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| ID | Type | Description | Link |
|---|---|---|---|
| T32DK063688 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| University of Pennsylvania | OTHER |
| Lawson Wilkins Pediatric Endocrine Society | OTHER |
| National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) | NIH |
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Investigators will assess the tolerability of oral Vitamin E supplementation in subjects with congenital hyperinsulinism (HI) and hyperammonemia (HA) syndrome.
Congenital hyperinsulinism (HI) is a rare disorder of pancreatic beta cell insulin secretion that causes persistent and severe hypoglycemia starting at birth. Hyperinsulinism/hyperammonemia (HI/HA) syndrome is the second most common type of congenital HI and is caused by activating mutations in glutamate dehydrogenase (GDH). Patients with HI/HA exhibit fasting hyperinsulinemic hypoglycemia, protein-induced hypoglycemia, hyperammonemia, seizures, and intellectual disability independent of hypoglycemia. These effects result from abnormal GDH activity in the beta cells, liver and kidney cells, neurons, and astrocytes. The only available treatment for HI/HA syndrome is diazoxide, which acts on the beta cells to decrease insulin secretion but has no effect on GDH activity itself or on other cell types. Thus, there remains a significant unmet need for improved therapies for this disorder. Preliminary data show that Vitamin E (alpha-tocopherol) inhibits GDH activity in cell lines and improves hypoglycemia in a GDH HI mouse model. Based on these preclinical studies, Investigators hypothesize that Vitamin E will inhibit GDH activity and may impact hyperinsulinemic hypoglycemia and hyperammonemia in subjects with HI/HA syndrome. This hypothesis will be tested in a future study. In this initial pilot study, investigators will assess the tolerability of oral Vitamin E supplementation in subjects with HI/HA syndrome.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Vitamin E Supplementation | Experimental | Daily oral supplementation with Vitamin E (alpha-tocopherol) for 2 weeks. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Vitamin E | Dietary Supplement | Subjects will take an oral Vitamin E (alpha-tocopherol) supplement once daily with a fat-containing meal for 2 weeks. The dose will be based on subject age (150 IU if 1-3 years old, 300 IU if 4-8 years old, 450 IU if 9-17 years old, 600 IU if >17 years old). Formulations include 50 IU/mL liquid and 200 IU capsules. The liquid formulation will be used for subjects who will receive <600 IU daily, or for any subjects who prefer liquid medication to capsules. |
| Measure | Description | Time Frame |
|---|---|---|
| Tolerability of Vitamin E Based on Responses to a Subject/Parent-reported Symptom Questionnaire After Vitamin E Supplementation Compared to Baseline | The following symptoms will be scored as either "none" (did not occur)=0, "mild" (minimal symptoms, no treatment needed)=1, "moderate" (symptoms requiring treatment at home or as an outpatient=2, or "severe" (symptoms requiring hospitalization or emergency room visit, or life-threatening or potentially life-threatening symptoms)=4: Seizure, Headache, Vision change/blurred vision, Weakness, Fatigue, Nausea, Vomiting, Diarrhea, Stomach pain, Constipation, Bruising, Bleeding, Rash, Itching, Other Symptom scores will be summed to yield a Tolerability Questionnaire Score for each participant. The Tolerability Questionnaire Score has a minimum score of 0 (symptoms did not occur) and a maximum score of 60 (all of the measured symptoms occurred, each with severe designation). The number (count) of participants with an increase in Tolerability Questionnaire Score from baseline to 2 weeks (following Vitamin E supplementation) will be reported. | 2 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Plasma Alpha-tocopherol Concentration | change in fasting plasma alpha-tocopherol concentration following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1]) | 2 weeks |
| Delta-plasma Glucose Concentration |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Elizabeth Rosenfeld, MD | Children's Hospital of Philadelphia | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Children's Hospital of Philadelphia | Philadelphia | Pennsylvania | 19104 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 20936362 | Background | Palladino AA, Stanley CA. The hyperinsulinism/hyperammonemia syndrome. Rev Endocr Metab Disord. 2010 Sep;11(3):171-8. doi: 10.1007/s11154-010-9146-0. | |
