A Prospective, Pilot Trial to Evaluate Safety and Tolerability of Tacrolimus Extended-Release (Astagraf XL) in HLA Sensitized Kidney Transplant Recipients
Phase: PHASE4
Conditions: End Stage Renal Disease
Sponsor: Cedars-Sinai Medical Center

 
 
 
 
 
 
 
 
Official Title: A Prospective, Pilot Trial to Evaluate Safety and Tolerability of Tacrolimus 
Extended-Release (Astagraf XL) in HLA Sensitized Kidney Transplant Recipients 
NCT #: NCT03194321 
Document Date: January 25, 2018 

1 
 
 
 
 
 
 
 
 
Astagraf XL Clinical Study Protocol 
  
 
 
A Prospective, Pilot Trial to Evaluate Safety and Tolerability of Tacrolimus 
Extended-Release (Astagraf XL) in HLA Sensitized Kidney Transplant 
Recipients 
 
 
Authors: 
Joseph Kahwaji, MD  
Ashley Vo, PharmD 
Jua Choi, PharmD 
Principle Investigator 
Stanley Jordan, MD 
  Co-Investigators 
Reiad Najjar, MD  
Alice Peng, MD 
Edmund Huang, MD 
Reiad Najjar, MD 
Supreet Sethi, MD 
Ashley Vo, PharmD 
Jua Choi, PharmD 
Nori Ammerman, PharmD 
Document type: 
Clinical Study Protocol 
Version number: 
3 
Release date: 
 
25JAN2018 
 
 
 

2 
 
Table of contents 
Table of contents.............................................................................................................2 
List of tables ....................................................................................................................4 
List of abbreviations ........................................................................................................5 
Glossary of terms ............................................................................................................6 
Protocol synopsis ............................................................................................................7 
Background ..........................................................................................................9  
2.  
Purpose and rationale ........................................................................................10 
3 
Objectives ..........................................................................................................10 
3.1 
Primary objectives ..............................................................................................10 
3.2 
Secondary objectives ...............................………………………………………....10 
4 
Study design ......................................................................................................10 
5 
Population ..........................................................................................................10 
5.1 
Inclusion criteria..................................................................................................11 
5.2 
Exclusion criteria ................................................................................................11 
6 
Treatment............................................................................................................12 
6.1 
Investigational and control drugs .......................................................................12 
6.1.1 Patient numbering...............................................................................................12 
6.1.2 Dispensing the study drug ..................................................................................12 
6.1.3 Study drug supply, storage and tracking.............................................................12 
6.1.4 Instructions for prescribing and taking the study drug.........................................13 
6.1.5 Permitted study drug dose adjustments and interruptions .................................14 
6.1.6 Treatment of acute rejection ..............................................................................14 
6.1.7 Treatment of patients unable to tolerate oral medication 
 
 
    14 
7 
Visit schedule and assessments ........................................................................14 
7.1 Patient demographics/other baseline characteristics ..............................................15 
7.2 
Treatment exposure and compliance .................................................................15 

3 
 
7.3 
 Safety ................................................................................................................15 
7.4 
Physical examination .........................................................................................15 
7.4.1 Vital signs ...........................................................................................................16 
7.4.2 Laboratory evaluations .......................................................................................16 
7.4.3 Pregnancy and assessments of fertility ..............................................................16 
8 
Safety monitoring ...............................................................................................16 
8.1 
Adverse events ..................................................................................................16 
8.2 
Serious adverse event reporting ........................................................................17 
8.3 
Pregnancies........................................................................................................17 
9 
Data review and database management............................................................18 
9.1 
Data collection ...................................................................................................18 
9.2 
Database management and quality control .......................................................18 
10  Data analysis ..........................................................................................................18 
10.1 Populations for analysis......................................................................................18 
10.2 Patient demographics/other baseline characteristics..........................................18 
10.3 Treatments (study drug, other concomitant therapies, compliance) ..................18 
10.4 Analysis of the primary objective(s) ...................................................................19 
10.4.1 Variable ..............................................................................................................19 
10.4.2 Safety .................................................................................................................19 
10.5 Sample size calculation ......................................................................................19 
11       Ethical considerations .......................................................................................19 
11.1 Regulatory and ethical compliance ....................................................................19 
11.2 Informed consent procedures ............................................................................19 
11.3 Responsibilities of the investigator and IRB/IEC/REB .......................................20 
11.4 Publication of study protocol and results ...........................................................20 
12       Protocol adherence ......................................................................................20 

4 
 
12.1 Protocol Amendments ........................................................................................20 
13       References......................................................................................................20 
Appendix 
Appendix 1: Data Safety Monitoring Board (DSMB) Charter…………………………….21 
Appendix 2: MedWatch Form………………………………………………………………..21 
Appendix 3: Tacrolimus Extended Release (Astagraf XL®) Package Insert………......21 
List of tables 
Table 1 Target Tacrolimus Extended Release Trough Levels.........................................8 
Table 2 Assessment Schedule………………………………………………………………14

5 
 
List of abbreviations 
HS 
 
Highly Sensitized 
IVIG  
Intravenous Immunoglobulin 
PLEX  
Plasma Exchange 
SAEs  
Serious Adverse Events 
BPAR  
Biopsy proven acute rejection 
DSA  
Donor Specific Antibodies 
PRA  
Panel reactive antibody 
CSMC 
Cedars-Sinai Medical Center 
TMP/SMX 
Trimethoprim/Sulfamethoxazole (Bactrim) 
HLA  
Human Leukocyte Antigen Antibodies 
RIS 
 
Relative Intensity Score 
MFI 
 
Mean Fluorescence Intensity 
CRF  
Case Report Form  
SOC  
Standard of Care 
SAE  
Significant Adverse Event  
FDA   
Federal Drug Administration 
WHO  
World Health Organization 
 
 
 

6 
 
Glossary of terms (correct format below) 
Assessment 
A procedure used to generate data required by the study 
Control drug 
A study drug used as a comparator to reduce assessment bias, 
preserve blinding of investigational drug, assess internal study 
validity, and/or evaluate comparative effects of the investigational 
drug 
Enrollment 
Point/time of patient entry into the study; the point at which 
informed consent must be obtained (i.e. prior to starting any of the 
procedures described in the protocol) 
Investigational drug 
The study drug whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and is 
synonymous with “investigational new drug.” 
Medication number 
A unique identifier on the label of each medication package in 
studies that dispense medication using an IVR system 
Patient number 
A number assigned to each patient who enrolls in the study. When 
combined with the center number, a unique identifier is created for 
each patient in the study. 
Stage 
A major subdivision of the study timeline; begins and ends with 
major study milestones such as enrollment, randomization, 
completion of treatment, etc. 
Period 
A minor subdivision of the study timeline; divides phases into 
smaller functional segments such as screening, baseline, titration, 
washout, etc. 
Premature patient 
withdrawal 
Point/time when the patient exits from the study prior to the 
planned completion of all study drug administration and 
assessments; at this time all study drug administration is 
discontinued and no further assessments are planned 
Randomization number 
A unique identifier assigned to each randomized patient, 
corresponding to a specific treatment arm assignment 
Stop study participation 
Point/time at which the patient came in for a final evaluation visit or 
when study drug was discontinued whichever is later 
Study drug 
Any drug administered to the patient as part of the required study 
procedures; includes investigational drug and any control drugs 
Study drug discontinuation Point/time when patient permanently stops taking study drug for 
any reason; may or may not also be the point/time of premature 
patient withdrawal 
Variable 
Information used in the data analysis; derived directly or indirectly 
from data collected using specified assessments at specified 
timepoints 
 
 
 

7 
 
Protocol synopsis 
  
 
Title of study: A Prospective, Pilot Trial to Evaluate the Safety and Tolerability of 
Tacrolimus Extended-Release in HLA Sensitized Kidney Transplant Recipients 
 
Purpose and rationale: 
 
The purpose of this study is to demonstrate the safety of tacrolimus extended-release 
in HLA sensitized (HS, defined as panel reactive antibody ≥ 30%), kidney transplant 
recipients after desensitization with intravenous immunoglobulin (IVIG) and rituximab 
+/- plasma exchange (PLEX) per the standard of care with alemtuzumab induction. 
   
Objectives: 
 
The primary objective is to determine the safety of tacrolimus extended-release in the 
HS patient population as measured by the rate of serious adverse events (SAEs) and 
treatment failure.  Treatment failure is defined as a composite of biopsy proven acute 
rejection (BPAR), graft failure, or death. BPAR is defined as ≥ Banff 1A using the Banff 
2007 criteria.   
 
