Chronic Hepatitis C Non-Responder Study With AdoMet and Betaine

NCT00310336 | Completed Phase 2

• 1 other identifier: EKBB 37/06
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

50-60% of patients with chronic hepatitis C are not cured by treatment with pegylated IFNα plus ribavirin. Retreatment of non-responders of previous (pegylated) IFNα plus ribavirin therapies with pegylated IFNα plus ribavirin results in a sustained response in less than 10% of the patients. Extensive analysis of IFNα signaling in cells expressing HCV proteins, in transgenic mice expressing HCV proteins, and in liver biopsies from patients with chronic hepatitis C point to STAT1 methylation as an important posttranslational modification targeted by HCV to inhibit IFNα signaling. STAT1 methylation can be increased and IFNα can be improved by adding AdoMet and betaine. The study is designed to test the hypothesis that a combination treatment with pegylated IFNα2b, ribavirin, AdoMet and betaine is superior to the current standard combination therapy with pegylated IFNα plus ribavirin.

Conditions

Hepatitis C

Outcome Measures

Primary Outcomes (1)

• Sustained response rate

Secondary Outcomes (1)

• Early virologic response after 12 weeks of therapy with PegIntron, Rebetol, AdoMet and betaine.

Interventions

S-adenosyl-L-methionine DRUG

betaine DRUG

pegylated interferon alpha2b DRUG

ribavirin DRUG

Eligibility Criteria

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

You may qualify if:

• Male and female between 18 and 65 years.
• Non-responders in previous treatments with IFNα plus ribavirin or pegylated IFNα plus ribavirin.
• Elevated ALT-levels on at least two occasions during \>6 months preceding entry.
• Detection of HCV RNA in serum (PCR).
• Compensated liver disease (Child-Pugh A) and a Child-Pugh score \<5.
• The following minimal hematologic and biochemical criteria:
• Hemoglobin for males and females \>11g/dl
• Absolute Neutrophil count \>1500 cells/mm3
• Platelets \>75'000/mm3
• HBs Ag negative.
• ANA \<1:320, and no evidence for autoimmune hepatitis.
• Fasting blood glucose within normal limits, if history of diabetes or hypertension, a pre-therapy ocular examination is indicated.
• TSH within normal limits or adequately controlled.
• Negative urine or blood pregnancy test (for women of childbearing potential) documented within the 2-3 week period prior to the first dose of study drug. Additionally, all fertile males and females must be using effective contraception during treatment and during the 6 months after treatment end. This may include, but is not limited to, using birth control pills, IUDs, condoms, diaphragms, or implants, being surgically sterilized, or being in a post-menopausal state.
• Willingness to give written informed consent and willingness to participate to and comply with the study

You may not qualify if:

• Women with ongoing pregnancy or breast feeding.
• Positive test at screening for anti-HAV IgM Ab, HBsAg, anti-HBc IgM Ab, HBe Ag.
• Positive test at screening for HIV.
• History or other evidence of a medical condition associated with chronic liver disease other than HCV (e.g., hemochromatosis, autoimmune hepatitis, alcoholic liver disease, toxin exposures).
• Hypersensitivity to study drugs.
• Participation in any other clinical trial within 30 days of entry into this protocol.
• Treatment with any investigational drug within 30 days of entry into this protocol.
• History or evidence of decompensated liver disease (Child-Pugh B/C) and a Child-Pugh score \>5. Ascites, coagulopathy, hyperbilirubinemia, hepatic encephalopathy, or hypoalbuminemia and a Child-Pugh score \>5 are conditions consistent with decompensated liver disease.
• History or other evidence of bleeding from esophageal varices or other conditions consistent with decompensated liver disease.
• Hepatocellular carcinoma (HCC) or α-Fetoprotein \>50μg/l.
• Patients with organ transplants other than cornea and hair transplant.
• Therapy with any antisystemic or immunomodulatory treatment (including supra-physiologic doses of steroids or radiation) \<6 months prior the first dose of study drug
• Hemoglobinopathy (e.g. thalassemia) or any other cause of or tendency for hemolysis.
• Any known preexisting medical condition that could interfere with the patient's participation in and completion of the study such as:
• Preexisting psychiatric condition, especially depression, or a history of severe psychiatric disorder, such as major psychosis, suicidal ideation and/or suicidal attempts (based on a mandatory psychiatric advice).

