Clinical trial NCT03437577
Conditions: Kidney Transplant Failure and Rejection
Keywords: Kidney Transplant
Sponsor: University of Minnesota
Start date: 2018-05-08; Completion date: 2020-03-31
Enrollment: 18 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective is to compare the effect of treatment with an immediate-release tacrolimus to an extended-release tacrolimus (i.e., Envarsus® XR) immunosuppressive regimen on cognitive and motor function in kidney transplant recipients

Detailed description:
Between four (4) months and 14 months after receiving a kidney transplant and, per standard of care (SOC), having been placed on an immediate-release (IR) tacrolimus immunosuppressant regimen, participants in this study will undergo cognitive and motor function testing and have a blood sample collected (BASELINE). Half of the participants will then be randomly converted to extended-release (XR) tacrolimus (Envarsus® XR) while the other half will remain on IR tacrolimus for the duration of the study. Both the IR and XR groups will repeat the cognitive and motor function testing and have a blood sample collected at 6, 12, and 24 weeks Post-BASELINE. A practice version of the cognitive and motor function tests will be administered no more than 60 days prior to the baseline visit (Pre-BASELINE). Alternate versions of the cognitive and motor tests will be used at each Post-BASELINE testing session to control for possible practice effects.

The primary objective is to compare the effect of treatment with an immediate-release tacrolimus to an extended-release tacrolimus (i.e., Envarsus® XR) immunosuppressive regimen on cognitive and motor function in kidney transplant recipients.

The secondary objective is to determine the factors that explain inter-individual variability in cognitive response. Pharmacokinetic and demographic factors will be explored. Variability in cognitive response between individuals can be large. A population approach (nonlinear, mixed effects) will be used. Measurement of drug concentration will be the dependent variable.

Arms: arm 1: This is standard of care arm 2: replace standard of care
Interventions: intervention 1: immediate-release tacrolimus intervention 2: extended release tacrolimus
Intervention descriptions: intervention 1: Standard of care for transplant patients intervention 2: Experimental care

Protocol documents:
Prot_SAP_000.pdf: 
PROTOCOL TITLE: CMET  
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PROTOCOL TITLE: 
Comparison of the cognitive and motor effects of treatment between an 
immediate- and extended-release tacrolimus (Envarsus® XR) based 
immunosuppression regimen in kidney transplant recipients 
PRINCIPAL INVESTIGATOR or FACULTY ADVISOR: 
Dr. Susan Marino, PhD 
Experimental and Clinical Pharmacology 
612-624-2964 
marin007@umn.edu 
STUDENT INVESTIGATOR: 
N/A 
VERSION NUMBER/DATE: 
Version 7.0 09/06/2019 
 
   CLINICAL TRIALS REGISTRATION: 
NCT03437577


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REVISION HISTORY 
 
Revision # 
Version Date 
Summary of Changes 
Consent Change? 
1 
11/07/2017 
 If subject consents to genetic 
portion of study, a portion of the 
baseline blood sample will be 
used to see if subject has 
variations of specific 
polymorphisms that are known 
to affect drug metabolism. 
Yes - Added to 
consent form dated 
11/07/2017 
2 
11/17/2017 
• Added a +/- 7 day visit window 
to add to flexibility for subject 
scheduling. 
• Updated the name of the 
research team from TRO to 
SurgCTO. 
• Removed the Revised Token 
Test from the list of 
assessments to be completed at 
study visits. 
• Removed sentence stating 
subjects may be approached 
with study specific information 
pre-transplant. Subjects may 
still be told pre-transplant that 
they may be approached for 
studies post-transplant. 
• Removed Prograf from the 
protocol and left the immediate- 
release as a general term 
because the subjects may be on 
a generic formulation instead of 
a brand name formulation 
No 
3 
05/01/2018 
 Subjects may now complete pre-
baseline visit up to 12 months 
post-transplant 
 Updated study visits to 
accommodate the expansion of 
the enrollment window to 12 
months post-transplant 
 
Yes – Added to 
consent form dated 
05/01/2018 
4 
06/04/2018 
 Fix wording issue – clarified 
that BASELINE occurs no 
more than 60 days AFTER 
PRE-BASELINE 
 Removed “standard of care” 
wording as this has changed 
Yes – Added to 
consent form dated 
06/04/2018 


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since the previous version 
5 
07/31/2018 
Added information into section 18.0 of 
the protocol. 
Yes – consent form 
dated 07/31/2018 
6 
09/11/2018 
 Subjects may now complete pre-
baseline visit up to 36 months 
post-transplant 
 Updated study visits to 
accommodate the expansion of the 
enrollment window to 36 months 
post-transplant 
7 
09/06/2019 
 Increase age range to “18 and 
above” 
 Eliminate study visit (#5) at 
24-weeks post baseline, which 
lowers total compensation to 
$200 and shortens total study 
duration 
Yes – consent form 
dates 09/06/2019 


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Table of Contents 
After completing your protocol, right click on the Table of Contents below and select 
“Update Field.” If prompted, select “Update entire table.” This will automatically 
update the protocol sections and page numbers for you. Do this also each time you 
modify your protocol after initial approval. 
1.0 
Objectives ................................................................................................................ 6 
2.0 
Background .............................................................................................................. 6 
3.0 
Study Endpoints/Events/Outcomes .......................................................................... 7 
4.0 
Study Intervention(s)/Investigational Agent(s) ........................................................ 8 
5.0 
Procedures Involved ................................................................................................. 8 
6.0 
Data and Specimen Banking .................................................................................. 11 
7.0 
Sharing of Results with Participants ...................................................................... 11 
8.0 
Study Duration ....................................................................................................... 11 
9.0 
Study Population .................................................................................................... 11 
10.0 Vulnerable Populations .......................................................................................... 11 
11.0 Local Number of Participants ................................................................................ 12 
12.0 Local Recruitment Methods ................................................................................... 12 
13.0 Withdrawal of Participants .................................................................................... 15 
14.0 Risks to Participants ............................................................................................... 15 
15.0 Potential Benefits to Participants ........................................................................... 16 
16.0 Data Management .................................................................................................. 16 
17.0 Confidentiality ....................................................................................................... 17 
18.0 Provisions to Monitor the Data to Ensure the Safety of Participants ..................... 17 
19.0 Provisions to Protect the Privacy Interests of Participants..................................... 18 
20.0 Compensation for Research-Related Injury ........................................................... 18 
21.0 Consent Process ..................................................................................................... 19 
22.0 Setting .................................................................................................................... 20 
23.0 Multi-Site Research ............................................................................................... 20 
24.0 Resources Available ............................................................................................... 20 
25.0 References .............................................................................................................. 20 


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ABBREVIATIONS/DEFINITIONS 
• COWA: Controlled Oral Word Association 
• Immediate Release: IR 
• Extended Release: XR 


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STUDY SUMMARY 
 
Study Title 
Comparison of the cognitive and motor effects of 
treatment between an immediate- and extended-release 
tacrolimus (Envarsus® XR) based immunosuppression 
regimen in kidney transplant recipients 
Study Design 
Between four (4) and 38 months after receiving a 
kidney transplant and having been placed on an 
immediate-release (IR) tacrolimus immunosuppressant 
regimen, participants in this study will undergo 
cognitive and motor function testing and have a blood 
sample collected (BASELINE). Half of the 
participants will then be randomly converted to 
extended-release (XR) tacrolimus (Envarsus® XR) 
while the other half will remain on IR tacrolimus for 
the duration of the study. Both the IR and XR groups 
will repeat the cognitive and motor function testing 
and have a blood sample collected at 6 and 12 weeks 
Post-BASELINE. A practice version of the cognitive 
and motor function tests will be administered no more 
than 60 days before the baseline visit (Pre- 
BASELINE). Alternate versions of the cognitive and 
motor tests will be used at each Post-BASELINE 
testing session to control for possible practice effects. 
Primary Objective 
The primary objective is to compare the effect of 
treatment with an immediate-release tacrolimus to an 
extended-release tacrolimus (i.e., Envarsus® XR) 
immunosuppressive regimen on cognitive and motor 
function in kidney transplant recipients. 
Secondary Objective(s) 
The secondary objective is to determine the factors 
that explain inter-individual variability in cognitive 
response. Pharmacokinetic and demographic factors 
will be explored. Variability in cognitive response 
between individuals can be large. A population 
approach (nonlinear, mixed effects) will be used. 
Measurement of drug concentration will be the 
dependent variable. 
Research 
Intervention(s)/Investigational 
Agents 
Immunosuppressant tacrolimus immediate release (IR) 
and extended release (XR) formulation 
(Envarsus® XR) 
IND/IDE # (if applicable) 
Exempt 
Study Population 
Male and non-pregnant female kidney transplant 
recipients ages 18 and above. 
Sample Size (number of 
participants) 
We expect to enroll 74 patients to achieve 65 
completers. 
Study Duration for Individual Six months (including pre-baseline testing) 


