoms resembling thyroid storm. Chronic excessive dosage 
will produce the signs and symptoms of hyperthyroidism.  
Dosage should be reduced or therapy temporarily discontinued if signs and symptoms of 
overdosage appear. Treatment may be reinstituted at a lower dosage. In normal individuals, 
normal hypothalamic-pituitary-thyroidaxis function is restored in 6 to 8 weeks after thyroid 
suppression. 
Thyroid hormones do not readily cross the placental barrier. The clinical experience to date 
does not indicate any adverse effect on fetuses when thyroid hormones are administered to 
pregnant women. 


Page 7 of 11 
 
 
Precautions: Thyroid hormones should be used with great caution in a number of circumstances 
where the integrity of the cardiovascular system, particularly the coronary arteries, is suspected. 
These include patients with angina pectoris or the elderly, in whom there is a greater likelihood 
of occult cardiac disease. In these patients, liothyronine sodium therapy should be initiated with 
low doses, with due consideration for its relatively rapid onset of action. 
Thyroid hormone therapy in patients with concomitant diabetes mellitus or insipidus or adrenal 
cortical insufficiency aggravates the intensity of their symptoms. Appropriate adjustments of the 
various therapeutic measures directed at these concomitant endocrine diseases are required. 
Hypothyroidism decreases, and hyperthyroidism increases the sensitivity to oral anticoagulants. 
Prothrombin time should be closely monitored in thyroid-treated patients on oral anticoagulants 
and dosage of the latter agents adjusted on the basis of frequent prothrombin time 
determinations.  
In cases of concomitant diabetes mellitus, the daily dosage of antidiabetic medication may need 
readjustment as thyroid hormone replacement is achieved. If thyroid medication is stopped, a 
downward readjustment of the dosage of insulin or oral hypoglycemic agent may be necessary to 
avoid hypoglycemia. At all times, close monitoring of urinary glucose levels is mandatory in such 
patients. 
Potential Benefits of Study Participation 
Direct benefits are unknown, but intervention may improve quality of life and prolong 
progression free survival.    
Indirect benefits for the greater good of society and science. 
Recruitment Strategy 
Patients with the diagnosis of metastatic breast cancer and estimated life expectancy of greater 
than 3 months will be identified either by the investigators from within their practice or referred 
by other oncologists in the community. 
Potential and eligible participants will be screened by collection of data (via medical record 
review, direct query or other procedures), and this screening will take place before subjects’ 
consent to participation in the study. 
Investigator will notify and coordinate care with all physicians involved in the patients care, 
specifically primary care physician (PCP), endocrinologist and cardiologist.  
Informed Consent/Assent and HIPAA Authorization 
In order to protect human rights this study will be conducted in full conformance with principles 
of “Declaration of Helsinki” and Good Clinical Practice. The investigator, or delegate, will obtain 
informed consent/ HIPAA Authorization. Patient privacy will be assured as per HIPPA. Potential 


Page 8 of 11 
 
participants will be permitted ample time to make a decision regarding participation. Every effort 
will be made to ensure that the patient comprehends the nature of the study and to avoid 
coercion and facilitate an informed consent process.  This study will comply with all 
policies/procedures set forth for research at Aultman Health Foundation under the guidance of 
the Human Research Review Board (HRRB). 
6.0 
Safety Management 
Data Monitoring 
The investigator will ask the HRRB/Compliance Office to assign a data monitor to review each 
case for eligibility, adherence to the protocol, occurrence of adverse events, and accuracy of 
data.  The first review will be conducted after enrolling the first 5 patients. Regular reviews will 
be scheduled at increments of 10 randomized patients until enrollment goals are met. 
Unscheduled random chart audits may be performed to ensure data integrity. Any deficiencies 
found during these reviews will be addressed and reported to the PI, HRRB and federal agencies 
as appropriate. 
Clinical Adverse Events 
Clinical adverse events (AEs) will be monitored throughout the study by the Principal 
Investigator.  
Definition of an Adverse Event 
An adverse event is any untoward medical occurrence in a subject who has received an 
intervention (drug, biologic, or other intervention).  The occurrence does not necessarily have to 
have a causal relationship with the treatment.  An AE can therefore be any unfavorable or 
unintended sign (including an abnormal laboratory finding, for example), symptom, or disease 
temporally associated with the use of a medicinal product, whether or not considered related to 
the medicinal product. 
All AEs (including serious AEs) will be noted in the study records with a full description including 
the nature, date and time of onset, determination of non-serious versus serious, intensity (mild, 
moderate, severe), duration, causality, and outcome of the event. 
Definition of a Serious Adverse Event (SAE) 
An SAE is any adverse drug experience occurring at any dose that results in any of the following 
outcomes:  
• 
death, 
• 
a life-threatening event (at risk of death at the time of the event),  
• 
requires inpatient hospitalization or prolongation of existing hospitalization, 
• 
a persistent or significant disability/incapacity, or 


