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

Study Overview
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Brief Summary
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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.

Detailed Description
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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: Mechanistic endpoints: TNF-α, immune-inflammatory markers, microbiome-metagenome 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 Safety related: tolerability, adverse events.

Official Title
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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

Conditions
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Hepatitis, Alcoholic

Intervention / Treatment
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* Drug: IMM 124-E (Hyperimmune Bovine Colostrum)
* Drug: Placebo (High protein milk powder)


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 21 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: IMM 124-E 2400 mg/day<br>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)<br>* Hyper-immune bovine colostrum enriched with anti-LPS antibodies and which has been designated by Immuron as IMM-124E.<br>Drug: Placebo (High protein milk powder)<br>* Subjects will receive a total of 4 sachets (2 in the morning and 2 in the evening) daily<br>|
| Experimental: IMM 124-E 4800 mg/day<br>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)<br>* Hyper-immune bovine colostrum enriched with anti-LPS antibodies and which has been designated by Immuron as IMM-124E.<br>|
| Placebo Comparator: Placebo (High protein milk powder)<br>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)<br>* Subjects will receive a total of 4 sachets (2 in the morning and 2 in the evening) daily<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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LPS, IMM 124-E, Bovine Colostrum, Alcoholic, Hepatitis, Hyper-immune