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

Renal Function Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00634920
• Other study ID #: CRAD001ASE01
• Secondary ID: 2007-000771-42
• Status: Completed
• Phase: Phase 4
• First received: March 6, 2008
• Last updated: August 12, 2014
• Start date: March 2008
• Est. completion date: May 2013

Study information

• Verified date: August 2014
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationSweden: Medical Products AgencyNorway: Norwegian Medicines AgencyDenmark: Danish Medicines AgencyFinland: Finnish Medicines Agency
• Study type: Interventional

Clinical Trial 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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 204
• Est. completion date: May 2013
• Est. primary completion date: May 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Renal Function

Intervention

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.
• 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
• 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)
• 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.
• Basiliximab
Induction therapy 20 mg basiliximab on Day 0 prior to reperfusion and 20 mg on Day 4 post-TX.

Locations

Country	Name	City	State
Denmark	Novartis Investigative Site	Aarhus N
Denmark	Novartis Investigative Site	Copenhagen
Denmark	Novartis Investigative Site	Herlev
Denmark	Novartis Investigative Site	Odense C
Norway	Novartis Investigative Site	Oslo
Sweden	Novartis Investigative Site	Goteborg
Sweden	Novartis Investigative Site	Malmo
Sweden	Novartis Investigative Site	Uppsala

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

Denmark,  Norway,  Sweden, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	Percentage of Participants With Treatment Failures	Treatment failure was defined as graft loss or death.	Months 12, 24, 36	No
Secondary	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	No
Secondary	Lipid Profile for Apolipoprotein	Blood lipid levels of patients in both groups for Apolipoprotein (Apo) A1 and B.	Months 12, 24, 36	No
Secondary	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	No
Secondary	Number of Lipid-lowering Drugs Taken		Months 12, 24, 36	No
Secondary	Percentage of Participants on Lipid-lowering Drugs		Months 12, 24, 36	No
Secondary	Number of Antihypertensive Drugs Taken		Months 12, 24, 36	No
Secondary	Percentage of Participants on Antihypertensive Drugs		Months 12, 24, 36	No
Secondary	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	No
Secondary	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	No
Secondary	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	No