Anti-LPS Antibody Treatment for Pediatric NAFLD

Study Overview
=================
Brief Summary
-----------------
The main objective of this pilot study is to evaluate whether 12 weeks of IMM-124E in children with nonalcoholic fatty liver disease (NAFLD) in combination with standard of care treatment will decrease inflammation in the liver as measured by alanine transaminase (ALT). Specifically, investigators will measure percent change in ALT from Week 0 to Week 12 in treatment compared to placebo.

Detailed Description
-----------------
This is a randomized, double blind, placebo controlled, three month treatment trial of children aged 6-19 years. Participants will be recruited from the Children's Healthcare of Atlanta pediatric liver clinical practice.The purpose of this study is to evaluate if a three month treatment with IMM-124E (a bovine colostrum enriched with anti-LPS antibodies) in combination with standard of care lifestyle advice is safe and leads to greater improvement in hepatic inflammation, insulin sensitivity, and blood lipids in children with nonalcoholic fatty liver disease (NAFLD) compared to placebo with standard of care treatment. Investigators also seek to define the mechanism of action in response to three months of treatment with IMM-124E.

Official Title
-----------------
Anti-LPS Antibody in Pediatric Nonalcoholic Fatty Liver Disease

Conditions
-----------------
Nonalcoholic Fatty Liver Disease (NAFLD)

Intervention / Treatment
-----------------
* Biological: IMM-124E
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Nonalcoholic fatty liver disease (NAFLD) diagnosis confirmed by liver biopsy or MRI ALT ≥ 2 x ULN at screening (girls ≥ 46, boys ≥ 54) Written informed parent consent and child assent Willingness to take IMM-124E or placebo powder 3 x daily for 12 weeks At least 2 months of attempted lifestyle changes after diagnosis Exclusion Criteria: Disease or condition deemed by physician to interfere with absorption, digestion, or mechanism of intervention of drug Diagnosis of diabetes and an HbA1c of > 9% Change in supplement or anti-oxidant therapy within past 90 days (must be on a stable dose and willing to continue it throughout the trial or not on any vitamin or supplement, includes SAMe, vitamin E, betaine, Milk thistle etc) Use of probiotics or antibiotics in the past 30 days Use of anti-NAFLD medications (metformin, thiazolidinediones, UDCA) in the 30 days prior to randomization Acute illness within past 2 weeks prior to enrollment (defined as fever > 100.4ºF) Planned pregnancy, nursing an infant, confirmed or suspected to be pregnant between screening and time of study enrollment Evidence of other chronic liver disease other than NAFLD (Hepatitis B and C, Alpha-1 antitrypsin, Wilson's disease) Intolerance to lactose or dairy-based products Unable to have blood drawn at study visits Unwillingness to provide and/or collect stool samples Current gastrointestinal (GI) bleeding or inflammatory bowel disease (irritable bowel disease (IBD), colitis) Current enrollment in another therapeutic clinical trial or receipt of an investigational study drug within 6 months prior to study enrollment Participants who are not able or willing to comply with the protocol or have any other condition that would impede compliance or hinder completion of the study, in the opinion of the investigator

