Once-a-day Regimen With Everolimus, Low Dose Cyclosporine and Steroids in Comparison With Steroid Withdrawal or Twice a Day Regimen With Everolimus, Low Dose Cyclosporine and Steroids.

Phase 3

Completed

Conditions: de Novo Kidney Transplant Recipients
Renal Transplantation

Interventions: Drug: everolimus
Drug: cyclosporine
Drug: Prednison (continuous steroids)

Registration Number: NCT01023815

Lead Sponsor: Novartis

Brief Summary: This study will compare the following immunosuppressive regimens in recipients of kidney transplantation: A) everolimus, cyclosporine and steroids given once-a-day; B) everolimus and cyclosporine given twice a day with steroid withdrawal; C) everolimus, cyclosporine given twice a day and continuous steroids. The purpose of this study is to evaluate regimens A and B in comparison with the control group (group C) for efficacy, using as main endpoint the treatment failure rate, a composite endpoint including death, graft loss, BPAR and lost to follow-up between randomization and Month 12.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 330

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group A -Once-a-day regimen	Prednison (continuous steroids)	Everolimus: in patients randomized to Group A before Amendment 1 approval, from the day following randomization, the whole daily dose of everolimus was taken in the morning, at the same time of the CsA and steroid dosing. At the Rand+1W visit, the everolimus dose was adjusted to reach and maintain everolimus blood levels between 5 and 8 ng/mL until end of Month 12. Cyclosporine: in patients randomized to Group A before Amendment 1 approval, from the day following randomization, the whole cyclosporine daily dose was taken in the morning. The dose was then adjusted to maintain C2 levels between 350 and 700 ng/mL. Prednisone: In patients randomized to Group A before Amendment 1 approval, the dose of prednisone was kept stable at 5 mg/day in the morning.
Group C - Standard twice-a-day group	Prednison (continuous steroids)	Everolimus: after randomization the everolimus dose was adjusted, if necessary, in order to maintain a C0 within 6-10 ng/mL until M12. Cyclosporine: after randomization the cyclosporine dose was gradually adjusted to reach and maintain C2 blood levels of 200-450 ng/mL between Month 6 and Month 12. Prednisone: the dose of prednisone was kept stable at 5 mg/day in the morning.
Group B - Steroid Withdrawal group	Prednison (continuous steroids)	Everolimus: after randomization the everolimus dose was adjusted, if necessary, to maintain a C0 within 6-10 ng/mL until M12. Cyclosporine:after randomization the cyclosporine dose was adjusted to maintain CsA C2 levels within 300-500 ng/mL until M12. Prednisone: starting from Visit 5 (day 90 ± 28 days), oral prednisone was tapered until complete stop. It was recommended to taper prednisone by 1 mg/week until complete stop in 5 to 6 weeks.
Group A -Once-a-day regimen	cyclosporine	Everolimus: in patients randomized to Group A before Amendment 1 approval, from the day following randomization, the whole daily dose of everolimus was taken in the morning, at the same time of the CsA and steroid dosing. At the Rand+1W visit, the everolimus dose was adjusted to reach and maintain everolimus blood levels between 5 and 8 ng/mL until end of Month 12. Cyclosporine: in patients randomized to Group A before Amendment 1 approval, from the day following randomization, the whole cyclosporine daily dose was taken in the morning. The dose was then adjusted to maintain C2 levels between 350 and 700 ng/mL. Prednisone: In patients randomized to Group A before Amendment 1 approval, the dose of prednisone was kept stable at 5 mg/day in the morning.
Group B - Steroid Withdrawal group	cyclosporine	Everolimus: after randomization the everolimus dose was adjusted, if necessary, to maintain a C0 within 6-10 ng/mL until M12. Cyclosporine:after randomization the cyclosporine dose was adjusted to maintain CsA C2 levels within 300-500 ng/mL until M12. Prednisone: starting from Visit 5 (day 90 ± 28 days), oral prednisone was tapered until complete stop. It was recommended to taper prednisone by 1 mg/week until complete stop in 5 to 6 weeks.
Group A -Once-a-day regimen	everolimus	Everolimus: in patients randomized to Group A before Amendment 1 approval, from the day following randomization, the whole daily dose of everolimus was taken in the morning, at the same time of the CsA and steroid dosing. At the Rand+1W visit, the everolimus dose was adjusted to reach and maintain everolimus blood levels between 5 and 8 ng/mL until end of Month 12. Cyclosporine: in patients randomized to Group A before Amendment 1 approval, from the day following randomization, the whole cyclosporine daily dose was taken in the morning. The dose was then adjusted to maintain C2 levels between 350 and 700 ng/mL. Prednisone: In patients randomized to Group A before Amendment 1 approval, the dose of prednisone was kept stable at 5 mg/day in the morning.
Group B - Steroid Withdrawal group	everolimus	Everolimus: after randomization the everolimus dose was adjusted, if necessary, to maintain a C0 within 6-10 ng/mL until M12. Cyclosporine:after randomization the cyclosporine dose was adjusted to maintain CsA C2 levels within 300-500 ng/mL until M12. Prednisone: starting from Visit 5 (day 90 ± 28 days), oral prednisone was tapered until complete stop. It was recommended to taper prednisone by 1 mg/week until complete stop in 5 to 6 weeks.
Group C - Standard twice-a-day group	everolimus	Everolimus: after randomization the everolimus dose was adjusted, if necessary, in order to maintain a C0 within 6-10 ng/mL until M12. Cyclosporine: after randomization the cyclosporine dose was gradually adjusted to reach and maintain C2 blood levels of 200-450 ng/mL between Month 6 and Month 12. Prednisone: the dose of prednisone was kept stable at 5 mg/day in the morning.
Group C - Standard twice-a-day group	cyclosporine	Everolimus: after randomization the everolimus dose was adjusted, if necessary, in order to maintain a C0 within 6-10 ng/mL until M12. Cyclosporine: after randomization the cyclosporine dose was gradually adjusted to reach and maintain C2 blood levels of 200-450 ng/mL between Month 6 and Month 12. Prednisone: the dose of prednisone was kept stable at 5 mg/day in the morning.
Not Randomized Population (NRP)	everolimus	NRP defined in whom a renal transplantation was performed, received at least one dose of study drug (everolimus) but who did not qualify for randomization at Visit 5, Day 90. This group was addressed as "not randomized patients" (NRP) and described with respect to baseline characteristics, treatment and outcome variables.

