Clinical trial NCT03823768
Conditions: Neurotoxicity Liver Transplant; Complications
Sponsor: Medical University of South Carolina
Start date: 2020-01-31; Completion date: 2024-01-30
Enrollment: 30 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will compare neurologic side effects associated with two immunosuppressant medications used in liver transplant patients. The standard therapy of twice daily immediate release Tacrolimus will be compared to Envarsus once daily. We hypothesize that Envarsus will show a lower rate of neurologic side effects than immediate release tacrolimus.

Detailed description:

Arms: arm 1: Tacrolimus immediate release twice daily for 6 months arm 2: Envarsus daily for 6 months.
Interventions: intervention 1: Envarsus intervention 2: Tacrolimus Immediate release
Intervention descriptions: intervention 1: Subjects in this group will take Envarsus daily for 6 months of treatment (goal 24 hour trough: 3-10 ng/mL) +/- adjunctive agent and prednisone. intervention 2: Subjects in this group will take Tacrolimus immediate release for 6 months of treatment (goal 12 hour trough: 3-10 ng/mL) +/- adjunctive agent and prednisone.

Protocol documents:
Prot_SAP_000.pdf: 
Protocol v1.5 
10September2020 
 
 
Title:  
The effect of conversion to once-daily Envarsus® on the neurologic toxicity burden in liver 
transplant recipients 
Institution: 
Medical University of South Carolina 
 
Principal Investigators: 
Derek DuBay 
Office: 843-792-4003 
Fax: 843-792-8596 
Email:  dubay@musc.edu 
 
 
 
 


Protocol v1.5 
10September2020 
1) Study Objectives  
a) Primary objective 
i) Estimate the change from baseline to six months in neurotoxicity burden measured by a 
composite Patient Global Impression of Improvement (PGI-I) (Appendix B) score in patients 
converted to Envarsus daily ± adjunctive agent ± prednisone  versus patients maintained on 
a standard therapy of Tacrolimus IR BID ± adjunctive agent ± prednisone 
b) Secondary objectives 
i) Estimate the change in the mean Fahn-Tolosa-Marin (FTM) score in patients with self-
reported tremor from baseline to 6 months after enrollment 
c) Exploratory Outcomes 
i) Examine subject specific change of self-reported adherence using the IMAB-Q 10 (Appendix 
C) at the time of the conversion versus six months post-conversion, compared between the 
two arms 
ii) Examine subject specific change in quality of life, using the SF-12  at the time of conversion 
versus six months post-conversion, compared between the two arms 
iii) Examine subject specific change in memory, using the Medical Symptom Validity Test, at the 
time of conversion versus six months post-conversion, compared between the two arms 
iv) Examine subject specific change in cognition, using the MoCA (Appendix E), at the time of 
conversion versus six months post-conversion, compared between the two arms 
v) Examine subject specific change in cognition, using the MMSE, at the time of conversion 
versus six months post-conversion, compared between the two arms 
vi) Measure and compare time-to-event analysis of secondary objective between the two arms 
(1) Patient death (time to event analysis) 
(2) Biopsy proven acute rejection (Banff RAI ≥ 5, time to event analysis) 
(3) Graft loss (time to event analysis) 
vii) Compare rates of adverse events and severe adverse events between the two arms 
viii) Examine subject specific change in renal function, using the 4 variable MDRD, at the time of 
conversion versus six months post-conversion, compared between the two arms 
2) Background 
a) Rationale 
 
Neurotoxicity associated with tacrolimus after liver transplant has been reported in 10 to 42% of 
recipients (1-7). These toxicities can range from mild (tremors, headaches) to severe (seizures, PRES 
memory loss) and are a significant cause of morbidity after liver transplantation. Neurotoxicities are 
the most frequent adverse events that lead to tacrolimus discontinuation in abdominal transplant 
recipients, which leads to an increased risk of acute rejection, including 31% in liver transplant 
recipients in the first year after conversion (8).  
Although the vast majority of literature in liver transplant neurotoxicities focus on the acute, severe 
neurotoxicities (PRES, seizures), there is evidence that more mild neurotoxicities can persist and 
lead to significantly worse visuospatial/constructional ability, impaired cognitive function, and white 
brain matter changes (9). 
In several chronic disease states, adverse drug events have clearly been established as a major risk 
factor for medication non-adherence (10-12). Additionally, adverse drug events are associated with 
significant healthcare utilization and costs (13,14). 
Tacrolimus LCP (Envarsus®) is a once-daily tacrolimus product that has demonstrated an ability to 
maintain a similar Cmin to tacrolimus IR in converted liver transplant recipients with an average 


Protocol v1.5 
10September2020 
conversion dosing ratio of 0.7, while also demonstrating significantly less variability in levels.  In an 
extension study of this group, the pharmacokinetics of tacrolimus LCP remained stable up to 26 
weeks post-conversion and there were no concerns for safety at up to 52 weeks on tacrolimus LCP 
(15). Tacrolimus LCP has also demonstrated a significant improvement in tremor compared to 
tacrolimus IR in kidney transplant recipients experiencing a clinically significant tremor (16). Hand 
tremors exist with a high incidence in liver transplant recipients, worsening after administration of 
cyclosporine or tacrolimus (16), and can be a major contributor to reduced quality of life. We 
hypothesize that tacrolimus LCP will show a lower neurotoxicity burden in multiple neurologic side 
effects, as compared to tacrolimus IR. 
 
 
 
Supporting Data 
 
Multicenter Open-label Conversion Trial for Abdominal Transplants Unable to Tolerate Tacrolimus  
Overall Distribution of ADRs Prompting Conversion from Tacrolimus 
 
Kidney (n=49) 
Liver (n=108 
Neurotoxicity 
20 (41) 
67 (62) 
Gastrointestinal 
9 (18) 
29 (27) 
Nephrotoxicity 
4 (8) 
20 (19) 
Diabetes 
21 (43) 
16 (15) 
 
ADRs in Multicenter Prospective, Randomized U.S. Trial 
 
Tacrolimus 
(n=250) 
Cyclosporine/AZA 
(n=250) 
Headache 
64% 
60% 
Insomnia 
64% 
68% 
Tremor 
56% 
46% 
Paresthesia 
40% 
30% 
 
 
3) Study interventions 
a) Interventions, administration, and duration 
i) 
Subjects will receive the current standard of care for up to 15 days and no longer than 1 
year post-transplant. Standard of care is described as a regimen of tacrolimus IR (goal 12 
hour trough:  3-10ng/mL) BID ± adjunctive agent ± prednisone. Subjects are randomized to 
one of the two arms to either receive their standard of care regimen or convert their 
tacrolimus IR BID to Envarsus QD  
(1) Both products FDA approved for preventing rejection in kidney transplant and are used 
as a standard of care for all organ transplants 
ii) Post-randomization, subjects will be converted to one of the two arms, as shown below, and 
followed for a total period of six months (primary endpoint), or until a terminal end point is 
reached. 
(1) Arm 1: Control-- Tacrolimus IR (goal 12 hour trough:  3-10ng/mL) BID ± adjunctive agent 
± prednisone x 6 months 
(2) Arm 2: Intervention-- Envarsus (goal 24 hour trough:  3-10 ng/mL) daily ± adjunctive 
agent ± prednisone x 6 months 


Protocol v1.5 
10September2020 
(a) Envarsus will be supplied from Veloxis Pharmaceuticals 
b) Neurotoxicity assessment 
i) 
Changes in neurotoxicity comorbidity burden will be assessed at all study visits noted on the 
Schedule of Evaluations, using the composite score from applying the PGI-I score to tremor, 
headache, insomnia, and paresthesia. 
 
4) Study Endpoints 
i) Primary outcome- Treatment efficacy, defined difference in change from baseline to six 
month measure by composite PGI-I in both arms. 
ii) Secondary outcomes 
(a) Change in the FTM score in patients with self-reported tremor between baseline 
and six months post-enrollment in both arms 
iii) Exploratory outcomes 
(1) Safety outcomes of treatment failure rate, defined as acute allograft rejection with a 
Banff RAI 5 or higher, graft loss, death, adverse events, or severe adverse events at six 
months post-conversion in both arms. 
(2) Change in self-reported medication adherence, defined as the IMAB-Q10, between 
baseline and six months post-conversion in both arms 
(3) Change in the subject specific quality of life, defined as the SF-12, between baseline and 
six months post-conversion in both arms 
(4) Change in subject specific memory, defined as the MSVT, between baseline and six 
months post-conversion in both arms 
(5) Change in subject specific cognitive function, defined as the MoCA, between baseline 
and six months post-conversion in both arms 
(6) Change in subject specific renal function, defined as the 4 variable MDRD, between 
baseline and six months post-conversion in both arms 
 
5) Inclusion & Exclusion Criteria 
i) Potentially eligible patients will be screened by the PI and study coordinator using 
inclusion and exclusion criteria below to determine if they qualify for the study.  
ii) Inclusion criteria 
(1) Male or female adult (≥18 years old) with a history of liver or liver/kidney transplant 
within 15 days to 12 months of transplant.  
(2) 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.  For those that consent virtually, subjects must be willing and able to use 
the Doxy.me platform and complete assessments virtually.  
iii) Exclusion criteria 
(1) Patients will be excluded if they are pregnant or nursing females or males with a 
pregnant female partner 
(2) HIV positive (HIV ab +) 
(3) Unable to tolerate oral medications 
(4) Use of another investigational product within thirty days prior to receiving study 
medication 
(5) Moderate acute cellular rejection (RAI ≥ 5) within the past month 
(6) A condition that is known to cause tremor such as essential tremor, Parkinson disease, 
or enhanced physiologic tremor.  
(7) Patients taking medications known to induce tremors or dopamine blocking agents 


