Effect of Switching to Certican® in Viremia of Hepatitis C Virus in Adult Renal Allograft Recipients

Study Overview
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Brief Summary
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Compare the viral load of hepatitis c virus in patients converted to certican versus patients who are maintained on calcineurin inhibitor.

Detailed Description
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The infection by hepatitis C virus (HCV) is the leading cause of chronic liver disease in renal transplant recipients. The prevalence of pretransplantation anti-HCV is 11% to 49%. The impact of HCV infection on patient survival after renal transplant remains controversial. Some studies also showed that patients undergoing renal transplantation anti-HCV positive are associated with a reduction in graft and patient survival.Chronic infection of HCV is associated with an increased number of infections. In HCV positive renal transplant patients have been shown that there is an increase from four to seven times in HCV viremia after transplantation compared to pretransplant. To prevent viral replication, immunosuppression must be adapted, involving a balance between control of viral replication and rejection. Biochemically, the NS5A protein has been linked to increased replication of the hepatitis C virus through p70S6K phosphopeptides. Sirolimus as inhibitor of pathway mTOR/p70S6K reduced in vivo phosphorylation of NS5A phosphopeptides and thus viral replication. Moreover, the mTOR protein has been proven in vitron to have a protective role against apoptosis in HCV infected cells (WAGNER et al., 2010). Wagner et al. (2010) showed a beneficial effect of sirolimus on viral recurrence monitored by transaminases and viral load as well as by histological data. They also reported the improved survival after liver transplantation due to hepatitis C for patients receiving sirolimus rather than calcineurin inhibitor-based regimens. In the literature there have already been reported good virological control of HCV among liver transplant recipients after conversion to SRL and the reduction of hepatitis C virus recurrence (GALLEGO et al., 2009; BENEDETTOET al., 2010). Everolimus has shown a potent inhibitor of mTOR and has been widely used as an immunosuppressive agent in kidney transplant, but no reported effects on HCV progression was found in the literature.

Official Title
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A Prospective, Single-center, Open-label, Pilot Study to Investigate the Effect of Switching to Certican® in Viremia of Hepatitis C Virus in Adult Renal Allograft Recipients.

Conditions
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Renal Allograft, Hepatitis C

Intervention / Treatment
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* Drug: Everolimus
* Drug: Cyclosporine
* Drug: Tacrolimus


