Conditions: End Stage Renal Disease Rejection of Renal Transplant
Keywords: immunosuppression
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 29
Healthy volunteers: no

Brief summary:
The overall aim of the study is to prospectively investigate the impact of two maintenance calcineurin inhibitor immunosuppressive regimens: once-daily extended release tacrolimus and twice-daily tacrolimus on subpopulations of T and B cells and alloreactive T cells as well as on renal allograft function.

Detailed description:
Kidney transplantation is the treatment of choice for most patients with end-stage renal disease. Lifelong immunosuppressive therapies are required to prevent organ rejection. However, long term exposure to immunosuppressive therapy after kidney transplantation can place patients at risk for multiple adverse events. The optimal immunosuppressive therapy is not well established. Tacrolimus, a calcineurin inhibitor (CNI) is highly effective in preventing acute rejection after organ transplantation (2). It is used as part of the immunosuppression regimen for the majority of kidney and liver transplant recipients (3). However, treatment with current formulation of Tacrolimus generates high peaks and low troughs in drug concentrations in the blood. It is known that high exposure to CNI is associated with renal toxicities and adverse events (4). New once-daily dosage formulations are now developed with the hope of minimizing side effects while maintaining excellent outcomes (5-8).

LCP-Tacro (Envarsus® XR, Veloxis Pharmaceuticals), a new once-daily formulation of tacrolimus, was approved by the FDA in 2015 for conversion from twice-daily tacrolimus in kidney transplant recipients. It is a prolonged-release tacrolimus formulation, utilizing a MeltDose drug delivery technology designed to improve the bioavailability of drugs with low water solubility (1). Recent clinical data demonstrated that once-daily LCP-Tacro has improved pharmacokinetic bioavailability, rapid achievement of therapeutic trough levels, less fluctuation and swing in whole blood concentration, non-inferior efficacy and similar safety, with lower tacrolimus dose than other tacrolimus formulations.

The target population is adult recipients of immediately functioning living and deceased donor renal allografts. Immediate function will be defined as the absence of the need for hemodialysis in the first week following renal transplantation.

Prospective randomized single center open label study of 2 groups of kidney transplant patients

* Group 1 : standard of care (SOC) control group will receive tacrolimus twice-daily (n=25)
* Group 2 : LCP-Tacro (Envarsus® XR) group will receive LCPT tablets once daily (n=25)

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Tacrolimus intervention 2: Tacrolimus Extended Release Oral Tablet [Envarsus]
Intervention descriptions: intervention 1: immunosuppressive agent tacrolimus, given twice-daily intervention 2: immunosuppressive agent extended-release tacrolimus, given once daily

Protocol document:
Prot_SAP_000.pdf: 
Northwestern University Feinberg School of Medicine: Extended-Release Tacrolimus Vs. Twice-Daily Tacrolimus
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PROTOCOL TITLE:  
ONCE-DAILY EXTENDED-RELEASE TACROLIMUS VS. TWICE-DAILY 
TACROLIMUS: IMPACT ON T-CELL SUBPOPULATIONS AND MARKERS OF 
RENAL TUBULE-TOXICITY IN KIDNEY TRANSPLANT PATIENTS 
PRINCIPAL INVESTIGATOR:
Lorenzo Gallon, MD
Professor, Medicine and Surgery
Director, Translational Medicine FCVRI; Director, International Relations DOM
Director, Transplant Nephrology Fellowship
Phone: (312) 695-4457
Email: l-gallon@northwestern.edu
CO-INVESTIGATORS:
Joseph R Leventhal MD PhD
Fowler McCormick Professor of Surgery; Director of Kidney Transplantation 
Office: (312) 695-9019 
Email: jleventh@nm.org 
&
M. Javeed Ansari, MD
Assistant Professor of Medicine
Office: (312) 695-0602 
Email: jansari@northwestern.edu 
&
James M. Mathew, PhD 
Associate Professor of Surgery & Microbiology-Immunology; 
Director: Immune Monitoring Core
Office: (312) 908-5180 
James-mathew@northwestern.edu
ADDRESS:
Comprehensive Transplant Center
Northwestern University Feinberg School of Medicine
Arkes Family Pavilion, Suite 19
676 North St. Clair Street
Chicago, IL, 60611-2923
SPONSOR:
Lorenzo Gallon, MD
Professor, Medicine and Surgery
Director, Translational Medicine FCVRI; Director, International Relations DOM
Director, Transplant Nephrology Fellowship
Phone: (312) 695-4457
Email: l-gallon@northwestern.edu
 
VERSION NUMBER: 3.3
VERSION DATE: October 3, 2019
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OBJECTIVES AND HYPOTHESIS:
The overall aim of the present study is to prospectively investigate the impact of two 
maintenance CNI immunosuppressive regimens (both prednisone-free, with MMF) on 
subpopulations of T and B cells and alloreactive T cells as well as on renal allograft function at 
week 2, 3 months and 12 months post-transplantation.
1.
To compare renal toxicity of once-daily LCP-Tacro/Envarsus XR vs. twice/day Tacrolimus by 
measured acute kidney injury markers.
2.
To compare the effect on T and B cell subpopulations of once-daily LCP-Tacro/Envarsus XR 
vs. twice /day Tacrolimus.  Specific studies to include prospective, serial flow cytometric 
analysis of T and B cell subpopulations, as well as high throughput sequencing T cell 
receptor repertoire analysis monitoring for presence or absence of donor-reactive T cells.
Our hypothesis is that that more consistent exposure with LCP-Tacro/Envarsus® XR avoiding 
under immunosuppression will prevent the emergence of alloreactive T cells, development of 
effector memory T cells, and a reduced incidence of immunologic allograft injury. We also posit 
that avoidance of the peaks associated with conventional twice daily tacrolimus will spare the 
renal allograft from drug induced nephrotoxicity. 
BACKGROUND:
Kidney transplantation is the treatment of choice for most patients with end-stage renal disease. 
Lifelong immunosuppressive therapies are required to prevent organ rejection. However, long 
term exposure to immunosuppressive therapy after kidney transplantation can place patients at 
risk for multiple adverse events. The optimal immunosuppressive therapy is not well 
established. Tacrolimus, a calcineurin inhibitor (CNI) is highly effective in preventing acute 
rejection after organ transplantation (2). It is used as part of the immunosuppression regimen for 
the majority of kidney and liver transplant recipients (3). However, treatment with current 
formulation of Tacrolimus generates high peaks and low troughs in drug concentrations in the 
blood. It is known that high exposure to CNI is associated with renal toxicities and adverse 
events (4).  New once-daily dosage formulations are now developed with the hope of minimizing 
side effects while maintaining excellent outcomes (5-8). 
LCP-Tacro/Envarsus® XR, a new once-daily formulation of tacrolimus, was approved by the 
Figure 1 Mean whole-blood tacrolimus concentration in patients on days 7, 14 & 21 vs time 
(1)
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FDA in 2015 for conversion from twice-daily tacrolimus in kidney transplant recipients. It is a 
prolonged-release tacrolimus formulation, utilizing a MeltDose drug delivery technology 
designed to improve the bioavailability of drugs with low water solubility (1). Recent clinical data 
demonstrated that once-daily LCP-Tacro/Envarsus XR has improved pharmacokinetic 
bioavailability, rapid achievement of therapeutic trough levels, less fluctuation and swing in 
whole blood concentration, non-inferior efficacy and similar safety, with lower tacrolimus dose 
than other tacrolimus formulations (1, 9-13). (Figure1). 
INCLUSION AND EXCLUSION CRITERIA:
The target population is adult recipients of immediately functioning living and deceased donor 
renal allografts. Immediate function will be defined as the absence of the need for hemodialysis 
in the first week following renal transplantation.
Inclusion Criteria:
1. Patients who are males or females aged 18-65 years. 
2. Donors aged 18-65 years. 
3. No prior organ transplant 
4. Patients who are single-organ recipients (kidney only). 
5. Women who are of childbearing potential must have a negative serum pregnancy test 
before transplantation and agree to use a medically acceptable method of contraception 
throughout the treatment period. 
6. Subject (recipient) is able to understand the consent form and give written informed 
consent 
Exclusion Criteria 
1.
Delayed graft function (please see above).
2.
Known sensitivity or contraindication to alemtuzumab, Envarsus® XR, tacrolimus or 
MMF.
3.
Use of the following induction medications: basiliximab and rituximab.
4.
Patient with significant or active infection. 
5.
Patients with a positive flow cytometric crossmatch using donor lymphocytes and 
recipient serum. 
6.
Patients with PRA > 40%
7.
Patients with current or historic donor specific antibodies 
8.
Body Mass Index (BMI) of < 18 or > 35 
9.
Patients who are pregnant or nursing mothers. 
10. Patients whose life expectancy is severely limited by diseases other than renal 
disease. 
11. Ongoing active substance abuse, drug or alcohol. 
12. Major ongoing psychiatric illness or recent history of noncompliance. 
13. Significant cardiovascular disease (e.g.): 
a.
Significant non-correctable coronary artery disease; 
b.
Ejection fraction below 30%; 
c.
History of recent myocardial infarction. 
14. Malignancy within 3 years, excluding non-melanoma skin cancers. 
15. Serologic evidence of infection with HIV or HBVs-Ag positive. 
16. Patients with a screening/baseline total white blood cell count < 4,000/mm3; platelet 
count < 100,000/mm3; triglyceride > 400 mg/dl; total cholesterol > 300 mg/dl. 
17. Investigational drug within 30 days prior to transplant surgery.
18. Anti-T cell therapy within 30 days prior to transplant surgery.
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19. Diagnosis of atypical-Hemolytic Uremic Syndrome (aHUS).
20. Subjects transplanted with a Hepatitis C NAT-positive kidney.
NUMBER OF PARTICIPANTS:
Prospective randomized single center open label study of 2 groups of kidney transplant patients