Protocol v1.5 
10September2020 
(8) 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 
 
6) Number of Subjects 
a) There will be 15 subjects in each arm, 30 subjects total 
 
7) Setting Where Research Will Be Conducted 
a) Study activities, including consent, enrollment, and randomization, will occur in the Liver 
Transplant Clinic at the Medical University of South Carolina or through Doxy.me. 
 
8) Recruitment Methods 
a) Study enrollment procedures 
i) 
Subject Identification/Recruitment: Members of the research team will identify potentially 
eligible patients who have undergone liver or liver/kidney transplantation within the past 
twelve months. An initial evaluation of existing patient information may be performed via 
chart review to determine potential eligibility. This initial review may be performed prior to 
consent; however no protocol driven tests or procedures may be performed until signed 
informed consent has been obtained. 
ii) Informed Consent: A qualified member of the research team, Human Subjects Protection 
Trained, will approach and explain the study and offer participation.  The study will be 
explained in a manner consistent with the level of education pertaining to the 
patient.  Enrollment procedure will involve face-to-face meetings of the patients to inform 
and review informed consent documentation.  The participant will sign the consent form 
prior to evaluation of self-reported measures.  Copies of the informed consent will be 
appropriately placed in the corresponding chart and the patient will be provided with a copy 
of the signed consent form.  Non-consenting individuals will also be ensured that no penalty 
will arise due to denying participation.  Those who choose to participate in the trial will be 
informed that at any point they reserve the right to leave the study.   
iii) Enrollment: Patients who give informed consent to study participation will go on to 
complete baseline procedures necessary to determine eligibility for randomization. Once 
deemed eligible for the study according to the inclusion/exclusion criteria, the patient will 
be enrolled as study participant.  Information to be entered upon enrollment includes 
demographic information and date of transplant surgery. Enrolled subjects will be 
randomized to one of the treatment arms in the applicable cohort.  
 
9) Consent Process 
a) Informed Consent: A qualified member of the research team, Human Subjects Protection 
Trained, will approach and explain the study and offer participation.  The study will be explained 
in a manner consistent with the level of education pertaining to the patient.  Enrollment 
procedure will involve face-to-face meetings of the patients to inform and review informed 
consent documentation.  The participant will sign the consent form prior to evaluation of self-
reported measures.  Copies of the informed consent will be appropriately placed in the 
corresponding chart and the patient will be provided with a copy of the signed consent 
form.  Non-consenting individuals will also be ensured that no penalty will arise due to denying 
participation.  Those who choose to participate in the trial will be informed that at any point 
they reserve the right to leave the study.  For patients who are being seen only virtually via Doxy 
telemedicine visits, they will be identified at a standard of care telemedicine visit by the liver 


Protocol v1.5 
10September2020 
transplant team and the study coordinator will follow up with the patient and set up a Doxy.me 
visit to obtain informed consent. 
b) Enrollment: Patients who give informed consent to study participation will go on to complete 
baseline procedures necessary to determine eligibility for randomization. Once deemed eligible 
for the study according to the inclusion/exclusion criteria, the patient will be enrolled as study 
participant.  Information to be entered upon enrollment includes demographic information and 
date of transplant surgery. Enrolled subjects will be randomized to one of the treatment arms in 
the applicable cohort.  
c) Human subjects 
i) Institutional review board (IRB) review and informed consent 
ii) This protocol, the ICF, and any subsequent modifications must be reviewed and approved by 
the IRB. A signed and dated ICF must be obtained from the subject as defined in 
21CFR50.3.  The ICF must also be signed and dated by a member of the study staff qualified 
to be delegated the authority to obtain informed consent.  A copy of the ICF must be given 
to the subject and the consent process must be documented in the subject’s medical 
record.  The PI or delegated sub-Investigator is responsible for ensuring that informed 
consent is obtained from each patient prior to conducting any study-related activities.  
(1) No deviations from or changes to the study protocol should be initiated except when 
necessary to eliminate immediate hazard to the subject.  However, the IRB and Study 
Sponsor must be informed of this as soon as possible thereafter.  It is the PI’s 
responsibility to report SAEs occurring during the study to the IRB, as required and as 
soon as possible.   
 
10) Study design 
i) Single-center, open-label, randomized comparative trial for a duration of 6 months. 
ii)  There will be 15 subjects in each arm, with a total study size of 30 subjects. 
b) Allocation: Three random permuted-blocks of ten, with equal arm allocation ratio will be used. 
In each block, REDCap will be used to ensure 1:1 randomization, with resulting 1:1 allocation in 
the overall cohort. 
c) Intervention Model: Parallel assignment 
d) Masking: This will be an open-label study as masking is not feasible given we are comparing 
twice-a-day to once-a-day regimen. 
e) Timing of evaluation 
i) 
Pre-Randomization Evaluations  
1. Baseline 
2. Evaluations listed under the baseline visit may be performed up to 14 days 
prior to randomization. Once the subject has been successfully screened 
and accepted for randomization, randomization must be completed within 
48 hours.   
 
ii) Intervention and Evaluations 
 
1. Once the subject has been successfully randomized, study medication will 
be picked up from IDS by the study team to be dispensed to the subject or 
study medication will be shipped to the subject by IDS.  Study evaluations 
must take place within the time window indicated on the Schedule of 
Evaluations (Section 3) 
f) Clinical and laboratory evaluations 


Protocol v1.5 
10September2020 
i) Schedule of evaluations 
 
 
 
 
 
Data Collection Schedule 
Report Form 
BaselineDays Post-Conversion 
7±2 14±3 30±560±790±10120±10150±10 180±10
Informed Consent Obtainedvi 
X 
Randomization 
X 
Review of Inclusion and Exclusion Criteria 
X 
Medical History 
X 
Liver Transplant Recipient 
X 
Review of Medications and Dosing 
X 
X 
Clinical assessment* Adverse events, 
rejection, graft loss, 
death 
 
 
 
 
 
X 
 
 
X 
PGI-I, IMAB-Q 10, 
MSVT, MoCA, and SF-
12, MMSEv 
X 
X 
Fahn-Tolosa-Mariniv 
X 
X 
Laboratory 
Assessments 
CBC and Chem-7i 
O 
O 
O 
O 
O 
O 
O 
O 
O 
LFTsii 
O 
O 
O 
O 
O 
O 
O 
O 
O 
Tacrolimus C0iii 
O 
O 
O 
O 
O 
O 
O 
O 
O 
End of Study 
X 
X=required ; 0=optional: data will be collected if performed as standard of care 
Footnotes: 
i) 
Includes sodium, potassium, chloride, CO2, BUN, SrCr, glucose, calcium, WBC, HgB, Hct, platelets 
ii) 
Includes AST, ALT, alkaline phosphatase, total bilirubin, albumin, total protein 
iii) Tacrolimus concentrations will be 12- or 24-hour levels, drawn in the morning of each assessment 
iv) Only required for patients with self-reported tremor 
v) 
MSVT,MMSE, MoCA, FTM will be completed through a Doxy.me visit.  PGI-I, IMAB-Q 10 and SF-10 will be sent 
to the subject through REDCap to be completed. Necessary materials (ball point pen and paper) to complete 
the MoCA, MMSE, and FTM will be shipped to the subject prior to the Doxy.me visit. 
vi) For subjects consented through Doxy.Me, this will be done prior to the baseline visit with the assessments. 
 
11) Specimen Collection and Assessments 
 
i) 
Clinical and Laboratory Assessments: 
(1) Laboratory evaluations will be performed at certified laboratories according to the study 
schedule. Required tests are specified in the Schedule of Evaluations.  Laboratory 


Protocol v1.5 
10September2020 
specimens will not be stored for the study or sent to any outside facilities.  Specimens 
will not be used for future research.   
(2) All subjects will undergo clinical assessment by the investigator or the investigator’s 
designee in the manner and at the times specified in the Schedule of Evaluations  
(a) Adverse events will be determined and defined according to the protocol 
(b) Doses will be recorded of all immunosuppressants.  
(c) Rejection and infection events will be recorded, as defined in the protocol 
(3) Renal function assessment will be monitored at regular intervals using the 4-variable 
abbreviated MDRD equation. It will be monitored at baseline and the end of the study 
for study outcomes and any time points dictated by standard of care follow-up in 
between those time points. 
ii) Definitions 
(1) Acute rejection is defined as a liver allograft biopsy showing RAI 5 or greater, by the 
1997 Banff Criteria and all updates since then. Biopsies will be performed when clinically 
warranted, based on changes in allograft function. 
(2) Rejection reversal is defined as return of liver function tests to within 20% of baseline 
and/or histologic clearance by Banff Criteria 
(3) Recurrent acute rejection is defined as rejection recurring more than two weeks after 
documented rejection reversal. 
iii) Treatment of Acute rejection: 
(1) Acute rejection will be treated per provider discretion. 
iv) Opportunistic Infections 
(1) Opportunistic infections will be defined as outlined in Appendix F 
 
v) Intervention Discontinuation Evaluations: At the scheduled time of intervention 
discontinuation (EOT, last date of study), the following evaluations must be completed: 
clinical assessment, CBC, CHEM-7, LFTs, Tacrolimus CO.  In case of subject withdrawal from 
study, the patient will return to standard of care medications and request to continue with 
final assessment using PGI-I, IMAB-Q 10, MSVT, MoCA, SF-12, MMSE, and FTM (if applicable) 
will be discussed with a qualified team member.     
 
