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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
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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4794150/ https://www.ncbi.nlm.nih.gov/pubmed/26983031 http://dx.doi.org/10.1371/journal.pone.0150733 |
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author | Nalpas, Bertrand Ichaï, Philippe Jamot, Laure Carbonell, Nicolas Rudler, Marika Mathurin, Philippe Durand, François Gerken, Guido Manns, Michael Trautwein, Christian Larrey, Dominique Radenne, Sylvie Duvoux, Christophe Leroy, Vincent Bernuau, Jacques Faivre, Jamila Moniaux, Nicolas Bréchot, Christian Amouyal, Gilles Amouyal, Paul Samuel, Didier |
author_facet | Nalpas, Bertrand Ichaï, Philippe Jamot, Laure Carbonell, Nicolas Rudler, Marika Mathurin, Philippe Durand, François Gerken, Guido Manns, Michael Trautwein, Christian Larrey, Dominique Radenne, Sylvie Duvoux, Christophe Leroy, Vincent Bernuau, Jacques Faivre, Jamila Moniaux, Nicolas Bréchot, Christian Amouyal, Gilles Amouyal, Paul Samuel, Didier |
author_sort | Nalpas, Bertrand |
collection | PubMed |
description | 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. DESIGN: 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). CONCLUSION: 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. TRIAL REGISTRATION: ClinicalTrials.gov NCT01318525 |
format | Online Article Text |
id | pubmed-4794150 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-47941502016-03-23 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 Nalpas, Bertrand Ichaï, Philippe Jamot, Laure Carbonell, Nicolas Rudler, Marika Mathurin, Philippe Durand, François Gerken, Guido Manns, Michael Trautwein, Christian Larrey, Dominique Radenne, Sylvie Duvoux, Christophe Leroy, Vincent Bernuau, Jacques Faivre, Jamila Moniaux, Nicolas Bréchot, Christian Amouyal, Gilles Amouyal, Paul Samuel, Didier PLoS One Research Article 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. DESIGN: 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). CONCLUSION: 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. TRIAL REGISTRATION: ClinicalTrials.gov NCT01318525 Public Library of Science 2016-03-16 /pmc/articles/PMC4794150/ /pubmed/26983031 http://dx.doi.org/10.1371/journal.pone.0150733 Text en © 2016 Nalpas et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Nalpas, Bertrand Ichaï, Philippe Jamot, Laure Carbonell, Nicolas Rudler, Marika Mathurin, Philippe Durand, François Gerken, Guido Manns, Michael Trautwein, Christian Larrey, Dominique Radenne, Sylvie Duvoux, Christophe Leroy, Vincent Bernuau, Jacques Faivre, Jamila Moniaux, Nicolas Bréchot, Christian Amouyal, Gilles Amouyal, Paul Samuel, Didier 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 |
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 |
title_full | 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 |
title_fullStr | 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 |
title_full_unstemmed | 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 |
title_short | 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 |
title_sort | 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 |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4794150/ https://www.ncbi.nlm.nih.gov/pubmed/26983031 http://dx.doi.org/10.1371/journal.pone.0150733 |
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