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

Primary Purpose

NAFLD - Nonalcoholic Fatty Liver Disease

Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Losartan potassium
Placebo losartan capsule
Sponsored by
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for NAFLD - Nonalcoholic Fatty Liver Disease focused on measuring Losartan, Nonalcoholic Fatty Liver Disease

Eligibility Criteria

8 Years - 17 Years (Child)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University of California, San Diego
  • University of California, San Francisco
  • Emory University
  • Northwestern Univ-Ann & Robert H. Lurie Children's Hospital of Chicago
  • Indiana University
  • St. Louis University
  • Columbia University
  • Cincinnati Children's Hospital Medical Center
  • Texas Children's Hospital
  • University of Washington

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Losartan potassium capsule

Placebo losartan capsule

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Change in Gamma-glutamyl Transpeptidase (GGT) Compared to Baseline
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
Change from baseline in serum aspartate aminotransferase, measured in U/L.
Relative Change in Serum Alanine Aminotransferase (ALT) Compared to Baseline ALT
Relative change from baseline in serum ALT, measured in percentage of change.
Change in ALT at 12 Weeks Compared to Baseline ALT
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.
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
Change from baseline in weight, measured in kg.
Change in Body Mass Index (BMI) at 24 Weeks Compared to Baseline.
Change from baseline in BMI, measured in kg/m^2.
Change in Waist Circumference at 24 Weeks Compared to Baseline
Change from baseline in waist circumference, measured in centimeters.
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.
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.
Frequency of Adverse Events Over 24 Weeks
Numbers of adverse events reported over 24 weeks.
Change in Total Cholesterol at 24 Weeks Compared to Baseline
Change from baseline in total cholesterol, measured in mg/dL
Change in Triglycerides at 24 Weeks Compared to Baseline
Change from baseline in triglycerides, measured in mg/dL
Change in HDL Cholesterol at 24 Weeks Compared to Baseline
Change from baseline in HDL cholesterol, measured in mg/dL
Change in LDL Cholesterol at 24 Weeks Compared to Baseline
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
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.

Full Information

First Posted
March 9, 2018
Last Updated
September 23, 2021
Sponsor
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Collaborators
Johns Hopkins University
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1. Study Identification

Unique Protocol Identification Number
NCT03467217
Brief Title
Losartan for the Treatment of Pediatric NAFLD
Acronym
STOP-NAFLD
Official Title
Losartan for the Treatment of Pediatric NAFLD (STOP-NAFLD): A Phase 2, Randomized, Placebo-Controlled Clinical Trial
Study Type
Interventional

2. Study Status

Record Verification Date
September 2021
Overall Recruitment Status
Terminated
Why Stopped
Trial stopped for futility
Study Start Date
October 2, 2018 (Actual)
Primary Completion Date
June 30, 2020 (Actual)
Study Completion Date
June 30, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Collaborators
Johns Hopkins University

4. Oversight

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
Data Monitoring Committee
Yes

5. 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).
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
NAFLD - Nonalcoholic Fatty Liver Disease
Keywords
Losartan, Nonalcoholic Fatty Liver Disease

