Clinical trial NCT03270462
Conditions: Renal Transplant Patients
Sponsor: University of Colorado, Denver
Start date: 2017-12-01; Completion date: 2020-06-02
Enrollment: 20 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a pilot study documenting the neurotoxic side effects including tremors in patients with a stable graft who are receiving Tacrolimus following kidney transplantation. A standardized questionnaire will be used to document these symptoms.

Detailed description:
Immunosuppressive therapies have burdensome side effects which may lead to sub-therapeutic dosing and non-compliance.

This study provides renal transplant patients the opportunity for an alternative treatment using tacrolimus, with possible less Central Nervous Symptom (CNS) side effects. CNS side effects are one of the main reasons that patients complain about after having a kidney transplant while on tacrolimus (Prograf). The side effects can be debilitating and can affect the patient's overall well-being. In severe cases it may lead to non-compliance. The advantage of the study of using Envarsus is the ability to avoid these debilitating CNS side effects and afford better compliance with the patients taking the medicine.

Arms: arm 1: A form of the anti-rejection drug, tacrolimus, for people who have had a kidney transplant.
Interventions: intervention 1: Envarsus XR
Intervention descriptions: intervention 1: Pilot study documenting the neurotoxic side effects including tremors in patients with stable graft who are receiving Tacrolimus (Envarsus XR) following kidney transplantation. Standardized questionnaire will be used to document these symptoms.

Protocol documents:
Prot_SAP_000.pdf: 
Protocol 8/15/17 
Page 1 
COMIRB #: 17-0781 
 
Project Title: A pilot study of stable kidney transplant recipients taking tacrolimus 
with CNS symptoms  switched to Envarsus  
 
 
 
Principal Investigator:  
Laurence Chan, MD 
 
Version Date: August 15, 2017 
 
COMIRB #: 17-0781  
 
 
 
  
 
Hypotheses and Specific Aims:   
 
The use of once-daily Envarsus XR® (tacrolimus extended-release tablets) will have 
significant improvement in the patients reported CNS symptoms. 
 
Background and Significance: 
Graft survival in renal transplant patients has improved steadily over the last decades as a 
result of improved immunosuppressive therapies. Immunosuppressive regimens continue 
to have side effects which patients find burdensome and which may lead to sub-therapeutic 
dosing and non-compliance by the patient. 
 
Patients on different immunosuppressant regimens may be bothered by Central Nervous 
System (CNS) side effects or report better health-related quality of life (HRQL). We will 
evaluate the reliability and validity CNS-specific outcome instruments (CNS Symptom 
Rating Scale; higher scores = increased severity) and Quality of Life Index (higher scores 
= better CNS-specific HRQL) in renal transplant patients. 
 
Neurotoxicity in transplant patients occurs in >40-50% of the patients treated with 
tacrolimus (1). Tacrolimus was approved by the US Food and Drug Administration (FDA) 
in April of 1994 for the prophylaxis of organ rejection in patients receiving allogeneic liver 
transplants under the brand name Prograf® (tacrolimus capsules, Astellas Pharma US, 
Inc.). 
 
The majority of the neurotoxicity events in tacrolimus treated transplant patients are 
headache and tremor, while less frequent and more severe neurotoxicity (encephalopathy, 
seizures) is also observed. (2) The current management of neurotoxicity varies by 
investigator and institution, but normally begins with a dose reduction of the tacrolimus, 
balancing increased risk of acute rejection and graft loss with the desire to improve the side 
effects observed for a given patient. (3, 4) In more severe cases, immunosuppressant 
regimens may be changed from tacrolimus to cyclosporine, an agent which also is 
associated with similar neurotoxicity and a reduced clinical effectiveness. Literature 
documents that the neurotoxicity is associated with peak tacrolimus concentrations in 
transplant as well as autoimmune diseases and shows that the neurotoxicity essentially 
abates when tacrolimus treatment is discontinued, providing proof that tacrolimus is a 
reversible neurotoxic agent. (5)  
 
 


Protocol 8/15/17 
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COMIRB #: 17-0781 
 
Envarsus XR (Veloxis Pharmaceuticals) is an extended-release formulation of 
tacrolimus designed for once-daily administration that has been developed utilizing 
Veloxis Pharma’s proprietary   MeltDose® drug-delivery technology (Veloxis 
Pharmaceuticals A/S, Hørsholm, DK). Envarsus XR is designed and has been 
approved by FDA to deliver equivalent whole blood concentrations to the immediate-
release formulation of tacrolimus over the 24-hour dosing interval.   As previously 
reported, The ASERTAA trial demonstrated that patients on Envarsus achieved 
therapeutic drug levels with a 30% lower peak concentration and 20% lower average dose 
compared to tacrolimus immediate-release regardless of genotype status. Importantly, 
patients expressing the CYP3A5*1 genotype on tacrolimus immediate-release reached a 
peak concentration as high as 26 ng/mL.  
 
