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Guselkumab (Anti-IL 23 Monoclonal Antibody) for Alcohol Associated Liver Disease

Primary Purpose

Alcoholic Liver Disease

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Guselkumab 30mg
Guselkumab 70mg
Guselkumab 100mg
Sponsored by
University of California, San Diego
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Alcoholic Liver Disease

Eligibility Criteria

21 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion 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 with BMI ≥ 20 to ≤ 45 kg/m2
  3. Patients with moderate alcohol use disorder (AUD) as defined by the AASLD Practice Guidance to have ≥ 4 symptoms out of 11:

    1. Alcohol is often taken in larger amounts and/or over a longer period than the patient intended.
    2. Persistent attempts or one or more unsuccessful efforts made to cut down or control alcohol use.
    3. A great deal of time is spent in activities necessary to obtain alcohol, use alcohol, or recover from effects.
    4. Craving or strong desire or urge to use alcohol
    5. Recurrent alcohol use resulting in a failure to fulfill major role obligations at work, school, or home.
    6. Continued alcohol use despite having persistent or recurrent social or interpersonal problem caused or exacerbated by the effects of the alcohol.
    7. Important social, occupational or recreational activities given up or reduced because of alcohol use.
    8. Recurrent alcohol use in situations in which it is physically hazardous.
    9. Alcohol use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the alcohol.
    10. Tolerance, as defined by either of the following:
    1. Markedly increased amounts of the alcohol in order to achieve intoxication or desired effect
    2. Markedly diminished effect with continued use of the same amount

    k. Withdrawal, as manifested by either of the following:

    1. The characteristic alcohol withdrawal syndrome or
    2. Alcohol (or a closely related substance) is taken to relieve or avoid withdrawal symptoms
  4. Evidence of end-organ damage to the liver as defined by

    a. MRI-PDFF ≥ 8% suggestive of significant hepatic accumulation of triglyceride within 3 months of screening; if patients cannot get an MRI, CAP ≥ 300dB/m

  5. Consumed alcohol within 12 weeks of entry into the study, AND

    a. AST and ALT less than 200 U/L AND

  6. No evidence of active infection as determined by the investigator.
  7. Women of child-bearing potential (defined as females who are not surgically sterile or who are not over the age of 52 and amenorrheic for at least 12 months) must utilize appropriate birth control throughout the study duration. Acceptable methods that may be used are abstinence, birth control pills ("The Pill") or patch, diaphragm, intrauterine device (IUD/ coil), vaginal ring, condom, surgical sterilization or progestin implant or injection, or sexual activity limited to a sterile (e.g., vasectomized) male partner.
  8. Male patients must agree to use a medically acceptable method of contraception/birth control throughout the study duration.

Exclusion Criteria:

  1. History or evidence of other or concomitant cause(s) of liver disease as a result of:

    1. Autoimmune liver disease
    2. Wilson disease (ceruloplasmin levels < 10 mcg/L)
    3. Vascular liver disease
    4. Drug induced liver disease
    5. Surface antigen positive hepatitis B (HBsAg+). Note: patients with isolated core antibody (HBcAb) are not excluded.
    6. Acute hepatitis A
    7. Acute HCV or chronic hepatitis C with a history of decompensated cirrhosis. (Note: patients with stable chronic Hep C Virus (HCV) or successfully treated HCV are not excluded. Anti-HBc antibody positive patients will be given a prophylaxis with entecavir 0.5mg PO once daily, starting one week prior to start of guselkumab to 6 months after the last dose of guselkumab)
  2. Noninvasive criteria to exclude cirrhosis:

    1. MRE ≥ 3.63 kPa; if MRE not available, VCTE ≥ 16 kPa
    2. FIB-4 ≥ 2.67
    3. Imaging evidence of varices, splenomegaly, ascites, or shrunken cirrhotic liver
  3. Co-infection with human immunodeficiency virus (HIV)
  4. History or evidence of positive Urine Drug Screen (amphetamines, barbiturates, benzodiazepines, cocaine and opiates) except THC and legal prescription medications.
  5. 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
  6. History or evidence of active tuberculosis
  7. Positive Quantiferon test
  8. 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
  9. Patients requiring the use of vasopressors or inotropic support.
  10. Any patient that has received any investigational drug within 30 days of dosing or who is scheduled to receive another investigational drug at any time during the study
  11. Patients who are taking drug products that are primarily the substrates of CYP2C8, such as chloroquine, paclitaxel, rosiglitazone, repaglinide
  12. If female, known pregnancy, or has a positive serum pregnancy test, or is lactating/breastfeeding
  13. Serum creatinine > 1.5 mg/dL
  14. Patients who have had organ transplantation (such as liver, kidney, lung, heart, bone marrow, or stem cell etc.), other than cornea transplant
  15. Presence of cirrhosis on imaging or any of following lab parameters:

    1. Albumin < 3.7 g/dL
    2. Direct bilirubin > 0.5 mg/dl unless due to Gilbert's syndrome
    3. Platelets < 140K
    4. INR > 1.3
  16. Presence of any features of portal hypertension such as ascites, history of ascites or varices, or encephalopathy
  17. Previous use of guselkumab ( or another IL-23 inhibitors) or hypersentivity to guselkumab
  18. Previous history of skin cancers in the last one year
  19. Previous history of breast or prostate cancer or any cancer within the last 5 years

Sites / Locations

  • University of California, San DiegoRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

Guselkumab 30mg

Guselkumab 70 mg

Guselkumab 100mg

Arm Description

Guselkumab administered by subcutaneous injection at Day 1 and Day 29

Guselkumab administered by subcutaneous injection at Day 1 and Day 29

Guselkumab administered by subcutaneous injection at Day 1 and Day 29

Outcomes

Primary Outcome Measures

Assess the safety and tolerability of Guselkumab
Incidence of treatment-emergent adverse events: Outcome measures will include incidence of treatment-emergent adverse events and the proportion of subjects prematurely withdrawn from the study due to adverse events.

Secondary Outcome Measures

Full Information

First Posted
January 19, 2021
Last Updated
September 1, 2023
Sponsor
University of California, San Diego
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1. Study Identification

Unique Protocol Identification Number
NCT04736966
Brief Title
Guselkumab (Anti-IL 23 Monoclonal Antibody) for Alcohol Associated Liver Disease
Official Title
A Phase I Clinical Trial to Determine the Safety and Tolerability of Anti-IL23 Monoclonal Antibody, for the Treatment of Patients With Alcohol Associated Liver Disease
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Recruiting
Study Start Date
March 3, 2021 (Actual)
Primary Completion Date
March 31, 2024 (Anticipated)
Study Completion Date
March 31, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of California, San Diego

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
A Phase I clinical trial to determine the safety and tolerability of an anti-IL23 antibody for the treatment of patients with alcoholic liver disease
Detailed Description
This is a phase I study of guselkumab, a humanized anti-IL23 monoclonal antibody, for patients with alcoholic liver disease. This drug is approved for the use in psoriatic arthritis but not for alcoholic liver disease. The investigators will be using a standard 3+3 phase I dose escalation trial design, the dose levels will start from 30 mg, 70 mg and to 100 mg, a maximum total of 24 patients will be evaluable. In this study the investigators propose to establish safety of the product in those with alcoholic liver disease and efficacy (secondary endpoint) will be determined by biomarkers for liver inflammation and fibrosis surrogate biomarkers.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Alcoholic Liver Disease

