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

NCT04225988 | Completed Phase 4 Results DMC FDA Drug

• 1 other identifier: Pro00054474
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

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.

Conditions

Kidney Transplant Rejection

Keywords

kidney transplant; rejection; donor-specific antibodies

Outcome Measures

Primary Outcomes (1)

• 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.

  12 months

Secondary Outcomes (4)

• Number of Participants With de Novo Donor-specific Antibodies

  12 months

• Number of Persistent Pre-existing Donor-specific Antibodies

  12 months

• Estimated Glomerular Filtration Rate (eGFR; Chronic Kidney Disease (CKD)-Epi Equation)

  12 months

• Level of Donor-derived Cell-free DNA (Allosure)

  6 months and 12 months

Study Arms (2)

Extended-release tacrolimus

EXPERIMENTAL

Kidney transplant recipients will receive extended-release tacrolimus in addition to standard-dose mycophenolate and prednisone for maintenance immunosuppression.

Drug: Extended-release tacrolimus

Immediate-release tacrolimus

ACTIVE COMPARATOR

Kidney transplant recipients will receive immediate-release tacrolimus in addition to standard-dose mycophenolate and prednisone for maintenance immunosuppression.

Drug: Immediate-release tacrolimus

Interventions

Extended-release tacrolimus DRUG

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

Extended-release tacrolimus

Immediate-release tacrolimus DRUG

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

Immediate-release tacrolimus

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Cedars-Sinai Medical Center: lead
• Veloxis Pharmaceuticals: collaborator

Study Sites (1)

Cedars-Sinai Medical Center

Los Angeles, California, 90048, United States

Location

Related Publications (9)

• Budde K, Bunnapradist S, Grinyo JM, Ciechanowski K, Denny JE, Silva HT, Rostaing L; Envarsus study group. Novel once-daily extended-release tacrolimus (LCPT) versus twice-daily tacrolimus in de novo kidney transplants: one-year results of Phase III, double-blind, randomized trial. Am J Transplant. 2014 Dec;14(12):2796-806. doi: 10.1111/ajt.12955. Epub 2014 Oct 2.

  PMID: 25278376 BACKGROUND

• Bunnapradist S, Ciechanowski K, West-Thielke P, Mulgaonkar S, Rostaing L, Vasudev B, Budde K; MELT investigators. Conversion from twice-daily tacrolimus to once-daily extended release tacrolimus (LCPT): the phase III randomized MELT trial. Am J Transplant. 2013 Mar;13(3):760-9. doi: 10.1111/ajt.12035. Epub 2012 Dec 21.

  PMID: 23279614 BACKGROUND

• Everly MJ, Rebellato LM, Haisch CE, Ozawa M, Parker K, Briley KP, Catrou PG, Bolin P, Kendrick WT, Kendrick SA, Harland RC, Terasaki PI. Incidence and impact of de novo donor-specific alloantibody in primary renal allografts. Transplantation. 2013 Feb 15;95(3):410-7. doi: 10.1097/TP.0b013e31827d62e3.

  PMID: 23380861 BACKGROUND

• Hidalgo LG, Campbell PM, Sis B, Einecke G, Mengel M, Chang J, Sellares J, Reeve J, Halloran PF. De novo donor-specific antibody at the time of kidney transplant biopsy associates with microvascular pathology and late graft failure. Am J Transplant. 2009 Nov;9(11):2532-41. doi: 10.1111/j.1600-6143.2009.02800.x.

  PMID: 19843031 BACKGROUND

• Schinstock CA, Cosio F, Cheungpasitporn W, Dadhania DM, Everly MJ, Samaniego-Picota MD, Cornell L, Stegall MD. The Value of Protocol Biopsies to Identify Patients With De Novo Donor-Specific Antibody at High Risk for Allograft Loss. Am J Transplant. 2017 Jun;17(6):1574-1584. doi: 10.1111/ajt.14161. Epub 2017 Jan 25.

  PMID: 27977905 BACKGROUND

• Wiebe C, Gibson IW, Blydt-Hansen TD, Pochinco D, Birk PE, Ho J, Karpinski M, Goldberg A, Storsley L, Rush DN, Nickerson PW. Rates and determinants of progression to graft failure in kidney allograft recipients with de novo donor-specific antibody. Am J Transplant. 2015 Nov;15(11):2921-30. doi: 10.1111/ajt.13347. Epub 2015 Jun 10.

  PMID: 26096305 BACKGROUND

• Loupy A, Hill GS, Jordan SC. The impact of donor-specific anti-HLA antibodies on late kidney allograft failure. Nat Rev Nephrol. 2012 Apr 17;8(6):348-57. doi: 10.1038/nrneph.2012.81.

  PMID: 22508180 BACKGROUND

• Sellares J, de Freitas DG, Mengel M, Reeve J, Einecke G, Sis B, Hidalgo LG, Famulski K, Matas A, Halloran PF. Understanding the causes of kidney transplant failure: the dominant role of antibody-mediated rejection and nonadherence. Am J Transplant. 2012 Feb;12(2):388-99. doi: 10.1111/j.1600-6143.2011.03840.x. Epub 2011 Nov 14.

  PMID: 22081892 BACKGROUND

• Einecke G, Sis B, Reeve J, Mengel M, Campbell PM, Hidalgo LG, Kaplan B, Halloran PF. Antibody-mediated microcirculation injury is the major cause of late kidney transplant failure. Am J Transplant. 2009 Nov;9(11):2520-31. doi: 10.1111/j.1600-6143.2009.02799.x.

  PMID: 19843030 BACKGROUND

MeSH Terms

Conditions

Rejection, Psychology

Condition Hierarchy (Ancestors)

Social Behavior; Behavior

Limitations and Caveats

Small sample size; Early withdrawal of participants.

Results Point of Contact

• Title: Dr. Edmund Huang, MD
• Organization: Cedars Sinai Medical Center

edmund.huang@cshs.org

310-423-2641

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Staff Physician II

Study Record Dates

• First Submitted: January 9, 2020
• First Posted: January 13, 2020
• Study Start: January 9, 2020
• Primary Completion: July 11, 2023
• Study Completion: July 11, 2023
• Last Updated: July 10, 2024
• Results First Posted: July 10, 2024

Record last verified: 2024-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)