Hepatitis, Alcoholic
Conditions
Keywords
IMM 124-E, Bovine Colostrum, Alcoholic, Hepatitis, LPS, Hyper-immune
Brief summary
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
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.
Interventions
DRUGIMM 124-E (Hyperimmune Bovine Colostrum)
Hyper-immune bovine colostrum enriched with anti-LPS antibodies and which has been designated by Immuron as IMM-124E.
DRUGPlacebo (High protein milk powder)
Subjects will receive a total of 4 sachets (2 in the morning and 2 in the evening) daily
Sponsors
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Immuron Ltd.
Virginia Commonwealth University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Gastrointestinal Safety Endpoints | 30 Days | Number of events and severity of gastrointestinal events, including nausea, vomiting, and diarrhea |
| Combined Kidney, Brain, and Lung Safety Endpoints | 30 Days | Number of incidents of the following: renal failure, encephalopathy or pulmonary compromise. |
| Infection Safety Endpoints | 30 Days | Number of incidents of sepsis. |
| Other Safety Endpoints | 30 Days | Number of incidents of all other serious adverse events and other adverse events not already assessed as a primary outcome. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Liver Function | 90 days | Model for end-stage liver disease (MELD) score ranges from 6 to 40 with higher number indicating worse liver function. |
| SOFA Score | 30 days | 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. |
| Bowel Gastrointestinal Safety Endpoints | 30 Days | Number of participants who experience diarrhea |
| Time to 50% Drop in Bilirubin | 180 days | Length of time to a drop in bilirubin of 50% measured in days |
| Cytokine Data | 28 days | Changes in cytokine profile across study arms at day 28 |
| Change in Serum Bile Acids | Baseline to 90 days | Serum bile acids levels as measured using standard blood serum assay |
| Change in Circulating Endotoxin Levels | Baseline, day 28 | Changes in endotoxin levels as measured using a standard blood assay |
| Lille Model Score | 7 days | Number of participants who meet Lille criteria indicating failure to respond to treatment |
| Mortality | 180 days | Number of deaths due to any cause |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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.
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 (High protein milk powder): Subjects will receive a total of 4 sachets (2 in the morning and 2 in the evening) daily | 18 |
| 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.
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. | 19 |
| 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.
Placebo (High protein milk powder): Subjects will receive a total of 4 sachets (2 in the morning and 2 in the evening) daily | 20 |
| Total | 57 |
Baseline characteristics
| Characteristic | IMM 124-E 2400 mg/Day | Total | Placebo (High Protein Milk Powder) | IMM 124-E 4800 mg/Day |
|---|---|---|---|---|
| Age, Continuous | 43.5 years STANDARD_DEVIATION 10.2 | 44.6 years STANDARD_DEVIATION 10.9 | 45.7 years STANDARD_DEVIATION 11.8 | 44.4 years STANDARD_DEVIATION 11 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 4 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 3 Participants | 3 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) White | 13 Participants | 48 Participants | 17 Participants | 18 Participants |
| Region of Enrollment United States | 18 participants | 57 participants | 20 participants | 19 participants |
| Sex: Female, Male Female | 8 Participants | 26 Participants | 8 Participants | 10 Participants |
| Sex: Female, Male Male | 10 Participants | 31 Participants | 12 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 5 / 18 | 2 / 19 | 2 / 20 |
| other Total, other adverse events | 18 / 18 | 19 / 19 | 17 / 20 |
| serious Total, serious adverse events | 11 / 18 | 9 / 19 | 12 / 20 |
Outcome results
Primary
Combined Kidney, Brain, and Lung Safety Endpoints
Number of incidents of the following: renal failure, encephalopathy or pulmonary compromise.