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Participants 


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1.0 
Objectives 
1.1 Purpose: The purpose of this study is to demonstrate whether or not the 
extended-release tacrolimus, namely, Envarsus XR, produces fewer adverse 
cognitive and motor effects than the commonly used immediate-release 
tacrolimus formulation in kidney transplant recipients. 
2.0 
Background. 
2.1 Significance of Research Question/Purpose: The calcineurin inhibitor (CNI) 
tacrolimus is one of the most frequently used immunosuppressants in kidney 
transplantation, both in early posttransplantation and as part of long-term maintenance 
regimens (Barraclough et al, 2011. Rostaing et al, 2016). Yet, like other CNIs, such as 
cyclosporine, tacrolimus is associated with numerous adverse effects 
including neurotoxicity, which affects approximately 10-28% of patients (Bechstein, 
2000). Yet, CNI-related neurotoxicity is not well characterized, and is generally 
diagnosed using subjective criteria around clinical symptoms rather than objective 
assessments, complicating the determination of its true incidence. Typically, tacrolimus- 
associated neurotoxicities present as cognitive impairment, including memory deficits, 
tremors, altered mental status, confusion, headaches, hallucinations and/or ataxia (Cheng 
et al, 2012; DiMartini et al 2008), any one of which can result in a substantial reduction 
in the recipient’s quality of life and negatively affect medication adherence. Moreover, 
the pathogenesis of CNI-related neurotoxicity is unclear and confounded and/or 
exacerbated by the presence of comorbid conditions, such as increasing age, 
hypomagnesemia (Thompson et al, 1984), and hypertension (Bechstein, 2000). 
 
The cellular mechanisms underlying the adverse neurologic effects associated with 
tacrolimus have not been conclusively established. Tacrolimus may modulate the activity 
of both excitatory (NMDA) and inhibitory (GABA) amino acid receptors via calcineurin. 
In turn, calcineurin may modulate glutamatergic neurotransmission pre- and 
postsynaptically (Sander et al, 1996) as well as regulate desensitization of GABA 
receptors (Martina et al, 1996). Tacrolimus also inhibits the induction of long-term 
potentiation, which can interfere with memory acquisition (Bechstein, 2000). There is 
also evidence that tacrolimus causes selective toxicity of glial cells (Stoltenburg-Didinger 
& Boegner, 1992) and induction of apoptosis of oligodendrocytes (McDonald et al, 1996) 
though it not known what role these mechanisms play in the clinical manifestation of 
tacrolimus-related neurotoxic effects. 
 
The lack of precise characterization of the neurotoxicities, specifically, the cognitive and 
motor dysfunctions associated with tacrolimus administration, as well as the gaps in our 
understanding of their pathogenesis severely limit the clinician’s ability to reduce or 
prevent their occurrence. Current strategies aimed at managing these adverse events are 
based on the assumption that most of the symptoms are dose-related and only occur at 
elevated and/or peak serum tacrolimus levels blood levels (Ayres et al, 1994; Guarino et 
al, 1996; Bechstein, 2000; Rostaing et al, 2016). In addition, the symptoms of tacrolimus-
associated neurotoxicity may be reversed in most patients by substantially reducing the 
dosage of immunosuppressant (Bechstein, 2000). 


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2.2 Preliminary Data: This study will, for the first time, compare cognitive and motor 
function in individuals placed on either an immediate- or an extended release formulation 
of a tacrolimus (Envarsus® XR ) based immunosuppressive regimen, after receiving a 
kidney transplant. In addition to subjective measures such as the NIH PROMIS scales 
and the SF-12, objective assessments not previously used in the renal transplant 
population will be administered in order to more precisely characterize drug related 
cognitive and motor impairments. 
 
2.3 Existing Literature: The widely used immediate-release, twice-daily capsule 
formulation of tacrolimus, while highly effective in preventing acute transplant rejection, 
has severe limitations, such as a narrow therapeutic window, interindividual variation in 
absorption, and low bioavailability (17% +/- 10%). Envarsus® XR (Veloxis 
Pharmaceuticals), an extended-release, once daily, tablet formulation, was developed 
using a proprietary drug delivery technology that critically affects drug dissolution and 
absorption. Consequently, Envarsus® XR shows a more consistent concentration-time 
profile over 24 hours, with reduced peak and peak-to-trough fluctuations, when compared 
to immediate-release tacrolimus (Rostaing et al, 2016) in de novo and stable kidney 
recipients similar to those participating in this study (Rostaing et al, 2016). Moreover, 
patients converted from immediate-release formulations to Envarsus® XR initially receive 
only 80% of prior immediate-release dosage orally once daily (Bunnapradist et al, 2013; 
Rostaing 2017). Therefore, compared to immediate-release tacrolimus, the extended- 
release formulation, Envarsus® XR , when taken once-daily, slows drug absorption and 
delivers more constant plasma concentrations with less frequent dosing, thereby 
potentially mitigating neurotoxic events associated with high peak drug concentrations. 
 
Our central hypothesis is that kidney transplant recipients, when placed on a regimen of 
Envarsus® XR q.d., will experience significantly fewer adverse cognitive and motor side 
effects than when on a regimen of immediate release tacrolimus b.i.d. 
 
 
3.0 
Study Endpoints/Events/Outcomes 
3.1 Primary Endpoint/Event/Outcome: The primary objective is to compare the 
effect of treatment with an immediate-release tacrolimus to an extended- 
release tacrolimus (Envarsus® XR) immunosuppressive regiment on 
cognitive and motor function in kidney transplant recipients. Our primary 
outcome measure is the Controlled Oral Word Association (COWA: 
phonemic generative fluency). COWA was chosen as the primary endpoint 
since in previous head-to-head studies of drug-induced cognitive 
impairment, this measure was sensitive to the differential effects of the 
study drugs (Meador et al, 2003; Marino et al, 2012) including patients on 
calcineurin inhibitors (Syrjala et al, 2004). The primary endpoint is a change 
in the COWA score from baseline to each post-transplant assessment). 
3.2 Secondary Endpoint(s)/Event(s)/Outcome(s): The secondary objective is to 
determine the factors that explain inter-individual variability in cognitive 


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response. Pharmacokinetic and demographic factors will be explored. 
Variability in cognitive response between individuals can be large. A 
population approach (nonlinear, mixed effects) will be used. Measurement 
of drug concentration will be the dependent variable. 
4.0 
Study Intervention(s)/Investigational Agent(s) 
4.1 Description: The cognitive and motor effects of two FDA-approved 
formulations of the immunosuppressant drug tacrolimus (on-label use for 
kidney transplant recipients) will be evaluated: an immediate-release 
formulation and the extended-release formulation, Envarsus®XR. 
4.2 Drug/Device Handling: Immediate-release tacrolimus will be prescribed by the 
treating physician and dispensed by the patient’s pharmacy of choice. Envarsus®XR 
will be supplied by the sponsor, namely, Veloxis Pharmaceuticals and shipped to 
the Investigational Drug Services (IDS), Pharmaceutical Service, Fairview-
University Medical Center, who will dispense it to patients in the XR group as 
prescribed by the treating physician (on- label use). Upon receipt of the study 
treatment supplies, the IDS staff will perform an inventory and a drug receipt log 
filled out and signed by the person accepting the shipment. The designated study 
staff will count and verify that the shipment contains all the items noted in the 
shipment inventory. Any damaged or unusable study drug in a given shipment will 
be documented in the study files. The study drug will be stored according to the 
stated FDA requirements as outlined in the “Storing Investigation Study Drugs” 
SOP dated 07/23/2003. 
 
Regular study drug reconciliation will be performed by the study team to document 
drug assigned, drug consumed, and drug remaining. This reconciliation will be 
logged on the drug reconciliation form, and signed and dated by the study team. 
 
At the completion of the study, there will be a final reconciliation of drug shipped, 
drug consumed, and drug remaining. This reconciliation will be logged on the drug 
reconciliation form, signed and dated. Any discrepancies noted will be 
investigated, resolved, and documented prior to return or destruction of unused 
study drug. Drug destroyed on site will be documented in the study files. 
 
4.3 IND/IDE: EXEMPT. 
5.0 
Procedures Involved 
Study Design: All subjects will undergo cognitive and motor function testing no 
earlier than two (2) months post-transplant and no later than 36 months post-
transplant to become familiar with the test battery (Pre-BASELINE). The Pre-
BASELINE session will take place no more than 60 days prior to the BASELINE 
visit. Between four (4) and 38 months post-transplant, subjects will have one blood 
sample taken, after which they will be administered the full battery of cognitive and 
motor function tests as well as self-report measures of health-related quality of life. 
5.1 (Baseline). Subjects will then be randomized to remain on immediate- 
release tacrolimus (IR group) or switched to Envarsus XR (XR group). Both 
groups will have one, approximately 10-mL blood sample collected and be 


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administered the cognitive, motor function, and self-assessments at 6 and 
12 weeks after BASELINE.. 
5.2 Study Procedures: 
Patients participating in this study are placed on immediate-release tacrolimus 
immediately following transplant. Four (4) to 38 months post- transplant, half of the 
patients will be randomly chosen to convert to Envarsus XR, while the other half will 
remain on immediate release tacrolimus. Both the IR and XR formulations of tacrolimus 
have been approved by the FDA for use as an immunosuppressant in kidney transplant 
recipients and will be prescribed/dosed by the treating physician as FDA indicated. 
Patients in both the IR group and the XR group will undergo cognitive and motor 
function testing at the following times: (1) at least Two (2) - three (3) months post-
transplant (maximum 36 months post-transplant): pre-BASELINE; (2) Four (4) to 38 
months post-transplant: BASELINE; (3) 6-weeks Post- BASELINE; (4) 12-weeks Post-
BASELINE. Since patients on either IR or XR require therapeutic drug monitoring as 
part of their SOC, the blood sample taken BASELINE and at 6 and 12 weeks post-
BASELINE may coincide with blood levels taken as SOC. Each visit will include a +/- 
seven (7) day window to increase flexibility for the subject’s schedule. At each visit, 
subjects will be administered the following: 
Executive function, processing speed, and word-level language/verbal tests: 
• Phonemic generative verbal fluency will be evaluated using the COWA test. 
COWA requires the subject to generate words other than proper names or 
numbers beginning with a specific letter of the alphabet; three 60-second trials are 
obtained, using three different letters, usually F-A-S or B-H-R. This is a primary 
Outcome Measure. 
• Symbol Digit Modalities Test (SDMT) is a test of psychomotor speed that requires 
the subject to transcribe symbols to numbers as quickly as possible with a 
combination of direct visual identification and short-term memorization. Symbols 
with empty squares are presented and the task is to fill in the corresponding 
number as quickly as possible.  This task is timed at 90 seconds.  This is a 
primary Outcome Measure. 
• Semantic generative verbal fluency will be evaluated using the Animal Fluency 
test. Subjects are asked to generate as many different animal exemplars as they 
can within 60 seconds. The primary dependent measure for both phonemic and 
semantic generative fluency is the number of correct words meeting scoring 
criteria normalized to individual (averaged) baseline. 
• Trails A and B will be used to assess visual search, mental flexibility, and task 
alternation. The subject is required to draw lines between circles in ascending 
order (“connect the dots”). Trail Making Part A requires the patient to connect the 
numbers from 1-25. Trail Making B requires subjects to alternate between 
numbered and lettered circles in ascending numerical/alphabetical order (e.g., 1- 
A-2-B, etc.) The primary dependent measure is time of completion. 
• Digit span subtest from the WAIS-IV will be used to assess immediate attention. 
It tests forward and backward digit span, includes a sequencing trial in which the 
subject is the repeat back the digits in ascending order. 


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Computerized psycholinguistic assessment: 
• Spontaneous narrative (SN) task presents the subject with an interpersonal 
conflict scenario (e.g., “a relative in the nursing home that is being mistreated”) 
and is asked to explain how he/she would address the conflict in a three (3) 
minute speech. Different but equivalent scenarios will be used for the different 
study sessions to minimize practice effect. 
• Picture Description task requires the subjects to describe a simple picture (e.g., 
The “Cookie Theft” stimulus from the Boston Diagnostic Aphasia Examination 
(Goodglass & Kaplan 1983). 
Linguistic analysis of speech and language functioning will be performed on speech 
samples recorded during discourse level language/verbal tests. Both what the subjects 
said (content) and how they said it (manner) in response to a task such as story recall or 
spontaneous narrative task will be analyzed. 
Motor Assessments 
• Tremor will be assessed as follows: Study staff will videotape the subject while 
the subject performs tasks such as sitting with hands and feet relaxed, extending 
the arms outstretched, pointing with the fingers, pointing with the feet, pouring 
water (with the hands), drawing lines and spirals (with the hands), writing (with 
the dominant hand), holding the head upright, extending the tongue. The videos 
and the drawing / writing samples will be coded to ensure blinding, then rated 
according to the Fahn Tolosa Marin scale (Fahn et al, 1988) by a blinded rater. 
Videos will be stored on a University-approved encrypted server. 
• Manipulative dexterity/fine motor coordination will be assessed using Grooved 
Pegboard Test, which involves placing 25 pegs as rapidly as possible into an 
equivalent number of similarly shaped holes, but varying in their orientation to 
the vertical. The primary dependent measure is the time it takes to complete the 
task. 
Quality of Life Assessment 
• Self-report measures of health-related quality of life will either be completed 
online using the brief, but highly reliable computer adapted tests of the NIH 
PROMIS system. [www.NIHpromis.org] or static short forms by pencil and 
paper. PROMIS scales will include: Physical Health (Physical function, pain 
intensity, pain interference, fatigue, sleep disturbance, sleep-related impairment); 
Mental Health (depression, anxiety); Social Health (satisfaction with social roles). 
These measures, along with the SF-12, will be administered at the times of the 
cognitive assessment and will take 15 minutes or less to complete. 
 
Blood Draw 
• One 7 to 10 mL blood sample will be collected at each visit. Over the course of 
the study, we will collect about 6 to 9 teaspoons of blood. 
• If the subject consents to the genetic portion of the study, a portion of the baseline 
blood draw will be used to study specific polymorphisms that are known to affect 
how tacrolimus metabolizes in the body. The subject may still participate in study 
even if they do not consent to the genetic option. 


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5.3 Follow-Up: After the last study session at 12 weeks Post-BASELINE, 
patients who were assigned to the Envarsus® XR group will have the 
opportunity to remain on the extended-release formulation at their own 
expense. 
6.0 
Data and Specimen Banking: N/A 
7.0 
Sharing of Results with Participants 
7.1 No results will be shared with study participants or others. 
8.0 
Study Duration 
• 
We anticipate that the duration for an individual subject’s participation 
in the study would be approximately 32 weeks. 
• 
We anticipate it will take two (2) years to enroll all study participants. 
• 
We anticipate it will take three (3) years from the study start date to 
complete all study procedures and data analysis. 
9.0 
Study Population 
9.1 Inclusion Criteria: (1) Male or female kidney transplant recipient; (2) 18 
years of age and above; (3) receiving a kidney transplant from a living or 
deceased donor; (4) if female, premenopausal and heterosexually active, 
must be using two forms of highly effective birth control (at least one of 
which must be a barrier method) which includes consistent and correct 
usage of established oral contraception, established intrauterine device or 
intrauterine system, or barrier methods of contraception: condom or 
occlusive cap (diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/suppository, starting at screening and throughout the 
study period and for 90 days after the final study drug administration; (5) 
written informed consent to participate in the study. 
9.2 Exclusion Criteria: (1) younger than 18 years of age;  (2) Non-native level 
English speaker; (3) pregnant women (4) breastfeeding women 
9.3 Screening: All patient enrollment will come from Dr. Matas’ patient 
population. Potential subjects will be identified by information contained in 
their medical records. The study will be introduced either in person or by 
mail and either the study staff or letter will thoroughly describe the 
requirements of the study along with the risks and benefits of participation. 
Study staff will be available to answer any questions from the potential 
participant. If the potential participant expresses interest in participating in 
the study, an initial study visit will be scheduled either as a stand alone visit 
or concurrently with a standard of care clinic visit in order to further discuss 
the study, address any questions, and determine the patient’s final eligibility. 
Also see sections 12.0 (Local Recruitment Methods) and 21.0 (Consent 
Process) for further details. 


