Clinical trial NCT02956005
Conditions: Renal Transplant Recipients
Sponsor: Georgetown University
Start date: 2016-09-01; Completion date: 2018-09-01
Enrollment: 18 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to collect data prospectively on African American patients who are taking the immunosuppressant Envarsus post kidney transplant. We are looking to see if African American renal transplant recipients that receive Envarsus will have less tubular injury and calcenurin inhibitor toxicity compared with patients that receive tacrolimus IR.

African americans have the higher rates of CYP3A5 which is associated with the need of higher tacrolimus dose to achieve an adequate level and this many times is associated with signs and symptoms of tacrolimus toxicity such as tremors, headaches and neuropathies.

The retrospective cohort will be African American patients that will be matched by age, gender, type of kidney transplant (living vs deceased) and level of sensitization

Detailed description:

Arms: arm 1: Open Label; Envarsus XR started at the time of transplant. Initial dosing of 0.17mg/kg. Target trough level of 8-10 ng/mL
Interventions: intervention 1: ENVARSUS®
Intervention descriptions: intervention 1: ENVARSUS XR is a form of the anti-rejection drug, tacrolimus, for people who have had a kidney transplant

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Envarsus XR in African American Renal Transplant Recipients  
 
NCT Number: NCT02956005 
 
Date: 07/25/2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Study Protocol 
 
 
Title: Envarsus XR in African American Renal Transplant Recipients 
 
 
 
Introduction 
 
Tacrolimus is overwhelmingly used as an immunosuppressant in kidney transplantation, 
both early posttransplantation and as part of long-term maintenance regimens. While 
highly effective in preventing acute transplant rejection, tacrolimus has several limitations, 
including a narrow therapeutic window (necessitating drug monitoring and individual dose 
titration), interindividual variation in absorption, and low bioavailability of the currently 
widely used immediate-release tacrolimus (IR-Tac) twice-daily capsule formulation 
(Prograf; Astellas Pharma US, Inc).1 In addition, both the IR-Tac formulation and another 
extended-release once-daily tacrolimus formulation (Advagraf/Astagraf XL; Astellas 
Pharma US, Inc) are associated with similar peak concentrations2; unwanted tacrolimus-
associated neurologic adverse events (AEs) have been noted to happen or be most 
pronounced at peak serum tacrolimus blood concentrations. Additionally, the twice-daily 
formulation adds further pill burden to a patient population already encumbered with taking 
many long-term medications. Multiple daily drug dosing is associated with increased risk 
for nonadherence; this may result in acute rejection and, in severe cases, transplant failure.  
 
The medication LCP-Tacro (LCPT; Envarsus XR; Veloxis Pharmaceuticals) is an 
extended-release tablet formulation of tacrolimus with once-daily dosing that has been 
developed using a proprietary MeltDose drug delivery technology (Veloxis 
Pharmaceuticals), distinguishing LCPT from other once-daily extended-release tacrolimus 


products (eg, Astagraf XL). The MeltDose technology decreases a drug’s particle size to 
the smallest possible units as single molecules. Drug particle size critically affects drug 
dissolution and absorption; if particle size is smaller, the surface area of the drug increases 
and the drug will be dissolved more quickly, resulting in better absorption. Results of the 
MeltDose technology are increased absorption and bioavailability associated with LCPT 
tablets compared with other extended-release and IR tacrolimus formulations currently 
available. Phase 1 and phase 2 trials confirmed that LCPT enables broader absorption 
throughout the gastrointestinal tract and sustains consistent tacrolimus concentrations4. In 
addition, LCPT showed a lack of diurnal variability common with other formulations.  
 
Phase 2 trials of de novo and stable kidney and liver recipients showed a steadier and more 
consistent concentration-time profile over 24 hours, with reduced peak and peak-to-trough 
fluctuations for LCPT compared to IR-Tac, increased bioavailability of ∼30%, and 
comparable efficacy and safety profiles. A robust correlation between the area under the 
curve at 24 hours and the minimum concentration was also shown, indicating that 
therapeutic drug monitoring of minimum concentration as a measure of tacrolimus 
exposure can be applied to LCPT. A phase 3 conversion trial showed that LCPT had 
noninferior efficacy and comparable safety profile to IR-Tac, with lower doses (∼20% 
lower than IR-Tac overall and 30% lower in white patients) of LCPT5.  
 
 
Hypothesis 


African American renal transplant recipients that receive Envarsus will have less tubular 
injury and calcenurin inhibitor toxicity compared with patients that receive tacrolimus IR. 
 
Study Type/Design 
This is a case control study where a prospective cohort will be started de novo on Envarsus 
at the time of renal transplantation. 
 
Endpoints 
Primary endpoint is to determine the rate of calcineurin inhibitor toxicity as measured by 
surveillance kidney biopsies. 
Secondary endpoint is to determine the rate of development of donor specific antibodies of 
the patients treated with Envarsus vs the patients treated with immediate release tacrolimus. 
 
Patient Recruitment 
We will prospectively consent 100 African American patients that will be receiving kidney 
transplants at our center. This cohort will be matched with a retrospective cohort of African 
American renal transplant recipients who received renal transplant and were treated with 
immediate release tacrolimus. 
Exclusion criteria will include patients that are not African American and patients that are 
younger than 18 years old.  
 
Inclusion Criteria 
1. African American race 


2. Adult renal transplant recipients (>18 y/o) 
3. Previous adverse reaction or contraindication to the use of tacrolimus 
 
Exclusion Criteria 
1. Non African American race 
2. Less than 18 y/o (pediatric patients) 
3. Recipients of liver and small bowel transplants 
4. Adverse reaction to tacrolimus 
 
Statistical analysis: 
Data will be analyzed using standard statistical methods using chi square test, students T-
square test, kaplan-meyer curve. No statistical analysis has been performed to achieve 
adequate power as this an observational study. 
 
Treatment Overview 
Screening will be performed by the Principal Investigators during the kidney transplant 
evaluation clinics, during the wait list kidney transplant evaluation clinic and prior to a 
schedule kidney transplant surgery. 
 
Dosage and Administration of Envarsus XR 
Patients enrolled in the prospective arm of the study will be started on Envarsus XR at 
0.17mg/kg. The dose will be targeted to achieve a tacrolimus level between 8-10 ng/mL. 


The tacrolimus level will be modified depending on the results of the surveillance biopsy, 
BK and CMV viruses, and donor specific antibody studies.  
Laboratory Testing and Study Schedule 
Schematic diagram of data that will be obtained during study: 
 


 
 
Data to be obtained at time 0 on the prospective and retrospective cohort 
1. BMI 
Patient 
enrolled 
in study 
and 
started on 
Envarsus 
XR.  
A case 
match 
patient 
will be 
identified 
simultane
ously. 
Data to be 
obtained 
includes 
BMI, 
weight, 
sex, age, 
reason for 
chronic 
kidney 
disease,  
induction 
agent, 
crossmatc
h results, 
type of 
donor, 
donor 
age, 
donor’s 
end 
creatinine
, donor’s 
biopsy 
result  
and 
donor’s 
gender. 
Data to be 
obtained 
includes 
creatinine, 
proteinuri
a, 
tacrolimus 
level, 
diabetes, 
HTN, BK 
virus,  
CMV virus, 
donor 
specific 
antibody, 
infections, 
any 
hospital 
admission
s. 
Data to be 
obtained 
includes 
creatinine, 
proteinuri
a, 
tacrolimus 
level, 
diabetes, 
HTN, BK 
virus,  
CMV virus, 
donor 
specific 
antibody, 
infections, 
any 
hospital 
admission
s, kidney 
biopsy 
results 
from 
surveillanc
e biopsy. 
Data to be 
obtained 
includes 
creatinine, 
proteinuri
a, 
tacrolimus 
level, 
diabetes, 
HTN, BK 
virus,  
CMV virus, 
donor 
specific 
antibody, 
infections, 
any 
hospital 
admission
s. 
Data to be 
obtained 
includes 
creatinine, 
proteinuri
a, 
tacrolimus 
level, 
diabetes, 
HTN, BK 
virus, CMV 
virus. 
donor 
specific 
antibody, 
infections, 
any 
hospital 
admission
s, kidney 
biopsy 
results 
from 
surveillanc
e biopsy. 
Time O 
Time 1 month 
Time 3 months Time 6 months Time 12 months 


2. Weight 
3. Sex 
4. Reason for chronic kidney disease 
5. Induction agent 
6. Crossmatch results 
7. Type of donor 
8. Donor age 
9. Donor sex 
10. Donor end creatinine 
11. Donor’s biopsy result if available 
 
Data to be obtained at time 1 month, 3 month, 6 month and 12 month on the 
prospective and restrospective cohort 
1. Creatinine level 
2. Proteinuria 
3. Tacrolimus level 
4. Diabetes 
5. Blood pressure 
6. BK virus serum 
7. CMV virus PCR  
8. Donor specific antibody 
9. Biopsy results (at 3 and 12 months surveillance and any other additional for cause 
biopsy that the patient may have had) 


10. Infections 
11. Hospital admissions 
12. Blood transfusions (if any) 
 
Patient Monitoring and Evaluation 
Patients will have a kidney biopsy at time 0 (at the time of implantation and prior to 
reperfusion), 3 months and 12 months. If at any other time it is clinically necessary to 
perform another biopsy, it will be performed. 
 
 
 
Potential Pitfalls and Contingencies 
If a patient develops side effects that are attributed to tacrolimus, then the patient may have 
to be switched to another immunosupression regimen. 
 
References 
1. Prograf [prescribing information]. Northbrook, IL: Astellas Pharma US, Inc; 
September 2013. 
2. Zaltzman JS, Lai V, Schulz MZ, Moon KH, Cherney DZ..A randomized cross-
over comparison of short-term exposure of once-daily extended release tacrolimus 
and twice-daily tacrolimus on renal function in healthy volunteers. Transpl Int. 
2014 Dec;27(12):1294-302. doi: 10.1111/tri.12435. Epub 2014 Sep 29 


3. Bechstein WO. Neurotoxicity of calcineurin inhibitors: impact and clinical 
management. Transpl Int. 2000;13(5):313-26.  
4. Nigro V, Glicklich A, Weinberg J. Improved bioavailability of MELTDOSE 
once-daily formulation of tacrolimus (LCP-Tacro) with controlled agglomeration 
allows for consistent absorption over 24 hrs: a scintigraphic and pharmacokinetic 
evaluation. Presented at: American Transplant Congress; May 18-22, 2013; 
Seattle, WA. Abstract B1034. 
5. 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 13 (3) (2013), pp.760-769.