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Study of Losartan in the Treatment of NAFLD in Children

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ClinicalTrials.gov Identifier: NCT01913470
Recruitment Status : Completed
First Posted : August 1, 2013
Results First Posted : May 15, 2017
Last Update Posted : May 15, 2017
Sponsor:
Collaborators:
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Children's Healthcare of Atlanta
Information provided by (Responsible Party):
Miriam Vos, MD, Emory University

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
NAFLD Drug: Losartan Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 12 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Pilot Study of Losartan in the Treatment of Pediatric NAFLD
Study Start Date : July 2013
Actual Primary Completion Date : December 2015
Actual Study Completion Date : December 2015


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




Primary Outcome Measures :
  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 Outcome Measures :
  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 Outcome Measures:
  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.



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Ages Eligible for Study:   11 Years to 19 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01913470


Locations
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United States, Georgia
Emory University / Children's Healthcare of Atlanta
Atlanta, Georgia, United States, 30322
Sponsors and Collaborators
Miriam Vos, MD
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Children's Healthcare of Atlanta
Investigators
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Principal Investigator: Miriam Vos, MD, MSPH Emory University / Children's Healthcare of Atlanta

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Miriam Vos, MD, Assistant Professor of Pediatrics, Emory University
ClinicalTrials.gov Identifier: NCT01913470     History of Changes
Other Study ID Numbers: IRB00062895
1R03DK096157-01A1 ( U.S. NIH Grant/Contract )
1R03DK096157-01 ( U.S. NIH Grant/Contract )
First Posted: August 1, 2013    Key Record Dates
Results First Posted: May 15, 2017
Last Update Posted: May 15, 2017
Last Verified: April 2017

Keywords provided by Miriam Vos, MD, Emory University:
NAFLD
Non-alcoholic Fatty Liver Disease
Obesity
Pediatrics
Children
Losartan
Cozaar

Additional relevant MeSH terms:
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Non-alcoholic Fatty Liver Disease
Fatty Liver
Liver Diseases
Digestive System Diseases
Losartan
Anti-Arrhythmia Agents
Antihypertensive Agents
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists
Molecular Mechanisms of Pharmacological Action