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10.0 Vulnerable Populations 
10.1 Vulnerable Populations: Identify which of the following populations will be 
involved in this study. (You may not include members of the populations 
below as participants in your research unless you indicate this in your 
inclusion criteria above.) 
☐ Children 
☐ Pregnant women/Fetuses/Neonates 
☐ Prisoners 
☐ Adults lacking capacity to consent and/or adults with diminished 
capacity to consent, including, but not limited to, those with acute 
medical conditions, psychiatric disorders, neurologic disorders, 
developmental disorders, and behavioral disorders 
☐ Non-English speakers 
☐ Those unable to read (illiterate) 
☐ Employees of the researcher 
☐ Students of the researcher 
☒ None of the above 
10.2 Adults lacking capacity to consent and/or adults with diminished capacity to 
consent: N/A 
10.3 Additional Safeguards: N/A 
11.0 Local Number of Participants 
11.1 Local Number of Participants to be Consented: Sample sized is based on the 
primary endpoint (COWA). In a longitudinal neurocognitive study of patient 
on immune suppressant drug therapy Syrjala et al (2004) found that the 
mean T score for the COWA (based on a population norm set at 50, with a 
standard deviation SD of ± 10) declined by 5 units (0.5SD) from 
pretransplanation to 80 days posttransplanation. Since a change of 0.5SD is 
considered standard clinical criteria for a medium effect size, we based our 
calculation of the power for the COWA upon a standard deviation of the 
difference score between baseline and follow up of a 5-point performance 
decline. Therefore, a total of 65 patients will yield a probability of 80 
percent that the proposed study will detect a treatment difference of 5 units 
in COWA at a two-sided 0.05 significance level. To account for possible 
dropouts, we will recruit 74 patients. 
12.0 Local Recruitment Methods 
12.1 Recruitment Process: All patients of the transplant center are told by 
clinical staff and educators that they will likely be approached for research 
studies pre- and post-transplant. Given the number of studies and sheer 
volume of patients seen at the transplant center, specifics of each study are 
not discussed in great detail. This is largely due to the fact that the amount 
of time between referral to our transplant program, being waitlisted or 


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scheduled for transplant, and actually receiving a transplant can vary 
drastically between cases. Therefore, the initial approach for this study by 
the research team will occur post-transplant. 
Eligible kidney transplant recipients will be initially contacted in person at a 
standard of care clinic visit or via mail. The ability to approach patients for 
the study either in person or via mail will allow the study team to capture all 
patients – those who routinely come into clinic for follow-up care and those 
who do not. 
Subjects contacted in person will be approached by a member of the study 
team at a regularly scheduled clinic visit to discuss the study and provide 
potential subjects with a copy of the consent form to review. If the subject 
expresses interest in participating, either at that time or at a later time, an 
initial study visit will be scheduled where the subject will sign the consent 
form prior to any study procedures. Subjects approached via mail will be 
sent an IRB-approved invitation letter and copy of the IRB-approved 
consent form at least one to two months (maximum 36 months) after their 
kidney transplant surgery. A follow-up phone call will be made to the 
potential participant after an appropriate amount of time has passed for the 
letter and consent form to be delivered and reviewed. Study staff will call 
the potential participant, identify themselves as affiliated with the University 
of Minnesota, and explain to the potential participant why they are calling. 
The study will be introduced and the study staff will thoroughly describe the 
requirements of the study along with the risks and benefits of participation 
and answer any questions from the potential participant. If the potential 
participant expresses interest in participating in the study, an initial study 
visit will be scheduled either as a stand alone visit or concurrently with a 
standard of care clinic visit. The potential participant will sign the consent 
form at the initial study visit. This will allow plenty of time for potential 
subjects to review the consent form and consider the study. For additional 
information regarding the consent process, see section 21.0 of this protocol. 
Potential participants may also choose to self-identify for this study. Our 
research group, the Surgery Clinical Trials Office (SurgCTO) has a website 
that lists our actively enrolling studies. This website is publicly available 
and can be reviewed by patients who want to know specifics about studies 
being conducted within the abdominal transplant division and contact 
information for the study team. Patients of the clinics are also referred to 
StudyFinder, which lists all active studies in which SurgCTO is participating 
and study team contact information. 
 
12.2 Source of Participants: Participants will be recruited from the patient 
population SurgCTO, where the co-PI (Matas) is a practicing physician. 
Participants will be identified through their medical records. 


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12.3 Identification of Potential Participants: Potential subjects will be identified 
by information contained in their medical records. The principal investigator 
and the UMN research team have permissible access to the medical records 
as the co-PI (Dr. Matas) has a treating relationship with the patient 
population eligible for this study. All potential subjects are patients of the 
University of Minnesota Transplant Clinic and Nephrology group. Only 
internal patients are recruited for this study. 
All members of the research team have access to EPIC. Within EPIC, 
researchers will first look at potential subjects’ patient type to determine if 
they have opted out of research. If the potential subject has not opted out of 
research, preliminary screening will take place and a letter may be sent to 
the potential subject. 
If the patient has opted out of research, the researcher will not look into the 
patient’s chart, preliminary screening will not take place, and a letter will 
not be sent. If the patient comes to clinic for a standard of care appointment, 
the patient may be approached in person by the clinical team to ascertain 
interest in the study. If the patient expresses interest in the study, the 
researcher will inform the patient that they need to review the patient’s 
medical record to determine eligibility. If the patient is eligible, the consent 
process will proceed. 
12.4 Recruitment Materials: Recruitment will begin at least one to two months 
(maximum 36 months) after potential subjects have had a kidney 
transplant. A letter will be sent briefly describing the study and include 
contact information for the research team. The IRB-approved consent 
form will also be included with the letter for review. A follow-up phone 
call will be made to the potential participant after an appropriate amount 
of time has passed for the letter and consent form to be delivered and 
reviewed. 
The recruitment letter, consent form, and script for the phone conversation 
will all be reviewed and approved by the IRB prior to subject recruitment. 
If a potential subject has a standard of care appointment at the University of 
Minnesota near the time he or she will be eligible for the study, study 
personnel may approach them in person. In that situation, the consent form 
will be provided to the patient to review. 
12.5 Payment: Subjects will not incur costs as a result of participation in the 
study. Compensation will be $50 for each of the four (4) study sessions (a 
total of $200 if they complete all 4 visits) for their time and inconvenience. 
Subjects will also be eligible for up to a total of $200 in travel expenses 
(reimbursed at $0.535 per mile round trip) for the four (4) post-transplant 
visits (excluding the pre-BASELINE visit) during which they are scheduled 
to receive a battery of cognitive, motor function, and self-assessments. If a 
subject cannot continue or chooses to drop out of the study, their payment 
will be prorated for the sessions completed. Compensation will be issued 
from the University of Minnesota. 
 


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13.0 Withdrawal of Participants 
13.1 Withdrawal Circumstances: Subjects will be asked to withdraw from the 
study if the treating physician and/or co-PI (Dr. Matas) determines that there 
is a reason to significantly alter the subject’s drug regimen at any time 
during the study, including switching to an alternate immunosuppressant. 
Subjects who are noncompliant with study visits or who, at any time during 
the study, feel that they can no longer complete the neurocognitive 
assessment battery may also be asked to withdraw from the study. 
13.2 Withdrawal Procedures: Every attempt will be made (phone calls, email) to 
connect to subjects who fail to appear at any visit or abruptly withdraw from 
the study. Once withdrawal is confirmed, an exit form will be completed, 
documenting the reason(s) for withdrawal. No attempt will be made to 
collect any data after withdrawal. 
13.3 Termination Procedures: Data collected from subjects who either withdraw 
from the study voluntarily or who are asked to withdraw will be analyzed 
and retained in the database. 
14.0 Risks to Participants 
For each risk or set of risks below, include the procedures to be performed to 
lessen the probability, magnitude, duration, or reversibility of those risks. 
14.1 Foreseeable Risks: 1. Possible bruising as a result of needle stick to obtain 
blood sample; 2. CNI-immunosuppressant therapy is SOC in this 
population, and there are risks associated with their use (refer to attached 
package inserts for both immediate- and extended-release tacrolimus). All 
participants will be monitored by Dr. Matas throughout this study as SOC, 
thus there is no added risk in switching from immediate-release to extended- 
release tacrolimus. 
14.2 Reproduction Risks: N/A 
14.3 Risks to Others: N/A 
15.0 Potential Benefits to Participants 
15.1 Potential Benefits: There are no direct benefits to study participation. 
16.0 Data Management 
16.1 Data Analysis Plan: In order to maintain conceptual control over the 
experiment-wise Type I error rate, we have identified our primary outcome 
measure as COWA. This measure was chosen because of its sensitivity to 
drug effects on cognitive performance (Meador et al, 2003; Syrjala et al, 
2004; Marino et al, 2012). Repeated measures analysis of variance methods 
will be used to compare our two treatments (tacrolimus IR vs tacrolimus 
XR) with respect to each of the cognitive (neuropsychological and speech) 
assessment variables outlined previously. These outcomes will be measured 
at four time points (time: Baseline; 6 weeks post-Baseline; 12 weeks post- 
Baseline; 24-weeks post-Baseline) and treatment effect as well as order, 


