Losartan for the Treatment of Pediatric NAFLD

Phase 2

Terminated

Conditions: NAFLD - Nonalcoholic Fatty Liver Disease

Interventions: Drug: Losartan potassium
Drug: Placebo losartan capsule

Registration Number: NCT03467217

Lead Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

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

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 83

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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Losartan potassium capsule	Losartan potassium	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.
Placebo losartan capsule	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.

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
Change in Gamma-glutamyl Transpeptidase (GGT) Compared to Baseline	Baseline and 24 weeks	Change from baseline in gamma-glutamyl transpeptidase (GGT), measured in U/L.
Change in Serum Aspartate Aminotransferase AST at 24 Weeks Compared to Baseline AST	Baseline and 24 weeks	Change from baseline in serum aspartate aminotransferase, measured in U/L.
Relative Change in Serum Alanine Aminotransferase (ALT) Compared to Baseline ALT	Baseline and 24 weeks	Relative change from baseline in serum ALT, measured in percentage of change.
Change in ALT at 12 Weeks Compared to Baseline ALT	Baseline and 12 weeks	Change from baseline in ALT at 12 weeks, measured in U/L.
Change in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) Compared to Baseline.	Baseline and 24 weeks	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.
Change in Weight at 24 Weeks Compared to Baseline	Baseline and 24 weeks	Change from baseline in weight, measured in kg.
Change in Body Mass Index (BMI) at 24 Weeks Compared to Baseline.	Baseline and 24 weeks	Change from baseline in BMI, measured in kg/m\^2.
Change in Waist Circumference at 24 Weeks Compared to Baseline	Baseline and 24 weeks	Change from baseline in waist circumference, measured in centimeters.
Change in Waist-to-hip Ratio at 24 Weeks Compared to Baseline	Baseline and 24 weeks	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.
Change in Pediatric Quality of Life Inventory (PedsQOL) Physical Health Score at 24 Weeks Compared to Baseline	Baseline and 24 weeks	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.
Frequency of Adverse Events Over 24 Weeks	Baseline and 24 weeks	Numbers of adverse events reported over 24 weeks.
Change in Total Cholesterol at 24 Weeks Compared to Baseline	Baseline and 24 weeks	Change from baseline in total cholesterol, measured in mg/dL
Change in Triglycerides at 24 Weeks Compared to Baseline	Baseline and 24 weeks	Change from baseline in triglycerides, measured in mg/dL
Change in HDL Cholesterol at 24 Weeks Compared to Baseline	Baseline and 24 weeks	Change from baseline in HDL cholesterol, measured in mg/dL
Change in LDL Cholesterol at 24 Weeks Compared to Baseline	Baseline and 24 weeks	Change from baseline in LDL cholesterol, measured in mg/dL
Change in Pediatric Quality of Life Inventory (PedsQOL) Psychosocial Health Score at 24 Weeks Compared to Baseline	Baseline and 24 weeks	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.

Trial Locations

Locations (10): Emory University
🇺🇸
Atlanta, Georgia, United States
Northwestern Univ-Ann & Robert H. Lurie Children's Hospital of Chicago
🇺🇸
Chicago, Illinois, United States
University of Washington
🇺🇸
Seattle, Washington, United States
University of California, San Diego
🇺🇸
San Diego, California, United States
St. Louis University
🇺🇸
Saint Louis, Missouri, United States
University of California, San Francisco
🇺🇸
San Francisco, California, United States
Indiana University
🇺🇸
Indianapolis, Indiana, United States
Columbia University
🇺🇸
New York, New York, United States
Cincinnati Children's Hospital Medical Center
🇺🇸
Cincinnati, Ohio, United States
Texas Children's Hospital
🇺🇸
Houston, Texas, United States