Clinical trial NCT03864926
Conditions: Delayed Graft Function
Keywords: Kidney Transplant
Sponsor: University of Wisconsin, Madison
Start date: 2019-03-18; Completion date: 2022-07-22
Enrollment: 100 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Envarsus XR is an extended release tacrolimus designed to deliver tacrolimus more consistently, thus avoiding large fluctuations of tacrolimus trough levels with Envarsus XR compared to immediate release tacrolimus. It is expected that patients with DGF on Envarsus XR will have more stable tacrolimus levels and facilitate early recover from DGF compared to immediate release tacrolimus.

Detailed description:
This is a single center randomized phase IV trial of comparing extended release Envarsus XR (study drug) once a day vs immediate release tacrolimus twice a day in a new kidney transplant recipients with delayed graft function (DGF). The primary study endpoint is the interval between first dialysis and last dialysis after kidney transplant (duration of DGF). The second end point is the number of tacrolimus or Envarsus XR dose adjustments required during the period of DGF.

Arms: arm 1: Standard of Care Tacrolimus arm 2: Envarsus XR
Interventions: intervention 1: Envarsus XR intervention 2: Tacrolimus
Intervention descriptions: intervention 1: Envarsus XR is FDA approved for the prophylaxis of organ rejection in kidney transplant recipients converted from tacrolimus immediate-release formulations, in combination with other immunosuppressants. Envarsus XR, is designed to deliver tacrolimus more smoothly over the whole day.

Envarsus XR, a calcineurin-inhibitor immunosuppressant, is available for oral administration as extended-release tablets containing the equivalent of 0.75 mg, 1 mg, or 4 mg of anhydrous tacrolimus USP. Inactive ingredients include hypromellose USP, lactose monohydrate NF, polyethylene glycol NF, poloxamer NF, magnesium stearate NF, tartaric acid NF, butylated hydroxytoluene NF, and dimethicone NF. Tacrolimus is the active ingredient in ENVARSUS XR. intervention 2: Tacrolimus (generic; immediate release) is FDA approved for the prophylaxis of organ rejection in heart, kidney and liver transplant recipients.

Protocol documents:
Prot_SAP_000.pdf: 
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Envarsus XR in Delayed Graft Function (E-DGF) 
 
 A phase IV, randomized, single center study among kidney transplant recipients with delayed graft function (DGF) to 
study the effect of Envarsus XR in the DGF recovery  
 
NCT03864926 
 
 
Principal Investigator: Sandesh Parajuli, MD, MBBS 
 
 
 
 
 
This document is confidential. No part of it may be transmitted, reproduced, published, or used by 
other persons without prior written authorization from the Sponsor or Principal Investigator. 
 
 
 
 
 
 
PROTOCOL VERSION and AMENDMENTS 
 
Protocol 
Version 
Date 
Change 
Initiated 
(Initials) 
Brief description of protocol modification/actions requested, if any 
Template 
V6 
9/6/16 
TNK 
Input from IRB, OCT, MARCH, IND/IDE services, PIs 
Version 1 
9/28/17 
TLO 
Draft reviewed by ICTR Data Monitoring Committee (DMC) and ICTR Study 
Monitoring Service (SMS) 
Version 2 
10-23-17 
SAJ 
Susan Johnston (PRC) edits 
Version 3 
09/24/18 
CLL 
Cassandra Leopard, OCT Edits 
Version 4 
04/24/19 
CLL 
Cassandra Leopard, OCT Edits 
Version 5 
06/17/22 
CLL 
Cassandra Leopard, Add Transplant Database as data source 
 
 
 
 
 
 
 
 


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Contents 
1. 
Study Summary ............................................................................................................................................................... 7 
2. 
Key Roles ......................................................................................................................................................................... 9 
2.1. 
Investigator and Study Center: ................................................................................................................................ 9 
3. 
Background and Introduction ......................................................................................................................................... 10 
3.1. 
Background and Rationale .................................................................................................................................... 10 
3.2. 
Hypothesis ............................................................................................................................................................. 10 
3.3. 
Study Agent ........................................................................................................................................................... 10 
3.4. 
Summary of Relevant Preclinical Data.................................................................................................................. 11 
3.5. 
Potential Risk and Benefits to Subjects ................................................................................................................ 11 
4. 
Study Objectives and Purpose ...................................................................................................................................... 12 
5. 
Study Design and Endpoints ......................................................................................................................................... 12 
5.1. 
General Design ..................................................................................................................................................... 12 
6. 
Study Subjects – Enrollment and Withdrawal ................................................................................................................ 13 
6.1. 
Subject Population ................................................................................................................................................ 13 
6.2. 
Inclusion Criteria.................................................................................................................................................... 13 
6.3. 
Exclusion Criteria .................................................................................................................................................. 14 
6.4. 
Subject Screening for Recruitment ....................................................................................................................... 14 
6.5. 
Subject Capacity ................................................................................................................................................... 14 
6.6. 
Informed Consent .................................................................................................................................................. 14 
6.7. 
Early Withdrawal of Subjects ................................................................................................................................ 15 
7. 
Study Agent ................................................................................................................................................................... 16 
7.1. 
Starting Dose and Dose Escalation Schedule ...................................................................................................... 16 
7.2. 
Description/Formulation/Packaging and Storage: ................................................................................................. 17 
7.3. 
Prior and Concomitant Therapy/ Standard of Care ............................................................................................... 17 
7.4. 
Randomization and Blinding of Study Drug .......................................................................................................... 18 
8. 
Study Procedures .......................................................................................................................................................... 18 
8.1. 
Laboratory Tests ................................................................................................................................................... 18 
Table 1.  Schedule of Study Procedures  .......................................................................................................................... 18 
Table 2.  Typical Schedule of Standard of Care Procedures ............................................................................................ 18 
8.2. 
Study Visits ............................................................................................................................................................ 19 
9. 
Study Analysis ............................................................................................................................................................... 20 
9.1. 
Sample Size Determination ................................................................................................................................... 20 
9.2. 
Statistical Methods ................................................................................................................................................ 20 
9.3. 
Subject Population(s) for Analysis ........................................................................................................................ 20 
9.4. 
Planned Interim Analysis ....................................................................................................................................... 20 
10. 
Data Collection, Handling and Record Keeping ........................................................................................................ 20 
10.1. 
Data Confidentiality ............................................................................................................................................... 20 
10.2. 
Data Capture ......................................................................................................................................................... 20 


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10.3. 
Data Management ................................................................................................................................................. 21 
10.4. 
Records Retention................................................................................................................................................. 21 
11. 
Assessment of Safety ............................................................................................................................................... 21 
11.1. 
Specifications of Safety Parameters ..................................................................................................................... 22 
11.2. 
Classification of an Adverse Event........................................................................................................................ 23 
11.3. 
Time period and frequency for event assessment and follow-up ......................................................................... 24 
11.4. 
Reporting procedures ............................................................................................................................................ 24 
11.5. 
Study Halting Rules ............................................................................................................................................... 26 
11.6. 
Safety Oversight .................................................................................................................................................... 26 
12. 
Study Monitoring, Auditing, and Inspecting ............................................................................................................... 27 
12.1. 
Medical Monitoring ................................................................................................................................................ 27 
12.2. 
Protocol Deviations ............................................................................................................................................... 28 
12.3. 
Auditing and Inspecting ......................................................................................................................................... 28 
12.4. 
Subject Compliance Monitoring ............................................................................................................................ 28 
13. 
Ethical Considerations .............................................................................................................................................. 28 
14. 
Study Finances .......................................................................................................................................................... 28 
14.1. 
Funding Source ..................................................................................................................................................... 28 
14.2. 
Conflict of Interest ................................................................................................................................................. 28 
14.3. 
Subject Stipends or Payments .............................................................................................................................. 29 
15. 
Publication Plan......................................................................................................................................................... 29 
16. 
References ................................................................................................................................................................ 30 
17. 
Appendices ................................................................................................................................................................ 31 
17.1. 
Appendix 1: Envarsus XR Package Insert ............................................................................................................ 32 
 
 
 


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STATEMENT OF COMPLIANCE 
 
The signature below constitutes confirmation that the research will be conducted in accordance with the approved 
protocol, applicable regulations, laws and institutional policies.  
 
I agree to ensure that all staff members involved in the conduct of this study are informed about their obligations in meeting 
the above commitments.  
 
 
Principal Investigator: _____________________________  
Print/Type Name  
 
 
 
Signed: _____________________________________  
  
 
 
 
 
 
 
 
 
 
 
 
 
     
          
 
 
 
 


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LIST OF TABLES and FIGURES  
 
Figure 1   
Schematic of Study Design 
 
 
Table 1   
Study Calendar 
Table 2 
Typical Schedule of Standard of Care Visits 
 
 
 


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List of Abbreviations 
 
 
AE 
Adverse event 
ANOVA 
Analysis of covariance 
BPAR 
Biopsy proven acute rejection 
CFR 
Code of Federal regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CNI 
Calcineurin Inhibitors 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
DBD 
Donation after brain death 
DCD 
Donation after cardiac death 
DGF 
Delayed Graft Function 
DHHS 
Department of Health and Human Services 
DMC 
Data Monitoring Committee 
DSMP 
Data and Safety Monitoring Plan 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICH E6 
International Conference on Harmonisation Guidance for Industry, Good Clinical Practice: 
Consolidated Guidance 
ICMJE 
International Committee of Medical Journal Editors  
ICTR 
Institute for Clinical and Translational Research 
IF/TA 
Tubulo-interstitial fibrosis/tubular atrophy 
IND 
Investigational New Drug Application 
IRB 
Investigational Review Board 
KDPI 
Kidney donor profile index 
MOP 
Manual of Procedures 
NIH 
National Institutes of Health  
NODAT 
New onset diabetes after transplant  
OHRP 
Office for Human Research Protections 
OnCore 
Online Collaborative Research Environment, clinical trial management software 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SMS 
Study Monitoring Service 
 
 
 


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1. Study Summary 
 
Title 
Envarsus XR in Delayed Graft Function (E-DGF) 
 
Short Title and Precis 
Envarsus in DGF (E-DGF) 
Protocol Number 
2018-0530 
ClinicalTrials.gov 
number 
NCT03864926 
Phase 
Phase IV 
Methodology 
Single center, open randomized trial  
Study Duration 
2.5 years  
Study Center(s) 
Single Center  
Objectives 
Envarsus XR is an extended release tacrolimus designed to deliver tacrolimus 
more consistently, thus avoiding large fluctuations of tacrolimus trough levels 
with Envarsus XR compared to immediate release tacrolimus.  It is expected 
that patients with DGF on Envarsus XR will have more stable tacrolimus levels 
and facilitate early recover from DGF compared to immediate release 
tacrolimus.  
Number of Subjects 
Total of 100, 50 in each arm  
Diagnosis  
Kidney transplant recipients with the diagnosis of DGF  
Main Inclusion Criteria 
New kidney transplant recipients with DGF transplanted at UW hospital  
Main Exclusion Criteria 
Multi-organs transplant recipients 
Patients not on or not planned to be on tacrolimus based regimen after 
transplant  
Complications requiring allograft nephrectomy  
Study Product, Dose, 
Route, Regimen 
Per UW Abdominal Transplant Immunosuppression Management Adult-
Inpatient/Ambulatory Clinical Practice Guideline:  immediate release tacrolimus 
(generic) 0.05 to 0.1 mg/kg/day in two-divided dose by mouth will be used in all 
patients after kidney transplant as the standard of care (SOC). All subject will 
receive at least one dose of SOC tacrolimus. Extended release Envarsus XR 
(study drug) 80% of the total daily dose of SOC tacrolimus or close to the 
available strength of 0.75 mg, 1 mg and 4 mg tablet as a single tablet or 
combination of two or more tablets of Envarsus XR once a day by mouth will 
be used in the study arm and SOC immediate release tacrolimus will be 
continued in the SOC arm.   
FDA status of product 
IND Exempt Determination 
Duration of 
administration 
Until recovery of DGF to a maximum of 3 months 
 
Reference therapy 
Immediate release tacrolimus  
Statistical 
Methodology 
Data Analysis: Descriptive statistics for the data will be compiled. Any trends 
for differences between two groups for the composite endpoints will be 
assessed. 
 
 
 
 


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Figure 1: Schematic of Study Design 
 
 Flow diagram: 
 
 
Prior to enrollment 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit 1 (Diagnosis of DGF) 
 
 
 
 
 
Visit 2 (Diagnosis of DGF) 
 
 
 
Visit 3 (Daily while inpatient 
Or in clinic visit) 
 
 
 
Visit 4 (recovery from DGF) 
 
 
 
 
 
 
 
Visit X (Time Point) 
 
 
Randomize 
Arm 1  
N=50: Tacrolimus 
(SOC) 
Total 100 patients: Obtain informed consent. Screen potential subjects by 
inclusion and exclusion criteria, review labs and documentation. All patients will 
have received or will be receiving immediate release tacrolimus as standard of 
care (SOC) 
Arm 2 
N=50: Envarsus XR 
(Study) 
Perform baseline assessments. 
Medical records and the Transplant Database will be reviewed for the following: 
Routine blood test, urine test and other radiological investigation based on the 
clinical judgment. Commonly used test include:  CBC, Lytes, BUN, Creatinine, 
glucose, urinalysis, urine protein/creatinine, immunosuppressive level 
Randomize into Tacrolimus (SOC) or Envarsus XR (study) group 
Medical records and the Transplant Database will be reviewed for the following:   
Follow up assessments of study endpoints and safety. 
Evaluate for need of dialysis or not. Review routine blood test performed in the 
morning along with urine output in last 24 hours and examinations to assess the 
Medical records and the Transplant Database will be reviewed for  study endpoints 
and safety, Routine blood test performed, H&P documenting discharged from the 
DGF clinic 
Medical records and the Transplant Database will be reviewed for the following; 
Interval between transplants to the recovery of DGF  
Interval between first and last dialysis 
Total number of dialysis 
Total number of tacrolimus or Envarsus XR dose adjustment required  


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2. Key Roles 
2.1. 
Investigator and Study Center: 
Principal Investigator: 
 
Sandesh Parajuli, MD, MBBS  
Assistant Professor (CHS) 
Department of Medicine-Nephrology 
UW Medical Foundation Centennial Building 
4175 MFCB  
1685 Highland Avenue 
Madison, WI 53705  
Phone Number: (608) 265-0152 
Email: sparajuli@medicine.wisc.edu 
Participating sites:  
University of Wisconsin Hospital and Clinics 
600 Highland Avenue 
Madison, WI 53792 
 
 
Local Laboratory Services:  
UW Health-University of Wisconsin Hospital and Clinics 
Clinical Laboratories 
600 Highland Ave., Room B4/251 
 
Madison, WI 53792 
ICTR Data Monitoring 
Committee Contact: 
Amy Siedschlag, MS 
2112 Health Sciences Learning Center 
School of Medicine and Public Health 
Madison, WI 53706 
Email: asiedschlag@wisc.edu 
ICTR Study Monitoring 
Service Contact: 
2112C Health Sciences Learning Center 
School of Medicine and Public Health 
Madison, WI 53706 
Ph: 608-262-4910 
 
Funding Sponsor: 
Veloxis Pharmaceuticals, Inc  
1001 Winstead Drive, Suite 310,   
Cary, North Carolina 27513, USA 
Phone: (919) 591-3090 
Fax: (919) 678-8026 
www.veloxis.com 
 


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3. Background and Introduction 
This document is a clinical research protocol for a human subjects study. This study is to be conducted according to 
the 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. 
3.1. 
Background and Rationale 
There are multiple definitions of delayed graft function (DGF), but the most common definition is the need for dialysis 
within the first seven days of kidney transplantation (1). The incidence of DGF ranges from 20% to 40% and is 
increasing as more donation after cardiac death (DCD) and higher kidney donor profile index (KDPI) kidneys are 
utilized. DGF is associated with significant adverse outcomes including increased risk of readmission, rejection, graft 
loss and even death (2-6). Addressing maintenance immunosuppression at time of DGF is challenging. Calcineurin 
inhibitors (CNIs) are the main maintenance immunosuppressive medication in the current era of transplant. But CNIs 
have recognized vasoconstrictive properties and their discontinuation in presence of DGF appears intuitive but may 
be non-beneficial or even harmful (6). There is diminishing evidence to support delayed introduction or avoidance or 
withdrawal of CNI in DGF. Supratherapeutic levels can increase the risk of infections, such as BK. Decreased levels 
of CNI, tacrolimus is recommended to achieve acceptably low rates of rejection in these patients.  Unfortunately, 
tacrolimus has a narrow therapeutic window. It can lead to acute as well as chronic nephrotoxicity if levels are 
supratherapeutic or rejection if levels are sub-therapeutic. Acute tacrolimus nephrotoxicity due to high tacrolimus 
levels typically presents early after kidney transplant with impaired renal function clinically and as isometric 
vacuolizations of tubular cells on the allograft biopsy. In fact, even as early as one month after kidney transplant, 
glomerulosclerosis in renal allografts can be associated with CNI nephrotoxicity. Typical chronic CNI-related allograft 
changes include tubule-interstitial fibrosis/tubular atrophy (IF/TA), tubular microcalcifications, glomerulosclerosis and 
arteriolar hyalinosis (7-10). Given all these adverse outcomes of DGF and deleterious effects of subtherapeutic or 
supratherapeutic tacrolimus levels, it is essential to achieve steady therapeutic levels of tacrolimus especially during 
the early phase of kidney transplant recipients with DGF.  
3.2. 
Hypothesis 
With extended release Envarsus XR,  designed to deliver tacrolimus more consistently, it is hypothesized that there will 
be less fluctuation of tacrolimus levels requiring less dose adjustment and ultimately early recovery of the DGF.  
3.3. 
Study Agent 
Tacrolimus is a macrolide immunosuppressant produced by Streptomyces tsukubaensis. Chemically, tacrolimus is 
designated as [3S-[3R*[E(1S*,3S*,4S*)], 4S*,5R*,8S*,9E,12R*,14R*,15S*,16R*,18S*,19S*,26aR*]]- 
5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy-3-[2-(4-hydroxy-3-methoxycyclo-
hexyl)-1-methylethenyl]-14,16-dimethoxy-4,10,12,18-tetramethyl-8-(2-propenyl)-15,19-epoxy-3H-pyrido[2,1- c] 
[1,4]oxaazacyclotricosine-1,7,20,21(4H,23H)-tetrone, monohydrate. Tacrolimus has an empirical formula of 
C44H69NO12•H2O and a formula weight of 822.03. Tacrolimus appears as white crystals or crystalline powder. It is 
practically insoluble in water, freely soluble in ethanol, and very soluble in methanol and chloroform. 
 