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time, order*treatment and time*treatment interaction effects will be 
examined. In the event that data on any of these variables does not satisfy 
the assumption of normality, transformations and/or non-parametric 
repeated measures ANOVA alternatives such as Friedman ANOVA by 
ranks may be utilized. Neuropsychological and speech change scores will 
each be summarized within each treatment at each assessment time with 
means and standard deviations (and/or medians and IQRs). As exploratory 
work, we will also examine whether clinical covariates such as age, gender, 
education, and concomitant medications modify any of the neurotoxicity 
effects using repeated measures analysis of covariance methods. Individual 
cognitive outcomes will be evaluated based upon reliable change index 
(RCI) criteria. RCIs control for practice effects, regression to the mean, and 
other measurement error sources to indicate individual performance that 
statistically exceeds chance fluctuation. We will use a 90th percentile RCI 
for both our primary and secondary dependent variables. A decline of 4 
points constitutes of statistically reliable decline for verbal fluency 
(Kockelmann et al, 2003)] and a decline of 6 points is the 90th percentile 
decline for SDMT (R.C. Martin, personal communication 2004; unpublished 
data Martin et al., 1999). The number of patients showing declines that 
statistically exceed the effects of test measurement error and practice will be 
analyzed non-parametrically using Fisher’s Exact Test. 
PK/PD Modeling: A pharmacokinetic (PK) pharmacodynamics (PD) 
approach can give insight in understanding how the body influences 
tacrolimus concentrations (PK step) and how variations of these 
concentrations influence neurocognitive performance (PD step). 
Single trough levels will be obtained at study visits, which in some 
instances may overlap with routine clinical care. Sparse sampling 
requires a non-linear mixed effects approach (i.e., NONMEM) that is 
robust with respect to missing data and sparse data sets. Covariates 
known to effect drug disposition in this population such as age, renal 
function, gender, co-medications, etc. will be included in the model 
building algorithms. These data will be collected from the patient 
medical record. PD modeling will investigate if a relationship exists 
between clinical covariates associated with the cognitive and motor 
measures (such as COWA) and drug concentration and derived 
measures of drug exposure. 
 
16.2 Power Analysis: Sample sized is based on the primary endpoint (COWA). 
In a longitudinal neurocognitive study of patient on immune suppressant 
drug therapy Syrjala et al (2004) found that the mean T score for the COWA 
(based on a population norm set at 50, with a standard deviation SD of ± 10) 
declined by 5 units (0.5SD) from pretransplanation to 80 days 
posttransplanation. Since a change of 0.5SD is considered standard clinical 
criteria for a medium effect size, we based our calculation of the power for 
the COWA upon a standard deviation of the difference score between 


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baseline and follow up of a 5-point performance decline. Therefore, a total 
of 65 patients will yield a probability of 80 percent that the proposed study 
will detect a treatment difference of 5 units in COWA at a two-sided 0.05 
significance level. To account for possible dropouts, we will recruit 74 
patients. 
16.3 Data Integrity: Data will be stored in REDCap, a database secured by the 
University of Minnesota. All data will be double entered by trained study 
staff. Specimens will be stored in the -80 freezer in lab 522C, 717 Delaware 
Street SE. Data and specimen will be kept until the completion and 
publication of final manuscripts. Primary investigators and study staff with 
proper training will have access to the data and specimens. Video (i.e., 
tremor assessments) and audio (cognitive testing/language) recordings will 
be stored on a University of Minnesota/HIPAA-approved encrypted server. 
17.0 Confidentiality 
17.1 Data Security: Study data will be maintained in source documents and case 
report forms (CRFs). Source documents will be maintained in paper and 
electronic formats and CRFs will be maintained electronically. 
Paper source documents will be kept in research offices. Access to the 
research offices is restricted. The suite can only be entered via card swipe or 
key pad access. All subject information recorded on paper is kept in a source 
binder and kept within file cabinets and shelving unites within the office. 
Electronic source documentation (labs, reports from physicals, etc) will 
either be stored in the subject EMR, EPIC, or as PDF files on the 
Department of Surgery’s secure, encrypted server, which part of the 
Academic Health Center’s (AHC) server. Access to all electronic data is 
password protected and all data are encrypted. 
A copy of the consent form will be placed in subjects’ medical record and 
study information will be included in subjects’ research window in EPIC per 
University requirements. This is included in the confidentiality section of 
the study consent form. 
Direct identifiers will be maintained locally both during and after this study. 
All documents that include these direct identifiers will only be kept locally 
at UMMC. Any information (CRFs or other reports) that is sent to the study 
sponsor will have PHI redacted. 
A unique subject number will be assigned to each participant. Monitors 
from the study sponsor, University oversight committees, regulatory 
authorities (FDA), or other regulatory bodies will have access to subject 
source documentation with data identifying study subjects during site 
monitoring or auditing visits. This information is included in the 
“Confidentiality” section of the consent form. 


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The study team will maintain a key which links the study code/identification 
number and subject initials to the subject’s name and medical record 
number. 
No directly identifying information will be maintained longer than 
necessary. Written and electronic records, reports, and data will be retained 
on site at the UMMC as per local, or at least two years after study 
completion or the study is terminated, whichever is longer. 
 
18.0 Provisions to Monitor the Data to Ensure the Safety of 
Participants: 
 
18.1 Data Integrity Monitoring: This study will be monitored 
according to GCP guidelines. The investigator will allocate time 
for such monitoring activities. The investigator will also ensure 
that the monitor or other compliance or quality assurance reviewer 
is given access to all the above noted study-related documents and 
study related facilities and has adequate space to conduct the 
monitoring visit. Additionally, case report forms will be 
periodically reviewed by the study team  
18.2 Data Safety Monitoring: All subjects have been recruited from 
Dr. Matas’ patient population and have regularly scheduled clinic 
visits to assess their health post-transplant. Tacrolimus levels are 
taken by Fairview staff and they have a protocol in place if a 
critical result is found. If randomized to XR group, physicians 
follow on-label dosing and monitoring guidelines.  
The monitoring plan will be conducted by the Principal 
Investigators and the Study Team. The monitoring plan will 
address the following: enrollment, adverse events, outcome data, 
protocol non-compliance, and new and relevant information to the 
study participants. Study coordinators will collect AEs and SAEs 
via EPIC and through conversation with the subjects during study 
visits. Study coordinators will record any AEs on CRFs and on 
CTSI provided AE log sheet. They will then report AEs and SAEs 
in a timely manner, according to GCP guidelines to the PIs and the 
IRB, when necessary. Unexpected SAEs are to be reported to the 
IRB at most 24 business hours after the event and expected AEs 
will be reported annually with the continuing reviews.  
Additionally, subjects may be removed from the study if 
determination by the treating physician deems there is a reason to 
significantly alter the subject’s drug regiment at any time during 
the study, including switching to an alternate immunosuppressant.  
 
19.0 Provisions to Protect the Privacy Interests of Participants 


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19.1 Protecting Privacy: If a potential participant is approached in person, the 
consent discussion will take place in a private room. By discussing the study 
in private, no information regarding the study and subsequently the subject 
can be heard by others in the clinic. Distractions will be kept to a minimum. 
If a potential participant is approached via mail and later by phone, the 
research team will verify that they are talking to the correct person over the 
phone. The study team will not leave messages containing PHI. If the study 
team leaves a message, they will only state that they are calling about study 
information that was sent in the mail, and ask for the potential participant to 
call them back. 
19.2 Access to Participants: All members of the research team will have access to 
the participants’ EMR in EPIC. Data will be extracted from the participants’ 
standard of care treatment in the EMR, so access is necessary to obtain this 
information. All study participants have a treating relationship with the 
principal investigator, and will likely maintain a treating relationship with 
the co-PI, Dr. Matas, after study participation. 
20.0 Compensation for Research-Related Injury 
20.1 Compensation for Research-Related Injury: N/A: The cognitive, motor and 
subjective testing and single blood draws present minimal risk to 
participants, as does, in the case of those patients in the XR group, switching 
from the IR to the XR tacrolimus formulation, which is often done in regular 
clinical practice. Participants will be monitored by the co-PI, Dr. Matas. 
21.0 Consent Process 
21.1 Consent Process (when consent will be obtained): 
As stated earlier in the application (section 12.0) the consent process, in 
accordance with SOP HRP-090, will begin either with a letter and the 
consent form sent to potential participants in the mail followed by a phone 
call or approaching a potential participant at a standard of care appointment 
in the clinic or hospital. After this initial approach, the study team will work 
with the subject to schedule an initial study visit. The study subject will be 


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encouraged to review the consent form and discuss the study with friends and family prior 
to the initial study visit. The time between initial approach will give subjects time to 
consider study participation and contact the research team with any questions. 
At this initial study visit, the consent form will be reviewed in detail with 
the study subject in a private clinic room and any questions will be 
answered. Subjects will be told that participation is voluntary and they may 
end their participation at any time without affecting their relationships with 
clinical or study staff. 
Subjects will be given time during the initial study visit to consider the 
study. If a subject joins the study, a copy of the consent form will be made 
and given to the subject. Study assessments will only begin after written 
documentation of consent is obtained. 
 
