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

NCT01318525 | Unknown Phase 2 DMC

• 1 other identifier: ALF-5755_P2_ALF
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 12

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.

Conditions

Liver Failure, Acute

Outcome Measures

Primary Outcomes (1)

• Rate of change of Prothrombin Rate initiation

  Over a period of 72 hours from baseline

Secondary Outcomes (5)

• 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

Study Arms (2)

ALF-5755

EXPERIMENTAL

Drug: ALF-5755

Saline solution (0.9% NaCl)

PLACEBO COMPARATOR

Drug: Saline solution (0.9% NaCl)

Interventions

ALF-5755 DRUG

10 mg (25 ml) given in slow intravenous infusion over 10 minutes with an automatic syringe

ALF-5755

Saline solution (0.9% NaCl) DRUG

25 ml given in slow intravenous infusion over 10 minutes with an automatic syringe

Saline solution (0.9% NaCl)

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• % ≤ 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Alfact Innovation: lead

Study Sites (12)

CHU de Besançon

Besançon, 25030, France

NOT YET RECRUITING

CHU Clermont-Ferrand

Clermont-Ferrand, 63003, France

NOT YET RECRUITING

Hôpital Beaujon

Clichy, 92110, France

RECRUITING

CHU de Grenoble

Grenoble, 38043, France

RECRUITING

Hôpital Claude Huriez

Lille, 59037, France

NOT YET RECRUITING

Hôpital Croix-Rousse

Lyon, 69004, France

RECRUITING

Hôpital Conception

Marseille, 13385, France

NOT YET RECRUITING

Hôpital Saint-Eloi

Montpellier, 34295, France

RECRUITING

Hôpital de l'Archet 2

Nice, 06202, France

NOT YET RECRUITING

Hôpital Saint Antoine

Paris, 75571, France

RECRUITING

Hôpital La Pitié Salpétrière

Paris, 75651, France

RECRUITING

Centre Hépatobiliaire Paul Brousse

Villejuif, 94804, France

RECRUITING

Related Publications (10)

• 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.

  PMID: 8276102 BACKGROUND

• Hoofnagle JH, Carithers RL Jr, Shapiro C, Ascher N. Fulminant hepatic failure: summary of a workshop. Hepatology. 1995 Jan;21(1):240-52.

  PMID: 7806160 BACKGROUND

• 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.

  PMID: 15715980 BACKGROUND

• 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.

  PMID: 9095174 BACKGROUND

• 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.

  PMID: 1325291 BACKGROUND

• 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.

  PMID: 16116631 BACKGROUND

• 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.

  PMID: 17133485 BACKGROUND

• 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.

  PMID: 15841455 BACKGROUND

• 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.

  PMID: 12890698 BACKGROUND

• 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.

  PMID: 26983031 DERIVED

MeSH Terms

Conditions

Liver Failure, Acute

Interventions

ALF-5755; Saline Solution

Condition Hierarchy (Ancestors)

Liver Failure; Hepatic Insufficiency; Liver Diseases; Digestive System Diseases

Intervention Hierarchy (Ancestors)

Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Study Officials

• Paul Amouyal

  Alfact Innovation

  STUDY DIRECTOR

Central Study Contacts

Paul Amouyal

CONTACT

+33 1 45 59 35 66; amouyal.paul@wanadoo.fr

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY

Study Record Dates

• First Submitted: March 17, 2011
• First Posted: March 18, 2011
• Study Start: October 1, 2010
• Primary Completion: May 1, 2012
• Study Completion: September 1, 2012
• Last Updated: April 5, 2011

Record last verified: 2011-04

Locations

FR (12)