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Relocation of Principal Investigator
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Triiodothyronine (T3) | Experimental | 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). |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Triiodothyronine (T3) | Drug | Participants will have their L-thyroxine (T4) discontinued and Triiodothyronine (T3)/liothyronine sodium initiated at 3: 1 and titrated. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Progression-free Survival at 12 Months Based Upon Clinical and Radiological Assessments Completed as Part of Routine Care | 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. | 12 months |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Patients With Both Metastatic Breast Cancer and Hypothyroidism in All Screened Patients. | To quantitate the prevalence of hypothyroidism in metastatic breast cancer patients at a community oncology practice. | Study duration, planned was 48 months but actual was 36 months [March 1, 2019 to March 9, 2022] due to premature closure due to planned relocation of the PI. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Shruti Trehan, MD | Aultman Health Foundation | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Aultman Medical Group Hematology and Oncology | Canton | Ohio | 44710 | United States |
All enrolled participants underwent a four day washout period of L-thyroxine (T4) prior to Triiodothyronine (T3) initiation. There were no enrolled participants who were excluded from the study.
7 participants from one local medical oncology practice were enrolled between March 1, 2019 and March 9, 2022.
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| ID | Title | Description |
|---|---|---|
| FG000 | Triiodothyronine (T3) | 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. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Triiodothyronine (T3) | 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number of Participants With Progression-free Survival at 12 Months Based Upon Clinical and Radiological Assessments Completed as Part of Routine Care | 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. | 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. | Posted | Count of Participants | Participants | 12 months |
|
Adverse event data was collected for each subject at every 3 monthly visit and is reported as below. Attribution or etiology under comments below. Study period was 12 months (9 months for last patient due to premature termination of study)
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.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Triiodothyronine (T3) | 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Pleural effusion | Respiratory, thoracic and mediastinal disorders | CTCAE (version 5.0) | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Edema limbs | General disorders | CTCAE (version 5.0) | Systematic Assessment |
Limitation is small sample size due to pandemic affecting clinical trial accrual. A larger sample is needed to adequately answer the research question.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Shruti Trehan MD | Aultman Hospital | 3303634162 | trehanshruti4@gmail.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Apr 8, 2020 | Mar 17, 2022 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Apr 14, 2022 | Apr 14, 2022 | SAP_003.pdf |
| ICF | No | No | Yes | Informed Consent Form | Oct 16, 2020 | Mar 16, 2022 | ICF_002.pdf |
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| ID | Term |
|---|---|
| D001943 | Breast Neoplasms |
| ID | Term |
|---|---|
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D001941 | Breast Diseases |
| D012871 | Skin Diseases |
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| ID | Term |
|---|---|
| D014284 | Triiodothyronine |
| ID | Term |
|---|---|
| D013970 | Thyronines |
| D013963 | Thyroid Hormones |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
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Triiodothyronine (T3) - IND Exempt
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N/A (not applicable)
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|
| Measurement of Quality of Life Total Score Across Time Using Validated FACT-B Questionnaire | 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. | Baseline, 3, 6, 9, and 12 months |
| Measurement of Energy Level Across Time Using FACT-B Question. | 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. | Baseline, 3, 6, 9, 12 months |
| Time to Achieve Euthyroid Hypothyroxinemia State | 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. | Number of days between initiation of triiodothyronine (T3) and documentation of first normal TSH value for each participant, assessed up to 12 months |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Duration of time since diagnosis of metastatic disease | Mean | Standard Deviation | months |
|
|
|
