Clinical trial NCT02953873
Conditions: Immunosuppression
Sponsor: Medical University of South Carolina
Start date: 2017-05-05; Completion date: 2018-12-14
Enrollment: 25 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Compare the difference in dose-normalized trough and total daily dose necessary to reach the steady state therapeutic goal after conversion from tacrolimus IR to Astagraf XL® in African American kidney transplant recipients.

Detailed description:
The purpose of this study is to compare the difference in medication dosage and total daily dose necessary of Astagraf XL® in order to reach therapy goal, when taken with other medications that are routinely used for kidney transplantation, which may stop the development of a substance that can cause long-term damage to the transplanted kidney. African American kidney transplant patients aged 18 and above who are underwent a kidney transplant are eligible to participate. The duration of the study is 3 months.

Arms: arm 1: Tacrolimus Extended Release Capsule (goal 5 - 12ng/mL) + Mycophenolate Mofetil ≥500mg twice a day OR Mycophenolate Sodium ≥360mg twice a day+ prednisone ≥ 5mg Daily
Interventions: intervention 1: Tacrolimus Extended Release Capsule intervention 2: Mycophenolate mofetil intervention 3: Prednisone intervention 4: Mycophenolate Sodium
Intervention descriptions: intervention 1: goal trough 5 - 12ng/mL intervention 2: ≥500mg twice a day intervention 3: goal dose 5mg daily intervention 4: ≥360mg twice a day

Protocol documents:
Prot_SAP_000.pdf: 
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INSTITUTIONS: 
Medical University of South Carolina 
 
 
INVESTIGATORS: 
 
Principal Investigators:   
James Fleming, PharmD 
 
 
Co-investigators: 
David Taber, PharmD 
John McGillicuddy, MD 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
 
I. 
Clinical Section 
a. Background and Rationale 
b. Objective 
c. 
Study Design 
i. Primary endpoints 
ii. Secondary endpoints 
iii. Safety endpoints 
d. Sample Population 
i. Sample size 
ii. Inclusion criteria 
iii. Exclusion criteria 
e. Study intervention 
i. Intervention, administration, and duration 
ii. Concomitant interventions 
iii. Prohibited and precautionary interventions 
f. 
Clinical and laboratory assessments 
i. Laboratory assessments 
ii. Clinical assessments 
iii. Acute renal dysfunction 
g. Acute rejection 
h. Treatment of acute rejection 
i. 
Safety monitoring 
Appendices 
 
 
 
 
 


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ABBREVIATIONS: 
CNI:  calcineurin inhibitor 
TDDR:  Total daily dose ratio 
TDD:  Total daily dose 
 
 
DEFINITIONS: 
Dose-normalized trough:  trough (ng/mL) divided by total daily dose 
Tacrolimus IR:  Immediate-release, or twice-daily, tacrolimus 
Total daily dose conversion ratio:  Total daily dose prior to conversion divided by total daily dose post-
conversion 
CYP3A5 expresser:  CYP3A5 *1 genotype, either homozygous or heterozygous 
 
 
 


