Clinical trial NCT03555448
Conditions: Kidney Transplant; Complications
Keywords: Immunosuppression
Sponsor: Washington University School of Medicine
Start date: 2018-06-04; Completion date: 2023-11-10
Enrollment: 51 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this research study is to determine whether an immunosuppressive maintenance regimen of Envarsus/azathioprine compared to a tacrolimus/ mycophenolic acid regimen is associated with better compliance, tolerability, and lower biopsy proven rejection.

Detailed description:

Arms: arm 1: Once daily medication regimen (Envarsus and azathioprine) arm 2: Twice daily medication regimen (Tacrolimus and mycophenolic acid)
Interventions: intervention 1: Once daily immunosuppression regimen intervention 2: Twice daily immunosuppression regimen
Intervention descriptions: intervention 1: Intervention focuses on the type of regimen, in this case the intervention arm will receive a once daily regimen for immunosuppression compared to the twice daily regimen. intervention 2: This is the arm which we are designating the standard, which will be the comparison to the active drug arm.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
______________________________________________________________________________________ 
 
1
 
 
 
Once a Day Immunosuppression Regimen: Outcomes and 
Compliance 
 
Principal Investigator: 
Rowena Delos Santos, MD 
 
 
 
 
 
 
NCT number: NCT03555448 
Version Date/Number:  
03/8/19 v3.0 
 


 
 
 
 
 
 
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2
 
 
TABLE OF CONTENTS 
 
A 
INTRODUCTION ............................................................................................................................... 4 
A1 
STUDY ABSTRACT ......................................................................................................................... 4 
A2 
PRIMARY HYPOTHESIS ................................................................................................................... 4 
A3 
PURPOSE OF THE STUDY PROTOCOL .............................................................................................. 4 
B 
BACKGROUND .................................................................................................................................. 4 
B1 
PRIOR LITERATURE AND STUDIES .................................................................................................. 4 
B2 
RATIONALE FOR THIS STUDY ......................................................................................................... 5 
C 
STUDY OBJECTIVES ....................................................................................................................... 5 
C1 
PRIMARY AIM ................................................................................................................................ 5 
C2 
SECONDARY AIM ........................................................................................................................... 5 
C3 
RATIONALE FOR THE SELECTION OF OUTCOME MEASURES ........................................................... 5 
D 
INVESTIGATIONAL AGENT .......................................................................................................... 6 
D1 
PRECLINICAL DATA ................................................................ERROR! BOOKMARK NOT DEFINED. 
D2 
CLINICAL DATA TO DATE .............................................................................................................. 6 
D3 
DOSE RATIONALE AND RISK/BENEFITS ......................................................................................... 6 
E 
STUDY DESIGN ................................................................................................................................. 7 
E1 
OVERVIEW OR DESIGN SUMMARY ................................................................................................. 7 
E2 
SUBJECT SELECTION AND WITHDRAWAL ....................................................................................... 7 
2.a 
Inclusion Criteria ..................................................................................................................... 7 
2.a 
Exclusion Criteria ..................................................................................................................... 8 
2.b 
Ethical Considerations ............................................................................................................. 8 
2.c 
Subject Recruitment Plans and Consent Process ..................................................................... 8 
2.d 
Randomization Method and Blinding ....................................................................................... 8 
2.e 
Risks and Benefits ..................................................................................................................... 8 
2.f 
Early Withdrawal of Subjects ................................................................................................... 9 
2.g 
When and How to Withdraw Subjects ....................................................................................... 9 
2.h 
Data Collection and Follow-up for Withdrawn Subjects .......................................................... 9 
E3 
STUDY DRUG ................................................................................................................................. 9 
3.a 
Description ............................................................................................................................... 9 
3.b 
Treatment Regimen ................................................................................................................... 9 
3.c 
Method for Assigning Subjects to Treatment Groups ............................................................. 10 
3.d 
Preparation and Administration of Study Drug ...................................................................... 10 
3.e 
Subject Compliance Monitoring ............................................................................................. 10 
3.f 
Prior and Concomitant Therapy ............................................................................................. 10 
3.g 
Packaging ............................................................................................................................... 10 
3.h 
Blinding of Study Drug ........................................................................................................... 11 
3.i 
Receiving, Storage, Dispensing and Return ........................................................................... 11 
F 
STUDY PROCEDURES ................................................................................................................... 11 
F1 
SCREENING FOR ELIGIBILITY ....................................................................................................... 11 


 
 
 
 
 
 
