Conditions: Kidney Transplant Rejection
Keywords: kidney transplant rejection donor-specific antibodies
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 20
Healthy volunteers: no

Brief summary:
This is a randomized, open-label, controlled clinical trial designed to compare clinical outcomes after kidney transplantation using extended-release tacrolimus (Envarsus XR) versus immediate tacrolimus among highly-sensitized kidney transplant recipients. Outcomes to be assessed include the incidence of biopsy-proven acute rejection at 12 months, the presence of de novo and pre-existing donor-specific HLA antibodies, estimated glomerular filtration rate, and the level of donor-derived cell-free DNA.

Detailed description:
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.

This is a randomized, open-label, controlled clinical trial designed to compare clinical outcomes after kidney transplantation using extended-release tacrolimus (Envarsus XR) versus immediate tacrolimus among highly-sensitized kidney transplant recipients. Twenty patients will be enrolled, with ten assigned to each study arm. Outcomes to be assessed include the incidence of biopsy-proven acute rejection at 12 months, the presence of de novo and pre-existing donor-specific HLA antibodies, estimated glomerular filtration rate, and the level of donor-derived cell-free DNA.

Arms:
arm 1: Kidney transplant recipients will receive extended-release tacrolimus in addition to standard-dose mycophenolate and prednisone for maintenance immunosuppression. arm 2: Kidney transplant recipients will receive immediate-release tacrolimus in addition to standard-dose mycophenolate and prednisone for maintenance immunosuppression.

Interventions: intervention 1: Extended-release tacrolimus intervention 2: Immediate-release tacrolimus
Intervention descriptions: intervention 1: Patients will receive the extended-release formulation of tacrolimus for maintenance immunosuppression. intervention 2: Patients will receive the immediate-release formulation of tacrolimus for maintenance immunosuppression.

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
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 
tacrolimus (LCPT): the phase III randomized MELT trial. Am J Transplant 2013;13:760-9. 
 
3. 
Everly MJ, Rebellato LM, Haisch CE, Ozawa M, Parker K, Briley KP, Catrou PG, Bolin 
P, Kendrick WT, Kendrick SA, Harland RC, Terasaki PI. Incidence and impact of de novo donor-
specific alloantibody in primary renal allografts. Transplantation 2013;95:410-7. 
 
4. 
Hidalgo LG, Campbell PM, Sis B, Einecke G, Mengel M, Chang J, Sellares J, Reeve J, 
Halloran PF. De novo donor-specific antibody at the time of kidney transplant biopsy associates 
with microvascular pathology and late graft failure. Am J Transplant 2009;9:2532-41. 
 
5. 
Schinstock CA, Cosio F, Cheungpasitporn W, Dadhania DM, Everly MJ, Samaniego-
Picota MD, Cornell L, Stegall MD. The Value of Protocol Biopsies to Identify Patients With De 
Novo Donor-Specific Antibody at High Risk for Allograft Loss. Am J Transplant 2017;17:1574-
84. 
 
6. 
Wiebe C, Gibson IW, Blydt-Hansen TD, Pochinco D, Birk PE, Ho J, Karpinski M, 
Goldberg A, Storsley L, Rush DN, Nickerson PW. Rates and determinants of progression to graft 
failure in kidney allograft recipients with de novo donor-specific antibody. Am J Transplant 
2015;15:2921-30. 
 
7. 
Loupy A, Hill GS, Jordan SC. The impact of donor-specific anti-HLA antibodies on late 
kidney allograft failure. Nat Rev Nephrol 2012;8:348-57. 
 
8. 
Sellares J, de Freitas DG, Mengel M, Reeve J, Einecke G, Sis B, Hidalgo LG, Famulski K, 
Matas A, Halloran PF. Understanding the causes of kidney transplant failure: the dominant role of 
antibody-mediated rejection and nonadherence. Am J Transplant 2012;12:388-99. 
 
9. 
Einecke G, Sis B, Reeve J, Mengel M, Campbell PM, Hidalgo LG, Kaplan B, Halloran PF. 
Antibody-mediated microcirculation injury is the major cause of late kidney transplant failure. Am 
J Transplant 2009;9:2520-31. 
 
10. 
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 
stable renal transplant recipients. Transplantation 2013;96:191-7. 
11. 
Dai Y, Hebert MF, Isoherranen N, Davis CL, Marsh C, Shen DD, Thummel KE. Effect of 
CYP3A5 polymorphism on tacrolimus metabolic clearance in vitro. Drug Metab Dispos 
2006;34:836-47. 


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12. 
Trofe-Clark J, Brennan DC, West-Thielke P, Milone MC, Lim MA, Neubauer R, Nigro V, 
Bloom RD. Results of ASERTAA, a Randomized Prospective Crossover Pharmacogenetic Study 
of Immediate-Release Versus Extended-Release Tacrolimus in African American Kidney 
Transplant Recipients. Am J Kidney Dis 2018;71:315-26. 
 
13. 
Rostaing L, Bunnapradist S, Grinyo JM, Ciechanowski K, Denny JE, Silva HT, Jr., Budde 
K, Envarsus Study G. Novel Once-Daily Extended-Release Tacrolimus Versus Twice-Daily 
Tacrolimus in De Novo Kidney Transplant Recipients: Two-Year Results of Phase 3, Double-
Blind, Randomized Trial. Am J Kidney Dis 2016;67:648-59. 
 
14. 
Pirsch JD, Miller J, Deierhoi MH, Vincenti F, Filo RS. A comparison of tacrolimus 
(FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation. FK506 
Kidney Transplant Study Group. Transplantation 1997;63:977-83. 
 

ICF_001.pdf: 
 
 
 
 
 
 
 
 
Official Title: 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 
NCT #: NCT04225988 
Document Date: September 17, 2020 


        
 
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Page 1 of 13
CONSENT FORM FOR RESEARCH
TITLE: 
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
STUDY SUPPORT PROVIDED BY: VELOXIS PHARMACEUTICALS
PRINCIPAL INVESTIGATOR:   EDMUND HUANG MD
STUDY CONTACT PHONE NUMBER AT CSMC:   EDMUND HUANG   310-423-2641
AFTER HOURS CONTACT (24 HOURS):  EDMUND HUANG   310-423-2641
This research study is supported by Veloxis Pharmaceuticals.  Veloxis Pharmaceuticals only 
reimburses Cedars-Sinai Medical Center for the costs associated with running the study; Veloxis 
Pharmaceuticals is not providing additional compensation to Cedars Sinai Medical Center or the 
Principal Investigator for their participation in the study.
1.
WHAT IS THE PURPOSE OF THIS RESEARCH STUDY?
We are doing this study to examine 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.
You are being asked to take part in this research study because you are a potential recipient of a 
kidney transplant and are considered highly-sensitized, which means that you are known to have 
antibodies against human kidney tissue.  
The study will enroll up to 20 people in total.
In this study, we want to compare extended release Envarsus XR to the Cedars-Sinai standard 
treatment of immediate-release tacrolimus to learn which works better for people with your 
condition.  Both drugs are FDA-approved for kidney transplant recipients to prevent organ 
rejection.  They are identical except Envarsus XR is taken once daily and immediate-release 
tacrolimus is taken twice daily.  
Research participants in this study will get either Envarsus XR or immediate-release tacrolimus. 
You will not get both.
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2.
WHAT WILL HAPPEN DURING THE STUDY?
This section provides a general overview of what will happen during your participation in this 
study.  Information included below should be considered along with the flowchart of procedures.  
The flowchart shows a timeline for research-related or standard of care procedures that are 
involved in your participation in this study.  Research-related procedures are those performed 
solely for the research.  They would not be performed if you did not take part in the study. 
Standard of care (routine) procedures would be performed both as part of this study and if you 
do not participate in this study.   
    