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Title:  Dosing requirements of Astagraf XL® in African American kidney transplant recipients converted from twice-daily 
tacrolimus 
I. 
Clinical Section 
a. Background and Rationale 
Pharmacokinetics from prospective clinical studies demonstrated similar drug exposure (AUC) and 
correlation between trough (C0) and AUC between twice daily tacrolimus and Astagraf XL, which led to 
1mg:1mg dose-conversion recommendations;  however more recent studies have shown a decrease in 
tacrolimus exposure after conversion, necessitating increased dosing requirements in 25-50% of patients (1-
4).  Variability in results from studies may be, in part, due to the type of assay used (LC-MS vs. 
immunoassays), time after transplant, CYP3A5 alleles (expressers vs. non-expressers), and ethnicity (4-6).  
In one study, Niioka, et.al. demonstrated that patients with the CYP3A5 expresser allele had a 25% lower 
dose-adjusted AUC in the daily tacrolimus group compared to the twice-daily tacrolimus group, while still 
maintaining good correlation between C0 and AUC (6).  These results are contradictory to Wehland, et.al.’s 
results that demonstrated a significant difference in CYP3A5 non-expressers after conversion, a study that 
was limited by small numbers of patients with the CYP3A5*1 allele  (5).   
In terms of ethnicity, African American kidney transplant recipients have shown decreased absorption of 
twice-daily tacrolimus, achieving lower peak concentrations (Cmax) and AUC  compared to Caucasian 
kidney transplant recipients, necessitating a higher total daily dose to achieve adequate C0 levels (7,8).  
Additionally, de novo dosing of the extended-release formulation Astagraf XL has revealed that African 
Americans require approximately 20-30%  higher doses than Caucasians from 1month to 12months after 
transplant to achieve similar C0 levels(9). 
One of the reasons for the alterations of tacrolimus absorption in African Americans is believed to be the 
much higher incidence of the CYP3A5*1 expresser allele compared to other ethnicities.  Because of the 
variability in conversion dosing based off of CYP3A5 alleles and the underrepresentation of African 
Americans in conversion studies, further study is needed so that appropriate conversion dosing can be 
provided to this at-risk population. 
b. Objective 
 
Compare the difference in dose-normalized trough and total daily dose necessary to reach the steady state 
therapeutic goal after conversion from tacrolimus IR to Astagraf XL® in African American kidney transplant 
recipients. 
 
c. 
Study Design 
Single-center, prospective, open-label pilot study 
 
 
Study duration: 
Estimated 12 month enrollment period, with a 90 day follow-up period. 
 
 
 
 
 
 
 


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i. Primary Endpoints 
1. Difference in dose-normalized trough at steady state before and after conversion from 
tacrolimus IR to Astagraf XL® 
a. Subcategorized by CYP3A5 expressers vs non-expressers 
ii. Secondary Endpoints 
1. Difference in TDD necessary for steady state therapeutic goal 
a. Subcategorized by CYP3A5 expressers vs non-expressers 
2. TDDR necessary to reach steady state therapeutic goal between CYP3A5 expressers vs. 
non-expressers 
3. Proportion of patients with a TDDR of 1mg:1mg  
a. Subcategorized by CYP3A5 expressers vs non-expressers 
4. Weight-based dose requirements to reach therapeutic goal pre- and post-conversion 
a. Subcategorized by CYP3A5 expressers vs. non-expressers 
5. Days to reach therapeutic goal after conversion 
6. Number of dose modifications in the follow-up period 
7. Morisky Medication Adherence Scale (MMAS-8) at the time of conversion compared to 90 
days after conversion (Appendix II) 
8. SF-36 survey at the time of conversion compared to 90 days after conversion (Appendix 
IV) 
iii. Safety endpoints 
1. Incidence of adverse effects related to conversion, including those necessitating a return 
to the original formulation 
2. Memphis Medication Side Effect scale at the time of conversion compared to 90 days 
after conversion (Appendix III) 
3. Incidence of rejection-free graft survival in the 90 days post-conversion 
4. Incidence of rejection in the 90 days post-conversion 
5. Change in serum creatinine from the time of conversion to 90 days after conversion 
 
d. Sample Population 
Male or female adult (≥18 years old) African American patients with a history of solitary kidney transplant at 
least 1 month post-transplant.  Patients must be on a stable tacrolimus dose for at least 2 weeks prior to 
randomization.  Patients must be capable of understanding the purposes and risks of the study and have the 
ability to give written informed consent and be willing to participate and comply with the study.   
 
i. Sample size  
25 subjects from a single-center 


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Statistical analysis plan:   
Based off of preliminary data from 7 patients that underwent conversion from tacrolimus IR to 
Astagraf XL, we utilized no difference in dose-normalized trough as the null hypothesis and a 20% 
decrease in dose-normalized trough as the alternative hypothesis.  Assuming a starting dose-
normalized trough of 0.9 and a standard deviation in each group of 0.35, it was determined that 21 
patients would be necessary to reach 80% power with an alpha of 0.05, 1-tailed.  This should also 
be sufficient patient data to present a change in mg/kg dosing, which will have a much smaller 
standard deviation, as well as a percent difference in TDD, assuming a 20% increase in dosage 
requirements with a standard deviation of 5mg, as evidenced in our preliminary data. 
 