| Secondary | Number of Patients With Both Metastatic Breast Cancer and Hypothyroidism in All Screened Patients. | To quantitate the prevalence of hypothyroidism in metastatic breast cancer patients at a community oncology practice. | 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. | Posted | Count of Participants | Participants | Study duration, planned was 48 months but actual was 36 months [March 1, 2019 to March 9, 2022] due to premature closure due to planned relocation of the PI. |
|
|
|
| Secondary | Measurement of Quality of Life Total Score Across Time Using Validated FACT-B Questionnaire | 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. | 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. | Posted | Mean | Standard Deviation | score on a scale | Baseline, 3, 6, 9, and 12 months |
|
|
|
| Secondary | Measurement of Energy Level Across Time Using FACT-B Question. | 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. | 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. | Posted | Mean | Standard Deviation | score on a scale | Baseline, 3, 6, 9, 12 months |
|
|
|
| Secondary | Time to Achieve Euthyroid Hypothyroxinemia State | 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. | Posted | Mean | Standard Deviation | days | Number of days between initiation of triiodothyronine (T3) and documentation of first normal TSH value for each participant, assessed up to 12 months |
|
|
|
| 1 |
| 7 |
| 2 |
| 7 |
| 7 |
| 7 |
| Cellulitis | Infections and infestations | CTCAE (version 5.0) | Systematic Assessment |
|
| ascites | Gastrointestinal disorders | CTCAE (version 5.0) | Systematic Assessment |
|
| Nail changes | Skin and subcutaneous tissue disorders | CTCAE (version 5.0) | Systematic Assessment |
|
| Memory Impairment | Nervous system disorders | CTCAE (version 5.0) | Systematic Assessment |
|
| Hypertension | Vascular disorders | CTCAE (version 5.0) | Systematic Assessment |
|
| Dyspepsia | Gastrointestinal disorders | CTCAE (version 5.0) | Systematic Assessment |
|
| Epistaxis | Respiratory, thoracic and mediastinal disorders | CTCAE (version 5.0) | Systematic Assessment |
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| Bronchial infection | Infections and infestations | CTCAE (version 5.0) | Systematic Assessment |
|
| Generalized muscle weakness | Musculoskeletal and connective tissue disorders | CTCAE (version 5.0) | Systematic Assessment |
|
| Dyspnea | Respiratory, thoracic and mediastinal disorders | CTCAE (version 5.0) | Systematic Assessment |
|
| Diarrhea | Gastrointestinal disorders | CTCAE (version 5.0) | Systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | CTCAE (version 5.0) | Systematic Assessment |
|
| Fatigue | General disorders | CTCAE (version 5.0) | Systematic Assessment |
|
| Nasal congestion | Respiratory, thoracic and mediastinal disorders | CTCAE (version 5.0) | Systematic Assessment |
|
| Insomnia | Psychiatric disorders | CTCAE (version 5.0) | Systematic Assessment |
|
| Abdominal pain | Gastrointestinal disorders | CTCAE (version 5.0) | Systematic Assessment |
|
| Bloating | Gastrointestinal disorders | CTCAE (version 5.0) | Systematic Assessment |
|
| Gastrointestinal disorder: Other hemoccult positive | Gastrointestinal disorders | CTCAE (version 5.0) | Systematic Assessment |
|
| Sinus tachycardia | Cardiac disorders | CTCAE (version 5.0) | Systematic Assessment |
|
| Bruising | Injury, poisoning and procedural complications | CTCAE (version 5.0) | Systematic Assessment |
|
| Pain in extremity | Musculoskeletal and connective tissue disorders | CTCAE (version 5.0) | Systematic Assessment |
|
| Skin disorder other: Contact dermatitis | Skin and subcutaneous tissue disorders | CTCAE (version 5.0) | Systematic Assessment |
|
| Endocrine disorder: Cold intolerance | Endocrine disorders | CTCAE (version 5.0) | Systematic Assessment |
|
| Dizziness | Nervous system disorders | CTCAE (version 5.0) | Systematic Assessment |
|
| Weight loss | Investigations | CTCAE (version 5.0) | Systematic Assessment |
|
| Headache | Nervous system disorders | CTCAE (version 5.0) | Systematic Assessment |
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| Chills | General disorders | CTCAE (version 5.0) | Systematic Assessment |
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| Fever | General disorders | CTCAE (version 5.0) | Systematic Assessment |
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| Arthalgia | Musculoskeletal and connective tissue disorders | CTCAE (version 5.0) | Systematic Assessment |
|
| Gastrointestinal disorders: Other - Gastroenteritis | Gastrointestinal disorders | CTCAE (version 5.0) | Systematic Assessment |
|
| Non-cardiac chest pain | General disorders | CTCAE (version 5.0) | Systematic Assessment |
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| Anxiety | Psychiatric disorders | CTCAE (version 5.0) | Systematic Assessment |
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| Depression | Psychiatric disorders | CTCAE (version 5.0) | Systematic Assessment |