Overview of study:
This is a randomized research study. 
“Randomized” means that you will be assigned to a study group by chance, like 
flipping a coin.  You will be randomized into one of two study groups, and will have 
an equal chance of being placed in one of the groups described above. 
This study has two study groups:
•
Group 1 will get the usual immediate-release tacrolimus drug used for the prevention of 
kidney transplant rejection
•
Group 2 will get Envarsus XR drug used for the prevention of kidney transplant rejection
A computer will randomly assign you to a study group. This is done because no one knows if the 
results experienced by the participants in one study group are better, the same, or worse than the 
results experienced by participants in the other. Once you are put in one group, you cannot 
switch to another group. Neither you nor your doctor can choose the group in which you will be 
placed.
Either of these different approaches could help your condition but could also cause side effects. 
This study will allow the researchers to learn whether the different approaches are better, the 
same, or worse than one another. Both drugs have already been tested for safety; however, 
Envarsus XR is not part of the current Cedars-Sinai standard of care.
Another way to find out what will happen to you during the study is to read the chart below. Start 
reading at the left side and read across to the right, following the lines and arrows.
Randomization
(The computer will 
randomly assign you to a 
study group)
Group 2
Envarsus XR
You agree to take 
part in the study
Group 1
Immediate-Release 
Tacrolimus
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How long will you be in the study
We think you will be in this study for about one year. The total time includes a screening visit, 
days 0 (transplant day), 2, 4, 7, 14, 30 and months 2, 3, 6, 9, 12 of treatment. 
3.
WHAT ARE THE POSSIBLE RISKS?
Risks of common medical procedures performed solely for research purposes are described in a 
table attached to the end of this consent form as Appendix A.  Side effects and risks of standard 
of care procedures are not described in this consent form. 
This section describes the possible risks and/or discomforts we anticipate you could experience 
that are related to the study procedures. 
Unknown Risks
There may be other side effects or risks that we cannot predict.  Many side effects may go away 
shortly after the study medication or procedure is stopped.  However, in some cases they can be 
serious, long-lasting, permanent, and/or fatal.
Risks of Envarsus XR
Likely, Some May Be Serious (Occurs in greater than 20% and up to 100 % of people)
Diarrhea
Constipation
Nausea
Abdominal pain
Hair loss
Headache
Difficulty sleeping
Tremor
Fever
Increased blood pressure
Edema (swelling)
Electrolyte abnormalities (may require electrolyte supplements) such as nausea, vomiting, 
mood changes, excessive thirst
Elevated cholesterol 
Elevated blood sugar
Less Likely, Some May Be Serious (Occurs in >3% - 20 % of people)

Vomiting

Reduced red blood cells (lead to fatigue)

Reduced platelets (increased risk of bleeding)

Reduced white blood cells (increased susceptibility to infections)  
In the list below, “Serious,” refers to those side effects that 
may require hospitalization, may be irreversible, long-term, 
life-threatening or fatal.
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
Rash

