Losartan for the Treatment of Pediatric NAFLD

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

Detailed Description
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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.

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

Conditions
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NAFLD - Nonalcoholic Fatty Liver Disease

Intervention / Treatment
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* Drug: Losartan potassium
* Drug: Placebo losartan capsule


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 8 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Losartan potassium capsule<br>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<br>* Losartan potassium is an angiotensin II receptor blocker acting on the AT 1 receptor subtype<br>* Other names: losartan, Cozaar,;|
| Placebo Comparator: Placebo losartan capsule<br>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<br>* Matching placebo losartan oral capsule<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Losartan, Nonalcoholic Fatty Liver Disease