FXR Effect on Severe Alcohol-Associated Hepatitis (FRESH) Study (FRESH)

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

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).

Study Overview

• Status: Recruiting
• Conditions: Alcohol Associated Hepatitis
• Intervention / Treatment: Drug: Placebo; Drug: INT-787

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.

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Steven Lauder; Phone Number: 858-652-6800; Email: steven.lauder@interceptpharma.com
• Study Contact Backup: Name: Thomas Capozza; Phone Number: 646-747-1000; Email: thomas.capozza@interceptpharma.com

Study Locations

• France
  • Angers, France, 49933
    • Recruiting
    • Chu Angers
    • Principal Investigator: Jerome Boursier
    • Contact: CHU Angers
  • Clichy, France, 92118
    • Recruiting
    • Hopital Beaujon
    • Principal Investigator: Francois Durand
    • Contact: Hopital Beaujon
  • Lille, France, 59037
    • Recruiting
    • Hopital Claude Huriez
    • Principal Investigator: Philippe Mathurin
    • Contact: Hopital Claude Huriez
  • Paris, France, 75013
    • Recruiting
    • Hopital Pitie Salpetriere
    • Principal Investigator: Marika Rudler
    • Contact: Hopital Pitie Salpetriere
  • Toulouse, France, 31059
    • Recruiting
    • Hopital Rangueil
    • Principal Investigator: Christophe Bureau
    • Contact: Hopital Rangueil
• United Kingdom
  • Cambridge, United Kingdom
    • Recruiting
    • Cambridge University NHS Foundation Trust
    • Principal Investigator: Michael Allison
    • Contact: Cambridge University NHS Foundation Trust
  • London, United Kingdom
    • Recruiting
    • Imperial College Healthcare NHS Trust
    • Contact: Imperial College Healthcare NHS Trust
    • Principal Investigator: Mark Thursz
  • Plymouth, United Kingdom
    • Recruiting
    • University Hospitals Plymouth NHS Trust
    • Principal Investigator: Ashwin Dhanda
    • Contact: University Hospitals Plymouth NHS Trust
• United States
  • Florida
    • Miami, Florida, United States, 33136
      • Recruiting
      • Clinical Translational Research Site
      • Principal Investigator: Paul Martin, MD
      • Contact: Clinical Translational Research Site
    • Tampa, Florida, United States, 33606
      • Recruiting
      • Tampa General Medical Group
      • Contact: Tampa General Medical Group
      • Principal Investigator: Nyingi M Kemmer, MD
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Recruiting
      • Rush University Medical Center
      • Contact: Rush University Medical Center
      • Principal Investigator: Steven Flamm
  • Maryland
    • Baltimore, Maryland, United States, 21202
      • Recruiting
      • Mercy Medical Center
      • Contact: Mercy Medical Center
      • Principal Investigator: Paul Thuluvath, M.D.
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Recruiting
      • Beth Israel Deaconess Medical Center
      • Principal Investigator: Michael Curry, MD
      • Contact: Beth Israel Deaconess Medical Center
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Recruiting
      • Henry Ford Health System
      • Contact: Henry Ford Health System
      • Principal Investigator: Syed-Mohammed Jafri, MD
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Recruiting
      • Mayo Clinic
      • Principal Investigator: Douglas Simonetto, MD
      • Contact: Mayo Clinic Hospital
  • New Jersey
    • Newark, New Jersey, United States, 07103
      • Recruiting
      • Rutgers-New Jersey Medical School
      • Contact: Rutgers New Jersey Medical School
      • Principal Investigator: Nikolaos Pyrsopoulos, MD
  • New York
    • Manhasset, New York, United States, 11030
      • Recruiting
      • Northwell Health Center for Liver Disease and Transplantation
      • Contact: Northwell Health Center for Liver Disease and Transplantation
      • Principal Investigator: Sanjaya Satapathy, MD
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Recruiting
      • Hospital of the University of Pennsylvania
      • Principal Investigator: Ethan Weinberg, MD
      • Contact: Hospital of the University of Pennsylvania
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Recruiting
      • Medical University of South Carolina
      • Contact: Medical University of South Carolina
      • Principal Investigator: Donald Rockey, MD
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Recruiting
      • Vanderbilt Digestive Disease Center
      • Principal Investigator: Manhal Izzy, MD
      • Contact: Vanderbilt Digestive Disease Center
  • Texas
    • Dallas, Texas, United States, 75390
      • Recruiting
      • University of Texas Southwestern Medical Center
      • Principal Investigator: Thomas G Cotter, MD
      • Contact: University of Texas Southwestern Medical Center
    • Dallas, Texas, United States, 75203
      • Recruiting
      • The Liver Institute At Methodist Dallas Medical Center
      • Contact: The Liver Institute at Methodist Dallas Medical Center
      • Principal Investigator: Parvez S Mantry, MD
    • Dallas, Texas, United States, 75235
      • Recruiting
      • Parkland Health and Hospital System
      • Contact: Parkland Health Hospital System
      • Principal Investigator: Thomas G Cotter, MD
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Recruiting
      • VCU Health Clinical Research Services Unit
      • Contact: VCU Health Clinical Research Services Unit
      • Principal Investigator: Amon Asgharpour, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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. Maddrey's Discriminant Factor (mDF) ≥32 and ≤70
3. MELD score 18 to 25 (inclusive)

