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

Non-alcoholic Steatohepatitis (NASH) Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02316717
• Other study ID #: IMM-124E-2001
• Status: Completed
• Phase: Phase 2
• Start date: December 2014
• Est. completion date: October 30, 2017

Study information

• Verified date: January 2020
• Source: Immuron Ltd.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 133
• Est. completion date: October 30, 2017
• Est. primary completion date: October 30, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 99 Years

Eligibility

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-TNFa 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.

Related Conditions & MeSH terms

• Fatty Liver
• Non-alcoholic Fatty Liver Disease
• Non-alcoholic Steatohepatitis (NASH)

Intervention

Biological:
• IMM-124E
IMM-124E

Other:
• Placebo
Matched placebo

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Immuron Ltd.

Countries where clinical trial is conducted

United States,  Australia,  Israel, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	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
Other	Gut Microbiome From Fecal Samples	Number of participants with measurable differences in gut microbiome constituents post-treatment	0, 4, 12 and 24 Weeks
Other	Serum Concentrations of LPS	Serum Concentrations of Lipopolysaccharide (LPS) (ng/mL) levels and change from Baseline	baseline to 24 Weeks
Other	Serum Concentrations of C-Reactive Protein (CRP)	Mean Serum Concentrations of C-Reactive Protein (CRP) at week 24	baseline to 24 Weeks
Other	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
Other	Serum Concentrations of Human Adiponectin	Change from Run-in to Post-treatment in serum concentration of human Adiponectin.	0 to 24 Weeks
Other	Serum Concentrations of Cytokine IL-6	Mean Change from baseline to week 24 of serum concentration of cytokine IL-6	24 weeks
Other	Serum Concentration of Cytokine IL-12p70	Mean change from baseline to week 24 of Serum concentration of Cytokine IL-12p70	24 weeks
Other	Serum Concentration of Interferon Gamma (IFN-?)	Mean Change from baseline to week 24 of serum concentration of IFN-gamma	24 weeks
Other	Serum Concentration of Tumor Necrosis Factor Alpha (TNF-a)	Mean Change from baseline to week 24 of serum concentration of TNF-a	24 weeks
Other	Serum Concentration of Glucagon-like Peptide-1 (GLP-1)	Mean Change from baseline to week 24 of serum concentration of GLP-1	24 weeks
Other	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
Primary	Safety Outcome Measure	Incidence of adverse events per arm/group	24 Weeks
Primary	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
Primary	Adverse Events	Number of patients with treatment-related adverse events	24 weeks
Primary	Severity of Adverse Events	Number of grade 3-5 adverse events	24 weeks
Secondary	Systolic Blood Pressure	Mean change in Systolic Blood Pressure	baseline and 24 weeks
Secondary	Pulse Rate	Mean change in Pulse Rate from baseline to week 24	baseline and 24 weeks
Secondary	Diastolic Blood Pressure	Change in Diastolic Blood Pressure	baseline and 24 weeks
Secondary	Respiratory Rate	Mean change in Respiratory Rate from baseline to week 24	baseline and 24 weeks
Secondary	Serum Alanine Aminotransaminase (ALT)	Mean change from Baseline in Serum Alanine Aminotransaminase (ALT) at Week 24	baseline and 24 weeks
Secondary	Peak Serum Concentration (Cmax)	Peak serum concentration (Cmax) of IMM-124E	0, 4, 12 and 24 Weeks
Secondary	Minimum Serum Concentration (Cmin)	Minimum serum concentration (Cmin) of IMM-124E	0, 4, 12 and 24 Weeks
Secondary	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
Secondary	Elimination Half Life (T1/2)	Elimination Half Life (T1/2) of IMM-124E	0, 4, 12 and 24 Weeks
Secondary	Body Mass Index (BMI)	Change from Baseline of Body Mass Index (BMI) at 24 weeks	24 Weeks
Secondary	Waist Circumference	Change from Baseline of Waist Circumference at 24 weeks	24 Weeks
Secondary	Waist:Hip Ratio	Change from Baseline of Waist:Hip Ratio at 24 weeks	24 Weeks
Secondary	Hemoglobin (HB)A1C	Change from Baseline of Hemoglobin(HB)A1C at 24 weeks	24 Weeks
Secondary	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
Secondary	Total Cholesterol	Change from Baseline of Total Cholesterol at 24 weeks	24 Weeks
Secondary	Triglycerides	Change from Baseline of Triglycerides at 24 weeks	24 Weeks
Secondary	Low Density Lipoprotein (LDL)	Change from Baseline of Low Density Lipoprotein (LDL) at 24 weeks	24 Weeks
Secondary	High Density Lipoprotein (HDL)	Change from Baseline of High Density Lipoprotein (HDL) at 24 weeks	24 Weeks
Secondary	Serum Alanine Aminotransaminase (ALT)	Mean change from Baseline of serum ALT	baseline to 24 weeks
Secondary	Serum Aspartate Aminotransaminase (AST)	Mean change from Baseline of Serum AST	baseline to 24 Weeks
Secondary	Bilirubin	Mean change from Baseline of Bilirubin	baseline to 24 Weeks
Secondary	Albumin	Mean change from Baseline of Albumin	baseline to 24 Weeks
Secondary	Gamma Glutamyl Transpeptidase (GGT)	Mean change from Baseline of Gamma Glutamyl Transpeptidase (GGT)	baseline to 24 Weeks
Secondary	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