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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).

Participants will have their L-thyroxine (T4) discontinued and Triiodothyronine (T3)/liothyronine sodium initiated at 3: 1 and titrated.

Triiodothyronine (T3)

Shruti Trehan, MD

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).

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.

Study of Euthyroid Hypothyroxinemia in Metastatic Breast Carcinoma

A Single Arm Phase II Pilot Study of Euthyroid Hypothyroxinemia in Metastatic Breast Carcinoma

To prospectively evaluate the progression-free survival in hypothyroid patients with metastatic breast carcinoma who are rendered euthyroid and hypothyroxinemic. Progression is defined using Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the nadir sum of the longest diameter (SLD) of target lesions, or unequivocal progression (overall level of substantial worsening) in existing non-target lesions, or the appearance of one or more new lesions.

To quantitate the prevalence of hypothyroidism in metastatic breast cancer patients at a community oncology practice.

Functional Assessment of Cancer Therapy - Breast (FACT-B) Total Score comprised of Physical Well Being (PWB), Social Well Being (SWB), Emotional Well Being (EWB), Functional Well Being (FWB), and Breast Cancer Subscale (BCS). Range is 0-148. A higher score indicates higher quality of life. Missing scores were handled by prorating values.

Functional Assessment of Cancer Therapy - Breast (FACT-B) Lack of energy on 5 point Likert scale as measured on FACT-B Physical Well-being subscale. Score of 0 indicates no lack of energy with score of 4 indicating total lack of energy.

To study the average time required to achieve euthyroid hypothyroxinemia state in qualifying patients. Thyroid function laboratory testing was performed at baseline and then at every 4 weekly intervals until 12 weeks then every 3 monthly thereafter, unless thyroid-stimulating hormone (TSH) was abnormal. If a normal TSH level was not achieved by the 12 week visit, repeat TSH measurements were ordered every 4-6 weeks until the TSH value was within the laboratory normal reference range. Initial euthyroid state defined by number of days between initiation of triiodothyronine (T3) and documentation of first normal TSH value.

Aultman Health Foundation

Shruti Trehan MD

112/124 - 88.7% of adverse events were deemed to be related to underlying metastatic breast cancer and/or treatment thereof.

0 events reported definitely related to the study drug 14/124 -11.3% events reported as possible or probably related to the study drug Cause of mortality reported due to metastatic breast cancer.

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).

Triiodothyronine (T3): Participants will have their L-thyroxine (T4) discontinued and Triiodothyronine (T3)/liothyronine sodium initiated at 3: 1 and titrated.

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Duration of time since diagnosis of metastatic disease

Limitation is small sample size due to pandemic affecting clinical trial accrual. A larger sample is needed to adequately answer the research question.

Last enrolled subject was only able to be followed for 9 months due to early termination of study. Subject not included in primary outcome measure.

Number of Participants With Progression-free Survival at 12 Months Based Upon Clinical and Radiological Assessments Completed as Part of Routine Care

Outcome was number of practice patients with both metastatic breast cancer and hypothyroidism. Of the 26 identified, 7 patients consented to enroll on the study.

Number of Patients With Both Metastatic Breast Cancer and Hypothyroidism in All Screened Patients.

Baseline

At 3 months

At 6 months

At 9 months

At 12 months

Of the 7 subjects enrolled only 5 of the patients completed Quality of Life FACT-B questionnaires for all five timepoint. Two subjects did not complete the 12 months surveys due to death or premature study termination.

Measurement of Quality of Life Total Score Across Time Using Validated FACT-B Questionnaire

3 months

6 months

9 months

12 months

Measurement of Energy Level Across Time Using FACT-B Question.

Time to Achieve Euthyroid Hypothyroxinemia State

Overall Study

Blood and Lymph Conditions

Immune System Diseases

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Thyroid Neoplasms

Thyroid Cancer, Papillary

Adenocarcinoma, Follicular

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Thyroid Cancer, Follicular

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Micronutrients

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Iodine

Cadexomer iodine

Adults with clinical indication for withdrawal from thyroid hormone replacement therapy in preparation for nuclear medicine imaging or therapeutic procedures with radioactive iodine

Kong Y Chen, Ph.D.

Background:

- Thyroid hormone is produced by the thyroid gland, an organ at the base of the neck. Thyroid hormone controls the body's metabolism and the function of many organs. The thyroid gland produces two forms of thyroid hormone: T4 and T3. People who have thyroid cancer are treated with thyroid hormone therapy (synthetic T4, levothyroxine), which at times needs to be stopped to allow for cancer treatments. At these times, a different form of thyroid hormone (synthetic T3, liothyronine) is used to reduce the symptoms caused by low levels of thyroid hormone. Researchers want to know more about how changes in T3 hormone affect the body and organ function.

