A Phase ll Study of IMM-124E for Patients With Non-alcoholic Steatohepatitis

A Phase ll, Randomized, Double-blind, Placebo-controlled Study of IMM-124E for Patients With Non-alcoholic Steatohepatitis.

This study will evaluate the safety and preliminary efficacy of two dose levels of IMM-124E in reducing liver fat and/or serum alanine aminotransaminase (ALT) compared with placebo.

Study Overview

• Status: Completed
• Conditions: Non-alcoholic Steatohepatitis (NASH)
• Intervention / Treatment: Other: Placebo; Biological: IMM-124E

Detailed Description

Subjects who provide voluntary written informed consent will be screened for eligibility. Subjects meeting all of the inclusion and none of the exclusion criteria will be eligible to participate.

Eligible subjects will be randomized at the Baseline visit to receive one of the three study treatments three times daily for a period of 24 weeks. Each subject will return to the study clinic for assessment and required study procedures on Day 7, 14 and 28 and every 4 weeks thereafter until Week 24.

• Study Type: Interventional
• Enrollment (Actual): 133
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Penrith, New South Wales, Australia, 2750
      • The Nepean Hospital
    • Westmead, New South Wales, Australia, 2145
      • Westmead Hospital
  • Queensland
    • Woolloongabba, Queensland, Australia, 4102
      • Princess Alexandra Hospital
  • Victoria
    • Box Hill, Victoria, Australia, 3128
      • Box Hill Hospital
    • Parkville, Victoria, Australia, 3050
      • Royal Melbourne Hospital
    • Prahran, Victoria, Australia, 3004
      • The Alfred Hospital
• Israel
  • Jerusalem, Israel
    • Hadassah Medical Centre
  • Tel Aviv, Israel, 64239
    • Sourasky medical center (Ichilov)
• United States
  • California
    • Chula Vista, California, United States, 91911
      • eStudySite
    • San Diego, California, United States, 92103
      • University of California San Diego
    • San Francisco, California, United States, 94115
      • Quest Clinical Research
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida Hepatology Research at CTRB
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern Memorial Hospital
  • Missouri
    • Kansas City, Missouri, United States, 64131
      • Kansas City Research Institute
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke Liver Centre
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor St Lukes Medical Centre
    • Houston, Texas, United States, 78234
      • Brooke Army Medical Centre
    • Live Oak, Texas, United States, 78233
      • Pinnacle Clinical Research
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia Medical Centre
    • Newport News, Virginia, United States, 23602
      • Mary Immaculate Hospital
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University
    • Richmond, Virginia, United States, 23226
      • Bon Secours St Marys Hospital
  • Washington
    • Seattle, Washington, United States, 98122
      • Swedish Medical Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age ≥ 18 years.
2. Provision of written informed consent.

3. Diagnosis of NASH, histologically proven within 12 months of Screening with

   • NASH activity score (NAS) of 4 or more
   • cytologic ballooning score of at least 1;
   • 10% or more macrovescicular steatosis.
   • Hematoxylin & Eosin (H&E) stained slides and/or paraffin block available for independent assessment.
4. HBA1C of <9.0
5. Agree to the use of effective contraceptive measures if either male or female of child bearing potential.

Exclusion Criteria:

1. Presence of vascular liver disease or cirrhosis;
2. Presence of liver disease with other cause (autoimmune, metabolic, medication induced);
3. BMI <25 kg/m^2;
4. Alcohol use >30 g/day;
5. Type 1 diabetes;
6. 6. History of major bariatric surgery (not including balloon / sleeve gastrectomy);
7. Weight loss or gain of 5kg or more in the past 6 months or >10% change in bodyweight in the past 12 months;
8. Contraindication for MRI;
9. Inadequate venous access;
10. Lactating/breastfeeding/pregnant at Screening or Baseline;
11. HIV antibody positive, hepatitis B surface antigen positive (HBsAg) or Hepatitis C virus (HCV)-RNA positive;
12. Receiving an elemental diet or parenteral nutrition;

13. Concurrent conditions

    • Inflammatory bowel disease;
    • Unstable angina, myocardial infarction, transient ischemic events, or stroke within 24 weeks of Screening;
    • Ongoing infectious, ongoing multi-systemic immune-mediated and/or concurrent or past malignant disease;
    • Any other concurrent condition which, in the opinion of the investigator, could impact adversely on the subject participating or on the interpretation of the study data;

14. Concurrent medications including:

    • anti-NASH therapy(s) taken for more than 10 continuous days in the last 3 months. These include S-adenosyl methionine (SAM-e), betaine, milk thistle, probiotic supplements (other than yoghurt), vitamin E and gemfibrozil.