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3
F2 
SCHEDULE OF MEASUREMENTS ................................................................................................... 11 
F3 
VISIT 1 ......................................................................................................................................... 11 
F4 
VISIT 2 ETC. ............................................................................ERROR! BOOKMARK NOT DEFINED. 
F5 
SAFETY AND ADVERSE EVENTS ................................................................................................... 12 
5.a 
Safety and Compliance Monitoring ........................................................................................ 13 
5.b 
Medical Monitoring ................................................................................................................ 13 
i 
Investigator only ..................................................................................................................................... 13 
ii 
Independent expert to monitor ................................................................. Error! Bookmark not defined. 
iii 
Institutional Data and Safety Monitoring Board ...................................... Error! Bookmark not defined. 
iv 
Independent Data and Safety Monitoring Board ...................................... Error! Bookmark not defined. 
5.c 
Definitions of Adverse Events ................................................................................................. 13 
5.d 
Classification of Events .......................................................................................................... 14 
i 
Relationship ............................................................................................................................................ 14 
ii 
Severity ................................................................................................................................................... 14 
iii 
Expectedness .......................................................................................................................................... 14 
5.e 
Data Collection Procedures for Adverse Events .................................................................... 14 
5.f 
Reporting Procedures ............................................................................................................. 14 
5.g 
Adverse Event Reporting Period............................................................................................. 15 
5.h 
Post-study Adverse Event .......................................................... Error! Bookmark not defined. 
F6 
STUDY OUTCOME MEASUREMENTS AND ASCERTAINMENT ......................................................... 15 
G 
STATISTICAL PLAN ....................................................................................................................... 15 
G1 
SAMPLE SIZE DETERMINATION AND POWER ................................................................................ 15 
G2 
INTERIM MONITORING AND EARLY STOPPING ........................ERROR! BOOKMARK NOT DEFINED. 
G3 
ANALYSIS PLAN ........................................................................................................................... 16 
G4 
STATISTICAL METHODS ............................................................................................................... 16 
G5 
MISSING OUTCOME DATA ......................................................ERROR! BOOKMARK NOT DEFINED. 
G6 
UNBLINDING PROCEDURES .....................................................ERROR! BOOKMARK NOT DEFINED. 
H 
DATA HANDLING AND RECORD KEEPING ............................................................................ 16 
H1 
CONFIDENTIALITY AND SECURITY ............................................................................................... 16 
H2 
TRAINING..................................................................................................................................... 16 
H3 
CASE REPORT FORMS AND SOURCE DOCUMENTS ........................................................................ 16 
H4 
RECORDS RETENTION .................................................................................................................. 17 
H5 
PERFORMANCE MONITORING .................................................ERROR! BOOKMARK NOT DEFINED. 
I 
STUDY MONITORING, AUDITING, AND INSPECTING ......................................................... 17 
I1 
STUDY MONITORING PLAN .............................................................................................................. 17 
I2 
AUDITING AND INSPECTING ........................................................ERROR! BOOKMARK NOT DEFINED. 
J 
STUDY ADMINISTRATION .......................................................................................................... 17 
J1 
ORGANIZATION AND PARTICIPATING CENTERS ................................................................................ 17 
J2 
FUNDING SOURCE AND CONFLICTS OF INTEREST ............................................................................. 17 
J3 
COMMITTEES ...............................................................................ERROR! BOOKMARK NOT DEFINED. 
J4 
SUBJECT STIPENDS OR PAYMENTS ................................................................................................... 17 
J5 
STUDY TIMETABLE .......................................................................................................................... 17 
K 
PUBLICATION PLAN ..................................................................................................................... 18 
L 
ATTACHMENTS .............................................................................................................................. 18 
L1 
TABLES ........................................................................................................................................ 18 
L2 
INFORMED CONSENT DOCUMENTS ................................................................................................ 18 
L3 
PATIENT EDUCATION BROCHURES...........................................ERROR! BOOKMARK NOT DEFINED. 
L4 
SPECIAL PROCEDURES PROTOCOLS .........................................ERROR! BOOKMARK NOT DEFINED. 
L5 
QUESTIONNAIRES OR SURVEYS .................................................................................................... 18 
M 
REFERENCES .................................................................................................................................. 18 


 
 
 
 
 
 
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4
 
A Introduction 
 
A1 Study Abstract 
Compliance with immunosuppression medications remains a major issue in kidney 
transplant recipients. Despite advanced technologies of reminders and alarms, many 
patients often miss doses of immunosuppression. This results in significant fluctuation in 
the level of immunosuppression which might increase the risk of rejection and graft loss. 
Azathioprine is a once a day medication that reduces purine synthesis through direct 
inhibition of the cell cycle. Similar kidney function and graft survival was found in long-
term follow up studies comparing azathioprine to mycophenolate mofetil. In addition, 
unlike mammalian target of rapamycin inhibitors, azathioprine is not associated with 
nephrotoxicity or proteinuria. This study aims to compare a once a day regimen of 
immunosupressents (Envarsus and azathioprine) versus a twice a day regimen 
(immediate release tacrolimus and mycophenolic acid), observing patient compliance 
and outcome. 
A2 Primary Hypothesis 
We hypothesize that a once a day immunosuppressive regimen of Envarsus and 
Azathioprine (in addition to prednisone) will increase compliance and improve outcomes 
compared to a twice a day immunosuppressive regimen. 
A3 Purpose of the Study Protocol 
The protocol provides us the ability to separate and follow patients who are on a once 
daily vs twice daily regimen of immunosuppression.  Patients are followed according to 
the usual follow-up in the clinics, and there are no additional other study visits included 
with the study.  
B Background 
 
B1 Prior Literature and Studies 
 
Kidney transplant recipients require a strict regimen of immune suppression which can 
lead to high pill burden and lack of medication adherence (Budde et al., 2014; Vrijens & 
Heidbuchel, 2015). Lack of medical adherence can result in increased transplant failure 
and is estimated to exceed 30% in kidney transplant patients (Jamieson et al., 2016). 
Once a day regimens are accosiated with higher medical adherence than twice a day 
regimens. For example, nonvalvular Atrial Fibrillation patients, who are similarly 
burdened with high pill burden, exhibited a 21-26% higher likelihood of medication 
adherence when treated with a once a day regimen compared to a twice a day regimen 
(Laliberté et al., 2012).  
 
Twice-daily Tacrolimus is a standard for most kidney transplant recipients as part of a  
normal immunosuppression regimen (Budde et al., 2014; Rostaing et al., 2016). 