Itching
Rare AND Serious (Occurs in 3% or less of people and may require hospitalization or may be 
irreversible, long-term, life-threatening or fatal)
Viral, bacterial and fungal infections
Sun sensitivity 
Viral kidney infection
Injury to kidneys
All immunosuppression treatments increase risk of developing lymphomas and other 
malignancies particularly skin cancer
Changes in the electrical activity of your heart (QT prolongation)
PRES (posterior reversible encephalopathy syndrome; a serious condition of the brain of which 
symptoms include altered mental status, headache, high blood pressure, seizures, and visual 
disturbances; symptoms are generally reversible with dose reduction or discontinuation of 
therapy
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In addition to the risks summarized above, the FDA has issued the following warning for 
Envarsus XR:
Reproductive and Lactation Risks 
Taking part in this research study can affect an unborn baby.  Therefore, you should not become 
pregnant or father a baby while on this study.  If you or your partner are capable of becoming 
pregnant you will need to use birth control.   Check with the researcher about approved birth 
control methods to use while participating in this study.   
Women should not breastfeed a baby while on this study.  
Unknown Risks to the Developing Embryo or Fetus (an unborn baby)
If you are pregnant, or become pregnant during participation in this research, the study drug 
might involve risks to an embryo or fetus, which are currently unknown.  It is important that you 
contact the researcher immediately if you believe you might be pregnant.
Incidental Findings
It is possible that the research procedures could uncover information related to your health that 
you did not know about before and that is unrelated to the Study. Some of these findings may be 
too preliminary to share.  Cedars-Sinai will carefully consider the research findings and 
determine if they should be shared with you.  Research findings would only be shared with you if 
such sharing is approved by the Cedars-Sinai IRB and is permitted by applicable law. In some 
cases, additional clinical testing may be required. The cost of any additional testing and any 
related treatment will be your responsibility.  
FDA Blackbox warning:   
Malignancies and serious infection:
Increased likelihood of bacterial, viral, fungal, and protozoal 
infections, including opportunistic infections and the possible 
development of malignancies such as lymphoma and skin 
cancer may result from immunosuppression and may lead to 
hospitalization or death.
Experienced physician:
Only health care providers experienced in immunosuppressive 
therapy and management of organ transplant patients should 
prescribe tacrolimus. Manage patients receiving the drug in facilities 
equipped and staffed with adequate laboratory and supportive 
medical resources. The health care provider responsible for 
maintenance therapy should have complete information requisite for 
the follow-up of the patient.
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4.
ARE THERE BENEFITS IN TAKING PART IN THE STUDY?
If you agree to take part in this research study, there may or may not be direct medical benefit to 
you.  The possible benefit of taking part in the research study is that, if you end up taking 
Envarsus XR, you will only have to take a pill once daily and this decreases pill burden. It is also 
possible that having to take the medication only once a day will help you to avoid missing doses 
by accident, which may decrease the chances of rejecting your kidney.  However, no benefit is 
guaranteed.  It is possible that your condition may remain unchanged or even get worse.
We hope the information learned from this research study will benefit other highly sensitized 
individuals with end-stage renal disease in the future by helping us to learn 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. 
5.
WHY WOULD MY PARTICIPATION BE STOPPED?
Your participation in this study may be stopped at any time by the researcher or the sponsor 
without your consent for any reason, including:
•    The study is stopped or suspended;
• 
Funding for the study is reduced, stopped or withdrawn;
•
If it is in your best interest;
• 
You do not consent to continue in the study after being told of changes in the research that 
may affect you;
• 
You do not follow the study procedures.
6.
ARE THERE ANY OTHER OPTIONS?
Your participation is voluntary so you have the right to decline to participate or to withdraw from 
this research study at any time without any penalty or loss of benefits to which you would be 
entitled outside of the study.  Choosing not to participate will not affect the care you receive at 
Cedars-Sinai Health System.
If you decide not to take part in this study, you have other choices. For example:
•
you may choose to be treated following the usual clinical approach (immediate-release 
tacrolimus) 
•
you may choose to take part in a different study at CSMC or elsewhere, if one is available
•
you could decide not to be treated.
The researcher will discuss these options and their risks and benefits with you.
7.
WILL MY INFORMATION BE KEPT CONFIDENTIAL?
We will do our best to make sure that the personal information collected as part of this study is 
kept private.  However, we cannot guarantee total privacy.  A copy of your research consent and 
authorization forms may be filed in your electronic medical record at CSMC.  Your personal 
information may be given out if required by law.  If information from this study is published or 
presented at scientific meetings, your name and other identifiable personal information will not 
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be used. Organizations that may look at and/or copy your medical records for research, quality 
assurance, and data analysis include: accrediting agencies, government and regulatory groups 
(such as Food and Drug Administration (FDA), Office for Human Research Protections (OHRP), 
etc.), safety monitors, companies that sponsor the study, and authorized representatives of the 
sponsor. 
The study team will facilitate any required access to your records by authorized representatives 
of the Sponsor to verify the information collected for the study.  
You will be asked to sign a separate “Authorization Form” that outlines with whom your 
information may be shared for the purposes of this research and under what circumstances.  
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This Website will not include information that can identify you.  At most, the 
Website will include a summary of the results.  You can search this Website at any time.
8.
WHAT IF I BECOME ILL OR INJURED BECAUSE OF TAKING PART IN 
THIS STUDY?
Contact your researcher at once if you feel that you are ill or have been injured because of taking 
part in this study.  If it is a medical emergency, call 911 or go to an emergency room.  Promptly 
notify your researcher of your situation at the phone number listed on page 1 of this consent 
form.
Who pays for my research related illness or injury?
Cedars-Sinai has no plans to pay for costs associated with the treatment of research-related injury 
or illness.  We will make every effort to seek reimbursement from your health plan.  However, 
you will be responsible for any deductibles and co-payments required under your health plan and 
for any claims ultimately denied by your health plan.  Financial assistance may be available 
under Cedars-Sinai’s Charity Care Policy and Procedure.  If you feel that you have had a 
research-related injury and need financial assistance, please contact the IRB Office at 310-423-
3783.
9.
FINANCIAL CONSIDERATIONS
Costs of Participation
Please review the attached flowchart for a listing of items, drugs and services that will be billed 
to you and/or your insurance and those that will be covered by the study sponsor.
Only items, drugs and services that are reasonable and necessary for your medical care 
throughout the study will be billed to your insurance.  You remain responsible for all 
deductibles, co-pays, and balances under your health benefit plan. If your insurance company 
does not pay, you will be billed for those charges.  You should check with your health benefit 
plan if you have questions or concerns about your insurance coverage.
You can elect to remain on Envarsus XR or be switched to immediate release tacrolimus after the 
completion of the study. Remaining on Envarsus XR after the study is completed may result in 
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higher out of pocket costs to you. Please discuss with your study doctor if you have more 
questions about medication therapy after the 12 month treatment period.
Compensation for Participating
You will not be paid for taking part in this research study.
Financial Interest in the Research
The PI and institution have no potential financial conflict of interest with respect to this study.
10.
WHAT IF I HAVE QUESTIONS OR PROBLEMS?
Please contact one of the investigators listed on the first page of this form for questions or 
concerns about the research.  
If you have questions, problems, or concerns that you want to discuss with someone who is not 
associated with this study, or want to offer suggestions or feedback, please contact:
Cedars-Sinai Human Research Protection Program (HRPP) Phone: (310) 423-3783
Email: ResearchConcerns@cshs.org
The Cedars-Sinai HRPP has been established to protect the rights and welfare of research 
participants.  You may also contact the Cedars-Sinai HRPP if you want to offer input or obtain 
information regarding the study.
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11.
CONSENT PROVISIONS 
If you sign this form below, it means that:  
(1) You have taken the time to carefully read and understand the information presented in this 
informed consent form; you should discuss it with others, and if appropriate seek a second 
opinion to make an informed decision;
(2) The information concerning the research study and its involved procedures has been fully 
explained to you and your questions have been answered to your satisfaction; 
(3) You have received and understand all of the information you desire regarding your 
participation in the research study; 
(4) You have considered the potential risks, any anticipated benefits and alternatives (and their 
relative risks and benefits) of participation;
(5) You are voluntarily agreeing to participate in this research study;
(6) You understand that by consenting to participate in the research, you are not giving up any of 
your legal rights (other than the postponement of your access to certain health information as 
described in this informed consent form); 
(7) You understand that you have the right to be informed of significant new findings related to 
this research study which may affect your willingness to continue participating in this study; and
(8) You have been provided with a copy of the “Experimental Subject’s Bill of Rights”, if 
applicable to this research study, and have been provided with an opportunity to ask questions 
regarding the Bill of Rights.
We will give you a copy of this signed and dated consent form and a copy of the Experimental 
Subject’s Bill of Rights.
SIGNATURE BY THE PARTICIPANT:
Name of Participant (Print)
Signature of Participant
Date of Signature
SIGNATURE BY THE INVESTIGATOR:
I have personally explained the research to the participant in non-technical terms, answered all 
questions, and attest that he/she freely consents to participate. The participant has been 
provided with the Experimental Subject’s Bill of Rights.
                           
