A Phase 2b Study in Subjects With Alcoholic Hepatitis to Evaluate Safety and Efficacy of DUR-928 Treatment

Phase 1

• Conditions: Alcoholic hepatitis; Therapeutic area: Diseases [C] - Nutritional and Metabolic Diseases [C18]; MedDRA version: 20.0Level: LLTClassification code 10001624Term: Alcoholic hepatitisSystem Organ Class: 100000004871

• Registration Number: EUCTR2020-004534-38-DE
• Lead Sponsor: DURECT Corporation

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2021-06-24
• Last Update Posted: 3 October 2023

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 300

Inclusion Criteria

1. Able to provide written informed consent (either from subject or subject’s legally acceptable representative)
2. Onset of jaundice within prior 8 weeks
3. Average daily consumption of > 40 (females) or > 60 (males) grams alcohol for 6 months or longer, with < 8 weeks of abstinence before the onset of jaundice. Judgment regarding daily and long-term alcohol use and onset of jaundice will be made by the site investigator.
4. The determination of AH may be based on typical serum chemistry (as determined by local laboratory) or liver biopsy at any time during the current episode of AH:
• Serum total bilirubin > 3.0 mg/dL
• 50 < AST < 400 IU/L
• ALT < 400 IU/L
• AST/ALT > 1.5
NOTE: Labs values on the day of randomization must include serum total bilirubin > 3.0 mg/dL and AST and ALT < 400 IU/L in addition to the MDF and MELD values in inclusion 5 and 6 below.
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.
6. Model for End-stage Liver Disease (MELD) score: 21-30
7. Liver biopsy is not required, but may be used to confirm the diagnosis of AH at the Investigator’s discretion. Biopsy, if used as a diagnostic criterion, must have occurred during the current episode. NOTE: Liver biopsy is not a study procedure and will not be reimbursed.
8. Male or female subjects 18 years of age or older
9. Women of child-bearing potential (defined as females who are not surgically sterile [i.e. hysterectomy, bilateral salpingectomy and/or bilateral oophorectomy] or who are not over the age of 52 and amenorrheic for at least 12 months) must utilize highly effective birth control methods (i.e. methods that can achieve a failure rate of less than 1% per year when used consistently and correctly) throughout the study duration. Highly effective birth control methods that may be used are: combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable),intrauterine device (IUD) (coil), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, sexual abstinence, or sexual activity limited to a vasectomized male partner with medical assessment of surgical success.
NOTE: Sexual abstinence should only be used as a contraceptive method if it is in line with the subject’s usual and preferred lifestyle. Periodic abstinence (calendar, symptothermal, post-ovulation methods) is not an acceptable method of contraception.
10. Male subjects must agree to use a medically acceptable method of contraception/birth control and refrain from sperm donation throughout the study duration
11. Subjects must agree to participate in an alcohol abstinence support program recommended by the local institution’s addiction specialists
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 200
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 100

Exclusion Criteria

1. Subjects taking systemic corticosteroids for a duration exceeding 8 days in the 30 days prior to screening. NOTE: Inhaled, topical, or local corticosteroid injections are permitted
2. Subjects 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], bacteremia, acute viral hepatitis, uncontrolled HIV, and active SARS CoV2 infection).
a. Subjects 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.
b. Patients with bacterial peritonitis may be considered for enrollment once the infection has been treated and follow up paracentesis confirms the absence of SBP.
c. Patients with fungal infection of any kind cannot be considered for this trial.
4. Serum creatinine >2.5 mg/dL
5. Criterion removed as part of Protocol Amendment 2, but placeholder kept to maintain consistency in subsequent criteria numbering
6. Subjects undergoing continuous veno-venous hemodialysis (CVVH)
7. Uncontrolled gastrointestinal bleeding
8. A history of pre-admission refractory ascites defined as more than 4 paracenteses in the previous 8 weeks despite diuretic therapy.
9. Liver biopsy (if carried out) with findings not compatible with AH
10. Stage = 3 hepatic encephalopathy by West Haven criteria
11. Any severe concomitant cardiovascular, renal, endocrine, pulmonary (including ventilator dependent or COPD Global Obstructive Lung Disease [GOLD] stage III or IV), psychiatric disorder, or multi-organ failure
12. Other concomitant cause(s) of liver disease as a result of:
a. Autoimmune liver disease
b. Ischemic hepatitis
c. Wilson disease or alpha 1 antitrypsin deficiency
d. Vascular liver disease (e.g., Budd-Chiari)
e. Drug induced liver disease
f. Surface antigen positive hepatitis B (HBsAg+). NOTE: subjects with isolated core antibody (anti-HBc) or who are on stable antiviral medication with known viral suppression are not excluded
g. Acute hepatitis A (if test performed per SOC)
h. Acute HCV or chronic hepatitis C with a history of decompensated cirrhosis. NOTE: subjects with stable chronic HCV or successfully treated HCV are not excluded
i. Acute hepatitis E (if test performed per SOC)
j. Acute cytomegalovirus (CMV) viral hepatitis (if test performed per SOC)
k. Acute Epstein-Barr virus (EBV) viral hepatitis (if test performed per SOC)
NOTE: A spurious finding, such as the incidental finding of moderately elevated antinuclear antibody (ANA) or anti-smooth muscle antibody (ASMA) titer is not, by itself, a mandatory exclusion criterion unless accompanied by other evidence suggestive of a probable disease other than AH.
13. Any active malignancy or any malignancy diagnosed within the last five years other than curable skin cancer (basal cell or squamous cell carcinomas)
14. Positive Urine Drug Screen (amphetamines, barbiturates, benzodiazepines, cocaine and opiates) except THC and prescription medications
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 a corneal transplant
18. Underlying diseases that, in the opinion of the site investigator, might be complicated or exacerbated by proposed treatments or might confound assessment of study drug

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: Evaluate the safety and efficacy, as determined by 90-day incidence of mortality or transplant, for intravenous (IV) DUR-928 (30 mg or 90 mg) in subjects with severe alcohol-associated hepatitis, also known as severe alcoholic hepatitis, (AH) with pre-treatment Maddrey Discriminant Function (MDF) score = 32 and MELD scores 21-30;Secondary Objective: Evaluate the efficacy, as determined by 90-day mortality and 28-day mortality with or without transplant for IV DUR-928 (30 mg or 90 mg) in subjects with severe AH;Primary end point(s): Difference in 90-day mortality or transplant between IV DUR-928, 30 mg or 90 mg, and placebo;Timepoint(s) of evaluation of this end point: 90-day

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): 1. Difference in 90-day mortality between IV DUR-928, 30 mg or 90 mg, and placebo<br>2. Difference in 28-day mortality or transplant between IV DUR-928, 30 mg or 90 mg, and placebo<br>3. Difference in 28-day mortality between IV DUR-928, 30 mg or 90 mg, and placebo;Timepoint(s) of evaluation of this end point: 28-day and 90 days