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

Primary Purpose

Alcoholic Hepatitis

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
DUR-928 30 mg
DUR-928 90 mg
DUR-928 150 mg
Sponsored by
Durect
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Alcoholic Hepatitis focused on measuring Alcoholic Hepatitis, acute alcoholic liver disease, progressive inflammatory liver injury, IV infusion

Eligibility Criteria

21 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • DURECT Study Site 0001
  • DURECT Study Site 007
  • DURECT Study Site 0004
  • DURECT Study Site 0002
  • DURECT Study Site 008
  • DURECT Study Site 0005
  • DURECT Study Site 006

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

Part A (Moderate AH) DUR-928 30 mg

Part A (Moderate AH) DUR-928 90 mg

Part A (Moderate AH) DUR-928 150 mg

Part B (Severe AH) DUR-928 30 mg

Part B (Severe AH) DUR-928 90 mg

Part B (Severe AH) DUR-928 150 mg

Arm Description

Lowest dose of 3 dose escalation arms: 30mg, 90 mg and 150 mg

Middle dose of 3 dose escalation arms: 30mg, 90 mg and 150 mg

Highest dose of dose escalation arms: 30mg, 90 mg and 150 mg

Lowest dose of dose escalation arms: 30mg, 90 mg and 150 mg

Middle dose of dose escalation arms: 30mg, 90 mg and 150 mg

Highest dose of dose escalation arms: 30mg, 90 mg and 150 mg

Outcomes

Primary Outcome Measures

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.
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.
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.

Secondary Outcome Measures

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.
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.
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.
Bilirubin - Percent Change From Baseline
ITT population

Full Information

First Posted
February 1, 2018
Last Updated
November 18, 2022
Sponsor
Durect
Collaborators
CTI Clinical Trial and Consulting Services
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1. Study Identification

Unique Protocol Identification Number
NCT03432260
Brief Title
A Research Study to Assess the Safety, Pharmacokinetics and Pharmacodynamics of DUR-928 in Patients With Alcoholic Hepatitis
Acronym
AH
Official Title
An Open- Label, Dose Escalation Study to Assess the Safety, Pharmacokinetics and Pharmacodynamic Signals of DUR-928 in Patients With Alcoholic Hepatitis
Study Type
Interventional

2. Study Status

Record Verification Date
November 2022
Overall Recruitment Status
Completed
Study Start Date
April 18, 2018 (Actual)
Primary Completion Date
September 9, 2019 (Actual)
Study Completion Date
September 9, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Durect
Collaborators
CTI Clinical Trial and Consulting Services

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Alcoholic Hepatitis
Keywords
Alcoholic Hepatitis, acute alcoholic liver disease, progressive inflammatory liver injury, IV infusion

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
Staggered parallel design.
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
19 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Part A (Moderate AH) DUR-928 30 mg
Arm Type
Experimental
Arm Description
Lowest dose of 3 dose escalation arms: 30mg, 90 mg and 150 mg
Arm Title
Part A (Moderate AH) DUR-928 90 mg
Arm Type
Experimental
Arm Description
Middle dose of 3 dose escalation arms: 30mg, 90 mg and 150 mg
Arm Title
Part A (Moderate AH) DUR-928 150 mg
Arm Type
Experimental
Arm Description
Highest dose of dose escalation arms: 30mg, 90 mg and 150 mg
Arm Title
Part B (Severe AH) DUR-928 30 mg
Arm Type
Experimental
Arm Description
Lowest dose of dose escalation arms: 30mg, 90 mg and 150 mg
Arm Title
Part B (Severe AH) DUR-928 90 mg
Arm Type
Experimental
Arm Description
Middle dose of dose escalation arms: 30mg, 90 mg and 150 mg
Arm Title
Part B (Severe AH) DUR-928 150 mg
Arm Type
Experimental
Arm Description
Highest dose of dose escalation arms: 30mg, 90 mg and 150 mg
Intervention Type
Drug
Intervention Name(s)
DUR-928 30 mg
Intervention Description
Lowest dose of 3 dose escalation arms.
Intervention Type
Drug
Intervention Name(s)
DUR-928 90 mg
Intervention Description
Middle dose of 3 dose escalation arms.
Intervention Type
Drug
Intervention Name(s)
DUR-928 150 mg
Intervention Description
Highest dose of 3 dose escalation arms.
Primary Outcome Measure Information:
Title
Lille Model for Alcoholic Hepatitis Score
Description
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.
Time Frame
Day 7
Title
Model for End Stage Liver Disease (MELD) Score
Description
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.
Time Frame
Baseline (Screening or Day 1 Pre-dose), Day 7 and Day 28
Title
Model for End Stage Liver Disease (MELD) Score - Percent Change From Baseline
Description
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.
Time Frame
Baseline (Screening or Day 1 Pre-dose), Day 7 and Day 28
Secondary Outcome Measure Information:
Title
Serum Cytokeratin 18 (M30)
Description
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.
Time Frame
Baseline (Screening or Day 1 Pre-dose), Day 7, Day 28
Title
Serum Cytokeratin 18 (M65)
Description
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.
Time Frame
Baseline (Screening or Day 1 Pre-dose), Day 7, Day 28
Title
International Normalized Ratio (INR) - Percent Change From Baseline
Description
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.
Time Frame
Baseline (Screening or Day 1 Pre-dose), Day 7, Day 28
Title
Bilirubin - Percent Change From Baseline
Description
ITT population
Time Frame
Baseline (Screening or Day 1 Pre-dose), Day 7, Day 28
Other Pre-specified Outcome Measures:
Title
Serum Creatinine (sCR)
Description
Serum Creatinine (sCR) at baseline is provided as part of the calculation for MELD
Time Frame
Baseline (Screening or Day 1 Pre-dose)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
21 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Robert Gordon, MD
Organizational Affiliation
CTI Clinical Trial and Consulting Services
Official's Role
Study Director
Facility Information:
Facility Name
DURECT Study Site 0001
City
San Diego
State/Province
California
ZIP/Postal Code
92118
Country
United States
Facility Name
DURECT Study Site 007
City
Miami
State/Province
Florida
ZIP/Postal Code
33136
Country
United States
Facility Name
DURECT Study Site 0004
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30309
Country
United States
Facility Name
DURECT Study Site 0002
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
DURECT Study Site 008
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46202
Country
United States
Facility Name
DURECT Study Site 0005
City
Louisville
State/Province
Kentucky
ZIP/Postal Code
40202
Country
United States
Facility Name
DURECT Study Site 006
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78215
Country
United States

12. IPD Sharing Statement

Learn more about this trial

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

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