Objectives:

- To study how changes in T3 hormone levels affect the body and organ function.

Eligibility:

- Individuals at least 18 years of age who have had most or all of their thyroid removed to treat thyroid cancer who need to stop taking their regular thyroid hormone dose in preparation for the treatment of thyroid cancer.

Design:

* The study involves a screening visit and a baseline evaluation. It also includes an 11-day inpatient hospital stay.
* Participants will be screened with a physical exam and medical history. They will also have blood tests and a neck ultrasound.
* Participants will be evaluated with a physical exam, blood tests, and the following procedures:
* Glucose tolerance test to measure blood sugar
* Tests of body fat, muscle strength, and calorie burning levels
* Imaging studies of the heart, liver, and thigh muscles
* Quality of life questionnaires
* Food preference and diet questionnaires
* After 4 weeks of treatment with T3 hormone, participants will have an 11-day inpatient hospital stay to study the effect of thyroid hormone on their metabolism. The stay will involve the same tests done in the baseline evaluation.

In human adults thyroid hormone action plays a critical role in the modulation of metabolism and the function of virtually all organ/systems. The specificity of the hormonal action is ultimately the result of the interaction of the active hormone, triiodothyronine (T3), with the receptors isoforms and the co-activators and co-repressors specific for the various cells target of the hormonal action. Circulating and tissue levels of T3 are the result of the secretion of T3 and its precursor, thyroxine (T4), from the thyroid gland, the peripheral conversion of T4 into T3, and the degradation of these hormones. This complex system has only been partially studied in humans and very little is known regarding the kinetics of T3, and in particular on the correlation between circulating levels of T3 and end-organ target tissue thyroid hormone action.

The aim of this protocol is to characterize the pharmacokinetics of T3 and its biological effects at various concentrations in a cohort of thyroidectomized patients undergoing thyroid hormone replacement therapy withdrawal for the management of thyroid cancer.

Sixteen patients with a clinical indication for thyroid hormone withdrawal in preparation for 131I therapy or 123I diagnostic scan for follow-up and management of differentiated thyroid cancer will be recruited for this study. After enrollment in the study, the patients baseline characteristics will be determined during an outpatient visit while receiving levothyroxine (L-T4) therapy. The L-T4 therapy then will be suspended and substituted with an equivalent thrice daily liothyronine (L-T3) therapy for one month. Patients will be admitted to the NIH Clinical Center on the day prior to withdrawal of the T3 therapy until the diagnostic scan or the administration of radioactive iodine. During the hospitalization for this research protocol, which is expected to last eleven days, the following studies will be performed: serial blood sampling for circulating thyroid hormones to obtain pharmacokinetic parameters of L-T3, lipids, glucose and insulin, resting energy expenditure, echocardiogram, skeletal muscle strength measurement, cardiac, hepatic and skeletal muscles MRI, and quality of life and well-being questionnaires. The pharmacokinetic parameters of L-T3 will also be assessed with the first dose after the diagnostic scan or the administration of radioactive iodine.

The results obtained from this study will help in understanding the effects of thyroid hormone on metabolism, and may lead to important information on how to optimize the duration of the thyroid hormone therapy withdrawal for the treatment of thyroid cancer.

Metabolic Effects of Synthetic Thyroid Hormone for Thyroid Cancer Treatment

Pharmacokinetic and Pharmacodynamic Studies of Liothyronine. A Study on the Metabolic Effects of Thyroid Hormone

to study T3 kinetics in thyroidectomized patients treated with liothyronine (L- T3) replacement therapy in preparation for diagnostic or therapeutic nuclear medicine procedures for the follow-up and management of differentiated thyroid cancer

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Study of Euthyroid Hypothyroxinemia in Metastatic Breast Carcinoma	NCT03787303	Metastatic Brea... Thyroid Dysfunc...	Triiodothyronin...	18 Years - 105 Years	Aultman Health Foundation
Study of Euthyroid Hypothyroxinemia in Metastatic Breast Carcinoma	NCT03787303	Metastatic Brea... Thyroid Dysfunc...	Triiodothyronin...	18 Years - 105 Years	Aultman Health Foundation
Metabolic Effects of Synthetic Thyroid Hormone for Thyroid Cancer Treatment	NCT01441154	Malignant Strum... Papillary Thyro... Hurthle Cell Th... Follicular Thyr... Tall Cell Varia...		18 Years - 99 Years	National Institutes of Health Clinical Center (CC)

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