Tacrolimus (generic; immediate release) is FDA approved for the prophylaxis of organ rejection in heart, kidney and 
liver transplant recipients. 
 
Envarsus XR is FDA approved for the prophylaxis of organ rejection in kidney transplant recipients converted from 
tacrolimus immediate-release formulations, in combination with other immunosuppressants. Envarsus XR, is designed 
to deliver tacrolimus more smoothly over the whole day.  
          
 
Envarsus XR, a calcineurin-inhibitor immunosuppressant, is available for oral administration as extended-release 
tablets containing the equivalent of 0.75 mg, 1 mg, or 4 mg of anhydrous tacrolimus USP. Inactive ingredients include 
hypromellose USP, lactose monohydrate NF, polyethylene glycol NF, poloxamer NF, magnesium stearate NF, tartaric 
acid NF, butylated hydroxytoluene NF, and dimethicone NF. Tacrolimus is the active ingredient in ENVARSUS XR. 
 
 


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Note: extended release products (Envarsus XR) are not interchangeable or substitutable with immediate release 
tacrolimus.  
 
3.4. 
Summary of Relevant Preclinical Data 
The FDA approval of Envarsus XR was based on a conversion study (11). The conversion study was a randomized, 
open-label, multinational study evaluating once daily Envarsus XR when used to replace immediate-release 
tacrolimus administered twice daily for maintenance immunosuppression to prevent acute allograft rejection in stable 
adult kidney transplant patients. Patients who received a kidney transplant 3 months to 5 years before study entry and 
on a stable dose of tacrolimus immediate-release of at least 2 mg per day and tacrolimus whole blood trough 
concentrations between 4 and 15 ng/mL were randomized to 1) switch from twice daily tacrolimus immediate-release 
to once daily Envarsus XR (N=163) or 2) continue tacrolimus immediate-release twice daily (N=163). Mycophenolate 
mofetil (MMF) or mycophenolate sodium (MPS), or azathioprine (AZA) and/or corticosteroids were allowed as 
concomitant immunosuppressants during the study period according to the standard of care at the participating site. In 
the conversion study, stable kidney transplant patients converted to Envarsus XR at an average daily dose that was 
80% of their tacrolimus immediate-release daily dose prior to conversion. Mean tacrolimus whole blood trough 
concentrations were maintained within a relatively narrow range throughout the duration of the study for both the 
Envarsus XR conversion group and the tacrolimus immediate-release continuation group. At week 1 (after 7 days of 
stable dosing), the mean ± SD tacrolimus trough concentrations were 7.2 ± 3.1 ng/mL for the Envarsus XR conversion 
group and 7.7 ± 2.5 for the tacrolimus immediate-release continuation group; the baseline values were 7.8 ± 2.3, and 
8.0 ± 2.3, respectively. The average daily mycophenolate equivalent doses in the conversion study were comparable 
between the Envarsus XR and tacrolimus immediate-release treatment groups. The efficacy failure rates including 
patients who developed biopsy proven acute rejection (BPAR), graft failure, death, and/or lost to follow-up at 12 
months, as well as the rates of the individual events were essentially the same between the tacrolimus immediate-
release and tacrolimus extended-release groups (Envarsus XR).  
 
In another large randomized control trial (12), once a day Envarsus XR in new kidney transplant recipients had a 
comparable efficacy and safety profile compared to that of immediate release twice a day tacrolimus even at 24% 
lower total dose suggesting Envarsus XR to have better absorption and bioavailability. In another, Phase III 
randomized trial, Envarsus XR achieved target tacrolimus trough levels more rapidly compared to twice daily 
tacrolimus group (13).   
 
Envarsus XR is a calcineurin-inhibitor immunosuppressant indicated for the prophylaxis of organ rejection in kidney 
transplant patients converted from tacrolimus immediate-release formulations in combination with other 
immunosuppressants. It is administered 80% of the pre-conversion daily dose of tacrolimus immediate-release by 
mouth once a day. Its side effects and drug interactions are similar to the immediate-release tacrolimus.  
3.5. 
Potential Risk and Benefits to Subjects 
3.5.1. 
Known Potential Risks 
Immunosuppressants, including extended release Envarsus XR, increase the risk of developing lymphomas and 
other malignancies, particularly of the skin. Other risks include, an increased risk of developing bacterial, viral, 
fungal, and protozoal infections, including opportunistic infections. Medication errors, including substitution and 
dispensing errors, between tacrolimus immediate-release products and tacrolimus extended-release products 
were reported outside the U.S. This led to serious adverse reactions, including graft rejection, or other adverse 
reactions due to under- or over-exposure to tacrolimus. Envarsus XR caused new onset diabetes after transplant 
(NODAT) in kidney transplant patients, which may be reversible in some patients. African-American and Hispanic 
kidney transplant patients are at an increased risk of NODAT. Envarsus XR, like other CNIs, can cause acute or 
chronic nephrotoxicity, may cause a spectrum of neurotoxicities. Other risks includes, hyperkalemia, rise in 
creatinine, electrolytes disturbance, hypertension, QT prolongation, drug interaction with CYP3A inducers and 
inhibitors. Live attenuated vaccines during treatment with Envarsus XR is contraindicated. Other post marketing 
experience includes- blood and lymphatic system disorders, ear disorders, eye disorders, gastrointestinal 


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disorders, hepatobiliary disorders, hypersensitivity reactions, immune system disorders, metabolic and nutrition 
disorders, musculoskeletal and connective tissue disorders, neoplasm, nervous system disorders, renal and 
urinary disorders, respiratory, thoracic and mediastinal disorders and skin and subcutaneous disorders. When 
comparing Envarsus XR with immediate release tacrolimus, potential risks were almost similar between the two 
groups.  
 
Refer to the FDA approved package insert for Envarsus XR in Appendix 1. 
                            
 
3.5.2. 
Protection Against Risks 
Together with the UW ICTR Data Monitoring Committee (DMC) we will develop a detailed data and safety 
monitoring plan (DSMP) which will ensure ongoing safety of participating patients commensurate with the level of 
risk and complexity of the protocol treatment to minimize risks, integrity of trial data and scientific validity of the 
trial. The development of the DSMP will be guided by the NIH Policy for Data and Safety Monitoring and by the 
FDA Guidance on the Establishment and Operation of Clinical Trial Data Monitoring Committees.  The plan will 
make certain that review of the conduct of research is rigorous, independent and objective, interim safety and 
efficacy data is collected and presented and progress towards achieving study goals is made.  It will cover 
policies and procedures for reporting adverse events to the DMC, IRB, and the FDA. Refer to Appendix 2: Data 
Monitoring Committee Charter and Appendix 3: Data and Safety Monitoring Plan (DSMP) 
3.5.3. 
Potential Benefits to the Subjects 
It is anticipated that the subject will benefit through early recovery of DGF, with shorter duration of dialysis 
treatment after transplant. This ultimately will lead to the prolonged graft survival.  
3.5.4. 
Risk Minimization 
Serious Adverse Events (SAEs) will be reviewed to determine if additional risk could be posed to the subject in 
question or others participating in the study. If it is determined that a serious adverse event, new information, or 
an unanticipated event could pose a potential risk to subjects, the DMC and/or the investigator may decide to stop 
the study. 
4. Study Objectives and Purpose 
• 
Primary Objective: Early recovery from DGF 
• 
Secondary Objective: To assess the efficacy of Envarsus XR in kidney transplant recipients with DGF in achieving 
steady state tacrolimus levels compared to immediate release tacrolimus administration (SOC). 
 
5. Study Design and Endpoints 
5.1. 
General Design  
This is a single center randomized phase IV trial of comparing extended release Envarsus XR once a day vs immediate 
release tacrolimus twice a day in a new kidney transplant recipients with DGF. The duration of study is expected to be 
around 2 to 2.5 years.  
5.1.1. 
Primary Study Endpoints 
The primary endpoint of the study will be the interval between first dialysis and last dialysis after kidney transplant 
(duration of DGF). 
 
5.1.2. 
Secondary Study Endpoints 
The secondary endpoint will be number of tacrolimus or Envarsus XR dose adjustments required during the period 
of DGF.  


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5.1.3. 
Primary Safety Endpoints 
Primary safety endpoints include: infections, malignancies, hematological complications including leukopenia, 
anemia, and thrombocytopenia, cardiovascular complications and events, neuropathy, tremors, gastrointestinal 
symptoms, uncontrolled hypertension, serious electrolytes abnormalities and immunosuppression-related adverse 
effects. 
 
6. Study Subjects – Enrollment and Withdrawal 
 
• 
A total of 100 subjects (50 subjects in each arm) with the diagnosis of DGF will be enrolled over a period of 2 
years.  
• 
DGF is defined as the need for a dialysis within the first week of transplant. Once potential DGF patients are 
identified, the transplant nephrology team will be consulted and the transplant nephrology provider will 
perform initial evaluation of a patient, discussion with the patient about his/her interest in participating in the 
research study and inform the research coordinator.  
• 
Subjects will participate in the study until the recovery of DGF as documented by the provider as “discharged 
from the DGF clinic” or no need for dialysis for more than one week (7 days).  
• 
Subject would be followed for maximum of 3 months. If they still need dialysis beyond 3 months, will be 
declared as primary dysfunction and will disqualify from the study.  
 
