Tacrolimus/Everolimus Versus Tacrolimus/Enteric-Coated Mycophenolate Sodium

Phase 3

Completed

Conditions: Transplant; Failure, Kidney

Interventions: Drug: Tacrolimus
Drug: Enteric Coated Mycophenolate Sodium (EC-MPS)
Drug: Everolimus
Drug: Corticosteroids

Registration Number: NCT01680861

Lead Sponsor: Gaetano Ciancio

Brief Summary: A recent therapeutic strategy following renal transplantation includes simultaneous use of reduced calcineurin inhibitor (CNI) dosing and maximized use of a non-nephrotoxic, antiproliferative drug (inosine monophosphate dehydrogenase (IMPDH) or TOR inhibitor), with the goals of reducing/avoiding CNI nephrotoxicity, the incidence of acute rejection, and chronic allograft injury (CAI) (i.e., interstitial fibrosis/tubular atrophy), leading to more favorable longer-term patient and graft survival.1-7 Early corticosteroid withdrawal has also been used in the attempt to avoid well-known side effects while maintaining favorable patient and graft survival.8-10 While the investigators center and numerous other centers have also included single agent, antibody induction utilizing the lymphodepleting polyclonal antibody rabbit anti-human thymocyte globulin (ATG), nondepleting human anti-interleukin-2 receptor (CD25) monoclonal antibody daclizumab (Dac) or basiliximab, or lymphodepleting humanized anti-CD52 monoclonal antibody alemtuzumab,11-17 evidence now suggests that an even more effective induction strategy may include the combined use of more than one induction agent (each with fewer doses than if used alone), with the goal of bringing the kidney transplant recipient even closer (through more effectively timed lymphodepletion) to an optimally immunosuppressed state, allowing further reduction in long-term maintenance drug dosing.18-25 The investigators have now successfully used dual ATG/Dac induction therapy in both kidney-alone23-24 and simultaneous kidney-pancreas (SPK) transplantation,18-20 and a recent report from the investigators center of kidney-alone and SPK recipients shows that the addition of anti-CD25 to ATG for induction therapy more effectively delays the return of peripheral blood CD25+ cells.25 In the kidney-alone recipient study 3 doses of ATG were combined with 2 doses of Dac for induction,23-24 vs. the investigators previous studies utilizing single agent induction with 7 doses of ATG or 5 doses of Dac.4,16,17 Successful combination of ATG/basiliximab as dual induction in kidney transplantation has also been reported elsewhere,21-22 along with equivalency in clinical outcomes using daclizumab vs. basiliximab.13

Detailed Description: A. Primary Objectives:

1. The percentage of patients who develop chronic allograft injury (CAI) progression during the first 12 months post-transplant protocol biopsy (i.e., higher grade of IF/TA at either the 6 or 12 month protocol biopsy in comparison with the baseline biopsy).

2. The incidence rate of biopsy-proven acute rejection (BPAR) during the first 12 months post-transplant.

B. Secondary Objectives:

1. Adverse events including graft loss (death-censored and death-uncensored), and death at 12 months post-transplant.

2. Incidence rate and severity (severity of CAI at 12 months as well), based upon careful review of all clinically indicated and protocol biopsies.

3. Renal function as determined by serum creatinine and estimated glomerular filtration rate (eGFR) (calculated using the abbreviated MDRD formula) at 12, months post-transplant. Use of multivariable analysis to compare renal function as well as BPAR and CAI progression will also be performed (particularly, after adjusting for the significant effects of donor age, recipient age, race/ethnicity, and any other predictors).

5. Adverse events including withholding (for ≥ 28 days) or discontinuance of study medications (and reasons why), new onset diabetes mellitus after transplantation (NODAT), infections requiring hospitalization, and requirement of anti-lipid medication at 12 months post-transplant.

6. Avoidance of the requirement for maintenance corticosteroid therapy after renal transplantation.

7. Allowance of reduced maintenance tacrolimus dosing (rTd).

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 32

Inclusion Criteria

Weight > 40 kg.
Deceased donor (SCD) or LD.
Donor-recipient 1 haplotype matched pairs with a minimum matching of 1 HLA DR antigen.
Negative standard cross match for T cells.
Pretransplant panel reactive antibodies of < 30%.
Graft required to be functional, producing at least 100ml of urine within 24hr after transplantation.

Exclusion Criteria

Previously received or is receiving an organ transplant other than a kidney.
Donor organ with a cold ischemic time > 48 hours.
ABO incompatible donor kidney.
Recipients of T cell, or B cell crossmatch positive transplant.
Panel reactive antibody (PRA) >30%
HIV or Hepatitis C virus, or Hepatitis B virus antigenemia.
Current malignancy or a history of malignancy
Liver disease
Uncontrolled concomitant infections and/or severe diarrhea, vomiting, active upper gastro-intestinal tract malabsorption or an active peptic ulcer
Use of warfarin, fluvastatin, or herbal supplements during the study.
Use of astemizole, pimozide, cisapride, terfenadine, or ketoconazole.
Hypersensitivity to thymoglobulin, IL-2 receptor inhibitor monoclonal antibodies, tacrolimus, everolimus, MPA, or corticosteroids.
Pregnant or lactating.
Abnormal screening/baseline labs WBC, platelet count, triglycerides, and cholesterol Double kidneys,ECD, pediatric en-block, and donation after cardiac death (DCD)

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Tacrolimus and Everolimus	Corticosteroids	Patients in both arms will receive reduced tacrolimus dosing (rTd), 0.1 mg/kg PO divided in two daily doses - beginning when serum Cr decreases to a level of \<4 mg/dl (i.e., acceptable renal transplant function) postoperatively. Target tacrolimus trough levels during the first year post-transplant and thereafter will be 5-8 ng/ml. Everolimus initiated within 24 hours post-transplant (i.e., immediately following randomization) at 0.75mg PO BID and will be adjusted in order to achieve target everolimus trough levels of 3-8 ng/ml.
Tacrolimus and Enteric-Coated Mycophenolate Sodium (EC-MPS)	Corticosteroids	Patients in both arms will receive reduced tacrolimus dosing (rTd), 0.1 mg/kg PO divided in two daily doses - beginning when serum Cr decreases to a level of \<4 mg/dl (i.e., acceptable renal transplant function) postoperatively. Target tacrolimus trough levels during the first year post-transplant and thereafter will be 5-8 ng/ml. EC-MPS will be initiated at 720 mg PO BID starting on the first post-operative day.
Tacrolimus and Enteric-Coated Mycophenolate Sodium (EC-MPS)	Enteric Coated Mycophenolate Sodium (EC-MPS)	Patients in both arms will receive reduced tacrolimus dosing (rTd), 0.1 mg/kg PO divided in two daily doses - beginning when serum Cr decreases to a level of \<4 mg/dl (i.e., acceptable renal transplant function) postoperatively. Target tacrolimus trough levels during the first year post-transplant and thereafter will be 5-8 ng/ml. EC-MPS will be initiated at 720 mg PO BID starting on the first post-operative day.
Tacrolimus and Everolimus	Tacrolimus	Patients in both arms will receive reduced tacrolimus dosing (rTd), 0.1 mg/kg PO divided in two daily doses - beginning when serum Cr decreases to a level of \<4 mg/dl (i.e., acceptable renal transplant function) postoperatively. Target tacrolimus trough levels during the first year post-transplant and thereafter will be 5-8 ng/ml. Everolimus initiated within 24 hours post-transplant (i.e., immediately following randomization) at 0.75mg PO BID and will be adjusted in order to achieve target everolimus trough levels of 3-8 ng/ml.
Tacrolimus and Everolimus	Everolimus	Patients in both arms will receive reduced tacrolimus dosing (rTd), 0.1 mg/kg PO divided in two daily doses - beginning when serum Cr decreases to a level of \<4 mg/dl (i.e., acceptable renal transplant function) postoperatively. Target tacrolimus trough levels during the first year post-transplant and thereafter will be 5-8 ng/ml. Everolimus initiated within 24 hours post-transplant (i.e., immediately following randomization) at 0.75mg PO BID and will be adjusted in order to achieve target everolimus trough levels of 3-8 ng/ml.
Tacrolimus and Enteric-Coated Mycophenolate Sodium (EC-MPS)	Tacrolimus	Patients in both arms will receive reduced tacrolimus dosing (rTd), 0.1 mg/kg PO divided in two daily doses - beginning when serum Cr decreases to a level of \<4 mg/dl (i.e., acceptable renal transplant function) postoperatively. Target tacrolimus trough levels during the first year post-transplant and thereafter will be 5-8 ng/ml. EC-MPS will be initiated at 720 mg PO BID starting on the first post-operative day.

Primary Outcome Measures

Name	Time	Method
BPAR (Biopsy-proven Acute Rejection) Incidence During the First 12 Months Post-transplant	1 year	BPAR (biopsy-proven acute rejection) incidence during the first 12 months post-transplant. Grading is determined using standard Banff criteria.

Secondary Outcome Measures

Name	Time	Method
Incidence of Chronic Allograft Nephropathy (CAI) at 12 Months Post-transplant	1 year	Incidence of (biopsy-proven) chronic allograft nephropathy (CAI) \[interstitial fibrosis and tubular atrophy, using standard Banff criteria\] at 12 months post-transplant.
Discontinuance of Any Study Medication (Tacrolimus, Everolimus, or EC-MPS)	during the first 12 months post-transplant
Graft Loss (Return to Permanent Dialysis or Death)	during the first 12 months post-transplant
eGFR (Calculated Glomerular Filtration Rate), i.e., Renal Function, at 1 Month Post-transplant.	at 1 month post-transplant	using the abbreviated MDRD formula.
eGFR (Renal Function) at Month 3 Post-transplant	at 3 months post-transplant	Renal function as determined by the estimated glomerular filtration rate (eGFR) at 3 months post-transplant, using the abbreviated MDRD formula.
eGFR (Renal Function) at 6 Months Post-transplant	at 6 months post-transplant	using the abbreviated MDRD formula.