DUR-928 in Patients With Alcoholic Hepatitis

NCT03917407 | Completed Phase 2 DMC FDA Drug

• 2 other identifiers: 19.07761U01AA026934-01
• Study Type: interventional
• Target: 43
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Alcoholic Hepatitis

Keywords

Alcoholic Hepatitis; Alcoholic Liver Disease

Outcome Measures

Primary Outcomes (10)

• 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).

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  33 days.

Study Arms (2)

Arm1: DUR-928 treatment for moderate alcoholic hepatitis

ACTIVE COMPARATOR

Enrolled alcoholic hepatitis patients would have MELD of 11-20; and have met inclusion and exclusion criteria. DUR-928 as a novel study treatment would be administered in patients with moderate alcoholic hepatitis (AH) as determined by the absence of suspected unexpected serious adverse reaction (SUSAR).

Drug: DUR-928 (Moderate AH)

Arm 2: DUR-928 treatment for severe alcoholic hepatitis.

ACTIVE COMPARATOR

Enrolled alcoholic hepatitis patients would have MELD of 21-30; and have met inclusion and exclusion criteria. DUR-928 as a novel study treatment would be administered in patients with severe alcoholic hepatitis (AH) as determined by the absence of suspected unexpected serious adverse reaction (SUSAR).

Drug: DUR-928 (Severe AH)

Interventions

DUR-928 (Moderate AH) DRUG

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.

Also known as: Sulfated oxysterol: 5 cholesten-3β, 25-diol 3-sulfate (25HC3S)

Arm1: DUR-928 treatment for moderate alcoholic hepatitis

DUR-928 (Severe AH) DRUG

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.

Also known as: Sulfated oxysterol: 5 cholesten-3β, 25-diol 3-sulfate (25HC3S)

Arm 2: DUR-928 treatment for severe alcoholic hepatitis.

Eligibility Criteria

• Age: 21 Years - 67 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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. If infection is initially suspected clinically,
• blood cultures, urine cultures, and peritoneal cultures should be without growth for 48 hrs, AND
• peritoneal cell count should be less than 250 Polymorphonuclear cell (PMN)/ml. If infection is diagnosed, then the infection must be
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• treated with antibiotics, AND
• documented negative blood cultures for 48 hrs, or for spontaneous bacterial peritonitis (SBP) 25% reduction in PMN count prior to enrollment.
• Women of child-bearing potential (defined as females who are not surgically sterile or who are not over the age of 52 and amenorrheic for at least 12 months) must utilize appropriate birth control throughout the study duration. Acceptable methods that may be used are abstinence, birth control pills ("The Pill") or patch, diaphragm, intrauterine device (IUD/ coil), vaginal ring, condom, surgical sterilization or progestin implant or injection, or sexual activity limited to a sterile (e.g., vasectomized) male partner.
• Male patients must agree to use a medically acceptable method of contraception/birth control throughout the study duration.

You may not qualify if:

• Other or concomitant cause(s) of liver disease as a result of:
• Autoimmune liver disease (positive anti-mitochondrial antibody and smooth muscle antibody, positive reading on anti-nuclear antibody titer \> 1:160)
• Wilson disease (ceruloplasmin levels \< 10 mcg/L)
• Vascular liver disease
• Drug induced liver disease
• Surface antigen positive hepatitis B (HBsAg+). Note: patients with isolated core antibody (HBcAb) are not excluded.
• Acute hepatitis A
• Acute HCV or chronic hepatitis C with a history of decompensated cirrhosis. Note: patients with stable chronic Hep C Virus (HCV) or successfully treated HCV are not excluded.
• Co-infection with human immunodeficiency virus (HIV)
• Positive Urine Drug Screen (amphetamines, barbiturates, benzodiazepines, cocaine and opiates) except THC and legal prescription medications.
• Any active malignancies other than curatively treated skin cancer (basal cell or squamous cell carcinomas) or any other malignancy diagnosed within the last five years
• Active tuberculosis on chest x-ray at study entry
• Significant systemic or major illness other than liver disease, including coronary artery disease, cerebrovascular disease, pulmonary disease, renal failure, serious psychiatric disease, that, in the opinion of the Investigator would preclude the patient from participating in and completing the study
• Patients requiring the use of vasopressors or inotropic support. Prior use of inotropic support will be allowed if the condition has stabilized within the first 7 days of admission to the hospital
• Liver biopsy, if carried out, showing findings not compatible with AH

Sponsors & Collaborators

• Craig James McClain: lead
• National Institute on Alcohol Abuse and Alcoholism (NIAAA): collaborator

Study Sites (1)

University of Louisville

Louisville, Kentucky, 40202, United States

Location

Related Publications (6)

• Liangpunsakul S. Clinical characteristics and mortality of hospitalized alcoholic hepatitis patients in the United States. J Clin Gastroenterol. 2011 Sep;45(8):714-9. doi: 10.1097/MCG.0b013e3181fdef1d.

  PMID: 21085006 RESULT

• Menon KV, Gores GJ, Shah VH. Pathogenesis, diagnosis, and treatment of alcoholic liver disease. Mayo Clin Proc. 2001 Oct;76(10):1021-9. doi: 10.4065/76.10.1021.

  PMID: 11605686 RESULT

• FDA, Draft guidance for Drug Interaction Studies. February 2012.

  RESULT

• Orman ES, Odena G, Bataller R. Alcoholic liver disease: pathogenesis, management, and novel targets for therapy. J Gastroenterol Hepatol. 2013 Aug;28 Suppl 1(0 1):77-84. doi: 10.1111/jgh.12030.

  PMID: 23855300 RESULT

• O'Shea RS, McCullough AJ. Treatment of alcoholic hepatitis. Clin Liver Dis. 2005 Feb;9(1):103-34. doi: 10.1016/j.cld.2004.11.004.

  PMID: 15763232 RESULT

• Thursz MR, Richardson P, Allison M, Austin A, Bowers M, Day CP, Downs N, Gleeson D, MacGilchrist A, Grant A, Hood S, Masson S, McCune A, Mellor J, O'Grady J, Patch D, Ratcliffe I, Roderick P, Stanton L, Vergis N, Wright M, Ryder S, Forrest EH; STOPAH Trial. Prednisolone or pentoxifylline for alcoholic hepatitis. N Engl J Med. 2015 Apr 23;372(17):1619-28. doi: 10.1056/NEJMoa1412278.

  PMID: 25901427 RESULT

MeSH Terms

Conditions

Hepatitis, Alcoholic; Liver Diseases, Alcoholic

Interventions

25-hydroxycholesterol 3-sulfate

Condition Hierarchy (Ancestors)

Hepatitis; Liver Diseases; Digestive System Diseases; Alcohol-Induced Disorders; Alcohol-Related Disorders; Substance-Related Disorders; Chemically-Induced Disorders

Study Officials

• Vatsalya Vatsalya, M.D.

  Department of Medicine, University of Louisville

  STUDY DIRECTOR

• Craig J McClain, M.D.

  Department of Medicine, University of Louisville

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: Dur-28 treated moderate AH: 7 Dur-28 treated severe AH: 12 Observational AH: 8 Steroid Treated AH: 16
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Model Details: An Open-Label, Dose Escalation Study to Assess the Safety, and Pharmacodynamics 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 2nddose, the patient will receive only one dose of DUR-928 instead of 2 doses.

Study Record Dates

• First Submitted: March 27, 2019
• First Posted: April 17, 2019
• Study Start: June 1, 2021
• Primary Completion: September 24, 2023
• Study Completion: September 30, 2023
• Last Updated: October 18, 2023

Record last verified: 2023-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)