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NCT Number: NCT01913470

Study of Losartan in the Treatment of NAFLD in Children

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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Key information

Conditions

NAFLD Body Weight Digestive System Diseases Fatty Liver Liver Diseases Non-alcoholic Fatty Liver Disease Nutrition Disorders Nutritional and Metabolic Diseases Obesity Overnutrition Overweight Pathological Conditions, Signs and Symptoms Signs and Symptoms

Age range

11 year–19 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

Emory University / Children's Healthcare of Atlanta

Atlanta, Georgia, 30322, United States

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

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.

Other names: Cozaar, Losartan Potassium Tablets, Serial Number: 74193404

Primary outcomes

  1. Change in Alanine Aminotransferase (ALT) From Baseline to End of Treatment (8 Weeks of Treatment)

    Time frame: Baseline (Weeks 0 and 14), Endpoint (Weeks 8 and 22)

    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.

Secondary outcomes

  1. Change in Cholesterol Levels From Baseline to End of Treatment (8 Weeks of Treatment)

    Time frame: Baseline (Week 0 and 14), End of treatment (Week 8 and 22)

    For children, a cholesterol level of less than 170 is considered acceptable, 170-199 is borderline high, and 200 and over is high.

  2. Change in Triglyceride Levels From Baseline to End of Treatment (8 Weeks of Treatment)

    Time frame: Baseline (Week 0 and 14), End of treatment (Week 8 and 22)

    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.

  3. Change in Fatty Acid Levels From Baseline to End of Treatment (8 Weeks of Treatment)

    Time frame: Baseline (Week 0 and 14), End of Treatment (Week 8 and 22)

    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.

  4. Changes in Homeostasis Model of Assessment - Insulin Resistance (HOMA-IR) Between Baseline and End of Treatment (8 Weeks of Treatment)

    Time frame: Baseline (Week 0 and 14), End of Treatment (Week 8 and 22)

    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.

  5. Changes in Plasminogen Activator Inhibitor-1 (PAI-1) Concentrations Between Baseline and End of Treatment

    Time frame: Baseline, Week 8, Week 14, Week 22

    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

Other outcomes

  1. Change in Aspartate Aminotransferase (AST) From Baseline to End of Treatment

    Time frame: Baseline, Week 8, Week 14, and Week 22

    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.

Sponsors and collaborators

Lead sponsor

Miriam Vos, MD

Other

Collaborators

  • Children's Healthcare of Atlanta
  • National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Registry information

Official study title

A Pilot Study of Losartan in the Treatment of Pediatric NAFLD

Important dates

Study start
2013
Primary completion
2015
Study completion
2015
First posted
Aug 1, 2013
Registry last updated
May 15, 2017

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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