Secondary objectives are to observe the following: 
 
1. Change in donor specific antibodies (DSA) as defined by the DSA relative 
intensity score[1,2] 
 
2. Tolerability as defined by the number of subjects discontinuing the study 
medication 
 
 
Population: 
 
The study population will consist of HS patients ( p a t i e n t s  w h o  h a v e  
r e c e i v e d  d e s e n s i t i z a t i o n )  with end- stage kidney disease undergoing kidney 
transplantation.  The study will begin at the time of transplantation while subjects are 
inpatients.  They will be followed post- transplantation as outpatients. 
  
 
Inclusion/Exclusion criteria: 
  
Key inclusion criteria are as follows: 
 
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 
 

8 
 
5. 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. 
 
Key exclusion criteria are as follows: 
 
1. Recipients of a dual simultaneous kidney/liver, kidney/heart, kidney/lung, or 
kidney/pancreas transplant 
 
2. History of hypersensitivity to any of the study drug or to drugs of similar 
chemical classes 
 
3. Patients 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. 
   
Investigational and reference therapy: 
 
Tacrolimus extended-release starting dose 5mg once daily by oral administration 
adjusted to target trough level. 
 
Table 1: Target Tacrolimus Extended-Release Trough Levels 
 
Time 
Tacrolimus 
Day 4 to Month 6 
7 – 9 ng/ml 
Months 6-12  
5 – 8 ng/ml 
 
 
 

9 
 
Study design: 
 
This is a single center, pilot trial. It will be an open label, single-arm, non-controlled 
design.  All HS patients age 18 and older requiring desensitization may be included in 
the study.  Twenty 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 as detailed below in the evaluation schedule.  Alemtuzumab (Campath 1H, 
Lemtrada) will be administered to all subjects for induction immunosuppression 
immediately post-transplant. Maintenance immunosuppression will consist of 
tacrolimus extended-release, mycophenolate mofetil, and prednisone.    Patients will 
receive antimicrobial prophylaxis as per Cedars-Sinai Medical Center (CSMC) protocol 
(valganciclovir x 6 months, TMP/SMX x 12months, and fluconazole x 1 month). 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 as described below.  Tacrolimus extended-release trough level, complete 
metabolic panel, complete blood count with differential, donor specific antibodies, and 
urinalysis with culture will be assessed according to the evaluation schedule below.  
Subjects will complete the study at one year post-transplant.  Consent may be 
withdrawn by the study participant at any time.  The investigator may also withdraw 
the study participant at any time if there are any safety concerns. 
 
 
Efficacy assessments: 
 
This is a pilot study and no efficacy assessments will be made. 
 
Data analysis: 
 
All outcomes will be reported as frequencies.  Safety will be assessed by measuring 
the frequency of serious adverse events at one year post transplant.  The frequency 
of BPAR, graft loss, and death will also be assessed at one year post transplant. 
 
 
1          Background 
 
Kidney transplantation remains the gold standard for the treatment of end-stage kidney 
disease.  Advances in immunosuppression are integral to the success of kidney 
transplantation.  Current immunosuppression regimens have reduced the number of 
rejections.  However, long-term allograft survival remains a challenge.  One limitation of 
immunosuppression regimens is the pill burden placed upon the recipients.  This leads 
to long-term non-adherence and late rejections that ultimately place the allograft at 
risk[1,2].   
 
Approximately 30% of the patients currently awaiting a kidney transplant are broadly 
HLA-sensitized.  These preformed HLA-antibodies create a difficult to match phenotype 
that results in a longer wait time for a kidney transplant and higher rates of rejection 

10 
 
after kidney transplant.  Broadly HLA-sensitized patients are often excluded from 
clinical trials due to their extended length of time on dialysis (associated with increased 
post-transplant morbidity) and increased rates of rejection. 
 
Tacrolimus twice daily is very effective in preventing allograft rejection and is 
administered as first line therapy as part of multidrug immunosuppression regimen.  
Tacrolimus twice daily has a narrow therapeutic index and frequent drug monitoring is 
necessary to maximize efficacy and prevent adverse effects.  There is high intra-
individual variability that can place the allograft at risk of deterioration due to rejection or 
toxicity[3].   
 
Tacrolimus extended-release (Astagraf XL, Astellas Pharma US, Inc., Northbrook, IL) is 
a once daily formulation of tacrolimus.  It is currently approved for the prophylaxis of 
organ rejection in kidney transplant recipients.  Short and long-term data support the 
efficacy and safety of the once daily formulation[4, 5].  However, patients with a panel 
reactive antibody > 30% were excluded from the studies.  It has therefore, not been 
studied in this patient population. 
 