      • NB: If vitamin E or gemfibrozil are used, the dose must be stable and liver biopsy confirming diagnosis of NASH subsequent to commencing treatment; commencing treatment;
      • Wash out for any of the anti-NASH therapies is as follows: under 10 days no washout required, more than 10 days and up to 3 months treatment requires 6 weeks washout. Any treatment of over 3 months would require to re-biopsy to ensure histological eligibility
    • thiazolidinediones (glitazones), dipeptidyl peptidase 4 inhibitors (gliptins) or glucagon-like peptide-1 analogs in the last 6 months. If treatment commenced and is stable for more than 6 month prior to the determinant biopsy and the dose is still stable at time of study entry, subjects will be eligible for recruitment.
    • Allowable anti-diabetic treatment includes metformin and/or sulfonylureas administered at constant dose for at least 2 months prior to study entry.
    • Subjects treated with Insulin are eligible if clinically stable on insulin treatment (i.e. no recurrent acute hypo-/hyperglycemic episodes diagnosed clinically and by Glucose serum levels of <50 mg/dL and >200 mg/dL respectively) for at least 2 months prior to study entry.

    • immune modulatory agents including

      • In the last 3 months:
      • systemic steroids for more than 7 days.
      • daily treatment with multiple non-steroidal anti-inflammatory drugs (such as aspirin >100mg/day, ibuprofen, naproxen, meloxicam, celecoxib) for more than 1 month within 3 months prior to study entry;
      • In the last 12 months:
      • azathioprine, 6-mercaptopurine, methotrexate, cyclosporin, anti-TNFα therapies (infliximab, adalimumab, etanercept) or anti-integrin therapies (namixilab) ;
    • more than 10 consecutive days oral or parenteral antibiotics within 4 weeks prior to study entry (Note: such subjects would not be included in the stool and PBMC analysis).
    • variable dose of antilipidemic agents (3-hydroxy-3-methyl-glutaryl (HMG)-Co-A reductase inhibitors - "statins") in the 3 months prior to study entry.