21.2 Waiver or Alteration of Consent Process (when consent will not be 
obtained): N/A 
21.3 Non-English Speaking Participants: N/A 
21.4 Participants Who Are Not Yet Adults (infants, children, teenagers under 18 
years of age): N/A 
21.5 Cognitively Impaired Adults, or adults with fluctuating or diminished 
capacity to consent: N/A 
21.6 Adults Unable to Consent: N/A 
22.0 Setting 
22.1 Research Sites: All research activities will be performed at the University of 
Minnesota Medical Center in the Clinics and Surgery Center or via mail. 
23.0 Multi-Site Research 
N/A 
24.0 Resources Available 
24.1 Resources Available: SOT Registry currently has approximately 3,000 
living kidney transplant recipients that were transplanted at the University of 
Minnesota. Many of these recipients will be eligible for the study, for which 
we require 65 completers. 
To assist with clinical trial management, the PI is utilizing services from the 
Surgery Clinical Trials Office (SurgCTO). SurgCTO is a central office in 
the Department of Surgery at the University of Minnesota designed to 
support the management and conduct of clinical research while promoting 
compliance. This is accomplished through standardizing the approach to 
clinical research across various divisions in the Department of Surgery, 
supporting investigators through regulatory and operational assistance, and 
providing enhancements in study management and oversight. SurgCTO will 


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provide assistance with study coordination and project, regulatory, data, and 
financial management of the trial. 
25.0 References 
Ayres RCS, Dousset B, Wixon S, et al. Peripheral neurotoxicity with tacrolimus. Lancet. 
1994;343:862-863. 
 
Barraclough KA, Isbel NM, Johnson DW, et al. Once- versus twice-daily tacrlimus: are 
the formulations truly equivalent? Drugs. 2011;71(12):1561-77. 
 
Bechstein, WO. Neurotoxicity of calcineurin inhibitors: impact and clinical 
management. Transp Int 2000;13:313-326. 
 
Bunnapradist S, Ciechanowski K, West-Thielke P, et al. Conversion from twice-daily 
tacrolimus to once-daily extended release tacrolimus (LCPT): the phase III randomized 
MELT trial. Am J Transplant. 2013;13(3):760-769. 
 
Bushara KO, Malik T, Exconde RE. The effect of levetiracetam on essential tremor. 
Neurology 2005;64;1078-1080. 
 
Caligiuri MP, Tripp RM. A portable hand-held device for quantifying and standardizing 
tremor assessment. Journal of Medical Engineering and Technology. 2004; 28(6):254- 
262. 
 
Cheng, CY, Lin, BYJ, Chang KH, Wu MJ. Awareness of memory impairment increases 
the adherence to immunosuppressants in kidney transplant recipients. Transplant 
Proceedings. 2012;44:746-748. 
 
DiMartini A, Fontes P, Dew MA, Lotrich FE, DeVera, M. Liver Transpl. 2008; 14(6): 
815–822. 
 
Fahn, S. et al. 1988. In Parkinson’s Disease and Movement Disorders, eds. Jankovic, J. et 
al., pp. 225-234. Baltimore: Urban & Schwarzenberg 
Gijtenbeek J et al. Cyclosporine neurotoxicity: a review. J Neurol, 1999;246: 339-346. 
Goodglass H, Kaplan E. 1983. The Assessment of Aphasia and Related Disorders. 
Philadelphia: Lea and Febiger 
 
Grinyo J, et al. An integrated safety profile analysis of belatacept in kidney transplant 
recipients. Transplantation 2010;12:1521-7. 
 
Guarinio M, Stracciari A, Pazzaglia P. Neurological complications of liver 
transplantation. J Neurol. 1996;243:137-142. 
 
Harclarek M, Williamson JB, Biedunkiewicz B, Lichodziejewska-Niemierko M. Debska- 
Slizien A, Rutkowski B. Risk factors for selective cognitive decline in dialyzed patients 


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with end-stage renal disease: evidence from verbal fluency analysis. J Int Neuropsychol 
Soc 2012;18(1):162-7. 
 
Kirschbaum C, Pirke KM, Hellhammer, DH. The 'Trier Social Stress Test'--a tool for 
investigating psychobiological stress responses in a laboratory setting. 
Neuropsychobiology, 1993;28: 76-81. 
 
Kockelmann E, Elger CE, Helmstaedter C. Significant improvement in frontal lobe 
associated neuropsychological functions after withdrawal of topiramate in epilepsy 
patients. Epilepsy Res 2003; 54:171-8. 
 
Marino SE, Pakhomov SVS, Han SM, Ding M, Eberly L, Loring DW, Hawkins-Taylor 
C, Anderson K, Rarick JO, Leppik IE, Cibula J, Birnbaum AK. Topiramate’s effect on 
linguistic behavior, verbal recall and working memory. Epilepsy and Behavior, [epub 31 
May 2012] http://dx.doi.org/10.1016/j.yebeh.2012.04.120. 
 
Martina M, Mozrzymas JW, Boddeke HW, Cherubim E. The calcineurin inhibitor 
cyclosporine A-cyclophilin A complex reduces desensitization of GABA-mediated 
responses in acutely dissociated rat hippocampal neurons. Neurosci Lett. 1996;215;95-98. 
 
McDonald JW, Goldberg MP, Gwag BJ, et al. Cyclosporine induces neuronal apoptosis 
and selective oligodendrocyte death in cortical cultures. Ann Neurol. 1996;40:750-758. 
 
Meador KJ, Loring DW, Abney OL, Allen ME, Moore EE, et al. Effects of 
carbamazepine and phenytoin on EEG and memory in healthy adults. Epilepsia. 
1993;34:153-7. 
 
Meador KJ, Loring DW, Moore EE, Thompson WO, Nichols ME, et al. Comparative 
cognitive effects of phenobarbital, phenytoin, and valproate in healthy adults. Neurology 
1995;45:1494-9. 
 
Meador KJ, Loring DW, Hulihan JF, Kamin M, Karim R. Differential cognitive and 
behavioral effects of topiramate and valproate. Neurology 2003;60;1483-1488 
 
Pakhomov, S., Marino, SE., Birnbaum, AK. Quantification of speech disfluency as a 
marker of medication-induced cognitive impairment: An application of computerized 
speech analysis in neuropharmacology. Computer Speech and Language (Special Issue 
on Natural Paralinguistics), 2013;27:116-134. 
 
Rostaing L, Bunnapradist S, Grinyo JM, et al. Novel once-daily extended-release 
tacrolimus versus twice-daily tacrolimus in de novo kidney transplant recipients: Two- 
year results of Phase 3, double-blind, randomized trial. Am J Kidney Dis. 
2016;67(4):648-659. 
 
Sander M., Lyson T, Thomas GD, Victor RG. Sympathetic neural mechanisms of 
cyclosporine-induced hypertension. Am J Hypertens. 1996;9:121S-138S. 


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Stoltenburg-Didinger G, Boegner F. Glia toxicity in dissociated cell cultures induced by 
cyclosporine. Neurotoxicology. 1992;13:179-184. 
 
Syrjala KL, Dikmen S, Langer SL, Roth-Roemer S, Abrams JR. Neuropsychologic 
changes from before transplantation to 1 year in patients receiving myeloablative 
allogeneic hematopoietic cell transplant. Blood 2004;104:3386-3392. 
 
Thompson CB, June CH, Sullivan KM, Thomas ED. Association between cyclosporine 
neurotoxicity and hypomagnesia. Lancet. 1984;2:1116-1120. 
 
Vincenti F, et al. Three year outcomes for BENEFIT, a randomized, active-controlled, 
parallel-group study in adult kidney transplant recipients. Am J Transplant 2012;12:210- 
217. 

ICF_001.pdf: 
Consent Form 
NCT03437577 
Version 3.0, dated 04/26/2018                   Page 1 of 10 
 
 
 
Title of Research Study:  
Comparison of the cognitive and motor effects of treatment 
between an immediate- and extended-release tacrolimus 
(Envarsus® XR) based immunosuppression regimen in kidney 
transplant recipients  
 
Researcher Team Contact Information: For questions about research appointments, the 
research study, research results, or other concerns, call the study team at:  
 
Researchers Name: Susan Marino, 
PhD (PI); Arthur Matas, MD (co-PI) 
Phone Number: 612-624-2964;612-
625-5151 
Email Address: marin007@umn.edu; 
matas001@umn.edu 
Study Staff: Surgery Clinical Trials Office (SurgCTO) 
Phone Number: 612-624-7463 
Email Address: surgcto@umn.edu 
 
Sponsored By: 
 
Veloxis Pharmaceuticals 
 
 
 
 
1001 Winstead Drive, Suite 310 
 
 
 
 
Cary, North Carolina 27513 
 
 
 
 
919-591-3090 
 
Financial Interest Disclosure:  The following disclosure is made to give you an opportunity to 
decide if this relationship will affect your willingness to participate in this research study: 
 
If your doctor is also the person responsible for this research study, please note that he is 
interested in both your clinical care and the conduct of this research study. You have the right to 
discuss this study with another person who is not part of the research team before deciding 
whether to participate in the research. 
 
