Clinical trial NCT03467217: Losartan for the Treatment of Pediatric NAFLD
Official title: Losartan for the Treatment of Pediatric NAFLD (STOP-NAFLD): A Phase 2, Randomized, Placebo-Controlled Clinical Trial
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: NAFLD - Nonalcoholic Fatty Liver Disease
Keywords: Losartan
Nonalcoholic Fatty Liver Disease
Lead sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Sponsor class: NIH
Collaborators: name: Johns Hopkins University
First posted: 2018-03-15
Enrollment: 83
Sex: ALL
Minimum age (years): 8
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Change in Serum Alanine Aminotransferase (ALT) From Baseline.
timeFrame: Baseline and 24 weeks
Secondary outcomes:
measure: Change in Gamma-glutamyl Transpeptidase (GGT) Compared to Baseline
timeFrame: Baseline and 24 weeks
measure: Change in Serum Aspartate Aminotransferase AST at 24 Weeks Compared to Baseline AST
timeFrame: Baseline and 24 weeks
measure: Relative Change in Serum Alanine Aminotransferase (ALT) Compared to Baseline ALT
timeFrame: Baseline and 24 weeks
measure: Change in ALT at 12 Weeks Compared to Baseline ALT
timeFrame: Baseline and 12 weeks
measure: Change in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) Compared to Baseline.
timeFrame: Baseline and 24 weeks
measure: Change in Weight at 24 Weeks Compared to Baseline
timeFrame: Baseline and 24 weeks
measure: Change in Body Mass Index (BMI) at 24 Weeks Compared to Baseline.
timeFrame: Baseline and 24 weeks
measure: Change in Waist Circumference at 24 Weeks Compared to Baseline
timeFrame: Baseline and 24 weeks
measure: Change in Waist-to-hip Ratio at 24 Weeks Compared to Baseline
timeFrame: Baseline and 24 weeks
measure: Change in Pediatric Quality of Life Inventory (PedsQOL) Physical Health Score at 24 Weeks Compared to Baseline
timeFrame: Baseline and 24 weeks
measure: Frequency of Adverse Events Over 24 Weeks
timeFrame: Baseline and 24 weeks
measure: Change in Total Cholesterol at 24 Weeks Compared to Baseline
timeFrame: Baseline and 24 weeks
measure: Change in Triglycerides at 24 Weeks Compared to Baseline
timeFrame: Baseline and 24 weeks
measure: Change in HDL Cholesterol at 24 Weeks Compared to Baseline
timeFrame: Baseline and 24 weeks
measure: Change in LDL Cholesterol at 24 Weeks Compared to Baseline
timeFrame: Baseline and 24 weeks
measure: Change in Pediatric Quality of Life Inventory (PedsQOL) Psychosocial Health Score at 24 Weeks Compared to Baseline
timeFrame: Baseline and 24 weeks
Other outcomes:
Locations:
city: San Diego
country: United States
facility: University of California, San Diego
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Chicago
country: United States
facility: Northwestern Univ-Ann & Robert H. Lurie Children's Hospital of Chicago
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Saint Louis
country: United States
facility: St. Louis University
state: Missouri
city: New York
country: United States
facility: Columbia University
state: New York
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
city: Seattle
country: United States
facility: University of Washington
state: Washington
Study officials:
affiliation: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
name: Edward Doo, MD
role: STUDY_DIRECTOR
References: