Efficacy and Safety Study of Everolimus Plus Reduced Cyclosporine Versus Mycophenolic Acid Plus Cyclosporine in Kidney Transplant Recipients
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Purpose
The purpose of this study was to compare the safety and efficacy of three immunosuppressive treatment regimens following a kidney transplant.
| Condition | Intervention | Phase |
|---|---|---|
|
Kidney Transplantation Graft Rejection |
Drug: Everolimus Drug: Mycophenolic Acid (MPA) Drug: Cyclosporine A (CsA) Drug: Basiliximab Drug: Corticosteroids |
Phase 3 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment |
| Official Title: | Efficacy and Safety Study Comparing Concentration-controlled Everolimus in Two Doses (1.5 and 3.0 mg/Day Starting Doses) With Reduced Cyclosporine Versus 1.44 g Mycophenolic Acid (as Sodium Salt) With Standard Dose Cyclosporine in de Novo Renal Transplant Recipients |
- Number of Participants With Composite Efficacy Endpoints - 12 Month Analysis [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]The primary efficacy endpoint was the 12 month analysis of primary efficacy failure defined as a composite endpoint including treated biopsy proven acute rejection (BPAR), graft loss, death or loss to follow-up. A treated BPAR episode was defined as a biopsy graded IA, IB, IIA, IIB, or III that was treated with anti-rejection therapy. Graft loss was defined as the allograft was presumed to be lost on the day the patient started dialysis and was not able to subsequently be removed from dialysis as well as re-transplant.
- Non-inferiority Analysis on Percentage of Participants With Composite Efficacy Endpoints [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]The primary efficacy endpoint was the 12 month analysis of primary efficacy failure defined as a composite endpoint including treated biopsy proven acute rejection (BPAR), graft loss, death or loss to follow-up. In the definition of composite efficacy failure, loss to follow-up includes patients who did not experience treated BPAR, graft loss or death on or after day 1 and whose last day of contact was prior to day 316, the start day of the 12 month visit window.
- Percentage of Participants With the Composite Incidence of Graft Loss, Death or Loss to Follow up at 12 Months Post-transplantation [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
Graft loss was defined as graft loss (the allograft was presumed to be lost on the day the patient started dialysis and was not able to subsequently be removed from dialysis) and re-transplant.
A loss to follow-up patient in the composite endpoint of graft loss, death or loss to follow-up (the main secondary efficacy endpoint) was a patient who did not experience graft loss or death from day 1 and whose last day of contact was prior to study day 316.
- Non-inferiority Analysis of Renal Function, Calculated by Glomerular Filtration Rate (cGFR) Using Modification of Diet in Renal Disease (MDRD) Formula [ Time Frame: at 12 months ] [ Designated as safety issue: No ]
Modification of Diet in Renal Disease (MDRD) formula is:
GFR [mL/min/1.73m^2] = 186.3*(C^-1.154)*(A^-0.203)*G*R where
- C is the serum concentration of creatinine [mg/dL],
- A is patient age at sample collection date [years],
- G=0.742 when gender is female, otherwise G=1,
- R=1.21 when race is black, otherwise R=1
| Enrollment: | 833 |
| Study Start Date: | October 2005 |
| Study Completion Date: | October 2009 |
| Primary Completion Date: | August 2009 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: Low-dose Everolimus Group
1.5 mg everolimus (one 0.75-mg tablet bis in diem/twice a day (bid)) + basiliximab + reduced-dose Cyclosporine A (CsA) ± corticosteroids. The CsA dose was adjusted to attain a trough (C0) value within the pre-specified target ranges: starting at the day 5 visit: 100-200 ng/mL, starting at the month 2 visit: 75-150 ng/mL, starting at the month 4 visit: 50-100 ng/mL and starting at the month 6 visit: 25-50 ng/mL. Patients received their first dose of basiliximab within 2 hours prior to transplant surgery and on day 4 post-transplant or according to local practice. Corticosteroids were administered according to local therapy. |
Drug: Everolimus
oral, bis in diem/twice a day (bid)
Other Name: Certican, Zotress
Drug: Cyclosporine A (CsA)
CsA dose adjustments were based on CsA trough levels (C0).
Other Name: Neoral
Drug: Basiliximab
All patients received two 20 mg doses of basiliximab administered intravenously. The first dose was to be given within 2 hours prior to transplant surgery and the second dose was to be administered on day 4, or each dose could have been administered according to local practice.
