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
Phase: NA
Conditions: Acute Graft Rejection, Diabetes
Sponsor: University of British Columbia

 
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Clinical Study Protocol 
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 
 
Principal 
Investigator(s): 
Jagbir Gill, MD MPH 
 
Co-
Investigator(s): 
John Gill, MD MS 
Olwyn Johnston, MD MS 
 
 
NCT01265537 

 
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Ethics and Good Clinical Practice 
This study will be performed according to the principles of Good Clinical Practice 
[Chapter 2 of the ICH Harmonized Tripartite Guideline for Good Clinical Practice 
(GCP)], the declaration of Helsinki, and national laws and regulations about 
clinical studies. The study may not start without written Ethics approval and the 
written informed consent of the patient. 
1. Title of Study 
A randomized prospective open label pilot study comparing the use of low-target 
versus conventional dose tacrolimus (Advagraf) dosing in a steroid-avoidance 
immunosuppressive protocol for de novo adult, non-diabetic, low immunological 
risk, kidney only transplant recipients. 
2. Introduction and Rationale 
Kidney transplantation is the treatment of choice for patients with end stage renal 
disease (ESRD) and is associated with a significant increase in life expectancy(1, 
2).  In the current era of immunosuppressant therapy, rates of acute rejection and 
early graft loss have improved dramatically.  However, significant improvements 
in long-term patient and allograft survival have not been achieved.  
 
Long-term outcomes are limited, in part, by high rates of cardiovascular disease 
and new onset diabetes after transplantation (NODAT).  Both corticosteroids and 
calcineurin inhibitors (CNI) significantly contribute to these problems and the 
desire to minimize these effects has led to the advent of immunosuppressant 
protocols that limit exposure to these agents(3-7). 
 
In the ELITE-Symphony trial, a maintenance protocol of Mycophenolate mofetil 
(MMF), low-dose tacrolimus, and corticosteroids was found to be advantageous 
for renal function, allograft survival, and acute rejection rates(8). A slight 
reduction in the rate of NODAT was reported between standard dose 
cyclosporine (6.4%) and low-dose cyclosporine (4.7%) in this trial. However, 
given the lower risks of biopsy proven acute rejection reported in the low-dose 
tacrolimus arm, the authors concluded that it may be feasible to further reduce 
the risk of NODAT with a reduction in corticosteroid exposure in the setting of 
low-dose tacrolimus. 
 
Existing data on corticosteroid withdrawal or avoidance strategies report a higher 
risk of acute rejection(9-11) but have failed to demonstrate a significant 
difference in graft survival between steroid free and steroid-based protocols(12-
14).  A number of studies have also demonstrated a lower risk of cardiovascular 
risk factors, such as hypertension with steroid withdrawal or avoidance(9, 14, 
15).  However, disappointingly NODAT remains a significant problem in 
corticosteroid withdrawal protocols. In a 5-year multicenter randomized trial 
comparing early steroid withdrawal with a steroid-based maintenance protocol 

 
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Woodle et al. reported an incidence of NODAT of 21.5%, with no significant 
difference between patients withdrawn from steroids versus those maintained on 
low dose steroids(10).  The high incidence of NODAT in the steroid avoidance 
arm of this study may, in part, be attributed to the high doses of tacrolimus used. 
During the first year post-transplant, serum tacrolimus levels were largely 
maintained above 10ng/ml in this study and may have contributed to a greater 
incidence of NODAT. 
 
The St. Paul’s Hospital and Vancouver Hospital programs have employed an 
early steroid withdrawal protocol, with basiliximab induction and standard dose 
calcineurin inhibitor for low immunologic risk transplant recipients for a number of 
years and remain the sole transplant programs in Canada using such a protocol.  
With this protocol we recognize an acute rejection rate of approximately 20%, 
and a NODAT rate of approximately 30%.   
 
We hypothesize, that a combined approach of early steroid withdrawal and low 
dose tacrolimus (Advagraf) for low immunologic risk transplant recipients will be 
effective in reducing the incidence of NODAT, while maintaining a low risk of 
acute rejection. 
 
We propose a pilot study to compare early post-transplant outcomes among low 
immunologic risk kidney transplant recipients undergoing early corticosteroid 
withdrawal in conjuction with low-target tacrolimus (Advagraf) versus standard 
target tacrolimus (Advagraf). 
 
