Clinical Outcome of Delayed or Standard Prograf Together With Induction Therapy Followed by Conversion to Advagraf in Donation After Cardiac (or Circulatory) Death (DCD) Kidney Transplant Recipients

Study Overview
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Brief Summary
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The purpose of this study is to confirm non-inferiority of delayed Prograf treatment to standard Prograf treatment in the incidence of delayed graft function (DGF) within 1 week between the 2 immunosuppressive (IS) treatment groups: delayed or standard Prograf together with induction therapy, and then convert to Advagraf usage in donation after cardiac (or circulatory) death (DCD) kidney transplant recipients. This study will also compare the clinical outcome within 6 month post-transplant between the 2 IS treatment groups and compare the safety throughout study period between the 2 IS treatment groups.

Official Title
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Clinical Outcome of Delayed or Standard Prograf Together With Induction Therapy Followed by Conversion to Advagraf in Donation After Cardiac (or Circulatory) Death (DCD) Kidney Transplant Recipients: A Randomized, Open-label, Multicenter Clinical Trial

Conditions
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Kidney Transplant

Intervention / Treatment
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* Drug: Tacrolimus immediate-release formulation
* Drug: Tacrolimus prolonged-release formulation
* Drug: Induction therapy
* Drug: Mycophenolic acid drugs
* Drug: Corticosteroids