12) Data Management 
a) Data management will be overseen and data analysis will be independently reviewed by an 
Investigator on the study who has no related financial interest. This member will serve as 
independent monitor to oversee data collection and management, and to verify the integrity of 
data and interpretation of study results. Data reports, including patient recruitment and 
randomization numbers, clinical outcomes (acute rejections, infections and hospitalizations), 
AEs and SAEs will be reviewed quarterly. 
b) Dichotomous data will be analyzed using Chi Square or Fischer Exact, when appropriate, and 
continuous data points will be analyzed using Student’s t-test or Mann Whitney U, for 
parametric and nonparametric data, respectively. 
c) Sample size estimation for the primary outcome 
i) The proposed sample size (n=30) would be able to demonstrate a mean difference in 
neurologic toxicity burden, using the Patient Global Impression of Improvement (PGI-I) 
rating of 20 ± 15 with greater than 80% power using a two-tailed t-test with an alpha set at 
0.05. Based on reported neurologic toxicities from the literature (headache 64%, insomnia 
64%, tremor 56%, paresthesia 40%), a mean score of 45 is expected at baseline. Using the 
independent samples t-test comparing two groups with a two-sided significance level of 


Protocol v1.5 
10September2020 
0.05, a sample size of 14 subjects per group would be required to obtain a power of at least 
0.8 if the two groups have a mean of 25 ± 15 neurologic toxicity burden in the Envarsus 
cohort at the conclusion of the study and mean of 45 ± 20 neurologic toxicity burden at 
baseline and follow up in the tacrolimus IR group. Estimating a 10% drop out rate, we 
propose a sample size of 15 subjects per group. This sample size will provide adequate 
power to show a statistical and clinical difference in the neurologic toxicity burden between 
the two groups. 
 
 
d) Missing data and imputation methods 
i) Under the intention-to-treat principle, all subjects are included in the analysis. Extensive 
efforts will be made to keep all missing data to a minimum and minimize loss to follow-up 
(LTFU).  However, it is likely that some missing data may occur. 
e) Data Handling and Record Keeping 
i) 
In order to protect subjects against any risk regarding loss of personal information, all 
obligations under the Health Portability and Accountability Act (HIPPA) will be met.  
Additionally, all data will be collected and stored through the secure network server and 
behind the MUSC firewall.  We will use electronic CRF forms to gather all study information 
(redcap.musc.edu).  Data will only be stored on campus computers under the MUSC secure 
network.  Data collection forms will be maintained within an office, which is a locked office 
facility on campus.  Only approved study members will have access to patient data.   
ii) Any data or information shared for dissemination will be de-identified and the 
confidentiality of all participants will be strictly maintained.  The only persons with access to 
protected health information (PHI) will include study investigators, research coordinators 
and those approved by the MUSC IRB.  All data will be secured on MUSC servers, behind 
firewalls, with passwords protecting entry in these systems.  All PHI will be obtained and 
managed in accordance with the HIPAA Privacy Rule (45 CFR Parts 160 and 164). 
 
13) Provisions to Monitor Data and Ensure Subject Safety 
a) Study modification/discontinuation 
(1) The study may be modified or discontinued at any time by the IRB, the sponsor, the 
OHRP, the FDA, or other government agencies as part of their duties to ensure that 
research subjects are protected. 
(2) After 16 subjects have been randomized and completed follow-up, efficacy and safety 
endpoints will be reviewed by a blinded Safety Monitor to identify if the risk profile is as 
expected. If significantly increased risk is identified in either or both arms of the study, 
sufficient to increase the risk over the potential benefit of the study, the study will be 
discontinued. Examples are included below: 
(a) A 6-month rejection rate difference between arms > 20% 
(b)  A difference in grade 3 or higher infections (based on CTCAE) between arms of > 
20% 
(c) A graft loss difference between arms > 20% 
 
 


