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

Phase 3

Terminated

• Conditions: Chronic Hepatitis C; Evidence of Liver Transplantation
• Interventions: Drug: ciclosporin

• Registration Number: NCT00375895
• Lead Sponsor: Rennes University Hospital

Brief Summary

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.

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.

Study Timeline

• Study Start: 2006-06
• Study First Submitted: 2006-09-12
• Study First Submitted QC: 2006-09-12
• Study First Posted: 2006-09-13
• Primary Completion: 2008-10
• Study Completion: 2009-12
• Status Verified: 2012-03
• Last Update Submitted: 2012-03-01
• Last Update Posted: 2012-03-02

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 11

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Ciclosporin	ciclosporin	-

Primary Outcome Measures

Name	Time	Method
Prolonged virological response	19 months	Percentage of patients with a negative qualitative PCR, 19 months after the initiation of cyclosporin treatment.

Secondary Outcome Measures

Name	Time	Method
Virological response 4, 7 and 13 months after the initiation of cyclosporin treatment	4, 7 and 13 months	Percentage of patient with negative or decreased quantitative PCR
Histological response: METAVIR score at 19 months	19 months
Biological response: liver function at 4, 7, 13 and 19 months	4, 7, 13 and 19 months	Transaminases, gammaGT, alcalin phosphatase, total bilirubin.
Incidence of acute or chronic graft rejection at 19 months	19 months
Incidence of death, graft loss and retransplantation at 13 and 19 months	13 and 19 months
Renal function at 4, 7, 13 and 19 months	4, 7, 13 and 19 months	Creatinin clearance
Incidence of treatment discontinuation at 4, 7, 13 and 19 months	4, 7, 13 and 19 months
Incidence of adverse events (cancers in particular).	19 months

Trial Locations

Locations (13)

Service d'Hépatologie - Hôpital Jean Minjoz; 🇫🇷 Besançon, France

Service d'Hépatogastroentérologie - Hôpital Beaujon; 🇫🇷 Clichy, France

Service d'Hépatologie et Gastroentérologie - CH Henri Mondor; 🇫🇷 Créteil, France

Service des Maladies de l'Appareil Digestif - CHRU Claude Huriez; 🇫🇷 Lille, France

Service de Chirurgie Générale - Hôpital Edouard Herriot; 🇫🇷 Lyon, France

Chirurgie Générale - Hôpital de la Conception; 🇫🇷 Marseille, France

Service d'Hépato-gastro-entérologie - Hôpital Saint Eloi; 🇫🇷 Montpellier, France

Chirurgie Viscérale et Digestive - Hôpital de l'Archet; 🇫🇷 Nice, France

Service de Chirurgie Générale - Hôpital Cochin; 🇫🇷 Paris, France

Service des Maladies du Foie - Hôpital Pontchaillou; 🇫🇷 Rennes, France

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