This high peak levels might related to the high incidence of CNS related side effects. The 
PK data collected for Envarsus XR® demonstrated similar exposure, lower Cmax, 
prolonged Tmax, and increased bioavailability when compared to tacrolimus immediate-
release.  
 
The study is designed in such a way that patient will report objectively their experience 
related to CNS symptoms using a standard questionnaire before staring on Envarsus XR. 
The OPTN/SRTR 2011 Annual Data Report shows that approximately 90% of 
Recipients transplanted in 2010 were initiated on tacrolimus as part of their 
immunosuppression regimen and were continuing to take tacrolimus at one-year post-
transplant.  
 
Envarsus XR is designed to deliver equivalent whole blood concentrations to the 
immediate-release formulation of tacrolimus over the 24-hour dosing interval. This 
formulation works better with the enzyme systems in the lower gastrointestinal (GI) tract, 
facilitating a constant stable absorption of tacrolimus through the GI tract leading to 
improved bioavailability and constant plasma levels over the full day.  
 
In a prior study in stable renal transplant recipients converted from Prograf to Envarsus XR 
(LCP-Tacro), showed 30% greater bioavailability compared to Prograf, as well as a 
steadier and more consistent concentration time profile over 24 hours, and reduced peak-
to-trough fluctuations and swing compared to Prograf, with good tolerability and a robust 
AUC/Cmin correlation (correlation coefficients from 0.86 to 0.91). 
 
A Phase III study in stable renal transplant recipients converted from Prograf to Envarsus 
XR demonstrated non-inferior efficacy and similar safety for Envarsus XR compared to 
Prograf. Total daily Envarsus XR dose was about 20% lower than preconversion Prograf 
twice-daily dose.  
 
The Expanded access Study Envarsus 3007 conducted to provide patients the opportunity 
for an alternative tacrolimus treatment and/or continuation of therapy for patients 
previously on Envarsus clinical studies.  
 
Envarsus XR tablets are an extended-release formulation of tacrolimus, intended for once-
daily administration, the anticipated risks of Envarsus XR are expected to be the same as 
for Prograf though the severity and frequency may be less due to reduced maximal blood 


Protocol 8/15/17 
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COMIRB #: 17-0781 
 
concentrations. Based on the Prograf package, insert and the overall experience with 
Prograf in solid organ transplantation the anticipated risks from Envarsus XR include: 
nephrotoxicity, new onset diabetes mellitus, hypertension, neurotoxicity, hyperkalemia, 
and latent viral infections. Given the low peak tacrolimus levels when taking Envarsus, we 
might expect less CNS side effects. (6.7). 
 
Overall, the study would provide renal transplant patients the opportunity to an alternative 
tacrolimus treatment with possible less CNS side effects.  
 
CNS side effects are one of the main reasons that patients complain after having a kidney 
transplant while on tacrolimus (Prograf). The side effects can be debilitating and can affect 
patients overall well-being. In severe cases may lead to non-compliance. So the advantage 
of the study of using Envarsus XR for the patients is the ability to avoid those debilitating 
CNS side effects, like tremor, headache, and difficulty in concentrating and sleep 
disturbances. Envarsus XR has been approved and has similar efficacy as tacrolimus 
(Prograf, so there is no disadvantages or risk to the patients. 
 
III. Preliminary Studies/Progress Report:   
 
This is the first study on Envarsus XR using Patients reported questionnaire 
methodology to examine the CNS side-effects of Tacrolimus (Prograf). There 
is no need for a cross over study and each patient will serve as its own control. 
The design and methodology will be similar to the PROGIS study that was 
published by Chan et al (8).  
 
Prior studies including the Phase III study in stable renal transplant recipients 
converted from Prograf to Envarsus XR demonstrated non-inferior efficacy 
and similar safety for Envarsus XR compared to Prograf. Total daily Envarsus 
XR dose was about 20% lower than preconversion Prograf twice-daily dose.  
Additional Expanded access Study Envarsus 3007 conducted to provide 
patients the opportunity for an alternative tacrolimus treatment and/or 
continuation of therapy for patients previously on Envarsus clinical studies. In 
addition to comparable efficacy and non-inferiority of Envarsus XR, there was 
better pharcokinetics and possible less CNS side effects. However, the studies 
were not specifically designed to test this hypothesis. 
 
IV. Research Methods 
 
Outcome Measure(s):   
This is a population-based, longitudinal, prospective, minimal risk interventional 
study of renal transplant patients in routine practice. This approach is designed to 
generate hypotheses (rather than test hypotheses) concerning the impact of current 
and newly emerging immunosuppressive regimens and decision-making on 
regimen tolerability, safety, patient co-morbidities, and graft and patient outcomes 
in the real world.  We expect patients will have improvement in quality of life 


Protocol 8/15/17 
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COMIRB #: 17-0781 
 
related to sleep disturbance and upper extremity fine motor skills/ADL.  
Tacrolimus drug levels, serum creatinine and other parameters related to graft 
function, graft function, and other adverse events will be documented during the 
study period.  Standard of care immunosuppression for kidney transplant recipients 
at UC Health is either Prograf twice a day or Envarsus XR once a day, Myfortic 
and steroids.  Serum creatinine and tacrolimus levels (drug level monitoring) is 
required for both Prograf and Envarsus XR and is standard of care for this 
population.   
 
Description of Population to be enrolled:   
 
Inclusion 
 Kidney transplant recipients with stable graft function will be switched from 
Prograf twice/day to Envarsus XR once a day per standard of care  
 More than 1 months post-transplant  
 18+ years of age with some CNS problems secondary to Prograf (tacrolimus) 
Exclusion 
 Multi-organ patients (kidney/pancreas, kidney/liver) 
 Evidence of graft rejection or treatment of acute rejection within 14 days prior to 
baseline visit 
 Inability to self-administer the QOL questionnaires 
 
 
Study Design and Research Method 
Pilot study documenting the neurotoxic side effects including tremors in patients with 
stable graft who are receiving Tacrolimus following kidney transplantation.  Standardized 
questionnaire will be used to document these symptoms.  Envarsus XR® will be provided 
to the subjects by Veloxis Pharmaceuticals (manufacture of the drug) for the duration of 
the study (6 months).  After a subject completes the study, they will continue taking 
Envarsus XR® through their insurance/self-pay.  
 
Description, Risks and Justification of Procedures and Data Collection Tools: 
After informed consent, the subject will complete the PROMIS questionnaire before 
switching to Envarsus XR.  Subjects will repeat questionnaires at 1 month and 6 months 
focusing on quality of life (QOL) questionnaire related to sleep disturbance and upper 
extremity fine motor skill/activities of daily living (ADL) 
Questionnaires 
 Sleep Disturbance-Short Form 8a 
 Upper Extremity Function (Fine Motor, ADL)-Short Form 
 Upper Extremity-Short Form 7a 
 Global Health Scale v1.2 
Review medical record for demographics, medical history (including kidney transplant) and 
other basic information:  
 vital signs,  


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 minimal lab collected as standard of care (serum creatinine, tacrolimus level) 
Adverse events 
Graft function 
    
Potential Scientific Problems:   
 
Each patient will serve as its own control. No scientific problem will be expected. 
Although the study is an open-label and no placebo group; but the patient reported 
outcomes will serve as its own control and any improvement in symptoms may not be 
placebo related as reported in previous studies using the same methodology.  
 
Data Analysis Plan:   
 
Research is conducted according to the ICH Harmonized Tripartite Guidelines for Good 
Clinical Practice and in compliance with the ethical principles of the Helsinki Declaration. 
Appropriate Institutional Review Board/Ethics Committee approval will be obtained prior 
to study initiation. Patients are eligible for participation if they are at least 18 years of age; 
willing to provide informed consent and adhere to study requirements; have received a 
renal transplant at least 1 month prior to the study enrollment; and have been on an 
immunosuppressive regimen including Tacrolimus (Prograf) for at least four weeks prior 
to enrollment. 
 