6.1. 
Subject Population  
All adult kidney only transplant recipients age 18 years or older at time of the transplant with the diagnosis of DGF will 
be determined if they are eligible for this study using the criteria described below. This study is not restricted based 
upon the race or ethnic origin.  
6.2. 
Inclusion Criteria  
 
Inclusion Criteria  
1 
Willing and able to provide written informed consent  
2 
Willing to comply with all study procedures and be available for the duration of the study  
3 
Male or female, at least 18 years of age 
4 
Documented diagnosis of DGF or need for dialysis or had dialysis within the first week of kidney 
transplant 
5 
Current treatment with tacrolimus based regimen or planned to start tacrolimus based 
immunosuppressive regimen  
6 
Females of childbearing potential must have a negative urine or serum pregnancy test prior to 
randomization and agree to use adequate contraception (hormonal or barrier method of birth control; 
abstinence) prior to randomization, for the duration of study participation, and for 7 days following 
completion of therapy.   
• 
A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a 
tubal ligation, or remaining celibate by choice) who meets the following criteria: 
o 
Has not undergone a hysterectomy or bilateral oophorectomy; or 
o 
Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had 
menses at any time in the preceding 12 consecutive months). 
 
 
 


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6.3. 
Exclusion Criteria 
 
Exclusion Criteria 
1. History of hypersensitivity or allergy to any of the study drugs or drugs of similar chemical classes 
2. Current use of non-tacrolimus based immunosuppressive regimen or no plan to start tacrolimus based 
regimen 
3. 
Women who are or plan to become pregnant or breast-feeding during the study period  
4. 
Not suitable for study participation due to other reasons at the discretion of the investigator  
5. 
Major post-surgical complications requiring allograft nephrectomy  
6. 
Multi-organ transplant recipients  
7. 
Non kidney transplant recipients  
 
6.4. 
Subject Screening for Recruitment  
6.4.1. 
Subject Identification 
The screening visit will occur within the first week of transplant when transplant nephrology service is consulted 
for the potential need of dialysis. Basic information about the study will be provided to the patients to assess their 
interest to participate in the study.  All of the recruitment will be performed while patient is still in the hospital after 
kidney transplant. The following procedures will occur as part of clinical care and will be collected from the 
subject’s medical record: 
o 
Physical exam 
o 
Vital Signs (Temperature, pulse, respirations, and blood pressure) 
o 
Medication History 
o 
Routine labs (CBC, serum pregnancy test for females of child-bearing potential, BMP, or any 
imaging performed recently) 
o 
Dialysis indicated or not  
6.4.2. 
Recruitment and Retention Strategies 
A total of 100 patients will be recruited from and enrolled at a single center, the University of Wisconsin Hospital 
and Clinics.  Patients will be recruited and enrolled through the UW hospital inpatient transplant service and will 
be followed until the recovery of DGF. Based on the demographics of the state of Wisconsin and previous 
transplant history, more than 80% are expected to be Caucasian, approximately 40% are expected to be female. 
6.5. 
Subject Capacity 
 
Patient’s capacity to consent will be assessed by the nephrology provider. If patient is unable to consent for the 
study, consent to enroll will be obtained only when they are capable of giving informed consent.  
6.6. 
Informed Consent 
The PI will be responsible for ensuring that valid consent is obtained and documented for all subjects. Consent will be 
obtained and documented during an in-person visit.  
6.6.1. 
Informed Consent Document 
The Informed Consent Document will include the required elements per 45 CFR 46, as well as Good Clinical 
Practice (GCP) Guidelines. 


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6.6.2. 
Process of Consent 
Written informed consent will be obtained by the research coordinator or the treatment team member after the 
potential subject has been presented the information necessary to make a voluntary decision and all questions 
have been addressed.   
 
6.6.3. 
HIPAA 
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).  The elements of the HIPAA Authorization 
Form will be included in the Informed Consent Document, allowing the use of one document to fulfill both 
requirements.  
6.6.4. 
Revoking HIPAA Authorization 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, retains the 
ability to use all information collected prior to the revocation of subject authorization.  For subjects that have 
revoked authorization to collect or use PHI, attempts should be made to obtain permission to collect at least vital 
status (i.e. that the subject is alive) at the end of their scheduled study period. 
6.6.5. 
Costs to the Subject 
There is no extra cost to the patients to be enrolled in the study. Extended release Envarsus XR will be provided 
through the Veloxis pharmacy for the entire period of the study. Immediate release tacrolimus will fall under the 
SOC and will be provided through the standard medication distribution system. 
6.6.6. 
Payment for Participation 
There are no reimbursements or payments such as cash payments, coupons and gift certificates that the subjects 
will receive for participation.  
6.7. 
Early Withdrawal of Subjects 
6.7.1. 
Premature termination of study 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable cause. 
Written notification, documenting the reason for study suspension or termination, will be provided by the 
suspending or terminating party to investigator, funding agency, or regulatory authorities. If the study is 
prematurely terminated or suspended, the PI will promptly inform the IRB and will provide the reason(s) for the 
termination or suspension.  
 
Circumstances that may warrant termination or suspension include, but are not limited to:  
• 
Determination of unexpected, significant, or unacceptable risk to participants  
• 
Demonstration of efficacy that would warrant stopping  
• 
Insufficient compliance to protocol requirements  
• 
Data that are not sufficiently complete and/or evaluable  
• 
Determination of futility  
 
Study may resume once concerns about safety, protocol compliance, data quality are addressed and satisfy the 
sponsor, IRB and/or regulatory authorities. Subject’s data will be stored in the secure place during this period.  
6.7.2. 
When and How to Withdraw Subjects 
If patient is unable to tolerate the study drug Envarsus XR or SOC drug tacrolimus, the subject will be withdrawn 
from the study, and likely be switched to other immunosuppressive medications for example cyclosporine, or 
belatacept or any other immunosuppressive medications based on the clinical discretion. Subjects that are 
withdrawn will be asked to return for one last study visit to conduct the procedures described in the last visit in the 
protocol.   


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6.7.3. 
Data Collection and Follow-up for Withdrawn Subjects 
Data for the study purpose will not be collected from subjects who have withdrawn from the study but have active 
treatment either with SOC tacrolimus or with study drug, Envarsus-XR.  
7. Study Agent 
Subjects will be randomized to receive (in a 1:1 manner) to either the standard of care arm or the experimental arm: 
• 
Standard of Care:  Immediate release tacrolimus 
• 
Experimental: Envarsus XR 
 
This study is exempt from the requirements of an IND based on meeting the criteria defined in the FDA information 
sheet “Off-Label and Investigational Use Of Marketed Drugs, Biologics, and Medical Devices”.  
 
21 CFR 312.2(b) Exemptions. (1) The clinical investigation of a drug product that is lawfully marketed in the United 
States is exempt from the requirements of this part if all the following apply: 
 
(i) The investigation is not intended to be reported to FDA as a well-controlled study in support of a new indication 
for use nor intended to be used to support any other significant change in the labeling for the drug; 
 
(ii) If the drug that is undergoing investigation is lawfully marketed as a prescription drug product, the investigation 
is not intended to support a significant change in the advertising for the product; 
 
(iii) The investigation does not involve a route of administration or dosage level or use in a patient population or 
other factor that significantly increases the risks (or decreases the acceptability of the risks) associated with the use 
of the drug product; 
 
(iv) The investigation is conducted in compliance with the requirements for institutional review set forth in part 56 
and with the requirements for informed consent set forth in part 50; and 
 
(v) The investigation is conducted in compliance with the requirements of 312.7. 
 
7.1. 
Starting Dose and Dose Escalation Schedule 
Tacrolimus Immediate Release: 
 
Dosing will be per institutional standards at a range from 0.05mg/kg/day to 0.1mg/kg/day in two divided 
doses by mouth.   
Dosage will be adjusted based upon trough levels per the UW Abdominal Transplant Immunosuppression 
Management Adult-Inpatient/Ambulatory Clinical Practice Guideline. Dosage adjustments will occur after a 
patient has received 4 doses of the current regimen.  Tacrolimus levels will be ordered daily while inpatient 
and patient has received daily tacrolimus doses (either post-operatively or during readmission) 
Once discharged, tacrolimus levels will be monitored as follows: 
• 
Day 0-90: not less than once weekly 
• 
Day 91-180_ not less than twice monthly  
• 
Day 181-240: not less than once monthly 
Additional monitoring of tacrolimus trough level is warranted if there is a change in medication formulation 
or patient status that may affect levels or if the creatinine has increased 0.3mgdL above baseline.  Levels 
must be checked within 3-7 days of each dose adjustment and potassium and creatinine levels will be 
monitored with each tacrolimus level.  Additional monitoring is per the UW Abdominal Transplant 
Immunosuppression Management Adult-Inpatient/Ambulatory Clinical Practice Guideline. 
The study team will make all modifications in dosage.  
 
Envarsus XR:  
To convert from a tacrolimus immediate-release product to Envarsus XR, administer a once daily dose that 
is 80% of the total daily dose of the tacrolimus immediate-release product. Tablets should be taken once 


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daily, preferably in the morning at the same time each day.  Tablets must be swallowed whole; subjects 
must be instructed not to chew, crush or split Envarsus XR tablets. Envarsus XR will be used in the patient 
population, dose and route of administration that it is FDA approved for, however it will be used in this study 
as a first line of treatment, rather than a second line of treatment (FDA approved).  
 
Monitor tacrolimus whole blood trough concentrations and titrate Envarsus XR dosage to achieve target 
whole blood trough concentration ranges of 4 to 11 ng/mL.  Measure tacrolimus whole blood trough 
concentrations at least two times on separate days during the first week after initiation of dosing and after 
any change in dosage, after a change in co-administration of CYP3A inducers and/or inhibitors, or after a 
change in renal or hepatic function. When interpreting measured concentrations, consider that the time to 
achieve tacrolimus steady state is approximately 7 days after initiating or changing the Envarsus XR dose.  
The study team will make all modifications in dosage.  
  
