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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Kidney Transplantation

Intervention / Treatment
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* Drug: Tacrolimus Modified Release (MR)
* Drug: Tacrolimus
* Drug: cyclosporine microemulsion
* Drug: mycophenolate mofetil


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tacrolimus<br>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<br>* 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.<br>* Other names: Prograf, FK506;Drug: mycophenolate mofetil<br>* Oral<br>* Other names: CellCept, MMF;|
| Active Comparator: Tacrolimus Modified Release<br>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: Tacrolimus Modified Release (MR)<br>* 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.<br>* Other names: Advagraf, FK506, FKMR, MR4, Astagraf XL;Drug: mycophenolate mofetil<br>* Oral<br>* Other names: CellCept, MMF;|
| Active Comparator: Cyclosporine<br>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: cyclosporine microemulsion<br>* 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.<br>* Other names: Neoral, CsA;Drug: mycophenolate mofetil<br>* Oral<br>* Other names: CellCept, MMF;|

What is the study measuring?
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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). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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De Novo Kidney Transplant, cyclosporine, Prograf®, mycophenolate mofetil, tacrolimus