Clinical trial NCT00375895: Switch From Tacrolimus to Cyclosporin in the Treatment of Recurrent Hepatitis C After Liver Transplantation
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 type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Chronic Hepatitis C
Evidence of Liver Transplantation
Keywords: Cyclosporin
Peginterferon
Ribavirin
Chronic hepatitis C
Liver transplantation
Lead sponsor: Rennes University Hospital
Sponsor class: OTHER
Collaborators: name: Novartis
First posted: 2006-09-13
Enrollment: 11
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility 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.

Primary outcomes:
measure: Prolonged virological response
timeFrame: 19 months
Secondary outcomes:
measure: Virological response 4, 7 and 13 months after the initiation of cyclosporin treatment
timeFrame: 4, 7 and 13 months
measure: Histological response: METAVIR score at 19 months
timeFrame: 19 months
measure: Biological response: liver function at 4, 7, 13 and 19 months
timeFrame: 4, 7, 13 and 19 months
measure: Incidence of acute or chronic graft rejection at 19 months
timeFrame: 19 months
measure: Incidence of death, graft loss and retransplantation at 13 and 19 months
timeFrame: 13 and 19 months
measure: Renal function at 4, 7, 13 and 19 months
timeFrame: 4, 7, 13 and 19 months
measure: Incidence of treatment discontinuation at 4, 7, 13 and 19 months
timeFrame: 4, 7, 13 and 19 months
measure: Incidence of adverse events (cancers in particular).
timeFrame: 19 months
Other outcomes:
Locations:
city: Besançon
country: France
facility: Service d'Hépatologie - Hôpital Jean Minjoz
city: Clichy
country: France
facility: Service d'Hépatogastroentérologie - Hôpital Beaujon
city: Créteil
country: France
facility: Service d'Hépatologie et Gastroentérologie - CH Henri Mondor
city: Lille
country: France
facility: Service des Maladies de l'Appareil Digestif - CHRU Claude Huriez
city: Lyon
country: France
facility: Service de Chirurgie Générale - Hôpital Edouard Herriot
city: Marseille
country: France
facility: Chirurgie Générale - Hôpital de la Conception
city: Montpellier
country: France
facility: Service d'Hépato-gastro-entérologie - Hôpital Saint Eloi
city: Nice
country: France
facility: Chirurgie Viscérale et Digestive - Hôpital de l'Archet
city: Paris
country: France
facility: Service de Chirurgie Générale - Hôpital Cochin
city: Rennes
country: France
facility: Service des Maladies du Foie - Hôpital Pontchaillou
city: Strasbourg
country: France
facility: Service de Chirurgie Générale et Transplantation Multi-organe - Hôpital de la Hautepierre
city: Toulouse
country: France
facility: Service d'Hépato-gastro-entérologie - Hôpital de Rangueil
city: Villejuif
country: France
facility: Centre Hépato-Biliaire - Hôpital Paul Brousse
Study officials:
affiliation: Hôpital Cochin, Paris
name: Yvon Calmus, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU Rennes
name: Eric Bellissant, MD, PhD
role: STUDY_CHAIR
References: