A Prospective, Pilot Trial to Compare the Efficacy of Tacrolimus Extended-Release (Envarsus XR) to Tacrolimus Immediate-Release on Suppression of Donor-Specific Antibodies in HLA Sensitized Kidney Transplant Recipients
Phase: PHASE4
Conditions: Kidney Transplant Rejection
Sponsor: Cedars-Sinai Medical Center

 
 
 
 
 
 
 
 
Official Title: A Prospective, Pilot Trial to Evaluate Safety and Tolerability of Tacrolimus 
Extended-Release (Astagraf XL) in HLA Sensitized Kidney Transplant Recipients 
NCT #: NCT03194321 
Document Date: January 03, 2022 

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STUDY PROTOCOL 
A Prospective, Pilot Trial to Compare the Efficacy of Tacrolimus Extended-Release (Envarsus 
XR) to Tacrolimus Immediate-Release on Suppression of Donor-Specific Antibodies in HLA 
Sensitized Kidney Transplant Recipients 
 
Principal Investigator 
Name: Edmund Huang, M.D. 
Institution/Organization: Cedars-Sinai Medical Center 
Address: 8900 Beverly Blvd., Los Angeles, CA  90048 
Phone: 310-248-6528 
Fax: 310-423-4678 
Email: edmund.huang@cshs.org 
 
Co-Investigators  
 
Ashley Vo, Pharm.D. 
Stanley Jordan, M.D. 
Reiad Najjar, M.D. 
Alice Peng, M.D. 
Supreet Sethi, M.D. 
Noriko Ammerman, Pharm.D. 
 
 
Institution/Organization:  
 
Cedars-Sinai Medical Center 
Address: 8900 Beverly Blvd., Los Angeles, CA  90048 
Phone: 310-423-2641 
Fax: 310-423-4678 
 
 
Research Coordinator  
 
Noriko Ammerman, Pharm.D. 
Comprehensive Transplant Center, Kidney Transplant Program 
Cedars-Sinai Medical Center 
8900 Beverly Blvd 
Los Angeles, CA 90048 
Phone: (310) 423-1518  Fax: (310) 423-4678  
Email: noriko.ammerman@cshs.org 
 
 
 

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TABLE OF CONTENTS 
1.    Background and rationale………………………………………………………………3 
1.1 Key differences between extended-release tacrolimus (Envarsus XR) and immediate-
release tacrolimus……………………………………………………………..………...3 
1.2 Pharmacokinetics of Envarsus XR compared to immediate-release tacrolimus 
………………..................................................................................................................3 
1.3 One-year results of a double-blind, randomized controlled trial of extended- and 
immediate 
release 
tacrolimus 
in 
de 
novo 
kidney 
transplant 
recipients.………………………………………………………………………….…....4 
1.4 One-year results among stable kidney transplant recipients converted from immediate-
release tacrolimus to Envarsus XR……………………………………………………..5 
2.    Primary objective..……………………………………………………………………...5 
2.1    Secondary objectives..………………………………………………………………….6 
3.    Inclusion criteria………………………………………………………………………..6       
3.1    Exclusion criteria……………………………………………………………………….6 
4.      Study design and methods……………………………………………………………....7    
4.1    Primary endpoint………………………………………………………………………..8 
4.2    Secondary endpoints……………………………………………………………………8 
4.3    Statistical analysis…………………………………………………………..…………..8 
5.      Monitoring for AE/SAEs………………………………………………………….……9 
6.      Project enrollment………………………………………………………………….…...9 
7.      Schedule of events……………………………………………………………….…….10 
8.      References……………………………………………………………………….……..11             
 
 
 
 

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1. Background and Rationale 
 
Extended-release tacrolimus (Envarsus XR) received FDA approval in July, 2015 for the 
prevention of allograft rejection in kidney transplantation on the basis of two separate phase 3 
trials of de novo and stable kidney transplant recipients that demonstrated non-inferiority to 
immediate-release tacrolimus for the composite outcome of death, graft failure, biopsy-proven 
acute rejection, or loss to follow-up within 12 months (1,2).    
 