Group 1 : standard of care (SOC) control group will receive tacrolimus twice-daily (n=25)

Group 2 : LCP-Tacro/Envarsus® XR group will receive LCPT tablets once daily (n=25)
RECRUITMENT METHODS:
The investigators will recruit patients in a manner that is sensitive to the inclusion of women and 
members of minority groups into this study. The renal failure population awaiting transplantation 
on the participating program waiting lists is representative of the renal failure population in 
general. Subjects will be recruited from the patients who present themselves to Northwestern 
University, Kovler Organ Transplantation Clinic, located in Arkes Pavilion, 676 N. St. Clair 
Street, Suite 1900, Chicago, IL 60611.
Subject Information and Consent 
Prior to any testing under this protocol, including screening tests and evaluations, written 
informed consent will be obtained from the subject in accordance with local practice and 
regulations. Whenever possible, the investigator(s) will also be involved in this procedure. 
The background of the proposed study and the benefits and risks of the procedures and 
study will be explained to the subject. A copy of the informed consent document signed and 
dated by the subject will be given to the subject. Confirmation of a subject’s informed 
consent will be documented in the subject’s medical records prior to any testing under this 
protocol. 
Avoidance of Coercion 
It will be made clear to all patients that they can receive transplantation therapy (contingent 
on their medical suitability) without participation in this trial.
STUDY TIMELINES:
We expect the total duration for this study not to exceed 2 years from the date of the last 
subject’s enrollment. Each individual subject will be part of the study for 12 months after 
transplantation.
STUDY ENDPOINTS:
Primary endpoints: 
One of the 2 primary end points Kidney transplant function assessed as kidney injury 
markers in urine samples collected at 12-hour and 24-hour trough levels and 2-hour peak 
levels at 2nd week, 3rd month,12th month post transplantation, and at any for-cause biopsy 
event. The injury markers will be assessed using Myriad-RBM KidneyMAP panel 
https://myriadrbm.com/products-services/humanmap-services/kidneymap/. 
The other primary end point is immune activation assessed through serial flow cytometric 
immunophenotyping for immune cells including T and B cell subpopulations as well as 
donor-reactive TCR repertoire analysis in biopsy, blood and urine.
Secondary endpoints:
Kidney biopsy will be performed per SOC at month 3 and 12 post-transplant. Biopsies will 
be evaluated and compared between two groups for CNI-related toxicities. Correlations 
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between kidney injury markers and biopsy data at 3 and 12 months post-transplant will be 
performed (details are below).
Antibody responses and correlation with CNI exposure by SOC donor specific antibody 
(DSA) assessment at months 3 and 12 post-transplant (performed at the Clinical 
Immunology Laboratory of the CTC).
PROCEDURES INVOLVED:
Study Design: 
Donors: 
Blood samples (50ml) from donor subjects will be obtained before 
transplantation. These donor leukocytes will be used as stimulator cells in studies of 
functional activity of recipient T-cells. These samples will be processed in the research 
laboratory of co-investigator, Dr. James Mathew.
Renal Transplant Recipients: All recipients will receive the same induction immunotherapy 
at the time of transplant. 
Mycophenolate (MMF, Myfortic®) 
The MPA/Myfortic will be initiated at 720- 1250 mg BID orally. The first dose will be 
given, per SOC. The agent will be given in an open label fashion. Once discharged from 
the hospital, the subject will obtain this medication via a prescription at a pharmacy of 
their choice. 
Alemtuzumab (Campath-1H®) 
One dose will be 30mg given IV, and administered intra-operatively during renal 
transplantation. The agent will be given in an open label fashion and will only be 
administered in the hospital. 
Corticosteroids 
Intravenous corticosteroids (prednisolone, Solumedrol®) 
Time: Dose 
Preop (Intraop) 500mg 
POD#1 250mg 
POD#2 125mg 
No further steroids will be given post-transplant unless indicated by the following medical 
conditions: acute renal allograft rejection, renal diseases necessitating the use of 
steroids, and other systemic diseases such as rheumatoid arthritis (RA), systemic lupus 
erythematosus (SLE), and asthma.
Tacrolimus (Prograf®) 
Tacrolimus will be given 1-2 mg BID, per SOC. The dose will be modified to achieve 12 
hour trough concentrations of 8-12 ng/ml. The agent will be given in an open label 
fashion. Half of the study subjects (randomized; n=25) will be on this drug treatment 
LCP-Tacrolimus/Envarsus® XR (Study related drug)
LCP-Tacro/Envarsus® XR a new once-daily formulation of tacrolimus, was approved by 
the FDA in 2015 for conversion from twice-daily tacrolimus (above) in kidney transplant 
recipients. It is a prolonged-release tacrolimus formulation, utilizing a MeltDose drug 
delivery technology designed to improve the bioavailability of drugs with low water 
solubility. The other half of the study subjects (randomized; n=25) will be on this drug 
treatment. LCP-Tacro/Envarsus XR will be given 5 mg QD to achieve a 24-hour trough 
concentration of 8-12 ng/ml.
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Study Drugs
None of the drugs given in conjunction with this study are provided by the study sponsor, 
including LCP-tacro/Envarsus XR.
Recipient Samples collection: 
Blood, urine and biopsies will be collected from the kidney transplant recipients as 
shown in Figure 2 (bottom). 
Enrollment and randomization at 1:1 in the trial
Renal Transplant
Renal Transplant
Induction: Alemtuzumab (Campath) + Rapid Steroid elimination
Standard Tacrolimus 
+ MMF (n=25)
LCP-Tacrolimus/Envarsus XR 
+ MMF (n=25)
50 ml of blood samples at baseline (pre-Tx), 3 and 12 months post-Tx*
(For FACS and donor-reactive TcR & B cell analyses. Also SOC DSA estimation.)
Up to 200 cc of urine at 2 weeks, 3 months and 12 months post-Tx*
(for renal injury markers & donor-reactive TcR analyses)
Kidney tissue samples at baseline, 3 and 12 months post-Tx*
(for SOC immuno-histochemical and experimental TcR Repertoire assessments)
At any for-cause biopsy, the blood, urine and tissue samples will be collected.
*Note: Sample collection may be adjusted by +/- 10 days, with the exception of the
2nd week urine sample, which may be adjusted by +/- 7 days.
Figure 2: Flow Chart of the Study
Kidney transplant function: 
For subjects receiving Standard Tacorolimus + MMF urine samples will be collected at 
12-hour trough levels and 2-hour peak levels at 2nd week, 3rd month, 12th month post 
transplantation, and at any for-cause biopsy event. 
For subjects receiving LCP-Tacrolimus/Envarsus XR + MMF, urine samples will be 
collected at 24-hour trough and 2-hour peak levels at 2nd week, 3rd month, 12th month 
post transplantation, and at any for-cause biopsy event.
Urine will be used for the analysis of kidney injury markers using Myriad-RBM 
KidneyMAP panel https://myriadrbm.com/products-services/humanmap-
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services/kidneymap/. [The samples will be used also for TcR repertoire analysis; (please 
see below).]
Blood Immunophenotyping. 
The approach will be to conduct a multi-parameter flow cytometric immunophenotyping 
of peripheral blood before and at 3 and 12 months post-transplant to analyze cellular 
changes. 
Methods (14-16): Our well-established 5-color flow cytometric analyses is performed 
using whole blood to delineate the cellular makeup in terms of both percentages and 
absolute numbers (Table 1). RBCs are lysed before flow acquisition. The analysis is 
for defining the T cell subsets, monocytes and natural killer cells (Tube 2), the B cells 
including naïve, transitional, memory and effector-memory subsets (Tube 3) and the 
dendritic cells including immature, monocytoid and plasmacytoid fractions (Tube 4). 
In addition to the whole blood analyses, PBMC are isolated from heparinized 40 cc 
blood samples by Ficoll-Hypaque gradients. Surface markers are identified with 
indicated monoclonal antibodies, and after fixation and permeabilization the 
intracellular protein ligands are detected with antibodies shown on the bottom row 
(Table 2). This panel delineates expression of markers for activated, effector, 
memory, anergic and exhausted cell fractions as well as myriad sub-sets of 
regulatory T and B cells. 
Donor-reactive TCR repertoire analysis The approach will be to identify and estimate 
the total T cell clonal repertoire that a patient is capable of mounting against the donor 
by performing MLR and purifying reactive cells followed by ImmunoSEQ analysis (17) 
prior to transplant. Then after transplant, monitor for the absence, presence or 
amplification of the pre-identified T cell clones in the post-transplant biopsies, blood 
and/or urine samples. This is a novel innovative technology that we have developed for 
profiling recipient’s immune status against the donor to correlate with the status of the 
graft. The methodological approach is follows:
Table 1: Whole blood immunophenotyping panel
Tube 1
Tube 2
Tube 3
Tube 4
IgG-FITC
CD4-FITC
CD38-FITC
CD3, 14, 16, 19, 20, 56 FITC
IgG-PE
CD14-PE
IgD-PE & IgM-PE
CD33-PE
IgG-ECD
CD56-ECD
CD19-ECD
HLA-DR-ECD
IgG-PC5
CD3-PC5
CD27-PC5
CD11b-PC5
IgG-PC7
CD8-PC7
CD24-PC7
CD123-PC7
Table 2: Immunophenotyping in using isolated PBMC (surface and 
intracellular)
Tube 5
Tube 6
Tube 7
Tube 8
Tube 9
Staining
CD4-ECD
IgD/M-PE
CD3-ECD
CD49b 
FITC
KLRG-1 
PE
CD25-PC5
CD19-ECD
CD28-PC5
LAG-3 PE
PD1-ECD
CD127-PC7
CD27-PC5
CD8-PC7
CD4 ECD
CD3-PC5
CTLA4-FITC
CD24-PC7
CD45RA -FITC
CD8  -PC7
Surface
FoxP3-PE
IL-10 -FITC
FoxP3-PE
FoxP3 PC5 
& IL10 PC7
Ki-67 FITC
Intra-
cellular
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Selection of donor-reactive T cells: Recipient pre-transplant peripheral blood 