Protocol v1.5 
10September2020 
b) Adverse Events 
i) 
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject 
or clinical investigation subject after providing written informed consent for participation in 
the study. Therefore, an AE may or may not be temporally or causally associated with the 
use of a medicinal (investigational) product. The occurrence of adverse events should be 
sought by non-directive questioning of the subject at each visit during the study. Adverse 
events also may be detected when they are volunteered by the subject during or between 
visits or through physical examination, laboratory test, or other assessments. Abnormal 
laboratory values or test results constitute adverse events only if they fulfill at least one of 
the following criteria: 
(1) they induce clinical signs or symptoms, 
(2) they are considered clinically significant, 
(3) they require therapy 
 
ii) Clinically significant abnormal laboratory values or test results should be identified through 
a review of values outside of normal ranges/clinically notable ranges, significant changes 
from baseline or the previous visit, or values which are considered to be non-typical in 
subject with underlying disease. Investigators have the responsibility for managing the 
safety of individual subject and identifying adverse events. Adverse events should be 
recorded in the Adverse Events CRF with them accompanied by the following information: 
(1) severity of adverse events will be determined using the grading system outlined in the 
NCI Common Terminology Criteria for Adverse Events Version 4.03 (CTCAE), as it best 
fits the diagnostic terminology used in naming the event at the site clinical level. 
(2) possibility of relationship to the study treatment (no/yes) 
(3) its duration (start and end dates) or if the event is ongoing an outcome of not recovered 
or not resolved should be reported. 
(4) whether it constitutes a serious adverse event (SAE), if so report date should be 
provided 
(5) action taken regarding study treatment 
(6) whether other medication or therapies have been taken (concomitant medication/non-
drug therapy) 
(7) its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown) 
iii) An SAE is any adverse event which meets any one of the following criteria: 
(1) An SAE is any adverse event that is life-threatening or that results in any of the following 
outcomes: death; in-patient hospitalization or prolongation of existing hospitalization; 
persistent or significant disability or incapacity; or a congenital anomaly or birth defect. 
Any other medical event that, in the medical judgment of the Principal Investigator, may 
jeopardize the subject or may require medical or surgical intervention to prevent one of 
the outcomes listed above is also considered an SAE.  A planned medical or surgical 
procedure is not, in itself, an SAE.  Also specifically excluded from this definition of SAE 


Protocol v1.5 
10September2020 
is any event judged by the Principal Investigator to represent progression of the 
malignancy under study, unless it results in death within the SAE Reporting Period. 
c) Reporting of Serious Adverse Events.  Within 24 hours of first awareness of the event 
(immediately if the event is fatal or life-threatening), certain SAEs will be reported to Veloxis by 
("SAEs," as defined below) that occur during the SAE reporting period (as defined below) in a 
Study subject assigned to receive the Veloxis Product.  The subset of SAEs to be reported for this 
Study are those that fit into either of the following categories: (1) a death, regardless of whether 
it is considered related to treatment with the Veloxis Product, or (2) an SAE that is assessed by 
the Principal Investigator as both related to treatment with the Veloxis Product and unexpected 
for that Product.  An event should be considered "related" to the Veloxis Product if a 
relationship is at least a reasonable possibility, and "unexpectedness" should be based upon 
current Product labeling.  Principal Investigator will report such SAEs using either Institution's 
Internal Adverse Event Report form or an FDA MEDWATCH form together with the Reportable 
Adverse Event Fax Cover Sheet provided by Veloxis. SAEs should be reported as soon as they are 
determined to meet the definition, even if complete information is not yet available. 
d) SAE Reporting Period.  The SAEs that are subject to this reporting provision are those that occur 
from after the first dose of the Veloxis Product through 72 hours after discontinuation of the 
Veloxis Product.  In addition, any and all related SAEs that occur after the reporting period of 
which the Principal Investigator becomes aware should also be reported. 
i) 
AEs and SAEs will be reported in accordance with the FDA Guidelines for Post-Marketing 
Reporting of Adverse Events 21 CRF 314.80 and 21 CRF 600.80 
http://www.fda.gov/medwatch/report/regs.htm.  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. 
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.   
 
14) Withdrawal of Subjects 
a) Criteria for intervention discontinuation 
(1) The intervention will be withheld/discontinued for AE of grade 3 or higher or if 
requested by the study participant. 
(2) Additionally, the intervention will be discontinued if the subject meets criteria for the 
following reasons: 
(a) Loss of graft:  Defined as death or need for retransplant. Patients will be deemed a 
treatment failure and the intervention will be discontinued. 
 
