title: 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.
abstract: OBJECTIVE
  No efficient medical treatment is available for severe acute hepatitis (SAH) except N-acetylcysteine for acetaminophen-induced acute liver failure. The human C-type lectin Reg3α, referred to as ALF-5755, improved survival in an animal model of acute liver failure and was well tolerated in a phase 1 trial in humans. We performed a phase 2a trial of ALF5755 in non-acetaminophen induced SAH.
  
  
  METHODS
  double-blind, randomized, placebo-controlled study. The primary end-point was the improvement in the coagulation protein synthesis assessed by the change of Prothrombin (PR) during the 72 hours following treatment initiation calculated as PRH0 minus PRH72 divided by 72 (PR slope H0H72). Intention to treat (ITT) and per-protocol (PP) analysis of the entire group and the Hepatitis B virus (HBV)/AIH (auto-immune hepatitis) sub-group were done separately.
  
  
  RESULTS
  57 patients were included. Twenty-eight received ALF-5755, 29 the placebo. Etiologies were: Hepatitis A (n = 10), HBV (n = 13), AIH (n = 9), drug-induced (n = 8), other (n = 17). On the whole group, nor the PR slope H0H72 (0.18±0.31 vs 0.25±0.32), nor the transplant-free survival rate at day 21 (75 vs 86%) differed between groups. Conversely, in the HBV-AIH subgroup, in which ALF was more severe, PR slope H0-H72 was higher in the ALF-5755 arm, the difference being significant in PP analysis (0.048±0.066 vs -0.040±0.099, p = 0.04); the median length of hospitalization was lower in the ALF-5755 group (8 vs 14 days, p = 0.02).
  
  
  CONCLUSIONS
  ALF-5755 was not efficient in a ITT analysis performed on the whole sample; however it led to a significant, although moderate, clinical benefit in a PP analysis of the sub-group of patients with HBV or AIH related SAH. As HBV is the major cause of SAH in Asia and Africa and AIH a growing cause, this study emphasizes the need to pursuit the evaluation of this novel medical treatment of SAH.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01318525.
authors.affiliation: Inserm, Département de l'Information Scientifique et de la Communication, Paris, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Nalpas
authors.affiliation: Centre Hépatobiliaire Paul Brousse and Inserm U 1193, Villejuif, France.|Hôpital Universitaire Paul Brousse, Villejuif, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Ichaï
authors.affiliation: Alfact Innovation, Paris, France.
authors.forename: Laure
authors.initials: L
authors.lastname: Jamot
authors.affiliation: Service Hépato-gastro-entérologie, Hôpital Saint Antoine, Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Carbonell
authors.affiliation: Service Hépatologie et de Gastroentérologie, Hôpital La Pitié Salpétrière, Paris, France.
authors.forename: Marika
authors.initials: M
authors.lastname: Rudler
authors.affiliation: Service des maladies de l'appareil digestif, Hôpital Claude Huriez, Lille, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Mathurin
authors.affiliation: Service Hépatologie, Hôpital Beaujon, Clichy, France.
authors.forename: François
authors.initials: F
authors.lastname: Durand
authors.affiliation: Gastroenterology and Hepatology Unit, University of Essen, Essen, Germany.
authors.forename: Guido
authors.initials: G
authors.lastname: Gerken
authors.affiliation: Gastroenterology and Hepatology Unit, University of Hanover, Hanover, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Manns
authors.affiliation: Medizinische Klinik III, University Clinic, RWTH-Aachen, Aachen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Trautwein
authors.affiliation: Service Hépato-Gastro-Entérologie, Hôpital Saint-Eloi, Montpellier, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Larrey
authors.affiliation: Service Hépatologie et Gastro-Entérologie, Hôpital Croix-Rousse, Lyon, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Radenne
authors.affiliation: Service d'Hépato-Gastro-Entérologie, Hôpital Henri MondorCréteil, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Duvoux
authors.affiliation: Département d'Hépato-Gastroentérologie, Hôpital de Grenoble, Grenoble, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Leroy
authors.affiliation: Service Hépatologie, Hôpital Beaujon, Clichy, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Bernuau
authors.affiliation: Centre Hépatobiliaire Paul Brousse and Inserm U 1193, Villejuif, France.|Hôpital Universitaire Paul Brousse, Villejuif, France.
authors.forename: Jamila
authors.initials: J
authors.lastname: Faivre
authors.affiliation: Centre Hépatobiliaire Paul Brousse and Inserm U 1193, Villejuif, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Moniaux
authors.affiliation: Institut Pasteur, Paris, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Bréchot
authors.affiliation: Alfact Innovation, Paris, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Amouyal
authors.affiliation: Alfact Innovation, Paris, France.
authors.forename: Paul
authors.initials: P
authors.lastname: Amouyal
authors.affiliation: Centre Hépatobiliaire Paul Brousse and Inserm U 1193, Villejuif, France.|Hôpital Universitaire Paul Brousse, Villejuif, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Samuel
mesh_terms: D000208:Acute Disease; D000328:Adult; D000951:Antigens, Neoplasm / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D000975:Antioxidants / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D019540:Area Under Curve; D014408:Biomarkers, Tumor / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D004311:Double-Blind Method; D005109:Extracellular Matrix / Q000187:drug effects*; D005260:Female; D006801:Humans; D037181:Lectins, C-Type / Q000627:therapeutic use*; D008107:Liver Diseases / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D000073718:Pancreatitis-Associated Proteins; D010919:Placebos; D011379:Prognosis; D011994:Recombinant Proteins / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000951:Antigens, Neoplasm; D000975:Antioxidants; D014408:Biomarkers, Tumor; D037181:Lectins, C-Type; D000073718:Pancreatitis-Associated Proteins; D010919:Placebos; C000612141:REG3A protein, human; D011994:Recombinant Proteins