Name of Investigator (Print)
Signature of the Investigator Who Obtained Consent
Date of Signature
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SIGNATURE BY THE INTERPRETER/WITNESS
(Signature of an interpreter is only required when a non-English speaking subject is consented 
with the assistance of an interpreter and an IRB-approved ‘short form.’  The witness may be 
any person who is conversant in both English and the language of the Non-English-speaking 
subject, such as the interpreter (the certified hospital interpreter), study staff, a family member, 
or other person.  The witness signs the consent forms to confirm that the oral interpretation 
occurred.)
                           
Name of Interpreter/Witness (Print)
Signature of Interpreter/Witness
Date of Signature
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EXPERIMENTAL SUBJECT’S BILL OF RIGHTS
In accordance with California Health and Safety Code 24172, any person who is required to 
consent to participate as a subject in a research study involving a medical experiment or who is 
requested to consent on behalf of another has the right to:
1.
Be informed of the nature and purpose of the experiment.
2.
Be given an explanation of the procedures to be followed in the medical experiment, and 
any drug or device to be utilized.
3.
Be given a description of any attendant discomforts and risks to the subject reasonably to 
be expected from the experiment.
4.
Be given an explanation of any benefits to the subject reasonably to be expected from the 
experiment, if applicable.
5.
Be given a disclosure of any appropriate alternative procedures, drugs or devices that 
might be advantageous to the subject, and their relative risks and benefits.
6.
Be informed of the avenues of medical treatment, if any, available to the subject after the 
experiment if complications should arise.
7.
Be given an opportunity to ask any questions concerning the experiment or the procedure 
involved.
8.
Be instructed that consent to participate in the medical experiment may be withdrawn at 
any time and the subject may discontinue participation in the medical experiment without 
prejudice.
9.
Be given a copy of any signed and dated written consent form used in relation to the 
experiment.
10.
Be given the opportunity to decide to consent or not to consent to a medical experiment 
without the intervention of any element of force, fraud, deceit, duress, coercion, or undue 
influence on the subject’s decision.
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Distribution instruction for researchers:
The signed (i) Consent form, (ii) Authorization for Use and Disclosure of Identifiable Health 
Information and (iii) "Experimental Subject’s Bill of Rights" (the latter required if the research 
study involves medical interventions)* should be distributed to:
1) Medical Chart
2) Research Participant
3) Pharmacy (if a drug study)
4) Principal Investigator’s research records (original)
 