| 23275527 | Background | Snider KE, Becker S, Boyajian L, Shyng SL, MacMullen C, Hughes N, Ganapathy K, Bhatti T, Stanley CA, Ganguly A. Genotype and phenotype correlations in 417 children with congenital hyperinsulinism. J Clin Endocrinol Metab. 2013 Feb;98(2):E355-63. doi: 10.1210/jc.2012-2169. Epub 2012 Dec 28. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Vitamin E Supplementation | Daily oral supplementation with Vitamin E (alpha-tocopherol) for 2 weeks. Vitamin E: Subjects will take an oral Vitamin E (alpha-tocopherol) supplement once daily with a fat-containing meal for 2 weeks. The dose will be based on subject age (150 IU if 1-3 years old, 300 IU if 4-8 years old, 450 IU if 9-17 years old, 600 IU if >17 years old). Formulations include 50 IU/mL liquid and 200 IU capsules. The liquid formulation will be used for subjects who will receive <600 IU daily, or for any subjects who prefer liquid medication to capsules. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Vitamin E Supplementation | Daily oral supplementation with Vitamin E (alpha-tocopherol) for 2 weeks. Vitamin E: Subjects will take an oral Vitamin E (alpha-tocopherol) supplement once daily with a fat-containing meal for 2 weeks. The dose will be based on subject age (150 IU if 1-3 years old, 300 IU if 4-8 years old, 450 IU if 9-17 years old, 600 IU if >17 years old). Formulations include 50 IU/mL liquid and 200 IU capsules. The liquid formulation will be used for subjects who will receive <600 IU daily, or for any subjects who prefer liquid medication to capsules. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| 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 | Tolerability of Vitamin E Based on Responses to a Subject/Parent-reported Symptom Questionnaire After Vitamin E Supplementation Compared to Baseline | The following symptoms will be scored as either "none" (did not occur)=0, "mild" (minimal symptoms, no treatment needed)=1, "moderate" (symptoms requiring treatment at home or as an outpatient=2, or "severe" (symptoms requiring hospitalization or emergency room visit, or life-threatening or potentially life-threatening symptoms)=4: Seizure, Headache, Vision change/blurred vision, Weakness, Fatigue, Nausea, Vomiting, Diarrhea, Stomach pain, Constipation, Bruising, Bleeding, Rash, Itching, Other Symptom scores will be summed to yield a Tolerability Questionnaire Score for each participant. The Tolerability Questionnaire Score has a minimum score of 0 (symptoms did not occur) and a maximum score of 60 (all of the measured symptoms occurred, each with severe designation). The number (count) of participants with an increase in Tolerability Questionnaire Score from baseline to 2 weeks (following Vitamin E supplementation) will be reported. | Posted | Count of Participants | Participants | 2 weeks |
|
Adverse event data were collected over the 2 week study period.
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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 | Vitamin E Supplementation (All Doses) | Daily oral supplementation with Vitamin E (alpha-tocopherol) for 2 weeks. Vitamin E: Subjects will take an oral Vitamin E (alpha-tocopherol) supplement once daily with a fat-containing meal for 2 weeks. The dose will be based on subject age (150 IU if 1-3 years old, 300 IU if 4-8 years old, 450 IU if 9-17 years old, 600 IU if >17 years old). Formulations include 50 IU/mL liquid and 200 IU capsules. The liquid formulation will be used for subjects who will receive <600 IU daily, or for any subjects who prefer liquid medication to capsules. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Otitis externa | Infections and infestations | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Lauren Mitteer | Children's Hospital of Philadelphia | 215-590-3174 | mitteerl@chop.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Dec 11, 2019 | Jun 22, 2022 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| C538375 | Hyperinsulinemic hypoglycemia, familial, 6 |
| D006946 | Hyperinsulinism |
| D022124 | Hyperammonemia |
| D007003 | Hypoglycemia |
| ID | Term |
|---|---|
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D010335 | Pathologic Processes |
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| ID | Term |
|---|---|
| D014810 | Vitamin E |
| D024502 | alpha-Tocopherol |
| ID | Term |
|---|---|
| D001578 | Benzopyrans |
| D011714 | Pyrans |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
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This open-label tolerability and feasibility pilot clinical study will use a before-and-after design, with blood tests and fasting oral protein tolerance test performed prior to and after 2 weeks of daily oral Vitamin E supplementation in individuals with HI/HA syndrome.