 
 
 
 
 
 
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5
Tacrolimus is effective in preventing acute rejection after kidney transplantation (Budde 
et al., 2014). Recently, an extended release version of tacrolimus has been produced for 
once a day administration (LCP-TacroTM tablets [LCPT], Veloxis Pharmaceuticals, 
Hørsholm, Denmark) (Bunnapradist et al., 2013). Multiple studies have shown LCPT to 
have a higher bioavailability, requiring lower doses to maintain the same trough levels as 
a twice a day regimen (Budde et al., 2014; Bunnapradist et al., 2013; Rostaing et al., 
2016). A phase three, double blind randomized trial showed the LCPT treatment group 
to have fewer treatment failures compared to the twice a day regimen (Rostaing et al., 
2016). These results were seen in black recipients, older recipients, and females, which 
are populations that are particularly high risk for rejection (Rostaing et al., 2016). 
Adverse events and kidney function was similar between the LCPT and twice a day 
groups, showing caomparable efficacy for the treatment (Rostaing et al., 2016).  
 
B2 Rationale for this Study 
Although the efficacy of LCPT has been shown for use in kidney transplant patients, 
there is still a need for observing medication adherence with regards to the once a day 
treatment. This study will look at medical adherence with regards to its outcomes in 
kidney transplant recipients in order to better understand how a once a day regimen of 
tacrolimus may be beneficial to patients. Drugs work in a dose and time dependent 
manor and more emphasis is being put on electronic monitoring of medication 
adherence (Vrijens & Heidbuchel, 2015). This study may utilize Medisafe Medication 
Manager to accurately track adherence of the study medication.  
 
C Study Objectives 
 
C1 Primary Aim 
Aim 1: To determine whether an immunosuppressive maintenance regimen of 
Envarsus/azathioprine regimen compared to a tacrolimus/ mycophenolic acid regimen is 
associated with better compliance and tolerability. This may be examined by a survey to 
the patients at 3 and 12 months. In addition, for patients with smart phone, we may 
examine their adherence through “Pill Manager by Medisafe” app. This app tracks 
missed/taken doses. 
C2 Secondary Aim 
Aim 2: To determine whether a an Envarsus/azathioprine regimen compared to a 
tacrolimus/ mycophenolic acid regimen is associated with a lower composite endpoint of 
biopsy proven acute rejection, graft loss, death and lost to follow up at 12 months after 
kidney transplantation. Biopsy will be performed if clinically indicated 
 
C3 Rationale for the Selection of Outcome Measures 
Acute Rejection: 
We do not perform a protocol biopsy in our center, however, we have a low threshold to 
do a biopsy if there is an increased creatinine, proteinuria (urine protein/ creatinine > 1 
gram), or de novo DSA with high level MFI. The decision of the biopsy will be based on 


 
 
 
 
 
 
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6
the decision of the clinician. Acute rejection can lead to failure and loss of the grafted 
kidney and is an important endpoint in many kidney transplant studies.  
 
Graft Failure:  
Graft failure will be defined by the return to hemodialysis, re-transplantation, or patient 
death. Death-censored graft failure will be defined as the return to hemodialysis or re-
transplantation. Graft failure was chosen due to it’s importance in patient outcome. 
 
Adherence:  
We may use “Pill Reminder by Medisafe” for recipients who havean  iphone or android 
smart device. Installing the app will take place before discharge. Records from the smart 
phone will be emailed from the device at the clinic visit at months 3 and 12. 
 
A survey may be distributed at months 3 and 12. Other surveys may also be distributed 
to examine any possible side effects. 
 
Average variability in tacrolimus levels for the follow-up period preceding each of the 
surveys may be calculated and compared between the two groups 
 
Pharmacies may be contacted to assess for timing between refills to ensure that patients 
have taken medication as scheduled. 
 
These methods were chosen due to their simplicity and usefulness in gaining information 
on patient adherence.  
D Investigational Agent  
 
D1 Clinical Data to Date  
Twice-daily Tacrolimus is a standard for most kidney transplant recipients as part of a  
normal immunosuppression regimen (Budde et al., 2014; Rostaing et al., 2016). 
Tacrolimus is effective in preventing acute rejection after kidney transplantation (Budde 
et al., 2014). Recently, an extended release version of tacrolimus has been produced for 
once a day administration (LCP-TacroTM tablets [LCPT], Veloxis Pharmaceuticals, 
Hørsholm, Denmark) (Bunnapradist et al., 2013). Multiple studies have shown LCPT to 
have a higher bioavailability, requiring lower doses to maintain the same trough levels as 
a twice a day regimen (Budde et al., 2014; Bunnapradist et al., 2013; Rostaing et al., 
2016). A phase three, double blind randomized trial showed the LCPT treatment group 
to have fewer treatment failures compared to the twice a day regimen (Rostaing et al., 
2016). These results were seen in black recipients, older recipients, and females, which 
are populations that are particularly high risk for rejection (Rostaing et al., 2016). 
Adverse events and kidney function was similar between the LCPT and twice a day 
groups, showing caomparable efficacy for the treatment (Rostaing et al., 2016).  
D2 Dose Rationale and Risk/Benefits  
Patients will be started on an antimetabolite in both arms (AZA or MPA) on post 
operation day 0 or 1 depending on the time they are able to take oral medication post 
surgery. Calcineurin inhibitors (Tac-IR or Tac-LCP) will be started on post operation day 
1. Starting dose for Tac-IR is started at 0.1 mg/kg divided into BID. Starting dose for 


 
 
 
 
 
 
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7
Tac-LCP will be 0.08 mg/kg. These are starting doses per the center usual starting 
doses. 
AZA starting dose will be between 1.5 - 2 mg/kg daily, rounded to nearest 50 mg. MPA 
(Myfortic) will be started 720 mg po BID and will be decreased to 360 mg BID when the 
Tac-IR trough level is therapeutic (according to the current goals in the center’s 
protocol). 
 
Immunosuppression administered at the study site will be recorded in the medical record 
and on a study drug diary. Immunosuppression doses administered at home will be 
recorded only on the study drug diary. 
 
Tacrolimus trough target levels in both arms will be 7 to 10 ng/dL in the first month, then 
5 to 7 afterward.  Higher or lower tacrolimus trough level goals will be adjusted during 
the study due to clinical reasons such as history of rejection or infections post transplant 
at the discretion of the transplant nephrologists.  
 
CBC, BMP or renal panel (including creatinine, eGFR) Tac trough levels will be checked 
once a week for the first four months then once every other weeks till the end of the 
study.  
 
Known medication side effects:  There are known common side effects to each 
medication.  Tacrolimus has known side effects of tremors, sleep difficulty irregardless of 
its therapeutic range.  Other side effects such as electrolyte abnormality in 
hyperkalemia, hypertension, and increased creatinine (if above therapeutic range) are 
known side effects as well.  Both azathioprine and mycophenolate mofetil/mycophenolic 
acid have side effect of leukopenia and anemia.  Azathioprine can also have elevated 
liver enzymes as a rarer side effect.  Mycophenolate mofetil/mycophenolic acid have a 
known side effect of gastrointestinal upset or diarrhea.   
E Study Design  
 
E1 Overview or Design Summary 
This will be an open label pilot study in which patients will be categorized into once a day 
regimen (Envarsus and azathioprine) or twice a day regimen (immediate release 
tacrolimus and mycophenolic acid) after kidney transplantation. We will enroll 50 patients 
in each arm after transplantation. Patients will be seen as per our usual follow up 
schedule untill month 12 (+/- 29 days) from the time of transplant (time from transplant: 
week 2-4, week 5-8, week 9-12, month 6, month 9 and month 12 all +/- 2 weeks) . 
Completion of the trial will be within 3 years. Outcomes can be reported/published by the 
end of the third year. 
 
E2 Subject Selection and Withdrawal  
2.a  Inclusion Criteria  
- 
Age ≥18 years 
- 
kidney transplant recipient 
- 
Thymoglubulin induction 


 
 
 
 
 
 
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8
2. b Exclusion Criteria  
- 
Non-renal organ transplant 
- 
Combined organ transplant 
- 
 
- 
Discharge to an acute-care facility after transplant 
2.a 
Ethical Considerations  
All patients will be given actual immunosuppressive medications (not placebo) in 
combinations that we have used in other patients at our transplant center.  The only 
difference is one group will have medications dosed once a day and the other group will 
be on medications that are dosed twice a day, as per the medication administration 
recommendations.   
2.b 
Subject Recruitment Plans and Consent Process 
We will enroll 50 patients in each arm at the time of transplantation. Accounting for 
dropout of 20% from the study, we plan to possibly need to consent 120 patients total to 
obtain the 100 patient total number who complete  the study.  Subjects that meet the 
study inclusion criteria and without exclusion criteria will be approached in person prior 
to discharge from the hospital. The consenting process will be done in person by a study 
team member. Patients will be given the opportunity to look over the consent form and 
ask questions. A copy of the signed consent form will be provided to the patient once 
signed. Patients will be seen as part of the study untill month 12 (+/- 29 days) from the 
time of transplant.  
 
2.c Randomization Method and Blinding 
We will approach patients after transplantation, prior to discharge.  If patients are eligible 
to receive either tacrolimus or Envarsus, then we will approach them for participation in 
the study.  If the patient consents to the study, we will enroll patients until we reach 50 
patients in each arm of the study. There is no randomization done.  Because this is an 
open label study, blinding is not conducted. 
2.d Risks and Benefits 
Patients will all be on an immunosuppression regimen that we have used for patients we 
currently manage at our center.  We have used both types of regimen on our patients, 
depending on tolerability and if there are any side effects that patients need switching to 
different regimens.  Each regimen has been well tolerated by other patients.  The major 
risks are with the side effects of the medications (see “11. d iii  Expectedness of side 
effects to medications and adverse events”).  It is expected that patients will adhere to 
the prescribed medication regimen, though some patients may not, especially to the 
twice daily regimen.  We will attempt to mitigate this by aking patients use the pill 
reminder application.  Patients are counselled on the importance of medication 
adherence for transplantation due to risk of rejection if they are not adherent.  The 
benefits to patients include for those on the once daily regimen, less overall pill burden.  
Otherwise there is no additional benefit to patients. 
 


 
 
 
 
 
 
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9
2.e Early Withdrawal of Subjects  
In the unlikely event that a patient is removed from study for unacceptable adverse 
event(s), such patient will be followed until resolution or stabilization of the adverse 
event. Participants that wish to withdraw from the study, or meet other early withdrawal 
material will have an End of Study/Early Termination Visit form filed. When possible or 
necessary, additional information about the patient (i.e. AEs, reason for withdrawal, etc.) 
will be gathered upon withdrawal of the study.  
2.f 
When and How to Withdraw Subjects  
Patients will be seen untill month 12 (+/- 29 days) from the time of transplant. At the end 
of this period, an End of Study/Early Termination Visit form will be filed. Subjects will be 
notified of their completion or withdrawal from the study and briefed appropriately on 
what final steps should be taken.  
2.g 
Data Collection and Follow-up for Withdrawn Subjects  
Once withdrawn from the study, for safety reasons, patients will be followed via their labs 
and regular clinic visits for 12 months post withdrawal. 
 
