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

Liver Failure, Acute Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01318525
• Other study ID #: ALF-5755_P2_ALF
• Status: Recruiting
• Phase: Phase 2
• First received: March 17, 2011
• Last updated: April 4, 2011
• Start date: October 2010
• Est. completion date: September 2012

Study information

• Verified date: April 2011
• Source: Alfact Innovation
• Contact: Paul Amouyal
• Phone: +33 1 45 59 35 66
• Email: amouyal.paul[@]wanadoo.fr
• Is FDA regulated: No
• Health authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 60
• Est. completion date: September 2012
• Est. primary completion date: May 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Liver Failure
• Liver Failure, Acute

Intervention

Drug:
• ALF-5755
10 mg (25 ml) given in slow intravenous infusion over 10 minutes with an automatic syringe
• Saline solution (0.9% NaCl)
25 ml given in slow intravenous infusion over 10 minutes with an automatic syringe

Locations

Country	Name	City	State
France	CHU de Besançon	Besançon Cedex
France	CHU Clermont-Ferrand	Clermont-Ferrand Cedex 1
France	Hôpital Beaujon	Clichy
France	CHU de Grenoble	Grenoble Cedex 9
France	Hôpital Claude Huriez	Lille cedex
France	Hôpital Croix-Rousse	Lyon
France	Hôpital Conception	Marseille Cedex 5
France	Hôpital Saint-Eloi	Montpellier Cedex 5
France	Hôpital de l'Archet 2	Nice
France	Hôpital Saint Antoine	Paris Cedex 12
France	Hôpital La Pitié Salpétrière	Paris Cedex 13
France	Centre Hépatobiliaire Paul Brousse	Villejuif Cedex

Sponsors (1)

Lead Sponsor	Collaborator
Alfact Innovation

Country where clinical trial is conducted

France, 

References & Publications (9)

Christa L, Felin M, Morali O, Simon MT, Lasserre C, Brechot C, Sève 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. — View Citation

Hoofnagle JH, Carithers RL Jr, Shapiro C, Ascher N. Fulminant hepatic failure: summary of a workshop. Hepatology. 1995 Jan;21(1):240-52. Review. — View 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. Epub 2005 Jan 21. Review. — View 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. — View Citation

Lasserre C, Christa L, Simon MT, Vernier P, Bréchot C. A novel gene (HIP) activated in human primary liver cancer. Cancer Res. 1992 Sep 15;52(18):5089-95. — View Citation

Lieu HT, Batteux F, Simon MT, Cortes A, Nicco C, Zavala F, Pauloin A, Tralhao JG, Soubrane O, Weill B, Bréchot C, Christa L. HIP/PAP accelerates liver regeneration and protects against acetaminophen injury in mice. Hepatology. 2005 Sep;42(3):618-26. — View Citation

Lieu HT, Simon MT, Nguyen-Khoa T, Kebede M, Cortes A, Tebar L, Smith AJ, Bayne R, Hunt SP, Bréchot 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. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Rate of change of Prothrombin Rate initiation		Over a period of 72 hours from baseline	No
Secondary	Rate of change of Factor V (FV) plasma level		Over a period of 72 hours from baseline	No
Secondary	Rate of change of international normalized ratio (INR)		Over a period of 72 hours from baseline	No
Secondary	Rate of change of alanine transaminases (ALT) plasma level		Over a period of 72 hours from baseline	No
Secondary	Rate of change of aspartate transaminases (AST) plasma level		Over a period of 72 hours from baseline	No
Secondary	Change of Hepatic Encephalopathy Grade (HE grade)		Over a period of 72 hours from baseline	No