- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03917407
DUR-928 in Patients With Alcoholic Hepatitis (DUR-928/AH)
U01 Pilot Trial of DUR-928 in Patients With Moderate and Severe Alcoholic Hepatitis
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
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
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Contact
- Name: Vatsalya Vatsalya, M.D.
- Phone Number: 502-488-0446
- Email: v0vats01@louisville.edu
Study Contact Backup
- Name: Steve Mahanes
- Phone Number: 502-852-1388
- Email: steve.mahanes@louisville.edu
Study Locations
-
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Kentucky
-
Louisville, Kentucky, United States, 40202
- University of Louisville
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-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
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. 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
- 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.
Exclusion Criteria:
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
- Any patient that has received any investigational drug or device within 30 days of dosing or who is scheduled to receive another investigational drug or device at any time during the study
- Patients who are taking drug products that are primarily the substrates of CYP2C8, such as chloroquine, paclitaxel, rosiglitazone, repaglinide
- If female, known pregnancy, or has a positive serum pregnancy test, or is 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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Active Comparator: Arm1: DUR-928 treatment for moderate alcoholic hepatitis
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).
|
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:
Other Names:
|
Active Comparator: Arm 2: DUR-928 treatment for severe alcoholic hepatitis.
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).
|
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:
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Assessment of Treatment-Emergent Adverse Events
Time Frame: 4.5 years.
|
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]
Time Frame: 33 days.
|
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"
Time Frame: 33 days.
|
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"
Time Frame: 33 days.
|
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"
Time Frame: 33 days.
|
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"
Time Frame: 33 days.
|
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).
Time Frame: 33 days.
|
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)
Time Frame: 33 days.
|
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
Time Frame: 33 days.
|
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
Time Frame: 33 days.
|
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.
|
Collaborators and Investigators
Sponsor
Investigators
- Study Director: Vatsalya Vatsalya, M.D., Department of Medicine, University of Louisville
- Principal Investigator: Craig J McClain, M.D., Department of Medicine, University of Louisville
Publications and helpful links
General Publications
- 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.
- 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.
- FDA, Draft guidance for Drug Interaction Studies. February 2012.
- 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.
- 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.
- 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.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
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
- 19.0776
- 1U01AA026934-01 (U.S. NIH Grant/Contract)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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