 
7.2. 
Description/Formulation/Packaging and Storage: 
 
 
Tacrolimus (immediate release) will be sourced locally by the institution and handled per standard of care.   
Immediate release tacrolimus is available in 0.5mg, 1mg and 5mg capsules; bottles all contain 30 capsules.  
Tacrolimus Immediate release is stored accordingly to the product label.    
 
Envarsus XR will be provided by Veloxis Pharmaceuticals in  0.75 mg, 1 mg and 4 mg tablets; bottles of 30 
tablets. Envarsus XR must be stored at controlled room temperature ([15 *C to 30*C] or [59*F to 86*F]).     
 
7.3. 
Prior and Concomitant Therapy/ Standard of Care 
The following medications and procedures are permitted during the study: 
• 
Antiemetics, including 5-HT3 serotonin receptor antagonists, may be used at the discretion of the primary 
provider 
• 
Loperamide or other antidiarrheal should be used for symptomatic diarrhea at discretion of the primary 
provider. 
• 
Growth factors (eg, granulocyte colony stimulating factor [G-CSF], granulocyte macrophage-colony 
stimulating factor [GM-CSF], recombinant erythropoietin) are permitted. Their use should follow published 
guidelines and/or institutional practice. 
• 
Subjects should be transfused with red cells and platelets as clinically indicated and according to 
institutional guidelines. 
• 
Antiviral therapy, antifungal and antibacterial therapy may be administered if medically appropriate. 
• 
Concomitant treatment with multivitamins, calcium, phosphorus, magnesium supplement will be permitted, 
as appropriate. 
• 
Hypertensive medications, medication to control blood sugar or pain will be permitted, as appropriate 
• 
Concomitant use of other immunosuppressive medications for induction (example, basiliximab, 
alemtuzumab or anti-thymocyte globulin) or maintenance (example: mycophenolic acid, steroids) will be 
acceptable   
• 
Dialysis as indicated  
• 
Kidney allograft biopsy as indicated 
• 
Supportive measures consistent with optimal patient care may be given throughout the study. 
• 
Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, 
and/or selection of alternative therapy  Concomitant use with strong CYP3A for inducers and/or inhibitors 
may alter tacrolimus whole blood concentrations, potential leading to rejection and/or increased toxicity 
respectively. Tacrolimus whole blood trough concentrations will be monitored closely. 
• 
Grapefruit juice, a CYP3A4 inhibitor may increase serum level and/or toxicity of tacrolimus, subjects must 
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7.4. 
Randomization and Blinding of Study Drug 
This study will be a randomized, unblinded study involving extended release tacrolimus called Envarsus XR once a 
day and immediate acting tacrolimus twice a day.  
8. Study Procedures 
8.1. 
Laboratory Tests 
Patients will have similar labs in both groups and will be drawn as part of the standard of care. Labs will be obtained 
on a daily basis while they are inpatient and on the day of clinic visit or before dialysis when they are outpatient. 
Commonly obtained labs include, CBC, BMP, magnesium, phosphorus level, tacrolimus level, serum calcium, 
urinalysis and protein/creatinine ratio. Imaging including chest x-ray, ultrasound of the transplanted kidney, CT 
abdomen and pelvis, CT chest, head may be obtained based on the clinical judgement. All labs and imaging will be 
obtained at UW Hospital and Clinics, including the use of a CAP and CLIA-certified laboratory.  Labs and imaging 
reports will be communicated to patients by the clinical care team.  
Table 1.  Schedule of Study Procedures   
Process 
Screening 
Baseline 
(Day 1) 
Follow-up (every 
other day or 3 times 
a week till recovery 
from DGF) ) 
Monthly 
Follow-up 
Visits until 
3 months 
after 
transplant 
Final Clinic 
Visit  
Informed Consent 
X 
 
 
 
 
Eligibility Determination 
X 
 
 
 
 
Obtain demographics 
X 
 
 
 
 
Study Drug Administration 
 
X 
X 
X 
X 
Dose adjustment of Envarsus XR or 
tacrolimus  
 
 
X 
X 
X 
 
 
Table 2.  Typical Schedule of Standard of Care Procedures   
 
Process 
Screening 
Baseline 
(Day 1) 
Follow-up (every 
other day or 3 times 
a week till recovery 
from DGF) ) 
Monthly 
Follow-up 
Visits until 
3 months 
after 
transplant 
Final Clinic 
Visit 
Results of Clinical Laboratory Tests  
X 
X 
X 
X 
X 
Medical History  
X 
X 
X 
X 
X 
Physical examination 
 
X 
X 
X 
X 
Vital Sign Measurement (Temperature, 
Pulse, Respirations, Blood Pressure) 
 
X 
X 
X 
X 
IR Tacrolimus Administration 
 
X 
X 
X 
X 
Dose adjustment of IR tacrolimus  
 
 
X 
X 
X 
Decision for dialysis  
 
X 
X 
X 
X 
 


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8.2. 
Study Visits 
8.2.1. 
Screening/Baseline  
At screening/baseline visit transplant nephrology provider will decide about the need of dialysis or not and based 
on that information will document patient to have DGF or not. In that visit, we will review the patient’s medical 
records. Patient will also be informed about the study and their interest will be gauged. If they are interested, then 
research coordinator will be informed about the potential subject.  
 
 
Table 2. Medical chart review of standard of care visits 
Visit* 
Window 
Data collection from medical record and 
Transplant Database 
Day 1 contact  
+/- 1 days 
H&P, brief updates about research project  
Day 3  
+/- 0 days  
H&P, decision for dialysis, decision to adjust 
study or SOC dose   
Day 5  
+/- 0 days  
H&P, decision for dialysis, decision to adjust 
study or SOC dose   
Day 7 
+/- 0 days  
H&P, decision for dialysis, decision to adjust 
study or SOC dose   
Additional visits every 2-
3 days until DGF 
recovery 
+/- 0 days  
H&P, decision for dialysis, decision to adjust 
study or SOC dose   
Monthly up through 
Month 3 post diagnosis 
of DGF 
+/- 30 days  
H&P, decision for dialysis, decision to adjust 
study or SOC dose   
*visits could be more or less depending upon the timing of DGF recovery for maximum of 3 months post-transplant.  
8.2.2. 
Unscheduled 
Subjects may have unscheduled standard of care visits due to lab results, an acute illness of undetermined 
cause, for other reasons, or at the discretion of the Investigator.  Data will be collected from unscheduled visits 
and may include any of the following information; 
• 
Adverse Event Assessment 
• 
Medication History 
• 
Drug Accountability 
• 
Physical Exam 
• 
Vital Signs (Temperature, Pulse, Respirations, Blood Pressure) 
• 
Lab work (CBC, LFTs, DSA , imaging, biopsy) 
 
8.2.3. 
Final Standard of Care Visit 
Patients will be off study once they recover from DGF as documented by the provider as discharged from the 
DGF clinic or no need for dialysis for more than 7 days. Patients will be given the opportunity to either continue on 
the study medication or switch to SOC after termination from the study. Envarsus XR will not be covered by the 
industry, but is covered by most of the health insurance coverage. If interested, Veloxis will provide discount 
coupons.  The final standard of care visit will also include primary evaluation, need for dose adjustment of 
medication and decision for dialysis. Each subject will be asked to participate in the study for up to 3 months after  
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9. Study Analysis 
9.1. 
Sample Size Determination 
Goal is to analyze 100 subjects total (50 in each group), with a goal to decrease DGF duration to less than 10 days in 
Envarsus XR group from current mean of 13.9 +/- 7 days with tacrolimus based on the power calculation.  
9.2. 
Statistical Methods 
Continuous data will be compared using Student’s t-test or the Wilcoxon Rank Sum test, as appropriate, while 
categorical data will be analyzed using Fisher’s exact test or chi-square test. P values < 0.05 will be considered 
statistically significant. Kaplan-Meier analyses will be performed to study graft survival if appropriate.  
9.3. 
Subject Population(s) for Analysis 
All randomized and completed study patient data will be used for primary and secondary analysis.  Primary analysis 
include needs for dose adjustment of the Envarsus XR or tacrolimus and secondary analysis include duration of 
recovery from the DGF.  
9.4. 
Planned Interim Analysis  
We will utilize the UW ICTR Data Monitoring Committee (DMC) to oversee the study and is described further 
in section 11.6.  Source documents may be reviewed to allow the DMC to independently judge whether the 
overall integrity and conduct of the protocol remain acceptable based on data provided and reported by the 
Principal Investigator.  The DMC will make recommendations to the Principal investigator that could include 
actions of continuation, modification, suspension or termination.  
10. Data Collection, Handling and Record Keeping 
10.1. Data Confidentiality 
Only PI and study team members will have access to the subject research records and the data entered in both the 
OnCore and REDCap systems. Data will not be shared with any other researchers outside of the study team. No 
personal identifiable information will be released to the third parties. Only summary of the data generated will be 
provided to the industry.  
 
10.1.1. 
Confidentiality of Subject Records 
By signing the protocol, the Investigator agrees that the, IRB, or Regulatory Agency representative may consult 
and/or copy study documents to verify case report form (CRF) data. By signing the consent form, the subject agrees 
to this process. If study documents will be photocopied during the process of verifying CRF information, the subject 
will be identified by unique code only and full names and similar identifying information (such as medical record 
number or social security number) will be masked. 
 
