A Research Study to Assess the Safety, Pharmacokinetics and Pharmacodynamics of DUR-928 in Patients With Alcoholic Hepatitis

Study Overview
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Brief Summary
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This is a research trial testing DUR-928 (an experimental medication). The purpose of this trial is to assess the dose related safety, Pharmacokinetics, and Pharmacodynamics of DUR 928 in patients with moderate and severe alcoholic hepatitis (AH).

Official Title
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An Open- Label, Dose Escalation Study to Assess the Safety, Pharmacokinetics and Pharmacodynamic Signals of DUR-928 in Patients With Alcoholic Hepatitis

Conditions
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Alcoholic Hepatitis

Intervention / Treatment
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* Drug: DUR-928 30 mg
* Drug: DUR-928 90 mg
* Drug: DUR-928 150 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able to provide written informed consent (either from patient or patient's legally acceptable representative) Male or female patients 21 years of age or older with BMI ≥ 20 to ≤ 40 kg/m2 Patients with alcoholic hepatitis defined as: History of heavy alcohol abuse: > 40 g/day in females or > 60 g/day in males for a minimum period of 6 months, AND Consumed alcohol within 12 weeks of entry into the study, AND Serum bilirubin > 3 mg/dL AND AST > ALT, but less than 300 U/L AND MELD score between 11-30, inclusive No evidence of active infection as determined by the investigator. Women of child-bearing potential must utilize appropriate birth control throughout the study duration. Male patients must agree to use a medically acceptable method of contraception/birth control throughout the study duration Exclusion Criteria: Other or concomitant cause(s) of liver disease as a result of: Autoimmune liver disease Wilson disease Vascular liver disease Drug induced liver disease Co-infection with human immunodeficiency virus (HIV) or Hepatitis B Any active malignancies other than curatively treated skin cancer (basal cell or squamous cell carcinomas) If female, known pregnancy, or has a positive serum pregnancy test, or lactating/breastfeeding Serum creatinine > 2.5 mg/dL Patients who have had organ transplantation (such as liver, kidney, lung, heart, bone marrow, or stem cell etc.), other than cornea transplant Stage 3 or greater encephalopathy by West Haven criteria