Both phase 3 trials involved mostly low immunologic risk recipients with follow-up to one year.  
It has been previously shown that the incidence of de novo donor-specific antibodies (DSA) in the 
first year after kidney transplant in low-immunologic patients is low, developing in only 2%-11% 
of unsensitized de novo kidney transplant recipients (3-6).  Donor-specific antibodies (DSA) are 
the primary mediator of antibody-mediated rejection and their development after transplant is a 
major risk factor for late allograft failure (7).   It is now believed that antibody-mediated rejection 
is the most common cause of late allograft failure (8,9).  However, neither of the two phase 3 trials 
were able to adequately assess the effect of Envarsus XR on the development of donor specific 
antibodies and therefore, the efficacy of Envarsus XR in higher immunologic risk recipients is not 
known.   Therefore, a comparative study of extended- and immediate-release tacrolimus in highly-
sensitized recipients is warranted. 
 
1.1  Key differences between Envarsus XR and immediate-release tacrolimus 
 
In contrast to the immediate-release formulation of tacrolimus, which is intended for twice-daily 
administration, Envarsus XR is an extended-release formulation designed for once-daily 
administration.   Envarsus XR is manufactured using the MeltDose® delivery technology, which 
is based upon the principle that a smaller particle size yields a greater surface area and facilitates 
more rapid dissolution and greater absorption in the gastrointestinal tract.  MeltDose® technology 
involves heating the active ingredient (tacrolimus) to create a “MELT” solution, which is then 
linked to a carrier before incorporation into a tablet.  In doing so, Envarsus XR is more readily 
absorbed upon ingestion and is associated with more consistent tacrolimus concentrations. 
 
1.2 Pharmacokinetics of Envarsus XR compared to immediate-release tacrolimus 
A phase 2, open-label, multicenter study of sixty adult stable kidney transplant recipients who were 
converted from immediate-release tacrolimus (Prograf)  to Envarsus XR was performed to 
compare the pharmacokinetics of Prograf compared to Envarsus XR (10).  In this study, a 30% 

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lower total daily dose of Envarsus XR was associated with a similar AUC24 as Prograf.  Envarsus 
XR was associated with a lower peak (Cmax), ranging from 71.6% to 73.9% of the Cmax associated 
with Prograf (figure 1).  The percent fluctuation (peak-to-trough change in drug concentration 
around the average concentration) and percent swing (peak-to-trough change in drug concentration 
relative to the minimum concentration) were significantly lower for Envarsus XR compared to 
Prograf (p=0.0001 and p=0.0004, respectively; figure 1).  Thus, Envarsus XR is associated with 
more stable whole blood concentrations compared to Prograf. 
 
 
1.3  Two-year results of a double-blind, randomized controlled trial of extended- and 
immediate release tacrolimus in de novo kidney transplant recipients. 
A phase 3 randomized, double-blind, double-dummy multicentre trial was performed to assess the 
efficacy and safety of Envarsus XR compared to immediate-release tacrolimus (13).  In this study, 
543 de novo kidney transplant recipients were randomized to receive Envarsus XR (n=268) or 
immediate-release tacrolimus (n=275) in conjunction with mycophenolate mofetil or 
mycophenolic acid, and corticosteroids.  The primary composite endpoint was composed of death, 
graft failure, biopsy-proved acute rejection, and loss to follow-up within 24 months.  Using a pre-

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specified 10% non-inferiority margin, Envarsus XR was non-inferior to immediate-release 
tacrolimus for the primary endpoint (at 24 months: Envarsus XR: 23.1%; immediate-release 
tacrolimus 27.3%; treatment difference -4.14%, 95% CI: -11.38%-3.17%).  There were no 
observed differences in each component of the primary endpoint between Envarsus XR and 
immediate-release tacrolimus [death, p=0.8); graft failure (p=0.5), biopsy-proven acute rejection 
(p=0.8), loss to follow-up (p=0.4)].  Furthermore, the mean number of adverse events per patient 
was similar between the two drugs (Envarsus XR: 14.3%; immediate-release tacrolimus: 14.4%) 
as were the mean number of serious adverse events per patient (Envarsus XR: 1.8%; immediate-
release tacrolimus: 1.9%). 
 
1.4  One-year results among stable kidney transplant recipients converted from immediate-
release tacrolimus to Envarsus XR 
A phase III, prospective, randomized, open-label study was performed among 324 patients (162 
in each arm) who were considered stable.  A stable patient was defined as one who was between 
3 months and 5 years post-transplant, on a stable tacrolimus dose, with an estimated glomerular 
filtration rate ≥30 ml/min, and without an episode of acute rejection requiring antibody therapy 
within 3 months of enrollment.  Patients were randomized to remain on immediate-release 
tacrolimus or convert to Envarsus XR.  The primary endpoint was a composite outcome of death, 
graft failure, biopsy-proven acute rejection, or loss to follow-up within 12 months.  There were 
only 4 events in each group, corresponding to a primary efficacy failure rate of 2.5% (95% CI: -
4.2%-4.2%) which fell within the pre-specified non-inferiority margin.  There was no difference 
in each component of the composite outcome – death, graft failure, or biopsy-proven acute 
rejection.  Furthermore, there was no difference in adverse events between the two groups. 
 
2.  Primary objective 
The primary objective is to assess whether the incidence of biopsy-proven acute rejection within 
the first 12 months of transplant is comparable between highly sensitized patients maintained on 
Envarsus XR and immediate-release tacrolimus.   
 
2.1  Secondary Objectives 
Secondary objectives of the study are to assess markers of immunosuppression efficacy between 
Envarsus XR-treated and immediate-release tacrolimus-treated highly sensitized recipients.  
Markers to be assessed include the presence of de novo and pre-existing donor-specific HLA 
antibodies, estimated glomerular filtration rate (eGFR; CKD-Epi equation), and the level of donor-
derived cell-free DNA (Allosure®), a biomarker with high sensitivity/specificity for rejection. 

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3.  Inclusion criteria 
1.   Recipient of a deceased or living donor kidney allograft 
 
2.   Patients must have undergone desensitization therapy with or without plasma exchange 
prior to transplant or be administered desensitization therapy peri-operatively post-transplant 
 
3.  Age 18 and over 
 
4.  Able to understand and provide informed consent 
 
5. At transplant, patient must have an acceptable crossmatch (as defined by a T- or B-FCMX 
≤ 225 MCS) from a non-HLA identical donor. A negative crossmatch is defined as a T pronase 
FCMX <70 MCS or a T- FCMX <50 MCS and a B pronase FCMX <130 MCS or a B-FCMX 
<100 MCS. 
 
 
3.1  Exclusion criteria 
1. Recipients of a dual simultaneous kidney/liver, kidney/heart, kidney/lung, or 
kidney/pancreas transplant 
 
2. History of hypersensitivity to any of the study drug or to drugs of similar chemical 
classes 
 
3. Patients with a clinically significant systemic infection within 30 days prior to 
transplant 
 
4. Patients who have any history of a surgical or medical condition that may affect 
absorption of drug, such as severe diarrhea, active peptic ulcer disease, or uncontrolled 
diabetes mellitus, which in the opinion of the investigator at the time of enrollment, might 
significantly alter the absorption, distribution, metabolism and/or excretion of study 

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medication. 
 
5. Women of childbearing potential who are either pregnant, lactating, planning to become 
pregnant during this trial, or with a positive serum or urine pregnancy test. Women of 
childbearing potential must be willing to agree to contraceptive practices. 
 
6. Patients who are PCR positive for hepatitis B, hepatitis C, or HIV. 
 
4.  Study design and methods 
This is a single center pilot study employing an open-label, randomized controlled trial design of 
twenty subjects assigned to receive either Envarsus XR or immediate-release tacrolimus as part 
of their maintenance immunosuppression regimen (10 subjects will be randomized to each arm).  
All patients aged 18 and older and requiring desensitization prior to or at kidney 
transplantation may be included in the study.    Subjects will take part in the study until they are 
one-year post-transplant.   All subjects will require informed consent.   
 
At the time of screening, subjects will receive a physical exam and undergo lab testing as detailed 
below in the evaluation schedule.  Alemtuzumab (Campath 1H, Lemtrada) or thymoglobulin will 
be administered to all subjects for induction immunosuppression immediately post-transplant. 
Maintenance immunosuppression will consist of Envarsus XR or immediate-release tacrolimus, 
mycophenolate mofetil (Cellcept) or mycophenolic acid (Myfortic), and prednisone. The starting 
dose of Envarsus XR will be 4 mg PO daily, immediate release tacrolimus will be started at 
0.1mg/kg/day PO BID; Envarsus XR and immediate release tacrolimus will be titrated based on 
drug levels as per usual standard practice.   Depending on the time of the kidney transplant, study 
drug or immediate release tacrolimus will be given the same day as transplant or next day. Study 
drug initiation may be delayed to post-operative day #2 per PI discretion. Patients will 
receive antimicrobial prophylaxis as per Cedars-Sinai Medical Center (CSMC) protocol 
(valganciclovir x 6 months, TMP/SMX x 9-12 months, and fluconazole x 1 month). Lab tests and 
physical exams for safety will take place according to the evaluation schedule below.   
Tacrolimus trough level, complete metabolic panel, complete blood count with differential, donor 
specific antibodies, and urinalysis with culture will be assessed according to the evaluation 
schedule below.  Subjects will complete the study at one year post-transplant.  Consent may be 
withdrawn by the study participant at any time.  The investigator may also withdraw the study 
participant at any time if there are any safety concerns. 
 