mononuclear cells (PBMC) will be labeled with CFSE dye and then stimulated with 
PKH266-labled donor irradiated PBMC in MLR. After 7 days, the proliferating responder 
cells that have diluted the CFSE are flow-sorted (at NU Flow Core) as shown in Figure 3 
(top middle). Based on previous results, it is expected that the proliferating cells will be 
>90% CD3+ T cells, distributed into CD4+ or CD8+ cells, with minimal contamination with 
CD19+ B cells or CD14+ monocytes but some CD56+ NK cells. Both the CD3+CD4+ and 
CD3+CD8+ cell subsets are sorted out separately and is shipped to Adaptive 
Biotechnologies in Seattle.
ImmunoSEQ analysis of donor-reactive T cells:  At Adaptive Biotechnologies total 
genomic DNA is purified from the flow-sorted CD3+CD4+ and CD3+CD8+ cell subsets 
from each culture using Qiagen DNeasy Blood extraction Kit following the 
manufacturer’s protocol. Then, a multiplex PCR assay that is capable of specifically 
amplifying rearranged 
TCRB genes from a 
complex background 
followed by deep 
sequencing is 
performed (Figure 4). 
The data is analyzed 
measuring clonality, 
proportion and 
diversity of the T cell 
repertoire (18-20). 
These represent the 
total T cell repertoire 
the recipient is capable 
of reacting to the 
donor. We have 
denoted the 
performance of the 
pre-transplant MLR, 
isolation of donor reactive clones and ImmunoSEQ analysis, collectively as 
AlloSEQ. 
Figure 3.  Flow Sorting and 
phenotypic subset analysis 
of donor reactive clones. 
Bulk MLRs were prepared and 
the cellular makeup of 
responder cell populations 
were delineated after 7 days in 
culture using fluorochrome 
coupled monoclonal 
antibodies. The cells were 
analyzed first by gating on 
lymphocytes and then after 
gating on CFSE diluted 
proliferating responder cells. 
The CFSE diluted donor 
reactive T cells were sorted for 
ImmunoSEQ analysis.
Figure 
4.  
TCRβ 
sequencing assay.  
(A) The assay is designed 
to identify the V D and J 
segments in recombined 
CDR3 TCRβ genes  
(B) Forward primers were 
designed to amplify all 45 
TCRβ 
V 
segments.   
Reverse primers were 
designed to each of the 
13 TCRβ J segments.  
(C) 
Custom 
software 
tools 
have 
been 
developed 
to 
verify, 
collapse, 
align 
and 
catalog 
the 
CDR3 
sequences for calculation 
of repertoire diversity.
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Enumeration of donor reactive T cell clones in post-transplant kidney biopsies, 
blood and urine: 
The transplant biopsy represents a sampling of the allograft and rejection is manifested 
as cellular infiltration, mostly of donor reactive T cells and B cells, classically detected 
through immunohistopathological staining and microscopic examination. An alternate 
approach that we have developed is to monitor the graft for infiltrating donor-reactive 
clonotype identified through AlloSEQ (17). This would entail isolation of total genomic 
DNA from the biopsies, performance of immunoSEQ analysis as above and monitoring 
for the presence and copy number of donor-reactive clones identified through the pre-
transplant AlloSEQ, and then correlating with the severity of rejection monitored through 
immunohistopathological examinations. 
We had proposed that transplant rejection can more easily be diagnosed through the 
sampling of the urine pellet or peripheral blood for clonal frequency and abundance of 
donor-reactive T cells pre-identified through AlloSEQ. This is to monitor rejection in a 
non-invasive manner.
We have already established the technology (17) and other investigators have used it to 
show that donor reactive clones are reduced or deleted in tolerant kidney transplants 
(21). Therefore, these proposed studies monitoring post-transplant graft rejection or its 
absence can be greatly leveraged to innovatively assess the relative efficacies of the 
drugs being compared. 
Analysis of HLA and Donor-Specific B cells 
Measurement of B cells in the peripheral blood with potential to make HLA antibodies 
against graft donor antigens might provide a way of analyzing antibody formation and 
shed light on the balance between production, inhibition and sequestration at any given 
time in the post-transplant period. Perry and coworkers have recently reported HLA 
antibody production in vitro by B cells from the bone marrow of sensitized kidney 
transplant recipients. T and B-cell ELISPOT have also been used to measure HLA 
specific B cell frequency against a given antigen. ELISPOT assay does not measure the 
frequency of cells that actually bind the antigen and only measures biological events 
such as cytokine release or production of immunoglobulin after differentiation in vitro. 
Furthermore, the estimated frequency is restricted to the cells that are able to be 
selectively stimulated by the antigen depending on read-out and thus may lead to an 
underestimation of the actual frequency of committed cells. Another approach based on 
the structural similarity between B cell receptor and immunoglobulin binding sites, it is 
postulated that HLA-specific B cells (HSB) should bind to HLA molecules with specificity 
comparable to that of the secreted immunoglobulin. Identification of HLA specific B cells 
by staining through binding of the B cell receptor using fluorescently labeled tetramers of 
identified HLA class I specificities has been described. A solid-phase assay utilizing 
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color-coded microspheres, each coated with a unique HLA antigen has become the 
main multiplex assay used for the detection of allo-specific antibodies against donor 
antigens. Its multiplexing power enables the analysis of the antibodies directed to all 
available synthetic HLA class I and class II alleles in one assay. Utilizing these single 
antigen HLA beads (SAB) Degauque et al. described a novel assay to identify HLA-
specific B cells in transplant recipients (22). We have further developed this novel 
multiplex bead-based assay to identify HSB (schematically described in Figures 5 and 
6), and propose here to study the circulating HSB in kidney transplant recipients with 
chronic AMR. 
Figure 5: Assay Design
Proposed studies: 
1. Frequency of Donor-specific B cells (DSB) by Novel HLA Bead Multiplex Assay: We 
will analyze the serial samples of peripheral blood mononuclear cells (PBMC) using 
our novel HLA-bead multiplex assay to identify and determine the changes in 
frequency of total B, HLA-specific B (HSB) and DSB cells in KT recipients with cAMR 
in each study arm. 
Figure 6: Analysis Strategy
2. Immunophenotyping of HLA-specific B cells and Donor-Specific B cells by Flow 
Cytometry: We will analyze serial samples of PBMC, before and at 3 and 12 months 
post-transplant, using multi-parameter flow-cytometry for immunophenotyping of (i) 
total B, HSB and DSB cells with surface expression of IgD, CD24, CD27 and CD38. 
DATA AND SPECIMEN BANKING:
Samples collected will be banked at the Immune Monitoring Core (IMC) (under the leadership of 
Co-I Dr. James Mathew) of the Comprehensive Transplant Center (CTC) of Northwestern 
University. The blood immunophenotyping will be performed prospectively on fresh samples.  
The pre-transplant donor-specific MLR and flow-sorting of reactive T cells will also be performed 
with fresh samples.  Cell pellets thus obtained (for AlloSEQ analysis) as well as post-transplant 
PBMC, urine sample pellets and biopsies will be frozen and sent blinded (de-identified) to 
Adaptive Biotechnologies, Seattle for DNA purification and ImmunoSEQ analyses. Leftover 
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samples of biopsies (paraffin-block after IHC staining), PBMC and urine pellets will be used for 
RNA isolation and gene expression profiling in a future study.  
DATA AND SPECIMEN MANAGEMENT:
Statistical analysis:
The primary endpoints of the study are graft function and subpopulations of T cells, 
including regulatory T cells and B cell subpopulations as well as immune functions at 3 and 
12 months post kidney transplant. 
The secondary endpoints of the study include 1) incidence of acute rejection, graft loss, and 
death at 3 and 12 months post kidney transplant; 2) allograft immunohistopathology profiles 
at 3 and 12 months post kidney transplant.
We will run univariate and bivariate analyses for all variables prior to our main analyses. We 
will evaluate continuous variables using t-tests or F-tests and categorical variables using 2. 
We will examine data distributions and test all variables for linear relationships or non-linear 
relationships.
Descriptive statistics (means, standard deviation, frequency) and correlations (both Pearson 
and Spearman) among variables will be calculated for preliminary data assessment.
Necessary transformation and imputations will be carried out based on the raw data 
distribution.
As missing data are inevitable in a longitudinal study, we will determine whether missing 
data are MCAR (data are missing completely at random), MAR (data are missing at 
random), or NMAR (not missing at random). If missing data are MCAR or MAR, it is likely 
that the standard multivariate computations using PROC MI (multiple imputations) will not 
result in biased standard error estimates. However, if missing data are NMAR, we will use 
the "pattern mixture" approach to compute a weighted average of the parameters that are 
associated with the missing data to estimate what the data would have been.
For the primary objective, we hypothesize that subjects receiving LCP-Tacro/Envarsus® XR 
will exhibit significantly greater graft function and lower frequency / abundance of AlloSeq 
pre-identified donor-reactive T cell clones in the graft, peripheral blood and /or urine at 3 and 
12 month post-transplant as compared to the standard of care tacrolimus group. A variety of 
covariance structures (first order regressive, compound symmetry, Toeplitz, variance 
components, unstructured) will be carefully examined and compared using the best fitting 
statistics, such as Akaike’s Information (AIC) and Bayesian Information Criteria (BIC). These 
