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The Investigators will measure hepatic glucose and fat metabolism in obese girls with Polycystic Ovarian Syndrome (PCOS) and hepatic steatosis (HS) after taking 4 weeks of an essential amino acid (EAA) supplement or placebo and test whether the EAA supplement can improve hepatic glucose metabolism in these girls.
Girls with Polycystic Ovarian Syndrome (PCOS) and hepatic steatosis (HS) will complete a 12 week double-blinded placebo controlled cross-over study with 4 weeks each of an essential amino acid (EAA) supplement and placebo, and will complete metabolic studies after each intervention. There will be a 4 week wash out period in-between. The metabolic tests after each intervention (EAA/placebo) will include an oral sugar tolerance test (OSTT) and an oral U-C13 glycerol tracer that is paired with Nuclear Magnetic Resonance (NMR) isotopomer analysis of serum samples to describe flux through the hepatic pentose phosphate pathway, tricarboxylic acid (TCA) cycle and fatty acid synthesis pathways in girls with PCOS and HS. Hepatic steatosis will be measured with magnetic resonance Imaging (MRI) and hepatic phosphate concentrations with magnetic resonance (MR) spectroscopy.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Essential Amino Acid (EAA) Supplement | Experimental | 4 weeks: Essential Amino Acid Supplement- 15g 2/day |
|
| Placebo | Placebo Comparator | 4 weeks: Placebo- 15g 2/day |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Essential Amino Acid (EAA) Supplement | Dietary Supplement | Powder supplement |
|
| Measure | Description | Time Frame |
|---|---|---|
| Hepatic Fat Fraction | Hepatic Fat Fraction measured after completing placebo and amino acid therapy measured with MRI, and calculated via the Dixon method as the proton density hepatic fat fraction, which ranges from 0-75%. Greater than 5% is considered extra fat | 4 weeks after completing the first intervention, and approximately 8 weeks later (4 weeks washout and 4 weeks of second intervention) |
| Measure | Description | Time Frame |
|---|---|---|
| Rate of De Novo Lipogenesis | The rate of overnight de novo lipogenesis will be measured utilizing stable isotope methods with deuterated water, and expressed as the rate of newly synthesized lipids in the serum triglyceride fraction measured after 4 weeks of placebo and after 4 weeks of EAA intervention. | 4 weeks after the first intervention, and approximately 8 weeks later (4 weeks washout and 4 weeks of second intervention) |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Melanie Cree-Green, MD, PhD | Department of Endocrinology | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Colorado, Anschutz Medical Campus | Aurora | Colorado | 80045 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 42014131 | Derived | Boster JM, Cree MG, Kelsey MM, Nadeau KJ, Chaidez A, Pan Z, Sundaram SS. Relative Skeletal Muscle Mass Is Associated With Hepatic Steatosis in Adolescents With Overweight and Obesity. Pediatr Obes. 2026 Apr;21(4):e70108. doi: 10.1111/ijpo.70108. |
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Data will only be shared with IRB approved personnel.
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This was a crossover study. There were a total of 27 participants enrolled in the study. Four participants were never randomized: 3 screen failed and 1 of withdrew. Two participants withdrew after completing the placebo phase of the study
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| ID | Title | Description |
|---|---|---|
| FG000 | Essential Amino Acid (EAA) Supplement Followed by Placebo | Participants completed: 4 weeks of Essential Amino Acid Supplement- 15g 2/day followed by 4 weeks washout period and then 4 weeks of Placebo- 15g 2/day. |
| FG001 | Placebo Followed by Essential Amino Acid (EAA) Supplement | Participants completed: 4 weeks of Placebo- 15g 2/day followed by 4 weeks washout period and then 4 weeks of Essential Amino Acid Supplement- 15g 2/day. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | All Study Participants: Essential Amino Acid (EAA) Supplement vs Placebo | All study participants completed two 4-week phases of the study in random order with a washout period in between each phase of the study. Each phase consisted of either: 4 weeks of Essential Amino Acid Supplement- 15g 2/day followed by 4 weeks: Placebo- 15g 2/day or vice versa. We are comparing the differences in the essential amino acid vs placebo between all participants. |
