Healthy Eating Through Reduction Of Excess Sugar

NAFLD Clinical Trial

— HEROES  

Official title:

Diets Based on PNPLA3 Genotype for Reducing Liver Fat in Hispanics With Pediatric Non-alcoholic Fatty Liver Disease

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02948647
• Other study ID #: HS-11-00446
• Status: Completed
• Phase: N/A
• Start date: November 2016
• Est. completion date: November 2021

Study information

• Verified date: December 2021
• Source: University of Southern California
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of the study is to determine the effect of dietary sugar reduction in obese children and examine whether there are differential effects based on genotype of a single amino acid substitution in the PNPLA3 gene that is highly prevalent in Hispanics and associated with significantly elevated liver fat.

Description:

This dietary intervention aims at developing a more personalized and targeted treatment for NAFLD in Hispanic children and adolescents who are GG for the PNPLA3 variant. The investigators previous publications have shown that this particular demographic has a greater than 2-fold higher liver fat compared to GC and CC individuals. They have also demonstrated a significant gene*dietary sugar interaction with a significant association between liver fat and dietary sugar intake in GG subjects with no such association in GC or CC individuals. These studies suggests that different dietary strategies may have differential effects on reducing liver fat, depending on PNPLA3 genotype. To confirm this, the investigators will complete a clinical trial in 120 overweight and obese Hispanic children (12 - 18 years) with clinically verified NAFLD who will be randomized to one of two 12-week interventions:

Group 1 (standard of care control group): Dietary intervention focused on healthy eating (n=60; 30GG + 30GC/CC)

Group 2 (standard of care + sugar reduction): Dietary intervention based on healthy eating and sugar reduction focused on reduction of sugary beverages and added sugar towards a goal of 10% of daily calories (n=60; 30GG + 30GC/CC)

The following outcomes will be measured before and after intervention: Total liver fat fraction, and visceral and subcutaneous abdominal adipose tissue volume by magnetic resonance imaging (MRI); liver fibrosis by magnetic resonance elastography (MRE); total body fat by DEXA; liver enzymes, fasting insulin, glucose, lipids, free fatty acids and inflammatory markers, gut microbiome, and insulin and glucose response to an oral glucose challenge. The investigators hypothesize that liver fat fraction, liver fibrosis, and metabolic outcomes, such as fasting and 2h-glucose and insulin, and inflammatory biomarkers, will show significantly greater improvements with sugar reduction relative to control. In addition, the investigators also hypothesize a treatment*genotype interaction whereby the reduction in liver fat will be significantly greater in GG relative to CC/CG subjects.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 113
• Est. completion date: November 2021
• Est. primary completion date: November 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years to 18 Years

Eligibility

Inclusion Criteria:

• Ethnicity: This study is limited to Hispanics because of their higher risk of NAFLD, higher frequency (~50%) of the at-risk PNPLA3 allele (G), and because no prior studies have targeted improvement in liver fat and NAFLD in this high-risk population. As with all of our ongoing studies, Hispanic ethnicity will be based on self-identity for the participants as well as their parents and grandparents.

• Gender: Males and females will be eligible for this study.

• Age: Children 12 to 18 years of age will be eligible. In our experience, children younger than around 10 years of age and greater than 18 years would require different intervention/counseling strategies. Therefore, we can develop a more consistent "age-neutral" approach if we limit the age range to 12-18 years.

• Weight status: Subjects will be eligible if they are obese, defined by a BMI > 95th percentile for age and gender.

Exclusion Criteria:

• Diabetes: Presence of type 1 or 2 diabetes, as defined by fasting plasma glucose > 126 mg/dl, or positive for diabetes related antibodies including ICA512 and GAD. Participants testing positive for diabetes will be referred for treatment. Subjects with pre-diabetes will be eligible for the study

• Pregnancy: Women who self-report as pregnant or obtain a positive pregnancy test result during Visit 1 will be excluded. Furthermore, should a woman become pregnant during the course of the intervention, she will be withdrawn from the study at that time and asked to no longer participate. This is in order to protect the mother and child from radiation involved with the DEXA scan and potential complications associated with a low-sugar diet.

