Conditions: Renal Transplant Infection
Keywords: Envarsus
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 89
Healthy volunteers: no

Brief summary:
The purpose of this study is to assess if the use of Envarsus in place of Tacrolimus-immediate release (IR) in rapid metabolizers post kidney transplant will reduce incidence of BK infection. Efficacy evaluations will include measurement of urine and serum BK values at specified time points and review of any biopsy for BK virus nephropathy. Incidence of rejection, graft failure, and graft dysfunction will also be measured at specified time points.

Detailed description:
This will be a single center prospective case control study. The investigators expect 40% of patients will develop BK viruria, 20% BK viremia, 5% BK viral nephropathy (BKVN). Patients will be managed using standard of care for the investigator's center (thymoglobulin induction, tacrolimus/mycophenolate/prednisone). Target tacrolimus level is 8-12 ng/mL for the first 6 months post transplant and 6-9 ng/mL thereafter. BK urine/serum is monitored at 1, 3, 6, 9, 2 months post transplant. A population of 100 patients is calculated to show significant difference for p value \< 0.05.

Population:

Study Group: Post transplant patients (kidney transplant alone) with standard of care immunosuppression, no prior rejection, prior BK or opportunistic infection, and negative BK screening at post-transplant month 1, who have a tacrolimus concentration/dose of \< 1 and a steady state therapeutic level will be eligible. Patients who consent will be converted to Envarsus at 20% reduction in tacrolimus dose.

Control Group: Post transplant patients (kidney transplant alone performed between 10-2016 and time of enrollment) with standard of care immunosuppression, no prior rejection, prior BK or opportunistic infection, whom had a negative BK screening at post-transplant month 1 and tacrolimus concentration/dose of \< 1 at post-transplant month 1, and BK data available for months 2, 3, 6, 9,12 post transplant.

Arms:
arm 1: Post transplant patients (kidney transplant alone) with standard of care immunosuppression, no prior rejection, prior BK or opportunistic infection, and negative BK screening at month 1, whom have a concentration/dose of \< 1 and a steady state therapeutic level will be eligible. Patients will be converted to envarsus at 20% reduction in dose. arm 2: Post transplant patients (kidney transplant alone) performed between 10-2016 and time of enrollment with standard of care immunosuppression, no prior rejection, prior BK or opportunistic infection, whom had a negative BK screening at month 1 and concentration/dose of \< 1 at month 1, and BK data available and month 2,3, 6,9,12.

Interventions: intervention 1: Study Group intervention 2: Control Group
Intervention descriptions: intervention 1: Patients will convert from current tacrolimus dose to an Envarsus dose that is 80% of the total tacrolimus dose. They will take envarsus once daily in the morning and have 24 hour trough levels monitored at the standard of care interval for tacrolimus. Dosing will be titrated to achieve goal levels. intervention 2: Post transplant patients (kidney transplant alone) performed between 10-2016 and time of enrollment with standard of care immunosuppression, no prior rejection, prior BK or opportunistic infection, whom had a negative BK screening at month 1 and concentration/dose of \< 1 at month 1, and BK data available and month 2,3, 6,9,12.

Protocol document:
Prot_SAP_000.pdf: 
Conversion to Envarsus Post Kidney Transplant Protects Against 
BK Infection 
 
 
Study Protocol & Statistical Analysis Plan 
 
NCT03762473 
 
 
Date of Last Protocol Approval: 01/05/2022 
 
 
PI:  Graham Towns, MD 
University of Alabama at Birmingham 
Birmingham, AL 35294 
 


Conversion from Tacrolimus to Envarsus in Rapid Metabolizers 
Post Kidney Transplant Protects Against BK Infection 
 
 
 
PROTOCOL VERSION / DATE: 
Version 2.0 / April 16, 2019 
 
 
SHORT STUDY TITLE: 
Conversion to Envarsus Post Kidney 
Transplant Protects Against BK Infection 
 
 
UAB PRINCIPAL INVESTIGATOR: 
Graham Towns, M.D. 
 
 
SITE LOCATION: 
University of Alabama at Birmingham (UAB) 
 
1900 University Blvd, THT 625 
 
Birmingham, AL 35294 USA 
 
 
UAB CO-PRINCIPAL 
INVESTIGATORS: 
Gaurav Agarwal, M.D. 
 
Song Ong, M.D. 
 
 
SUPPORTER: 
Veloxis Pharmaceuticals, Inc. 
 
 
 
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1. 
Study Hypotheses/Objectives  
1.1. 
Hypotheses  
 
High peak levels of tacrolimus predispose renal transplant recipients to BK 
infection.  Conversion of tacrolimus to Envarsus will reduce incidence of BK viruria, 
viremia, and nephropathy. 
 
1.2. 
Primary Safety Objective  
Envarsus has shown a lower side effect profile in the ASTCOFF study but still 
carries the same potential risks as tacrolimus.  Incidence of BK infection, graft loss, and 
other adverse events will be tracked. 
 
1.3. 
Primary Efficacy Objective  
The primary efficacy endpoint of the study is the composite of BK Virus infection, 
including viruria > 500 copies, viremia > 500 copies, or nephropathy as defined by Banff 
classification ( sv 40 positivity with or without tubulitis or if/ta). 
 
1.4. 
Secondary Efficacy Objective   
The secondary end-points will assess incidence of rejection, graft failure, graft 
dysfunction as defined by >15% decrease in estimated glomerular filtration rate (eGFR), 
and proteinuria. 
 
2. 
Background and Rationale 
2.1. 
Background and Scientific Rationale  
2.1.1. BK Viral Infection 
Development of BK Infection post transplant is largely attributed to reactivation 
of virus in the donor allograft.  Risk factors are multifactorial and can not be linked to an 
individual immunosuppression agent.  Degree of immunosuppression is the most 
consistent risk factor, and reduction of immunosuppression is the most effective 
treatment.  Rates of BK viruria, viremia, and nephropathy are 40%, 20%, and 1-10% 
respectively10,19.  BK virus nephropathy (BKVN) is strongly and independently associated 
with poor graft survival.  BKVN has a high graft failure rate at over 50%.  Peak incidence 
of BK infection is in the first year post transplant. 
 
2.1.2. Etiology of BK Infection 
Several different studies identify donor and recipient characteristics as risk 
factors for BK infection.  Several studies conflict on the role of depletional induction 
with thymoglobulin or campath versus non depletional induction with simulect as risk 
factors.  Several studies conflict regarding the number of immunosuppression agents 
(two vs. three, generally steroid free vs. not) as risk factors.  Studies show conflicting 
risks regarding tacrolimus vs cyclosporine regimens vs. CNI free regimens.  Injury to the 
uroepithelial pathway has also been reported as a risk factor.  There has not been one 
consistent identifiable cause of BK infection post transplant.  
 
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2.2. 
Rationale for use of Envarsus 
Rapid metabolizers have an allelic variation at cyp 450 3a5 and require higher 
doses of tacrolimus to achieve goal trough drug levels for prevention of rejection.  These 
patients have higher incidence of side effects related to high peak levels and have 
periods of heightened drug exposure.  The use of a concentration/drug dose ratio < 1 
for tacrolimus has been validated as an identifier for rapid metabolizers.1-4  The use of 
Envarsus in place of short acting tacrolimus has been shown to provide equitable drug 
exposure and efficacy with respect to prevention of rejection and decreased side effects 
due to lower peak levels.  It has also been shown to achieve therapeutic trough levels 
with lower dosing.5-9 
 
2.3. 
Clinical Studies of Concentration/Dose (C/D) Ratios and BK infection 
2.3.1. Validation of C/D Ratio 
In the paper by Tholking3 et al, renal transplant patients were grouped as slow or 
fast metabolizers according to their C/D ratio.  Fast metabolizers had higher incidence of 
graft dysfunction, calcineurin inhibitor toxicity, and BK virus nephropathy.  The use of 
C/D ratio as a marker of cyp 450 3a5 metabolism was further validated in several 
studies1,2,4. 
 
2.3.2. Clinical Studies of Rapid Metabolizers and BK Infection 
Tholking et al have demonstrated and increased association with BK infection 
among transplant patients with low C/D ratios compared to those with high C/D ratios. 
 
In a single center retrospective study1 of 248 patients designed to investigate effect of 
metabolism on renal function, patients were grouped according to their C/D ratio (< 1 
for fast metabolizers, and >1.55 for slow metabolizers) and had eGFR assessed at 2, 3, 6, 
12, and 24 months.  Incidence of BK viremia was 8% in the fast group and 1% in the slow 
group.  BKVN was only diagnosed in the fast group with a 4% incidence. 
 
The fast metabolizer group also had significantly higher rates of CNI nephrotoxicity.  The 
authors hypothesized that these findings are related to overexposure of tacrolimus 
during the peak hours after tacrolimus intake.   
 
A second retrospective study4 assessed C/D ratio in 192 renal transplant patients, 92 of 
whom had BK viremia and 92 whom did not.  Patients with BK viremia had lower 
tacrolimus C/D ratios at 1, 3, and 6 months post transplant.   
 
2.4 
Clinical Studies of Envarsus 
2.4.1 
Data from a randomized, double blinded study of Envarsus versus tacrolimus by 
Budde5 and data from the open label phase III MELT Trial both demonstrated non 
inferiority of Envarsus. 
 
In the phase III RCT by Budde, de novo kidney transplant patients were placed on 
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tacrolimus vs Envarsus along with mycophenolate mofetil (MMF) and prednisone and 
followed for endpoints of death, graft failure, or biopsy proven rejection.  At 12 months, 
overall survival was 97% in both Envarsus and tacrolimus recipients; graft survival was 
97 and 96%, respectively, and graft and patient survival combined was 94 % in both 
groups.  The incidence of clinically suspected and treated rejection was 14 versus 16% in 
Envarsus versus tacrolimus recipients, and no significant treatment differences were 
found in the number of biopsy-proven acute rejection episodes.  A total of 195 Envarsus 
and 199 tacrolimus recipients completed 24 months of follow-up on their assigned 
treatment.  At 24 months, the treatment failure rate was 23.1 versus 27.3 %, 
respectively, with a treatment difference of 4.14 (95 % CI 11.38 to +3.17), again 
demonstrating noninferiority.  The incidence of the individual events comprising 
treatment failure were similar between treatment groups at 24 months: biopsy-proven 
acute rejection occurred in 17.2 % of Envarsus and 18.2 % of tacrolimus recipients, graft 
failure in 4.1 and 5.5 %, respectively, death in 4.1 and 4.7 %, and lost to follow-up in 1.5 
and 2.9 %.  Renal function was also similar between treatment groups over the 24-
month period.  The total daily tacrolimus dose was 25 % lower in Envarsus than in 
tacrolimus recipients in the second year of treatment; Ctrough values remained similar. 
 
2.4.2 
In the conversion study or MELT Trial6, findings at 12 months were similar with 
respect to non inferiority for endpoints of death, graft failure or rejection.  The primary 
endpoint was the efficacy failure rate at 12 months (n= 162 in each group); efficacy 
failure comprised death, graft loss, loss to follow-up or locally read biopsy-proven acute 
rejection.  Envarsus was noninferior to tacrolimus with regard to the efficacy failure rate 
at 12 months in stable, previously treated kidney transplant recipients.  The biopsy-
proven acute rejection rate was 0.6 versus 2.5 %, respectively.  At 12 months, patient 
survival was 98.8 % in the Envarsus and 99.4 % in the tacrolimus group.  The death-
censored graft survival rate at 12 months was 100 % in both groups. 
 
Envarsus has an oral bioavailability that is 40% higher than that of tacrolimus in kidney 
transplant recipients.  Moreover, Envarsus is associated with a significantly reduced 
peak-trough fluctuation ratio and a significantly longer time to Cmax than tacrolimus, as 
well as significantly lower mean values for percentage degree of fluctuation and 
percentage degree of swing.  Envarsus was also associated with a significantly lower 
Cmax. 
 
2.4.3 Post Hoc Analyses 
Exploratory, post-hoc, subgroup analyses of pooled data from both phase III trials 
found that Envarsus was associated with a significantly lower treatment failure rate than 
tacrolimus in Black patients and patients older than 65.  Patient numbers were much 
lower for Black (93) than non-Black (768) patients and for patients aged >65 (84) than 
those aged <65 (777) years. 
 
 
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2.4.4 Pharmacokinetic Study 
The ASTCOFF7 is a cross over PK study that randomized stable kidney transplant 
patients in a 1:1:0.8 dose conversion for Tacrolimus-IR, Tacrolimus-ER, and Envarsus.  
Significantly higher exposure on a per mg basis, lower intraday fluctuation and longer 
time to Cmax were associated with Envarsus. 
 
3. 
Study Design  
3.1. 
Description of Study Design 
This will be a single center prospective case control study.  We expect 40% of 
patients will develop BK viruria, 20% BK viremia, 5% BK viral nephropathy (BKVN).  
Patients will be managed using standard of care for our center (thymoglobulin induction, 
tacrolimus/mycophenolate/prednisone).  Target tacrolimus level is 8-12 ng/mL for the 
first 6 months post transplant and 6-9 ng/mL thereafter.  BK urine/serum is routinely 
monitored during the first year post transplant.  A population of 100 patients is 
calculated to show significant difference for p value < 0.05. 
 
Population:  
 
Study Group:  Post transplant patients (kidney transplant alone) with standard of care 
immunosuppression, no prior rejection, prior BK or opportunistic infection, and negative 
BK screening at post-transplant month 1, who have a tacrolimus concentration/dose of < 
1 and a steady state therapeutic level will be eligible.  Patients who consent to 
participate will be converted to Envarsus at 20% reduction in tacrolimus dose. 
 
Control Group:  Post transplant patients (kidney transplant alone performed between 
10-2016 and time of consideration for study control group) with standard of care 
immunosuppression, no prior rejection, prior BK or opportunistic infection, who had a 
negative BK screening at post-transplant month 1 and tacrolimus concentration/dose of 
< 1 at post-transplant month 1, and BK data available for months 2, 3, 6, 9, 12 post 
transplant.  
 
Study visits:  Post-transplant Months 2, 3, 6, 9, 12 
 
3.2. 
Primary Safety Endpoints  
The safety of Envarsus treatment will be assessed by:  
The timing and incidence of study defined Grade 3 or higher infection 
 
3.3. 
Primary Efficacy Endpoint  
The efficacy primary endpoint of the study is the composite of BK Virus Infection, 
including viruria > 500 copies, viremia > 500 copies, or nephropathy as defined by Banff 
classification (g/msv 40 positivity with or without tubulitis or if/ta). 
 
3.4. 
Secondary Efficacy Endpoints  
The secondary end-points to evaluate the effect of Envarsus conversion will 
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include: incidence of rejection, graft failure, graft dysfunction as defined by a 15% 
decrease in estimated glomerular filtration rate (eGFR), and proteinuria. 
 
