Evaluation of Anti-rejection Drug, Tacrolimus, in African-Americans With Kidney Transplant

December 10, 2020 updated by: Ahmed Osama Gaber, MD, The Methodist Hospital Research Institute

Evaluation of Early Dose Escalation Using Extended-Release Tacrolimus (Envarsus XR®) to Reduce Acute Rejection and Donor Specific Antibodies in African American Renal Transplant Recipients

In spite of conventional immunosuppression with lymphocyte-depleting induction followed by tacrolimus- and mycophenolate-based regimens, African American (AA) renal transplant recipients experience higher rates of acute rejection (AR), donor specific antibodies (DSA), and graft failure. Envarsus Extended-Release (XR)® (ENV) is a novel extended-release formulation of tacrolimus with a favorable pharmacokinetic profile, even in the setting of CYP3A5*1 allele (rapid metabolizers). The investigator will evaluate the safety and efficacy of early dose escalation with ENV in AA recipients. The study hypothesis is that higher tacrolimus target concentrations may be achieved without typical dose-limiting toxicities, and this may ultimately result in lower incidence of early AR, DSA, and graft loss.

Study Overview

Status

Withdrawn

Conditions

Intervention / Treatment

Detailed Description

Phase 4 (post-marketing) De novo African American living or deceased donor renal transplant recipients 18 to 65 years of age Number of subjects to be enrolled: 60

All patients will receive standard induction immunosuppression according to institution protocol. Within one week of transplantation, all patients will be converted from immediate-release tacrolimus (TAC) to extended-release tacrolimus (ENV) at 20% reduction in total daily dosage. Patients will be randomized to low-, moderate-, or high-intensity ENV groups, stratified by peak panel reactive antibody (pPRA) greater than or equal to 75%. Target tacrolimus trough concentrations for the first month post-transplant will be 8-10 ng/mL in low-intensity group, 10-12 ng/mL in moderate-intensity group, and 12-14 ng/mL in high-intensity group; likewise from month 1-3 post-transplant, target trough concentrations will be 6-8 ng/mL, 8-10 ng/mL, and 10-12 ng/mL, respectively. Subjects experiencing dose-limiting adverse events (AEs) will be de-escalated as warranted. Following month 3, all patients will be maintained on ENV at target tacrolimus trough concentrations according to institution protocol. Additional maintenance immunosuppression will consist of mycophenolate mofetil (MMF) at a goal dose of 2000 mg daily along with an oral prednisone taper to 5-10 mg daily by the end of month 1. All patients will be followed for 6 months post-transplant.

Study Type

Interventional

Phase

  • Phase 4

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

18 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • • Primary live donor or deceased donor renal allograft

    • African American patients aged 18 to 65 years
    • Ability to take oral medications

    • Not currently on medications known to significantly interfere with tacrolimus metabolism, e.g. strong CYP3A4 inducers or inhibitors including but not limited to rifampin, rifabutin, phenytoin, carbamazepine, phenobarbital, protease inhibitors, azole antifungal (voriconazole, itraconazole, posaconazole, ketoconazole)

      o Note: All patients will be discharged on clotrimazole 10 mg three times daily for one month for thrush prophylaxis, a known mild-to-moderate CYP3A4 inhibitor

    • Female subjects of childbearing potential:

      • Not current pregnant
      • Agree not to try to become pregnant during the study period
      • Agree to consistently use two forms of highly effective birth control throughout the study period
    • Provision of signed and dated informed consent form
    • Stated willingness to comply with all study procedures and availability for the duration of the study

Exclusion Criteria:

  • • Presence of a positive T- or B-cell flow cytometry allogeneic crossmatch

    • Presence of pre-formed anti-human leukocyte antigen (HLA) donor-specific antibodies (DSAs)
    • Recipient of an ABO-incompatible organ
    • Receipt of a multi-organ or dual kidney transplant
    • Receipt of pediatric en bloc deceased donor kidneys
    • Receipt of deceased donor kidney with a kidney donor profile index (KDPI) greater than or equal to 85%
    • Has undergone desensitization, or received antibody removal, anti-B-cell, or anti-plasma cell therapy in the 90 days preceding the transplant
    • Planned initiation of antibody removal (i.e. plasmapheresis) within 7 days of the transplant procedure
    • Positive test for latent tuberculosis (TB) and has not previously received adequate anti-microbial therapy or would require TB prophylaxis after transplant
    • Uncontrolled concomitant infection that would not allow for targeting escalated tacrolimus trough concentrations, as deemed by prescriber
    • Known infection or seropositivity for hepatitis B virus (HBV, defined by positive HBsAg, anti-HBcAg, or positive viral load) or hepatitis C virus (HCV) with active viral load
    • Current malignancy
    • Use of an investigational study in the 30 days prior to the transplant procedure

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
Active Comparator: Group 1 - Low-Intensity

All patients will receive standard induction immunosuppression according to institution protocol. TAC will be started when clinically appropriate according to institution protocol.

TAC dosing will be 2 mg twice daily to be reduced by 20% after week 1 and start Envarsus XR once daily.

Target Tacrolimus Trough Concentrations:

Week 0 to Week 4: 8-10 mg/mL Month 1 to Month 3: 6-8 mg/mL
Drug: Envarsus XR
tacrolimus, extended-release tablets, a calcineurin inhibitor
Other Names:
  • Life Cycle Pharma (LCP)-tacrolimus
  • once-daily extended-release tacrolimus
  • once-daily prolonged-release tacrolimus
  • Tacrolimus-LCP
Active Comparator: Group 1 - Moderate-Intensity

All patients will receive standard induction immunosuppression according to institution protocol. TAC will be started when clinically appropriate according to institution protocol.

TAC dosing will be 3 mg twice daily to be reduced by 20% after week 1 and start Envarsus XR once daily.