3. Study Objectives 
Hypothesis:  
Objectives: 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. 
Hypothesis: Low target Advagraf in the setting of early corticosteroid withdrawal 
will be associated with equivalent rates of acute rejection, graft loss, and patient 
death, but lower rates of NODAT, compared to standard target Advagraf.   
Primary Outcome 
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 OGTT. 
Secondary Outcomes 
 Patient survival 

 
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 Graft survival 
 Frequency, severity, and treatment of hypertension 
 Frequency, severity, and treatment of hyperlipidemia (serum total cholesterol, 
HDL, LDL, and triglycerides) 
 Weight gain 
 Infections (CMV, opportunistic infections including urinary tract infections 
requiring treatment, pneumonia) 
 Malignancy, including PTLD 
 Leukopenia 
 Renal function as measured by serum creatinine and MDRD eGFR 
 Therapy with anti-diabetic medications beyond 1 month post transplant 
 
4. Investigational Plan 
4.1 Overall study design 
The study will take place at St. Paul’s Hospital and Vancouver Hospital, which 
together perform approximately 150 kidney transplants per year.  Before any 
study-related evaluations are performed, the patient must give written informed 
consent.   
A total of 34 patients who meet the inclusion criteria will be randomized into 2 
groups prior to transplantation:  
Group A will receive rabbit anti-thymocyte globulin (rATG) induction (3 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.  
Group B will receive basiliximab induction (40 mg total) with IV solumedrol, MPA 
(Mycophenolate Mofetil or Mycophenolate Sodium), and “standard target” 
Advagraf.  
Figure 1 outlines the study design and Table 1 outlines target serum Advagraf 
levels for each study group. In both groups patients will not receive maintenance 
corticosteroids and will be steroid free by day 14 post transplant. During the 6 
month treatment period, patients will be seen by study coordinators at baseline, 1 
month, 3 months, and 6 months post transplant. 
 

 
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Figure 1 
Study design 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 1. Target Advagraf (tacrolimus) serum trough levels 
Low Target (Group A) 
Standard Target (Group B) 
Months post tx 
Level 
Months post tx 
Level 
0-1 month 
5-7 
0-1 month 
8-12 
1-3 months 
4-5 
1-3 months 
6-9 
3-6 months 
3-4 
3-6 months 
5-8 
 
 
4.2. Discussion of design 
The purpose of this study is to compare early post transplant outcomes with low-
target versus standard target Advagraf.  The optimal induction agent has not 
been established in steroid free protocols.  A secondary analysis of the Astellas 
sponsored double-blinded study suggested a lower acute rejection rate with 
GROUP A 
rATG  (1) 
MPA 
Low target Advagraf 
Steroid discontinued 
within 14 days 
 
GROUP B (control) 
Basiliximab (2) 
MPA 
Standard target Advagraf 
Steroid discontinued 
within 14 days 
TX 
6 months  
Randomization 
Solumendrol 500mg IV 
Solumedrol 40mg IV 
1) The 1st dose of rATG will be given via single IV infusion on post operative day 0 
and 2 subsequent doses will be given between postoperative days 1-5. 
2) Basiliximab will be given via single IV infusion on post operative days 0 and 4. 

 
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rATG and it would appear that most centers are using rATG induction in this 
setting. As immunosuppressant protocols typically involve a combination of 
drugs, we have elected to use rATG in our low CNI exposure group in order to 
avoid any increased risk of rejection. We expect rATG will ensure no increase in 
acute rejection rates in the low target Advagraf group, but expect it will have no 
impact on the incidence of NODAT.   
In view of the exploratory nature of this study a randomized, open-label pilot 
study is appropriate and blinding of Advagraf doses would be extremely difficult. 
4.3. Study population 
4.3.1 Patient population 
All kidney-only living and deceased donor transplant recipients at St. Paul’s 
Hospital and Vancouver Hospital, aged over 18 years, with a current peak 
PRA<30%, and no evidence of diabetes mellitus (defined as no documented 
history of diabetes mellitus or the use of diabetic medications, and a random 
plasma glucose measurement <11.1 at the time of transplantation) are eligible for 
participation in the study.   
 
4.3.2. Sample Size  
For this pilot study, we aim to recruit a total of 34 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.  
4.3.3. Inclusion and exclusion criteria 
Each patient must meet all of the following inclusion criteria, and none of the 
following exclusion criteria in order to participate in this study.  
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<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 

 
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Exclusion criteria 
Patients meeting any of the following criteria at baseline will be excluded from 
study participation. 
 
