Switch From Tacrolimus to Cyclosporin in the Treatment of Recurrent Hepatitis C After Liver Transplantation

Condition(s) targeted: Chronic Hepatitis C; Liver Transplantation

Intervention: cyclosporin (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: Rennes University Hospital

Official(s) and/or principal investigator(s):
Yvon Calmus, MD, PhD, Principal Investigator, Affiliation: Hôpital Cochin, Paris
Eric Bellissant, MD, PhD, Study Chair, Affiliation: CHU Rennes

Overall contact:
Yvon Calmus, MD, PhD, Phone: 33-1-5841-1699, Email: yvon.calmus@cch.aphp.fr

In France, 50% of hepatitis C virus carriers develop chronic clinical hepatitis, which may lead to cirrhosis and liver transplantation. Transplant infection by hepatitis C virus is constant after transplantation and recurrence causes chronic liver disease in 50 to 80% of cases. The aim of this study is to assess the efficacy of cyclosporin on C virological response. Patients included in the Transpeg 1 study and non-responder or with a recurrent disease will be switched from their tacrolimus therapy to cyclosporin, in association with a 1 year peginterferon alfa-2a / ribavirin bitherapy. Efficacy will be assessed by the percentage of patients with a negative qualitative PCR after 19 months of cyclosporin treatment.

Official title: Prospective, Open-Label, Single Arm Pilot Study Evaluating the Effect on Virological Response of the Switch From Tacrolimus to Cyclosporin Associated With a Peginterferon Alfa-2a / Ribavirin Bitherapy, in Non-Responder or With Recurrent VHC+ Disease Liver Transplanted Patients.

Study design: Treatment, Non-Randomized, Open Label, Uncontrolled, Single Group Assignment, Efficacy Study

Primary outcome: Prolonged virological response: percentage of patients with a negative qualitative PCR, 19 months after the initiation of cyclosporin treatment.

Secondary outcome:

Virological response 4, 7 and 13 months after the initiation of cyclosporin treatment

Histological response: METAVIR score at 19 months

Biological response: liver function at 4, 7, 13 and 19 months

Incidence of acute or chronic graft rejection at 19 months

Incidence of death, graft loss and retransplantation at 13 and 19 months

Renal function at 4, 7, 13 and 19 months

Incidence of treatment discontinuation at 4, 7, 13 and 19 months

Incidence of adverse events (cancers in particular).

Detailed description: In France, 50% of hepatitis C virus carriers develop chronic clinical hepatitis, which may lead to cirrhosis and liver transplantation. Transplant infection by hepatitis C virus is constant after transplantation. A main factor determining the severity of recurrent hepatitis C after transplantation may be immunosuppression. Thus optimization of immunosuppressive regimens might be a key aspect to improve the prognosis of chronic hepatitis C in transplanted patients. The two most frequently used immunosuppressive drugs are cyclosporin and tacrolimus. However, it has been shown that virus replication could be inhibited by cyclosporin, through the blockade of cyclophilins, decreasing hepatitis C viral load and improving liver function. These effects were not found with tacrolimus.

The aim of our study is to assess the efficacy on C virological response of the switch from tacrolimus to cyclosporin associated with a peginterferon alfa-2a / ribavirin bitherapy, in non-responder or with a recurrent VHC+ disease liver transplanted patients.

Patients will receive a 19 month cyclosporin treatment, associated during 12 months with a peginterferon alfa-2a / ribavirin bitherapy. Efficacy will be assessed by the percentage of patients with a negative qualitative PCR after 19 months of cyclosporin treatment.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Adults aged 18 or over,

- Who had been included in the Transpeg 1 study,

- Non-responders after a three month peginterferon alfa-2a / ribavirin bitherapy or with

a recurrent disease during the Transpeg 1 maintenance phase, whatever the randomization group (ribavirin or placebo),

- With a positive qualitative PCR at inclusion,

- With a METAVIR histologic score of 1 or more on the last biopsy (done within the 6

months preceding inclusion),

- Treated with tacrolimus for at least 6 months prior to inclusion,

- Having given a written informed consent.