ii. Inclusion criteria 
1. At least 18 years of age 
2. Signed informed consent  
3. African American race 
4. History of a solitary renal transplant 
5. Stable tacrolimus dose for at least 2 weeks prior to randomization 
 
iii. Exclusion criteria  
1. A condition or disorder that, in the opinion of the investigator, may adversely affect the 
outcome of the study or the safety of the subject 
2. Currently enrolled in an investigational drug trial 
3. History of a non-renal organ transplant 
4. History of acute cellular rejection within 1 month prior to randomization 
5. An increase in serum creatinine by > 20% in the 2 weeks prior to randomization 
6. Maintenance immunosuppression that does not consist of tacrolimus IR given twice daily, 
mycophenolate mofetil or mycophenolate sodium, and prednisone ≥ 5mg daily 
 
e. Study intervention: 
i. Intervention, Administration, and Duration 
1. At the time of randomization, subjects will continue their tacrolimus IR orally BID for all 
scheduled doses that day.  The next morning, subjects will begin Astagraf XL® orally daily, 
with or without food, at a 1mg:1mg total daily dose conversion, with further dose 
adjustments based off of trough concentrations (goal 5-12ng/mL (using LC-MS)) according 
to the Schedule of Evaluations (appendix I).  The intervention will continue for 90 days 
post-randomization. 
2. Based on the mean daily dose of 11mg in our feasibility patients, we would expect to 
utilize at least 30,000mg of tacrolimus throughout the study.  
ii. Concomitant Interventions 
1. Mycophenolate mofetil or mycophenolate sodium must be active at the time of 
randomization.  Dose adjustments will be allowed based on side effects or toxicities, at 
the clinical judgement of the primary investigator.  Corticosteroids will be based on 
institutional protocol and will be continued in all patients at a minimum dose of 5mg daily 
of prednisone or equal potent exposure if a different corticosteroid is utilized.  
Antimicrobial and antiviral prophylaxis will be administered based on institutional 
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iii. Prohibited and Precautionary Interventions 
Drug/Substance Class or Name 
Drug Interaction Effect 
Recommendations 
Grapefruit or grapefruit juiceb 
May increase tacrolimus whole 
blood trough concentrations and 
increase the risk of serious 
adverse reactions (e.g., 
neurotoxicity, QT prolongation)  
Avoid grapefruit or 
grapefruit juice 
Alcohol 
May increase the rate of 
tacrolimus release and increase 
the risk of serious adverse 
reactions (e.g., neurotoxicity, QT 
prolongation )  
 
Avoid alcoholic beverages 
Strong CYP3A Inducersc: 
Antimycobacterials (e.g., 
rifampin, rifabutin), 
anticonvulsants (e.g., 
phenytoin, carbamazepine and 
phenobarbital), St John’s Wort 
May decrease tacrolimus whole 
blood trough concentrations and 
increase the risk of rejection  
Increase ASTAGRAF XL 
dose and monitor 
tacrolimus whole blood 
trough concentrations 
 
Strong CYP3A Inhibitorsc: 
Protease inhibitors (e.g, 
nelfinavir, telaprevir, 
boceprevir, ritonavir), azole 
antifungals (e.g., voriconazole, 
posaconazole, itraconazole, 
ketoconazole), antibiotics (e.g., 
clarithromycin, 
troleandomycin, 
chloramphenicol), nefazodone, 
schisandra sphenanthera 
extracts 
May increase tacrolimus whole 
blood trough concentrations and 
increase the risk of serious 
adverse reactions (e.g., 
neurotoxicity, QT prolongation)  
Reduce ASTAGRAF XL 
dose (for voriconazole and 
posaconazole, give one- 
third of the original dose) 
and adjust dose based on 
tacrolimus whole blood 
trough concentrations  
 
