Study of Losartan in the Treatment of NAFLD in Children

Study Overview
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Brief Summary
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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.

Official Title
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A Pilot Study of Losartan in the Treatment of Pediatric NAFLD

Conditions
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NAFLD

Intervention / Treatment
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* Drug: Losartan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Body Mass Index (BMI) > 85th% for age and gender History of definite or borderline nonalcoholic steatohepatitis (NASH) diagnosed by liver biopsy using NASH Clinical Research Network (CRN) criteria At least 2 months of attempted lifestyle changes after liver biopsy Current ALT ≥ 3 times normal (69 U/L for girls, 78 U/L for boys) at enrollment Glomerular filtration rate (GRF) > 90 Weight ≥ 62.5 kg Exclusion Criteria: Other chronic illness requiring daily medication (except medications for mild mental illness, acid reflux, allergies, stable attention deficit hyperactivity disorder (ADHD), or asthma) Supplement or anti-oxidant therapy within past 2 weeks Renal insufficiency Cirrhosis and liver synthetic dysfunction (International Normalized Ratio ≥ 1.5) History of hypotension Diabetes (or fasting glucose > 125 mg/dL) Acute illness within past 2 weeks prior to enrollment (fever > 100.4ºF) Pregnancy

Ages Eligible for Study
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Minimum Age: 11 Years
Maximum Age: 19 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Losartan then Placebo<br>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 | Drug: Losartan<br>* 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.<br>* Other names: Serial Number: 74193404;|
| Experimental: Sugar pill<br>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 | Drug: Losartan<br>* 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.<br>* Other names: Serial Number: 74193404;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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) | 

Secondary Outcome Measures

| Outcome Measure | 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) | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NAFLD, Non-alcoholic Fatty Liver Disease, Obesity, Pediatrics, Children, Losartan, Cozaar