Other Name: Simulect
Drug: Corticosteroids
Oral corticosteroids were administered according to local practice during the trial. At the same center, all patients were to follow the same steroid administration protocol.
|
|
Experimental: High-dose Everolimus Group
3.0 mg everolimus (two 0.75-mg tablets bid) + basiliximab + reduced-dose CsA ± corticosteroids. The CsA dose was adjusted to attain a trough (C0) value within the pre-specified target ranges: starting at the day 5 visit: 100-200 ng/mL, starting at the month 2 visit: 75-150 ng/mL, starting at the month 4 visit: 50-100 ng/mL and starting at the month 6 visit: 25-50 ng/mL. Patients received their first dose of basiliximab within 2 hours prior to transplant surgery and on day 4 post-transplant or according to local practice. Corticosteroids were administered according to local therapy. |
Drug: Everolimus
oral, bis in diem/twice a day (bid)
Other Name: Certican, Zotress
Drug: Cyclosporine A (CsA)
CsA dose adjustments were based on CsA trough levels (C0).
Other Name: Neoral
Drug: Basiliximab
All patients received two 20 mg doses of basiliximab administered intravenously. The first dose was to be given within 2 hours prior to transplant surgery and the second dose was to be administered on day 4, or each dose could have been administered according to local practice.
Other Name: Simulect
Drug: Corticosteroids
Oral corticosteroids were administered according to local practice during the trial. At the same center, all patients were to follow the same steroid administration protocol.
|
|
Active Comparator: Control Group
1.44 g Mycophenolic Acid (two 360-mg tablets bid) + basiliximab + standard-dose CsA ± corticosteroids. The CsA dose was adjusted to attain a C0 value within the following range for the time of the study: starting at the day 5 visit: 200-300 ng/mL, starting at the month 2 visit and thereafter: 100-250 ng/mL. Patients received their first dose of basiliximab within 2 hours prior to transplant surgery and on day 4 post-transplant or according to local practice. Corticosteroids were administered according to local therapy. |
Drug: Mycophenolic Acid (MPA)
2 oral capsules of mycophenolic acid 360mg administered bid
Other Name: Myfortic
Drug: Cyclosporine A (CsA)
CsA dose adjustments were based on CsA trough levels (C0).
Other Name: Neoral
Drug: Basiliximab
All patients received two 20 mg doses of basiliximab administered intravenously. The first dose was to be given within 2 hours prior to transplant surgery and the second dose was to be administered on day 4, or each dose could have been administered according to local practice.
Other Name: Simulect
Drug: Corticosteroids
Oral corticosteroids were administered according to local practice during the trial. At the same center, all patients were to follow the same steroid administration protocol.
|
Eligibility| Ages Eligible for Study: | 18 Years to 70 Years |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Male and female patients of any race between 18 to 70 years old (inclusive)
- Patients who gave written informed consent to participate in the study
Exclusion Criteria:
- Recipients of multi-organ transplantation
- Recipients of a primary cadaveric or primary non-human leucocyte antigen (HLA) identical living donor kidney transplantation.
- Graft cold ischemia time greater than 40 hours.
Other protocol-defined inclusion/exclusion criteria may apply.
Contacts and Locations More Information
No publications provided by Novartis
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | Novartis |
| ClinicalTrials.gov Identifier: | NCT00251004 History of Changes |
| Other Study ID Numbers: | CRAD001A2309 |
| Study First Received: | November 7, 2005 |
| Results First Received: | December 17, 2010 |
| Last Updated: | April 7, 2011 |
| Health Authority: | United States: Food and Drug Administration |
Keywords provided by Novartis:
|
Renal transplantation, kidney, and organ transplant Renal transplant rejection |
Additional relevant MeSH terms:
|
Cyclosporins Cyclosporine Mycophenolic Acid Mycophenolate mofetil Everolimus Sirolimus Basiliximab Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Pharmacologic Actions Immunosuppressive Agents |
Immunologic Factors Physiological Effects of Drugs Antifungal Agents Anti-Infective Agents Therapeutic Uses Dermatologic Agents Antirheumatic Agents Antibiotics, Antineoplastic Antineoplastic Agents Anti-Bacterial Agents |
ClinicalTrials.gov processed this record on May 22, 2013