The Clinical Site Investigators will ensure that the identity of subjects will be protected. All study records will be 
maintained in a secure fashion with access limited to essential study personnel only. The Clinical Site Investigators 
will maintain an enrollment log that includes subject identifying information and links subjects to their study-specific 
identification number. This information will also be available in the ICTR OnCore and REDCap systems.  
10.2. Data Capture  
10.2.1. 
Source Documents 
A majority of the study data will be captured through the electronic medical record (EMR) and Transplant Database. 
The data source for the Transplant Database are Transplant Data Mart and Organ and Tissue Donation Database.  
Data records include: hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, transcriptions, 


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microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the 
pharmacy, at the laboratories, and at medico-technical departments involved in the clinical trial. 
10.2.2. 
Case Report Forms 
The study CRF is a data-reporting instrument for the study.  All data requested on the CRF will be recorded.  All 
missing data will be explained.  All entries will be printed legibly in black ink.  If any entry error has been made, to 
correct such an error, a single straight line will be drawn through the incorrect entry and the correct data will be 
entered above it. All such changes will be initialed and dated. 
10.2.3. 
Electronic Case Report Forms (eCRFs) 
Some of the data that will be exported for analysis will not be captured on paper CRFs, rather directly entered into 
the ICTR OnCore or ICTR REDCap Data Management System, including but not limited to results of laboratory 
tests, physical examinations, imaging, etc.  
10.2.4. 
Missing Data 
Every attempt will be made to capture all data. If data is missing, additional review of available data from the 
electronic medical record and/or Transplant Database will be conducted.   
10.2.5. 
Data Collection Tools 
Online Collaborative Research Environment (OnCore) will serve as the Clinical Trial Management System for this 
study. ICTR OnCore is supported by the UW School of Medicine and Public Health Information Technology 
(SMPH-IT) staff and managed by UW ICTR.  
 
OnCore is a sophisticated, web-based data management system that: a) ensures secure, easy data entry at multiple 
sites; b) integrates multiple data sources; c) provides controlled, secure access to sensitive data using role-based 
access control; d) provides workflow automation; and e) allows export and reporting of data for Data and Safety 
Monitoring Boards and biostatisticians. This software provides protocol management functions (e.g. subject 
scheduling; screening, data organization), maintains updated forms, addresses budget development, billing, and 
fiscal management, generates summary reports, and provides essential links with other research administration 
and electronic medical records systems. ICTR OnCore eases the burden of the individual researcher and unifies 
protocol management within research programs and across research sites, enhancing protocol integrity and 
regulatory compliance efforts. 
 
Data extracted from the EMR will be entered into the REDCap system managed by ICTR. This data will be combined 
with the data exported from the OnCore system and imported in to the same project, allowing REDCap to serve as 
the final data repository for this study.  
10.3. Data Management 
The PI is responsible for implementing and maintaining quality control and quality assurance procedures to ensure 
that trial is conducted and data are generated, documented, and reported in compliance with the protocol, accepted 
standards of Good Clinical Practice (International Conference on Harmonization E6), and all applicable federal, state, 
provincial, and local laws, rules, and regulations relating to the conduct of the clinical trial in an ongoing and auditable 
manner. 
10.4. Records Retention 
Study records will be retained for a minimum of 7 years after study completion per the UW Madison policy and IRB 
guidance: https://kb.wisc.edu/sbsedirbs/page.php?id=42378. These documents should be retained for a longer period 
if required by an agreement with the sponsor.  In such an instance, it is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained. 
11.   Assessment of Safety 
The investigator is responsible for monitoring the safety of subjects who have enrolled in the study. For this study, 
adverse events will be solicited from subjects to identify an occurrence or worsening of an unintended sign or symptom, 


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related to the ingestion of the study drug as per standard of care. The clinical team will ask subjects in each visit if they 
experienced any new medical related signs or symptoms since taking the study drug. Subjects will be asked about any 
adverse events they may have experienced. Only the adverse events considered related (possibly, probably or definitely) 
to the ingestion of the study drug will be entered into and managed in the data management system.   
11.1. Specifications of Safety Parameters 
The risks to subjects in this trial will be minimized by compliance with eligibility criteria, clinical monitoring, 
adherence to protocol contraception requirements and investigator guidance regarding specific safety areas.  The 
specific safety areas that will be closely monitored in this subject population are; thrombocytopenia, diarrhea, 
fatigue, nausea, vomiting, rash, risk of reactivation of viral infection, neutropenia, fluid deficit, uncontrolled 
hypertension, posterior reversible encephalopathy syndrome (PRES).  
11.1.1. 
Definition of Adverse Events (AE)  
Adverse event (AE) means any untoward medical occurrence in a patient or subject administered a 
pharmaceutical product; the untoward medical occurrence does not necessarily have a causal relationship with 
this treatment.  An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of a medicinal (investigational) product whether or not it is related to the medicinal 
product.  This includes any newly occurring event, or a previous condition that has increased in severity or 
frequency since the administration of study drug.  AEs will be assessed at study visits and during the final follow-
up study visit. Only the adverse events considered related (possibly, probably or definitely) to the ingestion of the 
study drug will be entered into and managed in the data management system  
 
For the purposes of this study, baseline symptoms will be collected prior to the administration of study 
intervention. Only those symptoms identified as new or worsened compared to the baseline assessment will be 
recorded as an AE. In addition, only those abnormal laboratory values or physical examination assessments that 
are considered clinically significant will be recorded in the study documents. Pain and hematoma at transplant 
incision site will not be considered an AE. 
11.1.2. 
Definition of Serious Adverse Events (SAE)  
An AE or suspected adverse reaction is considered "serious" if, in the view of either the investigator or sponsor, it 
results in any of the following outcomes:  
• 
Death 
• 
Life-threatening adverse event* 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
o 
Subjects must be admitted to an inpatient unit to be eligible for the study, thus the initial 
hospitalization will not be considered an SAE in and of itself, rather it will only be 
considered an SAE if the subject is discharged and then re-admitted. 
• 
A congenital anomaly/birth defect 
• 
Persistent or significant disability or incapacity or substantial disruption of the ability to conduct 
normal life function 
• 
Important medical events that, may not result in death, be life-threatening, or require hospitalization 
may be considered when, based upon appropriate medical judgement, they may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition 
  
*Life-threatening adverse event:  An adverse event is considered “life-threatening” if, in the view of the 
investigator, its occurrence places the subject at immediate risk of death.  It does not include an adverse event 
which, had it occurred in a more severe form, might have caused death. 


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11.1.3. 
Definition of Unanticipated Problems (UP)  
OHRP considers unanticipated problems involving risks to participants or others to include, in general, any incident, 
experience, or outcome that meets all of the following criteria:  
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are described in 
the protocol-related documents, such as the IRB-approved research protocol and informed consent document; 
and (b) the characteristics of the participant population being studied;  
• 
Related or possibly related to participation in the research (“possibly related” means there is a reasonable 
possibility that the incident, experience, or outcome may have been caused by the procedures involved in 
the research); and  
• 
Suggests that the research places participants or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized.  
 
 
The following changes or actions will be considered in response to an UP: 
 
• 
Modification of inclusion or exclusion criteria to mitigate the newly identified risks  
• 
Implementation of additional safety monitoring procedures  
• 
Suspension of enrollment of new participants or halting of study procedures for enrolled participants  
• 
Modification of informed consent documents to include a description of newly recognized risks  
• 
Provision of additional information about newly recognized risks to previously enrolled participants. 
11.2. Classification of an Adverse Event 
11.2.1. 
Severity of Event 
All AEs will be assessed by the clinician using the Common Terminology Criteria for Adverse Events (CTCAE) 
Version 4, each event searchable using the Safety Profiler website (https://safetyprofiler-
ctep.nci.nih.gov/CTC/CTC.aspx). For AEs not included in the protocol defined grading system, the following 
guidelines will be used to describe severity.  
 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic measures. Moderate 
events may cause some interference with functioning.  
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug therapy or other 
treatment. Severe events are usually potentially life-threatening or incapacitating. 
11.2.2. 
Relationship to Study Agent 
In a clinical trial, the study product must always be suspect. To help assess, the following guidelines are used.  
 
For all collected AEs, the clinician who examines and evaluates the participant will determine the AE’s causality 
based on temporal relationship and his/her clinical judgment. The degree of certainty about causality will be 
graded using the categories below.  
 
• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other possible contributing 
factors can be ruled out. The clinical event, including an abnormal laboratory test result, occurs in a plausible 
time relationship to drug administration and cannot be explained by concurrent disease or other drugs or 
chemicals. The response to withdrawal of the drug (de-challenge) should be clinically plausible. The event 
must be pharmacologically or phenomenologically definitive, with use of a satisfactory re-challenge procedure 
if necessary.  
• 
Probably Related – There is evidence to suggest a causal relationship, and the influence of other factors is 
unlikely. The clinical event, including an abnormal laboratory test result, occurs within a reasonable time after 
administration of the drug, is unlikely to be attributed to concurrent disease or other drugs or chemicals, and 


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follows a clinically reasonable response on withdrawal (de-challenge). Re-challenge information is not 
required to fulfill this definition.  
• 
Possibly Related – There is some evidence to suggest a causal relationship (e.g., the event occurred within 
a reasonable time after administration of the trial medication). However, other factors may have contributed to 
the event (e.g., the participant’s clinical condition, other concomitant events). Although an AE may rate only 
as “possibly related” soon after discovery, it can be flagged as requiring more information and later be 
upgraded to “probably related” or “definitely related,” as appropriate. 
• 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose temporal 
relationship to drug administration makes a causal relationship improbable (e.g., the event did not occur 
within a reasonable time after administration of the trial medication) and in which other drugs or chemicals or 
underlying disease provides plausible explanations (e.g., the participant’s clinical condition, other concomitant 
treatments). 
• 
Not Related – The AE is completely independent of study drug administration, and/or evidence exists that the 
event is definitely related to another etiology. There must be an alternative, definitive etiology documented by 
the clinician. 
11.2.3. 
Expectedness 
PI will be responsible for determining whether an AE is expected or unexpected. An AE will be considered 
unexpected if the nature, severity, or frequency of the event is not consistent with the risk information previously 
described for the study agent in the clinical protocol, the package insert(s), the IRB application or the informed 
consent document. 
11.3. Time period and frequency for event assessment and follow-up 
The occurrence of an AE or SAE may come to the attention of study personnel during study visits and interviews of a 
study participant presenting for medical care, or upon review by a study monitor. All AEs including local and systemic 
reactions not meeting the criteria for SAEs will be captured on the appropriate CRF. Information to be collected 
includes event description, time of onset, clinician’s assessment of severity, relationship to study product (assessed 
only by those with the training and authority to make a diagnosis), and time of resolution/stabilization of the event. All 
AEs occurring while on study must be documented appropriately regardless of relationship. All AEs will be followed to 
adequate resolution.  
 
Any medical condition that is present at the time that the participant is screened will be considered as baseline and 
not reported as an AE. However, if the study participant’s condition deteriorates at any time during the study, it will be 
recorded as an AE. UPs will be recorded in the data collection system throughout the study.  
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event at each level 
of severity to be performed. AEs characterized as intermittent require documentation of onset and duration of each 
episode.  
 
The PI will record all reportable events with start dates occurring any time after the administration of the study drug 
and for up to 30 days after the date of the last dose of study drug. At each study visit, the investigator will inquire 
about the occurrence of AE/SAEs since the last visit. Events will be followed for outcome information until resolution, 
stabilization, or completion of study participation. 
11.4. Reporting procedures 
Together with the UW ICTR Data Monitoring Committee (DMC) we will develop a detailed a data and safety 
monitoring plan (DSMP) which will ensure ongoing safety of participating patients commensurate with the level of risk 
and complexity of the protocol treatment to minimize risks, integrity of trial data and scientific validity of the trial. The 
development of the DSMP will be guided by the NIH Policy for Data and Safety Monitoring and by the FDA Guidance 
on the Establishment and Operation of Clinical Trial Data Monitoring Committees.  The plan will make certain that 
review of the conduct of research is rigorous, independent and objective, interim safety and efficacy data is collected 
and presented, and progress towards achieving study goals is made.  It will cover policies and procedures for 
reporting adverse events to the DMC, IRB, and the drug manufacturer(s).  


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11.4.1. 
Adverse Event Reporting  
Only the adverse events considered related (possibly, probably or definitely) to the ingestion of the study drug will 
be entered into and managed in the data management system and be made available to the study team for 
cumulative review, as well as the DMC and SMS.  
 
Based on the subject population, it is anticipated that the laboratory results that will be abstracted from the EMR 
for study purposes will be abnormal. The PI will not make clinically significant/non-clinically significant 
determinations of these results, as this subject population is expected to be abnormal and clinically significant 
hence their current clinical treatment. All reportable events related to the study protocol and its associated 
procedures will be reported to the IRB.  It is the responsibility of the Investigator to promptly notify the Institutional 
Review Board of all unanticipated problems involving risk to human research subjects.  Reportable events, such 
as protocol noncompliance, serious adverse events, new information, and unanticipated problems will be reported 
to the IRB and DMC in accordance with the UW IRB guidelines.   
11.4.2. 
Serious adverse event reporting  
The study clinician will complete a SAE Form within the following timelines:  
 
All deaths and immediately life-threatening events, whether related or unrelated, will be recorded on the SAE Form 
and submitted to the funding sponsor and drug manufacturer(s) within 24 hours of site awareness. See Section 1, 
Key Roles for contact information.  
 
All SAEs will be followed until satisfactory resolution or until the site investigator deems the event to be chronic or 
the adherence to be stable. Other supporting documentation of the event may be requested by those providing 
regulatory oversight and should be provided as soon as possible. The funding sponsor and drug manufacturer(s) 
will be responsible for notifying FDA of any events that meet the applicable reporting criteria. 
 
The study investigator shall complete a Serious Adverse Event (SAE) Form and submit the information to the 
funding sponsor, drug manufacturer(s), DMC and to the reviewing IRB as soon as possible. Events that are 
considered Unexpected, Related and fatal, life threatening or severely debilitating must be immediately reported 
(within 24 hours) to the IRB and DMC. Events that are Unexpected, Related and Serious (not fatal, life threatening, 
or severely debilitating), must be reported to the IRB and DMC within fourteen (14) business days of learning of the 
event.  The funding sponsor contact information is provided in Section 1, Key Roles.  
11.4.3. 
Unanticipated Problem (UP) reporting  
 
Incidents that meet the OHRP criteria for UPs will be reported according to the funding sponsor and IRB 
requirements. UPs that are SAEs will be reported to the IRB and DMC within the required reporting timelines 
described above) 
 
The UP report will include the following information:  
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project number; 
• 
A detailed description of the event, incident, experience, or outcome; 
• 
An explanation of the basis for determining that the event, incident, experience, or outcome represents an 
UP; 
• 
A description of any changes to the protocol or other corrective actions that have been taken or are 
proposed in response to the UP. 
11.4.4. 
Events of special interest  
The safety data that will be reviewed includes the number and seriousness of infections, malignancies, 
hematological complications including leucopenia, anemia, and thrombocytopenia, cardiovascular 
complications and events, neurological symptoms, gastrointestinal symptoms, and immunosuppression-
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11.4.5. 
Reporting of pregnancy  
                    It is unlikely that patient will be pregnant during that period as most of the child bearing age group 
females are required to be on the birth control measure and are recommended not to be pregnant. If patient get 
pregnant during the study period, subject will be monitored through child birth and report any birth defect.  
11.5. Study Halting Rules 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable cause. These 
subjects are at high risk for multiple complications and decision to halt the study based on SAEs will be on PI 
discretion.  Written notification, documenting the reason for study suspension or termination, will be provided by the 
suspending or terminating party to investigator, funding agency and the regulatory authorities. If the study is 
prematurely terminated or suspended, the PI will promptly inform the IRB and DMC and will provide the reason(s) for 
the termination or suspension.  
 
Circumstances that may warrant termination or suspension include, but are not limited to:  
• 
Determination of unexpected, significant, or unacceptable risk to participants  
• 
Demonstration of efficacy that would warrant stopping  
• 
Insufficient compliance to protocol requirements  
• 
Data that are not sufficiently complete and/or evaluable  
• 
Determination of futility  
11.5.1. 
Subject Stopping Rules 
Subjects will be informed that they have the right to withdraw from the study at any time for any reason, without 
prejudice to their medical care. The investigator also has the right to withdraw patients from the study for any of 
the following reasons: 
• 
If study drug is discontinued due to AE 
• 
If a subject is withdrawn due to an adverse event, the dose adjustment, modification and withdrawal 
procedures related to adverse events will be followed and will be switched to other alternative medications.. 
• 
Protocol violation 
• 
Lost to follow-up 
• 
Study terminated 
• 
Non-compliance 
11.6. Safety Oversight 
We will utilize the UW ICTR Data Monitoring Committee (DMC) to oversee the study. The UW ICTR DMC is 
comprised of experienced members with expertise required to oversee this study. In providing oversight for the 
conduct of this study, the ICTR DMC will meet annually in which subjects will have any study procedures. At these 
annual meetings, the DMC members will review protocol-specific reports created by statisticians using data pulled 
from both the ICTR OnCore and the ICTR REDCap systems.  These standard reports will include an overview of 
study objectives, a review of actual and projected accrual rates, an evaluation of patient demographics, a summary of 
the number and seriousness of adverse events, and an analysis of the primary and secondary outcomes.  An interim 
analysis of study results may be performed and source documents may be reviewed to allow the DMC to 
independently judge whether the overall integrity and conduct of the protocol remain acceptable based on data 
provided and reported by the Principal Investigator. The DMC will make recommendations to the Principal Investigator 
that could include actions of continuation, modification, suspension, or termination. 
 
Serious adverse events will be reviewed by the DMC co-chairs once reported to the DMC.  An ad hoc meeting of the 
DMC may be scheduled to discuss the SAE(s) and any potential action that is needed pertaining to study 
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12. Study Monitoring, Auditing, and Inspecting 
12.1. Medical Monitoring 
The investigator is responsible for monitoring the safety of subjects who have enrolled in the study.   For this 
study, adverse events will be solicited from subjects to identify an occurrence or worsening of an unintended 
sign or symptom, related to the ingestion of the study drug.  The study team will ask subjects on each 
evaluation if they experienced any new medication related signs or symptoms since taking the study drug. 
Subjects will be asked about any adverse events they may have experienced on each visit.  Only the adverse 
events considered related  ( possible, probable or definite) to the ingestion of the study drug will be entered 
into and managed in the data management system.   
12.1.1. 
Study Monitoring Plan 
Clinical site monitoring is conducted to ensure that the rights and well-being of human subjects are protected, that 
the reported trial data are accurate, complete, and verifiable, and that the conduct of the trial is in compliance with 
the currently approved protocol/amendment(s), with GCP, and with applicable regulatory requirement(s).  
Monitoring for this study will be performed by ICTR study monitoring service 
While many institutions involved in clinical research conduct various types of quality assurance reviews and 
audits, University of Wisconsin Institute for Clinical and Translational Research (ICTR) is one of a few institutions 
to offer independent Study Monitoring Services, a robust academic equivalent to the industry Contract Research 
Organization (CRO) standards for ongoing study monitoring.  
 
