Comparison of Tacrolimus Extended-Release (Envarsus XR) to Tacrolimus Immediate-Release in Human Leukocyte Antigen (HLA) Sensitized Kidney Transplant Recipients

A Prospective, Pilot Trial to Compare the Efficacy of Tacrolimus Extended-Release (Envarsus XR) to Tacrolimus Immediate-Release on Suppression of Donor-Specific Antibodies in HLA Sensitized Kidney Transplant Recipients

Status

Completed

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04225988

Enrollment

Registered

2020-01-13

Start date

2020-01-09

Completion date

2023-07-11

Last updated

2024-07-10

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Kidney Transplant Rejection

Keywords

kidney transplant, rejection, donor-specific antibodies

Brief summary

This is a randomized, open-label, controlled clinical trial designed to compare clinical outcomes after kidney transplantation using extended-release tacrolimus (Envarsus XR) versus immediate tacrolimus among highly-sensitized kidney transplant recipients. Outcomes to be assessed include the incidence of biopsy-proven acute rejection at 12 months, the presence of de novo and pre-existing donor-specific HLA antibodies, estimated glomerular filtration rate, and the level of donor-derived cell-free DNA.

Detailed description

Extended-release tacrolimus (Envarsus XR) received FDA approval in July, 2015 for the prevention of allograft rejection in kidney transplantation on the basis of two separate phase 3 trials of de novo and stable kidney transplant recipients that demonstrated non-inferiority to immediate-release tacrolimus for the composite outcome of death, graft failure, biopsy-proven acute rejection, or loss to follow-up within 12 months (1,2). Both phase 3 trials involved mostly low immunologic risk recipients with follow-up to one year. It has been previously shown that the incidence of de novo donor-specific antibodies (DSA) in the first year after kidney transplant in low-immunologic patients is low, developing in only 2%-11% of unsensitized de novo kidney transplant recipients (3-6). Donor-specific antibodies (DSA) are the primary mediator of antibody-mediated rejection and their development after transplant is a major risk factor for late allograft failure (7). It is now believed that antibody-mediated rejection is the most common cause of late allograft failure (8,9). However, neither of the two phase 3 trials were able to adequately assess the effect of Envarsus XR on the development of donor specific antibodies and therefore, the efficacy of Envarsus XR in higher immunologic risk recipients is not known. Therefore, a comparative study of extended- and immediate-release tacrolimus in highly-sensitized recipients is warranted. This is a randomized, open-label, controlled clinical trial designed to compare clinical outcomes after kidney transplantation using extended-release tacrolimus (Envarsus XR) versus immediate tacrolimus among highly-sensitized kidney transplant recipients. Twenty patients will be enrolled, with ten assigned to each study arm. Outcomes to be assessed include the incidence of biopsy-proven acute rejection at 12 months, the presence of de novo and pre-existing donor-specific HLA antibodies, estimated glomerular filtration rate, and the level of donor-derived cell-free DNA.

Interventions

DRUGExtended-release tacrolimus

Patients will receive the extended-release formulation of tacrolimus for maintenance immunosuppression.

DRUGImmediate-release tacrolimus

Patients will receive the immediate-release formulation of tacrolimus for maintenance immunosuppression.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

1. Recipient of a deceased or living donor kidney allograft 2. Patients must have undergone desensitization with Intravenous Immunoglobulin (IVIG) and rituximab with or without plasma exchange prior to transplant or be administered IVIG and rituximab peri-operatively (within seven days of transplant) post-transplant 3. Age 18 and over 4. Able to understand and provide informed consent 5. At transplant, patient must have an acceptable crossmatch \[as defined by a T- or B-flow crossmatch ≤ 225 median channel shift (MCS)\] from a non-HLA identical donor. A negative crossmatch is defined as a T pronase flow crossmatch \< 70 MCS or a T- flow crossmatch \< 50 MCS and a B pronase flow crossmatch \<130 MCS or a B-flow crossmatch \<100 MCS.

