Conditions: Immunosuppression
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 40
Healthy volunteers: no

Brief summary:
With the availability of well-studied once-daily formulations of tacrolimus, the ability to achieve a true once-daily immunosuppressant regimen along with everolimus and steroids may finally be achievable and have the potential to optimize immunosuppression safety and efficacy in kidney transplantation.

Detailed description:
A once-daily immunosuppressant regimen comprising of Envarsus-everolimus-prednisone will have 6-month treatment failure rates that are non-inferior to the twice-daily regimen of Envarsus-mycophenolate mofetil-prednisone and will have improved patient-reported adherence.

Arms:
arm 1: Tacrolimus IR BID (5-12ng/mL) + mycophenolate mofetil 1g BID + prednisone x at least 3 months, then converted to Tacrolimus Daily (5 -12ng/mL) + mycophenolate mofetil 1g BID + prednisone x 6 months arm 2: Tacrolimus IR BID (5-12ng/mL) + mycophenolate mofetil 1g BID + prednisone x at least 3 months, then converted to Envarsus Daily (2-5ng/mL) + Everolimus Daily (3-8ng/mL) + prednisone x 6 months

Interventions: intervention 1: Tacrolimus intervention 2: Prednisone intervention 3: Mycophenolate mofetil intervention 4: Everolimus
Intervention descriptions: intervention 1: goal trough level 5-12ng/mL intervention 2: goal dose 5mg QD intervention 3: goal dose 1g BID intervention 4: goal trough level 3-8ng/mL

Protocol document:
Prot_SAP_000.pdf: 
Protocol Version 4.0 
11May2017 
 
 
Title:  
Once-daily regimen with Envarsus® to optimize immunosuppression management and 
adherence in kidney transplant recipients 
 
Institution: 
Medical University of South Carolina 
 
Principal Investigator: 
David J. Taber, PharmD 
Office: 843-792-2724 
Fax: 843-792-8596 
Email:  taberd@musc.edu 
 
Sub-Investigators: 
 
James N. Fleming, PharmD 
Office:  843-792-0312 
Fax: 843-792-0566 
Email: fleminj@musc.edu 
 
John McGillicuddy, MD 
Office: 843-792-4003 
mcgillij@musc.edu 
 
Maria Aurora Posadas Salas, MD 
Office: 843-792-6019 
Email:  posadas@musc.edu 
 
 


Protocol Version 4.0 
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1. Study Objectives 
1. Primary objective 
1. Estimate change from baseline to six months in adherence superiority measure by MMAS-8 
in patients converted to a once-daily immunosuppressant regimen of Envarsus®, 
everolimus, and prednisone versus patients converted to a twice-daily regimen of Envarsus® 
(once daily), MMF (twice daily), and prednisone (once daily). 
2. Secondary objectives 
1. Estimate the composite of treatment failure rate, defined as acute allograft rejection with a 
Banff grade 1A or higher, graft loss, or death at six months post-conversion, in patients 
converted to a once-daily immunosuppressant regimen of Envarsus®, everolimus, and 
prednisone versus patients converted to a twice-daily regimen of Envarsus®, MMF, and 
prednisone. 
3. Outcomes 3.3.2 through 3.3.11 are considered exploratory 
1. Examine subject specific change of the Memphis Medication Side Effect Scale (Appendix 
B2, 12) at the time of the conversion versus six months post-conversion, compared 
between the two arms (Appendix B2). 
2. Examine subject specific change in quality of life, using the SF-36 (Appendix B3) at the 
time of conversion versus six months post-conversion, compared between the two 
arms. 
3. Measure and compare time-to-event analysis of secondary objective between the two 
arms 
1. Patient death (time to event analysis) 
2. Biopsy proven acute rejection (Banff 1a or higher, time to event analysis) 
3. Graft loss (time to event analysis) 
4. Examine the medication possession ratio (MPR) of adjunctive immunosuppressants 
(Everolimus or mycophenolate) during follow up between the two arms 
1. Compare the prevalence of patients with MPR >80% 
5. Compare rates of adverse events and severe adverse events between the two arms 
6. Perform exploratory analysis of subclinical rejection and IF/TA in patients with one year 
protocol biopsies as compared to three month protocol biopsies between the two arms 
 
2. 
Background 
1. Rationale 
 
Non-adherence in renal transplant recipients has been widely reported, with conservative estimates 
reporting a prevalence between 20 and 67% (1,2). While it is difficult to determine the degree of 
nonadherence necessary to affect graft outcomes, there are several studies demonstrating the costs, 
with a graft loss rate 7 times greater than in adherent patients and an associated $15-100 million annual 
costs.  Due to the complex causes of nonadherence, no singular approach is likely to be effective (3). 
However, one of the most commonly cited reasons for nonadherence by patients is forgetfulness and 
disruptions in routine, with the evening dose of twice daily regimens the most likely to be affected (4). 
Tacrolimus LCP (Envarsus®) is a once-daily tacrolimus product that has demonstrated similar outcomes 
compared to twice-daily tacrolimus (tacrolimus IR) along with IL-2 receptor induction and 
mycophenolate mofetil adjunctive therapy with target concentrations of 4-11 ng/mL(5).   In clinical trials 
that have studied the combination of tacrolimus and everolimus, such as the CRAD01AUS09 and ASSET 
studies, lower exposure to tacrolimus has demonstrated equivalent efficacy compared to standard 