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| Skin disorder: Other - Chest wall redness | Skin and subcutaneous tissue disorders | CTCAE (version 5.0) | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | CTCAE (version 5.0) | Systematic Assessment |
|
| Dysgeusia | Nervous system disorders | CTCAE (version 5.0) | Systematic Assessment |
|
| Anosmia | Nervous system disorders | CTCAE (version 5.0) | Systematic Assessment |
|
| Malaise | General disorders | CTCAE (version 5.0) | Systematic Assessment |
|
| Palpitations | Cardiac disorders | CTCAE (version 5.0) | Systematic Assessment |
|
| Pain | General disorders | CTCAE (version 5.0) | Systematic Assessment |
|
| Mucositis Oral | Gastrointestinal disorders | CTCAE (version 5.0) | Systematic Assessment |
|
| Pruritis | Skin and subcutaneous tissue disorders | CTCAE (version 5.0) | Systematic Assessment |
|
| Palmar-plantar erythrodysesthesia syndrome | Skin and subcutaneous tissue disorders | CTCAE (version 5.0) | Systematic Assessment |
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| Skin disorder: Other-onycholysis | Skin and subcutaneous tissue disorders | CTCAE (version 5.0) | Systematic Assessment |
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| Rhinorrhea | Respiratory, thoracic and mediastinal disorders | CTCAE (version 5.0) | Systematic Assessment |
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| Watering eyes | Eye disorders | CTCAE (version 5.0) | Systematic Assessment |
|
| Alopecia | Respiratory, thoracic and mediastinal disorders | CTCAE (version 5.0) | Systematic Assessment |
|
| Urinary incontinence | Renal and urinary disorders | CTCAE (version 5.0) | Systematic Assessment |
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| Anorexia | Metabolism and nutrition disorders | CTCAE (version 5.0) | Systematic Assessment |
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| Neutrophil count decreased | Investigations | CTCAE (version 5.0) | Systematic Assessment |
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| White blood cell count decreased | Investigations | CTCAE (version 5.0) | Systematic Assessment |
|
| Alanine aminotransferase increased | Investigations | CTCAE (version 5.0) | Systematic Assessment |
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| Anemia | Blood and lymphatic system disorders | CTCAE (version 5.0) | Systematic Assessment |
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| Aspartate aminotransferase increased | Investigations | CTCAE (version 5.0) | Systematic Assessment |
|
| Platelet count decreased | Investigations | CTCAE (version 5.0) | Systematic Assessment |
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| Hypoalbuminemia | Metabolism and nutrition disorders | CTCAE (version 5.0) | Systematic Assessment |
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| Blood bilirubin increased | Investigations | CTCAE (version 5.0) | Systematic Assessment |
|
| Alkaline phosphatase increased | Investigations | CTCAE (version 5.0) | Systematic Assessment |
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| Hyperglycemia | Metabolism and nutrition disorders | CTCAE (version 5.0) | Systematic Assessment |
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| Hypoglycemia | Metabolism and nutrition disorders | CTCAE (version 5.0) | Systematic Assessment |
|
| Lymphocyte count decrease | Investigations | CTCAE (version 5.0) | Systematic Assessment |
|
| Blood urea nitrogen increase | Renal and urinary disorders | CTCAE (version 5.0) | Systematic Assessment |
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| Creatinine increase | Renal and urinary disorders | CTCAE (version 5.0) | Systematic Assessment |
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| Hyperkalemia | Metabolism and nutrition disorders | CTCAE (version 5.0) | Systematic Assessment |
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| Hypercalcemia | Metabolism and nutrition disorders | CTCAE (version 5.0) | Systematic Assessment |
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| Hypotension | Vascular disorders | CTCAE (version 5.0) | Systematic Assessment |
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| Nail peeling | Skin and subcutaneous tissue disorders | CTCAE (version 5.0) | Systematic Assessment |
|
| Tooth loss | Gastrointestinal disorders | CTCAE (version 5.0) | Systematic Assessment |
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| D017437 |
| Skin and Connective Tissue Diseases |
| D013974 | Thyroxine |
| D024322 | Amino Acids, Aromatic |
| D000598 | Amino Acids, Cyclic |
| D000596 | Amino Acids |
| D000602 | Amino Acids, Peptides, and Proteins |
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| At 6 months |
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| At 9 months |
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| At 12 months |
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| 6 months |
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| 9 months |
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| 12 months |
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