Exclusion criteria

1. Recipients of a dual simultaneous kidney/liver, kidney/heart, kidney/lung, or kidney/pancreas transplant. 2. History of hypersensitivity to any of the study drug or to drugs of similar chemical classes. 3. Patients with a clinically significant systemic infection within 30 days prior to transplant. 4. Patients who have any history of a surgical or medical condition that may affect absorption of drug, such as severe diarrhea, active peptic ulcer disease, or uncontrolled diabetes mellitus, which in the opinion of the investigator at the time of enrollment, might significantly alter the absorption, distribution, metabolism and/or excretion of study medication. 5. Women of childbearing potential who are either pregnant, lactating, planning to become pregnant during this trial, or with a positive serum or urine pregnancy test. Women of childbearing potential must be willing to agree to contraceptive practices. 6. Patients who are Polymerase Chain Reaction (PCR) positive for hepatitis B, hepatitis C, or HIV.

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants With Biopsy-proven Acute Rejection	12 months	To assess whether the occurence of biopsy-proven acute rejection within 12 months of transplant is comparable between HS patients maintained on Envarsus XR and immediate-release tacrolimus.

Secondary

Measure	Time frame	Description
Number of Participants With de Novo Donor-specific Antibodies	12 months	To assess the number of participants who developed a presence of de novo donor-specific antibodies developing between Envarsus XR-treated and immediate-release tacrolimus-treated HS recipients.
Number of Persistent Pre-existing Donor-specific Antibodies	12 months	To assess the number of participants who had persistent pre-existing donor-specific antibodies at 12 months in the Envarsus XR-treated and immediate-release tacrolimus-treated groups.
Estimated Glomerular Filtration Rate (eGFR; Chronic Kidney Disease (CKD)-Epi Equation)	12 months	To assess the mean eGFR (using the CKD-Epi equation) between Envarsus XR-treated and immediate-release tacrolimus-treated HS recipients.
Level of Donor-derived Cell-free DNA (Allosure)	6 months and 12 months	To assess the mean percentage of donor-derived cell-free DNA (Allosure) between Envarsus XR-treated and immediate-release tacrolimus-treated HS recipients.

Countries

United States

Participant flow

Recruitment details

Male and female HLA sensitized (HS) renal transplantation patients, 18 years of age and over, receiving a deceased or living donor kidney allograft may enter the study. Twenty patients will be enrolled at Cedars-Sinai Medical Center (CSMC) for this pilot study. Patients who discontinue the study prematurely will not be replaced.

Pre-assignment details

Of the total 28 participants ages 18 and older screened, 20 were enrolled in this single-center, open-label, randomized controlled trial design pilot study.

Participants by arm

Arm	Count
Extended-release Tacrolimus Kidney transplant recipients will receive extended-release tacrolimus in addition to standard-dose mycophenolate and prednisone for maintenance immunosuppression. Extended-release tacrolimus: Patients will receive the extended-release formulation of tacrolimus for maintenance immunosuppression.	10
Immediate-release Tacrolimus Kidney transplant recipients will receive immediate-release tacrolimus in addition to standard-dose mycophenolate and prednisone for maintenance immunosuppression. Immediate-release tacrolimus: Patients will receive the immediate-release formulation of tacrolimus for maintenance immunosuppression.	10
Total	20

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Withdrawal by Subject	2	0

Baseline characteristics

Characteristic	Extended-release Tacrolimus	Immediate-release Tacrolimus	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	1 Participants	1 Participants	2 Participants
Age, Categorical Between 18 and 65 years	9 Participants	9 Participants	18 Participants
Age, Continuous	49.6 years STANDARD_DEVIATION 15.02	46.1 years STANDARD_DEVIATION 11.6376	47.85 years STANDARD_DEVIATION 13.2
Ethnicity (NIH/OMB) Hispanic or Latino	4 Participants	7 Participants	11 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	6 Participants	3 Participants	9 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	1 Participants	0 Participants	1 Participants
Race (NIH/OMB) Black or African American	2 Participants	0 Participants	2 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	7 Participants	10 Participants	17 Participants
Region of Enrollment United States	10 participants	10 participants	20 participants
Sex: Female, Male Female	7 Participants	4 Participants	11 Participants
Sex: Female, Male Male	3 Participants	6 Participants	9 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 10	0 / 10
other Total, other adverse events	4 / 10	7 / 10
serious Total, serious adverse events	6 / 10	6 / 10

Outcome results

Primary

Number of Participants With Biopsy-proven Acute Rejection

To assess whether the occurence of biopsy-proven acute rejection within 12 months of transplant is comparable between HS patients maintained on Envarsus XR and immediate-release tacrolimus.

Time frame: 12 months