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

• ClinicalTrials.gov Identifier: NCT03467217
• Recruitment Status: Terminated
• First Posted: March 15, 2018
• Results First Posted: October 21, 2021
• Last Update Posted: October 21, 2021
• Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Collaborator: Johns Hopkins University
• Information provided by (Responsible Party): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
NAFLD - Nonalcoholic Fatty Liver Disease	Drug: Losartan potassium; Drug: Placebo losartan capsule	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 83 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Masking Description: Participants, investigators, clinical staff, and data monitoring committee will not have knowledge of the interventions assigned to individual participants.
• Primary Purpose: Treatment
• Official Title: Losartan for the Treatment of Pediatric NAFLD (STOP-NAFLD): A Phase 2, Randomized, Placebo-Controlled Clinical Trial
• Actual Study Start Date: October 2, 2018
• Actual Primary Completion Date: June 30, 2020
• Actual Study Completion Date: June 30, 2020

Arms and Interventions

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 Name: 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

Outcome Measures

Primary Outcome Measures :

1. Change in Serum Alanine Aminotransferase (ALT) From Baseline. [ Time Frame: Baseline and 24 weeks ]
   Change ALT value in U/L (24 weeks minus baseline). A negative score indicates improvement.

Secondary Outcome Measures :

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

Eligibility Criteria

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

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

Contacts and Locations

Locations

United States, California

University of California, San Diego

San Diego, California, United States, 92103

University of California, San Francisco

San Francisco, California, United States, 94143

United States, Georgia

Emory University

Atlanta, Georgia, United States, 30322

United States, Illinois

Northwestern Univ-Ann & Robert H. Lurie Children's Hospital of Chicago

Chicago, Illinois, United States, 60611-2605

United States, Indiana

Indiana University

Indianapolis, Indiana, United States, 46202

United States, Missouri

St. Louis University

Saint Louis, Missouri, United States, 63104

United States, New York

Columbia University

New York, New York, United States, 10032

United States, Ohio

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States, 45229-3039

United States, Texas

Texas Children's Hospital

Houston, Texas, United States, 77030

United States, Washington

University of Washington

Seattle, Washington, United States, 98195

Sponsors and Collaborators

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Johns Hopkins University

Investigators

• Study Director: Edward Doo, MD; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

  Study Documents (Full-Text)

Documents provided by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK):

Study Protocol and Statistical Analysis Plan  [PDF] February 18, 2019

Informed Consent Form: Parental Permission Form  [PDF] February 18, 2019

Informed Consent Form: Child Assent Form  [PDF] May 21, 2018

Informed Consent Form: HIPAA Authorization Form  [PDF] May 21, 2018

More Information

Additional Information:

Nonalcoholic Steatohepatitis Clinical Research Network Centers 

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 

• Responsible Party: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• ClinicalTrials.gov Identifier: NCT03467217
• Other Study ID Numbers: 9 STOP-NAFLD; U01DK061730 ( U.S. NIH Grant/Contract )
• First Posted: March 15, 2018
• Results First Posted: October 21, 2021
• Last Update Posted: October 21, 2021
• Last Verified: September 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• 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.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Analytic Code
• 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.
• Access Criteria: Apply through the NIDDK Central Repository:
• URL: https://repository.niddk.nih.gov/home/

• 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

Keywords provided by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK):

Losartan; Nonalcoholic Fatty Liver Disease

Additional relevant MeSH terms:

Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Digestive System Diseases; Losartan; Anti-Arrhythmia Agents; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Molecular Mechanisms of Pharmacological Action