ADI-PEG20, Obesity and Prediabetes

Study Overview
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Brief Summary
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Th purpose of this study is to determine whether ADI-PEG20 (PEGylated arginine deiminase), an arginine catabolizing enzyme preparation, improves insulin sensitivity, mitochondrial respiration, and energy utilization in adolescents with prediabetes.

Detailed Description
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Obesity, insulin resistance, and their complications are major causes of morbidity and mortality in children, adolescents, and adults. Although caloric restriction is an effective treatment, intensive lifestyle changes are rarely durable. The investigators and others have shown that: (i.) fasting incites arginine catabolism, and forced arginine catabolism recapitulates several therapeutic effects of fasting, (ii.) exogenous, forced arginine catabolism improves metabolic health, and (iii.) ADI-PEG20 (PEGylated arginine deiminase) is an arginine catabolizing enzyme preparation that improves insulin sensitivity, mitochondrial respiration, and energy utilization in obese mice. The study will determine whether ADI-PEG20 also exerts beneficial effects on metabolic healthy in people. The investigators will perform a 12-week, randomized, double-blind, placebo-controlled trial in boys and girls with pre-diabetes to evaluate the efficacy of ADI-PEG20 treatment on: 1) body composition; 2) resting energy expenditure; 3) multi-organ insulin sensitivity; 3) β-cell function; and 4) muscle mitochondrial function.

Official Title
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A Randomized Trial Using ADI-PEG20 to Improve Insulin- and Energy Homeostasis in Adolescents With Obesity

Conditions
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Obesity, PreDiabetes

Intervention / Treatment
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* Biological: ADI-PEG20
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age: ≥18 and ≤22 years; BMI 25.0 - 44.9 kg/m2; Prediabetes, defined as fasting plasma glucose of ≥100 mg/dL, or HbA1C ≥5.7%, or HOMA-IR ≥2.5. Exclusion Criteria: HbA1C ≥6.5%; Intolerance or allergies to ingredients in ADI-PEG20 or placebo; Taking dietary supplements or medications known to affect our study outcomes; Evidence of significant organ system dysfunction or diseases, Metallic implants, which would preclude MRI

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 22 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Single-center, randomized, double-blind, placebo-controlled study
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ADI-PEG20<br>ADI-PEG20 (ADI-PEG20 is arginine deiminase (ADI) conjugated to polyethylene glycol (PEG) of 20,000 molecular weight) will be weekly intramuscularly at a dose of 18 mg/m2 body surface area/week for 8-week. | Biological: ADI-PEG20<br>* Intramuscular injection weekly for 8 weeks<br>|
| Placebo Comparator: Placebo<br>Will be weekly intramuscularly for 8-week | Other: Placebo<br>* Intramuscular injection weekly for 8 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in insulin sensitivity | Insulin sensitivity will be assessed by using the hyperinsulinemic-euglycemic clamp procedure | Baseline and 8 weeks of ADI-PEG20 or placebo | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in oral glucose tolerance | Oral glucose tolerance will be assessed by measuring plasma glucose concentrations before and after ingesting 75 grams glucose | Baseline and 4 weeks of ADI-PEG20 or placebo | 
| Change in oral glucose tolerance | Oral glucose tolerance will be assessed by measuring plasma glucose concentrations before and after ingesting 75 grams glucose | Baseline and 8 weeks of ADI-PEG20 or placebo | 
| Change in β-cell function | β-cell function will be assessed from a modified oral glucose tolerance test | Baseline and 4 weeks of ADI-PEG20 or placebo | 
| Change in β-cell function | β-cell function will be assessed from a modified oral glucose tolerance test | Baseline and 8 weeks of ADI-PEG20 or placebo | 
| Change in resting energy expenditure | Resting energy expenditure (in kcal/min) will be assessed by using indirect calorimetry | Baseline and 8 weeks of ADI-PEG20 or placebo | 
| Change in muscle mitochondrial respiration | Muscle mitochondrial respiration (in pmol O2/mg tissue) will be assessed by using high resolution respirometry, conducted on permeabilized muscle fibers obtained by muscle biopsy. | Baseline and 8 weeks of ADI-PEG20 or placebo | 
| Change in intrahepatic triglyceride content | Intrahepatic triglyceride content will be assessed by magnetic resonance imagining (MRI) | Baseline and 8 weeks of ADI-PEG20 or placebo |