Target Tacrolimus Trough Concentrations:

Week 0 to Week 4: 10-12 mg/mL Month 1 to Month 3: 8-10 mg/mL
Drug: Envarsus XR
tacrolimus, extended-release tablets, a calcineurin inhibitor
Other Names:
  • Life Cycle Pharma (LCP)-tacrolimus
  • once-daily extended-release tacrolimus
  • once-daily prolonged-release tacrolimus
  • Tacrolimus-LCP
Active Comparator: Group 1 - High-Intensity

All patients will receive standard induction immunosuppression according to institution protocol. TAC will be started when clinically appropriate according to institution protocol.

TAC dosing will be 4 mg twice daily to be reduced by 20% after week 1 and start Envarsus XR once daily.

Target Tacrolimus Trough Concentrations:

Week 0 to Week 4: 12-14 mg/mL Month 1 to Month 3: 10-12 mg/mL
Drug: Envarsus XR
tacrolimus, extended-release tablets, a calcineurin inhibitor
Other Names:
  • Life Cycle Pharma (LCP)-tacrolimus
  • once-daily extended-release tacrolimus
  • once-daily prolonged-release tacrolimus
  • Tacrolimus-LCP
Active Comparator: Group 2 - Low-Intensity

All patients will receive standard induction immunosuppression according to institution protocol. TAC will be started when clinically appropriate according to institution protocol.

TAC dosing will be 2 mg twice daily to be reduced by 20% after week 1 and start Envarsus XR once daily.

Target Tacrolimus Trough Concentrations:

Week 0 to Week 4: 8-10 mg/mL Month 1 to Month 3: 6-8 mg/mL
Drug: Envarsus XR
tacrolimus, extended-release tablets, a calcineurin inhibitor
Other Names:
  • Life Cycle Pharma (LCP)-tacrolimus
  • once-daily extended-release tacrolimus
  • once-daily prolonged-release tacrolimus
  • Tacrolimus-LCP
Active Comparator: Group 2 - Moderate-Intensity

All patients will receive standard induction immunosuppression according to institution protocol. TAC will be started when clinically appropriate according to institution protocol.

TAC dosing will be 3 mg twice daily to be reduced by 20% after week 1 and start Envarsus XR once daily.

Target Tacrolimus Trough Concentrations:

Week 0 to Week 4: 10-12 mg/mL Month 1 to Month 3: 8-10 mg/mL
Drug: Envarsus XR
tacrolimus, extended-release tablets, a calcineurin inhibitor
Other Names:
  • Life Cycle Pharma (LCP)-tacrolimus
  • once-daily extended-release tacrolimus
  • once-daily prolonged-release tacrolimus
  • Tacrolimus-LCP
Active Comparator: Group 2 - High-Intensity

All patients will receive standard induction immunosuppression according to institution protocol. TAC will be started when clinically appropriate according to institution protocol.

TAC dosing will be 4 mg twice daily to be reduced by 20% after week 1 and start Envarsus XR once daily.

Target Tacrolimus Trough Concentrations:

Week 0 to Week 4: 12-14 mg/mL Month 1 to Month 3: 10-12 mg/mL
Drug: Envarsus XR
tacrolimus, extended-release tablets, a calcineurin inhibitor
Other Names:
  • Life Cycle Pharma (LCP)-tacrolimus
  • once-daily extended-release tacrolimus
  • once-daily prolonged-release tacrolimus
  • Tacrolimus-LCP

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of participants reaching the composite endpoint
Time Frame: 6 months
Composite endpoint of freedom from all of the following: i) biopsy-proven T-cell mediated rejection Banff Grade ≥1A, ii) antibody-mediated rejection, iii) de novo DSA, or iv) immune-mediated graft loss. The endpoint is a binary endpoint (Yes or No) of the composite of all 4 potential outcomes. The presence of any one of the four possible outcomes will be counted as a No for the binary endpoint (no freedom from the composite endpoint). The absence of all 4 possible outcomes will be counted as Yes for freedom from all of the possible outcomes.
6 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Proportion of subjects experiencing nephrotoxicity during the study
Time Frame: 6 months
Increase in serum creatinine of ≥0.3mg/dL
6 months
Proportion of subjects experiencing neurotoxicity during the study
Time Frame: 6 months
Clinical intolerability including headache or significant tremors that resolve with reduction of the dose of Envarsus
6 months
Proportion of subjects experiencing infectious complications during the study
Time Frame: 6 months
Participants requiring extended (>2 weeks) reduction in dose of Envarsus due to BK-polyomavirus or cytomegalovirus viral loads at 1, 3, and 6 months post-transplant
6 months
Difference in estimated glomerular filtration rate at 1, 3, and 6 months between groups of enrolled subjects
Time Frame: 6 months
Assessed as the Chronic Kidney Disease - Epidemiology Collaboration equation
6 months
Difference in immunosuppressant side effects between enrolled subjects
Time Frame: 6 months
Assessed using the "Immunosuppressant Side Effects Instrument - The Memphis Survey" questionnaire
6 months
Enrolled subject overall survival and Graft survival at 6 months
Time Frame: 6 months
Freedom from death and from graft loss at 6 months
6 months

Collaborators and Investigators

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

Sponsor

The Methodist Hospital Research Institute

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)

September 1, 2018

Primary Completion (Anticipated)

October 31, 2020

Study Completion (Anticipated)

October 31, 2022

Study Registration Dates

First Submitted

April 2, 2019

First Submitted That Met QC Criteria

December 10, 2020

First Posted (Actual)

December 11, 2020

Study Record Updates

Last Update Posted (Actual)

December 11, 2020

Last Update Submitted That Met QC Criteria

December 10, 2020

Last Verified

December 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Pro00018836

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

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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