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4.1  Primary endpoint 
The primary endpoint is the incidence of biopsy-proven acute rejection (cell-mediated and/or 
antibody-mediated) over twelve months among patients maintained on Envarsus XR and 
immediate-release tacrolimus. 
 
4.2   Secondary endpoints 
 
Secondary endpoints include: 
 
a) the proportion of patients in each arm who develop de novo donor specific antibodies (dnDSA) 
at one year after transplant;  
 
b) the time to development of de novo DSA; 
 
c) mean change in MFI of pre-existing DSA at transplant over one year among patients on 
Envarsus XR versus immediate-release tacrolimus;  
 
d) mean percentage of donor-derived cell-free DNA (Allosure®) at six months and one year among 
patients on Envarsus XR versus immediate-release tacrolimus;  
 
e) estimated GFR (CKD-EPI equation) over one year after transplant among patients on Envarsus 
XR versus immediate-release tacrolimus;  
 
f) graft survival over one year among patients on Envarsus XR versus immediate-release 
tacrolimus;  
 
g) patient survival over one year among patients on Envarsus XR versus immediate-release 
tacrolimus. 
 
 
 
4.3  Statistical analysis 
The Kaplan-Meier product limit method will be performed to assess freedom from biopsy-proven 
acute rejection (cell-mediated and/or antibody-mediated), graft loss, and death among patients 
maintained on Envarsus XR and immediate-release tacrolimus over twelve months.  Statistical 
comparison will be made with the log-rank test. 
 
 
The proportion of patients in each arm who develop de novo donor specific antibodies (dnDSA) 
at one year after transplant will be compared using Fisher’s exact test.  The Kaplan-Meier product 
limit method will be used to calculate time to development of de novo DSA, using the log-rank 
test for statistical comparison between patients receiving Envarsus XR and immediate-release 
tacrolimus. 
 

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The mean change in MFI of pre-existing DSA at transplant at baseline and at 12 months among 
patients on Envarsus XR versus immediate-release tacrolimus will be compared using the t-test. 
 
The mean percentage of donor-derived cell-free DNA (Allosure®) at six months and one year 
among patients on Envarsus XR versus immediate-release tacrolimus will be compared using the 
t-test. 
 
Estimated GFR (CKD-EPI equation) over one year after transplant among patients on Envarsus 
XR versus immediate-release tacrolimus will be assessed with a mixed linear effects model.  
 
 
 
5.  Monitoring for AE/SAEs 
 
Adverse events (AE) and serious adverse events (SAE) will be monitored with careful attention to 
calcineurin inhibitor side effects, nephrotoxicity, or infectious complications.  Side effects 
associated with Envarsus XR have not been reported to occur more frequently than with 
immediate-release tacrolimus (1,2).  Common side effects associated with tacrolimus include 
tremor, paresthesia, hypertension, new-onset diabetes after transplant, and acute kidney injury 
(14). 
 
6.  Project enrollment 
As patients receive treatment for desensitization, the study team will approach patients who meet 
Inclusion/ Exclusion criteria to evaluate patients’ interest in study participation. The screening visit 
will occur once patients are considered for kidney transplant offer.  
Twenty highly sensitized patients will be enrolled for this study.  We anticipate enrolling 
approximately two to three patients a month and estimate that all patients will be enrolled within 
10-12 months. Once eligible patients are identified and consented, they will be randomized 1:1 by 
the Kidney Transplant research pharmacist to study drug, Envarsus XR (N=10) or immediate 
release tacrolimus (N=10).  
The study is designed to follow each enrolled patient for 12 months.  Therefore, it is anticipated 
that the total time required for study completion will be approximately two years. 
7. Permitted drug dose adjustments and interruptions  
Dose adjustments and interruptions are permitted in order to keep the patient on study drug, per 
standard practice. The study drug may be temporarily interrupted if patient develops short term 
intolerance or is unable to take oral medication. Administration of alternative immunosuppression 
or alternative route per SOC is acceptable. Patients should be returned to study drug as soon as 
possible.  