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Age ≥ 18 years at the time of screening; Subjects between the first and tenth year after renal transplantation; Subjects with positive serology for hepatitis C; Subjects receiving calcineurin inhibitor (tacrolimus or cyclosporine) plus mycophenolate sodium or mofetil plus prednisone since the first month post-transplant; Subjects with no acute rejection episode in the last 3 month; Women of childbearing potential (CBP) with a negative pregnancy test at screening (urine or serum; Women of CBP and men with sexual partners of CBP must agree to use a medically acceptable method of contraception throughout the study. The investigator will determine which contraceptive method more effective and appropriate for each study subject. Acceptable methods of contraception include oral contraceptives, barrier methods (eg, diaphragm or condom with spermicide) and intrauterine devices. Exclusion criteria: Subjects who, in the opinion of the investigator, are not able to complete the study; Recipients of multiple organ transplant (i.e., prior or concurrent transplantation of a non-renal allograft; Subjects with a calculated GFR < 30ml/min (abbreviated MDRD formula; Subjects with Urinary protein/creatinine > 0.5; Renal biopsy with score ≥ Banff grade II interstitial fibrosis and tubular atrophy (Banff 2007; Subjects with a history of biopsy-proven acute rejection within 12 weeks of enrollment; Known or suspected hypersensitivity to inhibitor of mTOR; Subjects with a history of primary or recurrent FSGS, membranous glomerulonephritis (MGN) or membranoproliferative glomerulonephritis (MPGN); Evidence of any active systemic or localized major infection; Use of any investigational drug or treatment up to 4 weeks before enrollment; Immunosuppressive therapies other than those described by this protocol; Planned systemic treatment with voriconazole, cisapride or ketoconazole that will not be discontinued before randomization; Prior treatment with aminoglycosides, amphotericin B, cisplatin or other drugs associated with renal dysfunction that is not discontinued before screening; Subjects with a screening total white blood cell count (WBC) ≤ 2000/mm3, hemoglobin ≤ 10g/dL and platelet count ≤ 100000/mm3; TGO/AST, TGP/ALT and bilirubins with values three times higher than reference values; Fasting triglycerides ≥ 400 mg/dL, fasting total cholesterol ≥ 350 mg/dL or LDL-cholesterol ≥ 160mg/dL despite the use of optimal lipid-lowering therapy; History of malignancy within 3 years before enrollment other than adequately treated basal cell or squamous cell carcinoma of the skin; Subjects who are known to be human immunodeficiency virus (HIV) positive or hepatitis B positive; Chronic hepatic failure.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Certican®<br>Arm1(conversion):Certican®+mycophenolate+prednisone | Drug: Everolimus<br>* The conversion will be performed abruptly for all patients. Calcineurin inhibitor will be discontinued one day before the day of conversion (Day 1). Everolimus will be introduced on day 1 at dose of 3 mg/d (1,5mg bid), and then everolimus trough levels will be adjusted to achieve 6-10 ng/ml.<br>|
| Active Comparator: Tacrolimus or Cyclosporine<br>Arm2(maintained):Tacrolimus or Cyclosporine+mycophenolate+prednisone | Drug: Cyclosporine<br>* Trough level should be between 100 and 200ng/ml.<br>Drug: Tacrolimus<br>* Trough level should be between 5 and 10ng/ml.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in viral load of hepatitis C virus at 12 months after randomization. | HCV viremia will be measured by polymerase chain reaction (PCR) | Baseline,Months 3, 6, 9 and 12 after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of acute allograft rejection | All patients will perform at least 07 protocol visits and should be performed renal biopsy during screening phase and during the follow up if present renal dysfunction or proteinuria. | Weeks 1, 2, 3, months 1, 3, 6, 9 and 12 after randomization | 
| Incidence of significant infections | During the study visits the patient will be evaluated by a doctor and it will perform blood tests to assess their clinical conditions. | Weeks1, 2, 3 and months 1, 3, 6,9 and 12 after randomization | 
| Development of proteinuria | Spot urine sample for protein and creatinine will be performed. | Months 1, 3, 6, 9 and 12 after randomization | 
| Development of malignance | Medical evaluation will be performed during the protocol visits and if necessary biopsy and exams of imaging to confirm any suspected. | Weeks 1, 2, 3 and months 1, 3, 6, 9 and 12 after randomization | 
| Development of dyslipidemia | Lipid levels: total cholesterol, HLD, LDL and triglycerides will be performed. | Months 1, 3, 6, 9 and 12 after randomization | 
| Development of liver impairment | Blood chemistry: TGO/AST, TGP/ALT , GGT and alkaline phosphatase will be performed. | Months 1, 3, 6, 9, and 12 after randomization | 
| Development of post-transplant diabetes | Blood chemistry: Glucose will be performed. | Months 1, 3, 6, 9 and 12 | 
| Development of hypertension | Vital signs will be performed | Weeks 1, 2, 3 and months 1, 3, 6, 9 and 12 after randomization | 
| Graft loss survival | Graft survival will be evaluated by our team doctor. | Weeks 1, 2 , 3 and months 1, 3 ,6, 9 and 12 after randomization | 
| Patient survival | Subject survival will be evaluated by our team doctor | Weeks 1, 2, 3 and months 1, 3, 6, 9 and 12 after randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Renal allograft recipients, Hepatitis C virus (HCV), Certican, Calcineurin inhibitor(tacrolimus or cyclosporin)