Protocol Version 4.0 
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exposure tacrolimus, with a lower incidence of adverse effects. In these two studies, tacrolimus 
exposure after 3 months (the time of conversion for our study) was 4-6 ng/mL (US09) and 1.5-3 ng/mL 
(ASSET), both of which show adequate efficacy and safety in regards to biopsy-proven acute rejection 
(BPAR) and adverse events (6,7). Additionally, the currently enrolling TRANSFORM study 
(CRAD001A2433) utilizes a tacrolimus exposure of 2-5 ng/mL from month 2 to month 24 post-
transplant.   Envarsus, while demonstrating a unique drug-delivery profile, still maintains an equivalent 
correlation between exposure (AUC) and C0 values to tacrolimus IR, validating a low-exposure goal for 
Envarsus in combination with everolimus (8). 
However, the combination of a once-daily product along with twice-daily products such as 
mycophenolate mofetil does not reduce the number of times per day immunosuppressive therapy is 
necessary.  It has the potential, alternatively, to reduce adherence to the twice-daily product. 
Everolimus (Zortress®) is an mTOR inhibitor that has been studied and approved as an adjunctive 
immunosuppressant in kidney transplant recipients in a twice-daily regimen (6).  However, due to the 
prolonged elimination half-life of everolimus (28±7 hours), a number of researchers have evaluated its 
ability to be used as a once-daily medication from a pharmacokinetic point of view. Kahan et al. 
demonstrated that, at steady state, the 24-hour AUC, Cmin, and Cmax increased proportionately to the 
administered dose. In addition, the relationship between the Cmin and the AUC after once-daily 
administration was excellent; confirming the ability to use Cmin levels to as an accurate predictor of 
drug exposure in once-daily everolimus regimens (9). Given this information, there have been 
subsequent clinical studies investigating a once-daily dosing interval with everolimus therapy. Carmellini 
et al. converted 12 patients to a once-daily regimen of everolimus and compared these patients to 12 
subjects who maintained a twice-daily dosing regimen. The investigators demonstrated that conversion 
to once-daily everolimus in kidney transplant recipients did not significantly change their Cmin 
concentration. Further, there were no adverse events or acute rejection episodes 6 months after the 
conversion (12). In a larger study, Favi et al. compared 40 kidney transplant recipients randomized to 
once-daily everolimus with a target concentration of 2-6 ng/mL or twice-daily everolimus with a target 
concentration of 3-12 ng/mL. The investigators demonstrated equivalent renal function and acute 
rejection rates between the two groups, while the once-daily everolimus regimen demonstrated 
significantly improved cholesterol indices (13,14).  In combination with tacrolimus-based regimens, it 
has also demonstrated excellent efficacy in preventing acute rejection, with significantly reduced 
tacrolimus exposure (goal trough concentrations:   Everolimus 3-8 ng/mL) (6,7). 
With the availability of well-studied once-daily formulations of tacrolimus, the ability to achieve a true 
once-daily immunosuppressant regimen along with Everolimus and steroids may finally be achievable 
and have the potential to optimize immunosuppression safety and efficacy in kidney transplantation. 
2. 
Supporting data 
1. 24-month, multinational open-label, randomized trial 
1.  
 
Everolimus 1.5mg per 
day with reduced 
exposure CsA 
N=277 
Mycophenolic Acid 1.44 g 
per day with standard 
exposure CsA 
N=277 
Efficacy Failure  
70 (25.3) 
67 (24.2) 
     Treated Acute 
Rejection 
45 (16.2) 
47 (17) 
    Death 
7 (2.5) 
6 (2.2) 
    Graft loss 
12 (4.3) 
9 (3.2) 
 
 


Protocol Version 4.0 
11May2017 
 
Everolimus 1.5mg per 
day with reduced 
exposure CsA 
N=277 
Mycophenolic Acid 1.44 g 
per day with standard 
exposure CsA 
N=277 
Any adverse reaction  
271 (99) 
270 (99) 
Anemia 
70 (26) 
68 (25) 
Leukopenia 
8 (3) 
33 (12_ 
Diarrhea 
51 (19) 
54 (20) 
Nausea 
79 (29) 
85 (31) 
Infections and 
infestations 
169 (62) 
185 (68) 
    UTI 
60 (22) 
63 (23) 
    URI 
44 (16) 
49 (18) 
Blood creatinine 
increased 
48 (18) 
59 (22) 
Hyperkalemia 
49 (18) 
48 (18) 
Headache 
49 (18) 
40 (15) 
Hypertension 
81 (30) 
82 (30) 
 
2. Envarsus 
 
Envarsus XR +/- steroids, 
MMF/MPS or AZA 
N=162 
Tacrolimus IR +/- steroids, 
MMF/MPS or AZA 
N=162 
All infections 
46% 
48% 
 
     UTI 
10% 
14% 
     URI  
26% 
28% 
BK virus 
2% 
2% 
CMV 
2% 
1% 
Serious Infections 
8% 
9% 
NODAT 
10% 
11% 
Diarrhea 
14% 
9% 
Blood creatinine 
increased 
12% 
9% 
Headache 
9% 
7% 
Hypertension 
4% 
6% 
 
 
Envarsus XR +/- steroids, 
MMF/MPS or AZA 
N=162 
Tacrolimus IR +/- steroids, 
MMF/MPS or AZA 
N=162 
Treatment failure 
4 (2.5%) 
4 (2.5%) 
BPACR 
2 (1.2) 
2 (1.2) 
Graft failure 
0 
0 
Death 
2 (1.2) 
1 (0.6) 
eGFR at 12 months 
(ml/min) 
62 
61.4 
 


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3. In multiple chronic conditions it has been shown that once-daily 
regimens or dose reduction frequency through the selection of once-
daily medications has improved adherence.  Meta-analysis of 
medication adherence studies demonstrated that dose taking 
compliance decreases as medication regimens increase from QD, 
measured by MEMS (DOI: 10.1097/CRD.0b013e3180cabbe7). 
 
3. Study design 
1. Single-center, open-label, randomized comparative pilot trial. 
2.  There will be 20 subjects in each arm, with a total study size of 40 subjects. 
2. Allocation: Four random permuted-blocks of ten with equal arm allocation ratio will be used. 
Since no other stratification criteria are considered, larger block sizes will be appropriate. In 
each block, ten random numbers will be generated using SAS 9.4 with a range from zero to 
ninety nine. Even numbers will be assigned the intervention arm and odd numbers will be 
assigned the standard of care with resulting 1:1 allocation. 
3. Intervention Model: Parallel assignment 
4. Masking: This will be an open-label study as masking is not feasible given we are comparing 
twice-a-day to once-a-day regimen and its effect on adherence. 
5. Selection and enrollment of subjects 
1. Inclusion criteria 
1. Male or female adult (≥18 years old) with a history of solitary kidney 
transplant within 3 months (±2 months) of transplant. 
2. Patients must be capable of understanding the purposes and risks of 
the study and have the ability to give written informed consent and 
be willing to participate and comply with the study.  
3. Women of childbearing potential and sexually active males must be 
willing to use contraception, as indicated in Section 6 of the 
protocol.  Subjects who are not of reproductive potential (status 
post bilateral tubal ligation, bilateral oophorectomy, hysterectomy, 
or vasectomy), not sexually active, whose current partner(s) is not 
of reproductive potential, or whose sexual activity is exclusively 
homosexual are eligible without requiring the use of contraception. 
2. Exclusion criteria 
1. Patients will be excluded if they are pregnant or nursing females or 
males with a pregnant female partner 
2. Recipient of multiple organ transplant 
3. Recipient of a non-renal organ 
4. Proteinuria > 800 mg/24 hour 
5. eGFR < 30 ml/min 
6. WBC ≤ 2k/mm3 


Protocol Version 4.0 
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7. Plt ≤ 50k/mm3 
8. Triglycerides > 500 mg/dL 
9. HIV positive (HIV ab +) 
10. Unable to tolerate oral medications 
11. Use of another investigational product within thirty days prior to 
receiving study medication 
12. Acute graft rejection within the past month (Banff 1A or higher) or 
received an ABO incompatible donor organ. 
13. A condition or disorder that, in the opinion of the investigator, may 
adversely affect the outcome of the study or the safety of the 
subject 
2. Study enrollment procedures 
1. Subject Identification/Recruitment: Members of the research team will identify potentially 
eligible patients who have undergone solitary kidney transplantation in the past three 
months (±2 months). An initial evaluation of existing patient information may be performed 
to determine potential eligibility. This initial review may be performed prior to consent; 
however no protocol driven tests or procedures may be performed until signed informed 
consent has been obtained. 
2. Informed Consent: A qualified member of the research team, Human Subjects Protection 
Trained, will approach and explain the study and offer participation.  The study will be 
explained in a manner consistent with the level of education pertaining to the 
patient.  Enrollment procedure will involve face-to-face meetings of the patients to inform 
and review informed consent documentation.  The participant will sign the consent form 
prior to evaluation of adherence measures.  Copies of the informed consent will be 
appropriately placed in the corresponding chart and the patient will be provided with a copy 
of the signed consent form.  Non-consenting individuals will also be ensured that no penalty 
will arise due to denying participation.  Those who choose to participate in the trial will be 
informed that at any point they reserve the right to leave the study.   
3. Enrollment: Patients who give informed consent to study participation will go on to 
complete baseline procedures necessary to determine eligibility for randomization. Once 
deemed eligible for the study according to the inclusion/exclusion criteria, the patient will 
be enrolled as study participant.  Information to be entered upon enrollment includes 
demographic information and date of transplant surgery. Enrolled subjects will be 
randomized to one of the treatment arms in the applicable cohort.  
4. Study interventions 
1. Interventions, administration, and duration 
1. For the first three months (±2 months) post-transplant, the pool of patients from which 
subject of this study will be recruited will receive the current standard of care.  Standard of 
care is described as a regimen of tacrolimus IR BID (5-12ng/mL) + MMF 1g BID + prednisone 
QD Three months (±2 months) post-transplant and at the time of recruitment, they are 
randomized to one of the two arms to either receive a complete once-a-day regimen or to 
receive twice-daily regimen. 
2. Post-randomization, subjects will be converted to one of the two arms, as shown below, and 
followed for a total period of six months (primary endpoint), or until a terminal end point is 
reached. 
1. Arm 1: Control-- twice-daily regimen of Envarsus QD (5 - 12ng/mL) + MMF (goal dose 1g 
BID) + prednisone QD for 6 months 


Protocol Version 4.0 
11May2017 
2. Arm 2: Intervention-- once-a-day regimen of Envarsus QD (2- 5ng/mL) + everolimus QD 
(3-8ng/mL) + prednisone QD for 6 months 
1. Envarsus will be supplied for both Arms from Veloxis 
Pharmaceuticals 
2. Adherence assessment 
1. Adherence to the study intervention will be assessed at all study visits noted on the 
Schedule of Evaluations (Section 5.1), using the eight point Morisky Medication Adherence 
Scale (MMAS-8) (17). 
5. 
Clinical and laboratory evaluations 
1. Schedule of evaluations 
 
Data Collection Schedule 
Report Form 
Baseline Days Post-Conversion 
7±214±3 30±5 60±790±7120±7150±7 180±7
Informed Consent Obtained 
X 
Randomization 
X 
Review of Inclusion and Exclusion Criteria 
X 
Medical History 
X 
Kidney Transplant Recipient 
X 
Vital Signs 
X 
X 
X 
Review of Medications and Dosing 
X 
Clinical 
assessment* 
Adverse events, dosage and 
adherence, rejection, 
infection, hospitalization 
 
 
 
X 
X 
X 
X 
X 
X 
MMAS-8, MMSE Scale, and 
SF36 (15,16,20) 
X 
X 
Laboratory 
Assessments 
CBC and Chem-71 
X* 
O 
O 
O 
O 
O 
O 
O 
X* 
Everolimus CO2 
X* X* 
X* 
X* 
X 
X* 
X* 
X* 
Tacrolimus C02 
X* 
X* X* 
X* 
X* 
X 
X* 
X* 
X* 
End of Study 
x 
X=required; 0=optional: data will be collected if performed as standard of care; *=not current 
standard of care 
Footnotes: 
1. Includes sodium, potassium, chloride, CO2, BUN, SrCr, glucose, calcium, WBC, HgB, Hct, platelets 
2. Tacrolimus and Everolimus concentrations will be 12- or 24-hour levels , drawn in the morning of 
each assessment 
 
2. 
Timing of evaluation 
1. Pre-Randomization Evaluations  
Baseline 


Protocol Version 4.0 
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Evaluations listed under the baseline visit may be performed up to 14 days prior 
to randomization. Once the subject has been successfully screened and 
accepted for randomization, randomization must be completed within 48 hours.   
 