What is research?  
 
Doctors and researchers are committed to your care and safety. There are important differences 
between research and treatment plans: 
 
 
 
 
● The goal of research is to learn new things in order to help groups of people in the 
future. Researchers learn things by following the same plan with a number of 
participants, so they do not usually make changes to the plan for individual research 
participants. You, as an individual, may or may not be helped by volunteering for a 
research study. 
● The goal of treatment is to help you get better or to improve your quality of life. Doctors 
can make changes to your treatment plan as needed. 
 
 
 


Consent Form 
NCT03437577 
Version 3.0, dated 04/26/2018                   Page 2 of 10 
 
 
 
What should I know about a research study? 
● Someone will explain this research study to you. 
● Whether or not you take part is up to you. 
● You can choose not to take part. 
● You can agree to take part and later change your mind. 
● Your decision will not be held against you. 
● You can ask all the questions you want before you decide. 
 
Why am I being asked to take part in this research study? 
You are being asked to take part in this research study because you are between 18 and 65 years 
of age and have had a kidney transplant after which you were placed on the anti-rejection 
(known as an “immunosuppressant”) medication, tacrolimus. 
 
Why is this research being done? 
The purpose of this study is to find out if there is a difference between how two different 
formulations of tacrolimus, one that is taken twice a day (immediate release) and the other that 
is taken once a day (extended release), affect your thinking, motor function, and how well you 
feel in general.  
 
Though tacrolimus is one of the most frequently used medications to prevent the body from 
rejecting the transplanted kidney, like similar anti-rejection drugs that suppress the immune 
system, it may cause unwanted side effects such as memory problems, confusion, and tremor in 
approximately 10-28% of patients. 
  
How long will the research last? 
We expect that you will be in this research study for approximately eight (8) months. 
 
Number of Participants 
This study is only being conducted at the University of Minnesota. We expect about 74 people to 
participate. 
 
What happens if I say “Yes, I want to be in this research”? 
If you agree to participate in this study, we would ask you to complete the following tasks listed 
below. All of the visits will occur at University of Minnesota Health Clinics and Surgery Center, 
909 Fulton St SE, Minneapolis, MN 55455. 
 
If you do choose to sign consent, your doctor or another authorized member of the research 
team will also sign this consent, confirm you are suitable to take part in this study and collect the 
following information: 
 
 


Consent Form 
NCT03437577 
Version 3.0, dated 04/26/2018                   Page 3 of 10 
 
 Demographics – information such as your age, gender and ethnicity.  
 The medical history related to your renal disease. 
 Any treatments for your renal disease 
 We would then ask you to do the following:  After you receive your transplant and, as 
part of your standard care, are placed on the immunosuppressant tacrolimus, cognitive 
and motor function testing will be administered by the study coordinator on five (5) 
separate occasions (i.e., visits). Each visit, which may coincide with your regularly 
scheduled clinic visit, should not last longer than one (1) hour. The testing will occur as 
follows: 
 
Visit 1 (Pre-Baseline) can occur no sooner than two (2) to three (3) months after your 
transplant and after being placed on immediate-release tacrolimus.  The purpose of this visit 
is to familiarize you with the instructions and nature of the cognitive and motor function 
tests that you will be taking four (4) more times over the course of the study.  Visit 1 should 
last less than one (1) hour, after which the study coordinator will schedule you for Visit 2 
(Baseline).  
 
Visit 2 (Baseline) will occur no more than 60 days prior to Visit 1. One (1) 10-ml (approx. 2 
teaspoons) blood sample will be collected, which is standard care if the visit coincides with a 
regularly scheduled clinical visit. If you agree, a portion of this blood sample will be used to 
see if you have variations of specific genes that are known to affect how the drug works in 
your body.  The study coordinator will then administer the cognitive and motor function 
tests (see “Cognitive and motor testing” below), after which you will be asked to fill out self-
report measures of health-related quality of life.  The testing session should take 
approximately 30-45 minutes to complete. After the testing, you will be randomly assigned 
to either:  a) the group that will remain on immediate-release tacrolimus (twice daily) for the 
duration of the study (IR group) or b) be switched by your physician to the extended-release 
(once daily: Envarsus®XR) formulation of tacrolimus (XR group) for the remainder of the 
study. 
 
Envarsus®XR is an FDA approved form of the anti-rejection drug, tacrolimus, for people who 
have had a kidney transplant, that is taken once daily.  It has been shown to be as effective 
as immediate-release, twice-daily, tacrolimus and poses no additional risks when dosed and 
taken as prescribed by your doctor.  You will be chosen to switch to Envarsus®XR by chance, 
like flipping a coin. 
Visit 3 will occur approximately six (6) weeks after Visit 2.  For both the IR and XR groups, a 
single blood sample (approx. 2 teaspoons) will be collected.  The study coordinator will then 
administer alternate versions of the same cognitive and motor function tests you were given 
during Visit 2. You will once again be asked to complete self-report measures of health-
related quality of life.   
Visit 4 will occur approximately six (6) weeks after Visit 3.  The same procedures will be 


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followed as in Visit 3. 
Visit 5 will occur approximately 12 weeks after Visit 4.  The same procedures will be followed 
as in Visit 3. 
You will be in this study for approximately eight (8) months. 
A total of approximately eight (8) teaspoons of blood will be collected over the entire study. 
 Cognitive and motor function testing:  At each visit, you will be administered a number of 
tasks that you will be asked to complete.  They will be conducted in a private clinic room.  
Some of these will require you to write, others will be given orally.  These tasks are 
designed to measure various aspects of your thinking and motor function and will take 
less than one (1) hour to complete.  Your responses to these tests will be recorded on an 
iPAD.  Tremor assessment will require video recording.  
What are my responsibilities if I take part in this research? 
It is expected that you will: 
 Take all your medication as prescribed 
 Show up at all visits at your scheduled time  
 Contact the study coordinator at least 24 hours prior to your scheduled visit if you need 
to reschedule 
 Put forth your best effort on all testing procedures 
What happens if I do not want to be in this research? 
You can decide not to participate in this study or leave the research at any time and it will not be 
held against you. You will continue receiving standard of care treatment from your physician. 
 
What happens if I say “Yes”, but I change my mind later. 
You can leave the research at any time. Leaving will not be held against you. 
 
If you withdraw your consent you will not be able to continue with the study. Your decision to 
take part or not take part will in no way affect your current or future treatment and your doctor 
will continue to treat you for your condition. If you decide to withdraw from the study, please 
contact the study coordinator, your doctor or one of his staff. If your condition changes during 
the study or you are not taking part in the study as we would expect you to, you may be 
withdrawn from the study without your consent. 
 
If you withdraw your consent, your study doctor will no longer use or disclose any more of your 
medical information. However, the information that has already been sent to the sponsor 
cannot be retrieved or destroyed and may be used as part of the study. 
 


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Choosing not to be in this study or to stop being in this study will not result in any penalty to you 
or loss of benefit to which you are entitled. Meaning, your choice not to be in this study will not 
negatively affect your right to any present or future medical treatment. 
 
You will be informed, in a timely manner, if any information becomes available that may affect 
your willingness to participate in this study.  
 
What are the risks of being in this study? Is there any way being in this study could be 
bad for me? 
This study does not involve any medical treatment other than the ones prescribed by your 
doctor, nor does it involve any additional medical procedures. If you are chosen to switch to 
Envarsus®XR, you will do so under the supervision of your doctor, who will be following FDA on-
label dosing and monitoring guidelines. There are no risks to the administration cognitive and 
motor function tests or self-report measures. 
 
What do I need to know about reproductive health and/or sexual activity if I am in this study? 
 
There is no harm to a pregnancy or fetus from administering the cognitive and motor testing 
battery though becoming pregnant or childbirth may influence the outcomes of the study. As 
part of standard care, a serum or urine pregnancy test is administered within seven (7) days 
prior to transplant and potential subjects must have a negative result.  Moreover, if 
heterosexually active, you agree to consistently use two forms of highly effective birth control 
(at least one of which must be a barrier method) which includes consistent and correct usage of 
established oral contraception, established intrauterine device or intrauterine system, or barrier 
methods of  contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with 
spermicidal foam/gel/film/cream/suppository, starting at screening and throughout the study 
period and for 90 days after the final study drug administration. 
 
If you are considered to be postmenopausal (defined as at least 1 year without any menses), you 
are not required to use contraception while participating in this research study. 
 