E3 Study Drug  
 
3.a Description  
Twice-daily Tacrolimus is a standard for most kidney transplant recipients as part of a  
normal immunosuppression regimen (Budde et al., 2014; Rostaing et al., 2016). 
Tacrolimus is effective in preventing acute rejection after kidney transplantation (Budde 
et al., 2014). Recently, an extended release version of tacrolimus has been produced for 
once a day administration (LCP-TacroTM tablets [LCPT], Veloxis Pharmaceuticals, 
Hørsholm, Denmark) (Bunnapradist et al., 2013). Multiple studies have shown LCPT to 
have a higher bioavailability, requiring lower doses to maintain the same trough levels as 
a twice a day regimen (Budde et al., 2014; Bunnapradist et al., 2013; Rostaing et al., 
2016). 
 
Azathioprine is a once a day medication that reduces purine synthesis through direct 
inhibition of the cell cycle. Similar kidney function and graft survival was found in long-
term follow up studies comparing azathioprine to mycophenolate mofetil. In addition, 
unlike mammalian target of rapamycin inhibitors, azathioprine is not associated with 
nephrotoxicity or proteinuria.   
3.b 
Treatment Regimen  
Patients will be started on antimetabolite in both arms (AZA or MPA) on post operation 
day 0 or 1. Calcineurin inhibitors (Tac-IR or Tac-LCP) will be started on post operation 
day 1. Starting dose for Tac-IR will be 0.1 mg/kg divided into BID. Starting dose for Tac-
LCP will be 0.08 mg/kg. 
 
Immunosuppression administered at the study site will be recorded in the medical record 
and on a study drug diary. Immunosuppression doses administered at home will be 
recorded only on the study drug diary. 


 
 
 
 
 
 
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10
 
Tacrolimus trough target levels in both arms will be 7 to 10 ng/dL in the first month, then 
5 to 7 afterward.  
 
CBC, BMP or Renal panel (including creatinine, eGFR) Tac trough levels will be 
checked once a week for the first four months then once every other weeks as part of 
standard of care labs post transplant.   These will be collected as data points during the 
study duration. 
AZA starting dose will be 2 mg/kg, rounded to nearest 50 mg. MPA (Myfortic) will be 
started 720 mg po BID and will be decreased to 360 mg BID when the Tac-IR trough 
level is therapeutic (according to the current protocol). 
 
3.c 
Method for Assigning Subjects to Treatment Groups  
We will approach patients after transplantation.  Patients will either receive tacrolimus or 
Envarsus based on insurance coverage.  We will approach patients for the study after 
we have determined the form of calcineurin inhibitor they will be taking  If the patient 
consents to the study, we will enroll patients until we reach 50 patients in each arm of 
the study.  If needed, the antimetabolite may be transitioned to the once or twice daily 
dosed medication, prior to discharge so that they may receive the medications prior to 
their discharge from the hospital. Because this is an open label study, blinding is not 
conducted. 
3.d 
Preparation and Administration of Study Drug  
Study medications may be self-administered by the patient. When not on the study site, 
all medications will be ordered through patient’s preferred pharmacy. Suggestion will be 
made to utilize only subspecialty pharmacies. 
3.e 
Subject Compliance Monitoring  
We may use “Pill Reminder by Medisafe” for recipients who have I-phone or android 
smart device. Installing the app will take place before discharge. Records from the smart 
phone will be emailed from the device at the clinic visit at months 3 and 12.  We 
understand that not all paitents may have a smart device/phone, and so we plan to also 
use a survey – BAASIS.  The BAASIS survey may be distributed at months 3 and 12. 
Average variability in tacrolimus levels for the follow-up period preceding each of the 
surveys may be calculated and compared between the two groups. Pharmacies may be 
contacted to assess for timing between refills to ensure that patients have taken 
medication as scheduled. 
3.f 
Prior and Concomitant Therapy  
Patients will receive induction therapy with either anti-thymocyte globulin or basiliximab 
at the time of transplantation.  Depending on patient’s prior medical history, they may 
have had prior immunosuppression and may be on immunosuppression prior to their 
transplant.  This will not interfere with the study protocol or eligibility except if they meet 
exclusion criteria.   
3.g 
Packaging  
Study drugs will be packaged according to standard procedures for the medication. 


 
 
 
 
 
 
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11
3.h 
Blinding of Study Drug  
This is an open label pilot study. The patients and study members will not be blinded to 
the study drug.  
3.i 
Receiving, Storage, Dispensing and Return  
Study medications may be self-administered by the patient. Study medications may be 
administered at the study site or ordered through patient’s preferred pharmacy.  
 
F Study Procedures  
 
F1 Screening for Eligibility 
Patients may be screened by appropriate study team members such as clinical 
coordinators. Patient enrollement will be determined from study inclusion and exclusion 
criteria (Section E2). 
F2 Schedule of Measurements 
See Flowsheet for study procedure/measurements 
See individual attached Visit 0-6 for checklists 
F3 Visit 00 – post transplantation (prior to discharge) 
• 
Inclusion/Exclusion checklist 
• 
Informed consent obtained 
• 
Contact and Demographics Information form filled 
• 
Medical history collected 
• 
Physical Exam 
• 
Pill Manager by Medisafe downloaded and explained 
• 
Dosages given and recorded 
F4 Visit 01 – 2-4 weeks after transplant surgery 
• 
Verbally agreed to continue participation in study  
• 
Was re-consent if needed  
• 
Medical history collected 
• 
Evaluated for AEs 
• 
Physical Exam 
• 
Laboratory tests performed and recorded 
• 
Dosages updated and recorded 
 
F5 Visit 02 – 5-8 weeks after transplant 
• 
Verbally agreed to continue participation in study  
• 
Was re-consent needed?  
• 
Medical history collected 
• 
Evaluated for AEs 
• 
Physical Exam 


 
 
 
 
 
 
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12
• 
Laboratory tests performed and recorded 
• 
Dosages updated and recorded 
F6 Visit 03 – 12 weeks post transplant 
• 
Verbally agreed to continue participation in study  
• 
Was re-consent needed?  
• 
Medical history collected 
• 
Evaluated for AEs 
• 
Physical Exam 
• 
Laboratory tests performed and recorded 
• 
Dosages updated and recorded 
• 
Pill Manager by Medisafe records emailed 
• 
BAASIS Survey distributed 
F7 Visit 04 -  6 months post transplant 
• 
Verbally agreed to continue participation in study  
• 
Was re-consent needed?  
• 
Medical history collected 
• 
Evaluated for AEs 
• 
Physical Exam 
• 
Laboratory tests performed and recorded 
• 
Dosages updated and recorded 
F8 Visit 05 – 9 months post transplant 
• 
Verbally agreed to continue participation in study  
• 
Was re-consent needed?  
• 
Medical history collected 
• 
Evaluated for AEs 
• 
Physical Exam 
• 
Laboratory tests performed and recorded 
• 
Dosages updated and recorded 
F9 Visit 06 – 12 months post transplant 
• 
End of Study/Early Termination form completed  
• 
Was re-consent needed?  
• 
Medical history collected 
• 
Evaluated for AEs 
• 
Physical Exam 
• 
Laboratory tests performed and recorded 
• 
Dosages updated and recorded 
• 
Pill Manager by Medisafe records emailed 
• 
BAASIS Survey distributed 
 
F10 Safety and Adverse Events  
Monitored throughout the study. 


 
 
 
 
 
 
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13
 
10.a Safety and Compliance Monitoring 
At each study visit, we will collect the data as described in the study table and in the 
protocol description. The PI or study staff will review the data on an ongoing basis and 
every quarter for accuracy and completeness.  Adverse effects will be routinely reviewed 
and recorded at each visit.  Additionally any adverse event reported to the transplant 
physician, transplant coordinator or study coordinator including emergency department 
evaluation and/or hospitalization will be reviewed and documented by the principal 
investigator.  Adverse event reporting will be done per the study agreement.  
The study team will meet quarterly to review outcomes and safety of patients enrolled in 
the study as well as AEs.  SAEs will be reviewed per occurrence. 
 
Data on adherence to the treatment protocol may be collected via surveys and on Pill 
Reminder by Medisafe (emailed to research staff) at months 3 and 12. Adherence will be 
reviewed quarterly by the PI and the study statistician.  
 
10.b Medical Monitoring  
 
i 
Investigator and research team only 
Both arms will follow the standard protocol visits in our clinics and will be seen at week 
2-4, week 5-8, week 9-12, month 6, 9, and 12 (all +/- 2 weeks). These visits will include a 
focused physician exam, evaluation of adverse events as defined by the Common 
Toxicity Criteria of the National Cancer Institute and assessment of the patient’s 
Immunosuppression.  Labs are followed as per the center standard protocol and will be 
performed at the patients’ designated lab outpatient. 
10.c Definitions of Adverse Events 
Adverse event means any untoward medical occurrence associated with the use of a 
drug in humans, whether or not considered drug related. 
 
Life-threatening adverse event or life-threatening suspected adverse reaction. An 
adverse event or suspected adverse reaction is considered "life-threatening" if, in the 
view of either the investigator or sponsor, its occurrence places the patient or subject at 
immediate risk of death. It does not include an adverse event or suspected adverse 
reaction that, had it occurred in a more severe form, might have caused death. 
 
Serious adverse event or serious suspected adverse reaction. An adverse event or 
suspected adverse reaction is considered "serious" if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: Death, a life-
threatening adverse event, inpatient hospitalization or prolongation of existing 
hospitalization, a persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions, or a congenital anomaly/birth defect. Important medical 
events that may not result in death, be life-threatening, or require hospitalization may be 
considered serious when, based upon appropriate medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. Examples of such medical events 


 
 
 
 
 
 
______________________________________________________________________________________ 
 
14
include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or 
the development of drug dependency or drug abuse. 
 