2. Intervention and Evaluations 
 
Once the subject has been successfully randomized, the patients will be directed 
to the hospital pharmacy to pick up study medications.  Study evaluations must 
take place within the time window indicated on the Schedule of Evaluations 
(Section 5.1) 
3. 
Clinical and Laboratory Assessments: 
1. Laboratory evaluations will be performed at certified laboratories 
according to the study schedule. Required tests are specified in the 
Schedule of Evaluations (Section 5.1) 
2. All subjects will undergo clinical assessment by the investigator or the 
investigator’s designee in the manner and at the times specified in the 
Schedule of Evaluations (Section 5.1) 
1. Adverse events will be determined and defined according to 
Section 8 of the protocol 
2. Doses will be recorded of all immunosuppressants. The adjuvant 
immunosuppressant (mycophenolate or everolimus) will be 
counted and compared to the amount expected to be 
remaining based on the prescribed amount. An MPR will be 
calculated as follows: (Total Days’ Supply in Period/(Last Fill 
Date - First Fill Date + Last Fill Days’ Supply)) 
3. Rejection and infection events will be recorded, as defined in 
Section 5.4) 
4. Hospitalization events will be determined by questioning the 
subject and review of hospital admissions in the EHR. 
3. Graft function assessment will be monitored at regular intervals using 
the 4-variable abbreviated MDRD equation. It will be monitored at 
baseline and the end of the study for study outcomes and any time 
points dictated by standard of care follow-up in between those time 
points. 
4. 
Definitions 
1. Acute rejection is defined as a renal allograft biopsy showing grade 1A 
or greater, by the 1997 Banff Criteria and all updates since then. 
Biopsies will be performed when clinically warranted, based on changes 
in allograft function. 
2. Rejection reversal is defined as return of serum creatinine to within 10% 
of baseline and/or histologic clearance by Banff Criteria 
3. Resistant acute rejection is defined as no clinical or histologic 
improvement by renal biopsy within 7-10 days of initiation of 
treatment. 
4. Recurrent acute rejection is defined as rejection recurring more than 
two weeks after documented rejection reversal. 
5. Opportunistic Infections will be defined according the American Society 
of Transplant Recommendations for Screening, Monitoring, and 


Protocol Version 4.0 
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Reporting of Infectious Complications in Immunosuppression Trials in 
Recipients of Organ Transplantation (Appendix C1). 
5. 
Treatment of Acute rejection: 
1. Acute rejection will be treated per institutional protocol, listed in 
Appendix C2. 
6. 
Acceptable contraception methods 
Option 1 (monotherapy methods): 
1. Intrauterine devices (IUDs) 
2. Tubal sterilization 
3. Patient’s partner had a vasectomy 
 
Option 2 (Choice one from category A AND one from category B): 
1. Category A: 
a. Estrogen and progesterone 
i. Oral contraceptive pill 
ii. Transdermal patch 
iii. Vaginal ring 
b. Progesterone only 
i. Injection 
ii. Implant 
c. Barrier method 
i. Diaphragm with spermicide 
ii. Cervical cap with spermicide 
iii. Contraceptive sponge 
2. Category B: 
a. Male condom 
b. Female condom 
c. Diaphragm with spermicide (for use with hormone therapy) 
d. Cervical cap with spermicide (for use with hormone therapy) 
e. Contraceptive sponge (for use with hormone therapy) 
 
 
7. 
Intervention Discontinuation Evaluations: At the scheduled time of intervention discontinuation 
(EOT, last date of study), the following evaluations must be completed: vital signs, clinical assessment, 
CBC, CHEM-7, Everolimus CO, Tacrolimus CO.  In case of subject withdrawal from study, the patient will 
return to standard of care medications and request to continue with final assessment using MMAS-8, 
MMSE Scale and SF-36 will be discussed with a qualified team member.     
8. 
Adverse Events 
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. The occurrence of adverse events should be sought by non-
directive questioning of the subject at each visit during the study. Adverse events also may be 
detected when they are volunteered by the subject during or between visits or through physical 
examination, laboratory test, or other assessments. Abnormal laboratory values or test results 
constitute adverse events only if they fulfill at least one of the following criteria: 


Protocol Version 4.0 
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1. they induce clinical signs or symptoms, 
2. they are considered clinically significant, 
3. they require therapy. 
 
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in subject with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
subject and identifying adverse events. Adverse events should be recorded in the Adverse 
Events CRF with them accompanied by the following information: 
1. severity of adverse events will be determined using the grading system outlined in the 
NCI Common Terminology Criteria for Adverse Events Version 4.03 (CTCAE), as it best 
fits the diagnostic terminology used in naming the event at the site clinical level. 
2. possibility of relationship to the study treatment (no/yes) 
3. its duration (start and end dates) or if the event is ongoing an outcome of not recovered 
or not resolved should be reported. 
4. whether it constitutes a serious adverse event (SAE), if so report date should be 
provided 
5. action taken regarding study treatment 
6. whether other medication or therapies have been taken (concomitant medication/non-
drug therapy) 
7. its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown) 
An SAE is any adverse event which meets any one of the following criteria: 
• 
An SAE is any adverse event that is life-threatening or that results in any of the following 
outcomes: death; in-patient hospitalization or prolongation of existing hospitalization; 
persistent or significant disability or incapacity; or a congenital anomaly or birth defect. 
Any other medical event that, in the medical judgment of the Principal Investigator, may 
jeopardize the subject or may require medical or surgical intervention to prevent one of 
the outcomes listed above is also considered an SAE.  A planned medical or surgical 
procedure is not, in itself, an SAE.  Also specifically excluded from this definition of SAE 
is any event judged by the Principal Investigator to represent progression of the 
malignancy under study, unless it results in death within the SAE Reporting Period. 
• 
Reporting of Serious Adverse Events.  Within 24 hours of first awareness of the event 
(immediately if the event is fatal or life-threatening), certain SAEs will be reported to 
Veloxis by ("SAEs," as defined below) that occur during the SAE reporting period (as 
defined below) in a Study subject assigned to receive the Veloxis Product.  The subset of 
SAEs to be reported for this Study are those that fit into either of the following 
categories: (1) a death, regardless of whether it is considered related to treatment with 
the Veloxis Product, or (2) an SAE that is assessed by the Principal Investigator as both 


Protocol Version 4.0 
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related to treatment with the Veloxis Product and unexpected for that Product.  An 
event should be considered "related" to the Veloxis Product if a relationship is at least a 
reasonable possibility, and "unexpectedness" should be based upon current Product 
labeling.  Principal Investigator will report such SAEs using either Institution's Internal 
Adverse Event Report form or an FDA MEDWATCH form together with the Reportable 
Adverse Event Fax Cover Sheet provided by Veloxis. SAEs should be reported as soon as 
they are determined to meet the definition, even if complete information is not yet 
available. 
• 
SAE Reporting Period.  The SAEs that are subject to this reporting provision are those 
that occur from after the first dose of the Veloxis Product through 72 hours after 
discontinuation of the Veloxis Product.  In addition, any and all related SAEs that occur 
after the reporting period of which the Principal Investigator becomes aware should also 
be reported. 
• 
 