| 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 | Hepatic Fat Fraction | Hepatic Fat Fraction measured after completing placebo and amino acid therapy measured with MRI, and calculated via the Dixon method as the proton density hepatic fat fraction, which ranges from 0-75%. Greater than 5% is considered extra fat | adolescent girls with PCOS | Posted | Median | Inter-Quartile Range | percent hepatic fat | 4 weeks after completing the first intervention, and approximately 8 weeks later (4 weeks washout and 4 weeks of second intervention) |
|
12 weeks
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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 | All Participants: Essential Amino Acid (EAA) Supplement vs Placebo | All participants completed two 4-week phases of the study in random order with a washout period in between each phase of the study. Each phase consisted of either: 4 weeks of Essential Amino Acid Supplement- 15g 2/day followed by 4 weeks: Placebo- 15g 2/day or vice versa. We are comparing the differences in the essential amino acid vs placebo. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Melanie Cree-Green, PI | University of Colorado | 720-777-5743 | melanie.green@childrenscolorado.org |
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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 | Jun 9, 2020 | Apr 11, 2024 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D011085 | Polycystic Ovary Syndrome |
| D009765 | Obesity |
| D005234 | Fatty Liver |
| ID | Term |
|---|---|
| D010048 | Ovarian Cysts |
| D003560 | Cysts |
| D009369 | Neoplasms |
| D010049 | Ovarian Diseases |
| D000291 |
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| ID | Term |
|---|---|
| D000601 | Amino Acids, Essential |
| D018846 | Excitatory Amino Acids |
| ID | Term |
|---|---|
| D000596 | Amino Acids |
| D000602 | Amino Acids, Peptides, and Proteins |
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Investigational drug pharmacy will performed randomization and dispense the EAA or placebo.
| Placebo | Other | Powder that will be similar to the essential amino acid supplement |
|
| Evaluation of Mitochondrial Function | Mitochondrial function will be assessed via change in direct hepatic carbon flux in newly synthesized triglycerides (TGs) using an oral sugar tolerance test with an oral UC13 glycerol tracer after each intervention. Data from 180 minutes post-tracer drink is shown below. A higher direct percent means less indirect futile cycling through the TCA cycle. | 4 weeks after the first intervention, and approximately 8 weeks later (4 weeks washout and 4 weeks of second intervention) |
| Hepatic Phosphate Profile After EAA and Placebo Supplement | hepatic phosphate profile via 31 Phosphorus MR spectroscopy after each intervention Hepatic phosphate relative concentrations will be measured with 31 phosphorus magnetic resonance spectroscopy after each intervention. The Total phosphate (TP) concentration will be reported after each intervention and the ratio of the following phosphate metabolites will be reported over the total phosphate concentration: Phosphodiesterase (PDE), phosphomonoester (PME), Adenosine triphosphate (ATP), Inorganic Phosphate (Pi),Nicotinamide adenine dinucleotide phosphate (NADPH), Uridine diphosphate glucose (UDPG) | 4 weeks after the first intervention, and approximately 8 weeks later (4 weeks washout and 4 weeks of second intervention) |
| Whole Body Insulin Sensitivity | Participants will undergo a 75 gram oral glucose tolerance test, and whole body insulin sensitivity will be expressed as Si, calculated via the oral minimal model using 4 hour glucose and insulin data during the OGTT after each phase of the study (placebo vs EAA). | 4 weeks after the first intervention, and approximately 8 weeks later (4 weeks washout and 4 weeks of second intervention) |
| Change in Adipose Insulin Sensitivity | Change from baseline of adipose insulin sensitivity will be calculated as the percent suppression of free fatty acids (FFAs) during the oral glucose tolerance test. | 4 weeks after the first intervention, and approximately 8 weeks later (4 weeks washout and 4 weeks of second intervention) |
| Sleep Duration | Sleep duration will be assessed completing placebo and essential amino acid therapy using home actigraphy. Change in sleep duration reported in minutes. | 4 weeks after the first intervention, and approximately 8 weeks later (4 weeks washout and 4 weeks of second intervention) |