Mild or Moderate CYP3A 
Inhibitors: 
Clotrimazole, antibiotics (e.g., 
erythromycin, fluconazole), 
calcium channel blockers (e.g., 
verapamil, diltiazem, 
nifedipine, nicardipine), 
amiodarone, danazol, ethinyl 
estradiol, cimetidine, 
lansoprazole and omeprazole 
May increase tacrolimus whole 
blood trough concentrations and 
increase the risk of serious 
adverse reactions (e.g., 
neurotoxicity, QT prolongation)  
Monitor tacrolimus whole 
blood trough concentrations 
and reduce 
ASTAGRAF XL dose if 
needed  


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Other drugs, such as: 
Magnesium and 
aluminum hydroxide 
antacids 
Metoclopramide 
 
 
May increase tacrolimus whole 
blood trough concentrations and 
increase the risk of serious 
adverse reactions (e.g., 
neurotoxicity, QT prolongation) 
 
Monitor tacrolimus whole 
blood trough concentrations 
and reduce 
ASTAGRAF XL dose if 
Needed 
 
 
 
 
f. 
Clinical and laboratory assessments 
i. Laboratory assessments 
Laboratory evaluations will be performed at certified laboratories according to the Schedule of 
Evaluations (appendix I).  Required tests are specified in the Schedule of Evaluations. Results will 
be entered into REDCap. 
ii. Clinical assessments 
All patients will undergo clinical evaluation by the investigator or the investigator’s designee at the 
times specified in the Schedule of Evaluations (appendix I).  Results will be entered into REDCap. 
iii. Acute renal dysfunction  
To monitor graft function, serum creatinine will be assessed throughout the study according to the 
Schedule of Evaluations (appendix I).  All episodes of renal dysfunction, defined as an incremental 
increase in serum creatinine concentration 20% above baseline or ≥ 0.4mg/dL will be evaluated for 
rejection by renal biopsy, after the exclusion of other causes of renal graft dysfunction (infection, 
dehydration, CNI toxicity) 
 
g. Acute rejection 
i. Acute rejection is defined by histologic criteria, showing ≥ grade 1A by Banff Criteria 
ii. Renal biopsy should be performed in all cases of renal dysfunction (after exclusion of causes other 
than rejection), to confirm a rejection episode.  All subjects must have biopsy confirmation of 
rejection episodes either before or within 24 hours of onset of treatment for rejection 
iii. Rejection reversal is defined as return of serum creatinine to within 10% of baseline and/or 
histologic clearance by Banff criteria 
iv. Resistant acute rejection is defined as no histologic improvement documented by renal biopsy 
within 7-10 days after initiation of treatment 
v. Recurrent acute rejection is defined as rejection recurring more than two weeks after documented 
rejection reversal 
 
h. Treatment of acute rejection episode 
i. Acute rejection will be treated according to center protocol 
 
i. 
Safety monitoring 
Adverse events will be reported in accordance with the FDA Guidelines for Post-marketing Reporting of Adverse 
Events 21 CRF 310.305 and 314.80 
http://www.fda.gov/Safety/MedWatch/HowToReport/default.htm and will be recorded in REDCap.   Any 
serious adverse event or a non-serious adverse event that is related to the study and unexpected will be 
reported to the FDA, per reporting guidelines, as soon as possible, but no later than 15 working days.  Any 


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serious adverse event or a non-serious adverse event that is related to the study and unexpected will be 
reported to Astellas within 24 hours of occurrence.  Adverse events will be graded based upon the Common 
Terminology Criteria for Adverse Events (CTCAE version 4.03 http://evs.nci.nih.gov/ftp1/CTCAE/About.html ).  
Further, all serious adverse events that are related to the study and are unexpected must be reported to the 
Medical University of South Carolina  IRB within 10 days per The Medical University of South Carolina IRB 
Unanticipated Problems and Adverse Events Policy and Procedures reporting guidelines. 
 