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Masking Description
Participants, investigators, clinical staff, and data monitoring committee will not have knowledge of the interventions assigned to individual participants.
Allocation
Randomized
Enrollment
83 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Losartan potassium capsule
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Placebo losartan capsule
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Losartan potassium
Other Intervention Name(s)
losartan, Cozaar,
Intervention Description
Losartan potassium is an angiotensin II receptor blocker acting on the AT 1 receptor subtype
Intervention Type
Drug
Intervention Name(s)
Placebo losartan capsule
Intervention Description
Matching placebo losartan oral capsule
Primary Outcome Measure Information:
Title
Change in Serum Alanine Aminotransferase (ALT) From Baseline.
Description
Change ALT value in U/L (24 weeks minus baseline). A negative score indicates improvement.
Time Frame
Baseline and 24 weeks
Secondary Outcome Measure Information:
Title
Change in Gamma-glutamyl Transpeptidase (GGT) Compared to Baseline
Description
Change from baseline in gamma-glutamyl transpeptidase (GGT), measured in U/L.
Time Frame
Baseline and 24 weeks
Title
Change in Serum Aspartate Aminotransferase AST at 24 Weeks Compared to Baseline AST
Description
Change from baseline in serum aspartate aminotransferase, measured in U/L.
Time Frame
Baseline and 24 weeks
Title
Relative Change in Serum Alanine Aminotransferase (ALT) Compared to Baseline ALT
Description
Relative change from baseline in serum ALT, measured in percentage of change.
Time Frame
Baseline and 24 weeks
Title
Change in ALT at 12 Weeks Compared to Baseline ALT
Description
Change from baseline in ALT at 12 weeks, measured in U/L.
Time Frame
Baseline and 12 weeks
Title
Change in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) Compared to Baseline.
Description
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.
Time Frame
Baseline and 24 weeks
Title
Change in Weight at 24 Weeks Compared to Baseline
Description
Change from baseline in weight, measured in kg.
Time Frame
Baseline and 24 weeks
Title
Change in Body Mass Index (BMI) at 24 Weeks Compared to Baseline.
Description
Change from baseline in BMI, measured in kg/m^2.
Time Frame
Baseline and 24 weeks
Title
Change in Waist Circumference at 24 Weeks Compared to Baseline
Description
Change from baseline in waist circumference, measured in centimeters.
Time Frame
Baseline and 24 weeks
Title
Change in Waist-to-hip Ratio at 24 Weeks Compared to Baseline
Description
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.
Time Frame
Baseline and 24 weeks
Title
Change in Pediatric Quality of Life Inventory (PedsQOL) Physical Health Score at 24 Weeks Compared to Baseline
Description
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.
Time Frame
Baseline and 24 weeks
Title
Frequency of Adverse Events Over 24 Weeks
Description
Numbers of adverse events reported over 24 weeks.
Time Frame
Baseline and 24 weeks
Title
Change in Total Cholesterol at 24 Weeks Compared to Baseline
Description
Change from baseline in total cholesterol, measured in mg/dL
Time Frame
Baseline and 24 weeks
Title
Change in Triglycerides at 24 Weeks Compared to Baseline
Description
Change from baseline in triglycerides, measured in mg/dL
Time Frame
Baseline and 24 weeks
Title
Change in HDL Cholesterol at 24 Weeks Compared to Baseline
Description
Change from baseline in HDL cholesterol, measured in mg/dL
Time Frame
Baseline and 24 weeks
Title
Change in LDL Cholesterol at 24 Weeks Compared to Baseline
Description
Change from baseline in LDL cholesterol, measured in mg/dL
Time Frame
Baseline and 24 weeks
Title
Change in Pediatric Quality of Life Inventory (PedsQOL) Psychosocial Health Score at 24 Weeks Compared to Baseline
Description
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.
Time Frame
Baseline and 24 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
8 Years
Maximum Age & Unit of Time
17 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Edward Doo, MD
Organizational Affiliation
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Official's Role
Study Director
Facility Information:
Facility Name
University of California, San Diego
City
San Diego
State/Province
California
ZIP/Postal Code
92103
Country
United States
Facility Name
University of California, San Francisco
City
San Francisco
State/Province
California
ZIP/Postal Code
94143
Country
United States
Facility Name
Emory University
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
Northwestern Univ-Ann & Robert H. Lurie Children's Hospital of Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611-2605
Country
United States
Facility Name
Indiana University
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46202
Country
United States
Facility Name
St. Louis University
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63104
Country
United States
Facility Name
Columbia University
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
Cincinnati Children's Hospital Medical Center
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45229-3039
Country
United States
Facility Name
Texas Children's Hospital
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
University of Washington
City
Seattle
State/Province
Washington
ZIP/Postal Code
98195
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing 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 URL
https://repository.niddk.nih.gov/home/
Links:
URL
http://jhuccs1.us/nash/open/centers/centers.htm
Description
Nonalcoholic Steatohepatitis Clinical Research Network Centers
URL
http://www2.niddk.nih.gov/
Description
The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Learn more about this trial

Losartan for the Treatment of Pediatric NAFLD

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