4. 
Rationale for Study Population 
 
4.1. 
Enrollment Eligibility Criteria  
4.1.1. Inclusion Criteria  
Individuals who meet all of the following criteria are eligible for enrollment as 
study participants:   
1. Patient must be able to understand and provide informed consent 
2. Age ≥18 years of age at the time of study entry 
3. Recipient of a deceased or living donor kidney transplantation  
4. Maintenance immunosuppression consisting of tacrolimus/MMF/MPA 
(≥1000 mg/720 mg daily) ± prednisone (≤10 mg/day) 
5. Patient is less than or at 8 weeks post transplant with a negative serum 
BK Virus screen at 3-4 weeks post transplant 
6. Patient has a tacrolimus drug dose/concentration of > 1 with therapeutic 
tacrolimus levels. 
7. Women of childbearing potential defined as all women physiologically 
capable of becoming pregnant, must have reviewed Mycophenolate 
REMS and have a negative pregnancy test upon study entry. 
8. Female (and male) subjects with reproductive potential must agree to use 
a highly effective method of birth control for the duration of the study.  
Please note that according to the US product information for MMF/MPA, 
two reliable forms of contraception must be used simultaneously unless 
female sterilization, male sterilization, post-menopausal status or total 
abstinence is the chosen method. 
 
Acceptable methods of highly effective birth control include: 
• Condom with spermicide 
• Diaphragm and sperm ide 
• Cervical cap and spermicide 
• Use of oral, injected or implanted hormonal methods of contraception 
or other forms of hormonal contraception that have comparable 
efficacy (failure rate <1%), for example hormone vaginal ring or 
transdermal hormone contraction 
• Intrauterine device (IUD)  
 
Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks prior to screening. 
 
Male sterilization at least 6 months prior to screening.  For female subjects on the study, 
the vasectomized male partner should be the sole partner for that subject.  
 
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Post menopausal women defined as being not of child bearing potential if they have had 
12 months of natural (spontaneous) amenorrhea. 
 
4.1.2 Exclusion Criteria 
Individuals who meet any of these criteria are not eligible for enrollment 
as study participants:   
1. Inability or unwillingness of a patient to give written informed consent or 
comply with study protocol  
2. History of graft loss from acute rejection within 1 year after any previous 
kidney transplant 
3. History of previous liver, heart, pancreas, or lung transplant 
4. History of cellular rejection of current allograft prior to enrollment 
5. Serum BK virus ≥500 copies/mL by PCR at the time of study entry  
6. Female subjects who are pregnant or breast feeding 
7. Participation in any other studies with investigational drugs or regimens 
in the preceding year from the time of study entry 
8. Any condition or prior treatment which, in the opinion of the investigator, 
precludes study participation 
9. Patients requiring the use of azathioprine or mTOR inhibitors 
10. Patients with active peptic ulcer disease 
 
5. 
Investigational Agent: Envarsus 
5.1. 
Formulation of Envarsus 
Similar to tacrolimus, Envarsus is a macrolide antibiotic.  It has a unique drug 
delivery technology designed to enhance the bioavailability.  The technology breaks the 
drug particles down into the smallest possible units, which are then sprayed onto a 
carrier, forming a granulate, and then compressed into tablets with a stable dissolution 
profile and particle size.  The smaller drug particle size creates greater drug surface area 
and greater absorption. 
 
 
5.2. 
Dosage, Preparation, and Administration  
5.2.1. Dosage 
Envarsus pills come in 0.75 mg, 1 mg and 4 mg concentration tablets 
 
5.2.2. Conversion Plan 
Patients will convert from current tacrolimus dose to an Envarsus dose that is 
80% of the total tacrolimus dose.  They will take Envarsus once daily in the morning and 
have 24-hour trough levels monitored at the standard of care interval for tacrolimus.  
Dosing will be titrated to achieve goal levels. 
 
5.3. 
Premature Discontinuation of Envarsus 
Envarsus will be stopped and will not be restarted if there is a hypersensitivity 
reaction, a CTCAE >2, CRS or any serious adverse event. 
 
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6. 
Other Medications  
6.1. 
Immunosuppressive Medications  
6.1.1. Tacrolimus  
Target tacrolimus trough levels for this study are standard of care at the 
transplant center, 8-12 ng/mL the first 6 months post transplant and 6-9 ng/mL post-
transplant months 7-12. 
 
6.1.2 Mycophenolate Mofetil (MMF)/ Mycophenolic Acid (MPA) 
All enrolled subjects will be on MMF/MPA at the time of study entry at a 
minimum dose of 1000 mg/720 mg per day.  Once subjects are enrolled in the study, 
doses may be adjusted at the discretion of the study investigator for gastrointestinal 
intolerance, cytopenias, infections or other conditions that require dose adjustment.  All 
mycophenolate prescribers in the study will be required to enroll in the FDA 
mycophenolate REMS (risk evaluation and mitigation strategy) program. 
 
6.1.3 Prednisone  
Use of corticosteroids is standard of care at the center and considered part of the 
treatment regimen in this trial. 
 
6.1.4 Other Immunosuppressive Medications  
Patients requiring the use of azathioprine or mTOR inhibitors will not be enrolled 
in this study. 
 
6.2. 
Anti-Infective Prophylactic Medications  
Anti-infective prophylaxis medications will be per standard of care. 
 
6.3. 
Prohibited Medications  
6.3.1. Vaccinations  
The use of live vaccines will be prohibited during trial participation, as per 
standard of care for kidney transplant recipients.  Examples include (but are not limited 
to) the following: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow 
fever, varicella, and TY21a typhoid vaccines.  Subjects should not receive any vaccination 
(live or inactivated) within 5 days prior to study enrollment. 
 
6.3.2. Medication Interactions  
Administration of medications known to interact with tacrolimus and 
cyclosporine metabolism are allowed but tacrolimus and cyclosporine levels should be 
carefully monitored, and dosing titrated to maintain the target levels to minimize toxicity 
while maintaining efficacy.  
 
6.4. 
Treatment of Rejection  
Patients who are clinically suspected to have a rejection will undergo a kidney 
biopsy as part of their standard of care.  Biopsies will be read locally according to the 
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Banff criteria and if acute rejection is diagnosed, it will be treated according to the 
current standard of care. 
 
7. 
Standard Care Procedures While On Study 
7.1. 
Blood Draws  
Blood draws are necessary after kidney transplantation to monitor allograft 
function.   
 
7.2. 
Kidney Biopsy  
Study participants will have an allograft biopsy performed for medical indications 
such as allograft dysfunction or proteinuria and these results analyzed by an experienced 
renal pathologist.  Patients may undergo a routine surveillance biopsy per institutional 
protocol. 
 
8. 
Known and Potential Risks and Benefits to Participants  
8.1. 
Risks of Envarsus 
The most common adverse reactions to treatment with Envarsus are similar to 
the adverse reactions listed below with tacrolimus. 
 
8.2. 
Risks of Tacrolimus and Mycophenolate Mofetil/Mycophenolic Acid  
Subjects will be on tacrolimus and mycophenolate at the time of study entry.  
Potential risks applicable to their use in this study are listed below.  
 
8.2.1. Risks of Tacrolimus  
Post-Transplant Diabetes Mellitus:  Insulin-dependent post-transplant diabetes mellitus 
(PTDM) was reported in 20% of tacrolimus-treated kidney transplant patients without 
pre-transplant history of diabetes mellitus in the Phase III study.  The median time to 
onset of PTDM was 68 days.  Insulin dependence was reversible in 15% of these PTDM 
patients at one year and in 50% at 2 years post- transplant.  Black and Hispanic kidney 
transplant patients were at an increased risk of development of PTDM.  
 
