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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02316717
Recruitment Status : Completed
First Posted : December 15, 2014
Results First Posted : February 21, 2020
Last Update Posted : February 21, 2020
Sponsor:
Information provided by (Responsible Party):
Immuron Ltd.

Tracking Information
First Submitted Date  ICMJE November 6, 2014
First Posted Date  ICMJE December 15, 2014
Results First Submitted Date  ICMJE January 7, 2020
Results First Posted Date  ICMJE February 21, 2020
Last Update Posted Date February 21, 2020
Study Start Date  ICMJE December 2014
Actual Primary Completion Date October 30, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 8, 2020)
  • Safety Outcome Measure [ Time Frame: 24 Weeks ]
    Incidence of adverse events per arm/group
  • Percentage Fat Content of the Liver [ Time Frame: baseline and 24 weeks ]
    Mean change from Baseline in Percentage Fat Content of the Liver measured by Magnetic Resonance Imaging (MRI) at Week 24
  • Adverse Events [ Time Frame: 24 weeks ]
    Number of patients with treatment-related adverse events
  • Severity of Adverse Events [ Time Frame: 24 weeks ]
    Number of grade 3-5 adverse events
Original Primary Outcome Measures  ICMJE
 (submitted: December 10, 2014)
  • Body Temperature [ Time Frame: 24 Weeks ]
    Changes in body temperature
  • Percentage Fat Content of the Liver [ Time Frame: 24 Weeks ]
    Mean change from Baseline in Percentage Fat Content of the Liver measured by Magnetic Resonance Imaging (MRI) at Week 24
  • Adverse Events [ Time Frame: 24 weeks ]
    Number of patients with adverse events
  • Adverse Events [ Time Frame: 24 weeks ]
    Severity of adverse events
  • Respiratory Rate [ Time Frame: 24 weeks ]
    Change in Respiratory Rate
  • Pulse Rate [ Time Frame: 24 weeks ]
    Change in Pulse Rate
  • Systolic Blood Pressure [ Time Frame: 24 weeks ]
    Change in Systolic Blood Pressure
  • Diastolic Blood Pressure [ Time Frame: 24 weeks ]
    Change in Diastolic Blood Pressure
  • Hematology, Coagulation, Clinical Chemistry, Serum Lipids, Blood Glucose and Urinalysis [ Time Frame: 24 weeks ]
    Change in Clinical Laboratory tests (Hematology, Coagulation, Clinical Chemistry, Serum Lipids, Blood Glucose and Urinalysis)
  • Serum Alanine Aminotransaminase (ALT) [ Time Frame: 24 weeks ]
    Mean change from Baseline in Serum Alanine Aminotransaminase (ALT) at Week 24
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 8, 2020)
  • Systolic Blood Pressure [ Time Frame: baseline and 24 weeks ]
    Mean change in Systolic Blood Pressure
  • Pulse Rate [ Time Frame: baseline and 24 weeks ]
    Mean change in Pulse Rate from baseline to week 24
  • Diastolic Blood Pressure [ Time Frame: baseline and 24 weeks ]
    Change in Diastolic Blood Pressure
  • Respiratory Rate [ Time Frame: baseline and 24 weeks ]
    Mean change in Respiratory Rate from baseline to week 24
  • Serum Alanine Aminotransaminase (ALT) [ Time Frame: baseline and 24 weeks ]
    Mean change from Baseline in Serum Alanine Aminotransaminase (ALT) at Week 24
  • Peak Serum Concentration (Cmax) [ Time Frame: 0, 4, 12 and 24 Weeks ]
    Peak serum concentration (Cmax) of IMM-124E
  • Minimum Serum Concentration (Cmin) [ Time Frame: 0, 4, 12 and 24 Weeks ]
    Minimum serum concentration (Cmin) of IMM-124E
  • Area Under the Concentration Time Curve (AUC) [ Time Frame: 0, 4, 12 and 24 Weeks ]
    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.
  • Elimination Half Life (T1/2) [ Time Frame: 0, 4, 12 and 24 Weeks ]
    Elimination Half Life (T1/2) of IMM-124E
  • Body Mass Index (BMI) [ Time Frame: 24 Weeks ]
    Change from Baseline of Body Mass Index (BMI) at 24 weeks
  • Waist Circumference [ Time Frame: 24 Weeks ]
    Change from Baseline of Waist Circumference at 24 weeks
  • Waist:Hip Ratio [ Time Frame: 24 Weeks ]
    Change from Baseline of Waist:Hip Ratio at 24 weeks
  • Hemoglobin (HB)A1C [ Time Frame: 24 Weeks ]
    Change from Baseline of Hemoglobin(HB)A1C at 24 weeks
  • Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) [ Time Frame: baseline and 24 Weeks ]
    Change from Baseline of Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) at 24 weeks
  • Total Cholesterol [ Time Frame: 24 Weeks ]
    Change from Baseline of Total Cholesterol at 24 weeks
  • Triglycerides [ Time Frame: 24 Weeks ]
    Change from Baseline of Triglycerides at 24 weeks
  • Low Density Lipoprotein (LDL) [ Time Frame: 24 Weeks ]
    Change from Baseline of Low Density Lipoprotein (LDL) at 24 weeks
  • High Density Lipoprotein (HDL) [ Time Frame: 24 Weeks ]
    Change from Baseline of High Density Lipoprotein (HDL) at 24 weeks
  • Serum Alanine Aminotransaminase (ALT) [ Time Frame: baseline to 24 weeks ]
    Mean change from Baseline of serum ALT
  • Serum Aspartate Aminotransaminase (AST) [ Time Frame: baseline to 24 Weeks ]
    Mean change from Baseline of Serum AST
  • Bilirubin [ Time Frame: baseline to 24 Weeks ]
    Mean change from Baseline of Bilirubin
  • Albumin [ Time Frame: baseline to 24 Weeks ]
    Mean change from Baseline of Albumin
  • Gamma Glutamyl Transpeptidase (GGT) [ Time Frame: baseline to 24 Weeks ]
    Mean change from Baseline of Gamma Glutamyl Transpeptidase (GGT)
  • Serum Alanine Aminotransaminase (ALT) [ Time Frame: 24 Weeks ]
    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)
Original Secondary Outcome Measures  ICMJE
 (submitted: December 10, 2014)
  • Peak Serum Concentration (Cmax) [ Time Frame: 0, 4, 12 and 24 Weeks ]
    Peak serum concentration (Cmax) of IMM-124E
  • Minimum Serum Concentration (Cmin) [ Time Frame: 0, 4, 12 and 24 Weeks ]
    Minimum serum concentration (Cmin) of IMM-124E
  • Area Under the Concentration Time Curve (AUC) [ Time Frame: 0, 4, 12 and 24 Weeks ]
    Area Under the Concentration Time Curve (AUC) of IMM-124E
  • Elimination Half Life (T1/2) [ Time Frame: 0, 4, 12 and 24 Weeks ]
    Elimination Half Life (T1/2) of IMM-124E
  • Body Mass Index (BMI) [ Time Frame: 24 Weeks ]
    Change from Baseline of Body Mass Index (BMI) at 24 weeks
  • Waist Circumference [ Time Frame: 24 Weeks ]
    Change from Baseline of Waist Circumference at 24 weeks
  • Waist:Hip Ratio [ Time Frame: 24 Weeks ]
    Change from Baseline of Waist:Hip Ratio at 24 weeks
  • Hemoglobin (HB)A1C [ Time Frame: 24 Weeks ]
    Change from Baseline of Hemoglobin(HB)A1C at 24 weeks
  • Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) [ Time Frame: 24 Weeks ]
    Change from Baseline of Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) at 24 weeks
  • Total Cholesterol [ Time Frame: 24 Weeks ]
    Change from Baseline of Total Cholesterol at 24 weeks
  • Triglycerides [ Time Frame: 24 Weeks ]
    Change from Baseline of Triglycerides at 24 weeks
  • Low Density Lipoprotein (LDL) [ Time Frame: 24 Weeks ]
    Change from Baseline of Low Density Lipoprotein (LDL) at 24 weeks
  • High Density Lipoprotein (HDL) [ Time Frame: 24 Weeks ]
    Change from Baseline of High Density Lipoprotein (HDL) at 24 weeks
  • Serum Alanine Aminotransaminase (ALT) [ Time Frame: 0, 4, 8, 12, 16, 20 and 24 Weeks ]
    Mean change from Baseline of serum ALT
  • Serum Aspartate Aminotransaminase (AST) [ Time Frame: 0, 4, 8, 12, 16, 20 and 24 Weeks ]
    Mean change from Baseline of Serum AST
  • Bilirubin [ Time Frame: 0, 4, 8, 12, 16, 20 and 24 Weeks ]
    Mean change from Baseline of Bilirubin
  • Albumin [ Time Frame: 0, 4, 8, 12, 16, 20 and 24 Weeks ]
    Mean change from Baseline of Albumin
  • Gamma Glutamyl Transpeptidase (GGT) [ Time Frame: 0, 4, 8, 12, 16, 20 and 24 Weeks ]
    Mean change from Baseline of Gamma Glutamyl Transpeptidase (GGT)
  • Serum Alanine Aminotransaminase (ALT) [ Time Frame: 24 Weeks ]
    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)
Current Other Pre-specified Outcome Measures
 (submitted: February 8, 2020)
  • Serum Concentrations of Lipopolysaccharide (LPS) [ Time Frame: 0, 4, 12 and 24 Weeks ]
    The percentage of subjects reporting at least 15% reduction in LPS, from baseline to Week 24
  • Regulatory T Cells (FoxP3+ CD25-CD4+) in Peripheral Blood Mononuclear Cells [ Time Frame: 0 and 24 Weeks ]
    Change in percent of FoxP3+ CD25-CD4+ cells in Peripheral Blood Mononuclear Cells
  • Gut Microbiome From Fecal Samples [ Time Frame: 0, 4, 12 and 24 Weeks ]
    Number of participants with measurable differences in gut microbiome constituents post-treatment
  • Serum Concentrations of LPS [ Time Frame: baseline to 24 Weeks ]
    Serum Concentrations of Lipopolysaccharide (LPS) (ng/mL) levels and change from Baseline
  • Serum Concentrations of C-Reactive Protein (CRP) [ Time Frame: baseline to 24 Weeks ]
    Mean Serum Concentrations of C-Reactive Protein (CRP) at week 24
  • Serum Concentrations of CK-18 Fragments [ Time Frame: baseline to 24 weeks ]
    The proportion of subjects with significant reduction of CK-18 (≥ 15%) between IMP 1200mg group to placebo.