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
24 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Guselkumab 30mg
Arm Type
Experimental
Arm Description
Guselkumab administered by subcutaneous injection at Day 1 and Day 29
Arm Title
Guselkumab 70 mg
Arm Type
Experimental
Arm Description
Guselkumab administered by subcutaneous injection at Day 1 and Day 29
Arm Title
Guselkumab 100mg
Arm Type
Experimental
Arm Description
Guselkumab administered by subcutaneous injection at Day 1 and Day 29
Intervention Type
Drug
Intervention Name(s)
Guselkumab 30mg
Other Intervention Name(s)
Tremfya
Intervention Description
30mg of Guselkumab administered by subcutaneous injection
Intervention Type
Drug
Intervention Name(s)
Guselkumab 70mg
Other Intervention Name(s)
Tremfya
Intervention Description
70mg of Guselkumab administered by subcutaneous injection
Intervention Type
Drug
Intervention Name(s)
Guselkumab 100mg
Other Intervention Name(s)
Tremfya
Intervention Description
100mg of Guselkumab administered by subcutaneous injection
Primary Outcome Measure Information:
Title
Assess the safety and tolerability of Guselkumab
Description
Incidence of treatment-emergent adverse events: Outcome measures will include incidence of treatment-emergent adverse events and the proportion of subjects prematurely withdrawn from the study due to adverse events.
Time Frame
48 Weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
21 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Able to provide written informed consent (either from patient or patient's legally acceptable representative) Male or female patients 21 years of age or older with BMI ≥ 20 to ≤ 45 kg/m2 Patients with moderate alcohol use disorder (AUD) as defined by the AASLD Practice Guidance to have ≥ 4 symptoms out of 11: Alcohol is often taken in larger amounts and/or over a longer period than the patient intended. Persistent attempts or one or more unsuccessful efforts made to cut down or control alcohol use. A great deal of time is spent in activities necessary to obtain alcohol, use alcohol, or recover from effects. Craving or strong desire or urge to use alcohol Recurrent alcohol use resulting in a failure to fulfill major role obligations at work, school, or home. Continued alcohol use despite having persistent or recurrent social or interpersonal problem caused or exacerbated by the effects of the alcohol. Important social, occupational or recreational activities given up or reduced because of alcohol use. Recurrent alcohol use in situations in which it is physically hazardous. Alcohol use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the alcohol. Tolerance, as defined by either of the following: Markedly increased amounts of the alcohol in order to achieve intoxication or desired effect Markedly diminished effect with continued use of the same amount k. Withdrawal, as manifested by either of the following: The characteristic alcohol withdrawal syndrome or Alcohol (or a closely related substance) is taken to relieve or avoid withdrawal symptoms Evidence of end-organ damage to the liver as defined by a. MRI-PDFF ≥ 8% suggestive of significant hepatic accumulation of triglyceride within 3 months of screening; if patients cannot get an MRI, CAP ≥ 300dB/m Consumed alcohol within 12 weeks of entry into the study, AND a. AST and ALT less than 200 U/L AND No evidence of active infection as determined by the investigator. Women of child-bearing potential (defined as females who are not surgically sterile or who are not over the age of 52 and amenorrheic for at least 12 months) must utilize appropriate birth control throughout the study duration. Acceptable methods that may be used are abstinence, birth control pills ("The Pill") or patch, diaphragm, intrauterine device (IUD/ coil), vaginal ring, condom, surgical sterilization or progestin implant or injection, or sexual activity limited to a sterile (e.g., vasectomized) male partner. Male patients must agree to use a medically acceptable method of contraception/birth control throughout the study duration. Exclusion Criteria: History or evidence of other or concomitant cause(s) of liver disease as a result of: Autoimmune liver disease Wilson disease (ceruloplasmin levels < 10 mcg/L) Vascular liver disease Drug induced liver disease Surface antigen positive hepatitis B (HBsAg+). Note: patients with isolated core antibody (HBcAb) are not excluded. Acute hepatitis A Acute HCV or chronic hepatitis C with a history of decompensated cirrhosis. (Note: patients with stable chronic Hep C Virus (HCV) or successfully treated HCV are not excluded. Anti-HBc antibody positive patients will be given a prophylaxis with entecavir 0.5mg PO once daily, starting one week prior to start of guselkumab to 6 months after the last dose of guselkumab) Noninvasive criteria to exclude cirrhosis: MRE ≥ 3.63 kPa; if MRE not available, VCTE ≥ 16 kPa FIB-4 ≥ 2.67 Imaging evidence of varices, splenomegaly, ascites, or shrunken cirrhotic liver Co-infection with human immunodeficiency virus (HIV) History or evidence of positive Urine Drug Screen (amphetamines, barbiturates, benzodiazepines, cocaine and opiates) except THC and legal prescription medications. 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 History or evidence of active tuberculosis Positive Quantiferon test 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 Patients requiring the use of vasopressors or inotropic support. Any patient that has received any investigational drug within 30 days of dosing or who is scheduled to receive another investigational drug at any time during the study Patients who are taking drug products that are primarily the substrates of CYP2C8, such as chloroquine, paclitaxel, rosiglitazone, repaglinide If female, known pregnancy, or has a positive serum pregnancy test, or is lactating/breastfeeding Serum creatinine > 1.5 mg/dL Patients who have had organ transplantation (such as liver, kidney, lung, heart, bone marrow, or stem cell etc.), other than cornea transplant Presence of cirrhosis on imaging or any of following lab parameters: Albumin < 3.7 g/dL Direct bilirubin > 0.5 mg/dl unless due to Gilbert's syndrome Platelets < 140K INR > 1.3 Presence of any features of portal hypertension such as ascites, history of ascites or varices, or encephalopathy Previous use of guselkumab ( or another IL-23 inhibitors) or hypersentivity to guselkumab Previous history of skin cancers in the last one year Previous history of breast or prostate cancer or any cancer within the last 5 years
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Egbert Madamba
Phone
858-246-2227
Email
emadamba@health.ucsd.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Rohit Loomba
Organizational Affiliation
University of California, San Diego
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of California, San Diego
City
La Jolla
State/Province
California
ZIP/Postal Code
92093
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Egbert Madamba
Phone
858-246-2227
Email
emadamba@health.ucsd.edu

12. IPD Sharing Statement

Plan to Share IPD
No

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Guselkumab (Anti-IL 23 Monoclonal Antibody) for Alcohol Associated Liver Disease

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