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

Phase 4

Completed

Conditions: Kidney Transplant Rejection

Interventions: Drug: Immediate-release tacrolimus
Drug: Extended-release tacrolimus

Registration Number: NCT04225988

Lead Sponsor: Cedars-Sinai Medical Center

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 20

Inclusion Criteria

Recipient of a deceased or living donor kidney allograft
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
Age 18 and over
Able to understand and provide informed consent
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

Recipients of a dual simultaneous kidney/liver, kidney/heart, kidney/lung, or kidney/pancreas transplant.
History of hypersensitivity to any of the study drug or to drugs of similar chemical classes.
Patients with a clinically significant systemic infection within 30 days prior to transplant.
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.
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.
Patients who are Polymerase Chain Reaction (PCR) positive for hepatitis B, hepatitis C, or HIV.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Immediate-release tacrolimus	Immediate-release tacrolimus	Kidney transplant recipients will receive immediate-release tacrolimus in addition to standard-dose mycophenolate and prednisone for maintenance immunosuppression.
Extended-release tacrolimus	Extended-release tacrolimus	Kidney transplant recipients will receive extended-release tacrolimus in addition to standard-dose mycophenolate and prednisone for maintenance immunosuppression.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.