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

Chronic Hepatitis C Clinical Trial

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.

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00375895
• Other study ID #: EudraCT 2006-002714-35
• Secondary ID: LOC/06-05CIC0203
• Status: Terminated
• Phase: Phase 3
• First received: September 12, 2006
• Last updated: March 1, 2012
• Start date: June 2006
• Est. completion date: December 2009

Study information

• Verified date: March 2012
• Source: Rennes University Hospital
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 11
• Est. completion date: December 2009
• Est. primary completion date: October 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Chronic Hepatitis C
• Evidence of Liver Transplantation
• Hepatitis
• Hepatitis A
• Hepatitis C
• Hepatitis C, Chronic
• Hepatitis, Chronic

Intervention

Drug:
• ciclosporin
ciclosporin administered orally twice a day, at the initial dosing of 2.5 mg/kg/d, adjusted to obtain a C2 concentration of 600 ng/ml associated with the usual ribavirin and PEGinterferon bitherapy.

Locations

Country	Name	City	State
France	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	Service de Chirurgie Générale et Transplantation Multi-organe - Hôpital de la Hautepierre	Strasbourg
France	Service d'Hépato-gastro-entérologie - Hôpital de Rangueil	Toulouse
France	Centre Hépato-Biliaire - Hôpital Paul Brousse	Villejuif

Sponsors (2)

Lead Sponsor	Collaborator
Rennes University Hospital	Novartis

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Prolonged virological response	Percentage of patients with a negative qualitative PCR, 19 months after the initiation of cyclosporin treatment.	19 months	No
Secondary	Virological response 4, 7 and 13 months after the initiation of cyclosporin treatment	Percentage of patient with negative or decreased quantitative PCR	4, 7 and 13 months	No
Secondary	Histological response: METAVIR score at 19 months		19 months	No
Secondary	Biological response: liver function at 4, 7, 13 and 19 months	Transaminases, gammaGT, alcalin phosphatase, total bilirubin.	4, 7, 13 and 19 months	No
Secondary	Incidence of acute or chronic graft rejection at 19 months		19 months	No
Secondary	Incidence of death, graft loss and retransplantation at 13 and 19 months		13 and 19 months	No
Secondary	Renal function at 4, 7, 13 and 19 months	Creatinin clearance	4, 7, 13 and 19 months	Yes
Secondary	Incidence of treatment discontinuation at 4, 7, 13 and 19 months		4, 7, 13 and 19 months	Yes
Secondary	Incidence of adverse events (cancers in particular).		19 months	Yes