1 Patients with primary non-function 
2 Peak PRA>= 30% 
3 Multiple organ transplants 
4 HLA identical living donor transplant recipients 
5 Cold ischemia time over 24 hours 
6 Nonheart beating donor kidney recipients 
7 Pediatric donor kidney recipients 
8 Donor age>=60 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 
4.3.4 Discontinuation of study  
Prednisone will be routinely withdrawn within 5 days post transplant as per 
clinical protocol, but may be continued for up to two weeks post transplant if 
clinically indicated.  In cases where prednisone use exceeds 2 weeks, the 
subject will be deemed in violation of the study protocol and excluded from 
participation in the study.          
In the absence of a medical contraindication or significant protocol violation, 
every effort will be made by the Principal Investigators to continue the patient on 
study medications. 
It will be documented whether or not each patient completed the clinical study. If 
for any patient either study treatment or observations were discontinued the 
reason will be recorded.  
 
4.4.  Treatment 
4.4.1 Treatment assignment 

 
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Patients who fulfill all inclusion/exclusion criteria within the baseline period, will 
be asked for written consent to participate in the study.  Each patient will be 
assigned a unique identification number. Randomization will be 1:1 and stratified 
by donor type (living, deceased).  
4.4.2 Treatment Agents: 
1. 
Advagraf (0.25mg/kg) orally  once daily  dosed as per manufacturer’s 
recommendation to target trough levels as per Table 1 
2. 
Mycophenolate Mofetil (1g BID) or Mycophenolate Sodium (720mg BID) 
3. 
Basiliximab 20mg IV on post-operative days 0 and 4 
4. 
Rabbit antithymocyte globulin (total dose 4.5-6.0 mg/kg) 
5. 
Solumedrol 500mg IV at the time of transplantation, followed by 
methylprednisilone/prednisone to be discontinued within 14 days of 
transplantation 
During the study period Advagraf dosage will be adjusted according to 
manufacturer recommendations to achieve target levels in each group (Table 1).  
As per standard clinical practice the use of mycophenolate mofetil and 
mycophenolate sodium is interchangeable.  Mycophenolate use will be tailored 
based on routine clinical practice.  At completion of the study, patients will remain 
on their prescribed maintenance immunosuppressive protocol, consisting of 
Advagraf and Mycophenolate. 
4.4.3 Concomitant therapy 
No medication other than the study drugs and the usual medications of the 
patients should be given during the full treatment period of the study, i.e., from 
the initial day of screening until all of the final study evaluations have been 
completed. Exceptions to this rule apply to medication which may be needed to 
treat adverse events. The administration of any additional medication (including 
over-the-counter medications and vitamins) will be clearly documented.  
All immunosuppressive drugs other than those specified by protocol are 
disallowed. Permissible anti-rejection therapy includes methylprednisolone, 
antilymphocyte, and antibody therapy according to local practice.  
 
4.5 Visit schedule and assessments 
4.5.1. Visit schedule 
Patients will be encouraged to attend all evaluations as scheduled. However, visit 
windows of ± 2 days for Week 1, ± 3 days for remaining weekly or semiweekly 
visits, and ± 7 days for monthly visits will be allowed. Patients will be seen and 
evaluated in accordance with the study evaluation schedule.  

 
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Baseline 
All baseline assessments, including obtaining written informed consent, will be 
performed prior to the transplant.  Laboratory evaluations at baseline will be 
performed by the local laboratory. The patient’s medical history and transplant 
information will be reviewed.  The patient’s vital signs and physical exam will 
provide documentary evidence that the patient is in stable condition and not 
suffering from any disqualifying condition. 
Evaluation and visit schedule 
Visit Timepoint 
Baseline1 
12 3 
6 
Visit Number 
1 
2 
3 
4 
Informed Consent 
X 
 
 
 
Randomization  
X 
 
 
 
Background information – 
recipient 
X 
 
 
 
Demography 
+ 
Relevant 
medical 
history/Current 
medical conditions 
X 
 
 
 
Physical examination 
X 
 
 
 
Vital 
signs 
and 
clinical 
assessment 
X 
X 
X 
X 
Laboratory test (local) 3 
X 
X 
X 
X 
Immunosuppressive 
medications 
As per protocol 
Kidney allograft biopsy 
As needed per clinical 
practice 
Follow up 
 
Complete at 
6 months 
Study Completion 
 
 
X 
1 Baseline visit will occur pre-operatively 
2 The 1st follow up visit will be 1 month post transplant 
3 Drug levels will be monitored on a frequency based on routine clinical practice.  
Serum chemistry will be assessed as per routine clinical management post 
transplant. 
 
A Hemoglobin A1c test will be performed at each post transplant visit and be 
included in their regular clinic work. An Oral Glucose Tolerance Test will be 
performed at 6 months only if the patient is displaying borderline symptoms of 
NODAT as determined by an investigator.

