Dosing Strategies for de Novo Once-daily Extended Release Tacrolimus (LCPT) in Kidney Transplant Recipients
Phase: PHASE4
Conditions: Kidney Transplant
Sponsor: Temple University

 
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Dosing strategies for de novo once-daily extended release tacrolimus (LCPT) 
in kidney transplant recipients 
 
NCT Number: 03713645 
 
Date: August 21, 2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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1) Abstract of the study 
Outcomes after kidney transplantation have been significantly enhanced with the advances made 
in immunosuppressive therapies. Tacrolimus is currently marketed as an extended-release once-
daily formulation dosing option for patients, decreasing pill burden and possibly decreasing 
adverse effects. Some transplant recipients have been shown to have higher dosage 
requirements. According to the literature, this can be linked to genetic disparities in the 
metabolism of tacrolimus.. This potential complication, where differences on specific genes alters 
metabolism of tacrolimus, can increase difficulty in getting to a therapeutic drug level for 
immunosuppresants and is one large factor that contributes to the fact that kidney transplant 
survival rates differ between patients. Due to the enhanced bioavailability of Meltdose formulation 
once-daily extended-release tacrolimus, its de novo use in recent research and practice has been 
shown to expedite achievement of target tacrolimus trough concentrations. De novo use of once-
daily tacrolimus formulations is understudied. Through a prospective investigational study, we aim 
to determine the optimal strategy for de novo dosing of once-daily extended release tacrolimus 
(MeltDose formulation) for kidney transplant recipients at Temple University Hospital.  
 
2) Protocol Title 
Dosing strategies for de novo once-daily extended release tacrolimus (LCPT) in kidney transplant 
recipients 
 
3) Investigator(s)  
Principal Investigator(s): Adam Diamond, Pharm.D. BCPS 
Co-PI: Antonio Di Carlo, MD, CM, FACS, FRCSC 
4) Objectives 
 
Primary Objectives: 
Identify the target dose of de novo once-daily MeltDose formulation of tacrolimus that achieves 
therapeutic tacrolimus trough concentrations for kidney transplant patients at Temple University 
Hospital 
 
Secondary Objectives: 
Identify the time to achievement of therapeutic  trough concentrations for the de novo MeltDose 
formulation of tacrolimus  
Identify if the CYP3A5 genetic allele is expressed in enrolled participants to retrospectively 
determine correlation betweenCYP3A5 genotype expression and other factors (e.g., time to 
trough, tacrolimus dosing, patient outcomes, demographics) in  kidney transplant patients  
 
5) Rationale and Significance  
Tacrolimus is the most commonly utilized calcineurin inhibitor after kidney transplantation. It 
is used in combination with mycophenolate mofetil and prednisone in order to provide 
sufficient immunosuppression to prevent acute rejection of transplanted organs. The 
development of a MeltDose tablet formulation has been designed to enhance the 
bioavailability of tacrolimus due to the low water solubility of the drug. In clinical trials, the 
utilization of MeltDose tablet formulations of tacrolimus has been shown to provide rapid 
achievement of target tacrolimus trough concentrations. This once daily dosing regimen 
has also led to lower peak concentrations and equivalent overall exposure when compared 
to immediate release and other extended release formulations of tacrolimus. Similar 
efficacy and safety profiles have been demonstrated when comparing the MeltDose 
formulation of tacrolimus to other available formulations.  

 
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Some transplant recipients have been shown to metabolize tacrolimus at a higher or lower 
rate compared to other patients, which can greatly impact post-transplant outcomes. This 
can be prompted by the patient having polymorphisms of the cytochrome P450 3A5 
(CYP3A5) gene that they may possess moreso compared to others. If a patient is a  
CYP3A5*1 allele expressor, this leads to metabolically active CYP3A5 causing higher 
metabolism rates of tacrolimus. CYP3A5 expressors can require up to 2-fold higher 
tacrolimus doses to achieve similar trough concentrations compared to CYP3A5 non-
expressors.  This sparks the question as to what the optimal initial dosing of the MeltDose 
formulation of tacrolimus should be when used in the de novo setting for kidney transplant 
patients. Delayed achievement of target tacrolimus trough concentrations has been linked 
to higher rates of acute rejection as well as development of de novo donor-specific 
antibodies. Avoiding subtherapeutic and supratherapeutic concentrations of tacrolimus in 
the early post-transplant period will help to lower risk for acute rejection.  
Tacrolimus, the immunosuppressant drug, is used for kidney transplant recipients. 
MeltDose tacrolimus is a lawfully marketed formulation of the tacrolimus drug. The de novo, 
or initial, use of MeltDose tacrolimus is a permittedunlabeled indication that is within the 
scope of medical practice and often used for this population. However, data surrounding 
this initial dosing is lacking.  We hope to contribute to existing knowledge by identifying 
optimal dosing strategies for this more convenient once daily formulation of tacrolimus for 
kidney transplant patients. 
6) Resources and Setting  
Temple University Hospital performs approximately 60 kidney transplants (deceased and 
live donor) per year. As a result we intend to reach our target enrollment in 1-2 years.  The 
study staff includes myself, transplant surgeon, and research coordinators.  The clinicians 
have been working in kidney transplant for numerous years (ranging from 5 to 25 years), 
and the entire research team is CITI trained. Only investigators and members of the 
research team, who will be adequately informed about the protocol and study-related duties 
and are currently CITI trained, will have access to patient protected health information for 
the purposes of this study.  
This is a single center prospective observational study. As a result all research procedures 
will be conducted at Temple University Hospital. The collection and analysis of research 
data will be conducted at Temple University Hospital using data captured in Alpha Imaging 
and EPIC. Only prospective data, from subject enrollment until 30 day visit are collected. 
Participants enrolled are required to receive saliva sample for genetic testing, complete 
tremor questionnaire, and receive Meltdose formulation of tacrolimus. The difference 
between standard of care and the investigational procedures for this study are as follows:  
Standard of Care 
 All kidney transplant recipients at Temple University Hospital will receive a de novo combination 
maintenance immunosuppression regimen. This combination regimen includes tacrolimus 
immediate-release and mycophenolate mofetil with or without prednisone. Mycophenolate mofetil 
and prednisone are started on the day of transplantation. The day of initiation of tacrolimus 
immediate-release is decided per transplant surgeon discretion. Upon hospital discharge after 
transplant surgery, patients will be seen in the outpatient abdominal transplant surgery clinic three 
times weekly. Tacrolimus extended-release is associated with fewer tremors, has once-daily 
dosing to improve compliance, and requires lower total daily doses compared with tacrolimus 
immediate-release to achieve therapeutic tacrolimus trough concentrations. For those reasons, 
our current practice in patients who are receiving tacrolimus immediate release and require high 

 
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doses of tacrolimus immediate-release (10mg orally twice daily or greater), are experiencing 
significant tremors, or have medication non-compliance, those patients are converted from 
tacrolimus immediate-release to tacrolimus extended-release. Tacrolimus extended-release is not 
currently used de novo.  The following table portrays the laboratory parameters that are drawn per 
standard of care at Temple University Hospital for kidney transplant recipients. Average length of 
inpatient stay is 4 days.  
Table A 
Setting 
Tacrolimus 
immediate- 
release trough 
concentration 
Serum 
creatinine 
Glomerular 
filtration 
rate 
Potassium 
Blood 
glucose 
Hemoglobin 
A1C 
Day of Transplant 
 
  
  
  
  
  
Inpatient 
(lab parameters 
obtained every 24 
hours) 
  
(once tacrolimus 
initiated) 
  
  
  
  
 
Outpatient 
(lab parameters 
obtained three 
times weekly on 
Mon, Wed, Fri 
  
  
  
  
  