[Code of Federal Regulations] 
[Title 21, Volume 5] 
[Revised as of April 1, 2017] 
[CITE: 21CFR312.32] 
10.d Classification of Events 
 
i 
Relationship 
Relationship of adverse events to the study medication will be decided upon by the PI. 
ii 
Severity 
Severity of adverse events will be decided using the Common Terminology Criteria for 
Adverse Events (CTCAE). 
iii 
Expectedness of side effects to medications and adverse events 
There are known common side effects to each medication.  Tacrolimus has known side 
effects of tremors, sleep difficulty irregardless of its therapeutic range.  Other side effects 
such as electrolyte abnormality in hyperkalemia, hypertension, and increased creatinine 
(if above therapeutic range) are known side effects as well.  Both azathioprine and 
mycophenolate mofetil/mycophenolic acid have side effect of leukopenia and anemia.  
Azathioprine can also have elevated liver enzymes as a rarer side effect.  
Mycophenolate mofetil/mycophenolic acid have a known side effect of gastrointestinal 
upset or diarrhea.   
10.e Data Collection Procedures for Adverse Events 
At each study visit, we will collect the data as described in the study table and in the 
protocol description. The PI or study staff will review the data on an ongoing basis and 
every quarter for accuracy and completeness.  Adverse effects will be routinely reviewed 
and recorded at each visit.  Additionally any adverse event reported to the transplant 
physician, transplant coordinator or study coordinator including emergency department 
evaluation and/or hospitalization will be reviewed and documented by the principal 
investigator.  Adverse event reporting will be done per the study agreement.  
The study team will meet quarterly to review outcomes and safety of patients enrolled in 
the study as well as AEs. SAEs will be reviewed per occurrence. 
 
10.f Reporting Procedures 
Adverse events will be recorded at each medical visit. With the occurance of an AE, an 
Adverse Event Log will be filed for the patient and put up for review by the PI.  
 
In the instance of a SAE, an Serious Adverse Event Log will be filed and shown to the PI 
with every occurance.  


 
 
 
 
 
 
______________________________________________________________________________________ 
 
15
10.g Adverse Event Reporting Period 
AEs will be reported to the IRB at the time of continuing review. SAEs will be reported 
according to IRB policy.  
 
F11 Study Outcome Measurements and Ascertainment 
- 
Acute Rejection: 
We do not perform a protocol biopsy in our center, however, we have a low threshold to 
do a biopsy if there is an increased creatinine, proteinuria (urine protein/ creatinine > 1 
gram), or de novo DSA with high level MFI. The decision of the biopsy will be based on 
the decision of the clinician. 
 
- 
Graft Failure: Graft failure will be defined by the return to hemodialysis, re-
transplantation, or patient death. Death-censored graft failure will be defined as the 
return to hemodialysis or re-transplantation. 
 
- 
Adherence:  
App: We will use “Pill Manager by Medisafe” for recipients who have I-phone or android 
smart device. Installing the app will take place before discharge. Records from the smart 
phone will be emailed from the device at the clinic visit at months 3 and 12. 
 
Survey: Survey will be distributed at months 3 and 12. Other surveys will be also 
distributed to examine any possible side effects. 
 
Tacrolimus level variability: Average variability in tacrolimus levels for the follow-up 
period preceding each of the surveys will also be calculated and compared between the 
two groups 
 
Antimetabolite refill records: 
Pharmacies will be contacted to assess for timing between refills to ensure that patients 
have taken medication as scheduled. 
 
Additionally, CBC, BMP or Renal panel (including creatinine, eGFR) Tac trough levels 
will be checked once a week for the first four months then once every other weeks as 
part of standard of care labs post transplant.   These will be collected as data points 
during the study duration. 
 
G Statistical Plan  
 
G1  Sample Size Determination and Power 
This is a pilot study. The number of patients was chosen to see if any initial evidence 
can be found for further investigatrion.  
 


 
 
 
 
 
 
______________________________________________________________________________________ 
 
16
G2  Analysis Plan & Statistical Methods 
Recipient characteristics will be described using proportions for categorical variables, 
and means with standard deviations for continuous variables. Recipient and donor 
factors will be compared among the groups (one a day medication group vs twice a day 
medication group) using a χ2 or Fisher test for categorical variables and analysis of 
variance test or Kruskal Wallis tests for continuous variables, depending on the 
distribution of the variable. 
 
Allograft and recipient survival will be assessed using the Kaplan-Meier survival 
analysis, and P values will be calculated using the log-rank test. Multivariate analysis 
using the Cox model will be used to calculate the hazard ratio during the follow up period 
for allograft failure and recipient death.  
 
Adherence will be divided according to the level of adherence (score) into tertiles. 
Logistic regression will be used to examine the association between adherence and the 
medications group. 
 
H Data Handling and Record Keeping  
 
H1 Confidentiality and Security 
Subject privacy: During the study we will perform medical history and examination at 
each recurring visit as part of standard follow-up and usual care post-transplant. Labs 
will be done per standard of care, and collected at each time point until 12 months post-
transplant.  All information collected will be for research purposes only and data will be 
kept in strict confidence.  No information will be given to another party without the 
consent of the subject.  We will be assigning patients a unique study number for de-
identification purposes.  
 
Database protection:  We will be keeping a database that will be secured with password 
protection.  The person performing statistics will be receiving only de-identified 
information from the database.  For paper documents such as source documents and 
questionnaires, these will be kept in separate participant charts that will be secured in a 
locked cabinet in the locked study coordinator office with access only for study 
personnel.  
H2 Training  
All lab personel will be qualified to do their assigned work. All personel working with PHI 
will have documented HIPAA training. Each team member will be noted on the 
Department Signature Sheet. 
H3 Case Report Forms and Source Documents 
CRFs will be created and kept in each person’s file, tracking medications, FK levels, 
labs, and information regarding medication refills (See all attachments).  All source 
documents including labs near the time of each scheduled visit that patients get 
outpatient, surveys, medication adherence pill monitoring system information, outpatient 
notes will be placed into each person’s file. 