If you become pregnant while participating in this research study or for three (3) months after 
you complete the study, it is important that you tell the study doctor or other research team 
member immediately.  You may be required to stop participating in this study. 
 
If you are female, you must agree not to breastfeed or to donate ova starting at screening and 
throughout the study period, and for 90 days after the final study drug administration. 
 
Will it cost me anything to participate in this research study? 
There is no cost to you, your private medical insurance (if any), or the public health insurance 
plan, for study procedures.  There will be no additional medical costs to you for taking part in 
this study outside any usual costs related to any visit to your doctor.  


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Will being in this study help me in any way? 
No one knows if there will be any benefit to you from this study. We cannot promise any 
benefits to you or others from your taking part in this research. However, we hope that the 
information we learn from this study can be used in the future to help other kidney transplant 
recipients who are taking the anti-rejection medication, tacrolimus. 
 
What happens to the information collected for the research? 
Efforts will be made to limit the use and disclosure of your personal information, including 
research study and medical records, to people who have a need to review this information. We 
cannot promise complete secrecy. Organizations that may inspect and copy your information 
include the IRB and other representatives of this institution. In addition, other individuals such 
as monitors, auditors and representatives from the sponsor company, or regulatory authorities 
(such as the US Food and Drug Administration – US FDA) may also need access to your medical 
information. We will do everything we can to make sure that your medical information is kept 
confidential.   
 
We will not ask you about child [or elder] abuse, but if you tell us about child [or elder] abuse or 
neglect, we may be required or permitted by law or policy to report to authorities. 
 
You will be identified by a number on any forms used for this study and your personal 
information relating to this study will be kept in a secure location by the study team for a 
minimum of two years after completion of the research study. 
 
You have the right to check your study records and request changes if the information is not 
correct. 
 
The sponsor, monitors, auditors, the IRB, the University of Minnesota Research Compliance 
Office and other University compliance units, the US Office of Research Integrity (ORI), the US 
Office for the Protection of Human Research Protections (OHRP), the US Food and Drug 
Administration (FDA) may be granted direct access to your medical records to conduct and 
oversee the research.  By signing this document you are authorizing this access.  We may publish 
the results of this research, but your identity will remain confidential.  Only aggregated data will 
be published.   A description of this clinical trial will be available at http://www.ClinicalTrials.gov 
, as required by U.S. Law.  This website will not include information that can identify you.  At 
most, the website will include a summary of the results. You can search this website at any time. 
 
Your consent is required to take part in this study. By signing this information and consent form, 
you consent to the collection, access, use and disclosure of your information as described above. 
Your consent does not have an expiration date. You do not have to sign this information and 
consent form, but if you do not, you will not be able to take part in this research study. You will 
be able to withdraw your consent at any time, by communicating with your study team; in this 


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case you will stop taking part in this study.  
 
While every effort will be made to protect the privacy of your information, absolute 
confidentiality cannot be guaranteed. This does not limit the duty of the researchers and others 
to protect your privacy. 
 
Will anyone besides the study team be at my consent meeting? 
You may be asked by the study team for your permission for an auditor to observe your consent 
meeting (or a recording of your consent meeting).  Observing the consent meeting is one way 
that the University of Minnesota makes sure that your rights as a research participant are 
protected. The auditor is there to observe the consent meeting, which will be carried out by the 
people on the study team. The auditor will not record any personal (e.g., name, date of birth) or 
confidential information about you. The auditor will not observe your consent meeting (or a 
recording of your consent meeting) without your permission ahead of time. 
 
Who do I contact if I have questions, concerns or feedback about my experience? 
This research has been reviewed and approved by an Institutional Review Board (IRB) within the 
Human Research Protections Program (HRPP). To share feedback privately with the HRPP about 
your research experience, call the Research Participants’ Advocate Line at 612-625-1650 or go to 
https://research.umn.edu/units/hrpp/research-participants/questions-concerns. You are 
encouraged to contact the HRPP if:  
 
● Your questions, concerns, or complaints are not being answered by the research team. 
● You cannot reach the research team. 
● You want to talk to someone besides the research team. 
● You have questions about your rights as a research participant. 
● You want to get information or provide input about this research. 
 
Will I have a chance to provide feedback after the study is over? 
After the study, you might be asked to complete a survey about your experience as a research 
participant. You do not have to complete the survey if you do not want to. If you do choose to 
complete the survey, your responses will be anonymous. 
 
If you are not asked to complete a survey after the study is over, but you would like to share 
feedback, please contact the study team or the Human Research Protection Program (HRPP). 
See the “Who Can I Talk To?” section of this form for study team and HRPP contact information. 
 
Can I be removed from the research without my OK? 
The person in charge of the research study or the sponsor can remove you from the research 
study without your approval. Possible reasons for removal include failure to show up for study 
visits; unwillingness to complete the testing battery; pregnancy; determination by treating 
doctor that there is a reason to significantly alter your drug regimen at any time during the 
study, including switching to an alternate immunosuppressant.  


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What else do I need to know? 
In the event that this research activity results in an injury, treatment will be available, including 
first aid, emergency treatment and follow-up care as needed. Care for such injury will be billed 
in the ordinary manner to you or your insurance company.  If you think that you have suffered a 
research related injury, let the study physicians know right away. 
 
A federal law, called the Genetic Information Nondiscrimination Act (GINA), generally makes it 
illegal for health insurance companies, group health plans, and most employers to discriminate 
against you based on your genetic information. This law generally will protect you in the 
following ways:  
● Health insurance companies and group health plans may not request your genetic 
information that we get from this research.  
● Health insurance companies and group health plans may not use your genetic 
information when making decisions regarding your eligibility or premiums.  
● Employers with 15 or more employees may not use your genetic information that we 
get from this research when making a decision to hire, promote, or fire you or when setting the 
terms of your employment.  
 
Be aware that this federal law does not protect you against genetic discrimination by companies 
that sell life insurance, disability insurance, or long-term care insurance. 
 
Will I be compensated for my participation?  
If you agree to take part in this research study, we will pay you $50 for each of the five (5) study 
sessions (a total of $250 if you complete all 5 visits) for your time and effort. You will also be 
eligible for up to a total of $200 in travel expenses (reimbursed at $0.535 per mile round trip) for 
Visits 2-5.  If you cannot continue or choose to drop out of the study, your payment will be 
prorated for the sessions completed.  Compensation will be issued from the University of 
Minnesota. 
 
Use of Identifiable Health Information 
We are committed to respect your privacy and to keep your personal information confidential.  
When choosing to take part in this study, you are giving us the permission to use your personal 
health information that includes health information in your medical records and information 
that can identify you. For example, personal health information may include your name, 
address, phone number or social security number. Those persons who get your health 
information may not be required by Federal privacy laws (such as the Privacy Rule) to protect it. 
Some of those persons may be able to share your information with others without your separate 
permission. Please read the HIPAA Authorization form that we have provided and discussed.  
 
The results of this study may also be used for teaching, publications, or for presentation at 
scientific meetings.   
 


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Optional Elements: 
The following research activities are optional, meaning that you do not have to agree to them in 
order to participate in the research study. Please indicate your willingness to participate in these 
optional activities by placing your initials next to each activity. 
 
I agree       I disagree 
 
 
 
 
 _______ 
 
The researcher may audio or video record me for use in scholarly 
 
      ______ 
presentations or publications. My identity may be shared as part of this 
 
 
 
activity, although the researcher will attempt to limit such 
 
 
 
identification. I understand the risks associated with such identification. 
 
_______ 
 
The researcher may contact me in the future to see whether I am 
 
 
 
interested in participating in other research studies by the Principal 
 
    _______ 
Investigator of this study. 
 
_______ 
 
The researcher may retain any leftover blood samples taken 
 
 
 
during the study. These samples may be used for other research not 
 
 
 
related to this study. These samples will be retained in non-identifiable 
 
 
 
form, meaning that there will be no information associated with the 
 
    ________ 
blood or samples that will allow anyone to readily ascertain my identity. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Signature Block for Capable Adult: 
If you choose to participate in the genetics portion of the study we will not store the 
genetics sample indefinitely; in addition, no testing other than for specific RNA or DNA 
will be done unless we have contacted you and received permission to do so. Please 
check your preference below:  
 
_____ YES, it is okay to collect a blood sample for genetics testing, as described above.  
_____ NO, do not collect a blood sample for genetics testing, as described above.  
 
Your signature documents your permission to take part in this research.  You will be provided a 
copy of this signed document. 
 
_______________________________________________     
_________________ 
Signature of Participant                                                                 
Date 
 
_______________________________________________ 
Printed Name of Participant 
 
 
 
 
____________________________________________          
__________________ 
Signature of Person Obtaining Consent                                     
  Date 
 
____________________________________________ 
Printed Name of Person Obtaining Consent