2          Purpose and rationale 
 
The purpose of this pilot study is to determine safety and tolerability of tacrolimus 
extended-release in a population of HS renal transplant patients.  Recipients will 
receive desensitization therapy consisting of IVIG and rituximab +/- PLEX per the 
standard of care at CSMC.  All recipients will receive induction with alemtuzumab.  
Tacrolimus extended-release has not been studied in this patient population to date. 
 
   
3          Objectives 
 
3.1        Primary objectives 
 
The primary objective is to determine the safety of tacrolimus extended-release in HS 
kidney transplant recipients after desensitization with IVIG and rituximab +/- PLEX per 
the standard of care and alemtuzumab induction. 
 
3.2        Secondary objectives 
 
Secondary objectives are to observe the following: 
 
1. 
Change in DSA as defined by the DSA relative intensity score (RIS) defined by: 0 
points for no DSA, 2 points for each weak DSA (MFI <5,000), 5 points for each 
moderate DSA (MFI 5,000 -10,000), and 10 points for each strong DSA (MFI 
>10,000)[1,2].  
 
2. 
Tolerability as defined by the number of subjects discontinuing the study 
medication 

11 
 
4          Study design 
 
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, 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 as 
detailed below in the evaluation schedule.  Alemtuzumab (Campath 1H, Lemtrada) 
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 as described below. 
 
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.    
 
5          Population 
 
Male and female HS renal transplantation patients, 18 years of age and over, receiving 
a cadaveric or living donor kidney transplant may enter the study.    Patients must 

12 
 
receive desensitization therapy. Twenty patients will be enrolled at CSMC for this pilot 
study. Patients who discontinue the study prematurely will not be replaced. 
 
5.1        Inclusion Criteria 
 
Patients eligible for inclusion in this study have to fulfill all of the following 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. 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.  
 
5.2 
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. 
 

13 
 
6          Treatment 
 
6.1        Investigational drugs 
This is a pilot study. All patients will receive tacrolimus extended-release adjusted to 
target trough levels, mycophenolate mofetil or mycophenolate sodium, and prednisone 
per CSMC practice.  Tacrolimus extended-release will be supplied by Astellas with 
packs of open-label study drug. A prescription will be filled by the subject for all other 
drugs. 
 
6.1.1       Patient numbering 
Each patient is uniquely identified in the study by a unique subject ID. Upon signing the 
informed consent form, the patient is assigned a subject ID by the investigator. Once 
assigned to a patient, a patient number will not be reused. 
 
6.1.2       Dispensing the study drug 
Tacrolimus extended-release will be provided free of charge for the duration of the 
study. Study drug will only be provided up to 12 months post transplant which is the 
duration of the study. All subjects will be given a prescription for all other drugs to be 
filled at a local pharmacy after completion of the study. 
 
6.1.3       Study drug supply, storage and tracking 
Study drugs must be received by a designated person at the study site, handled and 
stored safely and properly, and kept in a secured location to which only the investigator 
and designated assistants have access. Upon receipt, all study drugs should be stored 
according to the instructions specified on the drug labels. Clinical supplies are to be 
dispensed only in accordance with the protocol. 
 
6.1.4       Instructions for prescribing and taking the study drug 
Medication labels will comply with the legal requirements.  The investigator must 
maintain an accurate record of the shipment and dispensing of study drug in a drug 
accountability ledger. Patients will be asked to return all unused study drug and 
packaging at the end of the study or at the time of study drug discontinuation. 
 
The investigator should instruct the patient to take the study drug exactly as prescribed. 
All dosages prescribed to the patient and all dose changes during the study must be 
recorded on the Study  Drug  Administration  Record  CRF.  Depending on when the 
subject gets transplanted, the investigational drug will either be given same day as 
transplant (Day 0) OR at the next scheduled dosing after transplantation at 8am.  It will 
be taken by mouth at the starting dose of 5mg orally or 0.07mg/kg (rounded to the 
nearest 1mg) daily.  A therapeutic drug level will be checked after two doses of the 
investigational drug and then daily as per SOC.  Tacrolimus trough levels will be 
adjusted to achieve a goal of 7 to 9 ng/ml for the first six months and goal of 5-8ng/ml 
thereafter (see Table 1). 
 
The investigator and co-investigators are responsible for instructing the patients 
regarding the exact dose and dosing schedule to be followed.  Instructions for taking 

14 
 
the drug will be given at the time of discharge and reinforced at subsequent office visits.  
Patients will be instructed to take the drug at 8am. They will be instructed to take the 
drug 2 hours after their last meal or 1 hour before their next meal preferably on an 
empty stomach and to swallow capsules whole (no crushing or chewing or dividing 
capsules). 
 
