Benefit of Immunoprophylaxis on Fibrosis to Reduce Viral Load After Liver Transplantation (BEFIRTH)

Evaluation of the Benefit of Antithymocyte Induction Therapy on Hepatic Fibrosis in de Novo Hepatitis C Virus Liver Transplant Patients.

An open-label randomized multicenter clinical study comparing three regimes of immunosuppression : (A) tacrolimus and steroids, (B) antithymocyte induction therapy and full dose of tacrolimus, (C) antithymocyte induction therapy with mycophenolate mofetil and a reduced dose of tacrolimus.

Study Overview

• Status: Completed
• Conditions: Liver Transplantation
• Intervention / Treatment: Drug: tacrolimus; Drug: tacrolimus, ATG; Drug: ATG+mycophénolate mofétil+tacrolimus

• Study Type: Interventional
• Enrollment (Anticipated): 100
• Phase: Phase 4

Contacts and Locations

Study Locations

• France
  • Bordeaux, France, 33076
    • Hopital Pellegrin Tripode
  • Marseille, France, 13385
    • La Conception Hospital
  • Montpellier, France, 34295
    • Hôpital Saint-Eloi
  • Nice, France, 06200
    • Hopital de l'Archet
  • Paris, France, 75000
    • Hôpital Cochin
  • Rennes, France, 35
    • Hôpital Pontchaillou
  • Toulouse, France, 31500
    • University Hospital
  • Villejuif, France, 94804
    • Hopital Paul Brousse

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• patients who received a first liver transplantation,
• presenting with a qualitative or quantitative PCR positive for hepatitis C virus at time of transplantation, whatever the transaminase activity,
• Women of childbearing potential with a negative pregnancy test,
• Male or female patients who agree to use an effective method of contraception,
• patients who signed a written informed consent form to participate in the study,
• patients who are compliant and likely to follow the visits specified by the study protocol

Exclusion Criteria:

• • Preoperative serious renal impairment (serum creatinine levels > 200 µmol/l),

  • repeat transplantation,
  • multiple organ transplantation,
  • transplantation performed with an organ transplant obtained from a living donor or a reduced or shared organ grafts,
  • serious concomitant disorder,
  • positive serology for HBs antigen or HIV positive at time of enrollment,
  • previous history of nonhepatic cancer (except for localized skin cancer),
  • presence of a hepatocellular carcinoma, for which the primary lesion exceeds 5 cm or is complicated by portal thrombosis or metastatic disease,
  • an investigational product or therapy administered less than one month before entry into the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: A; tacrolimus + steroids	Drug: tacrolimus; Tacrolimus started at 0.50 mg/kg b.i.d. starting at D0, by nasogastric tube and then 1 to 2 hours before meals. The dose of tacrolimus will be adjusted as soon as possible to obtain trough concentrations of the product between 10 and 20 µg/L between D0 and 6 months and then between 8 and 15 µg/L after 6 months; Other Names: PROGRAF
EXPERIMENTAL: B; ATG+ tacrolimus without steroids in maintenance therapy	Drug: tacrolimus, ATG; immunoprophylaxis allowing sparing of steroids in maintenance therapy combining induction therapy with 3 injections of antithymocyte globulins (ATG) (1.5 mg/kg/d at D0, D2 and D4) and tacrolimus at usual dosage. In this group of patients, the first injection of ATG will be infused over a period of at least 6 hours and will be started as soon as vascular anastomosis has been completed. It will be preceded by an injection of 3 mg/kg/d methylprednisolone. The second injection of ATG at D2, post transplantation will also be infused over 6 hours and will be preceded by an injection of 1 mg/kg methylprednisolone, and then subsequently steroids will be excluded from the treatment. The third and last injection at D4 post transplantation will be administered over a 6-hour period but will not be preceded by steroids. In this study arm, tacrolimus will be administered as in arm (A); Other Names: Thymoglobuline
EXPERIMENTAL: C; ATG+ Mycophenolate Mofetil + tacrolimus a reduced dosage without steroids in maintenance therapy	Drug: ATG+mycophénolate mofétil+tacrolimus; immunoprophylaxis allowing sparing of steroids in maintenance therapy combined with mycophenolate mofetil, at an initial dosage of 2 grams a day, and then adjusted to safety and tolerability in such a way so as to maintain PMN ≥ 750/mm3, and platelet counts ≥ 30000/mm3. In this study arm, the patients will receive the same doses of ATG and steroids (and according to the same methods) as in arm B. Tacrolimus started at 0.05 mg/kg b.i.d. starting at D0 by nasogastric tube and then 1 to 2 hours before meals. In this study arm, the tacrolimus dose will be reduced: targeted trough concentrations will be between 7 and 12 µg/L between D0 and 6 months and then between 3 et 7 µg/L after 6 months.; Other Names: Mycophénolate mofétil = Cellcept

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The primary endpoint will be degree of fibrosis = Ishak's histological score of hepatic biopsy at 1 year	1 year

Secondary Outcome Measures

Outcome Measure	Time Frame
• Ishak's degree of activity	1 year
Ishak's degree of fibrosis	2 years

Collaborators and Investigators

• Sponsor: University Hospital, Toulouse
• Investigators: Principal Investigator: Rostaing Lionel, PhD, University Hospital, Toulouse; Principal Investigator: Calmus Yvon, PhD, UHCochin, Paris

Study record dates

Study Major Dates

• Study Start: May 1, 2005
• Primary Completion (ACTUAL): January 1, 2010
• Study Completion (ACTUAL): January 1, 2011

Study Registration Dates

• First Submitted: October 1, 2007
• First Submitted That Met QC Criteria: October 1, 2007
• First Posted (ESTIMATE): October 2, 2007

Study Record Updates

• Last Update Posted (ESTIMATE): February 3, 2011
• Last Update Submitted That Met QC Criteria: February 2, 2011
• Last Verified: February 1, 2011

More Information

Terms related to this study

• Keywords: liver transplantation, hepatitis C virus, immunoprophylaxis
• Additional Relevant MeSH Terms: Pathologic Processes; Fibrosis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Tacrolimus; Mycophenolic Acid; Thymoglobulin
• Other Study ID Numbers: 0404003