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| ID | Type | Description | Link |
|---|---|---|---|
| 1R03DK096157-01A1 | U.S. NIH Grant/Contract | View source | |
| 1R03DK096157-01 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) | NIH |
| Children's Healthcare of Atlanta | OTHER |
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Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease among children and is closely associated with obesity and the metabolic syndrome. NAFLD increases risk of mortality and natural history studies of adults show that NAFLD is an independent risk factor for cardiovascular disease. Pediatric NAFLD is particularly concerning from a public health standpoint, as it represents an early and possibly more aggressive form of the disease. Currently there is no effective treatment for pediatric NAFLD.
Losartan is an orally-administered angiotensin II receptor antagonist which is currently on the market to treat high blood pressure. The renin-angiotensin-aldosterone (RAA) system has been shown to be important in many disease states including renal disease, cardiovascular disease, and NAFLD. Angiotensin antagonists are a class of medications that has been proposed as a novel treatment of NAFLD in part because they would treat both the factors increasing cardiovascular (CVD) risks as well as potentially improve steatosis, fibrosis and hepatic inflammation.
This study is a randomized, double-blinded, placebo-controlled pilot study to evaluate whether 8 weeks of Losartan will decrease inflammatory markers among children ages 12-19 with a current diagnosis of NAFLD. Efficacy will be assessed by improvement in alanine aminotransferase (ALT) from baseline. Secondary endpoints will include aspartate aminotransferase (AST), cytokeratin 18 levels, and fasting triglyceride levels among others. Safety will be assessed by the recording of adverse events, clinical laboratory parameters, vital signs and physical examinations.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Losartan then Placebo | Experimental | 0.4mg/kg/day (max 25mg) for one week and then increase to 0.8mg/kg/day (max 50mg) for 7 additional weeks then placebo pill for 8 weeks |
|
| Sugar pill | Experimental | placebo pill taken for 8 weeks then 0.4mg/kg/day (max 25mg) for one week and then increase to 0.8mg/kg/day (max 50mg) for 7 additional weeks |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Losartan | Drug | Oral tablet to be taken once daily at 0.4mg/kg/day (max 25mg) for one week and then increased to 0.8mg/kg/day (max 50mg) for 7 additional weeks. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Change in Alanine Aminotransferase (ALT) From Baseline to End of Treatment (8 Weeks of Treatment) | The principal objective of this blinded, placebo controlled, crossover pilot study is to evaluate whether 8 weeks of losartan in children with nonalcoholic steatohepatitis (NASH) will decrease inflammation as measured by ALT. | Baseline (Weeks 0 and 14), Endpoint (Weeks 8 and 22) |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Cholesterol Levels From Baseline to End of Treatment (8 Weeks of Treatment) | For children, a cholesterol level of less than 170 is considered acceptable, 170-199 is borderline high, and 200 and over is high. | Baseline (Week 0 and 14), End of treatment (Week 8 and 22) |
| Change in Triglyceride Levels From Baseline to End of Treatment (8 Weeks of Treatment) |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Aspartate Aminotransferase (AST) From Baseline to End of Treatment | The normal range for AST in children is 0 - 60 IU/L. AST can respond rapidly to treatment so decreases between Baseline and subsequent measurements indicate positive effects of treatment. | Baseline, Week 8, Week 14, and Week 22 |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Miriam Vos, MD, MSPH | Emory University / Children's Healthcare of Atlanta | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Emory University / Children's Healthcare of Atlanta | Atlanta | Georgia | 30322 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 29992039 | Derived | Vos MB, Jin R, Konomi JV, Cleeton R, Cruz J, Karpen S, Rodriguez DS, Frediani JK, McCracken C, Welsh J. A randomized, controlled, crossover pilot study of losartan for pediatric nonalcoholic fatty liver disease. Pilot Feasibility Stud. 2018 Jun 5;4:109. doi: 10.1186/s40814-018-0306-4. eCollection 2018. |
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Of the 16 individuals who signed the consent form, 4 were found to be ineligible to participate during screening process, resulting in 12 participants who began the study treatment.
Children were recruited from the patient population of Children's Healthcare of Atlanta and the Emory Children's Center Clinics.
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| ID | Title | Description |
|---|---|---|
| FG000 | Losartan Followed by Placebo | Recipients of treatment with losartan for 8 weeks followed by 8 weeks of treatment with a placebo |
| FG001 | Placebo Followed by Losartan | Recipients of treatment with a placebo for 8 weeks followed by 8 weeks of treatment with losartan. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
The baseline analysis population includes all participants who consented to participate in the study and met eligibility criteria.