15) Risks to Subjects 
a) An increased risk of getting some kinds of cancer, including skin and lymph gland cancer 
(lymphoma) 
b) An increased risk of infections. As immediate release tacrolimus can lower the ability of the 
immune system to fight infections, serious infections can happen in people taking immediate 


Protocol v1.5 
10September2020 
release tacrolimus that can cause death. Patients should call their doctor right away if they have 
symptoms of an infection such as fever; sweats or chills; cough or flu-like symptoms; muscle 
aches; or warm, red, or painful areas on their skin 
c) High blood sugar (diabetes) 
d) Kidney injury and decreased kidney function 
e) Nervous system problems including encephalopathy, delirium, seizures, coma, tremors, 
paresthesia, headache, mental status changes, and changes in motor and sensory functions  
f) High levels of potassium in the blood (potassium is important for nerve and muscle function) 
g) High blood pressure 
h) Heart problems (myocardial hypertrophy) 
 
i) 
The most common side effects for Envarsus® Daily and Tacrolimus IR in people receiving kidney 
transplant are  
 
                                            Envarsus XR 
       Tacrolimus IR 
Infection 
                                      70% 
                  65% 
Tremors 
                                      19%                              17% 
High Blood Pressure                               23% 
                  23% 
Kidney Problems                                     10% 
                  10% 
Constipation 
                                      18% 
                   25% 
Diarrhea 
                                      31% 
                   34% 
Headache 
                                      15% 
                   10% 
Trouble Sleeping 
                        13% 
                   11% 
Nausea                                                   13%                             15% 
Low levels of phosphate in blood      13% 
               15% 
Swelling of hands, ankles or legs       16% 
               21% 
Weakness 
                                    10% 
               10% 
High levels of potassium in blood      15% 
               11% 
Low red blood cell count (anemia)    26% 
               29% 
j) 
Unknown Risks  
k) Risk of loss of confidentiality 
 
16) Potential Benefits to Subjects/Others 
a) The subject may experience improved outcomes in the intervention group compared to the 
control group, however this cannot be guaranteed.  The intervention group may potentially 
show a lower neurotoxicity burden as compared to the control group.  The study is likely to 
improve knowledge of the neurological effects of extended release tacrolimus versus immediate 
release tacrolimus. 
 
17) Sharing Results with Participants 
a) Publication of the results of this trial will be reviewed and approved by all coinvestigators.  Final 
results will be submitted to ClinicalTrials.gov.  Any presentation, abstract, or manuscript will be 
made available for review by the sponsor prior to submission. 
b) Results are not shared with participants unless they necessitate a change in patient care 
References 


Protocol v1.5 
10September2020 
 
1. Vogt DP, Lederman RJ, Carey WD, et al. Neurologic complications of liver transplantation. 
Transplantation. 1988; 45: 1057-61. 
2. Lewis MB, Howdle PD. Neurologic complications of liver transplantation in adults. Neurology. 
2003; 61: 1174-8. 
3. Bronster DJ, Emre S, Boccagni P, et al. Central nervous system complications in liver transplant 
recipients – incidence, timing, and long-term follow-up. Clin Transplant. 2000; 14: 1-7. 
4. Saner FH, Nadalin S, Radtke A, et al. Liver transplantation and neurological side effects. Metab 
Brain Dis. 2009; 24: 183-7. 
5. Ghaus N, Bohlega S, Rezeig M. Neurological complications in liver transplantation. J Neurol. 
2001; 248: 1042-8. 
6. Stein DP, Lederman RJ, Vogt DP, et al. Neurological complications following liver transplantation. 
Ann Neurol. 1992; 31: 644-9. 
7. Yilmaz M, Cengiz M, Sanli S, et al. Neurological complications after liver transplantation. J Int 
Med Res. 2011; 39: 1483-9. 
8. Abouljoud MS, Kumar MSA, Brayman KL, Emre S, Bynon JS. Neoral rescue therapy in transplant 
patients with intolerance to tacrolimus. Clin Transpl. 2002; 16(3): 168-72. 
9. Pflugrad H, Schrader AK, Tryc AB, Ding X, Lanfermann H, Jackel E, Schrem H, Beneke J, Barg-Hock 
H, Klempnauer J, Weissenborn K. Longerm calcineurin inhibitor therapy and brain function in 
patients after liver transplantation. Liver Transpl. 2018; 24(1): 56-66. 
10. Bates DW, Cullen DJ, Laird N, Petersen LA, Small SD, et al. Incidence of adverse drug events and 
potential adverse drug events: implications for prevention. J Am Med Assoc 1995;274(1):29-34. 
PMID: 7791255. 
11. Bates DW, Boyle DL, Vander Vliet MB, Schneider J, Leape L. Relationship between medication 
errors and adverse drug events. J Gen Intern Med 1995;10(4):199-205. PMID: 7790981. 
12. Kaushal R, Bates DW, Landrigan C, McKenna KJ, Clapp MD, et al. Medication errors and adverse 
drug events in pediatric inpatients. J Am Med Assoc 2001;285(16):2114-120. PMID: 11311101. 
13. Formica D, Sultana J, Cutroneo PM, Lucchesi S, Angelica R, Crisafulli S, Ingrasciotta Y, Salvo F, 
Spina E, Trifiro G. The economic burden of preventable adverse drug reactions: a systematic 
review of observational studies. Expert Opin Drug Saf. 2018; 17(7): 681-95. 
14. Poudel DR, Acharya P, Ghimire S, Dhital R, Bharati R. Burden of hospitalizations related to 
adverse drug events in the USA: a retrospective analysis from a large inpatient database. 
Pharmacoepidemiol Drug Saf. 2017; 26(6): 635-41. 
15. Alloway RR, Eckhoff DE, Washburn WK, Teperman LW. Conversion from twice daily tacrolimus 
capsules to once daily extended-release tacrolimus (LCP-Tacro): phase 2 trial of stable liver 
transplant recipients. Liver Transpl. 2014; 20(5): 564-75. 
16. Langone A, Steinberg SM, Gedaly R, Chan LK, Sha T, Sethi KD, Nigro V, Morgan JC. Switching 
study of kidney transplant patients with tremor to LCP-Tacro (STRATO): an open-label, 
multicenter prospective phase 3b study. Clin Transplant. 2015; 29: 796-805. 
17. Paul F, MullerJ, Christe W, Steinmuller T, Poewe W, Wissel J. Postural hand tremor before and 
following liver transplantation and immunosuppression with cyclosporine or tacrolimus in 
patients without clinical signs of hepatic encephalopathy. Clin Transplant. 2004; 18(4): 429-33. 


