Losartan for the Treatment of Pediatric NAFLD
Condition: NAFLD - Nonalcoholic Fatty Liver Disease
MeSH terms: Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease
Intervention: Losartan potassium; Placebo losartan capsule
Intervention description: Losartan potassium is an angiotensin II receptor blocker acting on the AT 1 receptor subtype; Matching placebo losartan oral capsule
Intervention MeSH terms: Losartan
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Masking description: Participants, investigators, clinical staff, and data monitoring committee will not have knowledge of the interventions assigned to individual participants.
Enrollment: 83.0
Sex: All
Minimum age: 8 Years
Maximum age: 17 Years
Healthy volunteers: No
Keywords: Losartan; Nonalcoholic Fatty Liver Disease

Summary:

      A multicenter, randomized, double masked, placebo-controlled, parallel treatment groups phase
      2 trial of losartan for pediatric nonalcoholic fatty liver disease (NAFLD).
    

Eligibility criteria:

        Inclusion Criteria:

          -  Age 8-17 years at initial screening interview

          -  Histological evidence of NAFLD with or without fibrosis and a NAFLD activity score
             (NAS) of ≥3, on a liver biopsy obtained no more than 730 days prior to enrollment.

          -  Serum ALT at screening ≥ 50 IU/L

        Exclusion Criteria:

          -  Body weight less than 70 kg or greater than 150 kg at screening

          -  Significant alcohol consumption or inability to reliably quantify alcohol intake

          -  Use of drugs historically associated with NAFLD (amiodarone, methotrexate, systemic
             glucocorticoids, tetracyclines, tamoxifen, estrogens at doses greater than those used
             for hormone replacement, anabolic steroids, valproic acid, other known hepatotoxins)
             for more than 2 consecutive weeks in the past year prior to randomization

          -  New treatment with vitamin E or metformin started in the past 90 days or plans to
             alter the dose or stop over the next the 24 weeks. A stable dose is acceptable.

          -  Prior or planned bariatric surgery

          -  Uncontrolled diabetes (HbA1c 9.5% or higher)

          -  Presence of cirrhosis on liver biopsy

          -  History of hypotension or history of orthostatic hypotension

          -  Stage 2 Hypertension or >140 systolic or >90 diastolic at screening

          -  Current treatment with any antihypertensive medications including all angiotensin
             converting enzyme (ACE) inhibitors or aliskiren

          -  Current treatment with potassium supplements or any drug known to increase potassium

          -  Current daily use of nonsteroidal anti-inflammatory drugs (NSAIDs)

          -  Current treatment with lithium

          -  Platelet counts below 100,000 /mm3

          -  Clinical evidence of hepatic decompensation (serum albumin < 3.2 g/dL, international
             normalized ratio (INR) >1.3, direct bilirubin >1.3 mg/dL, history of esophageal
             varices, ascites, or hepatic encephalopathy)

          -  Evidence of chronic liver disease other than NAFLD:

               -  Biopsy consistent with histological evidence of autoimmune hepatitis

               -  Serum hepatitis B surface antigen (HBsAg) positive.

               -  Serum hepatitis C antibody (anti-HCV) positive.

               -  Iron/total iron binding capacity (TIBC) ratio (transferrin saturation) > 45% with
                  histological evidence of iron overload

               -  Alpha-1-antitrypsin (A1AT) phenotype/genotype ZZ or SZ

               -  Wilson's disease

          -  Serum alanine aminotransferase (ALT) greater than 300 IU/L

          -  History of biliary diversion

          -  History of kidney disease and/or estimated glomerular filtration rate (eGFR) < than 60
             mL/min/1.73 m2 using Schwartz Bedside GFR Calculator for Children isotope dilution
             mass spectroscopy (IDMS)-traceable

          -  Known Human Immunodeficiency Virus (HIV) infection

          -  Active, serious medical disease with life expectancy less than 5 years

          -  Active substance abuse including inhaled or injected drugs, in the year prior to
             screening

          -  Pregnancy, planned pregnancy, potential for pregnancy and unwillingness to use
             effective birth control during the trial, breast feeding

          -  Participation in an investigational new drug (IND) trial in the 150 days prior to
             randomization

          -  Any other condition which, in the opinion of the investigator, would impede compliance
             or hinder completion of the study

          -  Inability to swallow capsules

          -  Known allergy to losartan potassium or other angiotensin receptor blocker

          -  Failure of parent or legal guardian to give informed consent or subject to give
             informed assent