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

NCT04665310 | Active Not Recruiting Phase 4 FDA Drug

• 1 other identifier: Pro00018836
• Study Type: interventional
• Target: 46
• Locations: 0 countries
• Sites: N/A

Brief Summary

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.

Conditions

Kidney Disease, End-Stage; Donor Specific Antibodies; Acute Rejection of Renal Transplant

Keywords

Renal Transplant; Donor Specific Antibodies; African American; Acute Rejection of Renal Transplant; Kidney Transplant; End Stage Renal Disease

Outcome Measures

Primary Outcomes (1)

• Number of participants reaching the composite endpoint

  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 Outcomes (6)

• Proportion of subjects experiencing nephrotoxicity during the study

  6 months

• Proportion of subjects experiencing neurotoxicity during the study

  6 months

• Proportion of subjects experiencing infectious complications during the study

  6 months

• Difference in estimated glomerular filtration rate at 1, 3, and 6 months between groups of enrolled subjects

  6 months

• Difference in immunosuppressant side effects between enrolled subjects

  6 months

Study Arms (6)

Group 1 - Low-Intensity

ACTIVE COMPARATOR

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

Group 1 - Moderate-Intensity

ACTIVE COMPARATOR

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

Group 1 - High-Intensity

ACTIVE COMPARATOR

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

Group 2 - Low-Intensity

ACTIVE COMPARATOR

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

Group 2 - Moderate-Intensity

ACTIVE COMPARATOR

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

Group 2 - High-Intensity

ACTIVE COMPARATOR

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

Interventions

Envarsus XR DRUG

tacrolimus, extended-release tablets, a calcineurin inhibitor

Also known as: Life Cycle Pharma (LCP)-tacrolimus, once-daily extended-release tacrolimus, once-daily prolonged-release tacrolimus, Tacrolimus-LCP

Group 1 - High-Intensity; Group 1 - Low-Intensity; Group 1 - Moderate-Intensity; Group 2 - High-Intensity; Group 2 - Low-Intensity; Group 2 - Moderate-Intensity

Eligibility Criteria

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

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• The Methodist Hospital Research Institute: lead
• Veloxis Pharmaceuticals: collaborator

Related Publications (20)

• Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009 Nov;9 Suppl 3:S1-155. doi: 10.1111/j.1600-6143.2009.02834.x.

  PMID: 19845597 BACKGROUND

• Young CJ, Gaston RS. Renal transplantation in black Americans. N Engl J Med. 2000 Nov 23;343(21):1545-52. doi: 10.1056/NEJM200011233432107. No abstract available.

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• Narayanan M, Pankewycz O, Shihab F, Wiland A, McCague K, Chan L. Long-term outcomes in African American kidney transplant recipients under contemporary immunosuppression: a four-yr analysis of the Mycophenolic acid Observational REnal transplant (MORE) study. Clin Transplant. 2014 Feb;28(2):184-91. doi: 10.1111/ctr.12294. Epub 2013 Dec 24.

  PMID: 24372743 BACKGROUND

• Lamb KE, Lodhi S, Meier-Kriesche HU. Long-term renal allograft survival in the United States: a critical reappraisal. Am J Transplant. 2011 Mar;11(3):450-62. doi: 10.1111/j.1600-6143.2010.03283.x. Epub 2010 Oct 25.

  PMID: 20973913 BACKGROUND

• Patel SJ, Suki WN, Loucks-DeVos J, Graviss EA, Nguyen DT, Knight RJ, Kuten SA, Moore LW, Teeter LD, Gaber LW, Gaber AO. Disparate rates of acute rejection and donor-specific antibodies among high-immunologic risk renal transplant subgroups receiving antithymocyte globulin induction. Transpl Int. 2016 Aug;29(8):897-908. doi: 10.1111/tri.12791. Epub 2016 Jul 7.

  PMID: 27196395 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

• 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

• Gaber AO, Alloway RR, Bodziak K, Kaplan B, Bunnapradist S. Conversion from twice-daily tacrolimus capsules to once-daily extended-release tacrolimus (LCPT): a phase 2 trial of stable renal transplant recipients. Transplantation. 2013 Jul 27;96(2):191-7. doi: 10.1097/TP.0b013e3182962cc1.

