Clinical trial NCT01469884: Effect of Switching to Certican® in Viremia of Hepatitis C Virus in Adult Renal Allograft Recipients
Official title: 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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Renal Allograft
Hepatitis C
Keywords: Renal allograft recipients
Hepatitis C virus (HCV)
Certican
Calcineurin inhibitor(tacrolimus or cyclosporin)
Lead sponsor: Irmandade Santa Casa de Misericórdia de Porto Alegre
Sponsor class: OTHER
Collaborators: name: Novartis
First posted: 2011-11-10
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SUPPORTIVE_CARE

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

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Change from baseline in viral load of hepatitis C virus at 12 months after randomization.
timeFrame: Baseline,Months 3, 6, 9 and 12 after randomization
Secondary outcomes:
measure: Incidence of acute allograft rejection
timeFrame: Weeks 1, 2, 3, months 1, 3, 6, 9 and 12 after randomization
measure: Incidence of significant infections
timeFrame: Weeks1, 2, 3 and months 1, 3, 6,9 and 12 after randomization
measure: Development of proteinuria
timeFrame: Months 1, 3, 6, 9 and 12 after randomization
measure: Development of malignance
timeFrame: Weeks 1, 2, 3 and months 1, 3, 6, 9 and 12 after randomization
measure: Development of dyslipidemia
timeFrame: Months 1, 3, 6, 9 and 12 after randomization
measure: Development of liver impairment
timeFrame: Months 1, 3, 6, 9, and 12 after randomization
measure: Development of post-transplant diabetes
timeFrame: Months 1, 3, 6, 9 and 12
measure: Development of hypertension
timeFrame: Weeks 1, 2, 3 and months 1, 3, 6, 9 and 12 after randomization
measure: Graft loss survival
timeFrame: Weeks 1, 2 , 3 and months 1, 3 ,6, 9 and 12 after randomization
measure: Patient survival
timeFrame: Weeks 1, 2, 3 and months 1, 3, 6, 9 and 12 after randomization
Other outcomes:
Locations:
city: Porto Alegre
country: Brazil
facility: Irmandade Da Santa Casa de Misericórdia de Porto Alegre
state: Rio Grande Do Sul
Study officials:
affiliation: IRMANDADE DA SANTA CASA DE MISERICÓRDIA DE PORTO ALEGRE
name: Valter Garcia, Physician
role: PRINCIPAL_INVESTIGATOR
affiliation: IRMANDADE DA SANTA CASA DE MISERICÓRDIA DE PORTO ALEGRE
name: ELIZETE KEITEL, Physician
role: STUDY_CHAIR
affiliation: IRMANDADE DA SANTA CASA DE MISERICÓRDIA DE PORTO ALEGRE
name: MARIANA F RODRIGUES, PHARMACIST
role: STUDY_DIRECTOR
affiliation: IRMANDADE DA SANTA CASA DE MISERICÓRDIA DE PORTO ALEGRE
name: DIEGO GNATTA, PHARMACIST
role: STUDY_DIRECTOR
affiliation: IRMANDADE DA SANTA CASA DE MISERICÓRDIA DE PORTO ALEGRE
name: LARISSA S PACHECO, PHARMACIST
role: STUDY_DIRECTOR
affiliation: IRMANDADE DA SANTA CASA DE MISERICÓRDIA DE PORTO ALEGRE
name: BRUNA D CARDOSO, PHARMACIST
role: STUDY_DIRECTOR
affiliation: IRMANDADE DA SANTA CASA DE MISERICÓRDIA DE PORTO ALEGRE
name: RONIVAN L DAL PRA, PHARMACIST
role: STUDY_DIRECTOR
References:
citation: Benedetto, F. D.; Sandro, S. D.; Ballarin, R.; Guaraldi, G.; Gerunda, G. E. Rapamycin and HIV Replication in Liver Transplant Recipients. Transplantation, 9, 1040, 2010.
citation: Boletis JN, Iniotaki-Theodoraki A, Psichogiou M, Stamatiadis DN, Viglis JV, Kostakis A, Stavropoulos-Giokas C. Immune status in renal transplant recipients with hepatitis C virus infection. Transplant Proc. 2002 Dec;34(8):3205-8. doi: 10.1016/s0041-1345(02)03656-4. No abstract available.
citation: Gallego R, Henriquez F, Oliva E, Camacho R, Hernandez R, Hortal L, Sablon N, Quintana B, Santana R, Gonzalez F, Palop L, Vega N. Switching to sirolimus in renal transplant recipients with hepatitis C virus: a safe option. Transplant Proc. 2009 Jul-Aug;41(6):2334-6. doi: 10.1016/j.transproceed.2009.06.064.
citation: Ingsathit A, Thakkinstian A, Kantachuvesiri S, Sumethkul V. Different impacts of hepatitis B virus and hepatitis C virus on the outcome of kidney transplantation. Transplant Proc. 2007 Jun;39(5):1424-8. doi: 10.1016/j.transproceed.2007.02.068.
citation: Mas V, Alvarellos T, Chiurchiu C, Camps D, Massari P, de Boccardo G. Hepatitis C virus infection after renal transplantation: viral load and outcome. Transplant Proc. 2001 Feb-Mar;33(1-2):1791-3. doi: 10.1016/s0041-1345(00)02682-8. No abstract available.
citation: Meier-Kriesche HU, Ojo AO, Hanson JA, Kaplan B. Hepatitis C antibody status and outcomes in renal transplant recipients. Transplantation. 2001 Jul 27;72(2):241-4. doi: 10.1097/00007890-200107270-00013.
citation: Wagner D, Kniepeiss D, Schaffellner S, Jakoby E, Mueller H, Fahrleitner-Pammer A, Stiegler P, Tscheliessnigg KH, Iberer F. Sirolimus has a potential to influent viral recurrence in HCV positive liver transplant candidates. Int Immunopharmacol. 2010 Aug;10(8):990-3. doi: 10.1016/j.intimp.2010.05.006. Epub 2010 May 17.