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|
|
change in delta-glucose concentration (fasting plasma glucose - nadir plasma glucose during oral protein tolerance test) following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])
| 2 weeks |
| Fasting Plasma Glucose Concentration | change in fasting plasma glucose concentration following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1]) | 2 weeks |
| Nadir Plasma Glucose Concentration | change in nadir plasma glucose concentration during oral protein tolerance test following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1]) | 2 weeks |
| Fasting Plasma Insulin Concentration | change in fasting plasma insulin concentration following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1]) | 2 weeks |
| Peak Plasma Insulin Concentration | change in peak plasma insulin concentration during oral protein tolerance test following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1]) | 2 weeks |
| Delta-plasma Insulin Concentration | change in delta-plasma insulin concentration (peak plasma insulin - fasting plasma insulin during oral protein tolerance test) following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1]) | 2 weeks |
| Fasting Plasma Ammonia Concentration | change in fasting plasma ammonia concentration following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1]) | 2 weeks |
| Delta-plasma Ammonia Concentration | change in delta-plasma ammonia concentration (plasma ammonia at 60 minutes - fasting plasma ammonia during oral protein tolerance test) following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1]) | 2 weeks |
| Hypoglycemia Frequency | change in frequency of hypoglycemia (plasma glucose <70 mg/dL) detected on home glucose meter following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1]) | 2 weeks |
| 11241047 | Background | Hsu BY, Kelly A, Thornton PS, Greenberg CR, Dilling LA, Stanley CA. Protein-sensitive and fasting hypoglycemia in children with the hyperinsulinism/hyperammonemia syndrome. J Pediatr. 2001 Mar;138(3):383-9. doi: 10.1067/mpd.2001.111818. |
| 940710 | Background | Stanley CA, Baker L. Hyperinsulinism in infancy: diagnosis by demonstration of abnormal response to fasting hypoglycemia. Pediatrics. 1976 May;57(5):702-11. |
| 19531491 | Background | Li M, Smith CJ, Walker MT, Smith TJ. Novel inhibitors complexed with glutamate dehydrogenase: allosteric regulation by control of protein dynamics. J Biol Chem. 2009 Aug 21;284(34):22988-3000. doi: 10.1074/jbc.M109.020222. Epub 2009 Jun 15. |
| 26287975 | Background | McBurney MI, Yu EA, Ciappio ED, Bird JK, Eggersdorfer M, Mehta S. Suboptimal Serum alpha-Tocopherol Concentrations Observed among Younger Adults and Those Depending Exclusively upon Food Sources, NHANES 2003-20061-3. PLoS One. 2015 Aug 19;10(8):e0135510. doi: 10.1371/journal.pone.0135510. eCollection 2015. |
| 23642196 | Background | Ulatowski L, Manor D. Vitamin E trafficking in neurologic health and disease. Annu Rev Nutr. 2013;33:87-103. doi: 10.1146/annurev-nutr-071812-161252. Epub 2013 Apr 29. |
| 23596164 | Background | Pfeiffer CM, Sternberg MR, Schleicher RL, Haynes BM, Rybak ME, Pirkle JL. The CDC's Second National Report on Biochemical Indicators of Diet and Nutrition in the U.S. Population is a valuable tool for researchers and policy makers. J Nutr. 2013 Jun;143(6):938S-47S. doi: 10.3945/jn.112.172858. Epub 2013 Apr 17. |
| 8429120 | Background | Ferslew KE, Acuff RV, Daigneault EA, Woolley TW, Stanton PE Jr. Pharmacokinetics and bioavailability of the RRR and all racemic stereoisomers of alpha-tocopherol in humans after single oral administration. J Clin Pharmacol. 1993 Jan;33(1):84-8. doi: 10.1002/j.1552-4604.1993.tb03909.x. |
