Clinical trial NCT04225988: Comparison of Tacrolimus Extended-Release (Envarsus XR) to Tacrolimus Immediate-Release in Human Leukocyte Antigen (HLA) Sensitized Kidney Transplant Recipients
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Kidney Transplant Rejection
Keywords: kidney transplant
rejection
donor-specific antibodies
Lead sponsor: Cedars-Sinai Medical Center
Sponsor class: OTHER
Collaborators: name: Veloxis Pharmaceuticals
First posted: 2020-01-13
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

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

Primary outcomes:
measure: Number of Participants With Biopsy-proven Acute Rejection
timeFrame: 12 months
Secondary outcomes:
measure: Number of Participants With de Novo Donor-specific Antibodies
timeFrame: 12 months
measure: Number of Persistent Pre-existing Donor-specific Antibodies
timeFrame: 12 months
measure: Estimated Glomerular Filtration Rate (eGFR; Chronic Kidney Disease (CKD)-Epi Equation)
timeFrame: 12 months
measure: Level of Donor-derived Cell-free DNA (Allosure)
timeFrame: 6 months and 12 months
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
Study officials:
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.