DUR-928 in Patients With Alcoholic Hepatitis

The proposed study is An Open-Label, Dose Escalation Study to Assess the Safety, and Pharmacodynamics (PD) signals of DUR 928 in Patients with AH. DUR-928 will be administered in 100 mL 5% dextrose or 0.9% sodium chloride by slow intravenous infusion over 2 hrs (50mL/h) until entire dose is given at Day 1 and Day 4. If a patient meets the hospital discharge criteria prior to the 2nd dose, the patient will receive only one dose of DUR-928 instead of 2 doses.

The study will be conducted in 2 Parts using a staggered parallel design. Part A will include patients with MELD scores of 11-20, and Part B will include patients with MELD of scores 21-30.

Within each Part, the study will be conducted using a starting dose level of 30 mg with sequential dose escalation following review of safety results of the prior dose level by the sponsor, the principal investigators. The planned subsequent doses of DUR-928 after the starting dose are 90 mg and 150 mg.

Patients with a MELD score of 21-30 (Part B) receiving the 30 mg dose level will only be enrolled once safety review of the 30 mg dose of DUR-928 in patients with MELD score 11-20 (Part A) has been completed. The subsequent dose escalation in Part B will not proceed until the sponsor, and the principal investigators, and the medical monitor complete the review of safety of the 30 mg dose level and determine it is safe to do so.

At each dose level within a Part, 4 patients will be treated. If no SUSAR is observed, dose escalation to the next dose cohort within the Part will proceed. If 1 of the 4 patients demonstrates a SUSAR in a given dose level, an additional 2 patients will be treated at that dose level. If only 1 of the 6 patients demonstrates SUSAR, the next cohort of four patients will enter at the next dose level. If 6 patients are dosed and 2 or more demonstrate SUSAR at that dose level, the study will deescalate to a lower dose (but higher than the previous dose). At subsequent dose levels, the maximum tolerated dose (MTD) is defined as the dose level where no more than 1 of 6 patients experiences a SUSAR.

If no SUSAR is observed, dose escalation to the next dose cohort will proceed. All patients will be followed up to Day 28 (Total duration of patient engagement is 33 days).

Trial Population:

Patients with AH will be enrolled at Louisville associated hospitals in the US. The target number of participants to complete the study is 24-36. During the trial, patients should receive standard of care as determined by the PI (e.g. pentoxifylline or corticosteroids).

Eligibility Criteria:
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 ≤ 40 kg/m2
3. Patients with alcoholic hepatitis defined as:

   1. History of heavy alcohol abuse: \> 40 g/day in females or \> 60 g/day in males for a minimum period of 6 months, AND
   2. Consumed alcohol within 12 weeks of entry into the study, AND
   3. Serum bilirubin \> 3 mg/dL AND AST \> ALT, but less than 300 U/L AND
   4. MELD score between 11-30, inclusive
4. No evidence of active infection as determined by the investigator. If infection is initially suspected clinically,

   1. blood cultures, urine cultures, and peritoneal cultures should be without growth for 48 hrs, AND
   2. peritoneal cell count should be less than 250 Polymorphonuclear cell (PMN)/ml. If infection is diagnosed, then the infection must be

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   1. treated with antibiotics, AND
   2. documented negative blood cultures for 48 hrs, or for spontaneous bacterial peritonitis (SBP) 25% reduction in PMN count prior to enrollment.
5. 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.
6. Male patients must agree to use a medically acceptable method of contraception/birth control throughout the study duration.

Exclusion Criteria:

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

   1. Autoimmune liver disease (positive anti-mitochondrial antibody and smooth muscle antibody, positive reading on anti-nuclear antibody titer \> 1:160)
   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.
2. Co-infection with human immunodeficiency virus (HIV)
3. Positive Urine Drug Screen (amphetamines, barbiturates, benzodiazepines, cocaine and opiates) except THC and legal prescription medications.
4. 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
5. Active tuberculosis on chest x-ray at study entry
6. 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
7. Patients requiring the use of vasopressors or inotropic support. Prior use of inotropic support will be allowed if the condition has stabilized within the first 7 days of admission to the hospital
8. Liver biopsy, if carried out, showing findings not compatible with AH
9. Any patient that has received any investigational drug or device within 30 days of dosing or who is scheduled to receive another investigational drug or device at any time during the study
10. Patients who are taking drug products that are primarily the substrates of CYP2C8, such as chloroquine, paclitaxel, rosiglitazone, repaglinide
11. If female, known pregnancy, or has a positive serum pregnancy test, or is lactating/breastfeeding
12. Serum creatinine \> 2.5 mg/dL
13. Patients who have had organ transplantation (such as liver, kidney, lung, heart, bone marrow, or stem cell etc.), other than cornea transplant
14. Stage 3 or greater encephalopathy by West Haven criteria