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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Non-alcoholic Steatohepatitis (NASH)

Intervention / Treatment
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* Biological: IMM-124E
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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; 6. 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 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
Masking: Quadruple


Arms and Interventions

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

What is the study measuring?
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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 |