15. The following laboratory abnormalities:

    • Neutrophil count ≤1.0 x 10^9/L
    • Platelets <100 x 10^9/L
    • Hemoglobin <10 g/dL
    • Albumin <3.5 g/dL
    • International Normalized Ratio (INR) >1.5
    • Total bilirubin >1.5 x upper limit of reference range (unless Gilbert's syndrome or extrahepatic source as denoted by increased indirect bilirubin fraction)
    • Either creatinine clearance ≤60 mL/minute calculated by Cockroft Gault or creatinine >1.5x upper limit of reference range.
16. Known substance abuse, including inhaled or injected drugs in the year prior to Screening.
17. Cow milk allergy, lactose intolerance or any known or suspected hypersensitivity to study products.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment Arm A; IMM-124E, 600 mg three times daily, orally plus matching placebo	Biological: IMM-124E; IMM-124E
Experimental: Treatment Arm B; IMM-124E, 1200 mg three times daily, orally	Biological: IMM-124E; IMM-124E
Placebo Comparator: Treatment Arm C; Matching placebo, three times daily, orally	Other: Placebo; Matched placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety Outcome Measure	Incidence of adverse events per arm/group	24 Weeks
Percentage Fat Content of the Liver	Mean change from Baseline in Percentage Fat Content of the Liver measured by Magnetic Resonance Imaging (MRI) at Week 24	baseline and 24 weeks
Adverse Events	Number of patients with treatment-related adverse events	24 weeks
Severity of Adverse Events	Number of grade 3-5 adverse events	24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Systolic Blood Pressure	Mean change in Systolic Blood Pressure	baseline and 24 weeks
Pulse Rate	Mean change in Pulse Rate from baseline to week 24	baseline and 24 weeks
Diastolic Blood Pressure	Change in Diastolic Blood Pressure	baseline and 24 weeks
Respiratory Rate	Mean change in Respiratory Rate from baseline to week 24	baseline and 24 weeks
Serum Alanine Aminotransaminase (ALT)	Mean change from Baseline in Serum Alanine Aminotransaminase (ALT) at Week 24	baseline and 24 weeks
Peak Serum Concentration (Cmax)	Peak serum concentration (Cmax) of IMM-124E	0, 4, 12 and 24 Weeks
Minimum Serum Concentration (Cmin)	Minimum serum concentration (Cmin) of IMM-124E	0, 4, 12 and 24 Weeks
Area Under the Concentration Time Curve (AUC)	Area Under the Concentration Time Curve (AUC) of IMM-124E. Time points at which data were collected: baseline pre-dose, week 4, week 12 and week 24.	0, 4, 12 and 24 Weeks
Elimination Half Life (T1/2)	Elimination Half Life (T1/2) of IMM-124E	0, 4, 12 and 24 Weeks
Body Mass Index (BMI)	Change from Baseline of Body Mass Index (BMI) at 24 weeks	24 Weeks
Waist Circumference	Change from Baseline of Waist Circumference at 24 weeks	24 Weeks
Waist:Hip Ratio	Change from Baseline of Waist:Hip Ratio at 24 weeks	24 Weeks
Hemoglobin (HB)A1C	Change from Baseline of Hemoglobin(HB)A1C at 24 weeks	24 Weeks
Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)	Change from Baseline of Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) at 24 weeks	baseline and 24 Weeks
Total Cholesterol	Change from Baseline of Total Cholesterol at 24 weeks	24 Weeks
Triglycerides	Change from Baseline of Triglycerides at 24 weeks	24 Weeks
Low Density Lipoprotein (LDL)	Change from Baseline of Low Density Lipoprotein (LDL) at 24 weeks	24 Weeks
High Density Lipoprotein (HDL)	Change from Baseline of High Density Lipoprotein (HDL) at 24 weeks	24 Weeks
Serum Alanine Aminotransaminase (ALT)	Mean change from Baseline of serum ALT	baseline to 24 weeks
Serum Aspartate Aminotransaminase (AST)	Mean change from Baseline of Serum AST	baseline to 24 Weeks
Bilirubin	Mean change from Baseline of Bilirubin	baseline to 24 Weeks
Albumin	Mean change from Baseline of Albumin	baseline to 24 Weeks
Gamma Glutamyl Transpeptidase (GGT)	Mean change from Baseline of Gamma Glutamyl Transpeptidase (GGT)	baseline to 24 Weeks
Serum Alanine Aminotransaminase (ALT)	Number of patients with ALT within the normal reference range at Week 24 (defined a <19 IU/L for women and <30 IU/L for men)	24 Weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum Concentrations of Lipopolysaccharide (LPS)	The percentage of subjects reporting at least 15% reduction in LPS, from baseline to Week 24	0, 4, 12 and 24 Weeks
Regulatory T Cells (FoxP3+ CD25-CD4+) in Peripheral Blood Mononuclear Cells	Change in percent of FoxP3+ CD25-CD4+ cells in Peripheral Blood Mononuclear Cells	0 and 24 Weeks
Gut Microbiome From Fecal Samples	Number of participants with measurable differences in gut microbiome constituents post-treatment	0, 4, 12 and 24 Weeks
Serum Concentrations of LPS	Serum Concentrations of Lipopolysaccharide (LPS) (ng/mL) levels and change from Baseline	baseline to 24 Weeks
Serum Concentrations of C-Reactive Protein (CRP)	Mean Serum Concentrations of C-Reactive Protein (CRP) at week 24	baseline to 24 Weeks
Serum Concentrations of CK-18 Fragments	The proportion of subjects with significant reduction of CK-18 (≥ 15%) between IMP 1200mg group to placebo.	baseline to 24 weeks
Serum Concentrations of Human Adiponectin	Change from Run-in to Post-treatment in serum concentration of human Adiponectin.	0 to 24 Weeks
Serum Concentrations of Cytokine IL-6	Mean Change from baseline to week 24 of serum concentration of cytokine IL-6	24 weeks
Serum Concentration of Cytokine IL-12p70	Mean change from baseline to week 24 of Serum concentration of Cytokine IL-12p70	24 weeks
Serum Concentration of Interferon Gamma (IFN-γ)	Mean Change from baseline to week 24 of serum concentration of IFN-gamma	24 weeks
Serum Concentration of Tumor Necrosis Factor Alpha (TNF-α)	Mean Change from baseline to week 24 of serum concentration of TNF-α	24 weeks
Serum Concentration of Glucagon-like Peptide-1 (GLP-1)	Mean Change from baseline to week 24 of serum concentration of GLP-1	24 weeks
Regulatory T Cells (FoxP3+CD25-CD8+) in Peripheral Blood Mononuclear Cells	Change in percent of FoxP3+CD25-CD8+ cells in Peripheral Blood Mononuclear Cells	0 and 24 Weeks

Collaborators and Investigators

• Sponsor: Immuron Ltd.
• Investigators: Study Director: Dan Peres, Immuron Ltd.

Publications and helpful links

General Publications

• Jin L, Sun Y, Li Y, Zhang H, Yu W, Li Y, Xin Y, Alsareii SA, Wang Q, Zhang D. A synthetic peptide AWRK6 ameliorates metabolic associated fatty liver disease: involvement of lipid and glucose homeostasis. Peptides. 2021 Sep;143:170597. doi: 10.1016/j.peptides.2021.170597. Epub 2021 Jun 10.

Study record dates

Study Major Dates

• Study Start: December 1, 2014
• Primary Completion (Actual): October 30, 2017
• Study Completion (Actual): October 30, 2017

Study Registration Dates

• First Submitted: November 6, 2014
• First Submitted That Met QC Criteria: December 10, 2014
• First Posted (Estimate): December 15, 2014

Study Record Updates

• Last Update Posted (Actual): February 21, 2020
• Last Update Submitted That Met QC Criteria: February 8, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease
• Other Study ID Numbers: IMM-124E-2001