statistics are likelihood functions and can be compared across models. If, in spite of 
randomization, distributions of subjects’ baseline characteristics are found to be different 
between the two experimental groups, these variables will be entered as covariates in the 
statistical analysis.
For the secondary endpoints, we will use logistic regression, Kaplan-Meier method, and Cox 
proportional hazards models to analyze time-to-event outcomes (acute rejection, graft 
failure, and death). For allograft immunohistopathology outcomes, we will first develop a 
comprehensive immune profile of each participant by longitudinal analysis of frequency of T 
and B cell subsets and function. We will examine how these correlate with 
immunohistopathology and alloantibody production using Pearson or Spearman 
correlations. We will compare correlation coefficients between the two experimental groups 
using Z -tests to determine the distinct effects of each treatment arm. We will also compare 
the trajectory changes in cell populations and antibody production over 3 and 12 months 
using both repeated measures ANOVA and random mixed effect models. All tests will be 
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two-sided, and an error rate of α <0.05 will be considered statistically significant. All data 
analyses will be performed using SAS 9.2 statistical software (SAS Inc., Cary, NC).
Sample size and power:  
This proposal bases its sample size calculations on published data demonstrating increased 
peaks and troughs with conventional tacrolimus and absence of such peaks and troughs 
with LCP-Tacro/Envarsus® XR (1) and correlation with high doses and nephrotoxicity with 
conventional tacrolimus (4). Using a two-tailed α of 0.05, the anticipated effect sizes 
corresponding to each specific aim between the two treatment arms were calculated using a 
minimum of 80% statistical power and assumed 10% attrition at 12 months.
For the sample size of n= 25 in each group, the proposed study will have a power of 0.82 
and 0.99 to detect effect size of 1.0 and 2.0 for graft function and immune activation (in 
terms of T cell clonal repertoire change), respectively, between the two treatment arms. 
Because this is a pilot study, we do not consider the statistical power of secondary 
outcomes; It is anticipated that a much larger sample size will be needed in order to achieve 
statistical power for the secondary endpoints in this proposed study.
Data Handling and Record Keeping
This study is to be conducted according to US and international standards of Good Clinical 
Practice (FDA Title 21 part 312 and International Conference on Harmonization guidelines), 
applicable government regulations and Institutional research policies and procedures. This 
protocol and any amendments will be submitted to a properly constituted independent 
Institutional Review Board (IRB), for formal approval of the study conduct.  Information 
about study subjects will be kept confidential and managed according to the requirements of 
the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those regulations 
require a signed subject authorization informing the subject of the following: 1) What 
protected health information (PHI) will be collected from subjects in this study 2) Who will 
have access to that information and why 3) Who will use or disclose that information 4) The 
rights of a research subject to revoke their authorization for use of their PHI. All subjects for 
this study will be provided with a printed consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in 
this study. This consent form will be submitted with the protocol for review and approval by 
the IRB for the study.  The formal consent of a subject, using the IRB-approved consent 
form, will be obtained before the subject is submitted to any study procedures. This consent 
form will be signed by the subject and the investigator-designated research professional 
obtaining the consent.  The subject will be given a signed copy of the informed consent for 
their records. After study initiation, the electronic case report form (eCRF) will be the primary 
data collection instrument for the study.  Only the study staff will have access to this 
password protected file. No subject identifiers will be included in the eCRF and electronic 
databases that are used to record clinical data on participants. All clinical data will be kept 
completely confidential. The PI, Dr. Lorenzo Gallon and the Co-Is Drs. Joseph Leventhal 
and Dr. Javeed Ansari or their designees will be responsible for the clinical data 
management.
PROVISIONS TO MONITOR THE DATA TO ENSURE THE SAFETY OF PARTICIPANTS:
Safety:
Safety Endpoints: The primary safety endpoints will be assessed on the AEs and SAEs that 
are observed throughout the trial. For the purpose of this clinical trial, the National Cancer 
Institute Common Terminology Criteria for Adverse Events v4.0 3(CTCAE), dated June 14, 
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2010, will be used to grade all adverse events. The collection of AE’s and SAE’s is limited in 
this study to those Grade 3 or higher that are related to study mandated procedures.
Recording of Adverse Events
At each contact with the subject, the investigator/member of investigator’s team will seek 
information on adverse events by specific questioning and, as appropriate, by examination. 
Information on all adverse events will be recorded in the source document. All clearly related 
signs, symptoms, and abnormal diagnostic procedures results should be recorded in the 
source document, though should be grouped under one diagnosis.
All adverse events occurring during the study period that meet the criteria above will be 
recorded. The clinical course of each event should be followed until resolution, stabilization, 
or until it has been determined that the study treatment or participation is not the cause. 
Serious adverse events that are still ongoing at the end of the study period must be followed 
up to determine the final outcome. Any serious adverse event that occurs after the study 
period and is considered to be possibly related to the study treatment or study participation 
will be recorded and reported according to IRB requirements.
Stopping Rules
Subjects developing post-transplant infections (i.e., UTI, CMV, HSV, EBV, HCV, HBV, HIV, 
PCP), that in the opinion of the investigator are detrimental to the subject and his/her 
participation in this research trial, will be stopped from participating in this study (even 
though these adverse events expected to be lower in the experimental arm of the study).
Patient Authorization: This study is to be conducted according to US and international 
standards of Good Clinical Practice (FDA Title 21 part 312 and International Conference on 
Harmonization guidelines), applicable government regulations and Institutional research 
policies and procedures.
This protocol and any amendments will be submitted to a properly constituted independent 
Institutional Review Board (IRB), (Northwestern University Institutional Review Board), in 
agreement with local legal prescriptions, for formal approval of the study conduct. The 
decision of the IRB concerning the conduct of the study will be made in writing to the 
investigator and a copy of this decision will be provided to the investigator/sponsor before 
commencement of this study. The investigator will place a list of IRB members and their 
affiliate in the regulatory binder for the clinical trial. All subjects for this study will be provided 
with a printed consent form describing this study and providing sufficient information for 
subjects to make an informed decision.
WITHDRAWAL OF PARTICIPANTS:
Subjects may be withdrawn from the trial at any time for any reason, either by choice or due to 
medical indications. Subjects who are non-compliant with study guidelines, medications and 
clinic examinations will be withdrawn from the study. The IRB may also discontinue the study at 
any point. The subjects will be fully informed of these actions. If participants are withdrawn 
prematurely, they will still be followed through the follow-up time period of the study as per 
standard medical care. These data are important to collect to determine differences in this group 
compared to those who completed the study. 
RISKS TO PARTICIPANTS:
The risks to the subjects are limited to the risks related to venipuncture and at least two passes 
of renal biopsies. Also, the routine risk of rejection with either of the drugs is expected; in fact, 
lower risk of nephrotoxicity is anticipated with LCP-Tacro/Envarsus® XR.
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The National Cancer Institute Common Terminology Criteria for Adverse Events v4.03 
(CTCAE), dated June 14, 2010 will be used to grade all adverse (either serious or non-serious) 
events. It is the responsibility of the Principal Investigator to oversee the safety of the study. 
This safety monitoring will include careful assessment and appropriate reporting of adverse 
events as noted above. Medical monitoring will include a regular assessment of the number and 
type of serious adverse events. Information on all adverse events (signs, symptoms, abnormal 
diagnostic procedures, treatments) will be recorded in the appropriate adverse event module of 
the case report form (CRF).  The clinical course of each event will be followed until resolution, 
stabilization, or until it has been determined that the study participation is not the cause.  
Serious adverse events that are still ongoing at the end of the study period will be followed to 
determine the final outcome.  
Serious adverse events that are determined to be unexpected and at least possibly related to 
study participation will be submitted to the IRB within 5 business days of the investigator’s 
knowledge of the event. Follow-up information will be submitted to the IRB as required. The 