Nephrotoxicity:  Tacrolimus can cause nephrotoxicity, particularly when used in high 
doses.  Nephrotoxicity was reported in approximately 52% of kidney transplantation 
patients and in 40% and 36% of liver transplantation patients receiving tacrolimus in the 
U.S. and European randomized trials, respectively, and in 59% of heart transplantation 
patients in a European randomized trial.  In patients with persistent elevations of serum 
creatinine who are unresponsive to dosage adjustments, consideration should be given 
to changing to another immunosuppressive therapy.  Care should be taken in using 
tacrolimus with other nephrotoxic drugs.    
 
Hyperkalemia:  Mild to severe hyperkalemia was reported in 31% of kidney transplant 
recipients and in 45% and 13% of liver transplant recipients treated with tacrolimus in 
the U.S. and European randomized trials, respectively, and in 8% of heart transplant 
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recipients in a European randomized trial and may require treatment.  Serum potassium 
levels should be monitored and potassium-sparing diuretics should not be used during 
tacrolimus therapy.  
 
Neurotoxicity:  Tacrolimus can cause neurotoxicity, particularly when used in high doses.  
Neurotoxicity, including tremor, headache, and other changes in motor function, mental 
status, and sensory function were reported in approximately 55% of liver transplant 
recipients in the two randomized studies.  Tremor occurred more often in tacrolimus-
treated kidney transplant patients (54%) and heart transplant patients (15%) compared 
to cyclosporine-treated patients.  The incidence of other neurological events in kidney 
transplant and heart transplant patients was similar in the two treatment groups.  
Tremor and headache have been associated with high whole-blood concentrations of 
tacrolimus and may respond to dosage adjustment.  Seizures have occurred in adult and 
pediatric patients receiving tacrolimus.  Coma and delirium also have been associated 
with high plasma concentrations of tacrolimus.  Patients treated with tacrolimus have 
been reported to develop posterior reversible encephalopathy syndrome (PRES).  
Symptoms indicating PRES include headache, altered mental status, seizures, visual 
disturbances and hypertension.  Diagnosis may be confirmed by radiological procedure. 
If PRES is suspected or diagnosed, blood pressure control should be maintained and 
immediate reduction of immunosuppression is advised.  This syndrome is characterized 
by reversal of symptoms upon reduction or discontinuation of immunosuppression.  
 
Malignancy and Lymphoproliferative Disorders:  As in patients receiving other 
immunosuppressants, patients receiving tacrolimus are at increased risk of developing 
lymphomas and other malignancies, particularly of the skin.  The risk appears to be 
related to the intensity and duration of immunosuppression rather than to the use of 
any specific agent.  A lymphoproliferative disorder (LPD) related to Epstein-Barr Virus 
(EBV) infection has been reported in immunosuppressed organ transplant recipients.  
The risk of LPD appears greatest in young children who are at risk for primary EBV 
infection while immunosuppressed or who are switched to tacrolimus following long-
term immunosuppression therapy.  Because of the danger of oversuppression of the 
immune system which can increase susceptibility to infection, combination 
immunosuppressant therapy should be used with caution.  
 
Latent Viral Infections:  Immunosuppressed patients are at increased risk for 
opportunistic infections, including activation of latent viral infections.  These include BK 
virus associated nephropathy and JC virus associated progressive multifocal 
leukoencephalopathy (PML) which have been observed in patients receiving tacrolimus.  
These infections may lead to serious, including fatal, outcomes.  
 
8.2.2. Risks of Mycophenolate Mofetil/ Mycophenolic Acid 
Embryofetal Toxicity:  Mycophenolate mofetil (MMF) can cause fetal harm when 
administered to a pregnant female.  Use of MMF during pregnancy is associated with an 
increased risk of first trimester pregnancy loss and an increased risk of congenital 
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malformations, especially external ear and other facial abnormalities including cleft lip 
and palate, and anomalies of the distal limbs, heart, esophagus, kidney and nervous 
system.  
 
All prescribers at this center have already been enrolled in the MMF REMS program.  Of 
note, all study participants will already have been on a maintenance regimen containing 
MMF/MPA and will not be started on it as part of the study.  All females must be willing 
to use FDA approved methods of birth control acceptable during the entire period of the 
study.   
 
For those females who are discovered to be pregnant either at study screening or 
enrollment or during the study and who are on MMF/MPA or within 6 weeks of 
discontinuing therapy, the study investigators will report the pregnancy to the 
Mycophenolate Pregnancy registry (1-800-617-8191) and strongly encourage the patient 
to enroll in the pregnancy registry.  When appropriate, pregnant patients will be 
switched to alternative immunosuppression with less potential for embryo-fetal toxicity 
after a discussion of maternal and fetal risks and benefits.  
 
Lymphoma and Malignancy:  Patients receiving immunosuppressive regimens involving 
combinations of drugs, including MMF, as part of an immunosuppressive regimen are at 
increased risk of developing lymphomas and other malignancies, particularly of the skin.  
The risk appears to be related to the intensity and duration of immunosuppression 
rather than to the use of any specific agent.  As usual for patients with increased risk for 
skin cancer, exposure to sunlight and UV light should be limited by wearing protective 
clothing and using a sunscreen with a high protection factor.  Lymphoproliferative 
disease or lymphoma developed in 0.4% to 1% of patients receiving MMF (2 g or 3 g) 
with other immunosuppressive agents in controlled clinical trials of renal, cardiac, and 
hepatic transplant patients.  In pediatric patients, no other malignancies besides 
lymphoproliferative disorder (2/148 patients) have been observed.  
 
Combination with Other Immunosuppressive Agents:  MMF has been administered in 
combination with the following agents in clinical trials: antithymocyte globulin 
(ATGAM®), OKT3 (Orthoclone OKT® 3), cyclosporine (Sandimmune®, Neoral®), tacrolimus 
(Prograf®), and corticosteroids.  The efficacy and safety of the use of MMF in 
combination with other immunosuppressive agents have not been determined.  
 
Serious Infections:  Patients receiving immunosuppressants, including MMF, are at 
increased risk of developing bacterial, fungal, protozoal and new or reactivated viral 
infections, including opportunistic infections.  These infections may lead to serious, 
including fatal outcomes.  Because of the danger of over suppression of the immune 
system which can increase susceptibility to infection, combination immunosuppressant 
therapy should be used with caution.  
 
 
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New or Reactivated Viral Infections:  Polyomavirus associated nephropathy (PVAN), JC 
virus associated progressive multifocal leukoencephalopathy (PML), cytomegalovirus 
(CMV) infections, reactivation of hepatitis B (HBV) or hepatitis C (HCV) have been 
reported in patients treated with immunosuppressants, including MMF.  Reduction in 
immunosuppression should be considered for patients who develop evidence of new or 
reactivated viral infections.  Physicians should also consider the risk that reduced 
immunosuppression represents to the functioning allograft.  PML, which is sometimes 
fatal, commonly presents with hemiparesis, apathy, confusion, cognitive deficiencies, 
and ataxia.  Risk factors for PML include treatment with immunosuppressant therapies 
and impairment of immune function.  In immunosuppressed patients, physicians should 
consider PML in the differential diagnosis in patients reporting neurological symptoms 
and consultation with a neurologist should be considered as clinically indicated.  The risk 
of CMV viremia and CMV disease is highest among transplant recipients seronegative for 
CMV at time of transplant who receive a graft from a CMV seropositive donor.  
Therapeutic approaches to limiting CMV disease exist and should be routinely provided.  
Patient monitoring may help detect patients at risk for CMV disease.  Viral reactivation 
has been reported in patients infected with HBV or HCV.  Monitoring infected patients 
for clinical and laboratory signs of active HBV or HCV infection is recommended.  
 
