Evaluation Dose Adjustments in Kidney Transplant Patients on Immediate Release and Extended Release Tacrolimus

1. Background and Rationale- The novel once-daily extended-release tacrolimus (ERT) has
been shown to be non-inferior to twice-daily tacrolimus (TDT) during induction
immunotherapy for kidney transplantation. The ERT (Envarsus) has a MeltDose technology
that allows for steadier absorption of tacrolimus throughout the entire gastrointestinal
tract. This drug has decreased peak to trough fluctuation. This decrease in variability
and stabilized trough level should allow for easier achievement of target drug levels
with fewer clinic visits and drug level assays.

2. Objective

1. To assess the safety of ERT versus TDT and effectiveness in achieving tacrolimus
trough therapeutic range during the first 6 months after transplantation

2. Primary End-Point

i. Ability to achieve center specific target tacrolimus trough levels at the determined
intervals after transplantation.

1. Percent of levels in range 2. As most levels occur in the first 6 months, a 6-month time
frame will be used for the primary analysis.

c. Secondary End-Points i. Number of dose adjustments required ii. Time in therapeutic range
for tacrolimus trough levels during intervals after transplantation based on the Rosendaal
Method

1. Time within goal for each time period

2. Time within larger goal of 6-11 iii. Number of lab draws required to achieve trough
tacrolimus levels iv. Time to get in therapeutic range v. Cost associated with
maintaining therapeutic troughs of tacrolimus

3. Subject Selection a. Subjects will be selected from patients scheduled to receive a
living donor or deceased donor kidney transplants at Sentara Norfolk General Hospital b.
Inclusion Criteria i. Age 18-70 ii. Receiving a kidney transplant at Sentara Norfolk
General Hospital iii. Able to give informed consent c. Exclusion Criteria i. Multi-organ
transplant ii. Previous functioning transplant iii. Prior surgery to the
gastrointestinal tract that alters the normal anatomy with the exception of
cholecystectomy iv. Women of childbearing potential who cannot or are unwilling to
maintain adequate contraception during the course of this study.

d. Patients will be offered enrollment in the study prior to transplant and Informed
Consent will be obtained.

e. Patients will be randomized to standard twice-daily tacrolimus (Prograf) or
once-daily extended-release tacrolimus (Envarsus) at a ratio of 1:2.

4. Methods a. Informed Consent to participate in this study will be obtained prior to
transplant.

b. Study subjects will receive usual care induction immunosuppression with
Anti-thymocyte globulin or basiliximab, steroids and mycophenolate per the center's
protocol.

c. Subjects enrolled in the study will be randomized and started on tacrolimus within 72
hours after transplant.

i. Randomization

1. Prior to study initiation, numbered packets will be created including randomized group
and the Informed Consent Form.

2. The packets will be used in order.

3. The group will be determined using the random number generator using values from 1-99
where a value of 1-66 will have an ERT assignment in the study packet and a value of
67-99 will have a TDT assignment in the study packet.

ii. Subjects randomized to the study group will start ERT at 8mg (or 4mg if concern for
delayed graft function) as a single daily dose.

iii. Subjects randomized to the control group will start TDT at 8mg (or 4mg if concern
for delayed graft function) divided in half for a dose every 12 hours.

iv. If a subject weighs less than or equal to 55kg, then the subject will receive a
reduced dose of either ERT or TDT at the provider's discretion.

d. Subjects' tacrolimus levels in the study will follow our regular post-transplant
care. This center uses an outpatient nursing protocol for most patients. If a patient is
excluded from the nursing protocol, their tacrolimus levels will be managed individually
and changes will be made at the nephrologist's discretion.

i. Prograf protocol (appendix A) ii. Envarsus protocol (appendix B) e. All other care is
routine (nothing done solely for the purpose of research). Other routine care includes:
i. Weekly clinic visits and labs for the first month, every other week for the second
month then a minimum of monthly through 6 months post transplant.

ii. During those visits, labs will be drawn, including a tacrolimus level, regardless of
study arm. Subjects will receive our routine nephrologist and nurse visits while in
clinic. Other specialists (surgeon, dietician, pharmacist, diabetes educator) will see
the subjects, as needed.

iii. Dose changes will either be made in clinic or with a phone call to the subject
after clinic, if necessary. Tacrolimus dose changes will be directed by our nurse
protocols (appendix A and B). If the subject is excluded from the nursing protocol, the
level and dose will be managed by the nephrologist.

5. Investigator Responsibilities- The principal investigator will be responsible to ensure
that:

1. all IRB required training for staff and investigators is completed,

2. all staff and investigators comply with the institution's patient and subject safety
requirements,

3. the study is conducted in compliance with the protocol and

4. data collection requirements are maintained. 6. Data Analysis

a. Continuous variables will be analyzed using student's t-test or Mann-Whitney U, where
appropriate.

b. Categorical variables will be analyzed using the chi2 test or Fischer's Exact test where
appropriate.

c. Power analysis for the primary endpoint which will evaluate each level and whether it is
in range or not i. Alpha =0.05, beta =0.8 ii. Prior data shows 41% of levels in range for
TDT. We predict that ERT dosing will have 53% of levels in range.

iii. With a ratio of 2:1, the minimum will need 406 ERT levels (~38 patients) and 203 TDT
levels (~19 patients).

iv. The number of patients is based on patients having 11 levels in the first 6 months, the
minimum number of based on our protocol.

7. Data collected includes : i. Inclusion/Exclusion

1. If excluded, reason for exclusion ii. Randomization to Prograf or Envarsus iii.
Demographic information

1. Age

2. Height

3. Weight

4. Gender

5. Race

6. Induction (thymoglobulin/basiliximab)

7. CMV donor/recipient exposure status (+/+, +/-, -/+, or -/-)

8. Living or deceased donor iv. Transplant outcomes

1. Rejection (Yes/No and if yes, time interval post-transplant in days). Defined as requiring
steroids, thymoglobulin, and/or IVIG 2. BK viremia (Yes/No and if yes, time interval
post-transplant in days) 3. CMV viremia (Yes/No and if yes, time interval post-transplant in
days) v. Tacrolimus level with time interval post-transplant in days (Yes/No/Not timed
correctly) vi. Tacrolimus dose 8. HIPPA Concerns

1. This study will collect data on patient demographics, treatments and outcomes of
treatments. Patient data collected will be de-identified of Protected Health Information
(PHI) and will not alter patient treatment. This study is designed to address fully
HIPAA's requirements for health data that are collected with patient consent.

2. Study data may be made available to third parties, e.g., in the case of an audit
performed by regulatory authorities, provided the data are treated confidentially and
that the subject's privacy is guaranteed.

3. Subjects identities will not be identifiable or disclosed if results from the study are
published.

9. Data handling

a. The key to patient coding for identification (see Appendix C) and data collection forms
will be kept on a password protected computer in a locked office which is only accessible by
the investigators and research assistants. To maintain compliance with IRB requirements, the
study data will be maintained for the required period of three years. Once the study is
completed and data is retained for a minimum of 3 years per the requirements of the IRB, the
identifiable data will be destroyed .

10. Human Subjects

1. Due to the nature of the study, there is a potential risk in regards to breach of
patient confidentiality. This will be reduced with the collection of the patient's MRN
as the identifier, which will then be given a code (see Appendix C), and the storage of
this data on a password protected computer in a locked office. The records will be
secured for three years according to Federal regulation.

2. Risks

i. There are risks with blood draws that are bruising, swelling at site, and, in rare cases,
nerve damage.

ii. Both formulations of tacrolimus (ERT and TDT) are approved for this indication,
prevention of rejection after kidney transplant. Expected adverse events have been identified
from approval studies. Any serious adverse events will be reported to Veloxis's safety
partner, UBC. The study team has the forms to fill out. Any adverse events that require FDA
notification will be reported to MedWatch.

c. Benefits i. Subjects who are randomized to receive ERT will receive 6 months-worth of
study drug provided by the drug company. After 6 months, the subject's insurance company will
be billed for the drug and patients may be responsible for a copayment.

ii. Subjects will not have to pay to participate in the study. iii. Subjects will not be paid
to participate in the study. 11. Request for Support

a. The PI requests a 6-month supply of ERT for each subject randomized to the study group.

b. A request for funding for direct study activities will be requested when the research
center and the sponsor have agreed to the study protocol.

Inclusion Criteria:

- Age 18-70

- Receiving a kidney transplant at Sentara Norfolk General Hospital

- Able to give informed consent

Exclusion Criteria:

- Multi-organ transplant

- Previous functioning transplant

- Prior surgery to the gastrointestinal tract that alters the normal anatomy with the
exception of cholecystectomy

- Women of childbearing potential who cannot or are unwilling to maintain adequate
contraception during the course of this study.