IRB/Office for the Protection of Research Subjects at NU is under the direction of Nathalia 
Henry, MS, CIP, CHRC, (312) 503- 2578.
POTENTIAL BENEFITS TO PARTICIPANTS:
It is expected that participants in the experimental arm of LCP-Tacro/Envarsus® XR treatment 
will have lower nephrotoxicity, immune activation and associated improved clinical outcomes. 
These may be direct long-term benefits for participants, if they happen to be randomized into 
the study arm.
ECONOMIC BURDEN TO PARTICIPANTS:
None other than their own routine SOC expenses. A parking voucher will be given to the 
participants at their study visits.  
VULNERABLE POPULATIONS:
None (Please see Inclusion and Exclusion Criteria)
SHARING OF RESULTS WITH PARTICIPANTS:
At the end of the study, at the PIs discretion, the participants may be informed of the incidental 
findings. This study will be registered at clinicaltrials.gov.
PRIOR APPROVALS:
All required approvals such as laboratory, radiation safety, or biosafety are already in place. 
SETTING:
Renal transplantations will be performed by the co-I, Dr. Joseph Leventhal and his surgical 
colleagues at Northwestern Memorial Hospital. The clinical follow-up will be conducted as 
standard of care by the PI, Dr. Lorenzo Gallon and the transplant nephrologists including Dr. 
Javeed Ansari with the help of transplant nurse coordinator (TNC). The immune monitoring 
studies will be directed by Co-I, Dr. James Mathew with the help of Drs. Jie He and Xuemei 
Huang, two senior technologists in the Immune Monitoring Core of the CTC. Blinded (de-
identified) samples will also be sent to Adaptive Biotechnologies, Seattle for ImmunoSEQ 
analyses. Leftover samples, if any, are expected to be discarded at the end of the study.  
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RESOURCES AVAILABLE:
Successful completion of the project requires the following: a) Team of dedicated investigators: 
Drs. Gallon and Ansari are transplant nephrologists and Dr. Leventhal is a transplant surgeon 
and they have dedicated their careers to translational research to refine the management of 
renal transplant recipients. They will actively recruit all patients and, assisted by an RN research 
coordinator at the CTC, perform all of the clinical assessments in this cohort. They will maintain 
the clinical database with help from the assistant coordinators. They will work closely with the 
co-I, Dr. James Mathew and his trained technologists in the Immune Monitoring Core of the 
CTC performing and interpreting the assays. Dr. Lihui Zhao will perform the statistical analysis 
of the immunophenotyping and Dr. Yashpal Kanwar will interpret the biopsies and IHC staining. 
Northwestern has formed a collaborative partnership with Adaptive Biotechnologies, Seattle for 
ImmunoSEQ analyses to identify TcR repertoire usage in donor-specific immune responses. A 
similar partnership has been established with Myriad-RBM for the analysis of  kidney injury 
markers using their KidneyMAP panel,  b) Ideal patient population: The Northwestern CTC 
transplant center provide the ideal infrastructure and performs a high number (>220) of living 
and deceased donor kidney transplant procedures/year to conduct this prospective trial and to 
analyze fresh patient samples. This readily supports recruiting 50 patients within one year 
enrollment period, even when considering the inclusion/exclusion criteria and other concurrent 
studies; c) Institutional support: Dr. Michael Abecassis, division head of the CTC will provide the 
full infrastructural support to conduct all clinical and laboratory portions of the study. In 
summary, the investigators, patient availability, and environment afford the highest chance of 
success in this proposal. 
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Gaber AO, Alloway RR, Bodziak K, Kaplan B, Bunnapradist S. Conversion from twice-daily 
tacrolimus capsules to once-daily extended-release tacrolimus (LCPT): a phase 2 trial of 
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https://dx.doi.org/10.1097/TP.0b013e3182962cc1. PubMed PMID: 23715050.
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Webster AC, Woodroffe RC, Taylor RS, Chapman JR, Craig JC. Tacrolimus versus 
ciclosporin as primary immunosuppression for kidney transplant recipients: meta-analysis 
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https://dx.doi.org/10.1136/bmj.38569.471007.AE. PubMed PMID: 16157605.
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Cherikh WS, Wainright JL, Snyder JJ, Israni AK, Kasiske BL. OPTN/SRTR 2012 Annual 
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Garnock-Jones KP. Tacrolimus prolonged release (Envarsus): a review of its use in kidney 
and liver transplant recipients. Drugs. 2015;75(3):309-20. doi: 
https://dx.doi.org/10.1007/s40265-015-0349-2. PubMed PMID: 25613762.
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Grinyo JM, Petruzzelli S. Once-daily LCP-Tacro MeltDose tacrolimus for the prophylaxis of 
organ rejection in kidney and liver transplantations. Expert rev. 2014;10(12):1567-79. doi: 
https://dx.doi.org/10.1586/1744666X.2014.983903. PubMed PMID: 25407098.
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Staatz CE, Tett SE. Clinical Pharmacokinetics of Once-Daily Tacrolimus in Solid-Organ 
Transplant Patients. Clin Pharmacokinet. 2015;54(10):993-1025. doi: 
https://dx.doi.org/10.1007/s40262-015-0282-2. PubMed PMID: 26038096.
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8.
Singh N, Von Visger J, Zachariah M. Extended release once a day tacrolimus. Current 
Opinion in Organ Transplantation. 2015;20(6):657-62. doi: 
https://dx.doi.org/10.1097/MOT.0000000000000251. PubMed PMID: 26536429.
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Budde K, Bunnapradist S, Grinyo JM, Ciechanowski K, Denny JE, Silva HT, Rostaing L, 
Envarsus study g. 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;14(12):2796-806. doi: 
https://dx.doi.org/10.1111/ajt.12955. PubMed PMID: 25278376.
10. Bunnapradist S, Ciechanowski K, West-Thielke P, Mulgaonkar S, Rostaing L, Vasudev B, 
Budde K, investigators M. Conversion from twice-daily tacrolimus to once-daily extended 
release tacrolimus (LCPT): the phase III randomized MELT trial. Am J Transplant. 
2013;13(3):760-9. doi: https://dx.doi.org/10.1111/ajt.12035. PubMed PMID: 23279614.
11. Langone A, Steinberg SM, Gedaly R, Chan LK, Shah T, Sethi KD, Nigro V, Morgan JC, 
Investigators S. Switching STudy of Kidney TRansplant PAtients with Tremor to LCP-TacrO 
(STRATO): an open-label, multicenter, prospective phase 3b study. Clinical Transplantation. 
2015;29(9):796-805. doi: https://dx.doi.org/10.1111/ctr.12581. PubMed PMID: 26113208.
12. Tremblay S, Nigro V, Weinberg J, Woodle ES, Alloway RR. 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. Am J 
Transplant. 2017;17(2):432-42. doi: 10.1111/ajt.13935.
13. Wlodarczyk Z, Squifflet JP, Ostrowski M, Rigotti P, Stefoni S, Citterio F, Vanrenterghem Y, 
Kramer BK, Abramowicz D, Oppenheimer F, Pietruck F, Russ G, Karpf C, Undre N. 
Pharmacokinetics for once- versus twice-daily tacrolimus formulations in de novo kidney 
transplantation: a randomized, open-label trial. Am J Transplant. 2009;9(11):2505-13. doi: 
https://dx.doi.org/10.1111/j.1600-6143.2009.02794.x. PubMed PMID: 19681813.
14. Leventhal JR, Mathew JM, Salomon DR, Kurian SM, Friedewald JJ, Gallon L, Konieczna I, 
Tambur AR, Charette J, Levitsky J, Jie C, Kanwar YS, Abecassis MM, Miller J. Nonchimeric 
HLA-Identical Renal Transplant Tolerance: Regulatory Immunophenotypic/Genomic 
Biomarkers. Am J Transplant. 2016;16(1):221-34. doi: 10.1111/ajt.13416.
15. Levitsky J, Miller J, Huang X, Gallon L, Leventhal JR, Mathew JM. Immunoregulatory Effects 
of Everolimus on <italic>In Vitro</italic> Alloimmune Responses. PLoS ONE. 
2016;11(6):e0156535. doi: 10.1371/journal.pone.0156535.
16. Levitsky J, Miller J, Huang X, Chandrasekaran D, Chen L, Mathew JM. Inhibitory Effects of 
Belatacept on Allospecific Regulatory T-Cell Generation in Humans. Transplantation. 
2013;96(8):689-96 10.1097/TP.0b013e31829f1607.
17. Emerson RO, Mathew JM, Konieczna IM, Robins HS, Leventhal JR. Defining the 
Alloreactive T Cell Repertoire Using High-Throughput Sequencing of Mixed Lymphocyte 
Reaction Culture. PLoS One. 2014;9(11):e111943. doi: 10.1371/journal.pone.0111943.
18. Sherwood AM, Emerson RO, Scherer D, Habermann N, Buck K, Staffa J, Desmarais C, 
Halama N, Jaeger D, Schirmacher P, Herpel E, Kloor M, Ulrich A, Schneider M, Ulrich CM, 
Robins H. Tumor-infiltrating lymphocytes in colorectal tumors display a diversity of T cell 
receptor sequences that differ from the T cells in adjacent mucosal tissue. Cancer 
immunology, immunotherapy : CII. 2013;62(9):1453-61. PubMed PMID: 23771160.
19. Robins HS, Ericson NG, Guenthoer J, O'Briant KC, Tewari M, Drescher CW, Bielas JH. 
Digital genomic quantification of tumor-infiltrating lymphocytes. Science translational 
medicine. 2013;5(214):214ra169. PubMed PMID: 24307693.
20. Robins HS, Srivastava SK, Campregher PV, Turtle CJ, Andriesen J, Riddell SR, Carlson 
CS, Warren EH. Overlap and effective size of the human CD8+ T cell receptor repertoire. 
Science translational medicine. 2010;2(47):47ra64. PubMed PMID: 20811043; PMCID: 
3212437.
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21. Morris H, DeWolf S, Robins H, Sprangers B, LoCascio SA, Shonts BA, Kawai T, Wong W, 
Yang S, Zuber J, Shen Y, Sykes M. Tracking donor-reactive T cells: Evidence for clonal 
deletion in tolerant kidney transplant patients. Sci Transl Med. 2015;7(272):272ra10. 
PubMed PMID: 25632034; PMCID: PMC4360892.
22. Degauque N, Elong Ngono A, Akl A, Lepetit M, Crochette R, Giral M, Lepourry J, Pallier A, 
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Laplaud D, Nicot A, Brouard S, Soulillou JP. Characterization of antigen-specific B cells 
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https://dx.doi.org/10.1371/journal.pone.0084273. PubMed PMID: 24386360.
IRB #: STU00205327 Approved by NU IRB for use on or after 6/3/2022 through 6/2/2023.

