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

• ClinicalTrials.gov Identifier: NCT00634920
• Recruitment Status: Completed
• First Posted: March 13, 2008
• Results First Posted: August 13, 2014
• Last Update Posted: August 13, 2014
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Renal Function	Drug: everolimus; Drug: cyclosporine A; Drug: Enteric Coated Mycophenolate Sodium (EC-MPS); Drug: corticosteroids; Drug: Basiliximab	Phase 4

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 204 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: March 2008
• Actual Primary Completion Date: May 2013
• Actual Study Completion Date: May 2013

Arms and Interventions

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 Name: 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 Name: 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 Name: Prednisolone; Drug: Basiliximab; Induction therapy 20 mg basiliximab on Day 0 prior to reperfusion and 20 mg on Day 4 post-TX.; Other Name: 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: 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 Name: Sndimmun Neoral; 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 Name: 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 Name: Prednisolone; Drug: Basiliximab; Induction therapy 20 mg basiliximab on Day 0 prior to reperfusion and 20 mg on Day 4 post-TX.; Other Name: Simulect

Outcome Measures

Primary Outcome Measures :

1. Measured Glomerular Filtration Rate [ Time Frame: Month 12 ]
   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.

Secondary Outcome Measures :

1. Measured Glomerular Filtration Rate [ Time Frame: Month 36 ]
   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.
2. Calculated Glomerular Filtration Rate [ Time Frame: Months 12, 36 ]
   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.
3. Progression of Measured Glomerular Filtration Rate [ Time Frame: Week 7, Week 52, Month 36 ]
   Change in renal progression measured by mean mGFR from week 7 to Month 36
4. Percentage of Participants Who Developed CAN (Chronic Allograft Nephropathy) [ Time Frame: Month 12, Month 36 ]
   Assessed by protocol biopsies findings (Banff 1997 lesion scores and morphometry of the interstitial space)
5. Percentage of Participants With Biopsy Proven Acute Rejection (BPAR) [ Time Frame: Months 12, 24, 36 ]
   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.
6. Percentage of Participants With Graft Loss or Death [ Time Frame: Months 12, 24, 36 ]
   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).
7. Time to Treatment Failure [ Time Frame: Months 12, 24, 36 ]
   Treatment failure was defined as graft loss or death.Time to treatment failure is shown as mean time to treatment failure.
8. Percentage of Participants With Treatment Failures [ Time Frame: Months 12, 24, 36 ]
   Treatment failure was defined as graft loss or death.
9. Time to First Malignancy [ Time Frame: Months 12, 24, 36 ]
   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.
10. Lipid Profile for Apolipoprotein [ Time Frame: Months 12, 24, 36 ]
    Blood lipid levels of patients in both groups for Apolipoprotein (Apo) A1 and B.
11. Lipid Profile for HDL-C, LDL-C,Total Cholesterol, and Triglycerides [ Time Frame: Months 12, 24, 36 ]
    Blood lipid levels of patients in both groups: HDL-C, LDL-C,Total cholesterol, and triglycerides.
12. Number of Lipid-lowering Drugs Taken [ Time Frame: Months 12, 24, 36 ]
13. Percentage of Participants on Lipid-lowering Drugs [ Time Frame: Months 12, 24, 36 ]
14. Number of Antihypertensive Drugs Taken [ Time Frame: Months 12, 24, 36 ]
15. Percentage of Participants on Antihypertensive Drugs [ Time Frame: Months 12, 24, 36 ]
16. Proteinuria (Measured as Urine Albumin/Creatinine Ratio (mg/mmol)) [ Time Frame: Months 12, 24, 36 ]
    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.
17. Percentage of Participants Who Had Donor Specific Antibodies (DSA) [ Time Frame: Month 36 ]
    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.
18. Health-related Quality of Life (QoL) as Measured by EuroQoL EQ-5D [ Time Frame: Before randomization, Months 12, 36 ]
    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.

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Locations

Denmark

Novartis Investigative Site

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

Norway

Novartis Investigative Site

Oslo, Norway, 0424

Sweden

Novartis Investigative Site

Goteborg, Sweden, 413 45

Novartis Investigative Site

Malmo, Sweden, 205 02

Novartis Investigative Site

Uppsala, Sweden, 751 85

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

More Information

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT00634920
• Other Study ID Numbers: CRAD001ASE01; 2007-000771-42 ( EudraCT Number )
• First Posted: March 13, 2008
• Results First Posted: August 13, 2014
• Last Update Posted: August 13, 2014
• Last Verified: August 2014

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

De novo renal transplantation

Additional relevant MeSH terms:

Cyclosporine; Mycophenolic Acid; Prednisolone; Everolimus; Cyclosporins; Basiliximab; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antifungal Agents; Anti-Infective Agents; Dermatologic Agents; Antirheumatic Agents; Calcineurin Inhibitors; Antineoplastic Agents; Antibiotics, Antineoplastic; Antibiotics, Antitubercular; Antitubercular Agents; Anti-Bacterial Agents; Anti-Inflammatory Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal