Study Evaluating of Calcineurin Inhibitors Versus Sirolimus in Renal Allograft Recipient

Study Overview
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Brief Summary
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This study will evaluate whether conversion from cyclosporine, a calcineurin inhibitor (CI) to sirolimus (SRL) results in improved long-term renal function without a negative impact on safety or immunosuppressive efficacy, and to further examine the potential of SRL to reduce the severity and/or progression of chronic allograft nephropathy (CAN).

Detailed Description
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This open-label, randomized, parallel-group, comparative, outpatient study will be conducted in multiple centers in Taiwan. The study will randomize approximately 120 patients. 80 patients will be randomized to the SRL therapy group (conversion from CI- to SRL-based immunosuppression: group A) and 40 patients to the CI therapy group (continued CI therapy: group B). Dosage and Administration SRL Therapy: At the time of randomization on day 1, each patient will have been receiving: triple therapy with a CI (tacrolimus or CsA) that began at the time of transplantation or within 2 weeks thereafter AND corticosteroids corresponding to a dosage range of 2.5 to 15 mg/day for prednisone or prednisolone (2 to 12 mg/day for methylprednisolone) or the alternate day equivalent for at least 12 weeks before randomization, PLUS either MMF (minimum dose 500 mg/day)/MPS (minimum dose 360 mg/day) or AZA (minimum dose 50 mg/day) for at least 12 weeks before randomization. SRL will be added to the immunosuppressive regimen for Group A. Group B will continue on this CI immunosuppressive regimen.

Official Title
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A Randomized, Open-label, Comparative Evaluation of Conversion From Calcineurin Inhibitors to Sirolimus Versus Continued Use of Calcineurin Inhibitors in Renal Allograft Recipient

Conditions
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Kidney Transplantation

Intervention / Treatment
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* Drug: Sirolimus+MMF or MPS or AZA+Steroid
* Drug: Calcineurin Inhibitors (either cyclosporine or tacrolimus)+MMF or MPS or AZA+Steroid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must be at least 18 years of age. Subjects who are 6 to 60 months after renal transplantation. Subjects who have a stable graft function. Exclusion Criteria: Subjects with active major infection, including HIV, decreased platelets, elevated lipids, or multiple organ transplants.

Ages Eligible for Study
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Minimum Age: 18 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: 1<br>Sirolimus therapy | Drug: Sirolimus+MMF or MPS or AZA+Steroid<br>* Corticosteroids will be administered according to local practice, within a daily maintenance dosage range of 2.5 to15 mg for prednisone or prednisolone (2 to 12 mg/day for methylprednisolone) or the alternate day equivalent.<br>|
| Active Comparator: 2<br>Calcineurin Inhibitor therapy (either cyclosporine or tacrolimus) | Drug: Calcineurin Inhibitors (either cyclosporine or tacrolimus)+MMF or MPS or AZA+Steroid<br>* The maintenance dose of: MMF will not exceed 1500 mg/day or PMS will not exceed 1080 mg/day AZA will not exceed 75 mg/day Thereafter, at the discretion of the investigator, MMF/MPS or AZA may be: continued for the entire 104-week period of randomized therapy subsequently discontinued restarted after discontinuation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Glomerular Filtration Rate (GFR) Change From Baseline | GFR is an index of kidney function. GFR describes the flow rate of filtered fluid through the kidney. GFR can be measured directly or estimated using established formulas. GFR was calculated using Nankivell formula. A normal GFR is > 90 mL/min, although children and older people usually have a lower GFR. Lower values indicate poor kidney function. A GFR <15 is consistent with kidney failure. | 104 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Glomerular Filtration Rate (GFR) | GFR is an index of kidney function. GFR describes the flow rate of filtered fluid through the kidney. GFR can be measured directly or estimated using established formulas. GFR was calculated using Nankivell formula. A normal GFR is > 90 mL/min, although children and older people usually have a lower GFR. Lower values indicate poor kidney function. A GFR <15 is consistent with kidney failure. | Baseline and Week 24 | 
| Change in Glomerular Filtration Rate (GFR) | GFR is an index of kidney function. GFR describes the flow rate of filtered fluid through the kidney. GFR can be measured directly or estimated using established formulas. GFR was calculated using Nankivell formula. A normal GFR is > 90 mL/min, although children and older people usually have a lower GFR. Lower values indicate poor kidney function. A GFR <15 is consistent with kidney failure. | Baseline and Week 52 | 
| Change in Glomerular Filtration Rate (GFR) | GFR is an index of kidney function. GFR describes the flow rate of filtered fluid through the kidney. GFR can be measured directly or estimated using established formulas. GFR was calculated using Nankivell formula. A normal GFR is > 90 mL/min, although children and older people usually have a lower GFR. Lower values indicate poor kidney function. A GFR <15 is consistent with kidney failure. | Baseline and Week 104 | 
| Patient and Graft Survival | Patient survival defined as participants living with or without a functioning graft. Graft survival defined as those participants who did not experience graft loss. Graft loss defined as physical loss (nephrectomy), functional loss (necessitating maintenance dialysis for >8 weeks), retransplant or death during the first 12 months after randomization. | Week 24 | 
| Patient and Graft Survival | Patient survival defined as participants living with or without a functioning graft. Graft survival defined as those participants who did not experience graft loss. Graft loss defined as physical loss (nephrectomy), functional loss (necessitating maintenance dialysis for >8 weeks), retransplant or death during the first 12 months after randomization. | Week 52 | 
| Patient and Graft Survival | Patient survival defined as participants living with or without a functioning graft. Graft survival defined as those participants who did not experience graft loss. Graft loss defined as physical loss (nephrectomy), functional loss (necessitating maintenance dialysis for >8 weeks), retransplant or death during the first 12 months after randomization. | Week 104 | 
| Change From Baseline in Diastolic Blood Pressure at Week 24 | Value at Week 24 minus value at baseline. | Baseline and Week 24 | 
| Change From Baseline in Diastolic Blood Pressure at Week 52 | Value at Week 52 minus value at baseline. | Baseline and Week 52 | 
| Change From Baseline in Diastolic Blood Pressure at Week 104 | Value at Week 104 minus value at baseline. | Baseline and Week 104 | 
| Change From Baseline in Systolic Blood Pressure at Week 24 | Value at Week 24 minus value at baseline. | Baseline and Week 24 | 
| Change From Baseline in Systolic Blood Pressure at Week 52 | Value at Week 52 minus value at baseline. | Baseline and Week 52 | 
| Change From Baseline in Systolic Blood Pressure at Week 104 | Value at Week 104 minus value at baseline. | Baseline and Week 104 | 
| Change From Baseline in the Severity and Progression of Biopsy-Confirmed Chronic Allograft Nephropathy (CAN) at Week 104 |  | Baseline and Week 104 | 
| Occurence of Acute Rejection or Premature Withdrawal From Study Medication for Any Reason by Week 52 |  | Weeks 52 | 
| Occurence of Acute Rejection or Premature Withdrawal From Study Medication for Any Reason by Week 104 |  | Week 104 | 
| Incidence and Severity of Biopsy-Confirmed Acute Rejection at Week 24 |  | Week 24 | 
| Incidence and Severity of Biopsy-Confirmed Acute Rejection at Week 52 |  | Week 52 | 
| Incidence and Severity of Biopsy-Confirmed Acute Rejection at Week 104 |  | Week 104 |