Time frame: 30 Days
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IMM 124-E 2400 mg/Day | Combined Kidney, Brain, and Lung Safety Endpoints | Encephalopathy | 0 incidents |
| IMM 124-E 2400 mg/Day | Combined Kidney, Brain, and Lung Safety Endpoints | Renal failure | 9 incidents |
| IMM 124-E 2400 mg/Day | Combined Kidney, Brain, and Lung Safety Endpoints | Pulmonary compromise | 5 incidents |
| IMM 124-E 4800 mg/Day | Combined Kidney, Brain, and Lung Safety Endpoints | Encephalopathy | 1 incidents |
| IMM 124-E 4800 mg/Day | Combined Kidney, Brain, and Lung Safety Endpoints | Renal failure | 10 incidents |
| IMM 124-E 4800 mg/Day | Combined Kidney, Brain, and Lung Safety Endpoints | Pulmonary compromise | 6 incidents |
| Placebo (High Protein Milk Powder) | Combined Kidney, Brain, and Lung Safety Endpoints | Renal failure | 11 incidents |
| Placebo (High Protein Milk Powder) | Combined Kidney, Brain, and Lung Safety Endpoints | Pulmonary compromise | 8 incidents |
| Placebo (High Protein Milk Powder) | Combined Kidney, Brain, and Lung Safety Endpoints | Encephalopathy | 0 incidents |
Primary
Gastrointestinal Safety Endpoints
Number of events and severity of gastrointestinal events, including nausea, vomiting, and diarrhea
Time frame: 30 Days
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IMM 124-E 2400 mg/Day | Gastrointestinal Safety Endpoints | Moderate | 14 Incidents |
| IMM 124-E 2400 mg/Day | Gastrointestinal Safety Endpoints | Mild | 15 Incidents |
| IMM 124-E 2400 mg/Day | Gastrointestinal Safety Endpoints | Severe | 5 Incidents |
| IMM 124-E 4800 mg/Day | Gastrointestinal Safety Endpoints | Moderate | 25 Incidents |
| IMM 124-E 4800 mg/Day | Gastrointestinal Safety Endpoints | Mild | 27 Incidents |
| IMM 124-E 4800 mg/Day | Gastrointestinal Safety Endpoints | Severe | 3 Incidents |
| Placebo (High Protein Milk Powder) | Gastrointestinal Safety Endpoints | Mild | 7 Incidents |
| Placebo (High Protein Milk Powder) | Gastrointestinal Safety Endpoints | Severe | 6 Incidents |
| Placebo (High Protein Milk Powder) | Gastrointestinal Safety Endpoints | Moderate | 18 Incidents |
Primary
Infection Safety Endpoints
Number of incidents of sepsis.
Time frame: 30 Days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IMM 124-E 2400 mg/Day | Infection Safety Endpoints | 2 Incidents |
| IMM 124-E 4800 mg/Day | Infection Safety Endpoints | 1 Incidents |
| Placebo (High Protein Milk Powder) | Infection Safety Endpoints | 2 Incidents |
Primary
Other Safety Endpoints
Number of incidents of all other serious adverse events and other adverse events not already assessed as a primary outcome.
Time frame: 30 Days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IMM 124-E 2400 mg/Day | Other Safety Endpoints | 67 Events |
| IMM 124-E 4800 mg/Day | Other Safety Endpoints | 113 Events |
| Placebo (High Protein Milk Powder) | Other Safety Endpoints | 124 Events |
Secondary
Bowel Gastrointestinal Safety Endpoints
Number of participants who experience diarrhea
Time frame: 30 Days
Population: Data were not collected separately for participants who suffered diarrhea. All gastrointestinal events (including diarrhea) were recorded as generic gastrointestinal events and reported in primary outcome #1.
Secondary
Change in Circulating Endotoxin Levels
Changes in endotoxin levels as measured using a standard blood assay
Time frame: Baseline, day 28
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IMM 124-E 2400 mg/Day | Change in Circulating Endotoxin Levels | -361.06 ng/mL | Standard Deviation 1249.17 |
| IMM 124-E 4800 mg/Day | Change in Circulating Endotoxin Levels | -72.94 ng/mL | Standard Deviation 755.23 |
| Placebo (High Protein Milk Powder) | Change in Circulating Endotoxin Levels | 123.41 ng/mL | Standard Deviation 469.38 |
p-value: 0.3198ANOVA
Secondary
Change in Liver Function
Model for end-stage liver disease (MELD) score ranges from 6 to 40 with higher number indicating worse liver function.
Time frame: 90 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IMM 124-E 2400 mg/Day | Change in Liver Function | -8.89 score on a scale | Standard Deviation 5.35 |
| IMM 124-E 4800 mg/Day | Change in Liver Function | -6.82 score on a scale | Standard Deviation 4.87 |
| Placebo (High Protein Milk Powder) | Change in Liver Function | -7.78 score on a scale | Standard Deviation 12.12 |
p-value: 0.8462ANOVA
Secondary
Change in Serum Bile Acids
Serum bile acids levels as measured using standard blood serum assay
Time frame: Baseline to 90 days
Population: Data not collected
Secondary
Cytokine Data
Changes in cytokine profile across study arms at day 28
Time frame: 28 days
Population: Data not collected
Secondary
Lille Model Score
Number of participants who meet Lille criteria indicating failure to respond to treatment
Time frame: 7 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IMM 124-E 2400 mg/Day | Lille Model Score | 5 Participants |
| IMM 124-E 4800 mg/Day | Lille Model Score | 6 Participants |
| Placebo (High Protein Milk Powder) | Lille Model Score | 9 Participants |
Secondary
Mortality
Number of deaths due to any cause
Time frame: 180 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IMM 124-E 2400 mg/Day | Mortality | 5 Participants |
| IMM 124-E 4800 mg/Day | Mortality | 2 Participants |
| Placebo (High Protein Milk Powder) | Mortality | 2 Participants |
Secondary
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.
Time frame: 30 days
Population: Data not collected
Secondary
Time to 50% Drop in Bilirubin
Length of time to a drop in bilirubin of 50% measured in days
Time frame: 180 days
Population: Data not collected