Clinical trial NCT05639543: FXR Effect on Severe Alcohol-Associated Hepatitis (FRESH) Study
Official title: A Phase 2a, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Dose-Escalation, Proof-of-Concept Study Evaluating the Safety, Tolerability, Efficacy and Pharmacokinetics of INT-787 in Subjects With Severe Alcohol Associated Hepatitis
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Alcohol Associated Hepatitis
Keywords: Severe Alcohol associated Hepatitis (sAH)
Alcoholic Hepatitis (AH)
Hepatitis
Alcoholic
Lead sponsor: Intercept Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2022-12-06
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this trial is to assess dose related safety, efficacy, and pharmacokinetics (PK) of INT-787 in participants with severe alcohol-associated hepatitis (sAH).

Detailed description: This is a Phase 2a, randomized, double-blind, placebo-controlled, dose-escalation, proof-of-concept study to evaluate the safety, tolerability, efficacy, and PK of INT-787 in participants, initially admitted to the hospital, with severe alcohol-associated hepatitis (sAH). The study aims to demonstrate and provide rationale for the selection of optimal dose(s) of INT-787 in the target population of participants with sAH. INT-787 will be evaluated for safety and tolerability prior to dose escalation. Overall efficacy, compared to placebo, will be assessed for each dose cohort.

Additionally, PK measurements at various study timepoints will allow the Sponsor to better understand the systemic exposure of INT-787 and the relationship between exposure and efficacy and safety. Such insights in participants with more advanced liver disease will provide valuable information for future clinical trials of INT-787.

The placebo-treated participants will provide important natural history information on outcomes in this participant population with sAH treated with supportive care. The placebo-treated participants within cohorts are meant to blind the study drug administration while the data across dose cohorts will be used in the overall analysis.

Eligibility criteria: Inclusion Criteria:

1. Males or females aged 18 to 65 years (inclusive)
2. Clinical diagnosis of sAH based on all the following:

   1. History of ongoing excess alcohol (\>60 g/day \[male\] or \>40 g/day \[female\]) use for ≥6 months, with \<60 days of abstinence prior to the onset of jaundice
   2. Serum total bilirubin \>3.0 mg/dL
   3. Aspartate aminotransferase (AST) ≥50 U/L
   4. AST/Aspartate aminotransferase (ALT) ratio ≥1.5
   5. Onset of jaundice within prior 8 weeks
   6. Cohort 1 through Cohort 4: Maddrey's Discriminant Factor (mDF) ≥32 and ≤70
   7. Cohort 5 and Cohort 6: mDF ≥32
3. Cohort 1 through Cohort 4: MELD score ≥18 to ≤25 (inclusive) and Cohort 5 and Cohort 6: MELD score ≥21 to ≤30
4. Female participants must be postmenopausal, surgically sterile, or, if premenopausal (and not surgically sterile), be prepared to use ≥1 highly effective method of contraception from the initiation of Screening and for 90 days after the last dose of investigational product as follows:

   * Surgical sterilization (bilateral tubal occlusion, etc.)
   * Placement of an intrauterine device (IUD) or intrauterine system (e.g., intrauterine hormone-releasing system \[IUS\])
   * Combined (estrogen and progesterone containing) hormonal contraceptive associated with inhibition of ovulation:

     * Oral
     * Intravaginal
     * Transdermal
   * Progesterone-only hormonal contraception associated with inhibition of ovulation:

     * Oral
     * Injectable
     * Implantable
   * Sexual abstinence: When in line with the preferred and usual lifestyle of the participant, is defined as avoiding all types of activity that could result in conception (pregnancy) from the initiation of Screening and until at least 90 days after the last dose of investigational product
5. Male participants who are sexually active with female partners of childbearing potential must agree to use a condom with spermicide and to use 1 other approved method of highly effective contraception from the initiation of Screening and until at least 90 days after the dose of investigational product as listed in Inclusion Criteria #3.
6. Male participants must refrain from sperm donation from the initiation of Screening and until at least 90 days after the last dose of investigational product
7. Must provide written informed consent and agree to comply with the study protocol. In participants with hepatic encephalopathy which may impair decision-making, consent will be obtained per hospital procedures (e.g., by Legally Authorized Representative).
8. Participants must agree to participate in an alcohol use disorder program during the study period, as recommended by the local institution's addiction medicine specialists, including post-hospitalization

Exclusion Criteria:

1. Participants taking products containing obeticholic acid in the 30 days prior to randomization
2. Participants taking \>2 doses of systemic corticosteroids within 30 days prior to randomization.
3. Participants who have been inpatient at a referral hospital for \>7 days prior to transfer.
4. Pregnancy, planned pregnancy, potential for pregnancy (e.g., unwillingness to use effective birth control during the study), or current or planned breast feeding.
5. Abstinence from alcohol consumption for \>2 months before Day 1.
6. AST or ALT \>400 U/L.
7. Cohort 1 through Cohort 4: mDF \<32 or \>70.
8. Cohort 5 and Cohort 6: mDF \<32
9. Cohort 1 through Cohort 4: MELD score \<18 or \>25.
10. Cohort 5 and Cohort 6: MELD \<21 or \>30
11. Other causes of liver disease including chronic hepatitis B (hepatitis B surface antigen \[HBsAg\] positive), chronic hepatitis C virus (HCV) RNA positive, drug-induced liver injury (DILI), biliary obstruction, and autoimmune liver disease.
12. Current or previous history of hepatocellular carcinoma (HCC)
13. History of liver transplantation or currently listed for liver transplant
14. Untreated infection (e.g., has not initiated appropriate medical treatment for infection)
15. Known positivity for human immunodeficiency virus infection
16. Uncontrolled gastrointestinal (GI) bleeding or controlled GI bleeding that was associated with shock or required transfusion of more than 3 units of blood within 7 days of Screening.
17. Kidney injury defined as a serum creatinine \>133 μmol/L (\>1.5 mg/dL) or the requirement for renal replacement therapy whether prior to or after study screening.
18. Portal vein thrombosis
19. Acute pancreatitis or acute gallbladder disease (e.g., cholecystitis)
20. Severe, on-going associated disease (e.g., cardiac failure, acute myocardial infarction, severe cardiac arrhythmias, severe pulmonary disease, neurologic disease)
21. Malignancy within the 2 years prior to Screening, with the exception of specific cancers that have been cured by surgical resection (e.g., basal cell skin cancer). Participants under evaluation for possible malignancy are not eligible.
22. Positive urine drug screen (amphetamines, barbiturates, benzodiazepines, cocaine, and opiates) except tetrahydrocannabinol or in the setting of documented prescription medications (e.g., opiates, benzodiazepines, amphetamines, barbiturates), which also include medications prescribed as part of in-patient management. Participants being treated for alcohol withdrawal may be exempt for this reason, verify with Medical Monitor.
23. Participated in a clinical research study and received any active investigational product being evaluated for the treatment of sAH within 3 months before Day 1
24. Participation in a study of another investigational medicine or device within 30 days before Screening
25. Any other condition or clinical laboratory result that, in the opinion of the Investigator, might confound the results, or would impede compliance or hinder completion of the study
26. Participants treated in the Dose Escalation Phase (Cohort 1 through Cohort 4) are not eligible for enrollment into an Extension Cohort (Cohort 5 and Cohort 6), and participants treated in Cohort 5 are not eligible for enrollment into Cohort 6.

Primary outcomes:
measure: Lille model response based on Lille score by treatment group
timeFrame: Day 7
Secondary outcomes:
measure: Change from baseline in the Model for End-Stage Liver Disease (MELD) score at 28-days by treatment group
timeFrame: Baseline and at Day 28
measure: Change from Baseline in total bilirubin
timeFrame: Baseline and at Day 7, 14, 21, 28, 56 and 84
measure: Difference in 28-day, 56-day, and 84-day all-cause mortality or liver transplantation (TFS) between INT-787 and placebo
timeFrame: Day 28, 56, 84
measure: Number of participants with treatment emergent adverse events (TEAEs), serious adverse events (SAEs) and treatment emergent adverse event of special interest (AESIs)
timeFrame: During the study period, up to 12 weeks
measure: Number of participants reporting infectious adverse events by System organ class (SOC)/ preferred term by treatment group
timeFrame: During the study period, up to 12 weeks
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: Stanford Healthcare
state: California
city: Miami
country: United States
facility: Clinical Translational Research Site
state: Florida
city: Tampa
country: United States
facility: Tampa General Medical Group
state: Florida
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Baltimore
country: United States
facility: Mercy Medical Center
state: Maryland
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Worcester
country: United States
facility: UMass Memorial Medical Center
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Newark
country: United States
facility: Rutgers-New Jersey Medical School
state: New Jersey
city: Manhasset
country: United States
facility: Northwell Health Center for Liver Disease and Transplantation
state: New York
city: New York
country: United States
facility: Columbia University Medical Center/New York Presbyterian Hospital
state: New York
city: Philadelphia
country: United States
facility: Hospital of the University of Pennsylvania
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt Digestive Disease Center
state: Tennessee
city: Dallas
country: United States
facility: The Liver Institute at Methodist Dallas Medical Center
state: Texas
city: Dallas
country: United States
facility: Parkland Health and Hospital System
state: Texas
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah Hospital
state: Utah
city: Richmond
country: United States
facility: VCU Health Clinical Research Services Unit
state: Virginia
city: Angers
country: France
facility: CHU Angers
city: Clichy
country: France
facility: Hopital Beaujon
city: Lille
country: France
facility: Hopital Claude Huriez
city: Paris
country: France
facility: Hopital Pitie Salpetriere
city: Toulouse
country: France
facility: Hopital Rangueil
city: Cambridge
country: United Kingdom
facility: Cambridge University NHS Foundation Trust
city: London
country: United Kingdom
facility: Royal Free Hospital
city: London
country: United Kingdom
facility: Imperial College Healthcare NHS Trust
city: London
country: United Kingdom
facility: King's College Hospital
city: Plymouth
country: United Kingdom
facility: University Hospitals Plymouth NHS Trust
Study officials:
References: