Alcoholic Hepatitis
Conditions
Brief summary
Alcoholic hepatitis is a syndrome of progressive inflammatory liver injury associated with long-term heavy intake of ethanol. The pathogenesis is not completely understood. Patients who are severely affected present with subacute onset of fever, hepatomegaly, leukocytosis, marked impairment of liver function (e.g., jaundice, coagulopathy), and manifestations of portal hypertension (e.g., ascites, hepatic encephalopathy, variceal hemorrhage). However, milder forms of alcoholic hepatitis often do not cause any symptoms. Alcoholic hepatitis usually persists and progresses to cirrhosis if heavy alcohol use continues. If alcohol use ceases, alcoholic hepatitis resolves slowly over weeks to months, sometimes without permanent sequelae but often with residual cirrhosis. F-652 is a recombinant fusion protein containing human interleukin 22 (IL-22) and human Immunoglobulin G2 (IgG2)-Fc produced in CHO cells in serum-free culture. F-652 under development is intended to treat patients with graft vs host disease (GvHD) after bone marrow transplantation, and acute alcoholic hepatitis (AAH), a severe form of alcoholic liver disease (ALD). Both GvHD and AAH are diseases with unmet medical need. The current investigational new drug (IND) application is to conduct a phase Ia clinical study in GvHD patients to evaluate the safety and pharmacokinetic profile, and biomarkers of F-652 treatment by intravenous infusion (IV). IL-22 is a member of the IL-10 family of cytokines which control bacterial infection, homeostasis, and tissue repair. IL-22 may be used to treat patients with ALD because of its antioxidant, anti-apoptotic, anti-steatotic, anti-microbial, and proliferative effect that have been demonstrated in various experimental systems.
Detailed description
IL-22 is a member of the IL-10 family of cytokines which control bacterial infection, homeostasis, and tissue repair. IL-22 may be used to treat patients with ALD because of its antioxidant, anti-apoptotic, anti-steatotic, anti-microbial, and proliferative effect that have been demonstrated in various experimental systems. The sponsor has developed F-652, a recombinant human IL-22 IgG2 Fc fusion protein produced in serum-free culture of Chinese Hamster Ovary (CHO) cells. F-652 is able to protect tissue from damage and enhance tissue repair during the inflammation process and infection by activation of STAT3 mediated by the interleukin-22 receptor subunit 1 (IL-22R1) expressed on epithelial cells such as hepatocytes.
Interventions
DRUGF-652
Participants will receive 10 μg/kg, 30 μg/kg or 45 μg/kg of F-652 on Day 1 and Day 7 via slow intravenous infusion. Three patients will receive 10 μg/kg of F-652. Pharmacokinetic testing will be completed on these subjects. If evaluations demonstrate safety and efficacy signals, the next 3 patients will receive 30 μg/kg. If pharmacokinetic testing demonstrates safety and efficacy signals, the next 3 patients will receive 45 μg/kg.
Sponsors
Indiana University
Virginia Commonwealth University
Hennepin County Medical Center, Minneapolis
Mayo Clinic
Study design
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
A phase 2 dose escalating study was carried out. F-652 (10, 30 or 45 μg/kg) administered on day 1 and 7 was tested in 3 patients each with moderate (MELD scores: 11-20) and severe AH (MELD scores: 21-28).
Eligibility
Sex/Gender
ALL
Age
21 Years to No maximum
Healthy volunteers
No
Inclusion criteria
3.1 Inclusion Criteria To participate in this study, patients must meet all of the following criteria: 1. Able to provide written informed consent (either from patient or patient's legally acceptable representative) 2. Male or female patients 21 years of age or older 3. Patients with alcoholic hepatitis defined as: 1. History of heavy alcohol abuse use: \>40 g/day in females and \>60 g/day in males for a minimum period of 6 months 2. Consumed alcohol within 6 weeks of entry into the study 3. Serum bilirubin \> 3mg/dL AND AST \>ALT, but less than 500 U/L 4. MELD score between 11-28 5. Liver biopsy will be carried out to confirm diagnosis in all patients except those who meet criteria a-c and in whom other causes of liver disease have been excluded (viral, drug, autoimmune etc). 4. Women of child-bearing potential must utilize appropriate birth control. \*Patients on steroids and/or pentoxifylline will not be excluded from the study.