Ages Eligible for Study
-----------------
Minimum Age: 6 Years
Maximum Age: 19 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IMM-124E Group<br>Participants with nonalcoholic fatty liver disease (NAFLD) will receive 600mg of IMM-124E powder three times daily for twelve weeks. | Biological: IMM-124E<br>* IMM-124E is a hyper-immune, bovine colostrum (milk) powder with flavoring.<br>|
| Placebo Comparator: Placebo Group<br>Participants with nonalcoholic fatty liver disease (NAFLD) will receive placebo powder three times daily for twelve weeks. | Other: Placebo<br>* Matched Placebo<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change in Alanine Aminotransferase (ALT) Level | Percent change in ALT level from baseline to end of treatment. | Baseline (Week 0), End of Treatment (Week 12) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change in Fasting Glucose Level | Fasting glucose level will be collected via blood draw. Percent Change in glucose levels between baseline and end of treatment. | Baseline (Week 0), End of Treatment (Week 12) | 
| Change in Fasting Insulin Level | Fasting insulin level will be collected via blood draw. Change is the difference in insulin level from baseline to end of treatment. | Baseline (Week 0), End of Treatment (Week 12) | 
| Change in Hemoglobin A1C Level | Hemoglobin A1C Level will be collected via blood draw. Change is the difference in hemoglobin AIC level from baseline to end of treatment. | Baseline (Week 0), End of Treatment (Week 12) | 
| Change in Adipose Tissue Insulin Resistance (Adipo-IR) | Adipo-IR will be collected via blood draw. It is calculated as fasting non-esterified fatty acids x fasting insulin. | Baseline (Week 0), End of Treatment (Week 12) | 
| Change in Triglyceride/HDL (TG/HDL) Ratio | The TG/HDL ratio is the proportion of triglyceride levels in relation to HDL (good cholesterol). Change is defined as the difference in the TG/HDL ratio from baseline to the end of treatment. | Baseline (Week 0), End of Treatment (Week 12) | 
| Percent Change in Blood Glucose Level | The blood glucose level will be monitored via an oral glucose tolerance test (OGTT) at baseline and at the end of treatment. During the OGTT, the glucose level will be tested by a blood draw every thirty minutes for two hours. Percentage change between glucose measurements taken at baseline and at the end of treatment is reported. | Baseline (Week 0), End of Treatment (Week 12) | 
| Change in Insulin Levels | The insulin level will be monitored via an oral glucose tolerance test (OGTT) at baseline and at the end of treatment. During the OGTT, the insulin level will be tested by a blood draw every thirty minutes for two hours. Change is described as the difference between insulin measurements taken at baseline and at the end of treatment. | Baseline (Week 0), End of Treatment (Week 12) | 
| Percent Change in Body Mass Index (BMI) Z-Score | BMI will be calculated from height and weight and converted into a z-score. Body mass index z-scores are measures of relative weight adjusted for age and sex.Change is the difference in BMI z-scores from base line to end of treatment. | Baseline (Week 0), End of Treatment (Week 12) | 
| Percent Change in Visceral Adiposity | Visceral adiposity will be measured with a magnetic resonance imaging (MRI) scan. Visceral adipose tissue is a hormonally active component of total body fat. | Baseline (Week 0), End of Treatment (Week 12) | 
| Percent Change in Hepatic Fat Percent | Hepatic fat percent will be measured with a magnetic resonance imaging (MRI) scan. Hepatic fat percent is the percentage of fat within the liver. | Baseline (Week 0), End of Treatment (Week 12) | 
| Percent Change in Waist Circumference | Waist circumference will be measured in centimeters using measuring tape. | Baseline (Week 0), End of Treatment (Week 12) | 
| Percent Change in PROMIS Fatigue Questionnaire Score | The PROMIS Fatigue questionnaire evaluates a range of self-reported symptoms, from mild subjective feelings of tiredness to an overwhelming, debilitating, and sustained sense of exhaustion that likely decreases one's ability to execute daily activities and function normally in family or social roles. Fatigue is divided into the experience of fatigue (frequency, duration, and intensity) and the impact of fatigue on physical, mental, and social activities. It assesses fatigue over the past seven days. A higher score represents more symptoms of fatigue. | Baseline (Week 0), End of Treatment (Week 12) | 
| Percent Change in PROMIS Depression Questionnaire Score | The PROMIS Depression instruments assess self-reported negative mood (sadness, guilt), views of self (selfcriticism, worthlessness), and social cognition (loneliness, interpersonal alienation), as well as decreased positive affect and engagement (loss of interest, meaning, and purpose). It assesses depression over the past seven days. A higher score represents more symptoms of depression. | Baseline (Week 0), End of Treatment (Week 12) | 
| Percent Change in PROMIS Anxiety Questionnaire Score | The PROMIS Anxiety instruments measure self-reported fear (fearfulness, panic), anxious misery (worry, dread), hyperarousal (tension, nervousness, restlessness), and somatic symptoms related to arousal (racing heart, dizziness). Anxiety is best differentiated by symptoms that reflect autonomic arousal and experience of threat. Each assesses anxiety over the past seven days. A higher score represents more symptoms of anxiety. | Baseline (Week 0), End of Treatment (Week 12) | 
| Composite Metabolic Improvement | Composite metabolic improvement is defined as greater than 10% improvement in TG/HDL ratio, improvement in insulin resistance, and greater than 10% improvement in ALT. | End of Treatment (Week 12) |