 


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Appendix I.  Schedule of Evaluations 
 
 
 
 
 
Baseline 
 
Days Post-initiation 
 
 
 
 
 
 
 
 
 
5±3 
 
10±3 
 
15±3 
 
20±3 
 
25±3 
 
30±3 
 
60±5 
 
90±5 
History and 
Physical1,5 
 
 
X 
 
 
 
 
 
 
 
 
Vital Signs 
 
 
 
 
X 
 
 
X 
X 
X 
Clinical assessment4,5 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
Laboratory 
Assessments 
CBC and Chem-
72 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CYP3A5 
genotype5 
O 
O 
O 
O 
O 
O 
O 
O 
O 
Tacrolimus C03 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Foot notes: 
1. 
Includes vital signs, weight, height, medication dosing 
2. 
Includes sodium, potassium, chloride, CO2, BUN, SrCr, glucose, calcium, WBC, HgB, Hct, platelets 
3. 
Tacrolimus concentrations will be 24-hour levels, drawn in the morning of each assessment 
4. 
Includes assessments of adverse events, study drug doses, study drug dose modifications, allograft rejection, need for hospitalization, other 
immunosuppressant medications , MMAS-8, SF-36, and Memphis Medication Side Effect scale at the Baseline and Day 90 visit 
5. 
Not current standard of care, can be drawn at any time during the study 
 
 
 
 
 


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Appendix II.  Morisky Medication Adherence Score 
 
 
MMAS-8 
Points 
Do you sometimes forget to take your pills? 
1 
People sometimes miss taking their medications for 
reasons other than forgetting.  Thinking over the past 
two weeks, were there any days when you did not take 
your medicine? 
1 
Have you ever cut back or stopped taking your medicine 
without telling your doctor because you felt worse 
when you took it? 
1 
When you travel or leave home, do you sometimes 
forget to bring along your medicine 
1 
Did you take all your medicine yesterday? 
1 
When you feel like your symptoms are under control, 
do you sometimes stop taking your medicine? 
1 
Taking medicine every day is a real inconvenience for 
some people.  Do you ever feel hassled about sticking to 
your treatment plan? 
1 
How often do you have difficulty remembering to take 
all of your medicine? 
 
A.  Never/rarely 
B.  Once in a while 
C.  Sometimes 
D.  Usually 
E.  All the time 
0-5 
 
 
Adherence 
MMAS-8 Score 
High Adherence 
0 
Medium Adherence 
1-2 
Low Adherence 
3-8 
 
 
 
 
 
 
 


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Appendix III.  Memphis Medication Side Effect Scale 
 
The Memphis Survey 
SIDE EFFECTS BECAUSE OF TRANSPLANT MEDICINES 
 
The following questions describe problems you might be having because of the transplant or the medicine 
you are taking.  For each problem, you will be asked how frequently you experience it (the first row) and 
how troubling it is (the second row).  Please answer every question. 
 
 
Not  
at all 
Very  
little 
Sometimes 
or 
Moderately 
troubling 
Often 
or 
Very troubling 
All the time 
or 
Extremely 
troubling 
 
 
 
 
 
 
Enlarged gums 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
             How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Increased hunger 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
             How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Staying asleep 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Weight gain 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Increased hair growth 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Infections 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Trembling hands 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 


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High blood pressure 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Easy bruising 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Loss of interest in sex 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Sexual performance 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Diabetes 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Hair Loss 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
 
 


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Not  
at all 
Very  
little 
Sometimes 
or 
Moderately 
troubling 
Often 
or 
Very troubling 
All the time 
or 
Extremely 
troubling 
 
 
 
 
 
 
Stomach pain 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Nausea 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Diarrhea 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Vomiting 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Stomach gas 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Indigestion 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
 
 
 
 
 
 
Mood Changes 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Depression 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
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How troubling is it? 
□ 
□ 
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□ 
□ 
Nervousness or anxiety 
 
 
 
 
 
Do you have this problem? 
□ 
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□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
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Irritability 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
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□ 
□ 
Anger 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Keeping a positive attitude 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 


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Not  
at all 
Very  
little 
Sometimes 
or 
Moderately 
troubling 
Often 
or 
Very troubling 
All the time 
or 
Extremely 
troubling 
 
 
 
 
 
