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

Primary Purpose

Renal Allograft, Hepatitis C

Status
Completed
Phase
Phase 4
Locations
Brazil
Study Type
Interventional
Intervention
Everolimus
Cyclosporine
Tacrolimus
Sponsored by
Irmandade Santa Casa de Misericórdia de Porto Alegre
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional supportive care trial for Renal Allograft focused on measuring Renal allograft recipients, Hepatitis C virus (HCV), Certican, Calcineurin inhibitor(tacrolimus or cyclosporin)

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Irmandade Da Santa Casa de Misericórdia de Porto Alegre

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Certican®

Tacrolimus or Cyclosporine

Arm Description

Arm1(conversion):Certican®+mycophenolate+prednisone

Arm2(maintained):Tacrolimus or Cyclosporine+mycophenolate+prednisone

Outcomes

Primary Outcome Measures

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)

Secondary Outcome Measures

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.
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.
Development of proteinuria
Spot urine sample for protein and creatinine will be performed.
Development of malignance
Medical evaluation will be performed during the protocol visits and if necessary biopsy and exams of imaging to confirm any suspected.
Development of dyslipidemia
Lipid levels: total cholesterol, HLD, LDL and triglycerides will be performed.
Development of liver impairment
Blood chemistry: TGO/AST, TGP/ALT , GGT and alkaline phosphatase will be performed.
Development of post-transplant diabetes
Blood chemistry: Glucose will be performed.
Development of hypertension
Vital signs will be performed
Graft loss survival
Graft survival will be evaluated by our team doctor.
Patient survival
Subject survival will be evaluated by our team doctor

Full Information

First Posted
November 1, 2011
Last Updated
April 1, 2015
Sponsor
Irmandade Santa Casa de Misericórdia de Porto Alegre
Collaborators
Novartis
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1. Study Identification

Unique Protocol Identification Number
NCT01469884
Brief Title
Effect of Switching to Certican® in Viremia of Hepatitis C Virus in Adult Renal Allograft Recipients
Acronym
CONCERVIC
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

2. Study Status

Record Verification Date
April 2015
Overall Recruitment Status
Completed
Study Start Date
November 2011 (undefined)
Primary Completion Date
April 2015 (Actual)
Study Completion Date
April 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Irmandade Santa Casa de Misericórdia de Porto Alegre
Collaborators
Novartis

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Renal Allograft, Hepatitis C
Keywords
Renal allograft recipients, Hepatitis C virus (HCV), Certican, Calcineurin inhibitor(tacrolimus or cyclosporin)

7. Study Design

Primary Purpose
Supportive Care
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
30 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Certican®
Arm Type
Experimental
Arm Description
Arm1(conversion):Certican®+mycophenolate+prednisone
Arm Title
Tacrolimus or Cyclosporine
Arm Type
Active Comparator
Arm Description
Arm2(maintained):Tacrolimus or Cyclosporine+mycophenolate+prednisone
Intervention Type
Drug
Intervention Name(s)
Everolimus
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Cyclosporine
Intervention Description
Trough level should be between 100 and 200ng/ml.
Intervention Type
Drug
Intervention Name(s)
Tacrolimus
Intervention Description
Trough level should be between 5 and 10ng/ml.
Primary Outcome Measure Information:
Title
Change from baseline in viral load of hepatitis C virus at 12 months after randomization.
Description
HCV viremia will be measured by polymerase chain reaction (PCR)
Time Frame
Baseline,Months 3, 6, 9 and 12 after randomization
Secondary Outcome Measure Information:
Title
Incidence of acute allograft rejection
Description
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.
Time Frame
Weeks 1, 2, 3, months 1, 3, 6, 9 and 12 after randomization
Title
Incidence of significant infections
Description
During the study visits the patient will be evaluated by a doctor and it will perform blood tests to assess their clinical conditions.
Time Frame
Weeks1, 2, 3 and months 1, 3, 6,9 and 12 after randomization
Title
Development of proteinuria
Description
Spot urine sample for protein and creatinine will be performed.
Time Frame
Months 1, 3, 6, 9 and 12 after randomization
Title
Development of malignance
Description
Medical evaluation will be performed during the protocol visits and if necessary biopsy and exams of imaging to confirm any suspected.
Time Frame
Weeks 1, 2, 3 and months 1, 3, 6, 9 and 12 after randomization
Title
Development of dyslipidemia
Description
Lipid levels: total cholesterol, HLD, LDL and triglycerides will be performed.
Time Frame
Months 1, 3, 6, 9 and 12 after randomization
Title
Development of liver impairment
Description
Blood chemistry: TGO/AST, TGP/ALT , GGT and alkaline phosphatase will be performed.
Time Frame
Months 1, 3, 6, 9, and 12 after randomization
Title
Development of post-transplant diabetes
Description
Blood chemistry: Glucose will be performed.
Time Frame
Months 1, 3, 6, 9 and 12
Title
Development of hypertension
Description
Vital signs will be performed
Time Frame
Weeks 1, 2, 3 and months 1, 3, 6, 9 and 12 after randomization
Title
Graft loss survival
Description
Graft survival will be evaluated by our team doctor.
Time Frame
Weeks 1, 2 , 3 and months 1, 3 ,6, 9 and 12 after randomization
Title
Patient survival
Description
Subject survival will be evaluated by our team doctor
Time Frame
Weeks 1, 2, 3 and months 1, 3, 6, 9 and 12 after randomization

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Valter Garcia, Physician
Organizational Affiliation
IRMANDADE DA SANTA CASA DE MISERICÓRDIA DE PORTO ALEGRE
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
ELIZETE KEITEL, Physician
Organizational Affiliation
IRMANDADE DA SANTA CASA DE MISERICÓRDIA DE PORTO ALEGRE
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
MARIANA F RODRIGUES, PHARMACIST
Organizational Affiliation
IRMANDADE DA SANTA CASA DE MISERICÓRDIA DE PORTO ALEGRE
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
DIEGO GNATTA, PHARMACIST
Organizational Affiliation
IRMANDADE DA SANTA CASA DE MISERICÓRDIA DE PORTO ALEGRE
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
LARISSA S PACHECO, PHARMACIST
Organizational Affiliation
IRMANDADE DA SANTA CASA DE MISERICÓRDIA DE PORTO ALEGRE
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
BRUNA D CARDOSO, PHARMACIST
Organizational Affiliation
IRMANDADE DA SANTA CASA DE MISERICÓRDIA DE PORTO ALEGRE
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
RONIVAN L DAL PRA, PHARMACIST
Organizational Affiliation
IRMANDADE DA SANTA CASA DE MISERICÓRDIA DE PORTO ALEGRE
Official's Role
Study Director
Facility Information:
Facility Name
Irmandade Da Santa Casa de Misericórdia de Porto Alegre
City
Porto Alegre
State/Province
Rio Grande Do Sul
ZIP/Postal Code
90020090
Country
Brazil

12. IPD Sharing Statement

Citations:
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.
Results Reference
background
PubMed Identifier
12493421
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.
Results Reference
background
PubMed Identifier
19715912
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.
Results Reference
background
PubMed Identifier
17580153
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.
Results Reference
background
Citation
Mas, V.; Alvarellos, T.; Chiurchiu, C.; Camps, D.; Massari, P.; Boccardo, G. Hepatitis C Virus Infection After Renal Transplantation: Viral Load and Outcome. Transplantation Proceedings, 33, 1791-1793, 2001. Ridruejo, E.; Cusumano, A.; Diaz, C.; Dávalos Michel. M.; Jost, L.; Jost, L.; Soler Pujol, G.; Mandó, O. G.; Vilches, A. Hepatitis C Virus Infection and Outcome of Renal Transplantation. Transplantation Proceedings , 39, 3127-3130, 2007.
Results Reference
background
PubMed Identifier
11477346
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.
Results Reference
background
PubMed Identifier
20483386
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.
Results Reference
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Effect of Switching to Certican® in Viremia of Hepatitis C Virus in Adult Renal Allograft Recipients

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