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| ID | Title | Description |
|---|---|---|
| BG000 | Losartan Followed by Placebo | Recipients of treatment with losartan for 8 weeks followed by 8 weeks of treatment with a placebo. |
| BG001 | Placebo Followed by Losartan | Recipients of treatment with a placebo for 8 weeks followed by 8 weeks of treatment with losartan. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| 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 | Change in Alanine Aminotransferase (ALT) From Baseline to End of Treatment (8 Weeks of Treatment) | The principal objective of this blinded, placebo controlled, crossover pilot study is to evaluate whether 8 weeks of losartan in children with nonalcoholic steatohepatitis (NASH) will decrease inflammation as measured by ALT. | In this blinded, crossover treatment, study participants received losartan or a placebo for 8 weeks, then completed a 6 week washout period before crossing over to the other treatment for 8 weeks. The placebo results for four participants in the losartan followed by placebo arm were not usable due to carry over effects from the active treatment. | Posted | Mean | Standard Deviation | U/L | Baseline (Weeks 0 and 14), Endpoint (Weeks 8 and 22) |
|
Adverse event details were collected throughout the duration of study participation, from the Baseline visit through the Week 28 follow up visit.
For this study, an adverse event is considered any untoward medical occurrence in a subject participating in a clinical study that does not necessarily have a causal relationship with the study drug. It can also mean any unfavorable and unintended sign (including laboratory findings, symptom, or disease) temporarily associated with the use of losartan or placebo, whether or not directly related to losartan or not.
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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 | Losartan | Recipients of treatment with losartan for 8 weeks. | 0 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Ear ache | Ear and labyrinth disorders | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Miriam Vos, MD, MSPH | Emory University | 404-727-9930 | mvos@emory.edu |
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| ID | Term |
|---|---|
| D065626 | Non-alcoholic Fatty Liver Disease |
| D009765 | Obesity |
| ID | Term |
|---|---|
| D005234 | Fatty Liver |
| D008107 | Liver Diseases |
| D004066 | Digestive System Diseases |
| D050177 | Overweight |
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| ID | Term |
|---|---|
| D019808 | Losartan |
| ID | Term |
|---|---|
| D001713 | Biphenyl Compounds |
| D001555 | Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
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|
For children aged 10 to 19, triglyceride levels of less than 90 is considered acceptable, 90 to 129 is borderline high, and greater than or equal to 130 and over is high. |
| Baseline (Week 0 and 14), End of treatment (Week 8 and 22) |
| Change in Fatty Acid Levels From Baseline to End of Treatment (8 Weeks of Treatment) | In human studies, losartan has been shown to decrease serum free fatty acids, thus any decrease in this measurement indicates a positive response to losartan. | Baseline (Week 0 and 14), End of Treatment (Week 8 and 22) |
| Changes in Homeostasis Model of Assessment - Insulin Resistance (HOMA-IR) Between Baseline and End of Treatment (8 Weeks of Treatment) | Homeostasis Model of Assessment - Insulin Resistance (HOMA-IR) is an equation which indicates the degree of insulin resistance, where higher scores equate to greater insulin resistance. HOMA-IR is calculated as fasting glucose (mg/dl) × insulin (mU/L)/405. A HOMA-IR value >2.0 in prepubertal children and >2.6 in pubertal children, may be considered a warning sign for pediatricians to further investigate insulin resistance. | Baseline (Week 0 and 14), End of Treatment (Week 8 and 22) |
| Changes in Plasminogen Activator Inhibitor-1 (PAI-1) Concentrations Between Baseline and End of Treatment | PAI-1 is an acute-phase protein that is associated with both injury and inflammation, and has been found to be elevated in adolescents with significant hepatic steatosis. The reference range for PAI-1 in fasting adults is 3-72 ng/mL | Baseline, Week 8, Week 14, Week 22 |
| Withdrawal by Subject |
|
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 | Placebo | Recipients of treatment with a placebo for 8 weeks. |
|
|
| Secondary | Change in Cholesterol Levels From Baseline to End of Treatment (8 Weeks of Treatment) | For children, a cholesterol level of less than 170 is considered acceptable, 170-199 is borderline high, and 200 and over is high. | The placebo results for four participants in the losartan followed by placebo arm were not usable due to carry over effects from the active treatment. One additional participant in each treatment group is missing the end of treatment cholesterol level measurement. | Posted | Mean | Standard Deviation | mg/dL | Baseline (Week 0 and 14), End of treatment (Week 8 and 22) |
|
|
|