Protocol v1.5 
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18. Prograf [package insert]. Northbrook, IL: Astellas Pharma US, Inc; 2018. 
19. “SRTR: Medical University of South Carolina: A. Program Summary. Transplant (organ): 
Kidney”  N.p., n.d. Web. 19 September 2018. 
 
 
 
 


Protocol v1.5 
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Appendix A: Scientific Registry of Transplant Recipients 
Program Summary: MUSC 
 
 


Protocol v1.5 
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Appendix B: Patient Global Impression of Improvement (PGI-I) 
 
 
 
 
 


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Appendix C: IMAB-Q10 Questionnaire  
 
People have different experiences of trying to take their medicines as prescribed (right dose and right 
time). We understand that things can ‘get in the way’ of following your doctor’s recommendations 
about taking your medicines. This questionnaire lists 10 different statements about taking your 
medicines. 
 
Statement  
Strongly 
agree  
Agree  
Neither 
agree nor 
disagree  
Disagree  
Strongly 
disagree  
1  
I know how to take my 
medicines as prescribed  
 
 
 
 
 
2  
I am physically able to take 
my medicines as prescribed  
 
 
 
 
 
3  
I remember to take my 
medicines as prescribed  
 
 
 
 
 
4  
I can easily get hold of my 
prescribed medicines from 
the pharmacy or surgery  
 
 
 
 
 
5  
I feel confident about all 
aspects of managing 
(ordering, collecting and 
taking) my medicines  
 
 
 
 
 
6  
I worry about the unwanted 
effects (e.g. harmful effects 
or side effects) of taking my 
medicines  
 
 
 
 
 
7  
Taking my medicines as 
prescribed is a burden to me  
 
 
 
 
 
8  
Life gets in the way of me 
taking my medicines as 
prescribed  
 
 
 
 
 
9  
I don’t think I could cope if 
my medication regime kept 
changing  
 
 
 
 
 
10  I worry about what other 
people would think of me if 
they knew I took medicines  
 
 
 
 
 
 
 


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Appendix D: Fahn, Tolosa, Marin Tremor Rating Scale 
 
 


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Appendix E: Montreal Cognitive Assessment (MoCA) 
  
 
 


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Appendix F: SF-12  
 
 
 
 


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Appendix G: Mini-Mental Status Examination  
 


Protocol v1.5 
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Appendix H: Definitions for Opportunistic Infections 
I. Cytomegalovirus: 
A. Active Infection: 
 
1. Evidence of active viral replication (positive CMV DNA PCR, evidence of viral infection by on  
 
 
histologic samples) 
B. CMV Disease 
 
1. Evidence of Active Infection with attributable symptoms 
 
 
a. CMV Syndrome: one or more of the following: 
 
 
 
1. Fever > 38° C for at least 2 days 
 
 
 
2. New or increased malaise 
 
 
 
3. Leukopenia 
 
 
 
4. ≥ 5% atypical lymphocytes 
 
 
 
5. Thrombocytopenia 
 
 
 
6. Elevation of hepatic transaminases to 2x ULN plus evidence of viral  
replication 
 
 
b. CMV Tissue-invasive disease: 
 
 
 
1. Evidence of organ dysfunction in the absence of other documented cause 
 
 
 
 
AND 
 
 
 
 
Evidence of CMV in blood by viral culture or CMV DNA PCR 
II. Other Opportunistic Infections: 
 
A. For definitions of herpes simplex, varicella zoster, Epstein Barr Virus, parvovirus and adenovirus, see American 
Journal of Transplantation 2006; 6: 262–274