Evaluation of Early Conversion to Everolimus From Cyclosporine in de Novo Renal Transplant Recipients

A Controlled Randomized Open-label Multicenter Study Evaluating if Early Conversion to Everolimus (Certican) From Cyclosporine (Neoral) in de Novo Renal Transplant Recipients Can Improve Long-term Renal Function and Slow Down the Progression of Chronic Allograft Nephropathy

This study is designed to evaluate if early conversion to everolimus from cyclosporine in de novo renal transplant recipients can improve long-term renal function and slow down the progression of chronic allograft nephropathy

Study Overview

• Status: Completed
• Conditions: Renal Function
• Intervention / Treatment: Drug: everolimus; Drug: Enteric Coated Mycophenolate Sodium (EC-MPS); Drug: corticosteroids; Drug: Basiliximab; Drug: cyclosporine A

• Study Type: Interventional
• Enrollment (Actual): 204
• Phase: Phase 4

Contacts and Locations

Study Locations

• Denmark
  • Aarhus N, Denmark, 8200
    • Novartis Investigative Site
  • Copenhagen, Denmark, DK-2100
    • Novartis Investigative Site
  • Herlev, Denmark, 2730
    • Novartis Investigative Site
  • Odense C, Denmark, DK-5000
    • Novartis Investigative Site
• Norway
  • Oslo, Norway, 0424
    • Novartis Investigative Site
• Sweden
  • Goteborg, Sweden, 413 45
    • Novartis Investigative Site
  • Malmo, Sweden, 205 02
    • Novartis Investigative Site
  • Uppsala, Sweden, 751 85
    • 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:

• First or second single renal transplant from deceased or living donor

Exclusion criteria

• Recipient of organs other than a renal transplant
• Present malignancy (within the last 2 years) other than excised basal cell or squamous cell carcinoma of the skin
• Severe liver disease
• At the time of randomization 7 weeks after transplantation

In addition to the above criteria the following must be met at time of randomization:

Inclusion Criteria:

• Patients maintained on a triple immunosuppressive regime consisting of cyclosporine, Enteric coated mycophenolate, and corticosteroids
• Patients completed the first 7 weeks without experiencing any rejection

Exclusion Criteria:

• Graft loss
• Low hemoglobin value, low number of white blood cells or platelets
• High cholesterol values
• Proteinuria
• Wound healing problems
• Current severe major local or systemic infection
• Renal insufficiency

Other protocol-defined inclusion/exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Everolimus (CNI-free); Patients in this group were converted to everolimus immunosuppressive therapy. The patients in the everolimus group were treated with everolimus, off-label (CNI-free) use, and EC-MPS and corticosteroids in accordance with local practice and approved label. Conversion to everolimus was as follows: Day 1: begin everolimus 3 mg in the evening. Usual morning dose of CsA and 50% reduced evening dose of CsA Day 2: everolimus 2 mg in the morning and 2 mg in the evening, complete discontinuation of CsA Day 3 or 4, and onwards: everolimus according to trough level 6-10 ng/mL.The given total daily dose of the immunosuppressive drugs (everolimus) was divided into two (equal) doses, applied 12 hours apart.	Drug: everolimus; Everolimus (Certican®) tablets administered orally in two divided doses (b.i.d.) at a starting dose of 4 mg/day adjusted to target a trough blood concentration between 6 and 10 ng/mL in period 2.; Other Names: Certican; Drug: Enteric Coated Mycophenolate Sodium (EC-MPS); Target dose 1440 mg in the control group, target dose 1080 in the everolimus group (higher dose in the CsA group because of interactions of CsA on gastric reabsorption of mycophenolate); Other Names: Myfortic; Drug: corticosteroids; For both groups: minimum corticosteroid dose of 10 mg until week 12, 5-10 mg until month 12, month 12-36 corticosteroid treatment on investigator's descretion.; Other Names: Prednisolone; Drug: Basiliximab; Induction therapy 20 mg basiliximab on Day 0 prior to reperfusion and 20 mg on Day 4 post-TX.; Other Names: Simulect
Active Comparator: Control (CsA); Patients in the control group continued on an immunosuppressive regimen. The patients in this Control group were treated with CsA, EC-MPS and corticosteroids in accordance with local practice and approved label. The given total daily dose of the immunosuppressive drugs (CsA and EC-MPS) was divided into two (equal) doses, applied 12 hours apart.	Drug: Enteric Coated Mycophenolate Sodium (EC-MPS); Target dose 1440 mg in the control group, target dose 1080 in the everolimus group (higher dose in the CsA group because of interactions of CsA on gastric reabsorption of mycophenolate); Other Names: Myfortic; Drug: corticosteroids; For both groups: minimum corticosteroid dose of 10 mg until week 12, 5-10 mg until month 12, month 12-36 corticosteroid treatment on investigator's descretion.; Other Names: Prednisolone; Drug: Basiliximab; Induction therapy 20 mg basiliximab on Day 0 prior to reperfusion and 20 mg on Day 4 post-TX.; Other Names: Simulect; Drug: cyclosporine A; CsA (Sandimmun Neoral), based on C0-h levels 75-200 ng/mL or C2-h levels 700 900 ng/mL from randomization to Month 6, or C0-h levels 50-150 ng/mL or C2-h levels 600 800 ng/mL from Month 6 to Month 36, according to local method; Other Names: Sndimmun Neoral