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8. Schedule of events 
IRB No: Pro00054474 
Protocol: Envarsus XR Study 
FLOWCHART OF PROCEDURES 
Procedures 
Screening 
Visit 
Tx 
Day 0 
Day 2 
± 1 
day 
Day 4 
± 2 
day 
Day 
7± 3 
day 
Day 14 -
3 
day /+5 
days 
Day 
30± 7 
day 
Month 
2± 
14 day 
Month 
3± 14 
day 
Month 
6 ± 
14 day 
Month 9 
± 
14 day 
Month 
12 
± 14 day 
Informed Consent6 
R 
  
  
  
  
  
  
  
  
  
  
  
Inclusion/Exclusion6 
R 
  
  
  
  
  
  
  
  
  
  
  
Randomization 
R 
  
  
  
  
  
  
  
  
  
  
  
Physical Exam 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
Chest X‐ray1 
S 
  
  
  
  
  
  
  
  
  
  
  
EKG1 
S 
  
  
  
  
  
  
  
  
  
  
  
Alemtuzumab or 
thymoglobulin 
Administration 
  
S 
  
  
  
  
  
  
  
  
  
  
CBC with diff 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
Complete Metabolic Panel 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
Urinalysis 
  
  
  
S 
S 
S 
S 
S 
S 
S 
S 
S 
Tacrolimus trough level2 
  
  
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
Viral testing: Polyomavirus 
BK 
  
  
  
  
  
  
S 
  
S 
S 
S 
S 
Viral testing: 
Cytomegalovirus 
  
  
  
  
  
  
S 
  
S 
S 
S 
S 
Serum Pregnancy Test3 
S 
  
  
  
  
  
  
  
  
  
  
  
Donor Specific Antibody4 
S 
  
  
  
  
  
S 
  
S 
S 
S 
S 
Donor ‐derived cell‐free 
DNA (Allosure) 
  
  
  
  
  
  
S 
  
S 
S 
S 
S 
Adverse event monitoring 
R 
R 
R 
R 
R 
R 
R 
R 
R 
R 
R 
R 

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Valganciclovir 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
  
  
TMP/SMX (Bactrim) 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S* 
S* 
Fluconazole 
S 
S 
S 
S 
S 
S 
S 
  
  
  
  
  
Envarsus XR 5 
  
R2 
R 
R 
R 
R 
R 
R 
R 
R 
R 
R 
Immediate‐Release 
Tacrolimus5 
  
S2 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
Mycophenolate mofetil 
(cellcept) or 
mycophenolate acid 
(myfortic) 
  
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
Prednisone 
  
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
  
LEGEND 
R = Research item/procedure done only for research purposes and covered by the study 
S = Standard of care item/procedure that is part of regular care and billed to the patient/insurance 
Footnotes: 
*TMP/SMX (Bactrim) may be discontinued as per standard of care at months 9, 10, 11 or 12 
1: Can be done within 6 months of screening date 
2: Depending on the time of the kidney transplant, Envarsus XR and Immediate‐Release Tacrolimus will be given either same day as 
transplant or the next day or delayed to post‐operative day #2 per PI discretion 
3: If subject is of childbearing age. (Not required if subject has a histroy of hysterectomy). 
4: DSA will be doneat time of transplant and quarterly for the first year. For deceased donor, sample will be drawn pre‐op, prior to IVIG. 
Majority of pts would have received desensitization within the past 6‐9 months prior to transplant. For living donors, sample will be drawn 
prior to IVIG2 but pt would already have received IVIG1 and ritux 5 weeks prior to sample drawn 
5: Subject will be taking either Envarsus XR or Immediate‐Release Tacrolimus; not both. Envarsus XR will be provided by study staff. 
6: Consent & Inclusion/Exclusion can be obtained prior to screening visit. Inclusion/Exclusion will be reviewed at time of screening to 
confirm the patient remains a study candidate.  

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References 
1. 
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;14:2796-806. 
 
2. 
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 
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3. 
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4. 
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9. 
Einecke G, Sis B, Reeve J, Mengel M, Campbell PM, Hidalgo LG, Kaplan B, Halloran PF. 
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10. 
Gaber AO, Alloway RR, Bodziak K, Kaplan B, Bunnapradist S. Conversion from twice-
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11. 
Dai Y, Hebert MF, Isoherranen N, Davis CL, Marsh C, Shen DD, Thummel KE. Effect of 
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14. 
Pirsch JD, Miller J, Deierhoi MH, Vincenti F, Filo RS. A comparison of tacrolimus 
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