 
Investigational (Research) 
 All kidney transplant recipients at Temple University Hospital will receive a de novo combination 
maintenance immunosuppression regimen. This combination regimen includes tacrolimus 
extended-release and mycophenolate mofetil with or without prednisone. Mycophenolate mofetil 
and prednisone are started on the day of transplantation. The day of initiation of tacrolimus 
extended-release is decided per transplant surgeon discretion. The use of tacrolimus extended-
release de novo differs from the standard of care. Goal tacrolimus trough concentrations 
for tacrolimus extended-release are identical to the way that goal tacrolimus trough 
concentrations are drawn for tacrolimus immediate-release at Temple. Upon hospital 
discharge after transplant surgery, patients will be seen in the outpatient abdominal transplant 
surgery clinic three times weekly. Table B portrays the laboratory parameters that are drawn 
per research protocol which is identical to laboratory parameters drawn for all kidney 
transplant patients at Temple University Hospital (Refer to Table A). Average length of 
inpatient stay is expected to be 4 days. Table 2 portrays the timeline of data collection. The data 
collected that differs from standard of care includes the QUEST Tremor Questionnaire at 
Day 30 and the required oral swab for testing of CYP3A5 metabolic enzyme activity.  
Table B  
Setting 
Tacrolimus 
extended-
release trough 
concentration 
Serum 
creatinin
e 
Glomerul
ar 
filtration 
rate 
Potassiu
m 
Blood 
glucos
e 
Hemoglobi
n A1C 
Day of Transplant 
 
  
  
  
  
  
Inpatient 
(lab parameters 
obtained every 24 
hours; approximately 
   
(once 
tacrolimus 
initiated) 
  
  
  
  
 

 
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Days 0-4 
Outpatient 
(lab parameters 
obtained three times 
weekly on Mon, Wed, 
Fri; approx Days 4-30 
  
  
  
  
  
 
 
Table C 
Day 0 
Study drug (tacrolimus) initiated at 0.13/mg/kg/day for all patients 
(the day of initiation decided per transplant surgeon discretion) 
Day 0-4 
Inpatient laboratory parameters checked every 24 hours per Tables A and B  
Day 4-30 
Outpatient laboratory parameters checked three times weekly on Monday, 
Wednesday, and Friday per Tables A and B 
Day 30 visit 
(+/- 5 days)  
Draw tacrolimus trough levels, serum creatinine, estimated glomerular filtration 
rate, serum potassium, and blood glucose. Complete tremor questionnaire with 
participant. 
During or prior 
to Day 30 
visit 
Oral swab performed to be analyzed for testing of metabolic enzymatic activity  
(This will be performed  to see if genetic testing results reflect how the 
participant is metabolizing tacrolimus [determined from tacrolimus 
extended-release doses used ) 
All research procedures (e.g., data entry, data analysis) will be conducted at TUH. Temple 
University School of Pharmacy pharmacogenomics department will be used to store 
specimen for genetic testing. All specimen will be de-identified and stored in an appropriate 
and locked container at Temple University School of Pharmacy pharmacogenomics 
department—accessible only to research and pharmacogenomics department staff. 
Researchers involved in this study will possess a list that links the genetic testing results to 
the participant. This list will be stored in a password protected encrypted document on TUH 
computer.    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Dose Titration Protocol  
For the purpose of this study no changes will be made to dose titration strategies for 
enrolled patients. For enrolled participants tacrolimus will be titrated as per Temple 
University Hospital’s standardized dose titration protocol. The following dose titration 
strategy is used to titrate tacrolimus extended-release and tacrolimus immediate-release for 
patients receiving standard of care and for patients who are enrolled in this study:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7) Prior Approvals 
Veloxis Pharmaceuticals approved budget for funding of study   

 
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8) Study Design 
Single center prospective observational study 
a) Recruitment Methods 
Patients will be identified when an organ from live or deceased donor becomes available 
for kidney transplant. Prior to receiving their kidney transplant, subjects will be screened for 
inclusion/exclusion criteria on the day of transplantation. During the pre-operative 
preparation for transplant, patients will be consented for surgery and consented for the 
study at the same time if they volunteer to be included. The transplant surgeon performing 
the transplant operation will be responsible for screening the patients for inclusion and 
exclusion criteria as well as obtaining informed consent. Patients will need to provide 
informed consent to be included in the study, and will receive a copy of their consent. Each 
potential participant will be approached by the transplant surgeon and informed of all 
information pertinent to the study prior to providing consent. No advertisements for 
recruitment will be performed and no compensation will be provided for participation. 
b) Inclusion and Exclusion Criteria 
 
