Study to Evaluate the Safety and Efficacy of Larsucosterol in Participants With Alcohol-associated Hepatitis (AH)

Bausch Health

Status and phase: Enrolling; Phase 3

Conditions: Hepatitis

Treatments: Drug: Larsucosterol; Drug: Placebo

Study type: Interventional

Funder types: Industry

Identifiers

NCT07428538

LCAH3141

Details and patient eligibility

About

The primary purpose of this study is to evaluate the safety and efficacy of larsucosterol, as determined by transplant-free survival through Day 90 in participants with severe alcohol-associated hepatitis (AH) with pre-treatment Maddrey Discriminant Function (MDF) score greater than or equal to (>=) 32 and Model for End-stage Liver Disease (MELD) scores 21-30, inclusive.

Enrollment: 350 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria-

A participant will be eligible for inclusion in this study if he/she meets all the following criteria:

1. Able to provide written informed consent (either from participant or participant's legally acceptable representative).

2. Onset of jaundice within 8 weeks before hospital admission.

3. Average daily consumption of greater than (>) 40 (females) or >60 (males) grams alcohol for 6 months or longer, with less than (<) 8 weeks of abstinence before the onset of jaundice. Judgment regarding daily and long-term alcohol use and onset of jaundice will be made and documented by the site Investigator.

4. The determination of AH will be based on typical serum chemistry (as determined by local laboratory):

   1. Serum total bilirubin >3.0 milligrams per deciliter (mg/dL) (required at randomization)
   2. ALT <400 international unit per Liter (IU/L) (required at randomization)
   3. 50 <AST <400 IU/L
   4. AST <400 IU/L (required at randomization)
   5. AST >50 IU/L (at any time since current hospital admission or leading to this current hospitalization)
   6. AST/ALT >1.5 (at any time since current hospital admission or leading to this current hospitalization)

5. Maddrey discriminant function (MDF) >=32, assuming a control prothrombin time of 12 seconds.

   NOTE: If a local laboratory's control time differs from 12 seconds, then the local laboratory's control time should be used. If control time is not stated or is stated as a range, the control time should be calculated by the formula prothrombin time/INR.

6. Original Model for End-stage Liver Disease (MELD; not MELD-Na) score: 21-30 (inclusive).

7. Male or female participants 18 years of age or older.

8. 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 90-day portion of the study. Acceptable methods that may be used are abstinence, birth control pills ("The Pill") or patch, diaphragm, IUD (coil), vaginal ring, condom, surgical sterilization or progestin implant or injection, or sexual activity limited to a sterile (e.g., vasectomized) male partner.

9. Male participants must agree to use a medically acceptable method of contraception/birth control and refrain from sperm donation throughout the 90-day portion of the study.

10. Participants must agree to participate in an alcohol abstinence support program recommended by the local institution's addiction specialists.

11. Participants must be dosed within 9 calendar days (216 hours) of hospital admission inclusive of time spent in other hospital(s)

Exclusion Criteria-

A participant will be excluded from the study if he or she meets any of the following criteria:

1. Participants using systemic corticosteroids for current AH before enrollment or having a history of using systemic corticosteroids for more than 8 days in the last 30 days prior to screening.

   NOTE: Inhaled, topical, or local corticosteroid injections are permitted NOTE: A participant who has a confirmed diagnosis of hypoadrenalism and is taking a physiological replacement dose of hydrocortisone (or equivalent) is permitted to take part in the trial

2. Participants experiencing or considered at high risk for alcohol withdrawal seizures or delirium tremens.

3. Active infection (such as spontaneous bacterial peritonitis [SBP], urinary tract infection [UTI], cellulitis, pneumonia, bacteremia, acute viral hepatitis, uncontrolled HIV, and active SARS CoV2 infection).

   1. Participants who are febrile with leukocytosis are also excluded until active infection has been excluded to the satisfaction of the PI in consultation with the medical monitor.
   2. Participants with bacterial infections may be enrolled provided they remain in the enrollment window and the infection is adequately treated. For example, participants with bacterial peritonitis may be considered for enrollment once the infection has been treated and follow up paracentesis confirms the absence of SBP.
   3. Participants with systemic fungal infection of any kind cannot be considered for this trial.