ICF_001.pdf: 
RECIPIENT ICF
Veloxis Gallon ICF 17 Sep 2019
Recipient
Page 1 of 12
Title of Research Study: Once-Daily Extended-Release Tacrolimus Vs. Twice-Daily 
Tacrolimus: Impact On T-Cell Subpopulations And Markers Of Renal Tubule-
Toxicity In Kidney Transplant Patients 
Investigator:   Lorenzo Gallon, MD
Supported By: This research is supported by Veloxis Pharmaceuticals Inc.
Financial Interest Disclosure:  
If your doctor is also the person responsible for this research study, please note that he is 
interested in both your clinical care and the conduct of this research study. You have the right to 
discuss this study with another person who is not part of the research team before deciding 
whether to take part in the research. 
Key Information: 
The first few pages of this document include a summary of this study to help you 
decide whether or not to participate. Detailed information is provided after the 
summary.
Why am I being asked to take part in this research study?
We are asking you to take part in this research study to find out if the drug Envarsus® XR has 
beneficial effects in people, such as yourself, who are scheduled to receive a kidney transplant 
from from either a living or deceased donor.
What should I know about a research study?

Someone will explain this research study to you.

You can choose not to take part.

You can agree to take part and later change your mind.

Your decision will not be held against you.

You can ask all the questions you want before you decide.
Why is this research being done?
This research study is sponsored by the pharmaceutical company Veloxis. You have been 
scheduled to have kidney transplant surgery. After receiving a kidney transplant, patients must 
take medications known as immunosuppressants that work to prevent rejection of the 
transplant. There are a number of such medicines available, e.g., cyclosporine (Neoral), 
tacrolimus (Prograf), everolimus (Certican, Zortress), MMF (Cellcept), EC-MPS (Myfortic), 
basiliximab (Simulect), steroids and others. These medications are typically taken in 
combinations to help reduce side effects and help prevent kidney rejection. 
LCP-Tacro, also known as Envarsus® XR, is a new once-daily form of  the drug tacrolimus, and 
was approved by the U.S. Food and Drug Administration (FDA) in 2015 to prevent rejection in 
kidney transplant recipients. It is a prolonged-release drug, which uses Veloxis MeltDose 
technology to deliver the dose of the tacrolimus over a longer period of time. It is taken once a 
day rather than twice a day.
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The main purpose of this study is to compare the transplanted kidney function of recipients 
taking once-a-day or twice-a-day tacrolimus at 2 weeks, 3 months and 12 months post 
transplant.
How long will the research last and what will I need to do?
We expect that you will be in this research study for 12 months.
At your pre-transplant visit, you will be assigned to one of two study medication (or “treatment”) 
groups. The treatment you get will be chosen by chance, like flipping a coin. Neither you nor the 
study doctor will choose what treatment you get. You will have an equal chance of being give 
either treatment.
Depending on what treatment group you are assigned to, post-transplant you will receive either:

Twice daily Tacrolimus given according to standard of care dosing

Once daily extended release dose of tacrolimus (Envarsus® XR)
In either group you will receive MMF/myfortic according to standard of care dosing.
You will return to the clinic 3 times, at approximately 2 weeks, 3 months and 12 months post 
transplant. At each of these visits you will have blood and urine samples collected. In addition,  
tissue samples will be collected at your 3 and 12 month visits (from standard of care kidney 
biopsy scheduled at this visit). 
In addition, blood, urine and tissue samples will be collected at the time of any for cause biopsy 
you might be required to have. No biopsies will be performed solely for this research protocol.
More detailed information about the study procedures can be found under the section What 
happens if I say “Yes, I want to be in this research”?
Is there any way being in this study could be bad for me?
The most serious risks associated with either study group (either twice daily tacrolimus or 
Envarsus® XR)  include high blood pressure, kidney damage, or  diabetes. 
The most serious risk in your standard of care kidney biopsies and the collection of additional 
tissue samples for research includes bleeding in or around your kidney which can lead to a fall 
in blood pressure and rise in heart rate.
More detailed information about the risks of this study can be found under “Is there any way 
being in this study could be bad for me? (Detailed Risks)”
Will being in this study help me any way?
We cannot promise any benefits to you or others from your taking part in this research. 
However, you will receive close monitoring of your transplanted kidney and medical care during 
the study. 
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The benefits of LCP-Tacro/Envarsus XR are not known. Information from this study may help you 
and/or other people who receive a kidney transplant in the future.
What happens if I do not want to be in this research?
Taking part in research is completely voluntary. You decide whether or not to participate. If you 
choose to not participate, there will be no penalty to you or loss of benefit to which you are 
entitled.  
Detailed Information:
The rest of this document includes detailed information about this study (in addition to the 
information listed above).
Who can I talk to?
For urgent clinical concerns, please call 312-695-8900. 
If you have questions, concerns, or complaints, or think the research has hurt you, talk to Dr. 
Lorenzo Gallon at 312-695-4457. He is available Monday-Friday, 9am to 5pm. 
You can also call this clinic after hours, on weekends, and holidays at 312-695-8900 and ask to 
speak with the kidney transplant research nurse on call.
This research has been reviewed and approved by an Institutional Review Board (IRB). You 
may talk to them at (312) 503-9338 or irb@northwestern.edu if:

Your questions, concerns, or complaints are not being answered by the research team.

You cannot reach the research team.

You want to talk to someone besides the research team.

You have questions about your rights as a research participant.