Primary Outcome Measures

Name	Time	Method
Treatment Failure Rate	Between randomization (Month 3) and Month 12	Occurrence or not of treatment failure in each patient. Treatment failure was defined as a composite endpoint of biopsy-proven acute rejection (a biopsy graded IA, IB, IIA, IIB or III according to Banff '97 grading with 2007 update), graft loss, death or lost to follow-up occurring after randomization (V5) and within M12 (V9).

Secondary Outcome Measures

Name	Time	Method
Changes in the Estimated Glomerular Filtration Rate (eGFR) Between Randomization (Month 3) and Month 12	Month 3 to Month 12	eGFR by Nankivell, in terms of descriptive statistics and change vs randomization visit - to compare the changes in the estimated GFR (Nankivell) between randomization and Month 12 in the steroid withdrawal group (Group B) to the change observed in the standard twice-a-day group (Group C), for non-inferiority
Biopsy Proven Acute Rejection (BPAR) Rate Between Randomization and Month 12	Month 3 to Month 12	Occurrence of BPAR (after randomization) between arm B (steroid withdrawal group) and arm c (standard twice-a-day group). BPAR was defined as a biopsy graded IA, IB, IIA, IIB, or III according to Banff 1997 grading with 2007 update.
Number of Participants With Graft and Patient Survival After Randomization	Month 3 to Month 12	Graft Survival, calculated from the date of transplantation to the date of irreversible graft failure signified by return to long-term retransplantation or the date of the last follow-up during the period when the transplant was still functioning or to the date of death. Patient survival, calculated from the date of transplantation to the date of death or the date of the last follow-up.
Change in Estimated Creatine Clearance	M3, M12	At each visit, estimated creatinine clearance was measured in the local laboratory to analyze the evolution of the renal function. The following indirect measures of renal function were computed: estimated creatinine clearance according to Cockcroft and Gault formula and MDRD formula.
Change in Serum Creatinine	M3, M12	Serum creatinine (a blood measurement) is an important indicator of renal health because it is an easily-measured by-product of muscle metabolism. Measuring serum creatinine is a simple test and it is the most commonly used indicator of renal function.

Trial Locations

Locations (3): Novartis Investigative Site
🇮🇹
Vicenza, Italy
Novartis InvestigativeSite
🇮🇹
Udine, Italy
Novarits Investigative Site
🇮🇹
Pisa, Italy