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

Phase 2

Completed

Conditions: Non-alcoholic Steatohepatitis (NASH)

Interventions: Biological: IMM-124E
Other: Placebo

Registration Number: NCT02316717

Lead Sponsor: Immuron Ltd.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 133

Inclusion Criteria

Age ≥ 18 years.
Provision of written informed consent.
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.
HBA1C of <9.0
Agree to the use of effective contraceptive measures if either male or female of child bearing potential.

Exclusion Criteria

Presence of vascular liver disease or cirrhosis;
Presence of liver disease with other cause (autoimmune, metabolic, medication induced);
BMI <25 kg/m^2;
Alcohol use >30 g/day;
Type 1 diabetes;
1. History of major bariatric surgery (not including balloon / sleeve gastrectomy);
Weight loss or gain of 5kg or more in the past 6 months or >10% change in bodyweight in the past 12 months;
Contraindication for MRI;
Inadequate venous access;
Lactating/breastfeeding/pregnant at Screening or Baseline;
HIV antibody positive, hepatitis B surface antigen positive (HBsAg) or Hepatitis C virus (HCV)-RNA positive;
Receiving an elemental diet or parenteral nutrition;
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;
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.
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.
Known substance abuse, including inhaled or injected drugs in the year prior to Screening.
Cow milk allergy, lactose intolerance or any known or suspected hypersensitivity to study products.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Treatment Arm B	IMM-124E	IMM-124E, 1200 mg three times daily, orally
Treatment Arm C	Placebo	Matching placebo, three times daily, orally
Treatment Arm A	IMM-124E	IMM-124E, 600 mg three times daily, orally plus matching placebo

Primary Outcome Measures

Name	Time	Method
Safety Outcome Measure	24 Weeks	Incidence of adverse events per arm/group
Percentage Fat Content of the Liver	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	24 weeks	Number of patients with treatment-related adverse events
Severity of Adverse Events	24 weeks	Number of grade 3-5 adverse events

Secondary Outcome Measures

Name	Time	Method
Gamma Glutamyl Transpeptidase (GGT)	baseline to 24 Weeks	Mean change from Baseline of Gamma Glutamyl Transpeptidase (GGT)
Systolic Blood Pressure	baseline and 24 weeks	Mean change in Systolic Blood Pressure
Pulse Rate	baseline and 24 weeks	Mean change in Pulse Rate from baseline to week 24
Diastolic Blood Pressure	baseline and 24 weeks	Change in Diastolic Blood Pressure
Respiratory Rate	baseline and 24 weeks	Mean change in Respiratory Rate from baseline to week 24
Serum Alanine Aminotransaminase (ALT)	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)
Peak Serum Concentration (Cmax)	0, 4, 12 and 24 Weeks	Peak serum concentration (Cmax) of IMM-124E
Minimum Serum Concentration (Cmin)	0, 4, 12 and 24 Weeks	Minimum serum concentration (Cmin) of IMM-124E
Area Under the Concentration Time Curve (AUC)	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)	0, 4, 12 and 24 Weeks	Elimination Half Life (T1/2) of IMM-124E
Body Mass Index (BMI)	24 Weeks	Change from Baseline of Body Mass Index (BMI) at 24 weeks
Waist Circumference	24 Weeks	Change from Baseline of Waist Circumference at 24 weeks
Waist:Hip Ratio	24 Weeks	Change from Baseline of Waist:Hip Ratio at 24 weeks
Hemoglobin (HB)A1C	24 Weeks	Change from Baseline of Hemoglobin(HB)A1C at 24 weeks
Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)	baseline and 24 Weeks	Change from Baseline of Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) at 24 weeks
Total Cholesterol	24 Weeks	Change from Baseline of Total Cholesterol at 24 weeks
Triglycerides	24 Weeks	Change from Baseline of Triglycerides at 24 weeks
Low Density Lipoprotein (LDL)	24 Weeks	Change from Baseline of Low Density Lipoprotein (LDL) at 24 weeks
High Density Lipoprotein (HDL)	24 Weeks	Change from Baseline of High Density Lipoprotein (HDL) at 24 weeks
Serum Aspartate Aminotransaminase (AST)	baseline to 24 Weeks	Mean change from Baseline of Serum AST
Bilirubin	baseline to 24 Weeks	Mean change from Baseline of Bilirubin
Albumin	baseline to 24 Weeks	Mean change from Baseline of Albumin

Trial Locations

Locations (25): University of California San Diego
🇺🇸
San Diego, California, United States
University of Colorado
🇺🇸
Aurora, Colorado, United States
Northwestern Memorial Hospital
🇺🇸
Chicago, Illinois, United States
Box Hill Hospital
🇦🇺
Box Hill, Victoria, Australia
Royal Melbourne Hospital
🇦🇺
Parkville, Victoria, Australia
The Alfred Hospital
🇦🇺
Prahran, Victoria, Australia
Hadassah Medical Centre
🇮🇱
Jerusalem, Israel
eStudySite
🇺🇸
Chula Vista, California, United States
Quest Clinical Research
🇺🇸
San Francisco, California, United States
University of Florida Hepatology Research at CTRB
🇺🇸
Gainesville, Florida, United States
Duke Liver Centre
🇺🇸
Durham, North Carolina, United States
Kansas City Research Institute
🇺🇸
Kansas City, Missouri, United States
Cleveland Clinic
🇺🇸
Cleveland, Ohio, United States
Baylor St Lukes Medical Centre
🇺🇸
Houston, Texas, United States
Brooke Army Medical Centre
🇺🇸
Houston, Texas, United States
Bon Secours St Marys Hospital
🇺🇸
Richmond, Virginia, United States
University of Virginia Medical Centre
🇺🇸
Charlottesville, Virginia, United States
Virginia Commonwealth University
🇺🇸
Richmond, Virginia, United States
Pinnacle Clinical Research
🇺🇸
Live Oak, Texas, United States
Mary Immaculate Hospital
🇺🇸
Newport News, Virginia, United States
Swedish Medical Centre
🇺🇸
Seattle, Washington, United States
The Nepean Hospital
🇦🇺
Penrith, New South Wales, Australia
Princess Alexandra Hospital
🇦🇺
Woolloongabba, Queensland, Australia
Westmead Hospital
🇦🇺
Westmead, New South Wales, Australia
Sourasky Medical Center (Ichilov)
🇮🇱
Tel Aviv, Israel