Efficacy & Safety of ALF-5755 in Patients With Nonacetaminophen Severe Acute Hepatitis & Early Stage Acute Liver Failure

Study Overview
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Brief Summary
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Acute liver failure is a rare but dramatic disease, often affecting young people, marked by the sudden loss of liver function in a person without preexisting liver disease. ALF-5755 has been shown to promote cell survival after apoptotic or oxidative stress, and liver cell regeneration in primary cultures and in vivo. ALF-5755 may become, in this dramatic disease with high unmet medical need, a future therapy for the treatment of patients suffering from severe acute hepatitis (SAH) and acute liver failure (ALF) not due to acetaminophen overdose, where liver transplantation is the sole treatment in the absence of spontaneous recovery. The primary objective of the study is to evaluate the efficacy of ALF-5755 versus placebo. A minimum of 60 patients will be recruited into the study in the following two treatment groups: Group A: approximately 30 patients will receive ALF-5755 Group B: approximately 30 patients will receive placebo (physiological saline solution: 0.9% NaCl) Patients will receive 10 mg (25 ml) of ALF5755 or placebo every 12 hours over 3 days in slow intravenous infusions over 10 minutes using automatic syringes.

Official Title
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A Multicentre, Double-blind, Randomized, Placebo-controlled Study to Evaluate the Efficacy and the Safety of ALF-5755 in Patients With Nonacetaminophen Severe Acute Hepatitis and Early Stage Acute Liver Failure

Conditions
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Liver Failure, Acute

Intervention / Treatment
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* Drug: ALF-5755
* Drug: Saline solution (0.9% NaCl)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A signed written informed consent from patient or from patient's next of kin or from an authorized person according to local procedures Early stage acute liver failure OR severe acute hepatitis defined as: 15% ≤ PR < 50% No hepatic encephalopathy, OR grade I or II encephalopathy (Appendix E) Presumed acute illness onset of less than 26 weeks No evidence of underlying chronic liver disease Patient who can receive first treatment dose within the first 48 hours after biological baseline assessment Age ≥ 18 and ≤ 65 years Contraception (only for females of childbearing potential) to be taken throughout the study until D21. Sole mechanic contraceptives, such as condoms, are advised. Note: Oral contraceptives may have contraindications in case of severe acute hepatitis and acute liver failure Patient affiliated to social security insurance system. Exclusion Criteria: Acetaminophen-induced hepatitis defined as acetaminophen intake > 4 g/day, at least once in the 7 days prior to baseline Shock liver (ischemic hepatopathy) OR HELLP syndrome OR Budd-Chiari syndrome OR intrahepatic malignancy Serum creatinine ≥ 180 μmol/L Body Mass Index (BMI) ≥ 35 Septic shock requiring administration of inotropic drugs Uncontrolled active bleeding Patients who received fresh frozen plasma, PPSB (Prothrombin-Proconvertin-Stuart-B), or vitamin K infusion over the last 48 hours Patient receiving liver support device treatment, including but not exclusively bioartificial liver (BAL), Extracorporeal Liver Assist Device (ELAD), transgenic pig perfusion Patient receiving hemodialysis, hemofiltration or hemodiafiltration treatment Intractable arterial hypotension (arterial systolic blood pressure equal to or below 70 mmHg) present or require inotropic drugs at baseline Human Immunodeficiency Virus (HIV) positive patient Active cancer Pregnancy or breast-feeding Surgery within 4 weeks prior to baseline, or unsolved surgical disease outside liver transplantation. Patient included in another clinical trial within 4 weeks prior to baseline Patient with organ or bone-marrow allograft Absolute contra-indication to liver transplantation.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ALF-5755<br> | Drug: ALF-5755<br>* 10 mg (25 ml) given in slow intravenous infusion over 10 minutes with an automatic syringe<br>|
| Placebo Comparator: Saline solution (0.9% NaCl)<br> | Drug: Saline solution (0.9% NaCl)<br>* 25 ml given in slow intravenous infusion over 10 minutes with an automatic syringe<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of change of Prothrombin Rate initiation |  | Over a period of 72 hours from baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of change of Factor V (FV) plasma level |  | Over a period of 72 hours from baseline | 
| Rate of change of international normalized ratio (INR) |  | Over a period of 72 hours from baseline | 
| Rate of change of alanine transaminases (ALT) plasma level |  | Over a period of 72 hours from baseline | 
| Rate of change of aspartate transaminases (AST) plasma level |  | Over a period of 72 hours from baseline | 
| Change of Hepatic Encephalopathy Grade (HE grade) |  | Over a period of 72 hours from baseline |