 
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Study duration: We plan to enroll the first patient by September 1st, 2010. Last 
patient visit will be enrolled by December 31, 2017 
5. Data management and statistical methods 
This is a pilot study. Primary and secondary endpoints are stated previously in 
the proposal. The primary endpoint will be evaluated by time-to-event Kaplan 
Meier analysis and by Chi-squared analysis of final 6 month data. 
6. References 
1. 
Wolfe RA, Ashby VB, Milford EL, Ojo AO, Ettenger RE, Agodoa LY, et al. Comparison of 
mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of 
a first cadaveric transplant. N Engl J Med. 1999 Dec 2;341(23):1725-30. 
2. 
Port FK, Wolfe RA, Mauger EA, Berling DP, Jiang K. Comparison of survival probabilities 
for dialysis patients vs cadaveric renal transplant recipients. JAMA. 1993 Sep 15;270(11):1339-
43. 
3. 
Miller LW. Cardiovascular toxicities of immunosuppressive agents. Am J Transplant. 
2002 Oct;2(9):807-18. 
4. 
Arner P, Gunnarsson R, Blomdahl S, Groth CG. Some characteristics of steroid diabetes: 
a study in renal-transplant recipients receiving high-dose corticosteroid therapy. Diabetes Care. 
1983 Jan-Feb;6(1):23-5. 
5. 
Julian BA, Laskow DA, Dubovsky J, Dubovsky EV, Curtis JJ, Quarles LD. Rapid loss of 
vertebral mineral density after renal transplantation. N Engl J Med. 1991 Aug 22;325(8):544-50. 
6. 
Rostaing L, Cantarovich D, Mourad G, Budde K, Rigotti P, Mariat C, et al. Corticosteroid-
free immunosuppression with tacrolimus, mycophenolate mofetil, and daclizumab induction in 
renal transplantation. Transplantation. 2005 Apr 15;79(7):807-14. 
7. 
Shah T, Kasravi A, Huang E, Hayashi R, Young B, Cho YW, et al. Risk factors for 
development of new-onset diabetes mellitus after kidney transplantation. Transplantation. 2006 
Dec 27;82(12):1673-6. 
8. 
Ekberg H, Tedesco-Silva H, Demirbas A, Vitko S, Nashan B, Gurkan A, et al. Reduced 
exposure to calcineurin inhibitors in renal transplantation. N Engl J Med. 2007 Dec 
20;357(25):2562-75. 
9. 
Vincenti F, Schena FP, Paraskevas S, Hauser IA, Walker RG, Grinyo J. A randomized, 
multicenter study of steroid avoidance, early steroid withdrawal or standard steroid therapy in 
kidney transplant recipients. Am J Transplant. 2008 Feb;8(2):307-16. 
10. 
Woodle ES, First MR, Pirsch J, Shihab F, Gaber AO, Van Veldhuisen P. A prospective, 
randomized, double-blind, placebo-controlled multicenter trial comparing early (7 day) 
corticosteroid cessation versus long-term, low-dose corticosteroid therapy. Ann Surg. 2008 
Oct;248(4):564-77. 
11. 
Woodle ES, Vincenti F, Lorber MI, Gritsch HA, Hricik D, Washburn K, et al. A multicenter 
pilot study of early (4-day) steroid cessation in renal transplant recipients under simulect, 
tacrolimus and sirolimus. Am J Transplant. 2005 Jan;5(1):157-66. 
12. 
Vincenti F, Monaco A, Grinyo J, Kinkhabwala M, Roza A. Multicenter randomized 
prospective trial of steroid withdrawal in renal transplant recipients receiving basiliximab, 
cyclosporine microemulsion and mycophenolate mofetil. Am J Transplant. 2003 Mar;3(3):306-11. 

 
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13. 
Matas AJ, Kandaswamy R, Gillingham KJ, McHugh L, Ibrahim H, Kasiske B, et al. 
Prednisone-free maintenance immunosuppression-a 5-year experience. Am J Transplant. 2005 
Oct;5(10):2473-8. 
14. 
Kumar MS, Heifets M, Moritz MJ, Saeed MI, Khan SM, Fyfe B, et al. Safety and efficacy 
of steroid withdrawal two days after kidney transplantation: analysis of results at three years. 
Transplantation. 2006 Mar 27;81(6):832-9. 
15. 
Knight SR, Morris PJ. Steroid avoidance or withdrawal after renal transplantation 
increases the risk of acute rejection but decreases cardiovascular risk. A meta-analysis. 
Transplantation. 2010 Jan 15;89(1):1-14.