 
CSMC IRB No: Pro00054474 / MOD00002259
CSMC Date Effective: 9/17/2020


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APPENDIX A:  Detailed Description of Common Medical Procedures Performed for Research 
Purposes and Associated Risks
The procedures listed below are often performed as part of routine care for a person with your condition.  
They are being repeated, or performed more frequently as part of this research.  However, the risks 
associated with each procedure should be comparable to what you would experience even if you were 
undergoing the procedure outside this research study.
Study Procedure
Related Risks
Blood draw: A needle is placed in the vein 
in your arm to draw blood
Blood drawing may cause some pain and has a 
small risk of bleeding, bruising, or infection at the 
puncture site.  There is also a small risk of fainting.
Concomitant Medications: You will be 
asked about your previous and current 
medications that you take. 
There are no physical risks associated with these 
procedures.
Medical History Review: You will be 
asked about your medical and surgical 
history with attention to information about 
your kidney disease. 
There are no physical risks associated with this 
procedure.
Demographic Information: You will be 
asked about your age, gender, race, ethnicity
There are no physical risks associated with these 
procedures.
CSMC IRB No: Pro00054474 / MOD00002259
CSMC Date Effective: 9/17/2020


IRB No:  Pro00054474 
Approval Date:  1/9/2020 
 
  
Orcqi_HIPAA Authorization Template_04.04.2018 
  
Page 1 of 4 
 
 
 
AUTHORIZATION FOR USE  
AND DISCLOSURE OF 
IDENTIFIABLE HEALTH INFORMATION (RESEARCH) 
 
 
Use and Disclosure of Health Information 
 
This Authorization is being completed in connection with the Consent Form 
for Research relating to the “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” research study described 
in the Consent Form.  The principal investigator for the research study is 
Edmund Huang, MD (“Principal Investigator”).  The sponsor of the research 
study is Veloxis Pharmaceuticals (the “Study Sponsor”). You are being 
asked for your authorization to allow the research team acting under the 
direction of the Principal Investigator as described in the Consent Form to 
review your medical records and collect health information about you 
(“private information”) from the following sources:  
 
• laboratory tests [CBC with diff, metabolic panel, urinalysis, BKV, CMV] 
• other tests [CYP3A5 genotyping, DSA, Donor-derived cell-free DNA] 
• x-rays  [chest x-ray] 
• doctor/clinic records   
• hospital/medical records 
• pathology reports 
 
The following private information about you will be placed in the research 
study records: 
 
• Name;  
• Street address [city, county, precinct, zip code, and their equivalent 
geocodes]; 
• Birth date and other indicators of your age; 
• Admission date/ discharge date; 


IRB No:  Pro00054474 
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• Date of death;  
• Telephone numbers; 
• Fax numbers; 
• Electronic mail address;  
• Medical record numbers;  
• Codes assigned in connection with the study to only your information 
that could be used to identify you. 
 
Who will have access to your private information? 
 
Your private information will be used by and/or shared with the following 
specific investigators Stanley Jordan, MD; Alice Peng, MD; Edmund 
Huang, MD; Reiad Najjar, MD; Supreet Sethi, MD; Ashley Vo, 
PharmD; Noriko Ammerman, PharmD and their research team as part 
of the research study.  Reasonable efforts will be made to assure that the 
research team will have access only to the private information about you that 
is minimally necessary to conduct the research study.  In addition to the 
research team, various committees of Cedars-Sinai Medical Center, the 
Sponsor and governmental agencies that oversee research may ask for access 
to your private information from the research team.  These include one or 
more of the Institutional Review Boards (IRB’s) of Cedars-Sinai Medical 
Center, the Cedars-Sinai Office for Research Compliance, the U.S. Food and 
Drug Administration, the U.S. Department of Health and Human Services, 
and other agencies that must receive reports about certain diseases.  
Additionally, the following parties may receive information about you: 
 
