Tacrolimus/Everolimus Versus Tacrolimus/Enteric-Coated Mycophenolate Sodium

NCT01680861 | Completed Phase 3 Results DMC

• 1 other identifier: 20110126
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 1

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

Conditions

Transplant; Failure, Kidney

Keywords

Kidney transplant patients

Outcome Measures

Primary Outcomes (1)

• BPAR (Biopsy-proven Acute Rejection) Incidence During the First 12 Months Post-transplant

  BPAR (biopsy-proven acute rejection) incidence during the first 12 months post-transplant. Grading is determined using standard Banff criteria.

  1 year

Secondary Outcomes (6)

• Incidence of Chronic Allograft Nephropathy (CAI) at 12 Months Post-transplant

  1 year

• 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

• eGFR (Renal Function) at Month 3 Post-transplant

  at 3 months post-transplant

• eGFR (Renal Function) at 6 Months Post-transplant

  at 6 months post-transplant

Study Arms (2)

Tacrolimus and Everolimus

EXPERIMENTAL

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.

Drug: Tacrolimus; Drug: Everolimus; Drug: Corticosteroids

Tacrolimus and Enteric-Coated Mycophenolate Sodium (EC-MPS)

ACTIVE COMPARATOR

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.

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

Interventions

Tacrolimus DRUG

Tacrolimus dosing (rTd) is planned, 0.1 mg/kg PO BID - 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.

Also known as: Prograf (brand name)

Tacrolimus and Enteric-Coated Mycophenolate Sodium (EC-MPS); Tacrolimus and Everolimus

Everolimus DRUG

Everolimus initiated at 0.75 PO BID and will be adjusted in order to achieve target everolimus trough levels of 3-8 ng/ml.

Also known as: Zortress (brand name)

Tacrolimus and Everolimus

Enteric Coated Mycophenolate Sodium (EC-MPS) DRUG

EC-MPS 720 mg PO BID - beginning on 1st postoperative day.

Also known as: Myfortic (brand name)

Tacrolimus and Enteric-Coated Mycophenolate Sodium (EC-MPS)

Corticosteroids DRUG

Corticosteroids will be given as per our center protocol, i.e., a bolus of 500 mg of Methylprednisolone intravenously at surgery and daily x2, followed by 1.0 mg/kg, then 0.5 mg/kg orally until weaned off completely by 7-10 days postoperatively - the plan is for corticosteroids to be discontinued by 7-10 days postoperatively in both groups.

Also known as: Methylprednisolone

Tacrolimus and Enteric-Coated Mycophenolate Sodium (EC-MPS); Tacrolimus and Everolimus

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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)

Sponsors & Collaborators

• Gaetano Ciancio: lead

Study Sites (1)

University of Miami

Miami, Florida, 33136, United States

Location

MeSH Terms

Interventions

Tacrolimus; Everolimus; Mycophenolic Acid; Adrenal Cortex Hormones; Methylprednisolone

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals; Sirolimus; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Prednisolone; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Results Point of Contact

• Title: Jeffrey Gaynor, Ph.D. biostatistician
• Organization: Miami Transplant Institute

jgaynor@med.miami.edu

Study Officials

• Gaetano Ciancio, M.D.

  University of Miami

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor of Surgery

Study Record Dates

• First Submitted: March 6, 2012
• First Posted: September 7, 2012
• Study Start: November 1, 2012
• Primary Completion: December 1, 2014
• Study Completion: December 1, 2014
• Last Updated: December 15, 2016
• Results First Posted: December 15, 2016

Record last verified: 2016-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)