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: 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. mDF <32 or >70 at Screening
8. MELD score <18 or >25 at Screening.
9. 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.
10. Current or previous history of hepatocellular carcinoma (HCC)
11. History of liver transplantation or currently listed for liver transplant
12. Untreated infection (e.g., has not initiated appropriate medical treatment for infection)
13. Known positivity for human immunodeficiency virus infection
14. 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.
15. Kidney injury defined as a serum creatinine >133 μmol/L (>1.5 mg/dL) or the requirement for renal replacement therapy.
16. Portal vein thrombosis
17. Acute pancreatitis or acute gallbladder disease (e.g., cholecystitis)
18. Severe, on-going associated disease (e.g., cardiac failure, acute myocardial infarction, severe cardiac arrhythmias, severe pulmonary disease, neurologic disease)
19. 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.
20. 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.
21. 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
22. Participation in a study of another investigational medicine or device within 30 days before Screening
23. 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: INT-787; Participants will be randomized to receive INT-787 (escalating doses through the cohorts)	Drug: INT-787; Blinded Study Drug
Placebo Comparator: Placebo; Participants will be randomized to receive matching placebo	Drug: Placebo; Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Lille model response based on Lille score by treatment group	The Lille score response rate will be analyzed as a categorical variable. Participants with Lille score <0.45 will be counted as responders and those with Lille score ≥0.45 will be counted as non-responders.	Day 7

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference in 28-day, 56-day, and 84-day mortality or liver transplantation between INT-787 and placebo		Day 28, 56, 84
Total exposure (area under the curve) for INT-787, tauro-INT-787 and glyco-INT-787		During the study period, up to 12 weeks
Maximum Plasma Concentration (Cmax) for INT-787, tauro-INT-787 and glyco-INT-787		During the study period, up to 12 weeks
Elimination half-life for INT-787		During the study period, up to 12 weeks
Change from Baseline in total bilirubin		Baseline and at Day 7, 14, 21, 28
Number of participants with treatment emergent adverse events (TEAEs), serious adverse events (SAEs) and treatment emergent adverse event of special interest (AESIs)		During the study period, up to 12 weeks
Number of participants reporting infectious adverse events by System organ class (SOC)/ preferred term by treatment group		During the study period, up to 12 weeks
Change from baseline in the Model for End-Stage Liver Disease (MELD) score at 28-days by treatment group	The MELD scoring system is used to assess the severity of liver disease in participants in the setting of alcohol-associated hepatitis. The MELD score is derived from the participant's serum total bilirubin, serum creatinine, and international normalized ratio (INR). The MELD score ranges from 6 to 40 with higher scores indicating more severe liver disease and a worse outcome.	Baseline and at Day 28

Collaborators and Investigators

• Sponsor: Intercept Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): December 15, 2022
• Primary Completion (Estimated): December 31, 2024
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: November 9, 2022
• First Submitted That Met QC Criteria: November 28, 2022
• First Posted (Actual): December 6, 2022

Study Record Updates

• Last Update Posted (Actual): April 5, 2024
• Last Update Submitted That Met QC Criteria: April 4, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Hepatitis; Alcoholic; Severe Alcohol associated Hepatitis (sAH); Alcoholic Hepatitis (AH)
• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Liver Diseases; Hepatitis, Viral, Human; Enterovirus Infections; Picornaviridae Infections; Hepatitis; Hepatitis A
• Other Study ID Numbers: 787-201

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No