Study Drugs 
Patients will take tacrolimus extended-release daily on a consistent schedule with 
regard to time of day and relation to meals. No grapefruit or grapefruit juice should be 
taken throughout the study. 
 
6.1.5         Permitted study drug dose adjustments and interruptions 
Blood for tacrolimus extended-release trough levels will be obtained from all patients at 
the time points indicated in Flowchart of Procedures. Therapeutic drug monitoring will 
be mandatory for all patients throughout the study. For patients who are unable to 
tolerate the protocol-specified dosing scheme, dose adjustments and interruptions are 
permitted in order to keep the patient on study drug. PI will follow local practice 
guidelines for these adjustments and interruptions. 
 
The first tacrolimus level should be drawn after two doses are administered. Tacrolimus 
extended-release dose adjustments should be made based on results of the trough 
levels from the local laboratory. Follow-up tacrolimus trough levels should be rechecked 
after any dose adjustments are made to ensure that the recommended troughs are 
achieved.  
 
6.1.6   Treatment of Acute Rejection 
Rejection episodes will be managed as per local practice.   Solumedrol or anti- 
thymocyte globulin will be administered for cell-mediated rejection.   IVIG with or 
without rituximab may be administered for antibody mediated rejection. Plasma 
exchange +/- eculizumab may be used for severe antibody mediated rejection. 
 
6.1.7 Treatment of patients unable to tolerate oral medication  
 
The study drug may be temporarily interrupted if a patient develops a short-term 
intolerance of oral medication after the initial dose of study medication.  Alternatively, 
administration of tacrolimus twice daily suspension via nasogastric (NG) tube or if more 
serious cyclosporine or tacrolimus IV (per SOC) may be used. IV cyclosporine will be 
preferred due to difficulty checking IV tacrolimus levels (since it is a continuous 
infusion).  Patients should be returned to tacrolimus extended-release oral medication 
as soon as possible.   
 
7          Visit schedule and assessments 
 
Table 7-1 lists all of the assessments and indicates with an “x” or “SOC” 
(for standard of care) the visits when they are performed. Patients should 
be encouraged to attend all visits on the designated day. However, visit 
windows will be allowed of ± 1day for Day 2, ± 2 days for Day 4, ± 3 days for 

15 
 
Day 7, Day 14, ± 7 days for Day 30, Month 2 and ± 14 days for Month 6, 9, 
12.  
 
 
Table 2  Assessment Schedule 
 
Study Visit 
Pre-op 
Days 
Month 
Screening 
Tx 
Day 0 
2 ±1d 
4 ±2 d 
7±3d 14±3
d 
30±3d 2±3d 
6±7d 
9±14d 12±14d 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
SOC 
SOC 
SOC 
SOC 
SOC 
SOC SOC 
SOC 
SOC 
SOC 
SOC 
Chest X-ray/ EKG5 
SOC 
 
 
 
 
 
 
 
 
 
 
Transplant Serology / Donor 
Background 
SOC 
 
 
 
 
 
 
 
 
 
 
Alemtuzumab 
Administration 
 
SOC 
 
 
 
 
 
 
 
 
 
Safety Lab Tests1 
SOC 
SOC 
SOC 
SOC 
SOC 
SOC SOC 
SOC 
SOC 
SOC 
SOC 
Urine Tests2 
 
 
 
SOC 
SOC 
SOC SOC 
SOC 
SOC 
SOC 
SOC 
Tacrolimus extended-release 
Trough Level3 
 
 
SOC 
SOC 
SOC 
SOC SOC 
SOC 
SOC 
SOC 
SOC 
Viral Testing4 
 
 
 
 
 
 
 
 
 
SOC 
 
SOC 
SOC 
SOC 
SOC 
Serum Pregnancy Test6 
X 
 
 
 
 
 
 
 
 
 
 
DSA* 
SOC 
 
 
 
 
 
SOC 
SOC 
SOC 
SOC 
SOC 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1. 
CBC and complete metabolic panel 
2. 
Urinalysis 
3. 
Tacrolimus extended-release levels will be monitored 4 days after a dose change or stopping of fluconazole 
4. 
Blood test for: BKV, CMV 
* .DSA will be done at time of transplant, and quarterly for the first year. 
-For DD (diseased donor), sample will be drawn pre-op, prior to IVIG.  Majority of patients would have received desensitization within the past 6-9 
months prior to transplant. 
-For LD, sample will be drawn prior to IVIG-2, but patient would already have received IVIG-1 and ritux 5 weeks prior to sample drawn. 
5. 
Can be done within 6 months of screening date.  
6. 
If subject is of childbearing age. [Not required if subject has a history of hysterectomy].  
 