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Measured Glomerular Filtration Rate	To compare the efficacy between treatment regimens by assessing the difference in renal function evaluated by mean measured glomerular filtration rate (mGFR) 12 months after renal transplantation (TX). The mGFR was measured using Iohexol or Cr-EDTA clearance according to local practice.	Month 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Measured Glomerular Filtration Rate	Progression of renal function measured by mean mGFR at 36 months after renal TX. The mGFR was measured using Iohexol or Cr-EDTA clearance according to local practice.	Month 36
Calculated Glomerular Filtration Rate	The GFR was calculated according to the Modification of Diet in Renal Disease Study Group (MDRD) method, the Cockcroft-Gault method, and the Nankivell formula. cGFR was calculated from blood samples collected at predefined time points.	Months 12, 36
Progression of Measured Glomerular Filtration Rate	Change in renal progression measured by mean mGFR from week 7 to Month 36	Week 7, Week 52, Month 36
Percentage of Participants Who Developed CAN (Chronic Allograft Nephropathy)	Assessed by protocol biopsies findings (Banff 1997 lesion scores and morphometry of the interstitial space)	Month 12, Month 36
Percentage of Participants With Biopsy Proven Acute Rejection (BPAR)	A BPAR was defined as a biopsy graded IA, IB, IIA, IIB, or III (Banff 97 classification). Biopsy graded IA: Significant interstitial infiltration (> 25% of parenchyma) and foci of moderate tubulitis (> 4 mononuclear cells/tubular cross section or group of 10 tubular cells). Biopsy grade IB: Significant interstitial infiltration (> 25% of parenchyma) and foci of severe tubulitis (> 10 mononuclear cells/tubular cross section or group of 10 tubular cells). Biopsy grade IIA: Mild to moderate intimal arteritis. Biopsy graded IIB: Severe intimal arteritis comprising > 25% of the lumenal area.	Months 12, 24, 36
Percentage of Participants With Graft Loss or Death	The allograft was presumed to be lost on the day the patient started dialysis and was not able to subsequently be removed from dialysis. If the patient underwent a graft nephrectomy, the day of nephrectomy was the day of graft loss. Graft loss was considered an SAE (serious adverse event).	Months 12, 24, 36
Time to Treatment Failure	Treatment failure was defined as graft loss or death.Time to treatment failure is shown as mean time to treatment failure.	Months 12, 24, 36
Percentage of Participants With Treatment Failures	Treatment failure was defined as graft loss or death.	Months 12, 24, 36
Time to First Malignancy	This is the time to first diagnosed malignancy. Malignancies (skin- or solid cancer) were listed whether they reoccurred in situ, were metastatic or de novo. This is shown as mean time.	Months 12, 24, 36
Lipid Profile for Apolipoprotein	Blood lipid levels of patients in both groups for Apolipoprotein (Apo) A1 and B.	Months 12, 24, 36
Lipid Profile for HDL-C, LDL-C,Total Cholesterol, and Triglycerides	Blood lipid levels of patients in both groups: HDL-C, LDL-C,Total cholesterol, and triglycerides.	Months 12, 24, 36
Number of Lipid-lowering Drugs Taken		Months 12, 24, 36
Percentage of Participants on Lipid-lowering Drugs		Months 12, 24, 36
Number of Antihypertensive Drugs Taken		Months 12, 24, 36
Percentage of Participants on Antihypertensive Drugs		Months 12, 24, 36
Proteinuria (Measured as Urine Albumin/Creatinine Ratio (mg/mmol))	Proteinuria is when a large amount of protein, that should remain circulating in a person's blood, is "spilled" into their urine and eliminated from the body.	Months 12, 24, 36
Percentage of Participants Who Had Donor Specific Antibodies (DSA)	Venous blood was drawn for donor specific (DSA) measurements prior to transplantation and at the final visit (36 months). The blood sample was first screened for the presence of PRA i.e. donor specific Immunoglobulin-G antibodies against specific HLA antigens. If PRA antibodies were detected, the blood sample was tested for specific DSAs on single antigen Luminex beads (coated with single HLA class I or II molecules). In this way, the specificity of these antibodies could be determined.	Month 36
Health-related Quality of Life (QoL) as Measured by EuroQoL EQ-5D	Health-related QoL was assessed using the EQ-5D questionnaire. The EQ-5D self-report questionnaire consists of the EQ-5D descriptive system that measures health-related quality of life on 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) each of which can take one of three responses. The responses record three levels of severity (no problems/moderate problems/severe problems) within a particular EQ-5D dimension. Scores are transformed to a range of 0-1, in which higher scores reflect better health status.	Before randomization, Months 12, 36

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start: March 1, 2008
• Primary Completion (Actual): May 1, 2013
• Study Completion (Actual): May 1, 2013

Study Registration Dates

• First Submitted: March 6, 2008
• First Submitted That Met QC Criteria: March 12, 2008
• First Posted (Estimate): March 13, 2008

Study Record Updates

• Last Update Posted (Estimate): August 13, 2014
• Last Update Submitted That Met QC Criteria: August 12, 2014
• Last Verified: August 1, 2014

More Information

Terms related to this study

• Keywords: De novo renal transplantation
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Dermatologic Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Prednisolone; Mycophenolic Acid; Everolimus; Basiliximab; Cyclosporine; Cyclosporins
• Other Study ID Numbers: CRAD001ASE01; 2007-000771-42 (EudraCT Number)