Neutropenia:  Severe neutropenia [absolute neutrophil count (ANC)  <0.5 x 103/uL] 
developed in up to 2.0% of renal, up to 2.8% of cardiac, and up to 3.6% of hepatic 
transplant patients receiving MMF 3g daily.  Patients receiving MMF should be 
monitored for neutropenia.  The development of neutropenia may be related to MMF 
itself, concomitant medications, viral infections, or some combination of these causes.  If 
neutropenia develops (ANC <1.3 x 103/uL), dosing with MMF should be interrupted or 
the dose reduced, appropriate diagnostic tests performed, and the patient managed 
appropriately.  Neutropenia has been observed most frequently in the period from 31 to 
180 days post-transplant in patients treated for prevention of renal, cardiac, and hepatic 
rejection.  Patients receiving MMF should be instructed to report immediately any 
evidence of infection, unexpected bruising, bleeding or any other manifestation of bone 
marrow depression.  
 
Pure Red Cell Aplasia (PRCA):  Cases of pure red cell aplasia (PRCA) have been reported 
in patients treated with MMF in combination with other immunosuppressive agents.  
The mechanism for MMF induced PRCA is unknown; the relative contribution of other 
immunosuppressants and their combinations in an immunosuppression regimen are also 
unknown.  In some cases, PRCA was found to be reversible with dose reduction or 
cessation 
of 
MMF 
therapy. 
 
In 
transplant 
patients, 
however, 
reduced 
immunosuppression may place the graft at risk.  
 
Gastrointestinal Disorders:  Gastrointestinal bleeding (requiring hospitalization) has 
been observed in approximately 3% of renal, in 1.7% of cardiac, and in 5.4% of hepatic 
transplant patients treated with MMF 3 g daily.  In pediatric renal transplant patients, 
5/148 cases of gastrointestinal bleeding (requiring hospitalization) were observed.  
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Gastrointestinal perforations have rarely been observed.  Most patients receiving MMF 
were also receiving other drugs known to be associated with these complications.  
Patients with active peptic ulcer disease were excluded from enrollment in studies with 
MMF.  Because MMF has been associated with an increased incidence of digestive 
system adverse events, including infrequent cases of gastrointestinal tract ulceration, 
hemorrhage, and perforation, MMF should be administered with caution in patients 
with active serious digestive system disease.  
 
Patients with Renal Impairment:  Subjects with severe chronic renal impairment (GFR 
<25 mL/min/1.73 m2) who have received single doses of MMF showed higher plasma 
MPA and MPAG AUCs relative to subjects with lesser degrees of renal impairment or 
normal healthy volunteers.  No data are available on the safety of long-term exposure to 
these levels of MPAG.  Doses of MMF greater than 1 g administered twice a day to renal 
transplant patients should be avoided and they should be carefully observed.  
 
Patients with HGPRT Deficiency:  MMF is an IMPDH (inosine monophosphate 
dehydrogenase) inhibitor; therefore, it should be avoided in patients with rare 
hereditary deficiency of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) such 
as Lesch-Nyhan and Kelley-Seegmiller syndrome.  
 
Phenylketonurics:  MMF Oral Suspension contains aspartame, a source of phenylalanine 
(0.56 mg phenylalanine/mL suspension).  Therefore, care should be taken if MMF Oral 
Suspension is administered to patients with phenylketonuria.  
 
8.3. 
Risks of Standard Care Procedures While On Study  
8.3.1. Risks of Blood Draws  
Risks of blood draw or venipuncture are typically minimal with temporary local 
discomfort.  More serious risks would include ecchymosis and, rarely, localized infection.   
 
8.3.2. Risks of Kidney Biopsy  
There is a risk of bleeding associated with transplant kidney biopsies.  Transient 
hematuria occurs in 3 to 10% of patients and may prolong hospitalization, require 
bladder catheterization for clot drainage, or in approximately 1% of patients, require 
blood transfusion.  Ureteral obstruction from blood clot may require percutaneous 
nephrostomy in <1% of patients.  Massive hemorrhage requiring surgical exploration, 
transplant nephrectomy, or arterial embolization occurs in approximately 0.1 % of 
patients.  Death from massive hemorrhage is rare. 
 
8.4. 
Potential Benefits 
This study might not provide direct or immediate benefit to the participants, but 
it is hoped that the information gained may benefit future kidney transplant patients. 
 
8.4.1. Decrease in BK Infection 
It is possible that use of Envarsus in place of tacrolimus will reduce incidence of 
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BK viruria, viremia, and nephropathy. 
 
8.4.2. Prolongation in Graft Survival 
The reduced incidence of BK infection may result in improved graft function and 
ultimately survival.  It is difficult to predict the magnitude of this effect and it may not be 
apparent for months or years after treatment. 
 
9. 
Study Visits  
9.1. 
Enrollment 
The research study will be explained in lay terms to each potential research 
participant.  The potential participant will sign an informed consent form before 
undergoing any study procedures.  A participant is considered enrolled in the trial once 
the consent form has been signed.  
 
9.2. 
Follow -Up Visits 
The initial visit and subsequent visits on study days 30, 120, 210, and 300 will 
include routine evaluation with physical examination and laboratory studies.  These 
laboratory studies include BK urine and serum testing, CBC, renal function panel, eGFR, 
CNI and MPA drug levels, urinalysis, donor specific antibody testing, and urine 
protein/creatinine ratio according to the center's standard of care.   
 
Please refer to Appendix 1 for schedule of events. 
 
9.3. 
Unscheduled Visits 
If creatinine increases or other concerns arise between regularly scheduled visits, 
participants will return to the study site for an “unscheduled” visit. 
 
9.4. 
Visit Time Frames/ Windows 
Study visits should take place within the time frames specified below in Table 1.  
The designated visit windows for each scheduled study visit are indicated in Appendix 1 
Schedule of Events.  
 
Table 1.  Study Visits 
Visit No. 
Study Visit Label 
Time Frame Post Transplant 
Screen 
Study Eligibility 
Approximately 1 month 
1 
Enrollment Day 0/ Visit 1 
Approximately 2 months 
2 
Study Day 30/ Visit 2 
Approximately 3 months 
3 
Study Day 120/ Visit 3 
Approximately 6 months 
4 
Study Day 210/ Visit 4 
Approximately 9 months 
5 
Study Day 300/ Visit 5 
Approximately 12 months 
 
10. 
Criteria for Participant Completion and Premature Study Termination  
Participants may be prematurely terminated from the study for the following reasons:  
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• The participant elects to withdraw consent from all future study activities, including 
follow-up. 
• The participant is “lost to follow-up” 3 months after the date of a missed study visit 
(i.e., no further follow-up is possible because attempts to reestablish contact with 
the participant have failed). 
• The participant dies. 
• The Investigator no longer believes participation is in the best interest of the 
participant. 
• CTCAE Grade 3 or higher drug-related reaction 
• A decision is made by the investigators and/or study supporter to stop the study 
 
11. 
Safety Monitoring and Reporting  
11.1. Overview  
This section defines the types of safety data that will be collected under this 
protocol and outlines the procedures for appropriately collecting, grading, recording, 
and reporting those data.  Adverse events that are classified as serious according to the 
definition of health authorities must be reported promptly to the Supporter.  
Appropriate notifications per local institutional guidelines will also be made to 
Institutional Review Boards (IRBs) and health authorities. 
 