 
7.1        Patient demographics/other baseline characteristics 
After informed consent has been signed and the patient’s eligibility to participate in 
the study has been determined, baseline patient information will be obtained, such as 
date of birth, age, sex, race, full relevant medical history/current medical conditions, 
information on renal transplantation background of recipient and donor and on 
transplantation procedure. Results of a full physical examination at baseline, vital 
signs, blood chemistry and hematology, and serum creatinine. 
 
7.2        Treatment exposure and compliance 
All doses of study medication administered during the course of the study will be 

16 
 
recorded on the appropriate Study Drug Dosage Administration CRF. Compliance 
monitoring will be done during clinic visits via patients’ interview and drug levels. 
 
7.3        Safety 
 
7.3.1       Acute Rejection 
Renal biopsies will be collected for all cases of suspected acute rejection.  Biopsies 
will be read by the local pathologist according to the Banff 2013 criteria. The results 
will be used for patient management for acute rejection and for the safety analysis. 
 
7.3.2      Graft Loss 
The allograft will be presumed to be lost if the patient requires dialysis for three 
consecutive months or longer and is not able to subsequently be removed from 
dialysis. . If the patient undergoes a graft nephrectomy, then the day of nephrectomy 
is the day of graft loss. Graft loss is considered a Serious Adverse Event and should 
be reported on the Serious Adverse Event CRF and the SAE form. 
 
7.3.3      Death 
In the event of patient death, an SAE form should be completed and reported.  The 
events leading to the death should be entered on the Adverse Event CRF. 
 
7.3.4       Renal function 
Renal function will be assessed by measuring serum creatinine and by calculated 
GFR using the MDRD formula. 
  
7.3.5       Viral PCR 
CMV and BKV PCRs will be collected according to the schedule outlined in Table 2. 
 
7.4      Physical examination 
A thorough physical examination will be performed during the baseline period and at 
every subsequent study visit. Significant findings made after the start of study drug 
which meet the definition of an Adverse Event will be recorded on the Adverse Event 
monitoring log. 
 
7.4.1       Vital signs 
Vital signs (pulse rate, blood pressure and weight (to the nearest 0.1 kilogram [kg]) 
will be recorded at baseline, prior to the first morning administration of study 
medication, and at each subsequent visit.  
 
7.4.2       Laboratory evaluations 
A  local  laboratory  (Cedars-Sinai  Clinical  Reference  Laboratory)  will  be  used  to 
analyze the clinical laboratory data during the study. 
 
Hematology 
Hematology will include platelets, hemoglobin, red blood cell count, white blood cell 
count to be measured at every study visit. 
 
Clinical chemistry 

17 
 
Biochemistry parameters will include sodium, potassium, chloride, calcium, 
magnesium, inorganic phosphate, blood urea nitrogen, creatinine, glucose, AST, ALT, 
alkaline phosphatase, total bilirubin. 
 
Urinalysis 
Measurements will be taken for cell count, glucose, and protein. 
 
7.4.3       Pregnancy and assessments of fertility 
Any female patient that becomes pregnant after the start of study medication should 
be discontinued and the patient switched to standard treatment. All pre-menopausal 
women who are not surgically sterile will have a serum pregnancy test at screening 
and a urine pregnancy test, if suspected, and at the end of study visit. A positive urine 
pregnancy test requires immediate interruption of study medication until serum B- 
hCG is performed and found to be negative. If positive, the patient must be 
discontinued from the trial.  The pregnancy should be followed up to determine 
outcome, including spontaneous or voluntary termination, details of birth, and the 
presence or absence of any birth defects or congenital abnormalities. 
 
8          Safety monitoring 
 
8.1        Adverse events 
An adverse event is the appearance or worsening of any undesirable sign, symptom, 
or medical condition occurring after starting the study drug even if the event is not 
considered to be related to study drug. Study drug includes the investigational drug 
under evaluation. Medical conditions/diseases present before starting study drug are 
only considered adverse events if they worsen after starting study drug. Abnormal 
laboratory values or test results constitute adverse events only if they induce clinical 
signs or symptoms, are considered clinically significant, or require therapy. The 
occurrence of adverse events should be sought by non-directive questioning of the 
patient at each visit during the study. Adverse events also may be detected when 
they are volunteered by the patient during or between visits or through physical 
examination, laboratory test, or other assessments. 
 
