Comparative Study of Modified Release (MR) Tacrolimus/Mycophenolate Mofetil (MMF) in de Novo Kidney Transplant Recipients

A Phase III, Randomized, Open-Label, Comparative, Multi-Center Study to Assess the Safety and Efficacy of Prograf (Tacrolimus)/MMF, Modified Release (MR) Tacrolimus/MMF and Neoral (Cyclosporine)/MMF in de Novo Kidney Transplant Recipients

The purpose of this study is to compare the safety and efficacy of tacrolimus/mycophenolate mofetil (MMF), cyclosporine/MMF and tacrolimus modified release/MMF in de novo kidney transplant recipients.

Study Overview

• Status: Completed
• Conditions: Kidney Transplantation
• Intervention / Treatment: Drug: Tacrolimus; Drug: mycophenolate mofetil; Drug: Tacrolimus Modified Release (MR); Drug: cyclosporine microemulsion

Detailed Description

This was a 3 arm randomized, open-label, comparative, multi-center study in de novo kidney transplant recipients at 60 centers in the U.S., Canada and Brazil.

The study consisted of a 1-year post-transplant efficacy and safety study with a clinical continuation phase of a minimum of 2 years or until commercial availability of tacrolimus modified release, unless the Data Safety Monitoring Board or sponsor specified otherwise.

• Study Type: Interventional
• Enrollment (Actual): 668
• Phase: Phase 3

Contacts and Locations

Study Locations

• Brazil
  • Porto Alegre, Brazil, 90240-520
  • Rio de Janeiro, Brazil, 21041-003
  • Sao Paulo, Brazil, 04038-002
  • Sao Paulo, Brazil, 04013-043
  • Sao Paulo, Brazil, 05465-040
• Canada
  • Alberta
    • Edmonton, Alberta, Canada
  • British Columbia
    • Vancouver, British Columbia, Canada
  • Ontario
    • Toronto, Ontario, Canada
  • Quebec
    • Montreal, Quebec, Canada
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
    • Mobile, Alabama, United States, 36617
  • California
    • Loma Linda, California, United States, 92354
    • Los Angeles, California, United States, 90033
    • Los Angeles, California, United States, 90057
    • Los Angeles, California, United States, 90058
    • Los Angeles, California, United States, 90095-7306
    • Palo Alto, California, United States, 94304
    • San Diego, California, United States, 92103
    • San Diego, California, United States, 92123
    • San Francisco, California, United States, 94115
  • Colorado
    • Denver, Colorado, United States, 80262
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
  • Florida
    • Gainesville, Florida, United States, 32610-0224
    • Jacksonville, Florida, United States, 32216
  • Georgia
    • Augusta, Georgia, United States, 30912
  • Illinois
    • Chicago, Illinois, United States, 60637
    • Chicago, Illinois, United States, 60612
  • Indiana
    • Indianapolis, Indiana, United States, 46202
  • Kentucky
    • Lexington, Kentucky, United States, 40536
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
    • New Orleans, Louisiana, United States, 70121
  • Massachusetts
    • Boston, Massachusetts, United States, 02214
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-0364
    • Detroit, Michigan, United States, 48202
  • New Jersey
    • Livingston, New Jersey, United States, 07039
    • New Brunswick, New Jersey, United States, 08901
  • New York
    • Albany, New York, United States, 12208
    • Buffalo, New York, United States, 14203
    • New York, New York, United States, 10029
    • Valhalla, New York, United States, 10595
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599-7211
    • Durham, North Carolina, United States, 27710
  • Ohio
    • Cincinnati, Ohio, United States, 45267
  • Oregon
    • Portland, Oregon, United States, 97210
    • Portland, Oregon, United States, 97239-2940
  • Pennsylvania
    • Harrisburg, Pennsylvania, United States, 17104
    • Philadelphia, Pennsylvania, United States, 19104
    • Philadelphia, Pennsylvania, United States, 19107
  • Tennessee
    • Nashville, Tennessee, United States, 37212-4750
  • Texas
    • Dallas, Texas, United States, 75246
    • Dallas, Texas, United States, 75235
    • Houston, Texas, United States, 77030
    • San Antonio, Texas, United States, 78229-3900
  • Utah
    • Salt Lake City, Utah, United States, 84132
  • Virginia
    • Fairfax, Virginia, United States, 22031
  • Wisconsin
    • Madison, Wisconsin, United States, 53792-7375
    • Milwaukee, Wisconsin, United States, 53226

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Recipient of a primary or retransplanted non-human leukocyte antigen (HLA)-identical living or non-HLA-identical cadaveric kidney transplant
• Age greater or equal to 12 years

Exclusion Criteria:

• Recipient or donor is known seropositive for human immunodeficiency virus (HIV)
• Has current malignancy or history of malignancy
• Has significant liver disease
• Has uncontrolled concomitant infection or any other unstable medical condition
• Is receiving everolimus or enteric coated mycophenolic acid at any time during the study
• Received kidney with a cold ischemia time of equal or more than 36 hours
• Received kidney transplant from a cadaveric donor equal or more than 60 years of age
• Received intravenous immunoglobulin (IVIG) therapy prior to randomization

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tacrolimus; Participants received a first dose of tacrolimus between 0.075 and 0.10 mg/kg twice daily, orally prior to or within 48 hours of the completion of the transplant procedure, and subsequently as twice daily oral doses adjusted based on clinical evidence of efficacy, blood concentrations of tacrolimus and adverse events. Participants also received 1.0 g mycophenolate mofetil orally twice daily throughout the study.	Drug: Tacrolimus; The target range for whole blood tacrolimus trough concentrations was the recommended trough concentration range for Prograf: 7 to 16 ng/mL for days 0 through 90 and 5 to 15 ng/mL thereafter.; Other Names: Prograf, FK506; Drug: mycophenolate mofetil; Oral; Other Names: CellCept, MMF
Active Comparator: Tacrolimus Modified Release; Participants received a first dose of tacrolimus modified release between 0.15 and 0.20 mg/kg/day, given as a single oral dose in the morning, prior to or within 48 hours following the completion of the transplant procedure, and subsequently as once daily oral doses adjusted based on clinical evidence of efficacy, blood concentrations of tacrolimus and adverse events. Participants also received 1.0 g mycophenolate mofetil orally twice daily throughout the study.	Drug: mycophenolate mofetil; Oral; Other Names: CellCept, MMF; Drug: Tacrolimus Modified Release (MR); The target range for whole blood tacrolimus trough concentrations was 7 to 16 ng/mL for days 0 through 90, and 5 to 15 ng/mL thereafter.; Other Names: Advagraf, FK506, FKMR, MR4, Astagraf XL
Active Comparator: Cyclosporine; Participants received a first dose of cyclosporine between 4 to 5 mg/kg orally prior to or within 48 hours following the completion of the transplant procedure and subsequently as twice daily oral doses adjusted based on clinical evidence of efficacy, blood concentrations of tacrolimus and adverse events. Participants also received 1.0 g mycophenolate mofetil orally twice daily throughout the study.	Drug: mycophenolate mofetil; Oral; Other Names: CellCept, MMF; Drug: cyclosporine microemulsion; The target range for whole blood cyclosporine trough concentrations was 125 to 400 ng/mL for days 0 through 90, and 100 to 300 ng/mL thereafter.; Other Names: Neoral, CsA

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Efficacy Failure	Efficacy failure is defined as any participant who died, experienced a graft failure (permanent return to dialysis [> 30 days] or retransplant), had a biopsy-confirmed (Banff Grade ≥ I) acute rejection (BCAR), or was lost to follow-up. Biopsies were graded according to the 1997 Banff criteria: Borderline: No intimal arteritis present but foci of mild tubulitis; Grade I: Significant interstitial infiltration and foci of moderate to severe tubulitis; Grade II: Mild to severe intimal arteritis Grade III: Transmural arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells with accompanying lymphocytic infiltrate in vessel.	one year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patient Survival at One Year	Patient survival is defined as any participant who is known to be alive one year after the skin closure date. Participants who died or whose outcome was unknown at one year were considered to be non-survivors.	One year
Graft Survival at One Year	Graft survival defined as any participant who did not meet the criteria for graft loss, where graft loss is defined as any re-transplant, permanent return to dialysis (> 30 days), patient death, or participant whose outcome at one year was unknown. Participants were only counted once regardless of how many criteria were met.	One year
Percentage of Participants With Biopsy Confirmed Acute Rejection at 6 and 12 Months	Rejection episodes were confirmed by biopsy by the clinical site pathologist. Biopsies were graded according to the 1997 Banff criteria: Borderline: No intimal arteritis present but foci of mild tubulitis; Grade I: Significant interstitial infiltration and foci of moderate to severe tubulitis; Grade II: Mild to severe intimal arteritis Grade III: Transmural arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells with accompanying lymphocytic infiltrate in vessel. Acute rejection is defined as a grade ≥ I.	Six months and 12 months
Time to First Biopsy-confirmed Acute Rejection Episode	Time to first biopsy-confirmed acute rejection episode defined as the number of days from skin closure (Day 0) to the date of biopsy. Rejection episodes were confirmed by biopsy by the clinical site pathologist and graded according to the 1997 Banff criteria: Borderline: No intimal arteritis present but foci of mild tubulitis; Grade I: Significant interstitial infiltration and foci of moderate to severe tubulitis; Grade II: Mild to severe intimal arteritis Grade III: Transmural arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells with accompanying lymphocytic infiltrate in vessel. Acute rejection is defined as a grade ≥ I.	one year
Number of Participants Requiring Anti-lymphocyte Antibody Therapy for Treatment of Rejection	Rejection episodes were confirmed by biopsy by the clinical site pathologist. Participants with histologically-proven Banff Grade II or III rejection or participants with steroid-resistant rejection were treated with anti-lymphocyte antibody treatment according to institutional practice. Biopsies were graded according to the 1997 Banff criteria: Borderline: No intimal arteritis present but foci of mild tubulitis; Grade I: Significant interstitial infiltration and foci of moderate to severe tubulitis; Grade II: Mild to severe intimal arteritis Grade III: Transmural arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells with accompanying lymphocytic infiltrate in vessel.	one year
Severity of Acute Rejection	Rejection episodes were confirmed by biopsy by the clinical site pathologist. Biopsies were graded according to the 1997 Banff criteria: Borderline: No intimal arteritis present but foci of mild tubulitis; Grade IA: Significant interstitial infiltration and foci of moderate tubulitis; Grade IB: Significant interstitial infiltration and foci of severe tubulitis; Grade IIA: Mild to moderate intimal arteritis in at least 1 arterial cross section Grade IIB: Severe intimal arteritis comprising >25% of the luminal area lost in at least 1 arterial cross section; Grade III: Transmural arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells with accompanying lymphocytic infiltrate in vessel.	one year
Number of Participants Experiencing Multiple Rejection Episodes	This analysis includes rejection episodes that were either confirmed by biopsy by the clinical site pathologist or were clinically treated.	one year
Number of Participants With Clinically Treated Acute Rejection Episodes	A clinically treated acute rejection episode was any biopsy-confirmed or suspected rejection episode that was treated with immunosuppressive therapy.	one year
Number of Participants With Treatment Failure	Treatment failure was defined as the discontinuation of randomized study drug for any reason. Participants who met the definition of treatment failure were to be followed throughout the 12-month treatment period.	one year
Number of Participants Who Crossed Over Due to Treatment Failure	Participants were allowed to cross over to an alternative primary immunosuppressive regimen (either to the tacrolimus or cyclosporine treatment arms) to address an adverse event which led to randomized study drug discontinuation or in the case of severe or refractory rejection. Crossover to the modified release tacrolimus treatment arm was not permitted.	one year
Change From Month 1 in Serum Creatinine at Month 6 and Month 12	Renal function was assessed by the change from Month 1 in serum creatinine six months and 12 months after transplant.	Month 1, Month 6, and Month 12
Change From Month 1 in Creatinine Clearance at Month 6 and Month 12	Renal function was assessed by creatinine clearance, calculated using the Cockcroft-Gault formula.	Month 1, Month 6, and Month 12
Kaplan-Meier Estimate of Patient Survival at the End of the Study	Patient survival was defined as any participant who was alive at the end of the study. Patient survival was censored at the time of last follow-up contact.	End of study (maximum time on study was 1,941 days).
Kaplan-Meier Estimate of Graft Survival at the End of the Study	Graft survival was defined as any participant who did not meet the definition of graft loss, where graft loss was any retransplant or the permanent return to dialysis (more than 30 days) or patient death. Graft survival was censored at the time of last follow-up contact.	End of study (maximum time on study was 1,941 days).

Collaborators and Investigators

• Sponsor: Astellas Pharma Inc

Publications and helpful links

General Publications

• Silva HT Jr, Yang HC, Abouljoud M, Kuo PC, Wisemandle K, Bhattacharya P, Dhadda S, Holman J, Fitzsimmons W, First MR. One-year results with extended-release tacrolimus/MMF, tacrolimus/MMF and cyclosporine/MMF in de novo kidney transplant recipients. Am J Transplant. 2007 Mar;7(3):595-608. doi: 10.1111/j.1600-6143.2007.01661.x. Epub 2007 Jan 11. Erratum In: Am J Transplant. 2007 Jun;7(6):1682.

Study record dates

Study Major Dates

• Study Start: June 1, 2003
• Primary Completion (Actual): March 1, 2005
• Study Completion (Actual): March 1, 2009

Study Registration Dates

• First Submitted: July 10, 2003
• First Submitted That Met QC Criteria: July 11, 2003
• First Posted (Estimate): July 14, 2003

Study Record Updates

• Last Update Posted (Estimate): December 5, 2013
• Last Update Submitted That Met QC Criteria: November 12, 2013
• Last Verified: November 1, 2013

More Information

Terms related to this study

• Keywords: mycophenolate mofetil; tacrolimus; cyclosporine; Prograf®; De Novo Kidney Transplant
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Tacrolimus; Mycophenolic Acid; Cyclosporine; Cyclosporins
• Other Study ID Numbers: 02-0-158