Information in this section complies with ICH Guideline E2A: Clinical Safety Data 
Management: Definitions and Standards for Expedited Reporting, ICH Guideline E-6: 
Guideline for Good Clinical Practice, 21CFR Parts 312 and 320, and applies the standards 
set forth in the National Cancer Institute (NCI), Common Terminology Criteria for 
Adverse Events (CTCAE), Version 4.0:   
https://www.acrin.org/Portals/0/Administration/Regulatory/CTCAE_4.02_2009-09-
15_QuickReference_5x7.pdf 
 
11.2. Definitions 
11.2.1. Adverse Event (AE)  
Any untoward or unfavorable medical occurrence associated with the subject’s 
participation in the research, whether or not considered related to the subject’s 
participation in the research (modified from the definition of adverse events in the 1996 
International Conference on Harmonization E-6 Guidelines for Good Clinical Practice) 
(from OHRP "Guidance on Reviewing and Reporting Unanticipated Problems Involving 
Risks to Subjects or Others and Adverse Events (1/15/07)":   
https://www.hhs.gov/ohrp/sites/default/files/ohrp/policy/advevntguid.pdf 
 
11.2.1.1. 
Suspected Adverse Event 
Any adverse event for which there is a reasonable possibility that the 
investigational drug caused the adverse event.  For the purposes of safety reporting, 
‘reasonable possibility’ means there is evidence to suggest a causal relationship 
between the drug and the adverse event.  A suspected adverse reaction implies a lesser 
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degree of certainty about causality than adverse reaction, which means any adverse 
event caused by a drug (21 CFR 312.32(a)). 
 
11.2.1.2. 
Unexpected Adverse Event 
An adverse event or suspected adverse reaction is considered “unexpected” if it 
is not listed in the package insert or is not listed at the specificity, severity or rate of 
occurrence that has been observed.  “Unexpected” also refers to adverse events or 
suspected adverse reactions that are mentioned in the Investigator Brochure or package 
insert as occurring with a class of drugs or as anticipated from the pharmacological 
properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation (21 CFR 312.32(a). 
 
11.2.2. 
Serious Adverse Event (SAE)  
An adverse event or suspected adverse reaction is considered “serious” if, in the 
view of either the Investigator or Supporter, it results in any of the following outcomes 
(21 CFR 312.32(a)):  
• Death. 
• A life-threatening event: An AE or SAE is considered “life-threatening” if, in 
the view of either the investigator or Supporter, its occurrence places the 
subject at immediate risk of death.  It does not include an AE or SAE that, had 
it occurred in a more severe form, might have caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization.  
• Persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
• Congenital anomaly or 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 subject and may 
require medical or surgical intervention to prevent one of the outcomes listed 
above. 
• Elective hospitalizations or hospital admissions for the purpose of conduct of 
protocol mandated procedures are not to be reported as an SAE unless 
hospitalization is prolonged due to complications.  
 
11.3. Grading and Attribution of Adverse Events 
11.3.1. 
Grading Criteria  
The study site will grade the severity of adverse events experienced by the study 
subjects according to the criteria set forth in the National Cancer Institute’s Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0.  This document (referred to 
herein as the NCI-CTCAE manual) provides a common language to describe levels of 
severity, to analyze and interpret data, and to articulate the clinical significance of all 
adverse events.  The NCI-CTCAE has been reviewed by the Principal Investigator and has 
been deemed appropriate for the subject population to be studied in this protocol.   
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Infections will be graded using the study-specific scale as described below:  
Grade 1 = asymptomatic; clinical or diagnostic observation only; intervention with 
oral antibiotic, antifungal, or antiviral agent only; no invasive intervention required 
 
Grade 2 = symptomatic; intervention with intravenous antibiotic, antifungal, or 
antiviral agent; invasive intervention may be required 
 
Grade 3 = any infection associated with hemodynamic compromise requiring 
pressors; any infection necessitating ICU level of care; any infection necessitating 
operative intervention; any infection involving the central nervous system; any 
infection with a positive fungal blood culture; any proven or probable aspergillus 
infection; any tissue invasive fungal infection; any pneumocystis jiroveci infection 
 
Grade 4 = life-threatening infection  
 
Grade 5 = death resulting from infection  
 
All other adverse events will be graded on a scale from 1 to 5 according to the following 
standards in the NCI-CTCAE manual:  
Grade 1 = mild adverse event.  
 
Grade 2 = moderate adverse event.  
 
Grade 3 = severe and undesirable adverse event.  
 
Grade 4 = life-threatening or disabling adverse event.  
 
Grade 5 = death.  
 
Infection events grade 2 or higher; and all other events CTCAE grade 2 or higher will be 
recorded on the appropriate AE form for this study.  
 
For grading an abnormal value or result of a clinical or laboratory evaluation (including, 
but not limited to, a radiograph, an ultrasound, an electrocardiogram etc.), a treatment-
emergent adverse event is defined as an increase in grade from baseline or from the last 
post-baseline value that does not meet grading criteria.  Changes in grade from 
screening to baseline will also be recorded as adverse events, but are not treatment-
emergent.  If a specific event or result from a given clinical or laboratory evaluation is 
not included in the NCI-CTCAE manual, then an abnormal result would be considered an 
adverse event if changes in therapy or monitoring are implemented as a result of the 
event/result.  
 
11.3.2. Attribution Definitions  
The relationship, or attribution, of an adverse event to the study therapy 
regimen will initially be determined by the site investigator and recorded on the 
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appropriate AE/SAE form.  Final determination of attribution for safety reporting will be 
determined by the Supporter after consultation with the Investigator.  The relationship 
of an adverse event to study therapy regimen will be determined using the descriptors 
and definitions provided in Table 2 below.   
 
For additional information and a printable version of the NCI-CTCAE manual, consult the 
NCI-CTCAE web site: 
https://www.acrin.org/Portals/0/Administration/Regulatory/CTCAE_4.02_2009-09-
15_QuickReference_5x7.pdf 
 
Table 2.  Attribution of Adverse Events  
Code 
Descriptor 
Relationship (to primary 
investigational product 
and/or other concurrent 
mandated study therapy 
or study procedure)  
Unrelated Category  
 
 
1 
Unrelated 
The adverse event is 
clearly not related:  there 
is insufficient evidence to 
suggest a causal 
relationship.  
Related Categories  
 
 
2 
Possible 
The adverse event has a 
reasonable possibility to 
be related; there is 
evidence to suggest a 
causal relationship.  
3 
Definite 
The adverse event is 
clearly related.  
 
Attribution of adverse event to tacrolimus, MMF/MPA, and prednisone will not be 
assessed in this study because these medications are used as standard of care for kidney 
transplant recipients.  
 
Attribution assessment for the following study interventions will be made when a SAE is 
reported:  
 
Study Therapy:   
Envarsus 
 
11.4. Collection and Recording of Adverse Events  
11.4.1. 
Collection Period  
Adverse events will be collected from the time of first study mandated activity 
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until a subject completes study participation or until 30 days after he/she prematurely 
withdraws (without withdrawing consent), or is withdrawn from the study.  
 
