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

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

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.

Study Overview

• Status: Completed
• Conditions: Kidney Transplant
• Intervention / Treatment: Drug: Tacrolimus immediate-release formulation; Drug: Tacrolimus prolonged-release formulation; Drug: Induction therapy; Drug: Mycophenolic acid drugs; Drug: Corticosteroids

• Study Type: Interventional
• Enrollment (Actual): 284
• Phase: Phase 4

Contacts and Locations

Study Locations

• China
  • Beijing, China
    • Site CN08608
  • Beijing, China
    • Site CN08619
  • Changsha, China
    • Site CN08609
  • Guangzhou, China
    • Site CN08604
  • Hangzhou, China
    • Site CN08614
  • Hangzhou, China
    • Site CN08617
  • Nanjing, China
    • Site CN08610
  • Nanjing, China
    • Site CN08618
  • Shanghai, China
    • Site CN08612
  • Tianjin, China
    • Site CN08603
  • Wenzhou, China
    • Site CN08621
  • Wuhan, China
    • Site CN08602
  • Wuhan, China
    • Site CN08613
  • Xi'an, China
    • Site CN08605

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Standard Prograf group; 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; oral; Other Names: Prograf; FK506; Drug: Tacrolimus prolonged-release formulation; oral; Other Names: FK506; Advagraf; Drug: Induction therapy; All participants will receive induction therapy. The dosage and administration of induction immunotherapy will be a single kind of drug determined by the investigator.; Drug: Mycophenolic acid drugs; All participants will receive mycophenolic acid drugs in combination with corticosteroids. The dosage and administration of mycophenolic acid will be determined by the investigator.; Drug: Corticosteroids; All participants will receive corticosteroids in combination with mycophenolic acid drugs. The dosage and administration of corticosteroids will be determined by the investigator.
Experimental: Delayed Prograf group; 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; oral; Other Names: Prograf; FK506; Drug: Tacrolimus prolonged-release formulation; oral; Other Names: FK506; Advagraf; Drug: Induction therapy; All participants will receive induction therapy. The dosage and administration of induction immunotherapy will be a single kind of drug determined by the investigator.; Drug: Mycophenolic acid drugs; All participants will receive mycophenolic acid drugs in combination with corticosteroids. The dosage and administration of mycophenolic acid will be determined by the investigator.; Drug: Corticosteroids; All participants will receive corticosteroids in combination with mycophenolic acid drugs. The dosage and administration of corticosteroids will be determined by the investigator.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Astellas Pharma China, Inc.
• Investigators: Study Director: Medical Director, Astellas Pharma China, Inc.

Publications and helpful links

Helpful Links

• Link to plain language summary of the study on the Trial Results Summaries website.
• Link to results and other applicable study documents on the Astellas Clinical Trials website.

Study record dates

Study Major Dates

• Study Start (Actual): October 21, 2018
• Primary Completion (Actual): July 15, 2022
• Study Completion (Actual): July 15, 2022

Study Registration Dates

• First Submitted: August 22, 2018
• First Submitted That Met QC Criteria: August 22, 2018
• First Posted (Actual): August 23, 2018

Study Record Updates

• Last Update Posted (Actual): October 31, 2024
• Last Update Submitted That Met QC Criteria: October 29, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: Tacrolimus; Prograf; kidney transplant; FK506; Advagraf
• Additional Relevant MeSH Terms: Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics, Antineoplastic; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antibiotics, Antitubercular; Antitubercular Agents; Calcineurin Inhibitors; Mycophenolic Acid; Tacrolimus
• Other Study ID Numbers: 506-MA-3186

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Access to anonymized individual participant level data will not be provided for this trial. Further details on Astellas' data sharing policy can be found at https://www.clinicaltrials.astellas.com/transparency/.
• IPD Sharing Time Frame: Access to participant level data is offered to researchers after publication of the primary manuscript (if applicable) and is available as long as Astellas has legal authority to provide the data.
• IPD Sharing Access Criteria: Researchers must submit a proposal to conduct a scientifically relevant analysis of the study data. The research proposal is reviewed by an Independent Research Panel. If the proposal is approved, access to the study data is provided in a secure data sharing environment after receipt of a signed Data Sharing Agreement.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No