Clinical trial NCT01318525: Efficacy & Safety of ALF-5755 in Patients With Nonacetaminophen Severe Acute Hepatitis & Early Stage Acute Liver Failure
Official title: 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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Liver Failure, Acute
Lead sponsor: Alfact Innovation
Sponsor class: INDUSTRY
First posted: 2011-03-18
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Rate of change of Prothrombin Rate initiation
timeFrame: Over a period of 72 hours from baseline
Secondary outcomes:
measure: Rate of change of Factor V (FV) plasma level
timeFrame: Over a period of 72 hours from baseline
measure: Rate of change of international normalized ratio (INR)
timeFrame: Over a period of 72 hours from baseline
measure: Rate of change of alanine transaminases (ALT) plasma level
timeFrame: Over a period of 72 hours from baseline
measure: Rate of change of aspartate transaminases (AST) plasma level
timeFrame: Over a period of 72 hours from baseline
measure: Change of Hepatic Encephalopathy Grade (HE grade)
timeFrame: Over a period of 72 hours from baseline
Other outcomes:
Locations:
city: Besançon Cedex
country: France
facility: CHU de Besançon
city: Clermont-Ferrand Cedex 1
country: France
facility: CHU Clermont-Ferrand
city: Clichy
country: France
facility: Hôpital Beaujon
city: Grenoble Cedex 9
country: France
facility: CHU de Grenoble
city: Lille cedex
country: France
facility: Hôpital Claude Huriez
city: Lyon
country: France
facility: Hôpital Croix-Rousse
city: Marseille Cedex 5
country: France
facility: Hôpital Conception
city: Montpellier Cedex 5
country: France
facility: Hôpital Saint-Eloi
city: Nice
country: France
facility: Hôpital de l'Archet 2
city: Paris Cedex 12
country: France
facility: Hôpital Saint Antoine
city: Paris Cedex 13
country: France
facility: Hôpital La Pitié Salpétrière
city: Villejuif Cedex
country: France
facility: Centre Hépatobiliaire Paul Brousse
Study officials:
affiliation: Alfact Innovation
name: Paul Amouyal
role: STUDY_DIRECTOR
References:
citation: Christa L, Felin M, Morali O, Simon MT, Lasserre C, Brechot C, Seve AP. The human HIP gene, overexpressed in primary liver cancer encodes for a C-type carbohydrate binding protein with lactose binding activity. FEBS Lett. 1994 Jan 3;337(1):114-8. doi: 10.1016/0014-5793(94)80640-3.
citation: Hoofnagle JH, Carithers RL Jr, Shapiro C, Ascher N. Fulminant hepatic failure: summary of a workshop. Hepatology. 1995 Jan;21(1):240-52.
citation: Iovanna JL, Dagorn JC. The multifunctional family of secreted proteins containing a C-type lectin-like domain linked to a short N-terminal peptide. Biochim Biophys Acta. 2005 May 25;1723(1-3):8-18. doi: 10.1016/j.bbagen.2005.01.002. Epub 2005 Jan 21.
citation: Kondo T, Suda T, Fukuyama H, Adachi M, Nagata S. Essential roles of the Fas ligand in the development of hepatitis. Nat Med. 1997 Apr;3(4):409-13. doi: 10.1038/nm0497-409.
citation: Lasserre C, Christa L, Simon MT, Vernier P, Brechot C. A novel gene (HIP) activated in human primary liver cancer. Cancer Res. 1992 Sep 15;52(18):5089-95.
citation: Lieu HT, Batteux F, Simon MT, Cortes A, Nicco C, Zavala F, Pauloin A, Tralhao JG, Soubrane O, Weill B, Brechot C, Christa L. HIP/PAP accelerates liver regeneration and protects against acetaminophen injury in mice. Hepatology. 2005 Sep;42(3):618-26. doi: 10.1002/hep.20845.
citation: Lieu HT, Simon MT, Nguyen-Khoa T, Kebede M, Cortes A, Tebar L, Smith AJ, Bayne R, Hunt SP, Brechot C, Christa L. Reg2 inactivation increases sensitivity to Fas hepatotoxicity and delays liver regeneration post-hepatectomy in mice. Hepatology. 2006 Dec;44(6):1452-64. doi: 10.1002/hep.21434.
citation: Polson J, Lee WM; American Association for the Study of Liver Disease. AASLD position paper: the management of acute liver failure. Hepatology. 2005 May;41(5):1179-97. doi: 10.1002/hep.20703. No abstract available.
citation: Simon MT, Pauloin A, Normand G, Lieu HT, Mouly H, Pivert G, Carnot F, Tralhao JG, Brechot C, Christa L. HIP/PAP stimulates liver regeneration after partial hepatectomy and combines mitogenic and anti-apoptotic functions through the PKA signaling pathway. FASEB J. 2003 Aug;17(11):1441-50. doi: 10.1096/fj.02-1013com.
citation: Nalpas B, Ichai P, Jamot L, Carbonell N, Rudler M, Mathurin P, Durand F, Gerken G, Manns M, Trautwein C, Larrey D, Radenne S, Duvoux C, Leroy V, Bernuau J, Faivre J, Moniaux N, Brechot C, Amouyal G, Amouyal P, Samuel D. A Proof of Concept, Phase II Randomized European Trial, on the Efficacy of ALF-5755, a Novel Extracellular Matrix-Targeted Antioxidant in Patients with Acute Liver Diseases. PLoS One. 2016 Mar 16;11(3):e0150733. doi: 10.1371/journal.pone.0150733. eCollection 2016.