You want to get information or provide input about this research.
How many people will be studied?
We expect about 50 people here will be in this research study.
What happens if I say “Yes, I want to be in this research”?
As a subject in this study, you will be asked to come to Northwestern Medicine Kovler Organ 
Transplantation Center (676 North St. Clair Street, Suite 1900), Chicago, IL.
At your pre-transplant visit, you will be assigned to one of two study medication (or “treatment”) 
groups. The treatment you get will be chosen by chance, like flipping a coin. Neither you nor the 
study doctor will choose what treatment you get. You will have an equal chance of being give 
either treatment. Both forms of tacrolimus (twice daily tacrolimus or once daily extended release 
dose of tacrolimus) are FDA approved.
The standard of care induction immunotherapy you receive at the time of your transplant will be 
the same whether you are assigned to treatment Group 1 or Group 2. 
The post-transplant treatment groups (Group 1 and Group 2) are described below:
Group
Medication
Tacrolimus
MMF/myfortic
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1
Tacrolimus+MMF/myfortic
Twice daily 
Tacrolimus given 
according to 
standard of care 
dosing to achieve a 
12 hour trough 
concentration of 8-
12 ng/ml
Given according to 
standard of care 
dosing
2
LCP-Tacrolimus/
Envarsus® XR 
+MMF/myfortic
Once daily extended 
release dose of 
tacrolimus to 
achieve a 24-hour 
trough concentration 
of 8-12 ng/ml
Given according to 
standard of care 
dosing
Study Visit Schedule for All Subjects (Groups 1 and 2)
Regardless of the group you are assigned to (Group 1 or Group 2), you will have blood, urine 
and tissue samples collected for research as outlined below:
Time 
(all time points relative 
to transplant)
Blood Draw
(50 ml or about 4 
tablespoons)
Urine Samples
(Up to 200 cc or 1 
cup)
Kidney Biopsy
Pre-transplant
X
2 weeks post
(+/- 7 day)
X
3 months post
(+/- 10 Days)
X
X
X
12 months post
(+/- 10 Days)
X
X
X
Any For-Cause 
Biopsy
X
X
X
Blood Collection
We will collect and store a sample of your blood at the following study visits: Pre-transplant, 3 
month and 12 month post-transplant visits. In the case of any for-cause biopsy, we will also 
collect blood. At each of these visits we will collect 50 ml (about 4 Tablespoons) of blood. 
Urine Collection
We will collect and store samples of urine at the following study visits: 2 weeks, 3 months and 
12 months post transplant. In the case of any for-cause biopsy, we will also collect urine 
samples. At each of these visits we will collect up to 200 cc (about 1 cup) of urine.
Kidney Tissue Collection
We will collect a piece of kidney tissue from you during standard of care biopsy procedures at 
the following time points: 3 months and 12 months post transplant. In the case of any for-cause 
biopsy, we will also collect tissue. No biopsies will be performed solely for this research 
protocol. The biopsy will be obtained if needed at time of standard of care visits. 
Typically, only tissue viewed as excess for clinical purposes will be diverted for this study. If 
there is not enough tissue left from the biopsy for clinical purposes, study staff will ask your 
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permission for an additional pass to get biopsy tissue for the research study. A second biopsy 
pass can minimally increase the risk associated with the procedure. Samples will be obtained by 
trained practitioners fully informed of the needs for diagnosis and use of biopsies only in the 
situation where adequate biopsy samples are obtained.
From your blood, urine and tissue samples, we plan to examine the genes behind your body’s 
immune response (how your body recognizes and protects itself from germs and other things 
that seem foreign and unsafe). The blood samples will also be used to examine your white 
blood cell function. Additionally, we will analyze the urine samples for kidney injury markers.
What are my responsibilities if I take part in this research?
If you take part in this research, you will be responsible to take the study medication as directed. 
It is important that you tell the study site personnel about any other medication you are taking 
before and during the study including herbs and vitamins.
What happens if I do not want to be in this research?
You may choose not to take part in this research study. Your decision whether to take part or 
not will not affect your relationship with your study doctor or with Northwestern. You will not lose 
benefits to which you would be otherwise entitled and your choice not to be in this study will not 
negatively affect your right to any present or future medical treatment.
What happens if I say “Yes”, but I change my mind later?
You can withdraw from this research study at any time and it will not be held against you. 
However, per standard of care treatment, you may not stop taking anti-rejection medication.
You will be asked to return to the clinic as soon as possible to check how you and your kidney is 
doing. For this visit, you should bring your study medications to the clinic. During this visit, you 
and the study doctor may choose to change your treatment. Please be aware though that you 
cannot stop immunosuppressive treatment as you will have an increased risk of rejection. 
During this period data will be collected that will help the Sponsor understand the effect of study 
treatment on your health and the status of your transplanted kidney. This data would include 
vital signs, survival, graft loss/re-transplantation, any rejection of the kidney transplant or 
biopsies done, hospitalizations, laboratory assessments and certain side effects you may have 
during that time. 
Because all of your visits are also regularly scheduled standard of care (SOC) visits, you will 
keep your clinic visits even if you leave the study.
If you stop being in the research study, already collected data may not be removed from the 
study database. You will be asked whether the study staff can collect data from your routine 
medical care. If you agree, this data will be handled the same as research data. 
Detailed Risks:  Is there any way being in this study could be bad for me?
The risks of this study include any possible side effects of study medications and risks associated 
with the taking of your biological samples. Your doctor will discuss these risks with you before you 
begin taking the study medication.
You should report any side effects that you feel to your study staff as soon as possible. Every 
precaution will be taken to ensure that side effects will be acted upon immediately. As with all 
immunosuppressive medications, all patients are at an increased risk of infections and 
malignancies. In such situations, your doctor may have to treat you with other drugs and may 
have to stop or reduce your immunosuppressive drugs.
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Side effects of Tacrolimus (Prograf®, Envarsus® XR)

High blood pressure

High blood sugar

Diabetes

Kidney damage

Trembling

Headaches 

Burning in the hands and/or feet, 

Itchy skin

Increased levels of potassium in the 
blood (which can cause nausea and an 
irregular heartbeat)

Increase in cholesterol and or fat levels 
in the blood

Unsteady movements or clumsiness

Thickening of the heart muscle

Insomnia

Abdominal pain

Diarrhea

Nausea

Less common but more serious side effects include:
o
inflammation of the lung tissue
o
BK nephropathy (in subjects who receive a renal transplant), kidney damage caused by a 
BK virus infection
o
posterior reversible encephalopathy syndrome (PRES), a syndrome characterized by 
headache, seizures and vision changes
o
progressive multifocal leukoencephalopathy (PML), a serious infection that can lead to 
disability or death
Side effects of Corticosteroids: 

Fluid build-up

Facial swelling

Weight gain

Increased appetite 

High blood pressure

Muscle weakness

Bone problems 

Fragile skin

Wound healing problems

Mental problem
Side effects of MMF/Myfortic: 

Diarrhea or constipation

nausea/vomiting

Leucopenia (fewer white cells in your 
blood)

Pains in the abdomen, chest or back 

Headache

Anemia (decrease in red blood cells)

Tthrombocytopenia (fewer of the blood 
cells known as ‘platelets’) 

Hypertension (raised blood pressure)

Edema (swelling).
Blood Draws
The risks of drawing blood include a bruise at the point where the blood is taken, redness and 
swelling of the vein and infection. There is a rare chance of getting dizzy or fainting. Care will be 
taken to avoid these complications.
Urine Collections
There are no anticipated risks with collecting urine.
Biopsies and the Collection of Additional Tissue Samples for Research
When patients have kidney tissue samples taken, 3 – 4 out of 100 people have bleeding in the 
kidney (3.5% chance) and 2 – 3 out of 100 people have bleeding around the kidney (2.5% 
chance). Bleeding in or around the kidney can lead to a fall in blood pressure and rise in heart 
rate. One out of 100 people who have a transplant kidney biopsy require a blood transfusion or 
placement of a urinary catheter (1% chance). In 1 out of 1,000 people, a kidney biopsy may lead 
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to a need for surgery or loss of the kidney (0.1% chance). Additional risks include pain and/or 
bleeding at the site of the biopsy, infection, discomfort, and blood-stained urine.
This study involves the use of your identifiable, personal information and there is a chance that 
a loss of confidentiality could occur. The researchers have procedures in place to lessen the 
possibility of this happening.  See the section below titled: “What happens to the information 
collected for the research?”. 
What do I need to know about reproductive health and/or sexual activity if I am in 
this study? 
The research may hurt a pregnancy or fetus in ways that are unknown. These may be a minor 
inconvenience or may be so severe as to cause death. 
You should not be or become pregnant, father a baby or breastfeed while on the study and for 3 
months after the study is completed. If you are sexually active, both men and women should use 
a highly effective means of birth control while taking part in this research study and for 3 months 
after study participation is completed. 
If you are sexually active, both men and women should use at least one effective means of birth 
control while participating in this research study. According to the World Health Organization 
and the United States Center for Disease Control and Prevention, the most effective forms of 
birth control include complete abstinence, surgical sterilization (both male and female), 
intrauterine devices (IUDs), and the contraceptive implant.  The next most effective forms of 
birth control include injectables, oral contraceptive pills, the contraceptive ring, or the 
contraceptive patch.  Acceptable but least effective methods of birth control include male 
condoms (with or without spermicide) and female condoms.
If you or your partner become pregnant while taking part in this research study or for 3 months 
after you complete the study, it is important that you tell the study doctor or other research team 
member immediately. You may be required to stop participation in this study; however, other 
treatment options will be discussed with you at that time if necessary.
If you or your partner are considered to be postmenopausal, you are not required to use 
contraception while participating in this research study. Postmenopausal women rarely become 
pregnant. If you or your partner become pregnant while taking part in this research study or for 3 
months after you complete the study, it is important that you tell the study doctor or other 
research team member immediately. You may be required to stop participation in this study; 
however, other treatment options will be discussed with you at that time if necessary.
Will it cost me anything to participate in this research study?
There will be no additional costs to you for taking part in this study. You will not be charged for  
any of the tests and procedures performed solely for research purposes.
You and your insurance company will be charged for the health care services that you would 
ordinarily be responsible to pay. This would include charges for all drugs given as standard of 
care, including tacrolimus and tacrolimus-LCP/Envarsus XR.
In some cases, insurance will not pay for services ordinarily covered because these services 
were performed in a research study. You should check with your insurance to see what services 
will be covered by your insurance and what you will be responsible to pay.
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Will being in this study help me in any way?
We cannot promise any benefits to you or others from your taking part in this research. 
However, you will receive close monitoring of your transplanted kidney and medical care during 
the study. 
The benefits of LCP-Tacro/Envarsus XR are not known. Information from this study may help you 
and/or other people who receive a kidney transplant in the future.
What happens to the information collected for the research?
Efforts will be made to limit the use and disclosure of your personal information, including 
research study and medical records, to people who have a need to review this information. We 
cannot promise complete secrecy. Organizations that may inspect and copy your information 
include the IRB and other representatives of this institution, ethics committees, health authority 
inspectors, the FDA, Veloxis study monitors and auditors, and authorized clinical research 
organization representatives.
Your biological samples will be stored at the Immune Monitoring Core (IMC) under the 
leadership of Co-Investigator Dr. James Mathew of the Comprehensive Transplant Center 
(CTC) of Northwestern University. 
After certain tests have been performed, de-identified samples will be sent to Adaptive 
Biotechnoligies, Seattle, for DNA purification and ImmunoSEQ analyses.
Leftover samples at the CTC may be stored for future research studies, if you give your consent 
to this option.
If the sponsor pays any of your medical expenses, we may be required to give the sponsor your 
name, date of birth, and Medicare ID or social security number.
The sponsor, monitors, auditors, the IRB, the Northwestern University Office for Research 
Integrity, the US Office of Research Integrity (ORI), the US Office for the Protection of Human 
Research Protections (OHRP), the US Food and Drug Administration (FDA) may be granted 
direct access to your medical records to conduct and oversee the research. By signing this 
document you are authorizing this access. We may publish the results of this research. 
However, we will keep your name and other identifying information confidential.
A description of this clinical trial will be available at http://www.ClinicalTrials.gov, as required by 
U.S. Law. This Web site will not include information that can identify you. At most, the Web site 
will include a summary of the results. You can search this Web site at any time.
Data Sharing 
De-identified data from this study may be shared with the research community at large to 
advance science and health. We will remove or code any personal information that could 
identify you before files are shared with other researchers to ensure that, by current scientific 
standards and known methods, no one will be able to identify you from the information we 
share. Despite these measures, we cannot guarantee anonymity of your personal data.
Can I be removed from the research without my OK?
The person in charge of the research study or the sponsor can remove you from the research 
study without your approval. Possible reasons for removal include:
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1. Staying in the study would be harmful.
2. You need treatment not allowed in this study.
3. You fail to follow instructions.
4. You become pregnant.
5. The study is cancelled.
6. Your treatment arm is stopped.
We will tell you about any new information that may affect your health, welfare, or choice to stay 
in the research.
What else do I need to know? 
If you become ill or get injured as a result of this study (medications or procedures), you should 
seek medical treatment through your doctor or treatment center of choice. You should promptly 
tell the study doctor about any illness or injury.  
The hospital [university, researchers] will not pay for medical care required because of a bad 
outcome resulting from your participation in this research study. This does not keep you from 
seeking to be paid back for care required because of a bad outcome.
Travel Expenses:
You will receive a coupon for free parking for your study visits. It is only valid if you park in the 
222 E. Huron Street Garage which is connected to the Galter Pavilion (clinics) and the Feinberg 
Pavilion (hospital) by the street overpass on the second floor. The garage is also known as 
“University Parking Garage A.” If you park in any other garage, this parking coupon will not be 
valid and you will need to pay for your own parking. If you do not drive in for your study visits, 
the study staff will discuss other options of equal value.
A federal law, called the Genetic Information Nondiscrimination Act (GINA), generally makes it 
illegal for health insurance companies, group health plans, and most employers to discriminate 
against you based on your genetic information. This law generally will protect you in the 
following ways:

Health insurance companies and group health plans may not request your genetic 
information that we get from this research.

Health insurance companies and group health plans may not use your genetic 
information when making decisions regarding your eligibility or premiums.

Employers with 15 or more employees may not use your genetic information that we get 
from this research when making a decision to hire, promote, or fire you or when setting 
the terms of your employment.
HIPAA Authorization
We are committed to respect your privacy and to keep your personal information confidential.  
When choosing to take part in this study, you are giving us the permission to use your personal 
health information that includes health information in your medical records and information that 
can identify you. For example, personal health information may include your name, address, 
phone number or social security number. Your health information we may collect and use for 
this research includes: 

All information in a medical record 

Results of physical examinations

Medical history
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
Lab tests, or certain health information indicating or relating to a particular condition as 
well diaries and questionnaires

Records about study medication or drugs

Billing information

HIV testing results

Genetic health information: DNA Testing
During this study you may be coming to a Northwestern Memorial Healthcare Corporation entity 
(for example, Northwestern Memorial Hospital, Prentice Women’s Hospital) for research 
appointments or to get clinical services, such as lab tests, needed for the study.  When that 
happens, you will be scheduled for these services through the NMHC computer system.  When 
a clinical exam or lab is done by NMHC or one of its employees for the purpose of this research 
study, that information will be kept in both NMHC’s clinical records and in the study records.
The following clinical providers may give the researchers information about you:  all current and 
previous health care providers, including but not limited to the Shirley Ryan AbilityLab 
(SRALAB), Northwestern Medical Group (NMG), Northwestern Memorial Hospital (NMH), 
Northwestern Lake Forest Hospital (NLFH).
Once we have the health information listed above, we may share some of this information with 
the following offices or entities outside of Northwestern University and its clinical partners (or 
affiliates):  the Northwestern University Institutional Review Board Office and Office for 
Research Integrity; the US Office of Research Integrity; the US Office for Human Research 
Protections; the US Food and Drug Administration.  
Any research information shared with outside entities will not contain your name, address, 
telephone or social security number or any other personal identifier unless disclosure of the 
identifier is necessary for review by such parties or is required by law or University policy 
[except that such information may be viewed by the Study sponsor and its partners or 
contractors at the Principal Investigator’s office].
The following entities may receive your health information:

Authorized members of the Northwestern University workforce, who may need to see 
your information, such as administrative staff members from the Office for Research, 
Office for Research Integrity and members of the Institutional Review Board.

Clinical affiliates, including but not limited to the Shirley Ryan AbilityLab (SRALAB), 
Northwestern Medical Group (NMG), Northwestern Memorial Hospital (NMH), 
Northwestern Lake Forest Hospital (NLFH), and the Ann & Robert H. Lurie Children’s 
Hospital of Chicago (Lurie Children’s).  Your participation in this clinical trial may be 
tracked in an electronic database and may be seen by investigators running other trials 
that you are enrolled in and by your healthcare providers. 

Clinical affiliates, including but not limited to Northwestern Medical Group (NMG), 
Northwestern Memorial Hospital (NMH), and Northwestern Lake Forest Hospital (NLFH), 
for purposes including, but not limited to, the affiliate’s provision of care to you and/or the 
affiliate’s scheduling of appointments and/or billing activities.

Other University research centers and University contractors who are also working on 
the study,

Study monitors and auditors who make sure that the study is being done properly, 
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
Veloxis Pharmaceuticals, who is sponsoring the study, and that company’s contractors 
and partners.

Government agencies and public health authorities, such as the Food and Drug 
Administration (FDA) and the Department of Health and Human Services (DHHS).

The study doctor must report positive HIV tests to the Illinois Department of Public 
Health (IDPH)).  The IDPH keeps track of all persons in the state with positive HIV tests.  
Information provided to IDPH include name, social security number, current address, 
telephone number, age, date of birth, age at diagnosis, race, ethnicity, sex, current 
gender, country of birth, residence at diagnosis and facility where diagnosis of HIV or 
AIDS was established.
Those persons who get your health information may not be required by Federal privacy laws 
(such as the Privacy Rule) to protect it. Some of those persons may be able to share your 
information with others without your separate permission.
The results of this study may also be used for teaching, publications, or for presentation at 
scientific meetings.  
Unless you revoke your consent, it will not expire.
Although you may revoke consent to take part in this research at any time and in any format, 
you must revoke authorization for use or disclosure of your health information in writing. To 
revoke your authorization, write to:
Lorenzo Gallon, MD
Northwestern University Comprehensive Transplant Center
676 N. St. Clair St., Ste. 1900
Chicago, IL 60611
You do not have to authorize the use or disclosure of your health information; however, you will 
not be allowed to take part in this research study. If you do not authorize the use or disclosure of 
your health information, it will not affect your treatment by health care providers, or the payment 
or enrollment in any health plans, or affect your eligibility for benefits.
A copy of this signed consent document, information about this study, and the results of any test 
or procedure done may be included in your medical records and may be seen by your insurance 
company.
Optional Elements:
The following research activities are optional, meaning that you do not have to agree to them in 
order to take part in the research study. Please indicate your willingness to participate in these 
optional activities by placing your initials next to each activity.
I agree
I disagree
_______
_______
The researcher may contact me in the future to see whether I am 
interested in taking part in other research studies by the Principal 
Investigator of this study.
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I agree
I disagree
_______
_______
The researcher may retain any leftover blood or tissue samples 
taken during the study. These samples may be used for other 
research not related to this study. These samples will be retained 
in non-identifiable form, meaning that there will be no information 
associated with the blood or samples that will allow anyone to 
know my identity. 
_______
_______
If necessary, the researcher may take an additional tissue sample 
during a biopsy.
Your signature documents your permission to take part in this research.  You will be provided a 
copy of this signed document.
_______________________________________________      __________________
Signature of Participant                                                               Date
_______________________________________________
Printed Name of Participant
____________________________________________            __________________
Signature of Person Obtaining Consent                                     Date
______________________________________________________
Printed Name of Person Obtaining Consent
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