Standard- Versus Reduced-dose Tacrolimus Combined With Generic Mycophenolate Mofetil in De Novo Renal Transplantation

Overview

A prospective, multicenter, open-label, randomized and parallel-group clinical trial was conducted at four transplant centers in Korea. This clinical study was designed to compare the efficacy and tolerability of reduced-dose tacrolimus with standard-dose mycophenolate mofetil (MMF) versus standard-dose tacrolimus with reduced-dose MMF.

Full Title of Study: “Comparative Clinical Study of Reduced Dose of Tacrolimus and Standard Dose of Mycophenolate Mofetil vs. Conventional Dose of Tacrolimus and Reduced Dose of Mycophenolate Mofetil in De Novo Renal Transplant Recipients”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: November 11, 2016

Detailed Description

A prospective, multicenter, open-label, randomized and parallel-group clinical trial was conducted at four transplant centers in Korea. The total sample size was 108 and eligible patients were randomly assigned in a 1:1 ratio to either study or control group. For six months study period, graft function, the incidence of efficacy failure and adverse events were compared. The total sample size was 108 and eligible patients were randomly assigned in a 1:1 ratio to either study or control group: The study group (reduced-dose tacrolimus + standard-dose MMF) or the control group (standard-dose tacrolimus + reduced-dose MMF). Restricted block randomization was applied to this study and both the enrolled subjects and care providers were blinded until randomization was done. A difference in the mean estimated glomerular filtration rates (eGFR) of 16 mL/min/1.73m2 was considered a clinically meaningful margin of non-inferiority. A sample size of 108 for both groups was calculated for the primary endpoint by assuming a significance level of 0.025 with a power of at least 95% and adjusted for a potential dropout rate of 20%. The primary efficacy endpoint was the renal graft function assessed with eGFR by MDRD formula at 6 months post-transplant. The secondary endpoints included (1) the incidence of treatment failure that included biopsy-confirmed acute rejection (BCAR), graft loss, death, or loss to follow-up until 6 months post-transplant; (2) recipients and grafts' survival rates; (3) 24-hour urine proteinuria and creatinine clearance at 6 months post-transplant. Recipients with clinical findings suggestive of acute rejection underwent biopsies before initiation or within 48 hours of anti-rejection therapy and biopsy specimens were graded according to Banff Classification criteria. Safety endpoints included (1) all adverse event defined as any medical occurrence including worsening of a preexisting medical condition; (2) opportunistic infections; (3) malignancies; (4) abnormal laboratory findings; and (5) any abnormal physical findings or vital signs. Severe adverse events were defined as any adverse events with undesirable signs, symptoms, or medical conditions that met any one of the following criteria: 1) was fatal or life-threatening, 2) resulted in persistent or significant disability/incapacity, 3) required hospitalization or the prolongation of existing hospitalization, 4) was a congenital anomaly/birth defect, or 5) was an important medical event that might deteriorate the patient and require medical or surgical intervention to prevent one of the other outcomes listed above.18 All adverse events were coding using WHOART 2009 version.

Interventions

  • Drug: Tacrolimus(reduced), Mycophenolate mofetil(standard)
    • tacrolimus target trough blood level: 3~8ng/mL MMF dose: 1.5~2g/d
  • Drug: Tacrolimus(standard), Mycophenolate mofetil(reduced)
    • tacrolimus target trough blood level: 5~15ng/mL MMF dose: 0.5~1g/d

Arms, Groups and Cohorts

  • Experimental: reduced-dose tacrolimus + standard-dose MMF
    • Tacrolimus dose was individually adjusted with a target trough blood level of between 3ng/mL and 8ng/mL throughout the study period (6 months after transplantation). MMF started within 72 hours after transplantation and the dose of MMF was 1.5~2.0g per day.
  • Active Comparator: standard-dose tacrolimus + reduced-dose MMF
    • Control group, target trough blood level was between 5ng/mL and 15ng/mL throughout the study period. MMF dose was 0.5~1g per day and MMF started within 72 hours after transplantation.

Clinical Trial Outcome Measures

Primary Measures

  • renal graft function
    • Time Frame: 6 months post-transplant
    • assessed with eGFR by MDRD formula

Secondary Measures

  • incidence of treatment failure
    • Time Frame: 6 months post-transplant
    • biopsy-confirmed acute rejection (BCAR), graft loss, death, or loss
  • recipients and grafts’ survival rates
    • Time Frame: 6 months post-transplant
    • recipients and grafts’ survival rates
  • 24-hour urine proteinuria and creatinine clearance
    • Time Frame: 6 months post-transplant
    • 24-hour urine proteinuria and creatinine clearance

Participating in This Clinical Trial

Inclusion Criteria

  • Recipients (aged 20-65) of a single (first or second) renal allograft from living or deceased donor. Exclusion Criteria:

  • comprised of recipients with multiple organ transplants – double kidney transplant or organs donated after cardiac death – recipients previously organ transplanted except kidney – ABO-incompatible transplants – recipients with antibodies against the human leukocyte antigens of the donor organ – history of malignancy in the previous 5 years (except successfully treated localized non-melanoma skin cancer and thyroid cancer) – leukocyte counts of less than 2,500 per μL, or neutrophils less than 1,500 per μL, or platelets less than 50,000 per μL – evidence of active systemic infection requiring the use of antibiotics, human immunodeficiency virus infection, or chronic active hepatitis B or C

Gender Eligibility: All

Minimum Age: 20 Years

Maximum Age: 65 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Ajou University School of Medicine
  • Provider of Information About this Clinical Study
    • Principal Investigator: Chang kwon oh, Chang-Kwon Oh – Ajou University School of Medicine
  • Overall Official(s)
    • Chang-Kwon Oh, M.D, Principal Investigator, Department of surgery, Ajou University School of Medicine

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