| 20332361 | Background | Treberg JR, Clow KA, Greene KA, Brosnan ME, Brosnan JT. Systemic activation of glutamate dehydrogenase increases renal ammoniagenesis: implications for the hyperinsulinism/hyperammonemia syndrome. Am J Physiol Endocrinol Metab. 2010 Jun;298(6):E1219-25. doi: 10.1152/ajpendo.00028.2010. Epub 2010 Mar 23. |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| OG000 | Vitamin E Supplementation | Daily oral supplementation with Vitamin E (alpha-tocopherol) for 2 weeks. Vitamin E: Subjects will take an oral Vitamin E (alpha-tocopherol) supplement once daily with a fat-containing meal for 2 weeks. The dose will be based on subject age (150 IU if 1-3 years old, 300 IU if 4-8 years old, 450 IU if 9-17 years old, 600 IU if >17 years old). Formulations include 50 IU/mL liquid and 200 IU capsules. The liquid formulation will be used for subjects who will receive <600 IU daily, or for any subjects who prefer liquid medication to capsules. |
|
|
| Secondary | Plasma Alpha-tocopherol Concentration | change in fasting plasma alpha-tocopherol concentration following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1]) | The 2 week (visit 2) laboratory draw was unable to be obtained for 1 participant, yielding n=12 analyzed for this outcome | Posted | Mean | Standard Deviation | micromolar | 2 weeks |
|
|
|
| Secondary | Delta-plasma Glucose Concentration | change in delta-glucose concentration (fasting plasma glucose - nadir plasma glucose during oral protein tolerance test) following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1]) | Per the study protocol, the oral protein tolerance test was not repeated at 2 weeks (visit 2) if the baseline (visit 1) oral protein tolerance test was not tolerated. Of the 13 participants who completed the study, 7 did not tolerate the baseline (visit 1) oral protein tolerance test. The 2 week (visit 2) oral protein tolerance test was performed in 6 participants. Oral protein tolerance test parameters were analyzed for these 6 participants. | Posted | Mean | Standard Deviation | mg/dL | 2 weeks |
|
|
|
| Secondary | Fasting Plasma Glucose Concentration | change in fasting plasma glucose concentration following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1]) | The 2 week (visit 2) laboratory draw was unable to be obtained for 1 participant, yielding n=12 analyzed for this outcome | Posted | Mean | Standard Deviation | mg/dL | 2 weeks |
|
|
|
| Secondary | Nadir Plasma Glucose Concentration | change in nadir plasma glucose concentration during oral protein tolerance test following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1]) | Per the study protocol, the oral protein tolerance test was not repeated at 2 weeks (visit 2) if the baseline (visit 1) oral protein tolerance test was not tolerated. Of the 13 participants who completed the study, 7 did not tolerate the baseline (visit 1) oral protein tolerance test. The 2 week (visit 2) oral protein tolerance test was performed in 6 participants. Oral protein tolerance test parameters were analyzed for these 6 participants. | Posted | Mean | Standard Deviation | mg/dL | 2 weeks |
|
|
|
| Secondary | Fasting Plasma Insulin Concentration | change in fasting plasma insulin concentration following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1]) | The 2 week (visit 2) laboratory draw was unable to be obtained for 1 participant, yielding n=12 analyzed for this outcome | Posted | Mean | Standard Error | uIU/mL | 2 weeks |
|
|
|
| Secondary | Peak Plasma Insulin Concentration | change in peak plasma insulin concentration during oral protein tolerance test following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1]) | Per the study protocol, the oral protein tolerance test was not repeated at 2 weeks (visit 2) if the baseline (visit 1) oral protein tolerance test was not tolerated. Of the 13 participants who completed the study, 7 did not tolerate the baseline (visit 1) oral protein tolerance test. The 2 week (visit 2) oral protein tolerance test was performed in 6 participants. Oral protein tolerance test parameters were analyzed for these 6 participants. | Posted | Mean | Standard Deviation | uIU/mL | 2 weeks |
