ADI-PEG20, Obesity and Prediabetes

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

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.

Study Overview

• Status: Withdrawn
• Conditions: Obesity; PreDiabetes
• Intervention / Treatment: Biological: ADI-PEG20; Other: Placebo

Detailed Description

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.

• Study Type: Interventional
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ADI-PEG20; 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; Intramuscular injection weekly for 8 weeks
Placebo Comparator: Placebo; Will be weekly intramuscularly for 8-week	Other: Placebo; Intramuscular injection weekly for 8 weeks

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in the transcriptome in muscle	The transcriptome will be evaluated by using RNA sequencing techniques	Baseline and 8 weeks of ADI-PEG20 or placebo
Change in the transcriptome in adipose tissue	The transcriptome will be evaluated by using RNA sequencing techniques	Baseline and 8 weeks of ADI-PEG20 or placebo

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Collaborators: Children's Discovery Institute; Polaris Pharmaceuticals, Inc.
• Investigators: Principal Investigator: Samuel Klein, MD, Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2024
• Primary Completion (Actual): April 1, 2024
• Study Completion (Actual): May 1, 2024

Study Registration Dates

• First Submitted: November 11, 2022
• First Submitted That Met QC Criteria: April 24, 2023
• First Posted (Actual): April 25, 2023

Study Record Updates

• Last Update Posted (Estimated): November 7, 2024
• Last Update Submitted That Met QC Criteria: November 5, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Endocrine System Diseases; Nutrition Disorders; Metabolic Diseases; Overnutrition; Body Weight; Glucose Metabolism Disorders; Diabetes Mellitus; Overweight; Hyperglycemia; Obesity; Prediabetic State; Glucose Intolerance
• Other Study ID Numbers: 202304058

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No