Trial to Evaluate Safety and Tolerability of Tacrolimus Extended-Release (Astagraf XL) in HLA Sensitized Kidney Transplant Recipients

The study will be a single center, pilot trial. It will be an open label, single-arm, non-
controlled design. All HS kidney transplant recipients with a PRA ≥ 30%, age 18 and older,
requiring desensitization may be included in the study. Initial desensitization protocol for
LD or DD includes Intravenous Immunoglobulin (IVIG) 2g/kg (>70kg max 140g) given on day 0
(split over 2 days for peritoneal dialysis patients), rituximab 375mg/m2 (rounded to the
nearest 100mg vial) given on day 15, and IVIG 2g/kg (>70kg max 140g ) given on day 30.
Recipients for LD or DD who are unresponsive to IVIG/ritux (after 2 months for LD and after 6
months for DD) will require plasma exchange (PLEX) 5-7 sessions followed by IVIG 2g/kg (>70kg
max 140g) and rituximab 375mg/m2. Patients will be receiving acetaminophen, antihistamine,
and steroid as premedication for all infusions.

A total of 20 subjects will be enrolled in the study. Subjects will take part in the study
until they are one year post-transplant. All subjects will require informed consent. At the
time of screening, subjects will receive a physical exam and undergo lab testing. Alemtuzumab
30mg, will be administered subcutaneously to all subjects for induction immunosuppression
immediately post-transplant. Maintenance immunosuppression will consist of tacrolimus
extended-release, mycophenolate mofetil 500mg twice daily or mycophenolate sodium 360mg twice
daily, and prednisone. Patients will receive antimicrobial prophylaxis per CSMC protocol. Lab
tests and physical exams for safety will take place according to the evaluation schedule
below. Safety will be assessed by the reporting of serious adverse events.

Tacrolimus trough level, complete metabolic panel, liver function panel, complete blood count
with differential, DSA, and urinalysis with culture will be assessed according to the
evaluation schedule below. Subjects will complete the study at one year post-transplant.
Consent may be withdrawn by the study participant at any time. The investigator may also
withdraw the study participant at any time if there are any safety concerns.

Desensitization includes Intravenous Immunoglobulin (IVIG) 2g/kg (>70kg max 140g) given on
day 0 (split over 2 days for peritoneal dialysis patients), rituximab 375mg/m2 (rounded to
the nearest 100mg vial) given on day 15, and IVIG 2g/kg (>70kg max 140g ) given on day 30.
Patients will require plasma exchange (PLEX) 5-7 sessions if they have received
desensitization in the past. In this case, patients will receive PLEX daily x 5-7 sessions
followed by IVIG 2g/kg (>70kg max 140g) and rituximab 375mg/m2. Patients will be receiving
acetaminophen, antihistamine, and steroid as premedication for all infusions.

Inclusion Criteria:

1. Recipient of a deceased or living donor kidney allograft

2. Patients must have undergone desensitization with IVIG and rituximab with or without
plasma exchange prior to transplant or be administered IVIG and rituximab
peri-operatively (within seven days of transplant) post-transplant

3. Age 18 and over

4. Able to understand and provide informed consent

5. Calculated PRA (CPRA)> 30% demonstrated on 3 consecutive samples. The methodology to
measure PRA includes FLOW and Luminex Single Antigen Assay.

6. At transplant, patient must have an acceptable crossmatch (as defined as T-or B- FCMX
≤ 225 MCS) from non-HLA identical donor. Negative crossmatch is Tpronase FCMX <70; T-
FCMX <50 and Bpronase FCMX <130; B-FCMX <100.

Exclusion Criteria:

1. Recipients of a dual simultaneous kidney/liver, kidney/heart, kidney/lung, or
kidney/pancreas transplant

2. History of hypersensitivity to any of the study drugs or to drugs of similar chemical
classes

3. Patients being treated with drugs that are strong inducers or inhibitors of cytochrome
P450 3A4

4. Patients with a clinically significant systemic infection within 30 days prior to
transplant

5. Patients who have any surgical or medical condition that may affect absorption of
drug, such as severe diarrhea, active peptic ulcer disease, or uncontrolled diabetes
mellitus, which in the opinion of the investigator, might significantly alter the
absorption, distribution, metabolism and/or excretion of study medication

6. Women of childbearing potential who are either pregnant, lactating, planning to become
pregnant during this trial, or with a positive serum or urine pregnancy test. Women of
childbearing potential must be willing to agree to contraceptive practices.

7. Patients who are PCR positive for Hep B, Hep C, or HIV.