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

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2013 by Irmandade Santa Casa de Misericórdia de Porto Alegre
Sponsor:
Collaborator:
Novartis
Information provided by (Responsible Party):
Valter Duro Garcia, Irmandade Santa Casa de Misericórdia de Porto Alegre
ClinicalTrials.gov Identifier:
NCT01469884
First received: November 1, 2011
Last updated: March 27, 2013
Last verified: March 2013
  Purpose

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


Condition Intervention Phase
Renal Allograft
Hepatitis C
Drug: Everolimus
Drug: Cyclosporine
Drug: Tacrolimus
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Supportive Care
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.

Resource links provided by NLM:


Further study details as provided by Irmandade Santa Casa de Misericórdia de Porto Alegre:

Primary Outcome Measures:
  • Change from baseline in viral load of hepatitis C virus at 12 months after randomization. [ Time Frame: Baseline,Months 3, 6, 9 and 12 after randomization ] [ Designated as safety issue: No ]
    HCV viremia will be measured by polymerase chain reaction (PCR)


Secondary Outcome Measures:
  • Incidence of acute allograft rejection [ Time Frame: Weeks 1, 2, 3, months 1, 3, 6, 9 and 12 after randomization ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Weeks1, 2, 3 and months 1, 3, 6,9 and 12 after randomization ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Months 1, 3, 6, 9 and 12 after randomization ] [ Designated as safety issue: Yes ]
    Spot urine sample for protein and creatinine will be performed.

  • Development of malignance [ Time Frame: Weeks 1, 2, 3 and months 1, 3, 6, 9 and 12 after randomization ] [ Designated as safety issue: Yes ]
    Medical evaluation will be performed during the protocol visits and if necessary biopsy and exams of imaging to confirm any suspected.

  • Development of dyslipidemia [ Time Frame: Months 1, 3, 6, 9 and 12 after randomization ] [ Designated as safety issue: Yes ]
    Lipid levels: total cholesterol, HLD, LDL and triglycerides will be performed.

  • Development of liver impairment [ Time Frame: Months 1, 3, 6, 9, and 12 after randomization ] [ Designated as safety issue: Yes ]
    Blood chemistry: TGO/AST, TGP/ALT , GGT and alkaline phosphatase will be performed.

  • Development of post-transplant diabetes [ Time Frame: Months 1, 3, 6, 9 and 12 ] [ Designated as safety issue: Yes ]
    Blood chemistry: Glucose will be performed.

  • Development of hypertension [ Time Frame: Weeks 1, 2, 3 and months 1, 3, 6, 9 and 12 after randomization ] [ Designated as safety issue: Yes ]
    Vital signs will be performed

  • Graft loss survival [ Time Frame: Weeks 1, 2 , 3 and months 1, 3 ,6, 9 and 12 after randomization ] [ Designated as safety issue: Yes ]
    Graft survival will be evaluated by our team doctor.

  • Patient survival [ Time Frame: Weeks 1, 2, 3 and months 1, 3, 6, 9 and 12 after randomization ] [ Designated as safety issue: Yes ]
    Subject survival will be evaluated by our team doctor


Estimated Enrollment: 30
Study Start Date: November 2011
Estimated Study Completion Date: September 2013
Estimated Primary Completion Date: September 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Certican®
Arm1(conversion):Certican®+mycophenolate+prednisone
Drug: Everolimus
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.
Active Comparator: Tacrolimus or Cyclosporine
Arm2(maintained):Tacrolimus or Cyclosporine+mycophenolate+prednisone
Drug: Cyclosporine
Trough level should be between 100 and 200ng/ml.
Drug: Tacrolimus
Trough level should be between 5 and 10ng/ml.

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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01469884

Contacts
Contact: Valter Garcia, Physician 55 51 3214 8640 vdurogarcia@terra.com.br
Contact: Elizete Keitel, Physician 55 51 3214 8640 keitel@terra.com.br

Locations
Brazil
Irmandade Da Santa Casa de Misericórdia de Porto Alegre Recruiting
Porto Alegre, Rio Grande Do Sul, Brazil, 90020090
Contact: VALTER D GARCIA, PHYSICIAN    55 51 3214 8640    vdurogarcia@terra.com.br   
Contact: ELIZETE KEITEL, PHYSICIAN    55 51 3214 8640    keitel@terra.com.br   
Sub-Investigator: ELIZETE KEITEL, PHYSICIAN         
Principal Investigator: VALTER D GARCIA, PHYSICIAN         
Sub-Investigator: RONIVAN L DAL PRA, PHARMACIST         
Sub-Investigator: DIEGO GNATTA, PHARMACIST         
Sub-Investigator: MARIANA F RODRIGUES, PHARMACIST         
Sub-Investigator: LARISSA S PACHECO, PHARMACIST         
Sub-Investigator: BRUNA D CARDOSO, PHARMACIST         
Sponsors and Collaborators
Irmandade Santa Casa de Misericórdia de Porto Alegre
Novartis
Investigators
Principal Investigator: Valter Garcia, Physician IRMANDADE DA SANTA CASA DE MISERICÓRDIA DE PORTO ALEGRE
Study Chair: ELIZETE KEITEL, Physician IRMANDADE DA SANTA CASA DE MISERICÓRDIA DE PORTO ALEGRE
Study Director: MARIANA F RODRIGUES, PHARMACIST IRMANDADE DA SANTA CASA DE MISERICÓRDIA DE PORTO ALEGRE
Study Director: DIEGO GNATTA, PHARMACIST IRMANDADE DA SANTA CASA DE MISERICÓRDIA DE PORTO ALEGRE
Study Director: LARISSA S PACHECO, PHARMACIST IRMANDADE DA SANTA CASA DE MISERICÓRDIA DE PORTO ALEGRE
Study Director: BRUNA D CARDOSO, PHARMACIST IRMANDADE DA SANTA CASA DE MISERICÓRDIA DE PORTO ALEGRE
Study Director: RONIVAN L DAL PRA, PHARMACIST IRMANDADE DA SANTA CASA DE MISERICÓRDIA DE PORTO ALEGRE
  More Information

Publications:
Responsible Party: Valter Duro Garcia, PHYSICIAN NEPHROLOGY, Irmandade Santa Casa de Misericórdia de Porto Alegre
ClinicalTrials.gov Identifier: NCT01469884     History of Changes
Other Study ID Numbers: CRAD001, CRAD001ABR20T
Study First Received: November 1, 2011
Last Updated: March 27, 2013
Health Authority: Brazil: Ethics Committee

Keywords provided by Irmandade Santa Casa de Misericórdia de Porto Alegre:
Renal allograft recipients
Hepatitis C virus (HCV)
Certican
Calcineurin inhibitor(tacrolimus or cyclosporin)

Additional relevant MeSH terms:
Hepatitis
Hepatitis A
Hepatitis C
Digestive System Diseases
Enterovirus Infections
Flaviviridae Infections
Hepatitis, Viral, Human
Liver Diseases
Picornaviridae Infections
RNA Virus Infections
Virus Diseases
Cyclosporine
Cyclosporins
Everolimus
Sirolimus
Tacrolimus
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Antineoplastic Agents
Antirheumatic Agents
Dermatologic Agents
Enzyme Inhibitors
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on November 24, 2014