Exclusion criteria
1. Other or concomitant cause of liver disease as a result of: 1. Autoimmune liver disease 2. Wilson disease 3. Vascular liver disease 4. Drug induced liver disease Note: Concurrent viral hepatitis is not excluded. 2. Co-infection with human immunodeficiency virus (HIV) 3. Any active malignancies other than curatively treated skin cancer (basal cell or squamous cell carcinomas) or any other malignancy diagnosed within the last five years. 4. Active tuberculosis on chest x-ray at study entry 5. Significant systemic or major illness other than liver disease, including coronary artery disease, cerebrovascular disease, pulmonary disease, renal failure, serious psychiatric disease, that, in the opinion of the Investigator would preclude the patient from participating in and completing the study 6. Patients requiring the use of vasopressors or inotropic support 7. Liver biopsy, if carried out, showing findings not compatible with alcoholic hepatitis 8. Any patient that 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 Note: Investigational drug includes any drug that is used off-label. 9. If female, known pregnancy, or has a positive urine or serum pregnancy test, or lactating/breastfeeding 10. Serum creatinine \>2.5 mg/dL
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Number of Subjects With Unexpected Serious Adverse Events. | From day 1 up to 42 days following administration of last dose of study drug | The count of subjects who experience serious adverse events |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Period 1: F-652 10 μg/kg Participants will receive 10 μg/kg of F-652 on Day 1 and Day 7 via slow intravenous infusion. | 6 |
| Period 2: F-652 30 μg/kg Participants will receive 30 μg/kg of F-652 on Day 1 and Day 7 via slow intravenous infusion | 6 |
| Period 3: F-652 45 μg/kg Participants will receive 45 μg/kg of F-652 on Day 1 and Day 7 via slow intravenous infusion. | 6 |
| Total | 18 |
Baseline characteristics
| Characteristic | Period 2: F-652 30 μg/kg | Total | Period 1: F-652 10 μg/kg | Period 3: F-652 45 μg/kg |
|---|---|---|---|---|
| Age, Continuous | 50.5 years STANDARD_DEVIATION 12 | 49.1 years STANDARD_DEVIATION 9.8 | 46.8 years STANDARD_DEVIATION 6.9 | 50.3 years STANDARD_DEVIATION 11.3 |
| Alcohol Consumption by MELD grouping MELD 11-20 | 151.3 grams per day STANDARD_DEVIATION 28.8 | 160.4 grams per day STANDARD_DEVIATION 63.1 | 143.3 grams per day STANDARD_DEVIATION 75 | 186.6 grams per day STANDARD_DEVIATION 88.9 |
| Alcohol Consumption by MELD grouping MELD 21-28 | 212.6 grams per day STANDARD_DEVIATION 141.7 | 150.4 grams per day STANDARD_DEVIATION 123.2 | 181.3 grams per day STANDARD_DEVIATION 140 | 57.3 grams per day STANDARD_DEVIATION 28 |
| Hospitalized at screening by MELD grouping MELD 11-20 | 3 Participants | 8 Participants | 3 Participants | 2 Participants |
| Hospitalized at screening by MELD grouping MELD 21-28 | 1 Participants | 5 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 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 | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 17 Participants | 5 Participants | 6 Participants |
| Region of Enrollment United States | 6 participants | 18 participants | 6 participants | 6 participants |
| Sex: Female, Male Female | 2 Participants | 6 Participants | 2 Participants | 2 Participants |
| Sex: Female, Male Male | 4 Participants | 12 Participants | 4 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 1 / 6 | 0 / 6 |
| other Total, other adverse events | 2 / 6 | 5 / 6 | 4 / 6 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 | 0 / 6 |
Outcome results
Primary
The Number of Subjects With Unexpected Serious Adverse Events.
The count of subjects who experience serious adverse events
Time frame: From day 1 up to 42 days following administration of last dose of study drug
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Period 1: F-652 10 μg/kg | The Number of Subjects With Unexpected Serious Adverse Events. | 0 Participants |
| Period 2: F-652 30 μg/kg | The Number of Subjects With Unexpected Serious Adverse Events. | 0 Participants |
| Period 3: F-652 45 μg/kg | The Number of Subjects With Unexpected Serious Adverse Events. | 0 Participants |