Sponsors & Collaborators

• University Hospital, Basel, Switzerland: lead

Study Sites (1)

University Hospital Basel

Basel, Canton of Basel-City, 4031, Switzerland

Location

Related Publications (6)

• Duong FH, Christen V, Filipowicz M, Heim MH. S-Adenosylmethionine and betaine correct hepatitis C virus induced inhibition of interferon signaling in vitro. Hepatology. 2006 Apr;43(4):796-806. doi: 10.1002/hep.21116.

  PMID: 16557551 BACKGROUND

• Duong FH, Christen V, Berke JM, Penna SH, Moradpour D, Heim MH. Upregulation of protein phosphatase 2Ac by hepatitis C virus modulates NS3 helicase activity through inhibition of protein arginine methyltransferase 1. J Virol. 2005 Dec;79(24):15342-50. doi: 10.1128/JVI.79.24.15342-15350.2005.

  PMID: 16306605 BACKGROUND

• Duong FH, Filipowicz M, Tripodi M, La Monica N, Heim MH. Hepatitis C virus inhibits interferon signaling through up-regulation of protein phosphatase 2A. Gastroenterology. 2004 Jan;126(1):263-77. doi: 10.1053/j.gastro.2003.10.076.

  PMID: 14699505 BACKGROUND

• Blindenbacher A, Duong FH, Hunziker L, Stutvoet ST, Wang X, Terracciano L, Moradpour D, Blum HE, Alonzi T, Tripodi M, La Monica N, Heim MH. Expression of hepatitis c virus proteins inhibits interferon alpha signaling in the liver of transgenic mice. Gastroenterology. 2003 May;124(5):1465-75. doi: 10.1016/s0016-5085(03)00290-7.

  PMID: 12730885 BACKGROUND

• Heim MH, Moradpour D, Blum HE. Expression of hepatitis C virus proteins inhibits signal transduction through the Jak-STAT pathway. J Virol. 1999 Oct;73(10):8469-75. doi: 10.1128/JVI.73.10.8469-8475.1999.

  PMID: 10482599 BACKGROUND

• Filipowicz M, Bernsmeier C, Terracciano L, Duong FH, Heim MH. S-adenosyl-methionine and betaine improve early virological response in chronic hepatitis C patients with previous nonresponse. PLoS One. 2010 Nov 8;5(11):e15492. doi: 10.1371/journal.pone.0015492.

  PMID: 21079746 DERIVED

MeSH Terms

Conditions

Hepatitis C

Interventions

S-Adenosylmethionine; Betaine; peginterferon alfa-2b; Ribavirin

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Hepatitis, Viral, Human; Virus Diseases; Flaviviridae Infections; RNA Virus Infections; Hepatitis; Liver Diseases; Digestive System Diseases

Intervention Hierarchy (Ancestors)

Methionine; Amino Acids, Sulfur; Sulfur Compounds; Organic Chemicals; Adenosine; Purine Nucleosides; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Amino Acids; Amino Acids, Peptides, and Proteins; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Trimethyl Ammonium Compounds; Quaternary Ammonium Compounds; Amines; Onium Compounds

Study Officials

• Markus H Heim, MD

  University Hospital, Basel, Switzerland

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: March 31, 2006
• First Posted: April 3, 2006
• Study Start: August 1, 2006
• Primary Completion: August 1, 2009
• Study Completion: September 1, 2009
• Last Updated: October 28, 2010

Record last verified: 2010-10

Locations

CH (1)