Safety and Efficacy of IMM 124-E for Patients With Severe Alcoholic Hepatitis (TREAT)

A Multicenter Randomized, Double-Blind, Placebo-controlled, Dosing, Safety and Efficacy Study of IMM 124-E (Hyperimmune Bovine Colostrum) for Patients With Severe Alcoholic Hepatitis

Hypothesis: Oral administration of hyperimmune bovine colostrum enriched with anti-LPS antibodies will reduce endotoxemia, and improve pathophysiological and clinical parameters related to severe alcoholic hepatitis (SAH).

IMM 124-E is safe in subjects with severe alcoholic hepatitis being treated with steroids.

Aim: To perform a phase 2a "proof of concept" placebo-controlled, dose-ranging study of Imm 124-E (hyperimmune bovine colostrum enriched with IgG anti-LPS) in subjects with severe AH on steroids.

Study Overview

• Status: Completed
• Conditions: Hepatitis, Alcoholic
• Intervention / Treatment: Drug: IMM 124-E (Hyperimmune Bovine Colostrum); Drug: Placebo (High protein milk powder)

Detailed Description

Subjects with severe alcoholic hepatitis (20=> MELD <=28) about to receive prednisolone (40 mg/day x 28 days) will be randomized 1:1:1 to additionally receive either one of two doses of IMM 124-E (2400 mg/day or 4800 mg/day) orally or placebo for the same duration. Standard of care nutrition support and alcohol cessation recommendations will be provided to all subjects. Alcohol withdrawal will be managed per standard of care. Subjects who meet Lille criteria for failure of treatment on day 7 or side effects requiring discontinuation of steroids will be removed from the study. The primary endpoint is a decrease in plasma endotoxin levels.

The secondary endpoints will include:

1. Mechanistic endpoints: TNF-α, immune-inflammatory markers, microbiome-metagenome
2. Efficacy-related: number of subjects meeting Lille failure criteria at day 7 , mortality (at 30 days, 90 days, and 180 days), time to drop in conjugated bilirubin by 50%, bile acids, liver function tests, change in MELD, and sequential organ failure
3. Safety related: tolerability, adverse events.

• Study Type: Interventional
• Enrollment (Actual): 57
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Alcoholic hepatitis
• Men and women age 21 and above
• MELD >= 20 but <=28
• About to initiate prednisolone treatment, < 7 days of steroid treatment, or treatment naive.
• Actively consuming alcohol within 6 weeks of entry into the study
• Willing and able to comply with study requirements (including contraception)
• Subjects or their legally authorized representative (LAR) who have provided voluntary written informed consent.

Exclusion Criteria:

• Failure to obtain informed consent
• Subjects who are known to be HIV positive
• Active infection or sepsis (pneumonia by X-ray, positive blood or urine culture) or multi-organ failure
• Other or concomitant liver disease present: viral hepatitis, autoimmune liver disease, metabolic liver disease, vascular liver disease
• Cow milk allergy or severe lactose intolerance
• Active GI bleeding
• Untreated spontaneous bacterial peritonitis based on >250 polymorphonuclear cells or positive culture
• Acute kidney injury at time of randomization with Creatinine > 1.5 md/dL
• Evidence of acute pancreatitis (by imaging and lipase) or biliary obstruction (dilated bile ducts)
• Subjects who are pregnant or lactating
• Significant systemic or major illness, that, in the opinion of the Investigator would preclude the patient from participating in and completing the study
• Patients requiring the use of vasopressors or inotropic support in 12 hours prior to randomization
• Treatment for alcoholic hepatitis within 1 month of study entry with corticosteroids use>1 week immediately prior to the time of entry into the study.
• Any patient who has received any investigational drug or device within 30 days of dosing or who is scheduled to receive another investigational drug or device in the course of the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: IMM 124-E 2400 mg/day; Imm-124-E (2400 mg/day) will be provided in two divided doses daily in the form of powder to be mixed with water. Subjects will get 1 active drug powder and 1 placebo powder with each dosing for a total of 4 sachets daily.	Drug: IMM 124-E (Hyperimmune Bovine Colostrum); Hyper-immune bovine colostrum enriched with anti-LPS antibodies and which has been designated by Immuron as IMM-124E.; Drug: Placebo (High protein milk powder); Subjects will receive a total of 4 sachets (2 in the morning and 2 in the evening) daily
Experimental: IMM 124-E 4800 mg/day; Imm-124-E (4800 mg/day) will be provided in two divided doses daily in the form of 2400 mg in the form of a powder to be mixed with water. The total number daily will be 4 sachets.	Drug: IMM 124-E (Hyperimmune Bovine Colostrum); Hyper-immune bovine colostrum enriched with anti-LPS antibodies and which has been designated by Immuron as IMM-124E.
Placebo Comparator: Placebo (High protein milk powder); Subjects will receive 2 sachets of placebo powder to be mixed with water in the morning and 2 sachets of placebo powder (to be mixed with water) in the evening for a total of 4 sachets of placebo daily.	Drug: Placebo (High protein milk powder); Subjects will receive a total of 4 sachets (2 in the morning and 2 in the evening) daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Gastrointestinal Safety Endpoints	Number of events and severity of gastrointestinal events, including nausea, vomiting, and diarrhea	30 Days
Combined Kidney, Brain, and Lung Safety Endpoints	Number of incidents of the following: renal failure, encephalopathy or pulmonary compromise.	30 Days
Infection Safety Endpoints	Number of incidents of sepsis.	30 Days
Other Safety Endpoints	Number of incidents of all other serious adverse events and other adverse events not already assessed as a primary outcome.	30 Days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bowel Gastrointestinal Safety Endpoints	Number of participants who experience diarrhea	30 Days
Change in Circulating Endotoxin Levels	Changes in endotoxin levels as measured using a standard blood assay	Baseline, day 28
Lille Model Score	Number of participants who meet Lille criteria indicating failure to respond to treatment	7 days
Mortality	Number of deaths due to any cause	180 days
Change in Liver Function	Model for end-stage liver disease (MELD) score ranges from 6 to 40 with higher number indicating worse liver function.	90 days
SOFA Score	SOFA is a single score based on patient status of six different biological systems: respiratory, cardiovascular, hepatic, coagulation, renal, and neurological. Scores range from 0 to 24 with higher scores indicated worse status.	30 days
Change in Serum Bile Acids	Serum bile acids levels as measured using standard blood serum assay	Baseline to 90 days
Time to 50% Drop in Bilirubin	Length of time to a drop in bilirubin of 50% measured in days	180 days
Cytokine Data	Changes in cytokine profile across study arms at day 28	28 days

Collaborators and Investigators

• Sponsor: Virginia Commonwealth University
• Collaborators: National Institute on Alcohol Abuse and Alcoholism (NIAAA); Immuron Ltd.
• Investigators: Principal Investigator: Arun J Sanyal, MBBS MD, Virginia Commonwealth University

Study record dates

Study Major Dates

• Study Start: December 1, 2014
• Primary Completion (Actual): December 22, 2018
• Study Completion (Actual): December 22, 2018

Study Registration Dates

• First Submitted: August 30, 2013
• First Submitted That Met QC Criteria: October 18, 2013
• First Posted (Estimate): October 24, 2013

Study Record Updates

• Last Update Posted (Actual): January 27, 2020
• Last Update Submitted That Met QC Criteria: January 24, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Keywords: Hepatitis; LPS; Alcoholic; Bovine Colostrum; IMM 124-E; Hyper-immune
• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Digestive System Diseases; Alcohol-Related Disorders; Substance-Related Disorders; RNA Virus Infections; Virus Diseases; Infections; Liver Diseases; Hepatitis, Viral, Human; Enterovirus Infections; Picornaviridae Infections; Liver Diseases, Alcoholic; Alcohol-Induced Disorders; Hepatitis; Hepatitis A; Hepatitis, Alcoholic
• Other Study ID Numbers: HM20000157; U01AA021891 (U.S. NIH Grant/Contract); IMM-124-E (Other Identifier: VCU)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No