| Secondary | Change in Triglyceride Levels From Baseline to End of Treatment (8 Weeks of Treatment) | For children aged 10 to 19, triglyceride levels of less than 90 is considered acceptable, 90 to 129 is borderline high, and greater than or equal to 130 and over is high. | The placebo results for four participants in the losartan followed by placebo arm were not usable due to carry over effects from the active treatment. One participant is missing data for the endpoint measurement of triglyceride levels, following 8 weeks of losartan treatment. | Posted | Mean | Standard Deviation | mg/dL | Baseline (Week 0 and 14), End of treatment (Week 8 and 22) |
|
|
|
| Secondary | Change in Fatty Acid Levels From Baseline to End of Treatment (8 Weeks of Treatment) | In human studies, losartan has been shown to decrease serum free fatty acids, thus any decrease in this measurement indicates a positive response to losartan. | The placebo results for four participants in the losartan followed by placebo arm were not usable due to carry over effects from the active treatment. One participant is missing the endpoint measurement for free fatty acid levels, following the 8 week losartan treatment phase. | Posted | Mean | Standard Deviation | mEq/L | Baseline (Week 0 and 14), End of Treatment (Week 8 and 22) |
|
|
|
| Secondary | Changes in Homeostasis Model of Assessment - Insulin Resistance (HOMA-IR) Between Baseline and End of Treatment (8 Weeks of Treatment) | Homeostasis Model of Assessment - Insulin Resistance (HOMA-IR) is an equation which indicates the degree of insulin resistance, where higher scores equate to greater insulin resistance. HOMA-IR is calculated as fasting glucose (mg/dl) × insulin (mU/L)/405. A HOMA-IR value >2.0 in prepubertal children and >2.6 in pubertal children, may be considered a warning sign for pediatricians to further investigate insulin resistance. | The placebo results for four participants in the losartan followed by placebo arm were not usable due to carry over effects from the active treatment. An additional participant is missing HOMA-IR data from the placebo phase of the study. | Posted | Mean | Standard Deviation | units on a scale | Baseline (Week 0 and 14), End of Treatment (Week 8 and 22) |
|
|
|
| Secondary | Changes in Plasminogen Activator Inhibitor-1 (PAI-1) Concentrations Between Baseline and End of Treatment | PAI-1 is an acute-phase protein that is associated with both injury and inflammation, and has been found to be elevated in adolescents with significant hepatic steatosis. The reference range for PAI-1 in fasting adults is 3-72 ng/mL | The placebo results for four participants in the losartan followed by placebo arm were not usable due to carry over effects from the active treatment. One additional participant is missing PAI-1 data from the placebo phase of the study. | Posted | Mean | Standard Deviation | ng/mL | Baseline, Week 8, Week 14, Week 22 |
|
|
|
| Other Pre-specified | Change in Aspartate Aminotransferase (AST) From Baseline to End of Treatment | The normal range for AST in children is 0 - 60 IU/L. AST can respond rapidly to treatment so decreases between Baseline and subsequent measurements indicate positive effects of treatment. | In this blinded, crossover treatment, study participants received losartan or a placebo for 8 weeks, then completed a 6 week washout period before crossing over to the other treatment for 8 weeks. The placebo results for four participants in the losartan followed by placebo arm were not usable due to carry over effects from the active treatment. | Posted | Mean | Standard Deviation | IU/L | Baseline, Week 8, Week 14, and Week 22 |
|
|
|
| 9 |
| 0 |
| 9 |
| 9 |
| 9 |
| EG001 | Placebo | Recipients of treatment with a placebo for 8 weeks. | 0 | 5 | 0 | 5 | 5 | 5 |
| Blurred vision | Eye disorders | Non-systematic Assessment |
|
| Abdominal Pain | General disorders | Non-systematic Assessment |
|
| Chest Pain | General disorders | Non-systematic Assessment |
|
| Dizziness | General disorders | Non-systematic Assessment |
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| Fatigue | General disorders | Non-systematic Assessment |
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| Lack of Concentration | General disorders | Non-systematic Assessment |
|
| Nausea | General disorders | Non-systematic Assessment |
|
| Muscle Pain | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
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| Cough | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| Nasal Congestion | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| Sinus Infection | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| Upper Respiratory Infection | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| Hives | Skin and subcutaneous tissue disorders | Non-systematic Assessment |
|
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| D044343 |
| Overnutrition |
| D009748 | Nutrition Disorders |
| D009750 | Nutritional and Metabolic Diseases |
| D001835 | Body Weight |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D006838 |
| Hydrocarbons |
| D009930 | Organic Chemicals |
| D007093 | Imidazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D013777 | Tetrazoles |
| Cholesterol at end of treatment (week 8 and/or 22) |
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| Triglyceride at end of treatment (week 8 or 22) |
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| Fatty acid at end of treatment (week 8 and 22) |
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