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

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

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).

Study Overview

• Status: Completed
• Conditions: Alcoholic Hepatitis
• Intervention / Treatment: Drug: DUR-928 30 mg; Drug: DUR-928 90 mg; Drug: DUR-928 150 mg

• Study Type: Interventional
• Enrollment (Actual): 19
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • San Diego, California, United States, 92118
      • DURECT Study Site 0001
  • Florida
    • Miami, Florida, United States, 33136
      • DURECT Study Site 007
  • Georgia
    • Atlanta, Georgia, United States, 30309
      • DURECT Study Site 0004
  • Illinois
    • Chicago, Illinois, United States, 60611
      • DURECT Study Site 0002
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • DURECT Study Site 008
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • DURECT Study Site 0005
  • Texas
    • San Antonio, Texas, United States, 78215
      • DURECT Study Site 006

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.
5. Women of child-bearing potential must utilize appropriate birth control throughout the study duration.
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
   2. Wilson disease
   3. Vascular liver disease
   4. Drug induced liver disease
2. Co-infection with human immunodeficiency virus (HIV) or Hepatitis B
3. Any active malignancies other than curatively treated skin cancer (basal cell or squamous cell carcinomas)
4. If female, known pregnancy, or has a positive serum pregnancy test, or lactating/breastfeeding
5. Serum creatinine > 2.5 mg/dL
6. Patients who have had organ transplantation (such as liver, kidney, lung, heart, bone marrow, or stem cell etc.), other than cornea transplant
7. Stage 3 or greater encephalopathy by West Haven criteria

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum Creatinine (sCR)	Serum Creatinine (sCR) at baseline is provided as part of the calculation for MELD	Baseline (Screening or Day 1 Pre-dose)

Collaborators and Investigators

• Sponsor: Durect
• Collaborators: CTI Clinical Trial and Consulting Services
• Investigators: Study Director: Robert Gordon, MD, CTI Clinical Trial and Consulting Services

Study record dates

Study Major Dates

• Study Start (Actual): April 18, 2018
• Primary Completion (Actual): September 9, 2019
• Study Completion (Actual): September 9, 2019

Study Registration Dates

• First Submitted: February 1, 2018
• First Submitted That Met QC Criteria: February 7, 2018
• First Posted (Actual): February 14, 2018

Study Record Updates

• Last Update Posted (Estimate): December 14, 2022
• Last Update Submitted That Met QC Criteria: November 18, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: Alcoholic Hepatitis; acute alcoholic liver disease; progressive inflammatory liver injury; IV infusion
• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Digestive System Diseases; Alcohol-Related Disorders; Substance-Related Disorders; RNA Virus Infections; Virus Diseases; Infections; Liver Diseases; Hepatitis, Viral, Human; Enterovirus Infections; Picornaviridae Infections; Liver Diseases, Alcoholic; Alcohol-Induced Disorders; Hepatitis; Hepatitis A; Hepatitis, Alcoholic
• Other Study ID Numbers: C928-010

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No