Exclusion Criteria:

- Treatment with peginterferon or ribavirin within the 6 months preceding inclusion,

- Severe hepatocellular failure or decompensated cirrhosis,

- Acute graft rejection within the two months preceding inclusion, or signs of chronic

rejection on the last biopsy, or retransplantation since inclusion in the Transpeg 1 study,

- Treatment with cyclosporin for more than 6 months during the 24 months preceding

inclusion,

- Treatment with a mTOR inhibitor or with another investigational immunosuppressive

drug,

- Positive serology for HIV or HBV,

- Cancer (or history of other malignancy during the last 5 years) except patients

transplanted for hepatocellular carcinoma and basocellular or excised spinocellular carcinoma,

- Serious concomitant disease or acute or chronic disorder, other than the current

transplant, treated with steroids,

- Serious cardiac pathology within the last 6 months,

- Women with ongoing pregnancy or breast-feeding,

- Serious chronic renal failure (creatinine clearance < 30 ml/mn),

- Haemoglobin < 10 g/dl, platelets < 50 000/mm3 or neutrophils < 1000 / mm3,

- Abnormal TSH values,

- Inability to cooperate or to communicate with the investigator,

- Contraindications to ribavirin, peginterferon alfa-2a or cyclosporin.

Yvon Calmus, MD, PhD, Phone: 33-1-5841-1699, Email: yvon.calmus@cch.aphp.fr

Service de Chirurgie Générale - Hôpital Cochin, Paris 75679, France; Recruiting
Yvon Calmus, MD, Phone: 33-1-5841-1699, Email: yvon.calmus@cch.aphp.fr
Yvon Calmus, MD, PhD, Principal Investigator

Service des Maladies du Foie - Hôpital Pontchaillou, Rennes 35033, France; Recruiting
Richard Lorho, MD, Phone: 33-2-9928-5305, Email: richard.lorho@chu-rennes.fr
Richard Lorho, MD, Principal Investigator

Chirurgie Générale - Hôpital de la Conception, Marseille 13385, France; Recruiting
Danièle Botta-Fridlund, MD, Phone: 33-4-9138-3695, Email: dbotta@ap-hm.fr
Danièle Botta-Fridlund, MD, Principal Investigator

Service de Chirurgie Générale - Hôpital Edouard Herriot, Lyon 69437, France; Recruiting
Olivier Boillot, MD, Phone: 33-4-7211-6291, Email: boillot@cismsun.univ-lyon1.fr
Olivier Boillot, MD, Principal Investigator

Service des Maladies de l'Appareil Digestif - CHRU Claude Huriez, Lille 59037, France; Recruiting
Sébastien Dharancy, MD, Phone: 33-3-2044-5321, Email: s6@chru-lille.fr
Sébastien Dharancy, MD, Principal Investigator

Service d'Hépatogastroentérologie - Hôpital Beaujon, Clichy 92118, France; Recruiting
François Durand, MD, Phone: 33-1-4730-9440, Email: francois.durand@bjn.aphp.fr
François Durand, MD, Principal Investigator

Service d'Hépatologie et Gastroentérologie - CH Henri Mondor, Créteil 94010, France; Recruiting
Christophe Duvoux, MD, Phone: 33-1-4981-2353, Email: cduvoux@easynet.fr
Christophe Duvoux, MD, Principal Investigator

Chirurgie Viscérale et Digestive - Hôpital de l'Archet, Nice 06200, France; Recruiting
Jean Gugenheim, MD, Phone: 33-4-9203-6476, Email: gugenheim.j@chu-nice.fr
Jean Gugenheim, MD, Principal Investigator

Service d'Hépato-gastro-entérologie - Hôpital Saint Eloi, Montpellier 34295, France; Recruiting
Georges-Philippe Pageaux, MD, Phone: 33-4-6733-7381, Email: gp-pageaux@chu-montpellier.fr
Georges-Philippe Pageaux, MD, Principal Investigator

Service d'Hépato-gastro-entérologie - Hôpital de Rangueil, Toulouse 31403, France; Recruiting
Lionel Rostaing, MD, Phone: 33-5-6132-2677, Email: rostaing.l@chu-toulouse.fr
Lionel Rostaing, MD, Principal Investigator

Centre Hépato-Biliaire - Hôpital Paul Brousse, Villejuif 94804, France; Recruiting
Didier Samuel, MD, Phone: 33-1-4559-3331, Email: didier.samuel@pbr.aphp.fr
Didier Samuel, MD, Principal Investigator

Service d'Hépatologie - Hôpital Jean Minjoz, Besançon 25030, France; Recruiting
Claire Vanlemmens, MD, Phone: 33-3-8166-8594, Email: cvanlemmens@chu-besancon.fr
Claire Vanlemmens, MD, Principal Investigator

Service de Chirurgie Générale et Transplantation Multi-organe - Hôpital de la Hautepierre, Strasbourg 67098, France; Recruiting
Philippe Wolf, MD, Phone: 33-3-8812-7278, Email: philippe.wolf@chru-strasbourg.fr
Philippe Wolf, MD, Principal Investigator

Starting date: October 2006
Last updated: May 7, 2007