Losartan for the Treatment of Pediatric NAFLD (STOP-NAFLD)

Losartan for the Treatment of Pediatric NAFLD (STOP-NAFLD): A Phase 2, Randomized, Placebo-Controlled Clinical Trial

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

Study Overview

• Status: Terminated
• Conditions: NAFLD - Nonalcoholic Fatty Liver Disease
• Intervention / Treatment: Drug: Losartan potassium; Drug: Placebo losartan capsule

Detailed Description

Children ages 8-17 years weighing between 70 -149 kilograms will be enrolled and treated with losartan (100 mg orally once per day) or matching placebo for 24 weeks. The hypothesis is that losartan will improve serum alanine aminotransferase (ALT) in children with pediatric NAFLD.

• Study Type: Interventional
• Enrollment (Actual): 83
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • San Diego, California, United States, 92103
      • University of California, San Diego
    • San Francisco, California, United States, 94143
      • University of California, San Francisco
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
  • Illinois
    • Chicago, Illinois, United States, 60611-2605
      • Northwestern Univ-Ann & Robert H. Lurie Children's Hospital of Chicago
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University
  • Missouri
    • Saint Louis, Missouri, United States, 63104
      • St. Louis University
  • New York
    • New York, New York, United States, 10032
      • Columbia University
  • Ohio
    • Cincinnati, Ohio, United States, 45229-3039
      • Cincinnati Children's Hospital Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • Texas Children's Hospital
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 years to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Losartan potassium capsule; Dose will be one 50 mg capsule of losartan per day for one week and then increased to two capsules of 50 mg of losartan per day (100 mg total) for 23 weeks patients with baseline weight ≥ 70 kg to <150 kg.	Drug: Losartan potassium; Losartan potassium is an angiotensin II receptor blocker acting on the AT 1 receptor subtype; Other Names: losartan, Cozaar,
Placebo Comparator: Placebo losartan capsule; Dose will be one 50 mg capsule of placebo losartan per day for one week and then increased to two capsules of 50 mg of placebo losartan per day (100 mg total) for 23 weeks for patients with baseline weight ≥ 70 kg to <150 kg.	Drug: Placebo losartan capsule; Matching placebo losartan oral capsule

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Serum Alanine Aminotransferase (ALT) From Baseline.	Change ALT value in U/L (24 weeks minus baseline). A negative score indicates improvement.	Baseline and 24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Gamma-glutamyl Transpeptidase (GGT) Compared to Baseline	Change from baseline in gamma-glutamyl transpeptidase (GGT), measured in U/L.	Baseline and 24 weeks
Change in Serum Aspartate Aminotransferase AST at 24 Weeks Compared to Baseline AST	Change from baseline in serum aspartate aminotransferase, measured in U/L.	Baseline and 24 weeks
Relative Change in Serum Alanine Aminotransferase (ALT) Compared to Baseline ALT	Relative change from baseline in serum ALT, measured in percentage of change.	Baseline and 24 weeks
Change in ALT at 12 Weeks Compared to Baseline ALT	Change from baseline in ALT at 12 weeks, measured in U/L.	Baseline and 12 weeks
Change in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) Compared to Baseline.	Homeostasis Model Assessment of Insulin Resistance Index (HOMA-IR) measures insulin resistance, calculated by fasting insulin (umol/mL) multiplied by fasting glucose (mg/dL), and divided by a constant (405). A higher score indicates higher insulin resistance.	Baseline and 24 weeks
Change in Weight at 24 Weeks Compared to Baseline	Change from baseline in weight, measured in kg.	Baseline and 24 weeks
Change in Body Mass Index (BMI) at 24 Weeks Compared to Baseline.	Change from baseline in BMI, measured in kg/m^2.	Baseline and 24 weeks
Change in Waist Circumference at 24 Weeks Compared to Baseline	Change from baseline in waist circumference, measured in centimeters.	Baseline and 24 weeks
Change in Waist-to-hip Ratio at 24 Weeks Compared to Baseline	Change from baseline in waist-to-hip ratio, measured as the circumference of the waist in centimeters divided by the circumference of the hips in centimeters.	Baseline and 24 weeks
Change in Pediatric Quality of Life Inventory (PedsQOL) Physical Health Score at 24 Weeks Compared to Baseline	Pediatric Quality of Life Inventory (PedsQOL) version 4.0 is composed of 23 items comprising 4 dimensions: Physical Functioning, Emotional Functioning, Social Functioning, and School Functioning. Scores are transformed on a scale from 0 to 100, with higher scores indicating better health-related quality of life. Physical Health Summary Score =Physical Functioning Scale Score. The outcome is 24-week change from baseline in PedsQOL Physical Health Score, where higher values indicate improvement in quality of life.	Baseline and 24 weeks
Frequency of Adverse Events Over 24 Weeks	Numbers of adverse events reported over 24 weeks.	Baseline and 24 weeks
Change in Total Cholesterol at 24 Weeks Compared to Baseline	Change from baseline in total cholesterol, measured in mg/dL	Baseline and 24 weeks
Change in Triglycerides at 24 Weeks Compared to Baseline	Change from baseline in triglycerides, measured in mg/dL	Baseline and 24 weeks
Change in HDL Cholesterol at 24 Weeks Compared to Baseline	Change from baseline in HDL cholesterol, measured in mg/dL	Baseline and 24 weeks
Change in LDL Cholesterol at 24 Weeks Compared to Baseline	Change from baseline in LDL cholesterol, measured in mg/dL	Baseline and 24 weeks
Change in Pediatric Quality of Life Inventory (PedsQOL) Psychosocial Health Score at 24 Weeks Compared to Baseline	Pediatric Quality of Life Inventory (PedsQOL) version 4.0 is composed of 23 items comprising 4 dimensions: Physical Functioning, Emotional Functioning, Social Functioning, and School Functioning. Scores are transformed on a scale from 0 to 100, with higher scores indicating better health-related quality of life. Psychosocial Health Summary Score = Sum of items over the number of items answered in the Emotional, Social, and School Functioning Scales. The outcome is 24-week change from baseline in PedsQOL Psychosocial Health Score, where higher values indicate improvement in quality of life.	Baseline and 24 weeks

Collaborators and Investigators

• Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Collaborators: Johns Hopkins University
• Investigators: Study Director: Edward Doo, MD, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Publications and helpful links

Helpful Links

• Nonalcoholic Steatohepatitis Clinical Research Network Centers
• The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Study record dates

Study Major Dates

• Study Start (Actual): October 2, 2018
• Primary Completion (Actual): June 30, 2020
• Study Completion (Actual): June 30, 2020

Study Registration Dates

• First Submitted: March 9, 2018
• First Submitted That Met QC Criteria: March 14, 2018
• First Posted (Actual): March 15, 2018

Study Record Updates

• Last Update Posted (Actual): October 21, 2021
• Last Update Submitted That Met QC Criteria: September 23, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: Losartan; Nonalcoholic Fatty Liver Disease
• 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: 9 STOP-NAFLD; U01DK061730 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: This study will comply with the NIH Data Sharing Policy and Results information from this trial will be submitted to ClinicalTrials.gov and a public use database deposited with the NIDDK Central Repository.
• IPD Sharing Time Frame: Data from this study may be requested from the NIDDK Central Repository (https://www.niddkrepository.org/search/study/) two years after the completion of the primary outcome.
• IPD Sharing Access Criteria: Apply through the NIDDK Central Repository:
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Analytic Code

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No