 
AEs and SAEs will be reported in accordance with the FDA Guidelines for Post-Marketing 
Reporting of Adverse Events 21 CRF 314.80 and 21 CRF 600.80 
http://www.fda.gov/medwatch/report/regs.htm.  Any serious adverse event or a non-serious 
adverse event that is related to the study and unexpected will be reported to the FDA, per 
reporting guidelines, as soon as possible, but no later than 15 working days.. Further, all serious 
adverse events that are related to the study and are unexpected must be reported to The 
Medical University of South Carolina IRB within 10 days per The Medical University of South 
Carolina IRB Unanticipated Problems and Adverse Events Policy and Procedures reporting 
guidelines.   
 
9. 
Criteria for intervention discontinuation 
1. The intervention will be withheld/discontinued for AE of grade 3 or higher or if requested by the 
study participant. 
2. Additionally, the intervention will be discontinued if the subject meets criteria for the following 
reasons: 
1. Pregnancy:  If a woman becomes pregnant or a male’s female partner becomes pregnant 
while on-study, the subject will be required to instruct investigators immediately. 
2. Loss of graft:  Defined as death or need for retransplant. Patients will be deemed a 
treatment failure and the intervention will be discontinued.\ 
10. 
Statistical considerations 
1. Outcomes 
1. Primary outcome- Treatment efficacy, defined difference in change from baseline to six 
month measure by MMAS-8 in both arms. 
2. Secondary objectives 
1. Secondary outcome- Safety outcomes of treatment failure rate, defined as acute 
allograft rejection with a Banff grade 1A or higher, graft loss, or death at one year post-
conversion in both arms. 


Protocol Version 4.0 
11May2017 
2. Sample size estimation for the primary outcome 
1. No formal power analysis conducted since this is a pilot study. However, the sample size 
proposed (n=40) would be able to observe a mean difference between groups in the change 
of MMAS-8 scores of 2 ± 2 points (95% CI 0.73,3.27) with 87% power. Additionally, a mean 
difference between groups in the change in the Memphis Side Effect Scale (MSES) of 5 ± 5 
points (95% CI 1.83,8.17) would have 87% power in the current sample size. Given the 
average MSES score of 25 points in kidney transplant patients within 2 years of transplant, 
this appears to be a feasible outcome (11). In order to demonstrate noninferiority in 
treatment failure, it would require 400 subjects (200 in each group) to have 80% power, 
estimating a treatment failure rate of 20% and an acceptable difference of 10%. We expect 
that 70% of those approached meeting study inclusion/exclusion criteria will agree to 
participate and that 85% of those that consent and are enrolled in the study will complete 
all visits. If the 95% CIs for the actual enrollment and completion proportions are outside of 
these thresholds, then feasibility will not be met. If the 95% CIs encompass these expected 
values, then feasibility will be met. 
3. Missing data and imputation methods 
1. Under the intention-to-treat principle, all subjects are included in the analysis. Extensive 
efforts will be made to keep all missing data to a minimum and minimize loss to follow-up 
(LTFU).  However, it is likely that some missing data may occur. 
 
11. 
Human subjects 
1. 
Institutional review board (IRB) review and informed consent 
1. This protocol, the ICF, and any subsequent modifications must be reviewed and 
approved by the IRB. A signed and dated ICF must be obtained from the subject as 
defined in 21CFR50.3.  The ICF must also be signed and dated by a member of the study 
staff qualified to be delegated the authority to obtain informed consent.  A copy of the 
ICF must be given to the subject and the consent process must be documented in the 
subject’s medical record.  The PI or delegated sub-Investigator is responsible for 
ensuring that informed consent is obtained from each patient prior to conducting any 
study-related activities.  
2. No deviations from or changes to the study protocol should be initiated 
except when necessary to eliminate immediate hazard to the 
subject.  However, the IRB and Study Sponsor must be informed of this 
as soon as possible thereafter.  It is the PI’s responsibility to report SAEs 
occurring during the study to the IRB, as required and as soon as 
possible.   
2. Study modification/discontinuation 
1. The study may be modified or discontinued at any time by the IRB, the 
sponsor, the OHRP, the FDA, or other government agencies as part of 
their duties to ensure that research subjects are protected. 
2. After 20 subjects have been randomized and completed follow-up, 
efficacy and safety endpoints will be reviewed by a blinded Safety 
Monitor to identify if the risk profile is as expected. If significantly 
increased risk is identified in either or both arms of the study, sufficient 
to increase the risk over the potential benefit of the study, the study will 
be discontinued. Examples are included below: 


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1. A 6-month rejection rate difference between arms > 20%, or if > 
40% in either arm 
2.  A difference in grade 3 or higher infections (based on CTCAE) 
between arms of > 20% 
3. A graft loss difference between arms > 20% 
12. 
Publication of research findings 
1. Publication of the results of this trial will be reviewed and approved by all 
coinvestigators.  Final results will be submitted to ClinicalTrials.gov.  Any presentation, 
abstract, or manuscript will be made available for review by the sponsor prior to 
submission. 
 
 


Protocol Version 4.0 
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13. References 
 