11.4.2. 
Collecting Adverse Events  
Adverse events (including SAEs) may be discovered through any of these 
methods:  
• Observing the subject.  
• Interviewing the subject [e.g., using a checklist, structured questioning, diary, 
etc.]  .  
• Receiving an unsolicited complaint from the subject.  
• In addition, an abnormal value or result from a clinical or laboratory 
evaluation can also indicate an adverse event, as defined in Section 14.3, 
Grading and Attribution of Adverse Events.  
 
11.4.3. 
Recording Adverse Events  
Throughout the study, the investigator will record adverse events and serious 
adverse events as described previously (Section 14.2, Definitions) on the appropriate 
AE/SAE form regardless of the relationship to study therapy regimen or study procedure. 
 
Once recorded, an AE/SAE will be followed until it resolves with or without sequelae, or 
until the end of study participation, or until 30 days after the subject prematurely 
withdraws (without withdrawing consent)/or is withdrawn from the study, whichever 
occurs first.  
 
11.5. Reporting of Serious Adverse Events and Adverse Events  
11.5.1. 
Reporting of Serious Adverse Events to Sponsor   
This section describes the responsibilities of the site investigator to report 
serious adverse events to the Supporter via the AE/SAE form.  Timely reporting of 
adverse events is required by 21 CFR and ICH E6 guidelines.   
 
The PI will report all serious adverse events (see Section 13.2.3, Serious Adverse Event), 
to the Supporter, regardless of relationship or expectedness, within 24 hours of 
discovering the event. 
 
For serious adverse events, all requested information on the AE/SAE CRF will be 
provided.  However, unavailable details of the event will not delay submission of the 
known information.  As additional details become available, the AE/SAE form will be 
updated and submitted to the Supporter.  
 
11.5.2. 
Reporting of Adverse Events to IRB 
The investigator shall report adverse events, including expedited reports, in a 
timely fashion to their respective IRB in accordance with their local IRB guidelines.  
 
 
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11.6. Pregnancy Reporting  
The investigator shall be informed immediately of any pregnancy in a study 
participant or a partner of a study participant.  A pregnant participant shall not receive 
MMF.  The investigator shall counsel the participant and discuss the risks of continuing 
with the pregnancy and the possible effects on the fetus.  Monitoring of the pregnant 
participant shall continue until the conclusion of the pregnancy. 
 
The investigator shall report to the Supporter all pregnancies within 1 business day of 
becoming aware of the event.  All pregnancies identified during the study shall be 
followed to conclusion and the outcome of each must be reported.  When possible, 
similar information shall be obtained for a pregnancy occurring in a partner of a study 
participant. 
 
Information requested about the delivery shall include:  
• Gestational age at delivery  
• Birth weight, length, and head circumference  
• Gender  
• Appearance, pulse, grimace, activity, and respiration (APGAR) score at 1 minute, 
5 minutes, and 24 hours after birth, if available  
• Any abnormalities.  
 
For all pregnancy complications that result in a congenital abnormality, birth defect, 
miscarriage, and medically indicated abortion, an SAE shall be submitted to the 
Supporter using the SAE reporting procedures described above. 
 
11.7. Reporting of Other Safety Information  
An investigator shall notify the site IRB according to the site’s IRB guidelines 
when an “unanticipated problem involving risks to participants or others” is identified, 
which is not otherwise reportable as an adverse event. 
 
12. 
Statistical Considerations and Analytical Plan 
This is a single center prospective study comparing incidence of BK infection in rapid 
metabolizers converted from tacrolimus to Envarsus against a recent historical control of rapidly 
metabolizing recipients who had BK screening at similar points, but remained on tacrolimus.   
 
This study has both safety and efficacy endpoints. 
 
We will use standard descriptive statistics for continuous and categorical data to define adverse 
events, and clinical outcomes as noted above.  Analysis will be undertaken utilizing UAB 
statistical support in the School of Public Health and Transplant Quality, Informatics and 
Outcomes. 
 
The enrollment plan is based on a power calculation.  A population of 100 patients is calculated 
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to show significant difference for p value < 0.05. 
 
Our results will be submitted to national/international nephrology/transplant meetings, and as 
a primary manuscript reporting the primary efficacy and safety data, and secondary 
manuscripts reporting different secondary endpoints, as appropriate. 
 
We expect the changes over time in these assays to be approximately linear.  If after 
examination of the data, this appears to not be the case, then we will either transform the assay 
measures or model the time axis time points as an unordered factor (similar to repeated 
measures ANOVA, but without the requirement for fully balanced data).   
 
We will use descriptive analyses to summarize subject characteristics of our study population.  
Dichotomous variables will be summarized as proportions with 95% confidence intervals.  
Continuous variables will be summarized using means, standard deviations, and 95% confidence 
intervals if they are symmetric and unimodal.  Otherwise, they will be summarized using the 
median and the interquartile range.  Simple t-, chi-squared, or Fisher's exact test, as 
appropriate, will be used to compare quantitative measures across treatment groups.  The 
following variables will be summarized:   
• Baseline and demographic characteristics  
• Use of concomitant medications  
• Reasons for early termination  
• All reportable AEs 
 
No formal interim analyses of this study are planned.  
 
13. 
Identification and Access to Source Data  
13.1. Source Data  
Source documents and source data are considered to be the original 
documentation where subject information, visits consultations, examinations and other 
information are recorded.  Documentation of source data is necessary for the 
reconstruction, evaluation and validation of clinical findings, observations and other 
activities during a clinical trial.   
 
13.2. Access to Source Data  
The site investigator and site staff will make all source data available to 
representatives of the Supporter, as well as to relevant health authorities.  Authorized 
representatives as noted above are bound to maintain the strict confidentiality of 
medical and research information that may be linked to identified individuals. 
 
14. 
Protocol Deviations  
14.1. Protocol Deviation Definitions 
Protocol Deviation – The investigators and site staff will conduct the study in accordance 
to the protocol; no deviations from the protocol are permitted.  Any change, divergence, 
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or departure from the study design or procedures constitutes a protocol deviation.  As a 
result of any deviation, corrective actions will be developed by the site and implemented 
promptly.  
 
Major Protocol Deviation - A major protocol deviation is a variance from the IRB 
approved protocol that may affect the participant's rights, safety, or well-being and/or 
the completeness, accuracy and reliability of the study data.  In addition, protocol 
deviations include willful or knowing breaches of human subject protection regulations, 
or policies, any action that is inconsistent with the NIH Human Research Protection 
Program’s research, medical, and ethical principles, and a serious or continuing 
noncompliance with federal, state, local or institutional human subject protection 
regulations, policies, or procedures.   
 
Non-Major Protocol Deviation - A non-major protocol deviation is any change, 
divergence, or departure from the study design or procedures of a research protocol 
that does not have a major impact on the participant's rights, safety or well-being, or the 
completeness, accuracy and reliability of the study data.  
 
14.2. Reporting and Managing Protocol Deviations  
The study Principal Investigator has the responsibility to identify, document and 
report protocol deviations as directed by the study protocol to Supporter.  However, 
protocol deviations may also be identified during other forms of study conduct review.  
Upon determination that a protocol deviation has occurred, the Principal Investigator 
will be responsible for reporting deviations to the local IRB, per local IRB guidelines. 
 
15. 
Ethical Considerations and Compliance with Good Clinical Practice  
15.1. Statement of Compliance  
This clinical study will be conducted using good clinical practice (GCP), as 
delineated in Guidance for Industry: E6 Good Clinical Practice Consolidated Guidance, 
and according to the criteria specified in this study protocol.  Before study initiation, the 
protocol and the informed consent documents will be reviewed and approved by the 
IRB.  Any amendments to the protocol or to the consent materials will also be approved 
by the IRB before they are implemented.  
 
