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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Acute Graft Rejection, Diabetes

Intervention / Treatment
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* Drug: Tacrolimus
* Drug: Tacrolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients over 18 years of age who receive a deceased, living unrelated or living related donor renal transplant No history of pre-existing diabetes mellitus Not using diabetic medications (insulin, hypoglycemic agents) at the time of transplantation Random plasma glucose level <11.1 at the time of transplantation Peak PRA (panel reactive antibody) <30% 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 The patient has given written informed consent to participate in the study Exclusion Criteria: Patients with primary non-function Peak PRA>=30% Multiple organ transplants HLA (human leukocyte antigen) identical living donor transplant recipients Cold ischemia time over 36 hours Nonheart beating donor kidney recipients Pediatric donor kidney recipients Donor age>=65 years 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. Patients who are Epstein-Barr virus (EBV) negative and are receiving a transplant from an EBV-positive donor (mismatch). 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 Patients with systemic infections Existence of any surgical or medical condition, other than the current transplant, which in the opinion of the investigator, preclude enrollment in this trial Inability to cooperate or communicate with the investigator

Ages Eligible for Study
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Minimum Age: 19 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: Low target tacrolimus (Advagraf)<br>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<br>* 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<br>* Other names: Advagraf;|
| Active Comparator: Standard target tacrolimus (Advagraf)<br>This group will receive basiliximab induction (40 mg total) with IV solumedrol, MPA (Mycophenolate Mofetil or Mycophenolate Sodium), and standard target Advagraf. | Drug: Tacrolimus<br>* 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.<br>* Other names: Advagraf;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Transplant, Tacrolimus, Diabetes after transplant, Acute rejection prevention, New onset diabetes after transplant