  PMID: 23715050 BACKGROUND

• Bunnapradist S, Rostaing L, Alloway RR, West-Thielke P, Denny J, Mulgaonkar S, Budde K. LCPT once-daily extended-release tacrolimus tablets versus twice-daily capsules: a pooled analysis of two phase 3 trials in important de novo and stable kidney transplant recipient subgroups. Transpl Int. 2016 May;29(5):603-11. doi: 10.1111/tri.12770. Epub 2016 Apr 3.

  PMID: 26953629 BACKGROUND

• Trofe-Clark J, Brennan DC, West-Thielke P, Milone MC, Lim MA, Neubauer R, Nigro V, Bloom RD. Results of ASERTAA, a Randomized Prospective Crossover Pharmacogenetic Study of Immediate-Release Versus Extended-Release Tacrolimus in African American Kidney Transplant Recipients. Am J Kidney Dis. 2018 Mar;71(3):315-326. doi: 10.1053/j.ajkd.2017.07.018. Epub 2017 Nov 20.

  PMID: 29162334 BACKGROUND

• Langone A, Steinberg SM, Gedaly R, Chan LK, Shah T, Sethi KD, Nigro V, Morgan JC; STRATO Investigators. Switching STudy of Kidney TRansplant PAtients with Tremor to LCP-TacrO (STRATO): an open-label, multicenter, prospective phase 3b study. Clin Transplant. 2015 Sep;29(9):796-805. doi: 10.1111/ctr.12581. Epub 2015 Aug 6.

  PMID: 26113208 BACKGROUND

• Kuypers DR, Claes K, Evenepoel P, Maes B, Vanrenterghem Y. Clinical efficacy and toxicity profile of tacrolimus and mycophenolic acid in relation to combined long-term pharmacokinetics in de novo renal allograft recipients. Clin Pharmacol Ther. 2004 May;75(5):434-47. doi: 10.1016/j.clpt.2003.12.009.

  PMID: 15116056 BACKGROUND

• Winsett RP, Arheart K, Stratta RJ, Alloway R, Wicks MN, Gaber AO, Hathaway DK. Evaluation of an immunosuppressant side effect instrument. Prog Transplant. 2004 Sep;14(3):210-6, 240. doi: 10.1177/152692480401400306.

  PMID: 15495780 BACKGROUND

• Staatz CE, Tett SE. Clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplantation. Clin Pharmacokinet. 2004;43(10):623-53. doi: 10.2165/00003088-200443100-00001.

  PMID: 15244495 BACKGROUND

• Kuypers DR, Peeters PC, Sennesael JJ, Kianda MN, Vrijens B, Kristanto P, Dobbels F, Vanrenterghem Y, Kanaan N; ADMIRAD Study Team. Improved adherence to tacrolimus once-daily formulation in renal recipients: a randomized controlled trial using electronic monitoring. Transplantation. 2013 Jan 27;95(2):333-40. doi: 10.1097/TP.0b013e3182725532.

  PMID: 23263559 BACKGROUND

• Ho ET, Wong G, Craig JC, Chapman JR. Once-daily extended-release versus twice-daily standard-release tacrolimus in kidney transplant recipients: a systematic review. Transplantation. 2013 May 15;95(9):1120-8. doi: 10.1097/TP.0b013e318284c15b.

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MeSH Terms

Conditions

Kidney Failure, Chronic

Interventions

Tacrolimus

Condition Hierarchy (Ancestors)

Renal Insufficiency, Chronic; Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals

Study Officials

• Ahmed O Gaber, MD

  Houston Methodist Physicians Organization

  PRINCIPAL INVESTIGATOR

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: Director, Houston Methodist J.C. Walter Jr. Transplant Center

Model Details: Parallel Group - Dose Escalation with 2 groups stratified by pPRA \<75% and \>75% and then randomized into 3 Intensity Arms (Low, Moderate and High) based on dosing of Envarsus XR.

Study Record Dates

• First Submitted: April 2, 2019
• First Posted: December 11, 2020
• Study Start: September 1, 2018
• Primary Completion: July 31, 2025
• Study Completion: October 31, 2025
• Last Updated: March 14, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will not share