Page 9 of 11 
 
• 
a congenital anomaly/birth defect in the offspring of a subject.   
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug event when, based upon appropriate 
medical judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
Relationship of SAE to study drug or other intervention 
The relationship of each SAE to the study intervention should be characterized using one of the 
following terms: definitely, probably, possibly, unlikely or unrelated.  
Follow-up report 
If an SAE has not resolved at the time of the initial report and new information arises that 
changes the investigator’s assessment of the event, a follow-up report including all relevant new 
or reassessed information (e.g., concomitant medication, medical history) should be submitted to 
the HRRB. The Investigator is responsible for ensuring that all SAEs are followed until either 
resolved or stable.  
Adverse Event Reporting 
The Investigator is responsible for recording and reporting unanticipated problems related to 
research that occur during and after study treatment.  Given the safety profile of the 
investigational product Serious Adverse Events (SAEs) are not expected.   All local SAEs will be 
reported to the Aultman Health Foundation Human Research Review Board (HRRB) in accordance 
with policies. AEs that are not serious will be summarized in narrative, or other format, and 
submitted to the HRRB at the time of continuing review. 
If any unanticipated problems related to the research involving risks to subjects or others happen 
during the course of this study (including SAEs) these will be reported to the HRRB in accordance 
with Aultman Health Foundation policy: Unanticipated Problems Involving Risks to Subjects.  
7.0     Statistical Methods 
Baseline Data  
Baseline and demographic characteristics will be summarized by standard descriptive summaries 
(e.g., means and standard deviations for continuous variables such as age and percentages for 
categorical variables such as gender). 
Analysis of Primary Outcome of Interest 
The primary analysis will include all subjects meeting all inclusion and exclusion criteria and 
completing Visit 1.   
The primary endpoint will be the progression free survival at 12 months 
Secondary endpoints will include:  


Page 10 of 11 
 
• the prevalence of hypothyroidism in successive metastatic breast cancer patients,  
• the change in QOL measures between baseline, 3, 6, 9 and 12 months and  
• the duration of time to achieve the euthyroid hypothyroxiemic state  
Sample Size and Power 
The sample size is estimated to be approximately 30 patients. 
Given the many uncertainties to calculate power precisely, this is an estimate made, based on 
clinical experience.  
8.0 
Publication 
Investigator intends to publish. 
9.0 
References 
1. 
Chiappa, C.; Rovera, F.; Rausei, S.; DelFerraro, S.; Fachinetti, A.; Lavazza, M.; Marchionini, 
V.; Arlant, V.; Tanda, M. L.; Piantanida, E.; Kim, H. Y.; Anuwong, A.; & Dionigi, G. (2017, 
February). Breast cancer and thyroid diseases: analysis of 867 consecutive cases. J. Endo 
Invest, 40(2), 179-184. 
2. 
Hercbergs, A.; Davis, P. J.; Lin H. Y.; & Mousa S. A. (2016, December).  Possible 
contributions of thyroid hormone replacement to specific behaviors of cancer.  Biomed 
Pharm, 84, 655-659. 
3. 
Hercbergs, A.; Johnson, R. E.; Ashur-Fabian, O.; Garfield, D. H.; & Davis, P. J. (2015, Jan). 
Medically Induced Euthyroid Hypothyroxinemia May Extend Survival in Compassionate 
Need Cancer Patients: An Observational Study. Oncologist, 20, 72-76. 
4. 
Hercbergs, A.; Mousa, S. A.; Leinung, M. Lin, H. Y.; & Davis P. J.  (2018, June).  Thyroid 
Hormone in the Clinic and Breast Cancer. Horm Cancer, 9 (3), 139-143.  
5. 
Weng, C. H.; Chen, Y. H.; Lin C. H.; Luo, X.; & Lin T. H. (2018, Mar 30). Thyroid disorders 
and breast cancer risk in Asian population: a nationwide population-based case-control 
study in Taiwan. BMJ Open, 8(3), e20194. 
10.0 
Appendixes 
 
A.   
ECOG Performance Status 
B. 
FACT-B Questionnaire (http://www.facit.org/FACITOrg/Questionnaires) 
 
C.  
Package Insert Cytomel (liothyronine sodium) (accessdata.fda.gov) 
 
 
Package Insert Generic Liothyronine Sodium (Sigma, Mayne, Mylan) 
 
 


Page 11 of 11 
 
 
Summary of Changes Amendment Version 4.0 [1/6/2020] 
• 
Primary objective updated to match clinicaltrials.gov recommendation.  Now reads “To 
prospectively evaluate the progression-free survival in hypothyroid patients with metastatic 
breast carcinoma who are rendered euthyroid and hypothyroxinemic. 
• 
Anticipated recruitment period updated to four (4) years. 
• 
Exclusion criteria edited to allow history of thyroxicosis or adrenal insufficiency as long as 
previously treated > 5 years ago and resolved without active replacement hormonal therapy as 
per Principal Investigator discretion.   
• 
Corrected treatment period day calculation error to read 9 months (270 days). 
• 
Edited frequency of labs to every 4 weeks for the first 12 weeks and then every 12 weeks until 
the end of study.  This was amended to match the clinic visit frequency.  Additional labs can be 
drawn at the physician’s discretion. 
• 
Clarified that data collection will be recorded on paper case report forms and that a compilation 
of data will be stored in a password-protected excel file. 
• 
Clarified that the Data Monitoring Committee will monitor data integrity, however the Principal 
Investigator will be responsible for monitoring safety and adverse events.   
• 
Updated Analysis of Primary Outcome section to read “The primary endpoint will be the 
progression free survival at 12 months” to match clinicaltrials.gov approved record. 
• 
Minor grammatical corrections throughout. 
 
 
Summary of Changes Amendment Version 5.0 [4.8.20] 
• 
Corrected  page 4 making frequency of labs “every 12 weeks after first 12 weeks until study drug 
is discontinued” to align with amendment version 4.0.   
• 
Minor spelling corrections throughout.