All analyses will be performed with SAS version 8.02 (SAS Institute, Cary NC). 
Demographic variables and clinical conditions will be evaluated by descriptive analyses. 
For the descriptive analyses, chi-square tests will be used to evaluate categorical data; t-
tests and analyses of variance (ANOVA) will be used to evaluate continuous data. Scoring 
– including imputations for missing data if necessary – will be performed according to 
each questionnaire's guidelines. 
 
Reliability refers to the consistency of items within an instrument, either over time or 
internally within the instrument. Internal consistency reliability is the extent to which all 
items measure the same construct; values are presented descriptively, on an internal level 
scale from 0 to 1.0, with higher scores indicating a more reliable (precise) instrument 
 
Summarize Knowledge to be Gained:   
 
Immunosuppressive therapies have burdensome side effects which may lead to 
sub-therapeutic dosing and non-compliance. 
 
The study will provide renal transplant patients the opportunity to an 
alternative tacrolimus treatment with possible less CNS side effects. CNS side 
effects are one of the main reasons that patients complain after having a kidney 
transplant while on tacrolimus (Prograf). The side effects can be debilitating 
and can affect patients overall well-being. In severe cases may lead to non-
compliance. So the advantage of the study of using Envarsus for the patients is 


Protocol 8/15/17 
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COMIRB #: 17-0781 
 
the ability to avoid those debilitating CNS side effects and afford better 
compliance with the patients taking the medicine. 
 
 
 
 
 
 
Study Calendar 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Procedure  
Baseline
M1 
M6/EOS
Consent 
X 
 
 
VS (BP, P, weight) 
X 
X 
X 
Serum creatinine 
X 
X 
X 
Tacrolimus level 
X 
X 
X 
Pregnancy test (as needed) 
X 
 
 
 
 
 
 
Global health questionnaire X 
X 
X 
Sleep Disturbance-Short 
Form 8a 
X 
X 
X 
Upper Extremity Function 
(Fine Motor, ADL)-Short 
Form 
 
X 
X 
X 
Upper Extremity-Short 
Form 7a 
 
X 
X 
X 
Switch to Envarsus 
X 
 
 
Adverse events 
 
X 
X 


Protocol 8/15/17 
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References: 
 
1.    Prograf® [package label]. Astellas Pharma US, Inc. Deerfield (IL); 2009 
 
2   Wijdicks EFM, Weisner RH,  Dahlke LJ,  Krom RAF.  FK5  06-induced 
Neurotoxicity in  Liver 
Transplantation. Ann Neurol 1994;35.498-501. 
 
3.    Appignani B, Bhadelia R, Blacklow S, Wang A, Roland S, Freeman R. Neuroimaging 
findings in patients on immunosuppressive therapy: experience with tacrolimus toxicity. 
Am J Roentgenol 1996; 
166: 683-688. 
 
4.    Reinohs M, Straube T, Baum P, Berrouschot J, Wagner A. Recurrent reversible 
cerebral edema after long term immunosuppression with tacrolimus. J Neurol 
2002;249:780-781. 
 
5.    Bechstein WO. Neurotoxicity of calcineurin inhibitors: impact and clinical 
management. Transpl Int. 2000;13:313-326. 
 
6.      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.. Rostaing L, Bunnapradist S, Grinyó JM, Ciechanowski K, Denny JE, 
Silva HT Jr, Budde K; Envarsus Study Group.. Am J Kidney Dis. 2016 Apr;67(4):648-59. 
doi: 10.1053/j.ajkd.2015.10.024.. PMID: 26717860 
 
 7  Switching STudy of Kidney TRansplant Patients with Tremor to LCP-TacrO 
(STRATO): an open-label, multicenter, prospective phase 3b study.  Langone A, Steinberg 
SM, Gedaly R, Chan LK, Shah T, Sethi KD, Nigro V, Morgan JC; STRATO 
Investigators..Clin Transplant. 2015 Sep;29(9):796-805. doi: 10.1111/ctr.12581. PMID: 
26113208 Free PMC Article. 
 
8.  Chan L, Mulgaonkar S, Walker R, Arns W, Ambuhl P, Schiavelli R. Patient-reported 
gastrointestinal symptom burden and health-related quality of life following conversion 
from mycophenolate mofetil to enteric-coated mycophenolate sodium. Transplantation. 
2006;81:1290–1297. doi: 10.1097/01.tp.0000209411.66790.b3. [PubMed] [Cross Ref]