Ages Eligible for Study
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Minimum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Staggered parallel design.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A (Moderate AH) DUR-928 30 mg<br>Lowest dose of 3 dose escalation arms: 30mg, 90 mg and 150 mg | Drug: DUR-928 30 mg<br>* Lowest dose of 3 dose escalation arms.<br>|
| Experimental: Part A (Moderate AH) DUR-928 90 mg<br>Middle dose of 3 dose escalation arms: 30mg, 90 mg and 150 mg | Drug: DUR-928 90 mg<br>* Middle dose of 3 dose escalation arms.<br>|
| Experimental: Part A (Moderate AH) DUR-928 150 mg<br>Highest dose of dose escalation arms: 30mg, 90 mg and 150 mg | Drug: DUR-928 150 mg<br>* Highest dose of 3 dose escalation arms.<br>|
| Experimental: Part B (Severe AH) DUR-928 30 mg<br>Lowest dose of dose escalation arms: 30mg, 90 mg and 150 mg | Drug: DUR-928 30 mg<br>* Lowest dose of 3 dose escalation arms.<br>|
| Experimental: Part B (Severe AH) DUR-928 90 mg<br>Middle dose of dose escalation arms: 30mg, 90 mg and 150 mg | Drug: DUR-928 90 mg<br>* Middle dose of 3 dose escalation arms.<br>|
| Experimental: Part B (Severe AH) DUR-928 150 mg<br>Highest dose of dose escalation arms: 30mg, 90 mg and 150 mg | Drug: DUR-928 150 mg<br>* Highest dose of 3 dose escalation arms.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Lille Model for Alcoholic Hepatitis Score | The Lille score predicts response of AH subjects to treatment with glucocorticoids, such as prednisolone. This score is based on age, serum albumin, creatinine, PT, and the difference in bilirubin between pre-treatment and Day 7 post-treatment. The Lille score ranges from 0.01 to 1.00. A score >0.45 predicts a higher risk of death and the recommendation to stop steroid administration. Lille Score = Exp(-R)/(1 + Exp(-R)) Where: R = [3.19 - (0.101 x Age in years)] + (1.47 x Albumin in g/dL) + [0.28215 x (Bilirubin initial - Bilirubin day 7 in mg/dL)] - (0.206 x Creatinine in mg/dL) - (0.11115 x Bilirubin initial in mg/dL) - (0.0096 x PT in seconds) NOTE: When calculating Lille, use baseline values for ALL parameters EXCEPT bilirubin at Day 7. Baseline would be the Day 1 Pre-dose sample result, if available. If not available, then use the Screening sample result. | Day 7 | 
| Model for End Stage Liver Disease (MELD) Score | The MELD score at enrollment is a good predictor for AH patient prognosis. Laboratory values for international normalized ratio (INR), serum creatinine (sCr) and bilirubin are used to calculate the MELD score. The MELD score ranges from 6.0 to 40.0 (capped) with a higher score predicting a higher risk of death. A sequentially improving MELD score is associated with a better chance of recovery. MELD score will be calculated using the original formula (pre-2016) which does not include serum sodium level. Original MELD Score = (0.957 x Ln(Serum Creatinine in mg/dL) + 0. 378 x Ln(Serum Bilirubin in mg/dL) + 1.120 x Ln (INR) + 0.643) x 10 Note: (1) If patient received two or more dialysis treatments within the prior 7 days, then the value for serum creatinine will be set to 4.0. (2) If any laboratory value is less than 1.0, the value will be set to 1.0 for the MELD score calculation, in order to avoid negative values resulting from taking the natural log of values less than 1. | Baseline (Screening or Day 1 Pre-dose), Day 7 and Day 28 | 
| Model for End Stage Liver Disease (MELD) Score - Percent Change From Baseline | The MELD Score %change from baseline is a %change between 2 time points, baseline and value at a specific time point (Day 7 or Day 28). MELD score is a good predictor of outcome. A declining MELD score suggests disease improvement. Lab values for international normalized ratio (INR), serum creatinine (sCr) and bilirubin are used to calculate the MELD score. MELD score will be calculated using the original formula (pre-2016) which does not include serum sodium level. Original MELD Score = (0.957 x Ln(Serum Creatinine in mg/dL) + 0. 378 x Ln(Serum Bilirubin in mg/dL) + 1.120 x Ln (INR) + 0.643) x 10 Note: (1) If patient received two or more dialysis treatments within the prior 7 days, then the value for serum creatinine will be set to 4.0. (2) If any laboratory value is less than 1.0, the value will be set to 1.0 for the MELD score calculation, in order to avoid negative values resulting from taking the natural log of values less than 1. | Baseline (Screening or Day 1 Pre-dose), Day 7 and Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum Cytokeratin 18 (M30) | Analysis Population Description: Analysis has been severely delayed due to unavailable testing reagents. Baseline was defined as the last non-missing value prior to study drug administration, at Screening or Day 1 Pre-dose. | Baseline (Screening or Day 1 Pre-dose), Day 7, Day 28 | 
| Serum Cytokeratin 18 (M65) | Analysis Population Description: Analysis has been severely delayed due to unavailable testing reagents. Baseline was defined as the last non-missing value prior to study drug administration, at Screening or Day 1 Pre-dose. | Baseline (Screening or Day 1 Pre-dose), Day 7, Day 28 | 
| International Normalized Ratio (INR) - Percent Change From Baseline | ITT population. INR (international normalized ratio) is a standardized number based on the prothrombin time and calculated by the clinical lab. INR measures the time it takes for blood to clot in vitro and measures, among other things, liver synthetic function. | Baseline (Screening or Day 1 Pre-dose), Day 7, Day 28 | 
| Bilirubin - Percent Change From Baseline | ITT population | Baseline (Screening or Day 1 Pre-dose), Day 7, Day 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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acute alcoholic liver disease, progressive inflammatory liver injury, IV infusion, Alcoholic Hepatitis