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

Phase 2

Completed

• Conditions: Alcoholic Hepatitis
• Interventions: Drug: DUR-928 90 mg; Drug: DUR-928 150 mg; Drug: DUR-928 30 mg

• Registration Number: NCT03432260
• Lead Sponsor: Durect

Brief Summary

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).

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2018-02-01
• Study First Submitted QC: 2018-02-07
• Study First Posted: 2018-02-14
• Study Start: 2018-04-18
• Primary Completion: 2019-09-09
• Study Completion: 2019-09-09
• Disposition First Submitted: 2020-10-01
• Results First Submitted: 2022-09-29
• Status Verified: 2022-11
• Results First Submitted QC: 2022-11-18
• Disposition First Submitted QC: 2022-11-18
• Last Update Submitted: 2022-11-18
• Results First Posted: 2022-12-14
• Disposition First Posted: 2022-12-14
• Last Update Posted: 2022-12-14

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 19

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Part B (Severe AH) DUR-928 90 mg	DUR-928 90 mg	Middle dose of dose escalation arms: 30mg, 90 mg and 150 mg
Part A (Moderate AH) DUR-928 150 mg	DUR-928 150 mg	Highest dose of dose escalation arms: 30mg, 90 mg and 150 mg
Part B (Severe AH) DUR-928 30 mg	DUR-928 30 mg	Lowest dose of dose escalation arms: 30mg, 90 mg and 150 mg
Part A (Moderate AH) DUR-928 30 mg	DUR-928 30 mg	Lowest dose of 3 dose escalation arms: 30mg, 90 mg and 150 mg
Part B (Severe AH) DUR-928 150 mg	DUR-928 150 mg	Highest dose of dose escalation arms: 30mg, 90 mg and 150 mg
Part A (Moderate AH) DUR-928 90 mg	DUR-928 90 mg	Middle dose of 3 dose escalation arms: 30mg, 90 mg and 150 mg

Primary Outcome Measures

Name	Time	Method
Model for End Stage Liver Disease (MELD) Score	Baseline (Screening or Day 1 Pre-dose), Day 7 and Day 28	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.
Model for End Stage Liver Disease (MELD) Score - Percent Change From Baseline	Baseline (Screening or Day 1 Pre-dose), Day 7 and Day 28	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.
Lille Model for Alcoholic Hepatitis Score	Day 7	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.

Secondary Outcome Measures

Name	Time	Method
Serum Cytokeratin 18 (M30)	Baseline (Screening or Day 1 Pre-dose), Day 7, Day 28	Analysis Population Description: Baseline was defined as the last non-missing value prior to study drug administration, at Screening or Day 1 Pre-dose.
Serum Cytokeratin 18 (M65)	Baseline (Screening or Day 1 Pre-dose), Day 7, Day 28	Analysis Population Description: Baseline was defined as the last non-missing value prior to study drug administration, at Screening or Day 1 Pre-dose.
International Normalized Ratio (INR) - Percent Change From Baseline	Baseline (Screening or Day 1 Pre-dose), Day 7, Day 28	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.
Bilirubin - Percent Change From Baseline	Baseline (Screening or Day 1 Pre-dose), Day 7, Day 28	ITT population

Trial Locations

Locations (7)

DURECT Study Site 0004; 🇺🇸 Atlanta, Georgia, United States

DURECT Study Site 0002; 🇺🇸 Chicago, Illinois, United States

DURECT Study Site 0005; 🇺🇸 Louisville, Kentucky, United States

DURECT Study Site 006; 🇺🇸 San Antonio, Texas, United States

DURECT Study Site 0001; 🇺🇸 San Diego, California, United States

DURECT Study Site 007; 🇺🇸 Miami, Florida, United States

DURECT Study Site 008; 🇺🇸 Indianapolis, Indiana, United States