Inclusion Criteria 
 Adult patient who is 18 years of age or older receiving a kidney transplant at the Temple 
University Hospital’s Kidney Transplant Program who are capable of understanding consent 
and volunteer to take part in the study 
Exclusion Criteria 
 Scheduled for multiple organ transplant at enrollment 
 Non-English speaking 
 Pregnant women 
 Moderate-severe hepatic impairment (Child Pugh > 10 or bilirubin > 2) 
 Existing contraindications to tacrolimus-based products including known hypersensitivity to 
tacrolimus or any other component of the formulation  
 Receiving concomitant medications known to have strong drug-drug interaction potential with 
tacrolimus including fluconazole, voriconazole, posaconazole, isavuconazole, itraconazole, 
ketoconazole, diltiazem, verapamil, metronidazole, erythromycin, clarithromycin, rifampin, 
rifabutin, rifapentine, phenytoin, fosphenytoin, phenobarbital, primidone, carbamazepine, St. 
John’s Wort, efavirenz, neivrapine, etravirine, atazanavir, darunavir, fosamprenavir, indinavir, 
lopinavir, ritonavir, nelfinavir, saquinavir, tipranavir, cobicistat  
 
c) Study Timelines 
Study enrollment and informed consent process will begin once IRB approval is granted. 
Each subject will be active in the study until their one month visit—occurring day 30 +/- 5 
days. We anticipate it will take 12 months to enroll the first 35 subjects. After the first 35 
subjects are enrolled, an interim analysis will be performed to evaluate the efficacy and 
safety of the initial dose provided. A report of results will be distributed to Veloxis 
Pharmacuieticals® to assess the efficacy and safety of the utilization of tacrolius extended-
release. A statistical analysis will be completed to identify the correlation with achieving a 
therapeutic tacrolimus trough concentration with using tacrolimus extended-release in the 
de novo setting. If required, an additional 35 patients will be enrolled. We anticipate that 
after enrollment of all subjects, data analyses will be completed 3-6 months after 
recruitment has ceased.   
 
 

 
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d) Study Procedures and Data Analysis 
 
Study procedures:  
This study is a single center prospective observational study conducted at Temple University 
Hospital (TUH). All participants will be consented for all procedures involved in this study. This study 
will utilize the QUEST questionnaire (attached) to evaluate the severity of tremors at 1 month. Data 
to be collected includes tacrolimus trough levels, study drug dosing, hemoglobin A1c, incidence and 
severity of tremors, potassium, glomerular filtration rate, and rejection episodes (See Table B).  
Table C 
Day 0 
Study drug (tacrolimus) initiated at 0.13/mg/kg/day for all patients 
(the day of initiation decided per transplant surgeon discretion) 
Day 0-4 
Inpatient laboratory parameters checked every 24 hours per Tables A and B  
Day 4-30 
Outpatient laboratory parameters checked three times weekly on Monday, 
Wednesday, and Friday per Tables A and B 
Day 30 visit 
(+/- 5 days)  
Draw tacrolimus trough levels, serum creatinine, estimated glomerular filtration 
rate, serum potassium, and blood glucose. Complete tremor questionnaire with 
participant. 
During or prior 
to 
Day 30 visit 
Oral swab performed to be analyzed for testing of metabolic enzymatic activity  
(This will be performed  to determine ability of the patient to metabolize 
tacrolimus) 
 
Data and Specimen Banking:  
Saliva collection kits will be used to collect subject saliva samples and genetic testing will be 
performed and stored at Temple University School of Pharmacy pharmacogenomics department. 
Data to be collected from this swab is to identify CYP3A5 genotype for metabolism of tacrolimus. This 
information will assist in identifying dosage requirements for the extended-release tacrolimus product. 
Informed consent will be obtained separately for this procedure. Study coordinators will collect and 
analyze saliva from saliva collection kits and the results will be recorded and stored as part of the 
research dataset. These saliva samples will be obtained during outpatient study visits and then stored 
in a locked file cabinet in the locked research office. Each saliva collection kit will be de-identified 
before transport to Pharmacy for analysis. Researchers involved in this study will possess a list that 
links the genetic testing results to the participant. This list will be stored in a password protected 
encrypted document on TUH computer.    
When ready for genetic testing, within the week, the saliva will be analyzed and stored in a locked -70 
degree freezer in Temple University School of Pharmacy, accessible only to research and 
pharmacogenomics department staff. Subject results for genetic testing will not be transcribed into 
the electronic medical record or used to impact their care in any way . All de-identified data extracted 
from the medical record and the questionnaire data are stored in password protected and encrypted 
Temple University Hospital computer systems. The findings associated with genetic testing would 
only be used to analyze dose requirements and achievement of therapeutic concentrations for 
research purposes at the end of the study. This genetic information will not be known while the 
patient is within the one month time period by research staff or impact their clinical care at all.  
Patients will not be informed of the results of their genetic testing. Staff within the pharmacogenomics 
department will have access to these specimen. Informed consent will allow release of this data for 
purposes of this human research only.  
Data analysis: 
To ensure subject confidentiality, all information from electronic medical records will be stored 
in a de-identified fashion. Data collected from electronic medical record will include 