| Apnea Hypopnea Index (AHI) | Apnea Hypopnea Index (AHI) will be measured using WatchPAT after each intervention. In children and adolescents the scale that will be used is AHI>5 is considered mild sleep apnea. The higher the AHI, indicates more severe sleep apnea. The AHI is the number of times you have apnea or hypopnea during one night, divided by the hours of sleep. Normal sleep: An AHI of fewer than five events, on average, per hour Mild sleep apnea: An AHI of five to 14 events per hour Moderate sleep apnea: An AHI of 15 to 29 events per hour Severe sleep apnea: An AHI of 30 or more events per hour | 4 weeks after the first intervention, and approximately 8 weeks later (4 weeks washout and 4 weeks of second intervention) |
| Amino Acid Metabolomics: Alanine, Glutamate, Leucine, Valine Levels After 4 Weeks of Placebo and 4 Weeks of EAAs | Targeted amino acid metabolomics will be performed after each intervention and the levels of these 4 amino acids will be reported after each intervention. | 4 weeks after the first intervention, and approximately 8 weeks later (4 weeks washout and 4 weeks of second intervention) |
| Lipid Metabolomics: 16n1 | Targeted lipid metabolomics will be performed after each intervention to measure 16n1 lipids after completing 4 weeks of essential amino acid therapy and 4 weeks of placebo. | 4 weeks after the first intervention, and approximately 8 weeks later (4 weeks washout and 4 weeks of second intervention) |
| Bile Acid Metabolomics: Sphingosine-1-phospate After 4 Weeks of Placebo and 4 Weeks of EAAs | Targeted bile acid metabolomics will be performed after each intervention to measure levels of sphingosine-1-phospate | 4 weeks after the first intervention, and approximately 8 weeks later (4 weeks washout and 4 weeks of second intervention) |
| years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Count of Participants | Participants |
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|
| Secondary | Rate of De Novo Lipogenesis | The rate of overnight de novo lipogenesis will be measured utilizing stable isotope methods with deuterated water, and expressed as the rate of newly synthesized lipids in the serum triglyceride fraction measured after 4 weeks of placebo and after 4 weeks of EAA intervention. | We were only able to obtain results for this outcome for 19 participants in the study. | Posted | Mean | Standard Deviation | mg/dL | 4 weeks after the first intervention, and approximately 8 weeks later (4 weeks washout and 4 weeks of second intervention) |
|
|
|
| Secondary | Evaluation of Mitochondrial Function | Mitochondrial function will be assessed via change in direct hepatic carbon flux in newly synthesized triglycerides (TGs) using an oral sugar tolerance test with an oral UC13 glycerol tracer after each intervention. Data from 180 minutes post-tracer drink is shown below. A higher direct percent means less indirect futile cycling through the TCA cycle. | Posted | Mean | Standard Deviation | percent direct TG synthesis | 4 weeks after the first intervention, and approximately 8 weeks later (4 weeks washout and 4 weeks of second intervention) |
|
|
|
| Secondary | Hepatic Phosphate Profile After EAA and Placebo Supplement | hepatic phosphate profile via 31 Phosphorus MR spectroscopy after each intervention Hepatic phosphate relative concentrations will be measured with 31 phosphorus magnetic resonance spectroscopy after each intervention. The Total phosphate (TP) concentration will be reported after each intervention and the ratio of the following phosphate metabolites will be reported over the total phosphate concentration: Phosphodiesterase (PDE), phosphomonoester (PME), Adenosine triphosphate (ATP), Inorganic Phosphate (Pi),Nicotinamide adenine dinucleotide phosphate (NADPH), Uridine diphosphate glucose (UDPG) | We were only able to analyze 18 participants p-31 spectroscopy due to the quality of the spectra. | Posted | Mean | Standard Deviation | Ratio over Total Phosphate Concentration | 4 weeks after the first intervention, and approximately 8 weeks later (4 weeks washout and 4 weeks of second intervention) |
|
|
|
| Secondary | Whole Body Insulin Sensitivity | Participants will undergo a 75 gram oral glucose tolerance test, and whole body insulin sensitivity will be expressed as Si, calculated via the oral minimal model using 4 hour glucose and insulin data during the OGTT after each phase of the study (placebo vs EAA). | Only 20 participants analyzed because the OMM model cannot be run if we have missing insulin or glucose values during the oral sugar tolerance test. | Posted | Mean | Inter-Quartile Range | dl/kg/min per microU/ml | 4 weeks after the first intervention, and approximately 8 weeks later (4 weeks washout and 4 weeks of second intervention) |
