A Pilot Study Comparing the Use of Low-target Versus Conventional Target Advagraf (Astellas)

A Prospective, Open Label, Pilot Study Comparing the Use of Low-target Advagraf With Rabbit Antithymocyte Globulin Induction Versus Conventional Target Advagraf With Basiliximab Induction in a Steroid-avoidance Immunosuppressive Protocol for de Novo Renal Transplant Recipients

While the incidence of acute rejection and early graft loss have improved dramatically with the advent of newer immunosuppressant medications, improvements in long-term patient and allograft survival after kidney transplantation have not been achieved. The specific drug combination that provides the best outcomes with the least amount of side effects is not known. Each kidney transplant center uses the combination of drugs that they believe is optimal. This study is about identifying whether drugs that are currently approved for use in kidney transplantation can be used in a new combination safely and with potentially fewer side effects than the drug combinations that are currently used at St. Paul's Hospital and other transplant centres.

Study Overview

• Status: Completed
• Conditions: Diabetes; Acute Graft Rejection
• Intervention / Treatment: Drug: Tacrolimus; Drug: Tacrolimus

Detailed Description

Purpose This study has been designed to test whether using Thymoglobulin with low dose tacrolimus and early steroid withdrawal will minimize both kidney rejection and the development of new onset diabetes after transplant (NODAT).

Justification Experimental treatment is low target tacrolimus with thymoglobulin. Standard treatment is a standard target (higher dose) tacrolimus and basiliximab, instead of thymoglobulin.

The investigators hypothesize, that a combined approach of early steroid withdrawal and low dose tacrolimus in low immunologic risk transplant recipients will be effective in reducing the incidence of new onset diabetes mellitus, while maintaining a low risk of acute rejection.

Objective

The objective of this study is to compare early post-transplant outcomes with the use of low target versus standard target Advagraf in de novo kidney allograft recipients of low immunologic risk undergoing early corticosteroid withdrawal.

Research Method

This is a pilot study. Primary and secondary outcomes are as follows:

Primary Outcome Composite endpoint of biopsy proven acute rejection and NODAT at 6 months post transplantation.

Secondary Outcomes

• Patient survival
• Graft survival
• Frequency, severity, and treatment of hypertension
• Frequency, severity, and treatment of hyperlipidemia (serum total cholesterol, (high density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides)
• Weight gain
• Infections (cytomegalovirus (CMV), opportunistic infections including urinary tract infections requiring treatment, pneumonia)
• Malignancy, including post-transplant lymphoproliferative disease (PTLD)
• Leukopenia
• Renal function as measured by serum creatinine and estimated Glomerular Filtration Rate (eGFR)

The primary endpoint will be evaluated by time-to-event Kaplan Meier analysis and by Chi-squared analysis of final 6 month data.

Statistical Analysis

Sample size and power:

In the setting of early steroid withdrawal, Woodle et al. reported an acute rejection rate of 14% with rATG and 24% with an interleukin-2 receptor antibody induction(10). The incidence of NODAT was reported at 21% by Woodle, et al., and was reported 10% in the low dose tacrolimus arm of the ELITE-Symphony trial. The investigators, therefore expect a combined event rate of 24% in Group A and 45% in group B. With a power of 0.80 and alpha error of 0.05, the investigators determined that the investigators need 72 subjects in each arm to demonstrate a 20% difference in our composite primary outcome. For this initial pilot study, the investigators aim to recruit a total of 30 subjects After receiving informed consent, subjects will be randomized on a 1:1 basis to one of the two treatment groups. Subjects who discontinue the study prematurely will not be replaced.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6Z 1Y6
      • St. Paul's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Male or female patients over 18 years of age who receive a deceased, living unrelated or living related donor renal transplant
2. No history of pre-existing diabetes mellitus
3. Not using diabetic medications (insulin, hypoglycemic agents) at the time of transplantation
4. Random plasma glucose level <11.1 at the time of transplantation
5. Peak PRA (panel reactive antibody) <30%
6. Females capable of becoming pregnant must have a negative pregnancy test at baseline and are required to practice an approved method of birth control for the duration of the study and for a period of three months following discontinuation of study medication
7. The patient has given written informed consent to participate in the study

Exclusion Criteria:

1. Patients with primary non-function
2. Peak PRA>=30%
3. Multiple organ transplants
4. HLA (human leukocyte antigen) identical living donor transplant recipients
5. Cold ischemia time over 36 hours
6. Nonheart beating donor kidney recipients
7. Pediatric donor kidney recipients
8. Donor age>=65 years
9. Patients who are known to have a positive hepatitis C serology, who are human immunodeficiency virus (HIV) or Hepatitis B surface antigen positive. Laboratory results obtained within 6 months prior to study entry are acceptable. Recipients of organs from donors who test positive for Hepatitis B surface antigen or Hepatitis C will be excluded.
10. Patients who are Epstein-Barr virus (EBV) negative and are receiving a transplant from an EBV-positive donor (mismatch).
11. Presence of any severe allergy requiring acute (within 4 weeks of baseline) or chronic treatment, or hypersensitivity to drugs similar to those used in the study
12. Patients with systemic infections
13. Existence of any surgical or medical condition, other than the current transplant, which in the opinion of the investigator, preclude enrollment in this trial
14. Inability to cooperate or communicate with the investigator