8.2        Serious adverse event reporting 
An SAE is defined as an event which: 
• is fatal or life-threatening 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization greater than 24hours unless hospitalization 
is for: 
1.  routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
2.  elective or pre-planned treatment for a pre-existing condition that is unrelated to 
the indication under study and has not worsened since the start of study drug 
3.  treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
4.  social reasons and respite care in the absence of any deterioration in the patient’s 

18 
 
general condition is medically significant, i.e. defined as an event that jeopardizes 
the patient or may require medical or surgical intervention to prevent one of the 
outcomes listed above. 
 
 
All SAEs that are serious and reasonably or probably related to tacrolimus 
extended-release will be reported to FDA and Astellas Pharma using MedWatch 
3500A form (Appendix B). 
 
Recurrent episodes, complications, or progression of the initial SAE must be reported 
as follow-up to the original episode, regardless of when the event occurs. An SAE 
that is considered completely unrelated to a previously reported one should be 
reported separately as a new event. 
 
All SAEs will be reported to Astellas. Their contact information is listed below:  
 
Email:  Safety-US@astellas.com.  
Fax: 847.317.1241 
 
Protocol exempted events: Unusually severe rejection episodes 
Acute rejections are considered protocol exempted events. They should not be 
reported simply because they result in hospitalization thus meeting the criteria for 
SAEs. Acute rejection episodes will therefore not be routinely expedited to health 
authorities. However, acute rejections should be reported as SAEs if they are unusual 
in appearance, clinical course and/or are graft threatening. 
 
8.3        Pregnancies 
To ensure patient safety, each pregnancy in a patient on study drug must be reported 
within 24 hours of learning of its occurrence.  The pregnancy should be followed 
up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, 
or maternal and/or newborn complications. 
 
9          Data review and database management 
 
 
9.1        Data collection 
Designated research staff will enter data into a secure electronic database from 
source documents.  Only the PI and designated research staff will have access to the 
database.  All source documents will be kept in a secure, locked cabinet.  All data will 
be reviewed for accuracy.  Designated research staff will be trained in the use of the 
electronic database. 
 
If patients live far from CSMC and are unable to come to their designated study visits 
within study windows, the study team will try to obtain study labs from the patient’s 
local hospital/clinic.  The results will be forwarded to CSMC for analysis.  
 

19 
 
9.2        Database management and quality control 
Designated study staff will validate data on an ongoing basis.  Any errors noted will 
be reviewed, confirmed, and then corrected.  A statement noting the correction will be 
included.  This study will be monitored by a formal DSMB.  The DSMB will consist of 
the PI, appointed Co-PIs, and at least one member not part of the investigational group. 
The DSMB will review safety data quarterly and formulate a letter with 
recommendations for continuation. 
 
10        Data analysis 
A designated statistician will perform the statistical analysis. 
 
10.1      Populations for analysis 
All patients enrolled in the study will be included in the analysis. 
 
10.2      Patient demographics/other baseline characteristics 
Continuous variables will be summarized by sample size, mean, standard deviation, 
median, minimum, and maximum. Discrete variables will be summarized by 
frequencies and percentages. 
 
10.3 
Treatments (study drug, other concomitant therapies, compliance) 
The average daily dose  of  tacrolimus extended-release  will  be summarized within 
defined time windows.  These summaries will apply the following rule: On calculating 
dosage averages over a time period, zero doses will be used for periods of temporary 
interruption of study medication regardless of whether this was due to safety reasons, 
non-compliance or other reasons.  The reasons for tacrolimus extended-release dose 
adjustments will be assessed at these time points.   Other immunosuppressive 
medication will be summarized by WHO drug names.  All non-immunosuppressive 
medications or non-drug therapies will be grouped into prior medications and 
concomitant medications. 
 
10.4      Analysis of the primary objective(s) 
 
10.4.1     Variable 
The primary objective is treatment failure at one year post transplant.  Treatment failure 
is defined as a composite of biopsy proven acute rejection (BPAR), graft failure, or 
death. BPAR is defined as ≥ Banff 1A using the Banff 2007 criteria.  Discrete variables 
will be summarized by frequencies and percentages.   Serious adverse events will be 
summarized.  Categorical variables will be analyzed by Chi square and continuous 
variables by T-test.  
 
