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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Kidney Transplant Rejection

Intervention / Treatment
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* Drug: Extended-release tacrolimus
* Drug: Immediate-release tacrolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Recipient of a deceased or living donor kidney allograft Patients must have undergone desensitization with 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 PCR positive for hepatitis B, hepatitis C, or HIV.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Extended-release tacrolimus<br>Kidney transplant recipients will receive extended-release tacrolimus in addition to standard-dose mycophenolate and prednisone for maintenance immunosuppression. | Drug: Extended-release tacrolimus<br>* Patients will receive the extended-release formulation of tacrolimus for maintenance immunosuppression.<br>|
| Active Comparator: Immediate-release tacrolimus<br>Kidney transplant recipients will receive immediate-release tacrolimus in addition to standard-dose mycophenolate and prednisone for maintenance immunosuppression. | Drug: Immediate-release tacrolimus<br>* Patients will receive the immediate-release formulation of tacrolimus for maintenance immunosuppression.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients with biopsy-proven acute rejection at 12 months |  | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of de novo donor-specific antibodies | Mean number of de novo donor-specific antibodies per patient developing within the first post-transplant year | 12 months | 
| Number of persistent pre-existing donor-specific antibodies | Mean number of pre-existing donor-specific antibodies per patient that persist at twelve months. | 12 months | 
| Estimated glomerular filtration rate (eGFR) | Mean eGFR at 12 months | 12 months | 
| Percent donor-derived cell-free DNA at 6 months | Mean percentage donor-derived cell-free DNA at 6 months | 6 months | 
| Percent donor-derived cell-free DNA at 12 months | Mean percentage donor-derived cell-free DNA at 12 months | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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kidney transplant, rejection, donor-specific antibodies