• Medical and other health care professional students who are assisting 
with tasks for the research study  
• The Study Sponsor (in other words the organization that is paying for the 
costs of the research study) for matters related to research study oversight, 
data analysis and use of research results in product development 
• Representatives from regulatory agencies in other countries may join in 
the review of your research records, including research-related medical 
reports and information, with the Sponsor and/or the FDA. 
 
How long will my authorization for use of private information be in effect? 
 
By signing this document, you authorize the use and sharing of your private 
information until January 31, 2035.  
 


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Withdrawal of Authorization 
 
You have the right to withdraw your authorization for us to use your health 
information at any time.  You must write to the principal investigator to 
withdraw your authorization.  The mailing address is: 8900 Beverly Blvd, 
Los Angeles, CA 90048.  However, if we have provided your information to 
the sponsor of this research, the study's data coordinating center, or other 
outside entities, that information cannot be withdrawn.  Any information 
already obtained at the time you withdraw your authorization may continue 
to be used as necessary to ensure study integrity.  For example, it may be 
necessary to continue to use your information to conduct investigations or to 
report adverse events. 
 
Further disclosure (sharing) of your private information 
 
Your private information will be shared by the Principal Investigator and 
Cedars-Sinai Medical Center only as needed for the research study.  Cedars-
Sinai Medical Center makes an effort to ensure that recipients of your 
information take steps to maintain the confidentiality of your private 
information and only receive the information that they need, and not more.  
Certain individuals or organizations that may receive your private 
information could though, in very limited circumstances, reveal it for 
purposes not related to the research study.  This would be an unauthorized 
and illegal disclosure (sharing) of your information.  In this study, the 
Principal Investigator does not anticipate that this will happen.  Moreover, in 
California, the law prohibits such further disclosure of private information 
without another signed authorization from you (unless the law requires the 
particular disclosure, such as to report suspected child abuse).    
 
Notice of Rights and Other Information 
 
You may refuse to sign this Authorization.   If you refuse to sign this 
Authorization, you will not be able to participate in the research study.  
However, standard of care treatment by Cedars-Sinai Medical Center will 
still be made available to you regardless of whether you provide or refuse to 
sign this Authorization. 
 
You have a right to receive a copy of this Authorization.  


IRB No:  Pro00054474 
Approval Date:  1/9/2020 
 
  
Orcqi_HIPAA Authorization Template_04.04.2018 
  
Page 4 of 4 
 
 
The Principal Investigator and Cedars-Sinai Medical Center are required by 
law to protect your private information.  By signing below, you authorize the 
use or disclosure of your private information in connection with the research 
study as described above. 
 
SIGNATURE BY THE SUBJECT: 
 
 
 
 
 
 
 
Name of Subject (Print) 
Signature of Subject 
Date of Signature 
 
 
 
 
 
 
 
 
 
 
SIGNATURE BY THE INVESTIGATOR: 
 
I attest that all the elements of this have been discussed fully in non-
technical terms with the subject.  I further attest that all questions asked by 
the subject were answered to the best of my knowledge.    
 
 
 
Name of Investigator (Print) 
 
 
 
 
 
Signature of the Investigator 
Date of Signature 
 
 
SIGNATURE BY THE INTERPRETER/WITNESS 
(Signature of an interpreter is only required when a non-English speaking 
subject is consented with the assistance of an interpreter and an IRB-
approved ‘short form.’  The witness may be any person who is conversant 
in both English and the language of the Non-English speaking subject, 
such as the interpreter (the certified hospital interpreter), study staff, a 
family member, or other person.  The witness signs the consent forms to 
confirm that the oral interpretation occurred.) 
 
 
 
                            
 
Name of Interpreter/Witness (Print) 
 
 
 
 
 
 
Signature of Interpreter/Witness 
Date of Signature 
 


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 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
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
IRB No: Pro00054474
Protocol: Envarsus XR Study
FLOWCHART OF PROCEDURES
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. 
Page 1 of 1
CSMC IRB No: Pro00054474 / MOD00002259
CSMC Date Effective: 9/17/2020