1. Denhaerynck K, Dobbels F, Cleemput, et.al. Prevalence, consequences, and determinants of 
nonadherence in adult renal transplant patients: a literature review.  Trans Int.  2005; 18: 1121-
33. 
2. Chisholm MA, Vollenweider LJ, Mulloy LL, et.al. Renal transplant patient compliance with free 
immunosuppressive medications.  Transplantation. 2000; 70: 1240. 
3. Fine RN, Becker Y, De Geest S, et.al. Nonadherence consensus conference summary report. Am J 
Transplant. 2009; 9: 35-41. 
4. Muduma G, Shupo FC, Dam S, et.al. Patient survey to identify reasons for non-adherence and 
elicitation of quality of life concepts associated with immunosuppressant therapy in kidney 
transplant recipients. Patient Preference and Adherence. 2016; 10: 27-36. 
5. Budde K, Bunnapradist S, Grinyo JM, et.al. 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; XX: 1-11. 
6. Chan L, Greenstein S, Hardy M, et al. Multicenter, randomized study of the use of everolimus 
with tacrolimus after renal transplantation demonstrates its effectiveness. Transplantation. 
2008; 85: 821-6. 
7. Langer RM, Hene R, Vitko S, et al. Everolimus plus early tacrolimus minimization: a phase III, 
randomized, open-label, multicenter trial in renal transplantation. Trans Int. 2012; 25: 592-602. 
8. 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  Trans. 
2013; 13: 760-9. 
9. Kahan BD, Wong RL, Carter C, et al. A phase I study of a 4-week course of SDZ-RAD (RAD) 
quiescent cyclosporine-prednisone-treated renal transplant recipients. Transplantation. 1999; 
68: 1100-6. 
10. Zortress [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation, 2015. 
11. Kahan BD, Wong RL, Carter C, et.al. A phase I study of a 4-week course of SDZ-RAD (RAD) 
quiescent cyclosporine-prednisone-treated renal transplant recipients. Transplantation. 1999; 
68: 1100. 
12. Carmellini M, Collini A, Ruggieri G, Bernini M. Conversion of stable kidney transplant recipients 
from a twice- daily to once-daily everolimus regimen. Transplant Proc. 2010; 42: 1312-3. 
13. Corbetta G, Ponticelli C. Once-a-day administration of everolimus, cyclosporine, and steroid 
after renal transplantation: a review of the rationale. Transplant Proc. 2010; 42: 1303-7. 
14. Favi E, Spagnoletti G, Gargiulo A, et.al. Once daily everolimus is safe and effective in de novo 
renal transplant recipients: six-month results of a pilot study. Transplant Proc. 2010; 42: 1308-
11. 
15. Winsett RP, Stratta RJ, Alloway R, Wicks MN, Hathaway DK. Immunosuppressant side effect 
profile does not differ between organ transplant types. Clin Transplantation. 2001; 15(s6): 46-
50. 
16. Hathaway D, Winsett R, Prendergast M, Subaiya I. The first report from the patient outcomes 
registry for transplant effects on life (PORTEL): differences in side-effects and quality of life by 
organ type, time since transplant and immunosuppressive regimens. Clin Transplant. 
2003;17(3):183–94. 


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17. Morisky DE, Green LW, Levine DM.  Concurrent and Predictive Validity of a Self-Reported 
Measure of Medication Adherence and Long-Term Predictive Validity of Blood Pressure 
Control.  Med Care 1986; 24:67-74. 
18. "Adherence Enhancement for Renal Transplant Patients." Home. N.p., n.d. Web. 14 July 2016.  
19. “SRTR: Medical University of South Carolina: A. Program Summary. Transplant (organ): 
Kidney”  N.p., n.d. Web. 14 July 2016. 
 
14. 
Appendix A 
15. 
Appendix B 
 
 
 


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Appendix A: Scientific Registry of Transplant Recipients (15) 
Program Summary: MUSC
 
 
 


Protocol Version 4.0 
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Appendix B1: Morisky Medication Adherence (MMAS) Scale 
 
MMAS-8 
Points
Do you sometimes forget to take your pills? 
1 
People sometimes miss taking their medications for reasons other than forgetting. Thinking 
over the past two weeks, were there any days when you did not take your medicine? 
1 
Have you ever cut back or stopped taking your medicine without telling your doctor because 
you felt worse when you took it? 
1 
When you travel or leave home, do you sometimes forget to bring along your medicine 
1 
Did you take all your medicine yesterday? 
1 
When you feel like your symptoms are under control, do you sometimes stop taking your 
medicine? 
1 
Taking medicine every day is a real inconvenience for some people. Do you ever feel hassled 
about sticking to your treatment plan? 
1 
How often do you have difficulty remembering to take all of your medicine? 
A. 
Never/rarely 
B. 
Once in a while 
C. 
Sometimes 
D. 
Usually 
E. 
All the time 
0-5 
 
Adherence 
MMAS-8 Score
High Adherence 
0 
Medium Adherence 1-2 
Low Adherence 
3-8 
 
 
 
 


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Appendix B2: Memphis Medication Side Effect (MMSE) Scale  
The following questions describe problems you might be having because of the transplant or the 
medicine you are taking. For each problem, you will be asked how frequently you experience it (the 
first row) and how troubling it is (the second row).  Please answer every question. 
Not at all Very little
Sometimes or 
Moderately troubling
Often or 
Very troubling 
All the time 
or 
Extremely troubling 
Enlarged gums 
Do you have this problem?□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Increased hunger 
Do you have this problem?□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Staying asleep 
Do you have this problem?□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Weight gain 
Do you have this problem?□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Increased hair growth 
Do you have this problem?□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Infections 
Do you have this problem?□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Trembling hands 
Do you have this problem?□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
 
High blood pressure 


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Do you have this problem?□ □□ □ □ 
How troubling is it? 
□ □□ □ □ 
Easy bruising 
Do you have this problem?□ □□ □ □ 
How troubling is it? 
□ □□ □ □ 
Loss of interest in sex 
Do you have this problem?□ □□ □ □ 
How troubling is it? 
□ □□ □ □ 
Sexual performance 
Do you have this problem?□ □□ □ □ 
How troubling is it? 
□ □□ □ □ 
Diabetes 
Do you have this problem?□ □□ □ □ 
How troubling is it? 
□ □□ □ □ 
Hair Loss 
Do you have this problem?□ □□ □ □ 
How troubling is it? 
□ □□ □ □ 
 
Not at all Very little
Sometimes or 
Moderately troubling
Often or 
Very troubling 
All the time or 
Extremely troubling 
Stomach pain 
Do you have this problem?□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Nausea 
Do you have this problem?□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Diarrhea 
Do you have this problem?□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 


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Vomiting 
Do you have this problem?□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Stomach gas 
Do you have this problem?□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Indigestion 
Do you have this problem?□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Mood Changes 
Do you have this problem?□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Depression 
Do you have this problem?□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Nervousness or anxiety 
Do you have this problem?□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
 
Irritability 
Do you have this problem?□ □□ □ □ 
How troubling is it? 
□ □□ □ □ 
Anger 
Do you have this problem?□ □□ □ □ 
How troubling is it? 
□ □□ □ □ 
Keeping a positive attitude 
Do you have this problem?□ □□ □ □ 
How troubling is it? 
□ □□ □ □ 
 