|
|
|
| Secondary | Change in Adipose Insulin Sensitivity | Change from baseline of adipose insulin sensitivity will be calculated as the percent suppression of free fatty acids (FFAs) during the oral glucose tolerance test. | This measure was completed by 22 participants in the placebo phase of the study and 20 in the EAA phase of the study | Posted | Mean | Standard Deviation | percent suppression FFAs | 4 weeks after the first intervention, and approximately 8 weeks later (4 weeks washout and 4 weeks of second intervention) |
|
|
|
| Secondary | Sleep Duration | Sleep duration will be assessed completing placebo and essential amino acid therapy using home actigraphy. Change in sleep duration reported in minutes. | Out of these 3 participants 2 did not complete their EAA phase for this measurement, so results reported for EAA only include 21 participants. | Posted | Mean | Standard Deviation | minutes | 4 weeks after the first intervention, and approximately 8 weeks later (4 weeks washout and 4 weeks of second intervention) |
|
|
|
| Secondary | Apnea Hypopnea Index (AHI) | Apnea Hypopnea Index (AHI) will be measured using WatchPAT after each intervention. In children and adolescents the scale that will be used is AHI>5 is considered mild sleep apnea. The higher the AHI, indicates more severe sleep apnea. The AHI is the number of times you have apnea or hypopnea during one night, divided by the hours of sleep. Normal sleep: An AHI of fewer than five events, on average, per hour Mild sleep apnea: An AHI of five to 14 events per hour Moderate sleep apnea: An AHI of 15 to 29 events per hour Severe sleep apnea: An AHI of 30 or more events per hour | Out of these 3 participants 2 did not complete their EAA phase for this measurement, so results reported for EAA only include 21 participants. | Posted | Mean | Standard Deviation | events per hour | 4 weeks after the first intervention, and approximately 8 weeks later (4 weeks washout and 4 weeks of second intervention) |
|
|
|
| Secondary | Amino Acid Metabolomics: Alanine, Glutamate, Leucine, Valine Levels After 4 Weeks of Placebo and 4 Weeks of EAAs | Targeted amino acid metabolomics will be performed after each intervention and the levels of these 4 amino acids will be reported after each intervention. | Posted | Mean | Standard Deviation | micro molar | 4 weeks after the first intervention, and approximately 8 weeks later (4 weeks washout and 4 weeks of second intervention) |
|
|
|
| Secondary | Lipid Metabolomics: 16n1 | Targeted lipid metabolomics will be performed after each intervention to measure 16n1 lipids after completing 4 weeks of essential amino acid therapy and 4 weeks of placebo. | Posted | Mean | Standard Deviation | micro molar | 4 weeks after the first intervention, and approximately 8 weeks later (4 weeks washout and 4 weeks of second intervention) |
|
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|
| Secondary | Bile Acid Metabolomics: Sphingosine-1-phospate After 4 Weeks of Placebo and 4 Weeks of EAAs | Targeted bile acid metabolomics will be performed after each intervention to measure levels of sphingosine-1-phospate | Posted | Mean | Standard Deviation | micro molar | 4 weeks after the first intervention, and approximately 8 weeks later (4 weeks washout and 4 weeks of second intervention) |
|
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| 0 |
| 27 |
| 0 |
| 27 |
| 0 |
| 27 |
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| Adnexal Diseases |
| D005831 | Genital Diseases, Female |
| D052776 | Female Urogenital Diseases |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D000091662 | Genital Diseases |
| D006058 | Gonadal Disorders |
| D004700 | Endocrine System Diseases |
| D050177 | Overweight |
| D044343 | Overnutrition |
| D009748 | Nutrition Disorders |
| D009750 | Nutritional and Metabolic Diseases |
| D001835 | Body Weight |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D008107 | Liver Diseases |
| D004066 | Digestive System Diseases |
| Title | Measurements |
|---|---|
|
| PME/TP after Placebo |
|
| ATP/TP after EAA |
|
| ATP/TP after Placebo |
|
| Pi/TP after EAA |
|
| Pi/TP after Placebo |
|
| NADPH/TP after EAA |
|
| NADPH/TP after Placebo |
|
| UDPG/TP after EAA |
|
| UDPG/TP after Placebo |
|
|
| Title | Measurements |
|---|---|
|
| Valine after Placebo |
|
| Alanine after EAAs |
|
| Glutamate after EAAs |
|
| Leucine after EAAs |
|
| Valine after EAAs |
|