Study of Losartan in the Treatment of NAFLD in Children

A Pilot Study of Losartan in the Treatment of Pediatric NAFLD

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.

Study Overview

• Status: Completed
• Conditions: NAFLD
• Intervention / Treatment: Drug: Losartan

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University / Children's Healthcare of Atlanta

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 11 years to 19 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Losartan then Placebo; 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; 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
Experimental: Sugar pill; 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; 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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Miriam Vos, MD
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Children's Healthcare of Atlanta
• Investigators: Principal Investigator: Miriam Vos, MD, MSPH, Emory University / Children's Healthcare of Atlanta

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: July 1, 2013
• Primary Completion (Actual): December 1, 2015
• Study Completion (Actual): December 1, 2015

Study Registration Dates

• First Submitted: July 8, 2013
• First Submitted That Met QC Criteria: July 30, 2013
• First Posted (Estimate): August 1, 2013

Study Record Updates

• Last Update Posted (Actual): May 15, 2017
• Last Update Submitted That Met QC Criteria: April 6, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Keywords: Obesity; Children; Pediatrics; NAFLD; Losartan; Non-alcoholic Fatty Liver Disease; Cozaar
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Losartan
• Other Study ID Numbers: IRB00062895; 1R03DK096157-01A1 (U.S. NIH Grant/Contract); 1R03DK096157-01 (U.S. NIH Grant/Contract)