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: Low target tacrolimus (Advagraf); This group will receive rabbit anti-thymocyte globulin (rATG) induction (3 -4 doses of 1.5 mg/kg during the first post transplant week) with IV solumedrol, MPA (Mycophenolate Mofetil or Mycophenolate Sodium), and "low-target" Advagraf.	Drug: Tacrolimus; Low target tacrolimus Advagraf (0.25mg/kg) orally once daily dosed as per manufacturer's recommendation to target trough levels as per Table 1 Table 1 Months post tx: 0-1 month, level 5-7; 1-3 months, level 4-5; and 3-6 months, level 3-4; Other Names: Advagraf; Drug: Tacrolimus; Standard dose of tacrolimus Advagraf (0.25mg/kg) orally once daily dosed as per manufacturer's recommendation to target trough levels as per Table 1 Table 1 Months post tx 0-1 month; level 8-12; 1-3 months, level 6-9; and 3-6 months, level 5-8.; Other Names: Advagraf
Active Comparator: Standard target tacrolimus (Advagraf); This group will receive basiliximab induction (40 mg total) with IV solumedrol, MPA (Mycophenolate Mofetil or Mycophenolate Sodium), and "standard target" Advagraf.	Drug: Tacrolimus; Low target tacrolimus Advagraf (0.25mg/kg) orally once daily dosed as per manufacturer's recommendation to target trough levels as per Table 1 Table 1 Months post tx: 0-1 month, level 5-7; 1-3 months, level 4-5; and 3-6 months, level 3-4; Other Names: Advagraf; Drug: Tacrolimus; Standard dose of tacrolimus Advagraf (0.25mg/kg) orally once daily dosed as per manufacturer's recommendation to target trough levels as per Table 1 Table 1 Months post tx 0-1 month; level 8-12; 1-3 months, level 6-9; and 3-6 months, level 5-8.; Other Names: Advagraf

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With New Onset Diabetes After Transplant (NODAT) or Acute Rejection	Composite endpoint of biopsy proven acute rejection and NODAT at 6 months post transplantation. NODAT will be defined as either FPG >7.0mmol/L OR symptoms of hyperglycemia and a random plasma glucose of >11.1 OR 2-h plasma glucose >11.1 during an oral glucose tolerance test(OGTT).	6 months post transplant

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participant Deaths	Death of any participant by end of study.	6 months post transplant
Number of Participants With Graft Failure	Any graft failure by the end of the study.	6 months post transplant
Number of Participants With Dialysis Events	Any dialysis required by end of study.	6 months post transplant
Number of Participants With Infection Events	Any infection (CMV, opportunistic infections including urinary tract infections requiring treatment, pneumonia) by end of study.	6 months post transplant
Number of Participants With Hospitalization Events	Any hospitalization by end of study.	6 months post transplant
Number of Participants With Malignancy Events	Any malignancy (including post-transplant lymphoproliferative disease) by end of study.	6 months post transplant
Number of Participants With Cardiovascular Event	Any cardiovascular events by end of study.	6 months post transplant
Number of Any Leukopenia Events	Any leukopenia by end of study.	6 months post transplant
Number of Leukopenia Events on ≥2 Occasions	Any leukopenia on ≥2 occasions by end of study.	6 months post transplant
Change From Baseline in Weight	Any changes in weight by end of study.	baseline to 6 months post transplant
eGFR at 6 Months	Participant eGFR value by end of study.	6 months post transplant

Collaborators and Investigators

• Sponsor: University of British Columbia
• Collaborators: Astellas Pharma Canada, Inc.
• Investigators: Principal Investigator: Jagbir Gill, MD, UBC / Dept of Medicine / Nephrology

Study record dates

Study Major Dates

• Study Start (Actual): June 24, 2011
• Primary Completion (Actual): February 21, 2019
• Study Completion (Actual): October 11, 2019

Study Registration Dates

• First Submitted: December 21, 2010
• First Submitted That Met QC Criteria: December 22, 2010
• First Posted (Estimated): December 23, 2010

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 21, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: Tacrolimus; Transplant; Diabetes after transplant; Acute rejection prevention; New onset diabetes after transplant
• Additional Relevant MeSH Terms: Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Calcineurin Inhibitors; Tacrolimus
• Other Study ID Numbers: H10-03047