 
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demographic information, comorbidities related to transplant, cause of kidney disease, 
incidence and severity of tremors, study drug dosing, other immunosupressants prescribed, 
relevant labs (e.g., Cr, K, eGFR, HbA1c, blood glucose, tacrolimus level) and all other 
pertinent prospective data (e.g., rejection episodes). Only prospective data created between 
Day 0-Day 30 visit will be collected for the purpose of this research—no retrospective data will 
be collected. All PHI will be removed from this dataset and subjects will be assigned an 
arbitrary study ID number. This de-identified dataset will be kept in a separate locked drawer 
and locked office accessible to only research staff and entered into encrypted password-
protected online database, Research Electronic Data Capture (REDCap™, ©Vanderbilt 
University). Access to REDCAPTM will be granted to Adam Diamond, PharmD, BCPS, 
Amanda DeSenna, BA, BSN, RN, Hannah Sufrin, and Antonio Di Carlo MD, CM, FACS, 
FRCSC. Documents containing personal health information (e.g., consent, HIPAA form) will be 
kept in a separate locked drawer in a locked office accessible only to study investigators. Raw 
data will be exported into a password-protected Excel data sheet stored on Temple hospital 
computer in a locked research space for data analysis. 
Data analysis will be performed by study staff with the assistance of a hospital appointed 
statistician. From REDCap, raw data will be exported into an Excel sheet and analyzed in 
SPSS®, version 21.0 for Windows (SPSS, Inc., Chicago, IL).  Continuous data such as 
baseline demographics and laboratory values that are normally distributed will be presented as 
mean (SD) and non-normally distributed data as median (25-75% interquartile range).  Other 
baseline characteristics and outcomes will be analyzed with the following tests: Chi-square or 
Fisher’s exact tests for categorical data, and Student’s T-tests or Mann-Whitney U tests for 
continuous data. Kaplan Meier statistical testing will be utilized to evaluate time to therapeutic 
trough concentration. Subgroup analysis stratified by CYP3A5 genotype will be performed. All 
tests will be two-tailed, and p-values < 0.05 will be considered statistically significant. 
e) Withdrawal of Subjects 
Participants are volunteers and will be permitted to withdraw at any time during the duration of 
the study. Each participant will be made aware of the eligibility to withdraw at any time at the 
sole discretion of the participant. Participants will remain eligible for study participation even if 
they do not want to complete the saliva collection kit to determine CYP3A5 genotype. If this 
occurs we will write a note to file and not obtain their saliva sample. As volunteers, participants 
are not required to do any aspect of the study that they do not want to do. The participant will 
be withdrawn from the study only if they contact the Principal Investigator by phone or mail to 
decline further study participation. If notification of withdrawal is obtained from a subject, data 
collection on this subject will cease immediately and no data already collected will be utilized in 
data analysis.  
f) Privacy & Confidentiality 
Each participant will be made aware of rules and regulations regarding protected health 
information (PHI) as outlined under HIPAA. HIPAA authorizations will be obtained from each 
participant at the beginning of the study. All study staff and investigators will be CITI trained 
and receive training regarding HIPAA authorizations and the storage and protection of PHI. 
The information collected from each chart will be de-identified and assigned an arbitrary 
number. The dataset only with corresponding arbitrary number will be accessible only to study 
investigators within REDCap and in the form of a password-protected excel sheet. Consents, 
HIPAA form, and any other original copies with PHI will be stored in a locked separate drawer 
in a locked room accessible only to research staff.  All saliva collection kits will be deidentified 
before being sent to the lab for genetic testing. Results of genetic testing will not be recorded 
into their chart, and will be used for research purposes only. Genetic testing results will not be 
shared with participants. The protected health information will not be reused or disclosed to 