4. Serum creatinine >2.5 mg/dL.

5. Participants undergoing continuous veno-venous hemodialysis (CVVH).

6. Gastrointestinal bleeding not controlled by local therapy (i.e., band ligation or injection sclerotherapy). Participant who are at high risk of rebleeding or likely in need of TIPS insertion should be excluded.

7. TIPS insertion or variceal embolization within the last 4 weeks.

8. Known portal vein occlusion.

9. A history of pre-admission refractory ascites defined as more than 4 paracenteses in the previous 8 weeks despite diuretic therapy.

10. Liver biopsy (if carried out) with findings not compatible with AH. NOTE: A post-dose liver biopsy that is not compatible with AH will not be considered a protocol deviation.

11. Stage >=3 hepatic encephalopathy by West Haven criteria.

12. Participants with medical conditions that are expected to pose a high risk of short-term (less than or equal to [<=] 90 days) mortality unrelated to alcohol-associated hepatitis, or that may confound assessment of 90-day survival in the Investigator's judgement. Examples include, but are not limited to:

    1. Severe concomitant cardiopulmonary disease (e.g., New York Heart Association [NYHA] Class III or IV heart failure)
    2. Clinically significant cardiac arrhythmia (e.g., sustained ventricular tachycardia, unmanaged atrial fibrillation, QTc >=500 msec, or high-grade AV block)
    3. Ventilator-dependent respiratory failure, or Global Initiative for Chronic Obstructive Lung Disease [GOLD] Stage III or IV chronic obstructive pulmonary disease [COPD])
    4. End-stage renal disease requiring chronic, ongoing dialysis
    5. Severe uncontrolled endocrine or metabolic disorders
    6. Severe psychiatric illness likely to interfere with study participation
    7. Hypotension/shock as defined by the North American Consortium for the study of End-stage Liver Disease (NACSELD) criteria (i.e., Mean Arterial Pressure [MAP] <60 millimeter of mercury (mmHg), despite adequate fluid resuscitation and cardiac output)

13. Other concomitant cause(s) of liver disease as a result of:

    1. Autoimmune liver disease
    2. Ischemic hepatitis
    3. Wilson disease or alpha 1 antitrypsin deficiency
    4. Vascular liver disease (e.g., Budd-Chiari)
    5. Drug induced liver disease
    6. Surface antigen positive hepatitis B (HBsAg+). NOTE: Participants with isolated core antibody (anti-HBc) or who are on stable antiviral medication with known viral suppression are not excluded, but appropriate HBV prophylaxis should be considered if steroid dosing >4 weeks is anticipated.
    7. Acute hepatitis A (if test performed per SOC)
    8. Acute HCV or chronic hepatitis C with a history of decompensated cirrhosis. NOTE: participants with stable chronic HCV or successfully treated HCV are not excluded
    9. Acute hepatitis E (if test performed per SOC)
    10. Acute cytomegalovirus (CMV) viral hepatitis (if test performed per SOC)

14. Any known active malignancy or any malignancy diagnosed within the last five years other than curable skin cancer (basal cell or squamous cell carcinomas).

15. Existing or intended pregnancy or breast feeding.

16. Participation in another interventional clinical trial within 30 days of Screening.

17. History of organ transplantation other than corneal transplant.

18. Underlying disease that, in the opinion of the site Investigator, might be complicated or exacerbated by proposed treatments or might confound assessment of study drug.

19. Participant listed for liver transplant (LT) prior to study drug administration.

20. Concern of participant's willingness and ability to be compliant with the schedule of protocol assessments, per the Investigator's judgement.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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350 participants in 2 patient groups, including a placebo group

Larsucosterol 30 mg

Experimental group

Description:

Participants will receive Larsucosterol 30 milligrams (mg) intravenous infusion on Day 1.

Treatment:

Drug: Larsucosterol

Placebo

Placebo Comparator group

Description:

Participants will receive intravenous infusion of placebo matched to Larsucosterol on Day 1.

Treatment:

Drug: Placebo