 
Feelings of uselessness 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Being worried 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Worthlessness 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Hopelessness 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Ability to concentrate 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
 
 
 
 
 
 
Completing daily errands 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Participating in social activities 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
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□ 
Doing housework 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Doing yardwork 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 


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How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Performing my job 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Participating in physical activities 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Participating in leisure pastimes 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Driving 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 


 
 
 
 
 
19 
 
 
Not  
at all 
Very  
little 
Sometimes 
or 
Moderately 
troubling 
Often 
or 
Very 
troubling 
All the time 
or 
Extremely troubling 
 
 
 
 
 
 
Being independent 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Ability to travel on vacations 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Reading 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
 
 
 
 
 
 
Decreased muscle strength 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Climbing stairs 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Walking 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Bone pain 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Stiff joints 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Foot pain 
 
 
 
 
 


 
 
 
 
 
20 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Hip pain 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 


 
 
 
 
 
21 
 
Appendix IV. SF-36 Survey 
SF-36  
Choose one option for each questionnaire item. 
1. In general, would you say your health is: 
1 - Excellent  
2 - Very good  
3 - Good  
4 - Fair  
5 - Poor  
2. Compared to one year ago, how would you rate your health in general now? 
1 - Much better now than one year ago  
2 - Somewhat better now than one year ago  
3 - About the same  
4 - Somewhat worse now than one year ago  
5 - Much worse now than one year ago  
The following items are about activities you might do during a typical day. Does your health 
now limit you in these activities? If so, how much? 
  
Yes, limited 
a lot  
Yes, limited 
a little  
No, not 
limited at all  
3. Vigorous activities, such as running, lifting heavy 
objects, participating in strenuous sports 
1  
2  
3  
4. Moderate activities, such as moving a table, pushing 
a vacuum cleaner, bowling, or playing golf 
1  
2  
3  
5. Lifting or carrying groceries 
1  
2  
3  


 
 
 
 
 
22 
 
  
Yes, limited 
a lot  
Yes, limited 
a little  
No, not 
limited at all  
6. Climbing several flights of stairs 
1  
2  
3  
7. Climbing one flight of stairs 
1  
2  
3  
8. Bending, kneeling, or stooping 
1  
2  
3  
9. Walking more than a mile 
1  
2  
3  
10. Walking several blocks 
1  
2  
3  
11. Walking one block 
1  
2  
3  
12. Bathing or dressing yourself 
1  
2  
3  
During the past 4 weeks, have you had any of the following problems with your work or other 
regular daily activities as a result of your physical health? 
  
Yes  No  
13. Cut down the amount of time you spent on work or other activities 
1  
2  
14. Accomplished less than you would like 
1  
2  
15. Were limited in the kind of work or other activities 
1  
2  
16. Had difficulty performing the work or other activities (for example, it took extra 
effort) 
1  
2  
During the past 4 weeks, have you had any of the following problems with your work or other 
regular daily activities as a result of any emotional problems (such as feeling depressed or 
anxious)? 
  
Yes  No  
17. Cut down the amount of time you spent on work or other activities 
1 
2 
18. Accomplished less than you would like 
1 
2 
19. Didn't do work or other activities as carefully as usual 
1 
2 
20. During the past 4 weeks, to what extent has your physical health or emotional problems 
interfered with your normal social activities with family, friends, neighbors, or groups? 
1 - Not at all  
2 - Slightly  


 
 
 
 
 
23 
 
3 - Moderately  
4 - Quite a bit  
5 - Extremely  
21. How much bodily pain have you had during the past 4 weeks? 
1 - None  
2 - Very mild  
3 - Mild  
4 - Moderate  
5 - Severe  
6 - Very severe  
22. During the past 4 weeks, how much did pain interfere with your normal work (including 
both work outside the home and housework)? 
1 - Not at all  
2 - A little bit  
3 - Moderately  
4 - Quite a bit  
5 - Extremely  
These questions are about how you feel and how things have been with you during the past 4 
weeks. For each question, please give the one answer that comes closest to the way you have 
been feeling. 
How much of the time during the past 4 weeks... 