• Medication: Taking any medications known to influence liver function, insulin action or lipid levels

• Self-prescribed dietary supplements: Taking any non-prescription supplements that could potentially affect liver function and liver fat (eg vitamin E or fish oils)

• Other metabolic diseases: Diagnosis of other syndromes or diseases that may influence insulin action and secretion (e.g., maturity-onset diabetes of the young, lipoatrophic diabetes, cystic fibrosis), or body composition and fat distribution (e.g. Cushing syndrome, Down syndrome, lipodystrophy)

• Other medical condition: Previously diagnosed with any major illness since birth (e.g. severe intrauterine growth retardation, chronic birth asphyxia, cancer)

• Familial hyperlipidemia: Patients with a family history of hyperlipidemia will be excluded, due to the particular genetic background of this disease, which may bias our results. Familial hyperlipidemia will be defined as LDL/cholesterol > 160 mg/dL and/or triglycerides > 200 mg/dL in both the participant AND at least one family member (first degree: parents or siblings).

• Smoking or drinking: Self-reported current smoking participants (more than 1 cigarette in the past week) will be excluded due to the potential effect of smoking on weight control and inflammatory status. Consumption of alcohol on a regular basis (40g/day alcohol per day determined by questionnaire) will also be excluded due to its important role in liver disease. Use of recreational drugs will also be an exclusion criteria, due to the potent effect of cannabinoids receptors on weight status and food intake.

• Participation in a weight-loss or exercise program: participants who have participated to a weight-loss or exercise program in the past three months will be excluded due to its potential effect on weight status.

Related Conditions & MeSH terms

• Fatty Liver
• NAFLD

Intervention

Other:
• Standard of care plus sugar-reduction education
This is a 12-week intervention where subjects will be educated on how to monitor their added sugar consumption. They will be asked to eliminate consumption of sweetened beverages for the 12-week period and will be receiving a weekly delivery of water bottles to their homes to displace the sweetened beverages in their home environment.

Locations

Country	Name	City	State
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	Diabetes & Obesity Research Institute	Los Angeles	California

Sponsors (2)

Lead Sponsor	Collaborator
University of Southern California	Children's Hospital Los Angeles

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Total liver fat fraction by Magnetic resonance imaging (MRI) at baseline	Abdominal fat distribution (visceral fat versus subcutaneous abdominal fat), and liver fat fraction will be assessed by magnetic resonance imaging at the USC Radiology imaging center on a research-dedicated GE 3 Tesla scanner. Visceral adipose tissue, subcutaneous abdominal adipose tissue and fat in the entire liver will be determined using the 3D IDEAL method.	Baseline
Primary	Total liver fat fraction by Magnetic resonance imaging (MRI) at 12 weeks	Abdominal fat distribution (visceral fat versus subcutaneous abdominal fat), and liver fat fraction will be assessed by magnetic resonance imaging at the USC Radiology imaging center on a research-dedicated GE 3 Tesla scanner. Visceral adipose tissue, subcutaneous abdominal adipose tissue and fat in the entire liver will be determined using the 3D IDEAL method.	12 weeks
Primary	Change in total liver fat fraction by Magnetic resonance imaging (MRI) from baseline to 12 weeks	Abdominal fat distribution (visceral fat versus subcutaneous abdominal fat), and liver fat fraction will be assessed by magnetic resonance imaging at the USC Radiology imaging center on a research-dedicated GE 3 Tesla scanner. Visceral adipose tissue, subcutaneous abdominal adipose tissue and fat in the entire liver will be determined using the 3D IDEAL method.	Baseline and 12 weeks
Secondary	Liver fibrosis by Magnetic Resonance Enterography (MRE) at baseline	MRE is a non-invasive technology for measuring tissue stiffness that has been validated against liver fibrosis by biopsy; as liver stiffness by MRE increases systematically with fibrosis stage. MRE can also discriminate between patients with moderate and severe fibrosis (grades 2-4) and those with mild fibrosis (sensitivity, 86%; specificity, 85%). MRE will be performed during the same scan for adipose tissue on the research-dedicated 3.0 Tesla GE Scanner equipped with the Mayo Clinic MRE apparatus, and synchronized motion-encoded GRE sequence, based on published validation studies.	Baseline
Secondary	Liver fibrosis by Magnetic Resonance Enterography (MRE) at 12 weeks	MRE is a non-invasive technology for measuring tissue stiffness that has been validated against liver fibrosis by biopsy; as liver stiffness by MRE increases systematically with fibrosis stage. MRE can also discriminate between patients with moderate and severe fibrosis (grades 2-4) and those with mild fibrosis (sensitivity, 86%; specificity, 85%). MRE will be performed during the same scan for adipose tissue on the research-dedicated 3.0 Tesla GE Scanner equipped with the Mayo Clinic MRE apparatus, and synchronized motion-encoded GRE sequence, based on published validation studies.	12 weeks
Secondary	Change in Liver fibrosis by Magnetic Resonance Enterography (MRE) from baseline to 12 weeks	MRE is a non-invasive technology for measuring tissue stiffness that has been validated against liver fibrosis by biopsy; as liver stiffness by MRE increases systematically with fibrosis stage. MRE can also discriminate between patients with moderate and severe fibrosis (grades 2-4) and those with mild fibrosis (sensitivity, 86%; specificity, 85%). MRE will be performed during the same scan for adipose tissue on the research-dedicated 3.0 Tesla GE Scanner equipped with the Mayo Clinic MRE apparatus, and synchronized motion-encoded GRE sequence, based on published validation studies.	Baseline and 12 weeks
Secondary	Total body fat, soft lean tissue, and bone mineral content by dual-energy x-ray absorptiometry (DXA) at baseline	Total body fat, soft lean tissue, and bone mineral content will be measured by dual energy x-ray absorptiometry (DXA) using a Hologic QDR 5400 densitometer (Hologic, Inc., Bedford, MA).	Baseline
Secondary	Total body fat, soft lean tissue, and bone mineral content by dual-energy x-ray absorptiometry (DXA) at 12 weeks	Total body fat, soft lean tissue, and bone mineral content will be measured by dual energy x-ray absorptiometry (DXA) using a Hologic QDR 5400 densitometer (Hologic, Inc., Bedford, MA).	12 weeks
Secondary	Change in total body fat, soft lean tissue, and bone mineral content by dual-energy x-ray absorptiometry (DXA) from baseline to 12 weeks	Total body fat, soft lean tissue, and bone mineral content will be measured by dual energy x-ray absorptiometry (DXA) using a Hologic QDR 5400 densitometer (Hologic, Inc., Bedford, MA).	Baseline and 12 weeks
Secondary	Liver enzymes by fasting blood analysis at baseline	A fasting blood sample will be taken at the baseline visit (during the OGTT) for determination of excessively elevated liver enzymes and risk of hereditary liver disease (ALT>300 IU).	Baseline
Secondary	Liver enzymes by fasting blood analysis at 12 weeks	A fasting blood sample will be taken at 12 weeks (during the OGTT) for determination of excessively elevated liver enzymes and risk of hereditary liver disease (ALT>300 IU).	12 weeks
Secondary	Change in liver enzymes by fasting blood analysis from baseline to 12 weeks	A fasting blood sample will be taken at the baseline visit and 12 weeks (during the OGTT) for determination of excessively elevated liver enzymes and risk of hereditary liver disease (ALT>300 IU).	Baseline and 12 weeks
Secondary	Fasting glucose at baseline	A fasting blood sample will be taken at the baseline visit (during the OGTT) for determination of elevated fasting glucose (>126 mg/dL) and risk of type 2 diabetes.	Baseline
Secondary	Fasting glucose from 12 weeks	A fasting blood sample will be taken at the 12 week visit (during the OGTT) for determination of elevated fasting glucose (>126 mg/dL) and risk of type 2 diabetes.	12 weeks
Secondary	Change in fasting glucose from baseline to 12 weeks	A fasting blood sample will be taken at the baseline and 12 week visit (during the OGTT) for determination of elevated fasting glucose (>126 mg/dL) and risk of type 2 diabetes.	Baseline and 12 weeks
Secondary	Insulin and glucose response to an oral glucose challenge at baseline	Glucose tolerance as well as insulin secretion and clearance will be determined during a standard 2-hour oral glucose tolerance test using a glucose load of 1.75g per kg of body weight to a maximum of 75g glucose dissolved in water. Samples will be drawn at 0, 15, 30, 60, 90 and 120 minutes and will be assayed for glucose, insulin, and C-peptide.	Baseline
Secondary	Insulin and glucose response to an oral glucose challenge at 12 weeks	Glucose tolerance as well as insulin secretion and clearance will be determined during a standard 2-hour oral glucose tolerance test using a glucose load of 1.75g per kg of body weight to a maximum of 75g glucose dissolved in water. Samples will be drawn at 0, 15, 30, 60, 90 and 120 minutes and will be assayed for glucose, insulin, and C-peptide.	12 weeks
Secondary	Change in insulin and glucose response to an oral glucose challenge at baseline and 12 weeks	Glucose tolerance as well as insulin secretion and clearance will be determined during a standard 2-hour oral glucose tolerance test using a glucose load of 1.75g per kg of body weight to a maximum of 75g glucose dissolved in water. Samples will be drawn at 0, 15, 30, 60, 90 and 120 minutes and will be assayed for glucose, insulin, and C-peptide.	Baseline and 12 weeks
Secondary	Lipids at baseline	The fasting blood sample will be assessed for lipid composition.	Baseline
Secondary	Lipids at 12 weeks	The fasting blood sample will be assessed for lipid composition.	12 weeks
Secondary	Change in lipids from baseline to 12 weeks	The fasting blood sample will be assessed for lipid composition.	Baseline and 12 weeks
Secondary	Adipokines at baseline	The fasting blood sample will be assessed for adipocytokines.	Baseline
Secondary	Adipokines at 12 weeks	The fasting blood sample will be assessed for adipocytokines.	12 weeks
Secondary	Change in adipokines from baseline to 12 weeks	The fasting blood sample will be assessed for adipocytokines.	Baseline and 12 weeks
Secondary	Inflammatory markers at baseline	The fasting blood sample will be assessed for inflammatory markers.	Baseline
Secondary	Inflammatory markers at 12 weeks	The fasting blood sample will be assessed for inflammatory markers.	12 weeks
Secondary	Change in inflammatory markers from baseline to 12 weeks	The fasting blood sample will be assessed for inflammatory markers.	Baseline and 12 weeks
Secondary	Hormones at baseline	The fasting blood sample will be assessed for hormones.	Baseline
Secondary	Hormones 12 weeks	The fasting blood sample will be assessed for hormones.	12 weeks
Secondary	Change in hormones from baseline to 12 weeks	The fasting blood sample will be assessed for hormones.	Baseline and 12 weeks
Secondary	Blood pressure at baseline	Sitting blood pressure will be measured on the right arm after the subject has rested quietly for 5 minutes. Three readings of blood pressure will be obtained and the average of the two last readings will be recorded.	Baseline
Secondary	Blood pressure at 12 weeks	Sitting blood pressure will be measured on the right arm after the subject has rested quietly for 5 minutes. Three readings of blood pressure will be obtained and the average of the two last readings will be recorded.	12 weeks
Secondary	Change in blood pressure from baseline to 12 weeks	Sitting blood pressure will be measured on the right arm after the subject has rested quietly for 5 minutes. Three readings of blood pressure will be obtained and the average of the two last readings will be recorded.	Baseline and 12 weeks
Secondary	Resting heart rate at baseline	Resting heart rate will be measured on the right arm after the subject has rested quietly for 5 minutes. Three readings of heart rate will be obtained and the average of the two last readings will be recorded.	Baseline
Secondary	Resting heart rate at 12 weeks	Resting heart rate will be measured on the right arm after the subject has rested quietly for 5 minutes. Three readings of heart rate will be obtained and the average of the two last readings will be recorded.	12 weeks
Secondary	Change in resting heart rate from baseline to 12 weeks	Resting heart rate will be measured on the right arm after the subject has rested quietly for 5 minutes. Three readings of heart rate will be obtained and the average of the two last readings will be recorded.	Baseline and 12 weeks