| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Damage to your liver due to drinking too much alcohol over a long period of time |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10001624 |
| E.1.2 | Term | Alcoholic hepatitis |
| E.1.2 | System Organ Class | 100000004871 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| Evaluate the safety and efficacy, as determined by 90-day incidence of mortality or transplant, for intravenous (IV) DUR-928 (30 mg or 90 mg) in subjects with severe alcohol-associated hepatitis, also known as severe alcoholic hepatitis, (AH) with pre-treatment Maddrey Discriminant Function (MDF) score ≥ 32 and MELD scores 21-30 |
|
| E.2.2 | Secondary objectives of the trial |
| Evaluate the efficacy, as determined by 90-day mortality and 28-day mortality with or without transplant for IV DUR-928 (30 mg or 90 mg) in subjects with severe AH |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Able to provide written informed consent (either from subject or subject’s legally acceptable representative)
2. Onset of jaundice within prior 8 weeks
3. Average daily consumption of > 40 (females) or > 60 (males) grams alcohol for 6 months or longer, with < 8 weeks of abstinence before the onset of jaundice. Judgment regarding daily and long-term alcohol use and onset of jaundice will be made by the site investigator.
4. The determination of AH may be based on typical serum chemistry (as determined by local laboratory) or liver biopsy at any time during the current episode of AH:
• Serum total bilirubin > 3.0 mg/dL
• 50 < AST < 400 IU/L
• ALT < 400 IU/L
• AST/ALT > 1.5
NOTE: Labs values on the day of randomization must include serum total bilirubin > 3.0 mg/dL and AST and ALT < 400 IU/L in addition to the MDF and MELD values in inclusion 5 and 6 below.
5. Maddrey discriminant function (MDF) ≥ 32 assuming a control prothrombin time of 12 seconds NOTE: If a local laboratory’s control time differs from 12 seconds then the local laboratory’s control time should be used.
6. Model for End-stage Liver Disease (MELD) score: 21-30
7. Liver biopsy is not required, but may be used to confirm the diagnosis of AH at the Investigator’s discretion. Biopsy, if used as a diagnostic criterion, must have occurred during the current episode. NOTE: Liver biopsy is not a study procedure and will not be reimbursed.
8. Male or female subjects 18 years of age or older
9. 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, IUD (coil), vaginal ring, condom, surgical sterilization or progestin implant or injection, or sexual activity limited to a sterile (e.g., vasectomized) male partner.
10. Male subjects must agree to use a medically acceptable method of contraception/birth control and refrain from sperm donation throughout the study duration
11. Subjects must agree to participate in an alcohol abstinence support program recommended by the local institution’s addiction specialists |
|
| E.4 | Principal exclusion criteria |
1. Subjects taking systemic corticosteroids for a duration exceeding 8 days in the 30 days prior to screening. NOTE: Inhaled, topical, or local corticosteroid injections are permitted
2. Subjects experiencing or considered at high risk for alcohol withdrawal seizures or delirium tremens
3. Active infection (such as spontaneous bacterial peritonitis [SBP], urinary tract infection [UTI], bacteremia, acute viral hepatitis, uncontrolled HIV, and active SARS CoV2 infection).
a. Subjects who are febrile with leukocytosis are also excluded until active infection has been excluded to the satisfaction of the PI in consultation with the medical monitor.
b. Patients with bacterial peritonitis may be considered for enrollment once the infection has been treated and follow up paracentesis confirms the absence of SBP.
c. Patients with fungal infection of any kind cannot be considered for this trial.
4. Serum creatinine >2.5 mg/dL
5. Criterion removed as part of Protocol Amendment 2, but placeholder kept to maintain consistency in subsequent criteria numbering
6. Subjects undergoing continuous veno-venous hemodialysis (CVVH)
7. Uncontrolled gastrointestinal bleeding
8. A history of pre-admission refractory ascites defined as more than 4 paracenteses in the previous 8 weeks despite diuretic therapy.
9. Liver biopsy (if carried out) with findings not compatible with AH
10. Stage ≥ 3 hepatic encephalopathy by West Haven criteria
11. Any severe concomitant cardiovascular, renal, endocrine, pulmonary (including ventilator dependent or COPD Global Obstructive Lung Disease [GOLD] stage III or IV), psychiatric disorder, or multi-organ failure
12. Other concomitant cause(s) of liver disease as a result of:
a. Autoimmune liver disease
b. Ischemic hepatitis
c. Wilson disease or alpha 1 antitrypsin deficiency
d. Vascular liver disease (e.g., Budd-Chiari)
e. Drug induced liver disease
f. Surface antigen positive hepatitis B (HBsAg+). NOTE: subjects with isolated core antibody (anti-HBc) or who are on stable antiviral medication with known viral suppression are not excluded
g. Acute hepatitis A (if test performed per SOC)
h. Acute HCV or chronic hepatitis C with a history of decompensated cirrhosis. NOTE: subjects with stable chronic HCV or successfully treated HCV are not excluded
i. Acute hepatitis E (if test performed per SOC)
j. Acute cytomegalovirus (CMV) viral hepatitis (if test performed per SOC)
k. Acute Epstein-Barr virus (EBV) viral hepatitis (if test performed per SOC)
NOTE: A spurious finding, such as the incidental finding of moderately elevated antinuclear antibody (ANA) or anti-smooth muscle antibody (ASMA) titer is not, by itself, a mandatory exclusion criterion unless accompanied by other evidence suggestive of a probable disease other than AH.
13. Any active malignancy or any malignancy diagnosed within the last five years other than curable skin cancer (basal cell or squamous cell carcinomas)
14. Positive Urine Drug Screen (amphetamines, barbiturates, benzodiazepines, cocaine and opiates) except THC and prescription medications
15. Existing or intended pregnancy or breast feeding
16. Participation in another interventional clinical trial within 30 days of Screening
17. History of organ transplantation, other than a corneal transplant
18. Underlying diseases that, in the opinion of the site investigator, might be complicated or exacerbated by proposed treatments or might confound assessment of study drug |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Difference in 90-day mortality or transplant between IV DUR-928, 30 mg or 90 mg, and placebo |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. Difference in 90-day mortality between IV DUR-928, 30 mg or 90 mg, and placebo
2. Difference in 28-day mortality or transplant between IV DUR-928, 30 mg or 90 mg, and placebo
3. Difference in 28-day mortality between IV DUR-928, 30 mg or 90 mg, and placebo |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| United States |
| Austria |
| Belgium |
| France |
| Germany |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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