15.2. Informed Consent Process  
The consent process will provide information about the study to a prospective 
participant and will allow adequate time for review and discussion prior to his/her 
decision.  The Principal Investigator or designee listed on the FDA 1572 will review the 
consent and answer questions.  The prospective participant will be told that being in the 
trial is voluntary and that he or she may withdraw from the study at any time, for any 
reason.  All participants (or their legally acceptable representative) will read, sign, and 
date a consent form before undergoing any study procedures.  Consent materials will be 
presented in participants’ primary language.  A copy of the signed consent form will be 
given to the participant.  The consent process will be ongoing and documented.  The 
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consent form will be revised when important new safety information is available, the 
protocol is amended, and/or new information becomes available that may affect 
participation in the study. 
 
15.3. Privacy and Confidentiality  
A participant’s privacy and confidentiality will be respected throughout the study.  
Each participant will be assigned a unique identification number and these numbers 
rather than names will be used to collect, store, and report participant information 
whenever possible.  Site personnel will not transmit documents containing personal 
health identifiers (PHI) to the study Supporter, or their representatives. 
 
16. 
References 
1. 
Tholking, Gerold. Influence of tacrolimus metabolism rate on renal function after 
solid organ transplantation.  World journal of Transplantation.  2017 February 24; 
7(1):26-33 
2. 
Thölking G, Siats L, Fortmann C, Koch R, Hüsing A, Cicinnati VR, Gerth HU, Wolters 
HH, Anthoni C, Pavenstädt H, Suwelack B, Schmidt HH, Kabar I. Tacrolimus 
Concentration/Dose Ratio is Associated with Renal Function After Liver 
Transplantation. Ann Transplant 2016; 21: 167-179 [PMID: 27003330 DOI: 
10.12659/ AOT.895898]  
3. 
Thölking G, Fortmann C, Koch R, Gerth HU, Pabst D, Pavenstädt H, Kabar I, Hüsing 
A, Wolters H, Reuter S, Suwelack B. The tacrolimus metabolism rate influences 
renal function after kidney transplantation. PLoS One 2014; 9: e111128 [PMID: 
25340655 DOI: 10.1371/journal. pone.0111128]  
4. 
Thölking G, Schmidt C, Koch R, Schuette-Nuetgen K, Pabst D, Wolters H, Kabar I, 
Hüsing A, Pavenstädt H, Reuter S, Suwelack B. Influence of tacrolimus metabolism 
rate on BKV infection after kidney transplantation. Sci Rep 2016; 6: 32273   
5. 
Budde, K.  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.  Am J Transplant. 2014 Dec;14(12):2796-806. doi: 
10.1111/ajt.12955. Epub 2014 Oct 2. 
6. 
Bunnapradist S, Ciechanowski K, West-Thielke P, et al. Conversion from twice-
daily tacrolimus to once-daily extended release tacrolimus (LCPT): the phase III 
randomized MELT trial. Am J Transplant. 2013;13 
7. 
Tremblay, S.  A Steady-State Head –to-Head Pharmacokinetic Comparison of All FK-
506 (Tacrolimus) Formulations ( ASTCOFF): An Open-Label, Prospective, 
Randomized, Two-Arm, Three-Period Crossover Study.  AJT 2017 Feb;17(2):432-442 
8. 
Baraldo M. Meltdose Tacrolimus Pharmacokinetics.  Transplant Proc. 2016 
Mar;48(2):420-3. doi: 10.1016/j.transproceed.2016.02.002. 
9. 
Rostaing, L. 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.  Am J Kidney Dis. 2016 Apr;67(4):648-59. doi: 
10.1053/j.ajkd.2015.10.024. Epub 2015 Dec 22. 
10. Nankivell.  BK Virus Nephropathy: Histological Evolution by Sequential Pathology.  
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Am J Transplant.  2017 Aug;17(8):2065-2077. doi: 10.1111/ajt.14292 
11. Hirsch HH, Brennan DC, Drachenberg CB, et al. Polyomavirus-associated 
nephropathy in renal transplantation: Interdisciplinary analyses and 
recommendations.  Transplantation 2005; 79: 1277–1286. 
12. Johnston O, Jaswal D, Gill JS, Doucette S, Fergusson DA, Knoll GA. Treatment of 
polyomavirus infection in kidney transplant recipients: A systematic 
review. Transplantation 2010; 89: 1057–1070. 
13. Hirsch HH, Steiger J. Polyomavirus BK. Lancet Infect Dis 2003; 3: 611–623. 
14. Brennan DC, Agha I, Bohl DL, et al. Incidence of BK with tacrolimus versus 
cyclosporine and impact of preemptive immunosuppression reduction. Am J 
Transplant 2005; 5: 582–594. 
15. Hirsch HH, Knowles W, Dickenmann M, et al. Prospective study of polyomavirus 
type BK replication and nephropathy in renal-transplant recipients. N Engl J 
Med 2002; 347: 488–496. 
16. Drachenberg RC, Drachenberg CB, Papadimitriou JC, et al. Morphological spectrum 
of polyoma virus disease in renal allografts: Diagnostic accuracy of urine 
cytology. Am J Transplant 2001; 1: 373–381. 
17. Nankivell BJ, Renthawa J, Jeoffreys N, et al. Clinical utility of urinary cytology to 
detect S 
18. Comoli P, Cioni M, Basso S, et al. Immunity to polyomavirus BK infection: Immune 
monitoring to regulate the balance between risk of BKV nephropathy and 
induction of alloimmunity. Clin Dev Immunol 2013; 2013: 256923. 
19. Hirsch HH, Randhawa P. BK polyomavirus in solid organ transplantation. Am J 
Transplant 2013; 13(Suppl 4): 179–188. 
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APPENDIX 1:  SCHEDULE OF EVENTS 
 
Visit Label 
Study 
Eligibility 
Enrollment 
Day 0 
Study Day 
Days after Randomization 
--- 
--- 
30 
120 
210 
300 
Visit Number 
Screen 
1 
2 
3 
4 
5 
Visit Window 
≤ 4 weeks 
post 
transplant 
≤ 8 weeks 
post 
transplant 
± 14 days 
Study Eligibility 
X 
 
 
 
 
 
Informed Consent 
 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical/Transplant History 
X 
 
 
 
 
 
Physical Examination/Vital Signs 
 
X 
X 
X 
X 
X 
Review/Collect Immunosuppressive 
Medication Data 
 
X 
X 
X 
X 
X 
Review/Collect Biopsy Results 
 
X1 
X1 
X1 
X1 
X1 
Adverse Event/Serious Adverse 
Event Assessment 
 
X 
X 
X 
X 
X 
BKV by PCR in urine and serum 
X 
X 
X 
X 
X 
X 
CBC (with differential and platelets) 
X 
X 
X 
X 
X 
X 
Renal Function Panel 
(to include Na, K, Cl, CO2, BUN, 
Glucose, Creatinine, eGFR) 
X 
X 
X 
X 
X 
X 
Hepatic Function Panel 
(to include ALT, T Bilirubin, 
D Bilirubin) 
X 
 
 
X 
 
X 
Tacrolimus Level 
X 
X 
X 
X 
X 
X 
Urine Protein/Creatinine Ratio 
X 
X 
X 
X 
X 
X 
 
1 Biopsy results will only be collected if a standard care ‘for cause’ or surveillance biopsy is performed while the 
participant is on the study. 
 
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