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

September 13, 2023 updated by: Edmund Huang, Cedars-Sinai Medical Center

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

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.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

20

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • California
      • Los Angeles, California, United States, 90048
        • Cedars-Sinai Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Recipient of a deceased or living donor kidney allograft
  2. 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
  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 PCR positive for hepatitis B, hepatitis C, or HIV.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Cedars-Sinai Medical Center

Collaborators

Veloxis Pharmaceuticals

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 9, 2020

Primary Completion (Actual)

July 21, 2023

Study Completion (Estimated)

July 21, 2024

Study Registration Dates

First Submitted

January 9, 2020

First Submitted That Met QC Criteria

January 9, 2020

First Posted (Actual)

January 13, 2020

Study Record Updates

Last Update Posted (Actual)

September 15, 2023

Last Update Submitted That Met QC Criteria

September 13, 2023

Last Verified

September 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Pro00054474

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

There are no plans to share individual participant data with other researchers.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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