The sponsor-investigator has contracted with ICTR Study Monitoring Service (SMS) for the proposed study to 
provide ongoing monitoring services throughout the life cycle of the study. Refer to the Study Monitoring Plan in 
Appendix 4. .  
 
For this study, UW ICTR SMS personnel will conduct a Site Initiation Visit (SIV) and ongoing Interim Monitoring 
Visits (IMVs), either on-site, remotely, centrally or a combination thereof, throughout the duration of the study. 
During IMVs, the monitors will review study materials, including but not limited to: regulatory files, consent forms, 
case report forms, and drug accountability logs.  UW ICTR SMS personnel will conduct a Close-Out Visit (COV) 
upon completion of the study at the study site.  
 
Monitoring will consist of all (100%) of the study-related records representing 10-20% of those enrolled at a 
minimum. SMS personnel could increase the percentage of study or subject records to be reviewed if warranted 
by the ongoing monitoring findings, resulting in a partial or full review of up to 100% of the study-related subject 
records.  Based on the plan to review approximately 10-20% of the subject records, it is anticipated that the 
following monitoring visit schedule will implemented; 1 SIV, 1 IMV following the enrollment of the first subject(s), 
followed by approximately 12 IMVs through the end of the study, planned on an approximate quarterly basis.  The 
frequency of the IMVs could increase based on subject enrollment and previous monitoring visit findings, but will 
not decrease. 
 
The SMS will review the accuracy and completeness of completed consent and HIPAA documents for each 
enrolled subject.  For approximately 10-20% of enrolled subjects, the SMS will evaluate the completeness and 
accuracy of the data collected and conduct a comparison with the electronic data captured, resulting in electronic 
queries with resolution or validation. In addition, the SMS staff will verify adherence to protocol eligibility criteria, 
verify documentation for the accountability and administration of the study product, verify documentation of study 
procedures, and verify that FDA required SAE reports were appropriately submitted.  
 
The study monitor(s) will work closely with the ICTR DMC statistician and the study statistician to conduct periodic 
central data reviews, with follow-up conducted by the study monitors for any data discrepancies identified. 
 
The PI will be provided copies of monitoring reports within 30 days of visit.  
 
Details of clinical study monitoring are documented in a SMP (Study Monitoring Plan) that can be found in Appendix 
4. The SMP describes in detail who will conduct the monitoring, at what frequency monitoring will be done, at what 
level of detail monitoring will be performed, and the distribution of monitoring reports.  


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12.2. Protocol Deviations 
A protocol deviation is any noncompliance with the applicable regulations, clinical trial protocol, GCP, or MOP 
requirements. The noncompliance may be either on the part of the participant, the investigator, or the study site staff. 
As a result of deviations, corrective actions are to be developed by the site and implemented promptly.  
These practices are consistent with ICH E6:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
 
The site PI/staff will be responsible for continuous vigilance to identify and report deviations to the protocol. These will 
be reported within 5 working days of identification of the protocol deviation, or within 5 business days of the scheduled 
protocol-required activity. All deviations must be addressed in study source documents. Protocol deviations will be 
sent to the local IRB per their guidelines. The PI and study staff are responsible for knowing and adhering to their IRB 
requirements. Further details about the handling of protocol deviations will be included in the MOP.  
 
12.3. Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB (or their representatives), the 
sponsor, government regulatory bodies, of all study related documents (e.g. source documents, regulatory 
documents, data collection instruments, study data etc.).  The investigator will ensure the capability for inspections of 
applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
12.4. Subject Compliance Monitoring 
UW ICTR SMS will review to ensure compliance with applicable regulations, guidelines, and institutional policies.  UW 
ICTR SMS personnel will conduct a Close-Out Visit (COV) upon completion of the study at the study site.  
13. Ethical Considerations 
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, applicable local and state 
laws, and Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted independent Institutional Review Board (IRB), 
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 funding 
sponsor before commencement of this study.  
 
All subjects for this study will be provided a consent form describing this study and providing sufficient information for 
subjects to make an informed decision about their participation in this study.  .  The 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, must be obtained before that subject undergoes any study procedure.  The consent form must be signed by the 
subject, and the investigator-designated research professional obtaining the consent.  
14. Study Finances 
14.1. Funding Source 
 This study is financed through a grant from the Veloxis pharmaceuticals as an investigator initiative study.  
14.2. Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or financial gain greater   
than the minimum allowable by their institution, etc.) must have the conflict reviewed by a properly constituted Conflict 
of Interest Committee with a Committee-sanctioned conflict management plan that has been reviewed and approved 


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by the study sponsor prior to participation in this study.  All UW investigators will follow the UW conflict of interest 
policy. 
14.3. Subject Stipends or Payments 
None  
15. Publication Plan 
Neither the complete nor any part of the results of the study carried out under this protocol, nor any of the information 
provided by the sponsor for the purposes of performing the study, will be published or passed on to any third party without 
the consent of the study sponsor.  Any investigator involved with this study is obligated to provide the sponsor with complete 
test results and all data derived from the study. 
 
 
 


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16. References 
 
1. Yarlagadda SG, Coca SG, Garg AX, Doshi M, Poggio E, Marcus RJ, et al. Marked variation in the definition and 
diagnosis of delayed graft function: a systematic review. Nephrol Dial Transplant. 2008;23(9):2995-3003. 
2. Muth BL, Astor BC, Turk J, Mohamed M, Parajuli S, Kaufman DB, et al. Outpatient Management of Delayed Graft 
Function Is Associated With Reduced Length of Stay Without an Increase in Adverse Events. Am J Transplant. 
2016;16(5):1604-11. 
3. Siedlecki A, Irish W, Brennan DC. Delayed graft function in the kidney transplant. Am J Transplant. 
2011;11(11):2279-96. 
4. Novick AC, Hwei HH, Steinmuller D, Streem SB, Cunningham RJ, Steinhilber D, et al. Detrimental effect of 
cyclosporine on initial function of cadaver renal allografts following extended preservation. Results of a randomized 
prospective study. Transplantation. 1986;42(2):154-8. 
5. Andres A, Budde K, Clavien PA, Becker T, Kessler M, Pisarski P, et al. A randomized trial comparing renal function 
in older kidney transplant patients following delayed versus immediate tacrolimus administration. Transplantation. 
2009;88(9):1101-8. 
6. Gonwa TA, Mai ML, Smith LB, Levy MF, Goldstein RM, Klintmalm GB. Immunosuppression for delayed or slow 
graft function in primary cadaveric renal transplantation: use of low dose tacrolimus therapy with post-operative 
administration of anti-CD25 monoclonal antibody. Clin Transplant. 2002;16(2):144-9. 
7. Nankivell BJ, Borrows RJ, Fung CL, O'Connell PJ, Allen RD, Chapman JR. Evolution and pathophysiology of renal-
transplant glomerulosclerosis. Transplantation. 2004;78(3):461-8. 
8. Nankivell BJ, Borrows RJ, Fung CL, O'Connell PJ, Allen RD, Chapman JR. The natural history of chronic allograft 
nephropathy. N Engl J Med. 2003;349(24):2326-33. 
9. Naesens M, Kambham N, Concepcion W, Salvatierra O, Jr., Sarwal M. The evolution of nonimmune histological 
injury and its clinical relevance in adult-sized kidney grafts in pediatric recipients. Am J Transplant. 2007;7(11):2504-
14. 
10. Parajuli S, Redfield RR, Astor BC, Djamali A, Kaufman DB, Mandelbrot DA. Outcomes in the highest panel reactive 
antibody recipients of deceased donor kidneys under the new kidney allocation system. Clin Transplant. 2017;31(3). 
11. Bunnapradist S, Ciechanowski K, West-Thielke P, Mulgaonkar S, Rostaing L, Vasudev B, et al. Conversion from 
twice-daily tacrolimus to once-daily extended release tacrolimus (LCPT): the phase III randomized MELT trial. Am 
J Transplant. 2013;13(3):760-9. 
12. Budde K, Bunnapradist S, Grinyo JM, Ciechanowski K, Denny JE, Silva HT, et al. Novel once-daily extended-
release tacrolimus (LCPT) versus twice-daily tacrolimus in de novo kidney transplants: one-year results of Phase 
III, double-blind, randomized trial. Am J Transplant. 2014;14(12):2796-806. 
13.  Rostaing L, Bunnapradist S, Grinyo JM, Ciechanowski K, Denny JE, Silva HT, Jr., et al. 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(4):648-59. 
 
 
 
 


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17. Appendices 
 
Appendix 1 
Envarsus XR Package Insert 
Appendix 2 
Data Monitoring Committee Charter 
Appendix 3 
Data and Safety Monitoring Plan (DSMP) 
Appendix 4 
Study Monitoring Plan 
 
 
 
 
 
 
 
 
 
 
 


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17.1. Appendix 1: Envarsus XR Package Insert 
                             http://www.envarsusxr.com/