10.4.2     Safety 
Safety variables to be assessed include discontinuation from study, discontinuation 
from treatment, renal function, SAEs, notable events, and laboratory tests.  The 
number of serious adverse events will be reported as an observation since this is a 
pilot study. Safety data will be reviewed quarterly by a PI and designated Co-PIs. 
 
10.5        Sample size calculation 
This is a pilot study therefore sample size calculation is not applicable.  Twenty 

20 
 
patients will be enrolled. 
 
 
11        Ethical considerations 
 
11.1      Regulatory and ethical compliance 
This clinical study was designed and shall be implemented and reported in 
accordance with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, 
with applicable local regulations (including European Directive 2001/20/EC, US Code 
of  Federal  Regulations  Title  21,  and  Japanese  Ministry  of  Health,  Labor,  and 
Welfare), and with the ethical principles laid down in the Declaration of Helsinki. 
 
11.2      Informed consent procedures 
Eligible patients may only be included in the study after providing written (witnessed, 
where required by law or regulation), IRB/IEC/REB-approved informed consent, or, if 
incapable of doing so, after such consent has been provided by a legally acceptable 
representative of the patient. In cases where the patient’s representative gives 
consent, the patient should be informed about the study to the extent possible given 
his/her understanding. If the patient is capable of doing so, he/she should indicate 
assent by personally signing and dating the written informed consent document or a 
separate assent form. Informed consent must be obtained before conducting any 
study-specific procedures (i.e. all of the procedures described in the protocol). The 
process of obtaining informed consent should be documented in the patient source 
documents. 
 
Women of child bearing potential should be informed that taking the study medication 
may involve unknown risks to the fetus if pregnancy were to occur during the study 
and agree that in order to participate in the study they must adhere to the 
contraception requirement for the duration of the study and 8 weeks after study drug 
discontinuation. If there is any question that the patient will not reliably comply, they 
should not be entered in the study. 
 
 
11.3      Responsibilities of the investigator and IRB/IEC/REB 
The protocol and the proposed informed consent form must be reviewed and 
approved by a properly constituted Institutional Review Board/Independent Ethics 
Committee/Research Ethics Board (IRB/IEC/REB) before study start. A signed and 
dated statement that the protocol and informed consent have been approved by the 
IRB/IEC/REB must be given to Astellas before study initiation. 
 
11.4      Publication of study protocol and results 
The results of this trial will be submitted for publication upon completion of the trial 
and after all data have been analyzed. The study protocol will be summarized as part 
of the submission. 
 
 
12        Protocol adherence 

21 
 
 
 
12.1      Protocol Amendments 
Any change or addition to the protocol can only be made in a written protocol 
amendment that must be approved by Astellas, Health Authorities where required, 
and the IRB/IEC/REB. Only amendments that are required for patient safety may be 
implemented prior to IRB/IEC/REB approval. Notwithstanding the need for approval 
of formal protocol amendments, the investigator is expected to take any immediate 
action required for the safety of any patient included in this study, even if this action 
represents a deviation from the protocol. 
 
13        References 
 
1. 
Vo, A.A., et al., Benefits of rituximab combined with intravenous immunoglobulin for 
desensitization in kidney transplant recipients. Transplantation, 2014. 98(3): p. 312-9. 
2.  
Vo, AA. Sinha, A., Haas, M., et al. Factors predicting risk for antibody mediated rejection and 
graft loss in highly human leukocyte antigen sensitized patients transplanted after 
desensitization. Transplantation 2015 (Epub ahead of print). 
3. 
Sapir-Pichhadze, R., A. Young, and S. Joseph Kim, Living donor age and kidney transplant 
outcomes: an assessment of risk across the age continuum. Transpl Int, 2013. 26(5): p. 493-501. 
4. 
Budde, K., 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): p. 2796-806. 
5. 
Silva, H.T., et al., Long-term follow-up of a phase III clinical trial comparing tacrolimus extended-
release/MMF, tacrolimus/MMF, and cyclosporine/MMF in de novo kidney transplant recipients. 
Transplantation, 2014. 97(6): p. 636-41. 
 
14        Appendices 
A. DSMB Charter 
Astagraf DSMB 
Charter 5.15.15.pdf  
B. FDA Med Watch (Form 3500A) 
____BLANK_FDA 
MedWatch Form MAN 
C. Tacrolimus Extended Release (Astagraf XL) Package Insert 
Astagraf package 
insert.pdf