Losartan for the Treatment of Pediatric Nonalcoholic Fatty Liver Disease (STOP-NAFLD)

General Description

The STOP-NAFLD (Losartan for the Treatment of Pediatric NAFLD) trial was a multicenter, double-masked, placebo-controlled, randomized phase 2 trial designed by the NASH Clinical Research Network to determine whether treatment with losartan improves measures of NAFLD in children. Children between the ages of 8 and 17 years with biopsy-proven NAFLD were eligible for the STOP-NAFLD study. Participants were enrolled and randomized to treatment with either 100 mg of losartan or matching placebo orally once daily for 24 weeks. Improvement in NAFLD at 24 weeks, defined as a decrease in serum alanine aminotransferase (ALT), was assessed as the primary outcome measure. Secondary outcome measures, also assessed at 24 weeks, included relative change in ALT; changes in serum aspartate aminotransferase (AST) and gamma-glutamyl transpeptidase (GGT); change in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR); changes in anthropometric measurements, BMI z-score, and serum lipid profiles; and self-reported quality of life.

Objectives

Primary objective(s): The STOP-NAFLD trial aimed to determine whether 24 weeks of treatment with losartan compared to treatment with placebo improves measures of NAFLD in children, as determined by improvement in serum ALT from baseline.

Secondary objective(s): The secondary objectives of the STOP-NAFLD trial were to determine safety of losartan in children with pediatric NAFLD over 24 weeks and to measure other biomarkers of response to losartan.

Outcome Measure

The primary outcome measure was change in serum alanine aminotransferase (ALT) from baseline to 24 weeks.

Secondary outcome measures, also assessed at 24 weeks, included relative change in ALT, proportion of patients achieving normalization of ALT, change in serum aspartate aminotransferase (AST) and gamma-glutamyl transpeptidase (GGT), change in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), change in anthropometric measurements (weight, waist to hip ratio, waist circumference) and BMI z-score, change in serum lipid profiles, change in C-reactive protein (serum marker of inflammation), change in Pediatric Quality of Life (Ped-QoL) scores, and change in frequency of adverse events. Change in ALT was also assessed at 12 weeks compared to baseline.

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 within 60 days prior to enrollment)
• 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 any clinical/investigational trial within the prior 150 days and during the STOP-NAFLD Trial
• 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

Outcome

Losartan did not significantly reduce ALT in children with NAFLD when compared with placebo. The STOP-NAFLD trial was stopped early after an unplanned interim analysis, necessitated by the 2019 coronavirus pandemic, showed low probability (7%) of significant group difference. Baseline characteristics were similar between groups. The 24-week change in ALT did not differ significantly between losartan versus placebo groups, although alkaline phosphatase decreased significantly in the losartan group. Systolic blood pressure decreased in the losartan group but increased in the placebo group. Compliance by pill counts and numbers and types of adverse events did not differ by group.