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).
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
43
A total of no more than two doses of DUR-928 will be given, with 72 hrs between each dose. A second dose of the assigned study treatment (test drug) will be repeated 3 days after Dose 1 to patients who are still hospitalized. If a patient meets the discharge criteria prior to Day 4, the patient will receive only one dose of DUR 928. Patients of Part A (MELD 11-20) will follow the dose escalation procedure based on cohort; each patient will receive an intravenous infusion dose of: * Cohort 1A: 30 mg of DUR-928in 100 mL 5% dextrose or 0.9% sodium chloride administered over approximately 2 hrs via IV infusion. * Cohort 2A: 90 mg of DUR 928 in 100 mL5% dextrose or 0.9% sodium chloride administered over approximately 2 hrs via IV infusion. * Cohort 3A: 150 mg of DUR 928 in 100 mL5% dextrose or 0.9% sodium chloride administered over approximately 2 hrs via IV infusion.
Dose escalation to the next cohort will be determined after review of safety, tolerability and pharmacokinetic data of the previous cohort. Dose escalation for Part B will follow the same requirements as for Part A. The dose levels for Part B are planned to be the same as Part A. Patients of Part B (MELD 21-30) will follow the dose escalation procedure based on cohort; each patient will receive an intravenous infusion dose of: * Cohort 1B: 30 mg of DUR-928 in 100 mL 5% dextrose or 0.9% sodium chloride administered over approximately 2 hrs via IV infusion. * Cohort 2B: 90 mg of DUR 928 in 100 mL5% dextrose or 0.9% sodium chloride administered over approximately 2 hrs via IV infusion. * Cohort 3B: 150 mg of DUR 928 in 100 mL5% dextrose or 0.9% sodium chloride administered over approximately 2 hrs via IV infusion More details on preparation and administration of study drug will be provided in the Investigation Product Manual for this study.
University of Louisville
Louisville, Kentucky, United States
Assessment of Treatment-Emergent Adverse Events
Assess the safety and tolerability of DUR-928 in patients with alcoholic hepatitis (AH) as determined by the absence of suspected unexpected serious adverse reaction (SUSAR).
Time frame: 4.5 years.
Pharmacodynamic signals of DUR-928: Model for End-Stage Liver Disease [MELD]
Drivers of the Model for End-Stage Liver Disease \[MELD\] score individually using a formula (3.78×ln\[serum bilirubin (mg/dL)\] + 11.2×ln\[INR\] + 9.57×ln\[serum creatinine (mg/dL)\] + 6.43 that incorporates following lab measures: International Normalized Ratio \[INR\], and Serum Creatinine and Serum Total Bilirubin \[units for both: mg/dl\]) at baseline, Day 7 and Day 28. Participant's involvement in study: 33 days maximum.
Time frame: 33 days.
Pharmacodynamic signals of DUR-928: Liver Biochemical Biomarker "Alanine Aminotransferase"
Improvement in liver biochemistry at baseline, Day 7 and Day 28 (Alanine Aminotransferase \[ALT, unit: IU/L\]. Participant's involvement in study: 33 days maximum.
Time frame: 33 days.
Pharmacodynamic signals of DUR-928: Liver Biochemical Biomarker "Aspartate Aminotransferase"
Improvement in liver biochemistry at baseline, Day 7 and Day 28 for Aspartate Aminotransferase \[AST, unit: IU/L\]. Participant's involvement in study: 33 days maximum.
Time frame: 33 days.
Pharmacodynamic signals of DUR-928: Liver Biochemical Biomarker "Total Bilirubin"
Improvement in liver biochemistry at baseline, Day 7 and Day 28 for Total Bilirubin \[unit: mg/dl\]. Participant's involvement in study: 33 days maximum.
Time frame: 33 days.
Pharmacodynamic signals of DUR-928: Liver Biochemical Biomarker "Albumin"
Improvement in liver biochemistry at baseline, Day 7 and Day 28 for Albumin \[unit: g/L\]. Participant's involvement in study: 33 days maximum.
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Time frame: 33 days.
Quality of life biomarkers: 36-item Short Form Survey (SF-36).
Quality of Life biomarkers (eg. SF-36) at Baseline, Day 7 and Day 28. Participant's involvement in study: 33 days maximum.
Time frame: 33 days.
Biomarkers of liver cell death: Cytokeratin 18 (CK18)
Novel liver cell death markers: Cytokeratin18M65 (K18M65), and Cytokeratin18M30 (K18M30). Units: IU/L. Evaluation at baseline, day 7 and day 28. Participant's involvement in study: 33 days maximum.
Time frame: 33 days.
Biomarkers of Inflammation (Interleukins): Interleukin 6 and Interleukin 8
interleukin 6 (IL6, unit: pg/mL) and Interleukin 8 (IL8, unit: pg/mL) at baseline, day 7 and day 28. Participant's involvement in study: 33 days maximum.
Time frame: 33 days.
Biomarkers of Inflammation: C-reactive Protein
C-reactive Protein (CRP, unit: mg/dL) assessed at baseline, day 7 and days 28. Participant's involvement in study: 33 days maximum.
Time frame: 33 days.