  • Serum Concentrations of Human Adiponectin [ Time Frame: 0 to 24 Weeks ]
    Change from Run-in to Post-treatment in serum concentration of human Adiponectin.
  • Serum Concentrations of Cytokine IL-6 [ Time Frame: 24 weeks ]
    Mean Change from baseline to week 24 of serum concentration of cytokine IL-6
  • Serum Concentration of Cytokine IL-12p70 [ Time Frame: 24 weeks ]
    Mean change from baseline to week 24 of Serum concentration of Cytokine IL-12p70
  • Serum Concentration of Interferon Gamma (IFN-γ) [ Time Frame: 24 weeks ]
    Mean Change from baseline to week 24 of serum concentration of IFN-gamma
  • Serum Concentration of Tumor Necrosis Factor Alpha (TNF-α) [ Time Frame: 24 weeks ]
    Mean Change from baseline to week 24 of serum concentration of TNF-α
  • Serum Concentration of Glucagon-like Peptide-1 (GLP-1) [ Time Frame: 24 weeks ]
    Mean Change from baseline to week 24 of serum concentration of GLP-1
  • Regulatory T Cells (FoxP3+CD25-CD8+) in Peripheral Blood Mononuclear Cells [ Time Frame: 0 and 24 Weeks ]
    Change in percent of FoxP3+CD25-CD8+ cells in Peripheral Blood Mononuclear Cells
Original Other Pre-specified Outcome Measures
 (submitted: December 10, 2014)
  • Inflammatory Cytokines and other markers [ Time Frame: 0, 4, 12 and 24 Weeks ]
    Serum Concentrations of Lipopolysaccharide (LPS), C-Reactive Protein (CRP), CK-18 fragments, C-peptide, Adiponectin and Cytokines IL6, IL12, IFN gamma and TNF alpha
  • Regulatory T cells in Peripheral Blood Mononuclear Cells [ Time Frame: 0, 12 and 24 Weeks ]
    Relative levels of Regulatory T cells in Peripheral Blood Mononuclear Cells
  • Gut Microbiome From Fecal Samples [ Time Frame: 0, 4, 12 and 24 Weeks ]
    Characterization of the gut microbiome from fecal samples by DNA extraction and Bacterial ribosomal DNA amplification and sequencing
  • Gastrointestinal LPS levels [ Time Frame: 0, 4, 12 and 24 Weeks ]
    Gastrointestinal LPS levels from fecal samples
 
Descriptive Information
Brief Title  ICMJE A Phase ll Study of IMM-124E for Patients With Non-alcoholic Steatohepatitis
Official Title  ICMJE A Phase ll, Randomized, Double-blind, Placebo-controlled Study of IMM-124E for Patients With Non-alcoholic Steatohepatitis.
Brief Summary 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.
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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Non-alcoholic Steatohepatitis (NASH)
Intervention  ICMJE
  • Biological: IMM-124E
    IMM-124E
  • Other: Placebo
    Matched placebo
Study Arms  ICMJE
  • Experimental: Treatment Arm A
    IMM-124E, 600 mg three times daily, orally plus matching placebo
    Intervention: Biological: IMM-124E
  • Experimental: Treatment Arm B
    IMM-124E, 1200 mg three times daily, orally
    Intervention: Biological: IMM-124E
  • Placebo Comparator: Treatment Arm C
    Matching placebo, three times daily, orally
    Intervention: Other: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: November 19, 2017)
133
Original Estimated Enrollment  ICMJE
 (submitted: December 10, 2014)
120
Actual Study Completion Date  ICMJE October 30, 2017
Actual Primary Completion Date October 30, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 99 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Israel,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02316717
Other Study ID Numbers  ICMJE IMM-124E-2001
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Immuron Ltd.
Study Sponsor  ICMJE Immuron Ltd.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Dan Peres Immuron Ltd.
PRS Account Immuron Ltd.
Verification Date January 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP