Comparison of CNI-based Regimen Versus CNI-free Regimen in Kidney Transplant Recipients.

Multi-center, Open-label, Prospective, Randomized, Parallel Group Study Investigating a CNI-free Regimen With Enteric-coated Mycophenolate Sodium and Everolimus in Comparison to Standard Therapy With Enteric-coated Mycophenolate Sodium and Ciclosporin Microemulsion in Stable Renal Transplant Patients

Calcineurin inhibitors (CNI), a potent immunosuppressive drug used in kidney transplant recipients to prevent graft rejection, may cause renal impairment. The aim of this study is to assess whether a CNI-free regimen with enteric-coated mycophenolate sodium and everolimus is as safe and well tolerated as a standard regimen consisting of enteric-coated mycophenolate sodium and cyclosporine microemulsion without a compromise in therapeutic efficacy while resulting in an improved renal function.

Study Overview

• Status: Terminated
• Conditions: Renal Transplantation
• Intervention / Treatment: Drug: Cyclosporin A (CsA); Drug: Tacrolimus; Drug: Enteric Coated - Mycophenolate Sodium (EC-MPS); Drug: Corticosteroids; Drug: Everolimus

• Study Type: Interventional
• Enrollment (Actual): 93
• Phase: Phase 4

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 10098
    • Novartis Investigative Site
  • Berlin, Germany, 13353
    • Novartis Investigative Site
  • Erlangen, Germany, 91054
    • Novartis Investigative Site
  • Essen, Germany, 45122
    • Novartis Investigative Site
  • Hannover, Germany, 30625
    • Novartis Investigative Site
  • Heidelberg, Germany, 69115
    • Novartis Investigative Site
  • Heilbronn, Germany, 74076
    • Novartis Investigative Site
  • Kaiserslautern, Germany, 67655
    • Novartis Investigative Site
  • Kiel, Germany, 24105
    • Novartis Investigative Site
  • Koeln, Germany, 51109
    • Novartis Investigative Site
  • Muenster, Germany, 48149
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Males or females, aged > 18 years, Maintenance renal transplant recipients at least 6 months post-transplantation, Patients with a serum creatinine < 2,5 mg/dL stable for at least three month (according to the investigator), Females capable of becoming pregnant had to have a negative serum pregnancy test within seven days prior to or at baseline, and were required to practice an approved method of birth control for the duration of the study and for a period of six weeks following discontinuation of study medication, even where there had been a history of infertility, Patients receiving Myfortic® (Myfortic dose . 720 mg/d) and Sandimmun® Optoral with or without corticosteroids as part of their immunosuppressive regimen for at least 1 month before baseline;

Exclusion Criteria:

More than one previous renal transplantation, Multi-organ recipients (e.g., kidney and pancreas) or previous transplant with any other organ, different from kidney, Patient with proteinuria > 1000 mg/day at baseline, Hypersensitivity to Certican®, Sandimmun® Optoral, Prograf®, mycophenolic acid, or other components of the formulation, Patients who had received an investigational drug within four weeks prior to baseline, Severe rejection (≥ Banff II acute rejection), recurrent acute rejection, or steroid resistant rejection within six months of enrollment, Thrombocytopenia (platelets < 100,000/mm³), with an absolute neutrophil count of < 1,500/mm³ or leukopenia (leukocytes < 4,000/mm³), or hemoglobin < 8 g/dL, Abnormal physical or laboratory findings of clinical significance within two weeks of study inclusion which at the investigator's discretion would interfere with the objectives of the study, Symptoms of significant somatic or mental illness. Inability to cooperate or communicate with the investigator, or patients who were unlikely to comply with the study requirements, or who were unable to give informed consent, History of malignancy during the last five years, except squamous or basal cell carcinoma of the skin, Patients who were HIV positive, or hepatitis C, or hepatitis B surface antigen positiveEvidence of severe liver disease (including abnormal liver enzyme profile, i.e. aspartate transaminase (AST), alanine aminotransferase (ALT) or total bilirubin > 3 times upper limit of normal (ULN), Females of childbearing potential who were planning to become pregnant, who were pregnant or lactating and/or who were unwilling to use effective means of contraception, Presence of a clinically significant infection requiring continued therapy, severe diarrhea, active peptic ulcer disease or uncontrolled diabetes mellitus that in the opinion of the investigator would interfere with the appropriate conduct of the study, Evidence of drug or alcohol abuse

Other protocol-defined exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Calcineurin Inhibitor (CNI) group; Participants received Cyclosporine A (CsA) plus Enteric Coated Mycophenolate Sodium (EC-MPS) plus corticosteroids, or Tacrolimus A (CsA) plus Enteric Coated Mycophenolate Sodium (EC-MPS) plus corticosteroids.	Drug: Cyclosporin A (CsA); The dose was based on the participants' blood level of C0h (80-150 ng/ml).; Other Names: Sandimmun Optoral; Drug: Tacrolimus; The dose was based on the participants' blood level of C0h (5-10 ng/ml).; Other Names: Prograf; Drug: Enteric Coated - Mycophenolate Sodium (EC-MPS); The dose was ≥ 720 mg/day.; Other Names: Myfortic; Drug: Corticosteroids; Corticosteroids were given according to local standard and/or the Investigators' discretion.
Experimental: Certican group; Participants were switched in a step-wise fashion from the CNI based regimen to Everolimus (RAD001).	Drug: Enteric Coated - Mycophenolate Sodium (EC-MPS); The dose was ≥ 720 mg/day.; Other Names: Myfortic; Drug: Corticosteroids; Corticosteroids were given according to local standard and/or the Investigators' discretion.; Drug: Everolimus; Participants, switching from the CsA based treatment, initially received everolimus 1.5 mg/day and then from day 7, 3 mg/day, and then from day 14, the dose was based on the participants' blood level (6-10 ng/ml). Participants, switching from the tacrolimus based treatment, initially received 3 mg/day and then from day 14, the dose was based on the participants' blood level (6-10 ng/ml).; Other Names: RAD001, Certican

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Renal Function	The analysis for this outcome measure was not perfomed because the analyses could not be powered for efficacy due to low recruitment.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biopsy Proven Acute Rejection, Graft Loss, and Death	The analysis for this outcome measure was not perfomed because the analyses could not be powered for efficacy due to low recruitment.	12 months
Occurrence of Treatment Failures	The analysis for this outcome measure was not perfomed because the analyses could not be powered for efficacy due to low recruitment.	12 months
Evolution of Renal Function	The analysis for this outcome measure was not perfomed because the analyses could not be powered for efficacy due to low recruitment.	Baseline, 12 months
Number of Participants Who Experienced Adverse Events and Death	Participants were monitored for adverse events, serious adverse events and deaths thorughout the prospective and follow-up phases of the study.	12 months
Changes in Cardiovascular Risk	The analysis for this outcome measure was not perfomed because the analyses could not be powered for efficacy due to low recruitment.	Baseline, 12 months
Changes in Proteinuria	The analysis for this outcome measure was not perfomed because the analyses could not be powered for efficacy due to low recruitment.	Baseline, 12 months

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start: November 1, 2005
• Primary Completion (Actual): March 1, 2013
• Study Completion (Actual): March 1, 2013

Study Registration Dates

• First Submitted: May 31, 2006
• First Submitted That Met QC Criteria: May 31, 2006
• First Posted (Estimate): June 2, 2006

Study Record Updates

• Last Update Posted (Estimate): August 28, 2014
• Last Update Submitted That Met QC Criteria: August 15, 2014
• Last Verified: August 1, 2014

More Information

Terms related to this study

• Keywords: enteric-coated mycophenolate sodium, everolimus, CNI-free regimen
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Tacrolimus; Mycophenolic Acid; Everolimus; Cyclosporine; Cyclosporins
• Other Study ID Numbers: CRAD001ADE02; 2005-001013-18

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No