 
 
 
 
 
 
______________________________________________________________________________________ 
 
17
H4 Records Retention 
All research records, including signed consent forms, will be kept in their 
original form or a certified scanned electronic form for at least seven years 
beyond close of the study. 
 
 
I Study Monitoring, Auditing, and Inspecting  
 
I1 
Study Monitoring Plan  
The PI and study members will review the data on an ongoing basis and every quarter 
for accuracy and completeness.   
 
J Study Administration 
 
J1 Organization and Participating Centers 
This study will be performed at Washington University School of Medicine. 
J2 Funding Source and Conflicts of Interest 
This study is funded by Veloxis Pharmaceuticals. Each study team member will declare 
any conflicts of interest to the IRB.  
J3 Subject Stipends or Payments  
Participants will not receive any payment for the study nor study medication, which 
patients will receive through their insurance coverage.  
 
J4 Study Timetable – Table 1 
Study event 
Visit number 
 
Visit 0 – 
post 
surgery 
Visit 1- 
2-4 
weeks 
Visit 2 – 
5-8 
weeks 
Visit 3 – 
9-12 
weeks 
Visit 4 – 
6 
months 
Visit 5 – 
9 
months 
Visit 6 – 
12 
months 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
Contact/demographics 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Physical exam 
X 
 
 
 
 
 
 
Medisafe med 
manager taught 
x 
 
 
 
 
 
 
Med dosages 
given/recorded 
x 
 
 
 
 
 
 


 
 
 
 
 
 
______________________________________________________________________________________ 
 
18
Patient verbal consent 
to continue study 
 
X 
X 
X 
X 
X 
X 
Reconsent if needed 
 
X 
X 
X 
X 
X 
X 
Evaluate for AEs 
 
X 
X 
X 
X 
X 
X 
Lab tests recorded 
from most recent labs 
X 
X 
X 
X 
X 
X 
X 
Med doses updated 
and recorded 
 
x 
X 
X 
X 
X 
X 
Medisafe records 
obtained 
 
X 
x 
X 
x 
X 
X 
Survey completed 
 
 
 
x 
 
 
X 
End of 
study/Termination 
form completed 
 
 
 
 
 
 
X 
 
 
 
Figure 1. Timeline of study procedures. 
K Publication Plan  
 
We plan to submit abstracts on the results of our study to the following meetings: 
American Transplant Congress and American Society of Nephrology meetings.  We plan 
to publish our results in one of the following journals: American Journal of 
Transplantation, Transplantation, Clinical Transplantation, Transplant International, NDT 
after completion of the study and final analysis of study results.   
 
 
L  Attachments  
 
L1  Tables  
Table 1 – study timeline 
 
L2  Informed consent documents 
See attached  
L3  Questionnaires or surveys 
See attached BAASIS survey used for 3 and 12 month  
 
M References 
 


 
 
 
 
 
 
______________________________________________________________________________________ 
 
19
 
Budde, K., Bunnapradist, S., Grinyo, J. M., Ciechanowski, K., Denny, J. E., Silva, H. T., 
… Envarsus study group. (2014). Novel Once-Daily Extended-Release Tacrolimus 
(LCPT) Versus Twice-Daily Tacrolimus in de novo Kidney Transplants: One-Year 
Results of Phase III, Double-Blind, Randomized Trial. American Journal of 
Transplantation, 14(12), 2796–2806. https://doi.org/10.1111/ajt.12955 
Bunnapradist, S., Ciechanowski, K., West-Thielke, P., Mulgaonkar, S., Rostaing, L., 
Vasudev, B., … MELT investigators. (2013). Conversion From Twice-Daily 
Tacrolimus to Once-Daily Extended Release Tacrolimus (LCPT): The Phase III 
Randomized MELT Trial. American Journal of Transplantation, 13(3), 760–769. 
https://doi.org/10.1111/ajt.12035 
Jamieson, N. J., Hanson, C. S., Josephson, M. A., Gordon, E. J., Craig, J. C., Halleck, 
F., … Tong, A. (2016). Motivations, Challenges, and Attitudes to Self-management 
in Kidney Transplant Recipients: A Systematic Review of Qualitative Studies. 
American Journal of Kidney Diseases, 67(3), 461–478. 
https://doi.org/10.1053/J.AJKD.2015.07.030 
Laliberté, F., Nelson, W. W., Lefebvre, P., Schein, J. R., Rondeau-Leclaire, J., & Duh, M. 
S. (2012). Impact of Daily Dosing Frequency on Adherence to Chronic Medications 
Among Nonvalvular Atrial Fibrillation Patients. Advances in Therapy, 29(8), 675–
690. https://doi.org/10.1007/s12325-012-0040-x 
Rostaing, L., Bunnapradist, S., Grinyó, J. M., Ciechanowski, K., Denny, J. E., Silva, H. 
T., … Parmjeet, R. (2016). Novel Once-Daily Extended-Release Tacrolimus Versus 
Twice-Daily Tacrolimus in De Novo Kidney Transplant Recipients: Two-Year 
Results of Phase 3, Double-Blind, Randomized Trial. American Journal of Kidney 
Diseases, 67(4), 648–659. https://doi.org/10.1053/J.AJKD.2015.10.024 
Vrijens, B., & Heidbuchel, H. (2015). Non-vitamin K antagonist oral anticoagulants: 
considerations on once- vs. twice-daily regimens and their potential impact on 
medication adherence. Europace, 17(4), 514–523. 
https://doi.org/10.1093/europace/euu311