Study of ADI-PEG 20 Versus Placebo in Subjects With NASH

Study Overview
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Brief Summary
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Evaluate efficacy and safety of ADI-PEG 20 in patients with NASH

Detailed Description
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The safety of ADI-PEG 20 will be assessed during the study through the reporting of adverse events (AEs), clinical laboratory tests, electrocardiogram (ECG), vital sign assessments, body weight, and concomitant medication usage. An external Data Safety and Monitoring Committee (DSMB) that consists of two hepatologists and a statistician will review the safety of the study. The DSMB will convene after 10 subjects (approximately 5 per treatment group) have completed the Week 4 assessments. The DSMB will receive all reports of serious adverse events (SAEs) and convene as needed to monitor for safety. The primary efficacy will be assessed via the absolute change from baseline in hepatic fat fraction measured by MRI-PDFF at Week 24.

Official Title
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A Phase 2A, Randomized, Double-Blind, Placebo-Controlled, Multi-Center Trial of ADI-PEG 20 or Placebo in Subjects With Nonalcoholic Steatohepatitis (NASH)

Conditions
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Nonalcoholic Steatohepatitis (NASH)

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and non-lactating, pregnancy test negative females between 18 - 80 years of age with biopsy proven F1 - F3 NASH. Limit F1 fibrosis to ≤ 20% of total subject population. Willingness to use appropriate contraceptive measures though out study treatment and for 90 days thereafter (see Appendix A). Body mass index (BMI) > 25 kg/m2 Must have confirmation of ≥ 10% liver fat content on MRI-PDFF at screening. Biopsy-proven NASH. Must have had a liver biopsy within 4 weeks of randomization with fibrosis stage 1 to 3 and a non-alcoholic fatty liver disease (NAFLD) activity score (NAS) of ≥ 4 with at least a score of 1 in each of the following NAS components: Steatosis (scored 0 to 3), Ballooning degeneration (scored 0 to 2), and Lobular inflammation (scored 0 to 3). Must have no evidence of worsening of ALT and AST (within 50%) measurements at the screening (-4 weeks) and pre-baseline (-2 weeks) visits. Screening laboratory parameters, as determined by the central laboratory: Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min, as calculated by the Cockcroft- Gault equation; HbA1c ≤ 9.5% (or serum fructosamine ≤ 381 µmol if HbA1c is unable to be resulted); Hemoglobin ≥ 11 g/dL; INR ≤ 1.3, unless due to therapeutic anticoagulation; Direct bilirubin ≤ 0.5 mg/dL; Total bilirubin ≤ 1.3 x upper limit of normal (ULN), unless due to an alternate etiology such as Gilbert's syndrome or hemolytic anemia; Creatinine kinase < 3 x ULN; Platelet count ≥ 150,000/µL; Serum triglyceride level ≤ 500 mg/dL; ALT < 5 x ULN; AST < 5 x ULN; ALP < 2 x ULN. FibroScan® measurement > 7.0 kPa Subjects on non-insulin dependent diabetic, weight loss, or lipid-modifying medication(s) must be on stable dose(s) for at least 3 months prior to the diagnostic liver biopsy through randomization. Exclusion Criteria: Weight gain or loss > 5% in the 3 months prior to randomization or > 10% in the 6 months prior to screening. Type 1 and insulin-dependent Type 2 diabetes. Presence of cirrhosis on liver biopsy (stage 4 fibrosis). Poorly controlled hypertension (blood pressure [BP] > 160/100 mmHg). Prior history of decompensated liver disease including ascites, hepatic encephalopathy (HE), or variceal bleeding. Chronic hepatitis B virus (HBV) infection (hepatitis B surface antigen [HBsAg] positive). Chronic hepatitis C virus (HCV) infection (HCV antibody [Ab] and HCV ribonucleic acid [RNA] positive). Subjects cured of HCV infection less than 2 years prior (based on date of RNA polymerase chain reaction [PCR] negative confirmation following conclusion of treatment) to the screening visit are not eligible. Prior or planned (during the study period) bariatric surgery (e.g., gastroplasty, roux-en-Y gastric bypass), surgery reversal or removal of intragastric balloon > 2 years prior to enrollment would be eligible. Other causes of liver disease based on medical history and/or centralized review of liver histology, including but not limited to: alcoholic liver disease, autoimmune disorders (e.g., primary biliary cholangitis [PBC], primary sclerosing cholangitis [PSC], autoimmune hepatitis), drug-induced hepatotoxicity, Wilson disease, clinically significant iron overload, or alpha-1-antitrypsin deficiency requiring treatment. History of liver transplantation. Current or prior history of hepatocellular carcinoma (HCC). Alcohol intake above an average limit of 2 drinks per day for women and 3 drinks per day for men. Human immunodeficiency virus (HIV) infection. Unstable cardiovascular disease in the 6 months prior to screening. Life expectancy less than 2 years. Use of any investigational medication within 30 days or within 5 half-lives of the investigational medication, whichever is longer, prior to screening and throughout the study is prohibited. Subjects with a history of (12 months prior to screening) or current use of prescription drugs associated with liver steatosis (e.g. methotrexate, amiodarone, high-dose estrogen, tamoxifen, systemic steroids, anabolic steroids, valproic acid) should be excluded.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: To evaluate efficacy and safety of ADI-PEG 20 or Placebo in patients with NASH
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Drug: ADI-PEG 20<br>Dose: 36 mg/m2 given weekly Route of Administration: Intramuscular (IM) | Drug: ADI-PEG20<br>* Treatment for NASH<br>* Other names: Pegargiminase;|
| Placebo Comparator: Drug: Placebo<br>Dose: 36 mg/m2 given weekly Route of Administration: Intramuscular (IM) | Other: Placebo<br>* Treatment for NASH<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine Efficacy of ADI-PEG 20 vs Placebo in the treatment of fatty liver as assessed by change in hepatic fat fraction | Evaluate absolute change from baseline in hepatic fat fraction assessed by Magnetic Resonance Imaging - Proton Density Fat Fraction (MRI-PDFF) at Week 24 | 24 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess the Efficacy of ADI-PEG 20 vs Placebo reflected in the percent change from baseline in hepatic fat fraction at week 24 | Evaluate percent change from baseline in hepatic fat fraction assessed by MRI-PDFF at Week 24 | 24 Weeks | 
| Assess the safety of ADI-PEG 20 in subjects with NASH | Evaluate the change from baseline in ALT at Weeks 12 and 24. | 24 Weeks | 
| Assess the safety and tolerability of ADI-PEG 20 in subjects with NASH | Laboratory tests and clinical adverse events | 24 Weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Nonalcoholic Steatohepatitis (NASH), Arginine, Arginine Deiminase, ADI-PEG 20, Pegargiminase