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Not at 
all 
Very 
little 
Sometimes or 
Moderately 
troubling 
Often or 
Very 
troubling 
All the time 
or 
Extremely 
troubling 
Feelings of uselessness 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Being worried 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Worthlessness 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Hopelessness 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Ability to concentrate 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Completing daily errands 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Participating in social 
activities 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Doing housework 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 


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Doing yardwork 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
 
How troubling is it? 
□ □□ □ □ 
Performing my job 
Do you have this problem? 
□ □□ □ □ 
How troubling is it? 
□ □□ □ □ 
Participating in physical activities
Do you have this problem? 
□ □□ □ □ 
How troubling is it? 
□ □□ □ □ 
Participating in leisure pastimes 
Do you have this problem? 
□ □□ □ □ 
How troubling is it? 
□ □□ □ □ 
Driving 
Do you have this problem? 
□ □□ □ □ 
How troubling is it? 
□ □□ □ □ 
 
 
Not at allVery little
Sometimes or 
Moderately troubling
Often 
or Very 
troubling
All the time or 
Extremely troubling
Being independent 
Do you have this problem? □ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Ability to travel on vacations
Do you have this problem? □ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Reading 
Do you have this problem? □ 
□ 
□ 
□ 
□ 


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How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Decreased muscle strength 
Do you have this problem? □ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Climbing stairs 
Do you have this problem? □ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Walking 
Do you have this problem? □ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Bone pain 
Do you have this problem? □ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Stiff joints 
Do you have this problem? □ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Foot pain 
Do you have this problem? □ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Hip pain 
Do you have this problem? □ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
 
 
 


Protocol Version 4.0 
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Appendix B3: RAND 36-Item Health Survey 1.0 Questionnaire Items 
SF-36 Resources 
• 
Terms and Conditions for Using the SF-36 
• 
MOS 36-Item Short Form Survey Instrument (SF-36) (English PDF) 
• 
MOS 36-Item Short Form Survey Instrument (SF-36) (Arabic PDF) 
• 
Scoring Instructions for MOS 36-Item Short Form Survey Instrument (SF-36)  
Choose one option for each questionnaire item. 
1. In general, would you say your health is: 
1 - Excellent  
2 - Very good  
3 - Good  
4 - Fair  
5 - Poor  
2. Compared to one year ago, how would you rate your health in general now? 
1 - Much better now than one year ago  
2 - Somewhat better now than one year ago  
3 - About the same  
4 - Somewhat worse now than one year ago  
5 - Much worse now than one year ago  
The following items are about activities you might do during a typical day. Does your health now limit 
you in these activities? If so, how much? 


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Yes, limited 
a lot  
Yes, limited a 
little  
No, not 
limited at all  
3. Vigorous activities, such as running, lifting heavy objects, 
participating in strenuous sports 
1  
2  
3  
4. Moderate activities, such as moving a table, pushing a 
vacuum cleaner, bowling, or playing golf 
1  
2  
3  
5. Lifting or carrying groceries 
1  
2  
3  
6. Climbing several flights of stairs 
1  
2  
3  
7. Climbing one flight of stairs 
1  
2  
3  
8. Bending, kneeling, or stooping 
1  
2  
3  
9. Walking more than a mile 
1  
2  
3  
10. Walking several blocks 
1  
2  
3  
11. Walking one block 
1  
2  
3  
12. Bathing or dressing yourself 
1  
2  
3  
During the past 4 weeks, have you had any of the following problems with your work or other regular 
daily activities as a result of your physical health? 
  
Yes  No  
13. Cut down the amount of time you spent on work or other activities 
1 
2 
14. Accomplished less than you would like 
1 
2 
15. Were limited in the kind of work or other activities 
1 
2 
16. Had difficulty performing the work or other activities (for example, it took extra effort) 
1 
2 
During the past 4 weeks, have you had any of the following problems with your work or other regular 
daily activities as a result of any emotional problems (such as feeling depressed or anxious)? 


Protocol Version 4.0 
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Yes  No  
17. Cut down the amount of time you spent on work or other activities 
1 
2 
18. Accomplished less than you would like 
1 
2 
19. Didn't do work or other activities as carefully as usual 
1 
2 
20. During the past 4 weeks, to what extent has your physical health or emotional problems 
interfered with your normal social activities with family, friends, neighbors, or groups? 
1 - Not at all  
2 - Slightly  
3 - Moderately  
4 - Quite a bit  
5 - Extremely  
21. How much bodily pain have you had during the past 4 weeks? 
1 - None  
2 - Very mild  
3 - Mild  
4 - Moderate  
5 - Severe  
6 - Very severe  
22. During the past 4 weeks, how much did pain interfere with your normal work (including both work 
outside the home and housework)? 
1 - Not at all  
2 - A little bit  


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3 - Moderately  
4 - Quite a bit  
5 - Extremely  
These questions are about how you feel and how things have been with you during the past 4 weeks. 
For each question, please give the one answer that comes closest to the way you have been feeling. 
How much of the time during the past 4 weeks... 
  
All of 
the time 
Most of 
the time  
A good bit 
of the time  
Some of 
the time  
A little of 
the time  
None of 
the time  
23. Did you feel full of pep? 
1  
2  
3  
4  
5  
6  
24. Have you been a very nervous 
person? 
1  
2  
3  
4  
5  
6  
25. Have you felt so down in the 
dumps that nothing could cheer you 
up? 
1  
2  
3  
4  
5  
6  
26. Have you felt calm and peaceful? 
1  
2  
3  
4  
5  
6  
27. Did you have a lot of energy? 
1  
2  
3  
4  
5  
6  
28. Have you felt downhearted and 
blue? 
1  
2  
3  
4  
5  
6  
29. Did you feel worn out? 
1  
2  
3  
4  
5  
6  
30. Have you been a happy person? 
1  
2  
3  
4  
5  
6  
31. Did you feel tired? 
1  
2  
3  
4  
5  
6  
32. During the past 4 weeks, how much of the time has your physical health or emotional problems 
interfered with your social activities (like visiting with friends, relatives, etc.)? 
1 - All of the time  
2 - Most of the time  


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3 - Some of the time  
4 - A little of the time  
5 - None of the time  
How TRUE or FALSE is each of the following statements for you. 
  
