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

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.

Arzneimittel: 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.

Andere Namen:

• Prograf, FK506

Arzneimittel: mycophenolate mofetil

Oral

Andere Namen:

• CellCept, MMF

Aktiver Komparator: 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.

Arzneimittel: mycophenolate mofetil

Oral

Andere Namen:

• CellCept, MMF

Arzneimittel: 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.

Andere Namen:

• Advagraf, FK506, FKMR, MR4, Astagraf XL

Aktiver Komparator: 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.

Arzneimittel: mycophenolate mofetil

Oral

Andere Namen:

• CellCept, MMF

Arzneimittel: 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.

Andere Namen:

• Neoral, CsA

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.