 
 
 
 
 
24 
 
  
All of 
the time 
Most of 
the time  
A good bit 
of the time  
Some of 
the time  
A little of 
the time  
None of 
the time  
23. Did you feel full of pep? 
1  
2  
3  
4  
5  
6  
24. Have you been a very nervous 
person? 
1  
2  
3  
4  
5  
6  
25. Have you felt so down in the 
dumps that nothing could cheer you 
up? 
1  
2  
3  
4  
5  
6  
26. Have you felt calm and 
peaceful? 
1  
2  
3  
4  
5  
6  
27. Did you have a lot of energy? 
1  
2  
3  
4  
5  
6  
28. Have you felt downhearted and 
blue? 
1  
2  
3  
4  
5  
6  
29. Did you feel worn out? 
1  
2  
3  
4  
5  
6  
30. Have you been a happy person? 
1  
2  
3  
4  
5  
6  
31. Did you feel tired? 
1  
2  
3  
4  
5  
6  
32. During the past 4 weeks, how much of the time has your physical health or emotional 
problems interfered with your social activities (like visiting with friends, relatives, etc.)? 
1 - All of the time  
2 - Most of the time  
3 - Some of the time  
4 - A little of the time  
5 - None of the time  
How TRUE or FALSE is each of the following statements for you. 
  
Definitely 
true  
Mostly 
true  
Don't 
know  
Mostly 
false  
Definitely 
false  
33. I seem to get sick a little easier 
than other people 
1  
2  
3  
4  
5  
34. I am as healthy as anybody I 
know 
1  
2  
3  
4  
5  
35. I expect my health to get worse 
1  
2  
3  
4  
5  


 
 
 
 
 
25 
 
  
Definitely 
true  
Mostly 
true  
Don't 
know  
Mostly 
false  
Definitely 
false  
36. My health is excellent 
1  
2  
3  
4  
5  
 
 
 


 
 
 
 
 
26 
 
References: 
 
1.  van Hoof J, Van der Walt I, Kallmeyer J, et.al.  Pharmacokinetics in stable kidney transplant recipients after 
conversion from twice-daily to once-daily tacrolimus formulations.  Ther Drug Monit. 2012; 34(1): 46-52. 
2.  Hougardy JM, Broeders N, Kianda M, et.al.  Conversion from Prograf to Advagraf among kidney transplant 
recipients results in sustained decrease in tacrolimus exposure.  Transplantation. 2011; 91(5): 566-9. 
3.  Alloway R, Steinberg S, Khalil K, et.al.  Conversion of stable kidney transplant recipients from a twice daily 
Prograf-based regimen to a once daily modified release tacrolimus-based regimen.  Transplant Proc. 2005; 37(2): 
867-70. 
4.  Staatz CE, Tett SE.  Clinical pharmacokinetics of once-daily tacrolimus in solid-organ transplant patients.  Clin 
Pharmacokinet. 2015; 54: 993-1025. 
5.  Wehland M, Bauer S, Brakemeier S, et.al.  Differential impact of the CYP3A5*1 and CYP3A5*3 alleles on pre-
dose concentrations of two tacrolimus formulations.  Pharmacogenet Genomics. 2011; 21(4): 179-84. 
6.  Niioka T, Satoh S, Kagaya H, et.al.  Comparison of pharmacokinetics and pharmacogenetics of once- and twice-
daily tacrolimus in the early stage after renal transplantation.  Transplantation.  2012; 94(10): 1013-9. 
7.  Mancinelli LM, Frassetto L, Floren LC, et.al.  The pharmacokinetics and metabolic disposition of tacrolimus:  a 
comparison across ethnic groups.  Clin Pharmacol Ther. 2001; 69(1): 24-31. 
8.  Beermann KJ, Ellis MJ, Sudan DL, Harris MT.  Tacrolimus dose requirements in African American and Caucasian 
kidney transplant recipients on mycophenolate and prednisone.  Clin Transplant.  2014; 28(7): 762-7. 
9.  Astagraf XL [package insert].  Northbrook, IL:  Astellas Pharma, Inc; 2015.