|
|
|
| Secondary | Delta-plasma Insulin Concentration | change in delta-plasma insulin concentration (peak plasma insulin - fasting plasma insulin during oral protein tolerance test) following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1]) | Per the study protocol, the oral protein tolerance test was not repeated at 2 weeks (visit 2) if the baseline (visit 1) oral protein tolerance test was not tolerated. Of the 13 participants who completed the study, 7 did not tolerate the baseline (visit 1) oral protein tolerance test. The 2 week (visit 2) oral protein tolerance test was performed in 6 participants. Oral protein tolerance test parameters were analyzed for these 6 participants. | Posted | Mean | Standard Deviation | uIU/mL | 2 weeks |
|
|
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| Secondary | Fasting Plasma Ammonia Concentration | change in fasting plasma ammonia concentration following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1]) | The 2 week (visit 2) laboratory draw was unable to be obtained for 1 participant, yielding n=12 analyzed for this outcome | Posted | Mean | Standard Deviation | micromolar | 2 weeks |
|
|
|
| Secondary | Delta-plasma Ammonia Concentration | change in delta-plasma ammonia concentration (plasma ammonia at 60 minutes - fasting plasma ammonia during oral protein tolerance test) following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1]) | The 2 week (visit 2) plasma ammonia at 60 minutes was not obtained in 1 participant in whom the visit 2 oral protein tolerance test was performed, yielding n=5 for analysis of this outcome. | Posted | Mean | Standard Deviation | micromolar | 2 weeks |
|
|
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| Secondary | Hypoglycemia Frequency | change in frequency of hypoglycemia (plasma glucose <70 mg/dL) detected on home glucose meter following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1]) | Home glucose meter testing was not performed by 3 participants, yielding n=10 analyzed for this outcome. | Posted | Mean | Standard Deviation | Hypoglycemia events | 2 weeks |
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|
| 0 |
| 14 |
| 0 |
| 14 |
| 9 |
| 14 |
| EG001 | Vitamin E 150 IU | Daily oral supplementation with Vitamin E (alpha-tocopherol) 150 IU for 2 weeks. | 0 | 2 | 0 | 2 | 1 | 2 |
| EG002 | Vitamin E 300 IU | Daily oral supplementation with Vitamin E (alpha-tocopherol) 300 IU for 2 weeks. | 0 | 5 | 0 | 5 | 2 | 5 |
| EG003 | Vitamin E 450 IU | Daily oral supplementation with Vitamin E (alpha-tocopherol) 450 IU for 2 weeks. | 0 | 3 | 0 | 3 | 3 | 3 |
| EG004 | Vitamin E 600 IU | Daily oral supplementation with Vitamin E (alpha-tocopherol) 600 IU for 2 weeks. | 0 | 4 | 0 | 4 | 3 | 4 |
| Headache | Nervous system disorders | Systematic Assessment |
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| Vomiting | Gastrointestinal disorders | Systematic Assessment |
|
| Increased menstrual bleeding | Reproductive system and breast disorders | Systematic Assessment |
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| Abdominal pain | Gastrointestinal disorders | Systematic Assessment |
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| Diarrhea | Gastrointestinal disorders | Systematic Assessment |
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| Fatigue | General disorders | Systematic Assessment |
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| Rash | Skin and subcutaneous tissue disorders | Systematic Assessment |
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| D013568 | Pathological Conditions, Signs and Symptoms |
| D006574 |
| Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D024505 | Tocopherols |