Clinical trial NCT02316717: A Phase ll Study of IMM-124E for Patients With Non-alcoholic Steatohepatitis
Official title: A Phase ll, Randomized, Double-blind, Placebo-controlled Study of IMM-124E for Patients With Non-alcoholic Steatohepatitis.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Non-alcoholic Steatohepatitis (NASH)
Lead sponsor: Immuron Ltd.
Sponsor class: INDUSTRY
First posted: 2014-12-15
Enrollment: 133
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Safety Outcome Measure
timeFrame: 24 Weeks
measure: Percentage Fat Content of the Liver
timeFrame: baseline and 24 weeks
measure: Adverse Events
timeFrame: 24 weeks
measure: Severity of Adverse Events
timeFrame: 24 weeks
Secondary outcomes:
measure: Systolic Blood Pressure
timeFrame: baseline and 24 weeks
measure: Pulse Rate
timeFrame: baseline and 24 weeks
measure: Diastolic Blood Pressure
timeFrame: baseline and 24 weeks
measure: Respiratory Rate
timeFrame: baseline and 24 weeks
measure: Serum Alanine Aminotransaminase (ALT)
timeFrame: baseline and 24 weeks
measure: Peak Serum Concentration (Cmax)
timeFrame: 0, 4, 12 and 24 Weeks
measure: Minimum Serum Concentration (Cmin)
timeFrame: 0, 4, 12 and 24 Weeks
measure: Area Under the Concentration Time Curve (AUC)
timeFrame: 0, 4, 12 and 24 Weeks
measure: Elimination Half Life (T1/2)
timeFrame: 0, 4, 12 and 24 Weeks
measure: Body Mass Index (BMI)
timeFrame: 24 Weeks
measure: Waist Circumference
timeFrame: 24 Weeks
measure: Waist:Hip Ratio
timeFrame: 24 Weeks
measure: Hemoglobin (HB)A1C
timeFrame: 24 Weeks
measure: Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)
timeFrame: baseline and 24 Weeks
measure: Total Cholesterol
timeFrame: 24 Weeks
measure: Triglycerides
timeFrame: 24 Weeks
measure: Low Density Lipoprotein (LDL)
timeFrame: 24 Weeks
measure: High Density Lipoprotein (HDL)
timeFrame: 24 Weeks
measure: Serum Alanine Aminotransaminase (ALT)
timeFrame: baseline to 24 weeks
measure: Serum Aspartate Aminotransaminase (AST)
timeFrame: baseline to 24 Weeks
measure: Bilirubin
timeFrame: baseline to 24 Weeks
measure: Albumin
timeFrame: baseline to 24 Weeks
measure: Gamma Glutamyl Transpeptidase (GGT)
timeFrame: baseline to 24 Weeks
measure: Serum Alanine Aminotransaminase (ALT)
timeFrame: 24 Weeks
Other outcomes:
measure: Serum Concentrations of Lipopolysaccharide (LPS)
timeFrame: 0, 4, 12 and 24 Weeks
measure: Regulatory T Cells (FoxP3+ CD25-CD4+) in Peripheral Blood Mononuclear Cells
timeFrame: 0 and 24 Weeks
measure: Gut Microbiome From Fecal Samples
timeFrame: 0, 4, 12 and 24 Weeks
measure: Serum Concentrations of LPS
timeFrame: baseline to 24 Weeks
measure: Serum Concentrations of C-Reactive Protein (CRP)
timeFrame: baseline to 24 Weeks
measure: Serum Concentrations of CK-18 Fragments
timeFrame: baseline to 24 weeks
measure: Serum Concentrations of Human Adiponectin
timeFrame: 0 to 24 Weeks
measure: Serum Concentrations of Cytokine IL-6
timeFrame: 24 weeks
measure: Serum Concentration of Cytokine IL-12p70
timeFrame: 24 weeks
measure: Serum Concentration of Interferon Gamma (IFN-γ)
timeFrame: 24 weeks
measure: Serum Concentration of Tumor Necrosis Factor Alpha (TNF-α)
timeFrame: 24 weeks
measure: Serum Concentration of Glucagon-like Peptide-1 (GLP-1)
timeFrame: 24 weeks
measure: Regulatory T Cells (FoxP3+CD25-CD8+) in Peripheral Blood Mononuclear Cells
timeFrame: 0 and 24 Weeks
Locations:
city: Chula Vista
country: United States
facility: eStudySite
state: California
city: San Diego
country: United States
facility: University of California San Diego
state: California
city: San Francisco
country: United States
facility: Quest Clinical Research
state: California
city: Aurora
country: United States
facility: University of Colorado
state: Colorado
city: Gainesville
country: United States
facility: University of Florida Hepatology Research at CTRB
state: Florida
city: Chicago
country: United States
facility: Northwestern Memorial Hospital
state: Illinois
city: Kansas City
country: United States
facility: Kansas City Research Institute
state: Missouri
city: Durham
country: United States
facility: Duke Liver Centre
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Houston
country: United States
facility: Baylor St Lukes Medical Centre
state: Texas
city: Houston
country: United States
facility: Brooke Army Medical Centre
state: Texas
city: Live Oak
country: United States
facility: Pinnacle Clinical Research
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia Medical Centre
state: Virginia
city: Newport News
country: United States
facility: Mary Immaculate Hospital
state: Virginia
city: Richmond
country: United States
facility: Bon Secours St Marys Hospital
state: Virginia
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
city: Seattle
country: United States
facility: Swedish Medical Centre
state: Washington
city: Penrith
country: Australia
facility: The Nepean Hospital
state: New South Wales
city: Westmead
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Box Hill
country: Australia
facility: Box Hill Hospital
state: Victoria
city: Parkville
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Prahran
country: Australia
facility: The Alfred Hospital
state: Victoria
city: Jerusalem
country: Israel
facility: Hadassah Medical Centre
city: Tel Aviv
country: Israel
facility: Sourasky Medical Center (Ichilov)
Study officials:
affiliation: Immuron Ltd.
name: Dan Peres
role: STUDY_DIRECTOR
References:
citation: 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.