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject has end-stage kidney disease who is a suitable candidate for primary DCD kidney transplantation. Subject is a resident of China. Subject is scheduled to undergo DCD renal allograft transplantation with compatible ABO blood type. Subject has peak panel-reactive antibodies (PRA) < 10% or Negative test result. Subject must be a recipient of a DCD kidney and receive the organ distributed by China Organ Transplant Response System only. Female subject must either: Be of non-childbearing potential: Postmenopausal (defined as at least 1 year without any menses for which there is no other obvious pathological or physiological cause) prior to screening, or documented surgically sterile Or, if of childbearing potential: Agree not to try to become pregnant throughout the study period and have a negative blood pregnancy test at screening. A sexually active male or female subject is utilizing highly effective forms of birth control starting at screening and throughout the study period if the risk of conception exists. Subject agrees not to participate in another interventional study while participating in the present study from 1 month before randomization to 1 month after the last dose of investigational drug. Exclusion Criteria: Subject has previously received or is receiving an organ transplant other than kidney. Subject is receiving double-kidney transplant. Recipients of Maastricht Class I, II, and V donor organs. Recipients of Maastricht Class III and IV donor organs without a full complement of intensive care unit and intraoperative records. Subject has cold ischemia time of allograft > 24 hours before kidney transplantation surgery. Subject has known contraindication to administration of tacrolimus (Prograf or Advagraf), or other macrolides. Subject is unlikely to comply with the visits scheduled in the protocol or has a history of non-compliance. Subject has evidence of active liver disease or the presence of a chronic active hepatitis B or C within 1 month prior to kidney transplant surgery. Recipient or donor is seropositive for human immunodeficiency virus. Subject has active systemic infection requiring the use of antimicrobial agents within 1 week prior to kidney transplant surgery. Subject has current malignancy or a history of malignancy (within the past 5 years), except non- metastatic basal or squamous cell carcinoma of the skin or carcinoma in-situ of the cervix that has been treated successfully. Subject has medical or psychological conditions which would preclude compliance with the study requirements. Subject has any condition, including any uncontrolled disease state other than end-stage kidney disease, that constitutes an inappropriate risk or a contraindication for participation in the study, or that could interfere with the study objectives, conduction, or evaluation. Female subject who breastfeed or donate ova starting at screening and throughout the study period. Male subject who donate sperm starting at screening and throughout the study period.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Standard Prograf group<br>Participants received from day 1 tacrolimus immediate-release formulation (Prograf) 0.1 - 0.15 milligrams/kilograms/day (mg/kg/day) orally at 12-hour interval (twice daily 1 hour before meal or 2 hours after meal) for approximately 1 month. At 1 month after Kidney transplant, Prograf was converted to Advagraf on a 1:1 (mg: mg) total daily dose basis. The Advagraf was administered orally once daily in the morning, 1 hour before the breakfast; the whole blood target trough level for Advagraf was maintained as 6 - 12 nanograms/milliliter(ng/mL) within months 2 to 3, and 6 - 8 ng/mL within months 4 to 6. | Drug: Tacrolimus immediate-release formulation<br>* oral<br>* Other names: FK506;Drug: Tacrolimus prolonged-release formulation<br>* oral<br>* Other names: FK506;Drug: Induction therapy<br>* All participants will receive induction therapy. The dosage and administration of induction immunotherapy will be a single kind of drug determined by the investigator.<br>Drug: Mycophenolic acid drugs<br>* All participants will receive mycophenolic acid drugs in combination with corticosteroids. The dosage and administration of mycophenolic acid will be determined by the investigator.<br>Drug: Corticosteroids<br>* All participants will receive corticosteroids in combination with mycophenolic acid drugs. The dosage and administration of corticosteroids will be determined by the investigator.<br>|
| Experimental: Delayed Prograf group<br>Participants received from day 3 to 5 Prograf 0.1 - 0.15 mg/kg/day orally at 12-hour interval (twice daily 1 hour before meal or 2 hours after meal) for approximately 1 month. At 1 month after Kidney transplant, Prograf was converted to Advagraf on a 1:1 (mg: mg) total daily dose basis. The Advagraf was administered orally once daily in the morning, 1 hour before the breakfast; the whole blood target trough level for Advagraf was maintained as 6 - 12 ng/mL within months 2 to 3, and 6 - 8 ng/mL within months 4 to 6. | Drug: Tacrolimus immediate-release formulation<br>* oral<br>* Other names: FK506;Drug: Tacrolimus prolonged-release formulation<br>* oral<br>* Other names: FK506;Drug: Induction therapy<br>* All participants will receive induction therapy. The dosage and administration of induction immunotherapy will be a single kind of drug determined by the investigator.<br>Drug: Mycophenolic acid drugs<br>* All participants will receive mycophenolic acid drugs in combination with corticosteroids. The dosage and administration of mycophenolic acid will be determined by the investigator.<br>Drug: Corticosteroids<br>* All participants will receive corticosteroids in combination with mycophenolic acid drugs. The dosage and administration of corticosteroids will be determined by the investigator.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of delayed graft function (DGF) | DGF is defined as dialysis requirement during the first post-transplant week (7 days). | Up to Day 7 after transplantation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of acute rejection (AR) | The reporting of AR includes any biopsy-proven or clinically-suspected rejection of a subject after transplantation. | Up to Month 6 after transplantation | 
| Renal function assessed by estimated glomerular filtration rate (eGFR) | eGFR will be derived using the abbreviated Modification of Diet in Renal Disease (MDRD) formula. | Up to Month 6 after transplantation | 
| Renal function assessed by serum creatinine | Serum creatinine will be measured from serum sample collected. | Up to Month 6 after transplantation | 
| Renal function assessed by urea nitrogen | Urea nitrogen will be measured from serum sample collected. | Up to Month 6 after transplantation | 
| Subject survival | Subject survival is the time from the date of transplantation to the date of death or the date of the last follow-up. Subject survival will be estimated using Kaplan Meier estimates and compared by log rank test. | Up to Month 6 after transplantation | 
| Graft survival | Graft survival is an estimate of the probability of the transplant functioning at a finite time after transplantation. Graft survival will be calculated from the date of transplantation to the date of irreversible graft failure or the date of the last follow-up during the period when the transplant is still functioning or to the date of death. | Up to Month 6 after transplantation | 
| Safety assessed by incidence of treatment-emergent adverse events (TEAEs) | Adverse events (AEs) will be coded using the latest version of MedDRA. TEAE is defined as any AE following the transplantation until the end of the study. | Up to Month 7 after transplantation | 
| Safety assessed by incidence of serious adverse events (SAEs) | AE is considered serious if the investigator or sponsor view any of the following outcomes: Death, life-threatening, persistent or significant disability/incapacity, congenital anomaly or birth defect, hospitalization, or medically important event. | Up to Month 7 after transplantation | 
| Number of participants with laboratory test abnormalities and/or AEs | Number of participants with potentially clinically significant laboratory values. | Up to Month 7 after transplantation | 
| Number of participants with vital sign abnormalities and/or AEs | Number of participants with potentially clinically significant vital sign values. | Up to Month 7 after transplantation | 
| Number of participants with 12-lead electrocardiograms (ECG) abnormalities and/or AEs | ECG will be performed in the supine position after the subject has been breathing quietly for 5 minutes. Any clinically significant adverse changes on the ECG will be reported as AEs. | Up to Month 7 after transplantation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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kidney transplant, Tacrolimus, Prograf, Advagraf, FK506