 
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any other person or entity, except as required by law, for authorized oversight of the research 
study, or for other research for which the use or disclosure of the protected health information 
would be permitted. 
9) Risks to Subjects 
The use of tacrolimus extended-release de novo  for the investigational purpose of conducting this 
research study will not involve more than minimal risk to the patient.  
The currently known risks of tacrolimus extended-release (Envarsus®) include: 
 Headache 
 Diarrhea 
 Swelling in the legs 
 Tremors 
 High blood pressure 
 High cholesterol 
 High blood sugars 
 High potassium 
 Increased serum creatinine 
 Upper respiratory tract infection 
 Urinary tract infection 
 Common cold  
 Viral infections 
 Fungal infections 
 Increased risk of lymphoma 
 Increased risk of skin cancer 
Risks associated with the use of all tacrolimus products which includes tacrolimus-extended 
release (Envarsus®) and tacrolimus immediate-release: 
 Headache 
 Diarrhea 
 Swelling in the legs 
 Tremors 
 High blood pressure 
 High cholesterol 
 High blood sugars 

 
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 High potassium 
 Increased serum creatinine 
 Upper respiratory tract infection 
 Urinary tract infection 
 Common cold  
 Viral infections 
 Fungal infections 
 Increased risk of lymphoma 
 Increased risk of skin cancer 
The risk for acute organ rejection is present in all patients after kidney transplant on any 
immune suppressing therapies. Tacrolimus extended-release doses will be adjusted to 
achieve blood concentrations consistent with standard of care to minimize risk for organ 
rejection.  
The greatest additional risk provided to participants enrolled in this study is maintaining 
confidentiality due to data collection for Epic and Alpha EMR as well as the collection of saliva 
samples for genetic testing. The Temple University and the study investigators will protect all 
patient records and personal information to the extent permitted by law. Patient identifiers will 
be kept private and physical forms will be filed in a locked cabinet and electronically stored in a 
password protected and encrypted manner. Personal health information will be kept 
confidential.  
In the event of research related injury, the patient should immediately notify research team and 
they will arrange for them to receive medical care. Temple University, Temple University 
Health System and its subsidiaries will not provide monetary compensation or free medical 
care in the event of research-related injury. The patient or their insurance company will be 
billed for medical care if this occurs. Potential Benefits to Subjects 
This prospective study will not directly benefit enrolled subjects. 
10) Costs to Subjects 
The subject may also be responsible pay for the cost of the study medication, which is the 
tacrolimus extended-release form. This depends on their insurance, as the copay of the study 
medication (tacrolimus extended-release form) may be higher than tacrolimus immediate-
release form. In most cases the copay would be a similar cost for the study medication.  
11) Informed Consent  
No procedure will be performed if informed consent is not obtained. During the pre-operative 
preparation for transplant, patients will be consented for surgery and consented for the study if 
they volunteer to be included. The transplant surgeon performing the transplant operation will 
be responsible for screening the patients for inclusion and exclusion criteria as well as 
obtaining the informed consent. Non-English speaking patients will not be enrolled. 
Investigator Guidance for informed consent (HRP-802) will be followed.  
 

 
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12) Vulnerable Populations 
Not applicable. Participants who are pregnant, under 21 years, cannot consent for themselves, 
or prisoners will not be included. 
13) Sharing of Results or Incidental Findings with Subjects 
 
The genetic testing will not be included in their medical record, so this will not impact subject care in 
any way. Results of required genetic testing will not be shared with participants. All prospective data 
collected for this study is included in the medical record so incidental findings are not anticipated. In 
the event that any incidental findings are discovered in your medical record or by any other means 
during the study process by research staff you will be notified within 24 hours by the Principal 
Investigator by phone.