Definitely 
true  
Mostly 
true  
Don't 
know  
Mostly 
false  
Definitely 
false  
33. I seem to get sick a little easier than 
other people 
1  
2  
3  
4  
5  
34. I am as healthy as anybody I know 
1  
2  
3  
4  
5  
35. I expect my health to get worse 
1  
2  
3  
4  
5  
36. My health is excellent 
1  
2  
3  
4  
5  
 
 


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Appendix C1: Definitions for Opportunistic Infections 
I. Cytomegalovirus: 
A. Active Infection: 
 
1. Evidence of active viral replication (positive CMV DNA PCR, evidence of viral infection by on  
 
 
histologic samples) 
B. CMV Disease 
 
1. Evidence of Active Infection with attributable symptoms 
 
 
a. CMV Syndrome: one or more of the following: 
 
 
 
1. Fever > 38° C for at least 2 days 
 
 
 
2. New or increased malaise 
 
 
 
3. Leukopenia 
 
 
 
4. ≥ 5% atypical lymphocytes 
 
 
 
5. Thrombocytopenia 
 
 
 
6. Elevation of hepatic transaminases to 2x ULN plus evidence of viral  
replication 
 
 
b. CMV Tissue-invasive disease: 
 
 
 
1. Evidence of organ dysfunction in the absence of other documented cause 
 
 
 
 
AND 
 
 
 
 
Evidence of CMV in blood by viral culture or CMV DNA PCR 
II.  BK Virus: 
A. BK Viremia: 
1. Quantitative BK viral DNA load in blood above the detection threshold for the laboratory  
assay on two separate occasions. 
B. BK Virus Associated Nephropathy (BKVAN) 
 
1. Renal biopsy associated  with BKVAN per current Banff criteria. 
III. Other Opportunistic Infections: 
 
A. For definitions of herpes simplex, varicella zoster, Epstein Barr Virus, parvovirus and adenovirus, see American 
Journal of Transplantation 2006; 6: 262–274 
 


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Appendix C2: Treatment of Acute Cellular Rejection 
Treatment of Acute Cellular Rejection 
 
Banff 1997 Diagnostic Categories for Acute Cellular Rejection 
Per Banff 1997 diagnostic categories, acute/active cellular rejection (T-cell mediated rejection) histopathological findings include: 
IA:  Cases with significant interstitial infiltration (>25% of parenchyma affected) and foci of moderate tubulitis (>4 mononuclear 
cells/tubular cross section or group of 10 tubular cells)  
IB:  Cases with significant interstitial infiltration (>25% of parenchyma affected) and foci of severe tubulitis (>10 mononuclear 
cells/tubular cross-section or group of 10 tubular cells) 
IIA: Cases with mild to moderate intimal arteritis (v1)  
IIB: Cases with severe intimal arteritis comprising >25% of the luminal area (v2)  
III:  Cases with ‘transmural’ arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells with accompanying 
lymphocytic inflammation (v3) 
 
Biopsy Results* 
Treatment 
Other Requirements 
Follow-Up 
 
 
 
 
Borderline rejection  
Methylprednisolone 250 mg 
every 24 hours  
for 3 doses 
 Increase level of maintenance 
immunosuppression (maximize 
MMF dosing, increase tacrolimus 
levels to upper limit of target range. 
 Assess for non-adherence. 
 If diabetic, ensure patient is 
monitoring blood sugars frequently. 
 Consider re-biopsy in 7 
days if inadequate 
response to therapy 
 Patient should have labs 
weekly 
 Patient should be seen in 
clinic with labs one week 
after completing treatment 
 
 
 
 
Banff ’97 1A 
cellular rejection 
Methylprednisolone 500 mg 
every 24 hours  
for 3 doses 
 Increase level of maintenance 
immunosuppression (maximize 
MMF dosing, increase tacrolimus 
levels to upper limit of target range. 
 Assess for non-adherence. 
 If diabetic, ensure patient is 
monitoring blood sugars frequently. 
 Consider re-biopsy in 7 
days if inadequate 
response to therapy 
 Patient should have labs 
weekly 
 Patient should be seen in 
clinic with labs one week 
after completing treatment 
 
 
 
 
Banff ’97 1B or 
greater rejection 
 
(with viable tissue 
and ability to obtain 
maintenance 
immunosuppressants 
in order to be 
adherent going 
forward) 
Thymoglobulin® 1.5 
mg/kg/day for 7 doses  
(10 mg/kg) or 7 days of total 
suppression  
Pre-medicate patient with 
methylprednisolone 500 mg 
IV x 1 prior to first dose of 
Thymoglobulin® in addition to 
acetaminophen and 
diphenhydramine. 
May consider giving 
additional doses of 
methylprednisolone 250 mg 
IV prior to subsequent doses. 
 
*Always consider patient’s 
prior Thymoglobulin 
exposure when determining 
treatment 
 Must have daily CBCs for 
Thymoglobulin® dosing.  If WBC 
2,000-3,000 or PLT 50,000-75,000, 
give half dose.  If WBC <2,000 or 
PLT <50,000, hold dose.   
 Increase level of maintenance 
immunosuppression (maximize 
MMF dosing, increase tacrolimus 
levels to upper limit of target range 
(tacrolimus levels must be > 8 
ng/mL at the time of last 
Thymoglobulin® dose). 
 Assess for non-adherence. 
 Patient must be restarted on anti-
microbial prophylaxis including 
CMV prophylaxis, PCP 
prophylaxis, and fungal 
prophylaxis (follow initial protocols 
with regards to dosing and 
duration). 
 Consider re-biopsy in 7 
days if inadequate 
response to therapy 
 Patient should have labs 
weekly 
 Patient should be seen in 
clinic with labs one week 
after completing treatment 
 
 
 
 
Features of AMR 
and cellular 
rejection 
Please refer to AMR protocol for details. 
 
 
 
 
Calcineurin 
inhibitor toxicity 
with no evidence of 
rejection 
(vacuolization of 
tubules, arteriolar 
hyalinosis) 
Consider patient’s candidacy for mTOR conversion.   
Refer to mTOR conversion/CNI minimization protocol for details. 
 
* Note:  Biopsy should be performed within 48 hours of suspicion for acute rejection