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Use of F-652 in Patients With Alcoholic Hepatitis (TREAT 008)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02655510
Recruitment Status : Completed
First Posted : January 14, 2016
Results First Posted : September 9, 2019
Last Update Posted : September 9, 2019
Sponsor:
Collaborators:
Indiana University
Virginia Commonwealth University
Hennepin County Medical Center, Minneapolis
Information provided by (Responsible Party):
Vijay Shah, M.D., Mayo Clinic

Tracking Information
First Submitted Date  ICMJE January 7, 2016
First Posted Date  ICMJE January 14, 2016
Results First Submitted Date  ICMJE June 11, 2019
Results First Posted Date  ICMJE September 9, 2019
Last Update Posted Date September 9, 2019
Study Start Date  ICMJE February 2016
Actual Primary Completion Date June 30, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 5, 2019)
The Number of Subjects With Unexpected Serious Adverse Events. [ Time Frame: From day 1 up to 42 days following administration of last dose of study drug ]
The count of subjects who experience serious adverse events
Original Primary Outcome Measures  ICMJE
 (submitted: January 12, 2016)
Absence of unexpected serious adverse events. [ Time Frame: Day 42 of study ]
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE
 (submitted: January 12, 2016)
  • Total exposure (area under the curve) [ Time Frame: Day 42 of study ]
  • Maximum serum concentration [ Time Frame: Day 42 of study ]
  • Time at maximum serum concentration [ Time Frame: Day 42 of study ]
  • Last measurable serum concentration [ Time Frame: Day 42 of study ]
  • Time at last measurable serum concentration [ Time Frame: Day 42 of study ]
  • Mean plasma clearance [ Time Frame: Day 42 of study ]
  • Volume of distribution [ Time Frame: Day 42 of study ]
  • Elimination half-life [ Time Frame: Day 42 of study ]
  • Accumulation ratio [ Time Frame: Day 42 of study ]
  • Dose proportionality [ Time Frame: Day 42 of study ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures
 (submitted: January 12, 2016)
  • Change in Model for End Stage Liver Disease (MELD) score [ Time Frame: baseline, Day 42 of study ]
  • Change in Lille Model for Alcoholic Hepatitis Score [ Time Frame: baseline, Day 42 of study ]
  • Change in Triglycerides [ Time Frame: baseline, Day 42 of study ]
  • Change in C-Reactive Protein (CRP) [ Time Frame: baseline, Day 42 of study ]
  • Change in Aspartate Aminotransferase (AST) [ Time Frame: baseline, Day 42 of study ]
  • Change in Alanine Aminotransferase (ALT) [ Time Frame: baseline, Day 42 of study ]
  • Change in Serum Amyloid A1 (SAA1) [ Time Frame: baseline, Day 42 of study ]
 
Descriptive Information
Brief Title  ICMJE Use of F-652 in Patients With Alcoholic Hepatitis
Official Title  ICMJE An Open-Label, Cohort Dose Escalation Study to Assess the Safety and Efficacy of F-652 in Patients With Alcoholic Hepatitis
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Intervention Model: Sequential Assignment
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).
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Alcoholic Hepatitis
Intervention  ICMJE Drug: F-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.
Study Arms  ICMJE Experimental: F-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 with MELD 11-20 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. After demonstrating absence of side effects in this group, patients in MELD 21-28 will follow the same dose escalation regiment as the MELD 11-20 group.
Intervention: Drug: F-652
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: September 5, 2019)
18
Original Estimated Enrollment  ICMJE
 (submitted: January 12, 2016)
24
Actual Study Completion Date  ICMJE June 30, 2018
Actual Primary Completion Date June 30, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 21 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02655510
Other Study ID Numbers  ICMJE 15-003249
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Vijay Shah, M.D., Mayo Clinic
Study Sponsor  ICMJE Mayo Clinic
Collaborators  ICMJE
  • Indiana University
  • Virginia Commonwealth University
  • Hennepin County Medical Center, Minneapolis
Investigators  ICMJE
Principal Investigator: Vijay Shah, MD Mayo Clinic
PRS Account Mayo Clinic
Verification Date September 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP