Evaluate Efficacy Study of Combination Therapy of Everolimus and Low Dose Tacrolimus in Renal Allograft Recipients

Study Overview
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Brief Summary
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To evaluate prevention effect of combination therapy of Everolimus and low-dose Tacrolimus in comparison with standard-dose Tacrolimus therapy with Mycophenolic acid on the New Onset Diabetes Mellitus after transplantation in the renal allograft recipients

Detailed Description
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An open-label, randomized, multi-center, comparative parallel study to evaluate prevention effect of combination therapy of Everolimus and low-dose Tacrolimus in comparison with standard-dose Tacrolimus therapy with Mycophenolic acid on the New Onset Diabetes Mellitus after transplantation in the renal allograft recipients: PROTECT study

Official Title
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To Evaluate Prevention Effect Of Everolimus and Low-dose Tacrolimus in Comparison With Standard-dose Tacrolimus Therapy With Mycophenolic Acid on the New Onset Diabetes Mellitus After Transplantation in the Renal Allograft Recipients

Conditions
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Kidney; Complications, Allograft

Intervention / Treatment
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* Drug: Everolimus
* Drug: Tacrolimus
* Drug: Mycophenolic acid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 20 year old At least 3 months after kidney transplantation Subject who is using Tacrolimus ± purine synthesis inhibitor + steroid without change within the past 3 months (except the dosage) MDRD eGFR ≥ 50 mL/min or serum creatinine < 2.0mg/dL within the past 3 months in the 6months after kidney transplantation Rate of change of serum creatinine < +30% within the past 3 months in the 6months after kidney transplantation (if serum creatinine decreased, without rate of change is inclusion possible. if serum creatinine result was normal,regardless of the rate of change is able to register.) Urine protein/creatinine ratio < 1g/g Cr (spot urine) Subject who is not applicable to the diagnostic criteria NODAT on the baseline in the 6months after kidney transplantation Subjects who agree with written informed consent Exclusion Criteria: Subjects who received combined non-renal transplantation Subject who received re-transplantation ABO blood group incompatible(when anti-ABO Antibody titer <1:128 is inclusion possible.) Sensitized patients before transplantation Pretransplant or peak PRA titer > 50% Pretransplant T cell cytotoxicity crossmatch (+) HLA-identical living related donor Subject who has diabetes mellitus / NODAT before transplantation Subject who has suffered acute rejection episode within the past 3 months in the 6months after kidney transplantation Subject with hypersensitivity to everolimus Subject who should continue nephrotoxic drug until enrollment (Aminoglycoside, amphotericin B, cisplatin) Subject with GI disorder that might interfere with the ability to absorb oral medication. (eg, gastrectomy or insufficiently treated diabetic gastroenteropathy) Subjects with active peptic ulcer HIV, HBsAg, or HCV Ab tests (+) Abnormal liver function test (AST or ALT or total bilirubin> upper normal limit x3) ANC <1.5*109/L or WBC <2.5*109/L or platelet <75*109/L Treatment with an investigational drug within 30 days preceding the first dose of trial medication Women who are either pregnant, lactating, planning to become pregnant in the next 12 months. Subjects with history of cancer(except successfully treated), localized nonmelanocytic skin cancer, PTLD(Post-transplant lymphoproliferative disorder) Subjects with clinically significant infections within the past 4 weeks in the 6months after kidney transplantation Subjects who took major surgery within the past 4 weeks in the 6months after kidney transplantation

Ages Eligible for Study
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Minimum Age: 20 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tacrolimus plus Everolimus<br>Low dose Tacrolimus + Everolimus | Drug: Everolimus<br>* Decrease the level of Tacrolimus and add on Everolimus instead of Mycophenolic acid which is standard treatment.<br>* Other names: Certican;Drug: Tacrolimus<br>* Decrease the level of Tacrolimus and add on Everolimus instead of Mycophenolic acid which is standard treatment.<br>* Other names: Tacroli;|
| Active Comparator: Tacrolimus plus Mycophenolic acid<br>standard dose Tacrolimus + Mycophenolic acid | Drug: Tacrolimus<br>* Decrease the level of Tacrolimus and add on Everolimus instead of Mycophenolic acid which is standard treatment.<br>* Other names: Tacroli;Drug: Mycophenolic acid<br>* Decrease the level of Tacrolimus and add on Everolimus instead of Mycophenolic acid which is standard treatment.<br>* Other names: Cellcept;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in Development of NODAT (Fasting glucose ≥ 126 mg/dL, Random glucose ≥ 200 mg/dL) at 12 months | To evaluate prevention effect of combination therapy of Everolimus and low-dose Tacrolimus in comparison with standard-dose Tacrolimus therapy with Mycophenolic acid on the New Onset Diabetes Mellitus after transplantation at 12 months after date of randomization. | 0 to 12 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin resistance by HOMA-IR | Change from Baseline(V2) in Insulin resistance by HOMA-IR at 12months(V6) | 0 to 12 months | 
| Insulin secretion by HOMA-beta | Change from Baseline(V2) in insulin secretion by HOMA-beta at 12 months(V6) | 0 to 12 months | 
| OGTT (Fasting and PP2hr) | Change from baseline in OGTT (Fasting and PP2hr) at 12 months(V6) | 0 to 12 months | 
| Needs for anti-diabetic medication or insulin | Needs for anti-diabetic medication or insulin at Baseline(V2) | at Baseline(V2) | 
| Needs for anti-diabetic medication or insulin at 3 month(V3) | Needs for anti-diabetic medication or insulin at 3 month(V3) | at 3 month(V3) | 
| Needs for anti-diabetic medication or insulin at 6 month(V4) | Needs for anti-diabetic medication or insulin at 6 month(V4) | at 6 month(V4) | 
| Needs for anti-diabetic medication or insulin at 9 month(V5) | Needs for anti-diabetic medication or insulin at 9 month(V5) | at 9 month(V5) | 
| Needs for anti-diabetic medication or insulin at 12 month(V6) | Needs for anti-diabetic medication or insulin at 12 month(V6) | at 12 month(V6) | 
| Creatinine clearance (MDRD eGFR) at Baseline(V2) | Creatinine clearance (MDRD eGFR) at Baseline(V2) | at Baseline(V2) | 
| Creatinine clearance (MDRD eGFR) at 3 month(V3) | Creatinine clearance (MDRD eGFR) at 3 month(V3) | at 3 month(V3) | 
| Creatinine clearance (MDRD eGFR) at 6 month(V4) | Creatinine clearance (MDRD eGFR) at 6 month(V4) | at 6 month(V4) | 
| Creatinine clearance (MDRD eGFR) at 9 month(V5) | Creatinine clearance (MDRD eGFR) at 9 month(V5) | at 9 month(V5) | 
| Creatinine clearance (MDRD eGFR) at 12 month(V6) | Creatinine clearance (MDRD eGFR) at 12 month(V6) | at 12 month(V6) | 
| 12 month graft survival | After date of randomization, evaluate graft survival rate at 12 months(V6) | at 12 months(V6) | 
| 12 month patient survival rate | After date of randomization, evaluate patient survival rate at 12 months(V6) | at 12 months(V6) | 
| Change from baseline in Microalbuminuria(MAU) at 12 months | Change from baseline in Microalbuminuria(MAU) at 12 months | at 12 months(V6) | 
| Proportion of patients with significant proteinuria greater than 1g/gCr at Baseline(V2) | Proportion of patients with significant proteinuria greater than 1g/gCr at Baseline(V2) | at Baseline(V2) | 
| Proportion of patients with significant proteinuria greater than 1g/gCr at 3 month(V3) | Proportion of patients with significant proteinuria greater than 1g/gCr at 3 month(V3) | at 3 month(V3) | 
| Proportion of patients with significant proteinuria greater than 1g/gCr at 6 month(V4) | Proportion of patients with significant proteinuria greater than 1g/gCr at 6 month(V4) | at 6 month(V4) | 
| Proportion of patients with significant proteinuria greater than 1g/gCr at 9 month(V5) | Proportion of patients with significant proteinuria greater than 1g/gCr at 9 month(V5) | at 9 month(V5) | 
| Proportion of patients with significant proteinuria greater than 1g/gCr at 12 month(V6) | Proportion of patients with significant proteinuria greater than 1g/gCr at 12 month(V6) | at 12 month(V6) | 
| Number of episode of biopsy proven acute rejection (BPAR) | Cumulative incidence rate of Biopsy Proven Acute Rejection(BPAR) at 12months(V6) after date of randomization. | at 12 month(V6) | 
| Number of hospitalization of any cause (except admission for protocol biopsy) at Baseline(V2) | Number of hospitalization of any cause (except admission for protocol biopsy) at Baseline(V2) | at Baseline(V2) | 
| Number of hospitalization of any cause (except admission for protocol biopsy) at 3 month(V3) | Number of hospitalization of any cause (except admission for protocol biopsy) at 3 month(V3) | at 3 month(V3) | 
| Number of hospitalization of any cause (except admission for protocol biopsy) at 6 month(V4) | Number of hospitalization of any cause (except admission for protocol biopsy) at 6 month(V4) | at 6 month(V4) | 
| Number of hospitalization of any cause (except admission for protocol biopsy) at 9 month(V5) | Number of hospitalization of any cause (except admission for protocol biopsy) at 9 month(V5) | at 9 month(V5) | 
| Number of hospitalization of any cause (except admission for protocol biopsy) at 12 month(V6) | Number of hospitalization of any cause (except admission for protocol biopsy) at 12 month(V6) | at 12 month(V6) | 
| Number of opportunistic infections (BKVN) at Baseline(V2) | Number of opportunistic infections (BKVN) at Baseline(V2) | at Baseline(V2) | 
| Number of opportunistic infections (BKVN) at 12month(V6) | Number of opportunistic infections (BKVN) at 12month(V6) | at 12 month(V6) | 
| Prevalence of NODAT at Baseline(V2) | Prevalence of NODAT at Baseline(V2) | at Baseline(V2) | 
| Prevalence of NODAT at 3 month(V3) | Prevalence of NODAT at 3 month(V3) | at 3 month(V3) | 
| Prevalence of NODAT at 6 month(V4) | Prevalence of NODAT at 6 month(V4) | at 6 month(V4) | 
| Prevalence of NODAT at 9 month (V5) | Prevalence of NODAT at 9 month (V5) | at 9 month (V5) | 
| Prevalence of NODAT at 12 month(V6) | Prevalence of NODAT at 12 month(V6) | at 12 month(V6) |