Renal Tubular Injury and Transplant Outcomes in Cardiac Recipients Converting From IR Tacrolimus to XR Tacrolimus

Chronic Kidney Diseases Clinical Trial

Official title:

Assessment of Renal Tubular Injury and Transplant Outcomes in Cardiac Recipients Converting From Immediate Release Tacrolimus to Extended Release Tacrolimus.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04917718
• Other study ID #: 212781
• Status: Recruiting
• Phase: Phase 4
• Start date: August 16, 2021
• Est. completion date: December 31, 2024

Study information

• Verified date: April 2022
• Source: Loyola University
• Contact: Sanjeev Akkina, MD
• Phone: 708-327-4897
• Email: sanjeev.akkina[@]lumc.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Immediate release (IR) tacrolimus peaks in the first two hours after administration. These peak levels are influenced by CYP3A5 expression with expressors requiring higher total daily doses with higher peak levels compared to non-expressors. Tacrolimus XR (Envarsus) is a once daily formulation with delayed absorption and lower peak levels while maintaining similar trough levels as seen with IR tacrolimus. A randomized trial of conversion from IR tacrolimus to tacrolimus XR in kidney transplant recipients have shown similar efficacy and adverse events between the two groups but no improvement in estimated GFR. However, urinary biomarkers of acute kidney injury associated with changes in tacrolimus dosing may be more sensitive then serum creatinine. The objective of this study is to assess renal tubular injury in heart transplant recipients who are converted from immediate release to tacrolimus XR. The hypothesis is that the delayed absorption and lower peak levels of tacrolimus XR will lead to less tubular injury and improved renal function without increased risk to the heart allograft.

Description:

The primary outcome is change in urinary NGAL expression with conversion from IR tacrolimus to tacrolimus XR. In aim 1, changes in urinary biomarkers of tubular injury at 4 weeks after conversion to tacrolimus XR with stable trough levels will be assessed. These changes will be assessed by CYP3A5 expressor category that will be determined by genotyping of a single gene for variants. The changes in GFR using the creatinine-cystatin C CKD-EPI equation will be assessed. In aim 2, the rate of rejection as defined as treated rejection within the last 30 days for any grade > 1R or AMR or acute graft dysfunction (LV ejection fraction drop > 10%) will be looked. The cardiac allograft vasculopathy based on coronary angiography +/- IVUS and right heart catheterization hemodynamics at baseline and 1 year post conversion will also be evaluated. In addition to changes in cardiac function, the changes in blood pressure, serum glucose, and cholesterol in the first year after conversion will be assessed.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 42
• Est. completion date: December 31, 2024
• Est. primary completion date: December 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

• Stable, heart-only transplant recipient within 10 years of transplantation
• 18 -80 years old
• Currently taking IR Tacrolimus
• Baseline eGFR> 30mL/min/1.73m2

Exclusion Criteria:

• Multiple organ transplant recipients
• Less than 18 years old
• Greater than 80 years old
• Heart-only transplants recipients with active malignancy, rejection, or greater than 10 years from transplantation

Related Conditions & MeSH terms

• Chronic Kidney Diseases
• Heart Transplant
• Kidney Diseases
• Renal Insufficiency, Chronic

Intervention

Drug:
• Conversion from IR Tacrolimus to XR Tacrolimus
All participants will be consented to the study on IR Tacrolimus. After their baseline visit, they will be converted to XR Tacrolimus

Locations

Country	Name	City	State
United States	Loyola University Medical Center	Maywood	Illinois

Sponsors (2)

Lead Sponsor	Collaborator
Loyola University	Veloxis Pharmaceuticals

Country where clinical trial is conducted

United States, 

References & Publications (10)

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. — View Citation

Câmara NO, Matos AC, Rodrigues DA, Pereira AB, Pacheco-Silva A. Early detection of heart transplant patients with increased risk of ciclosporin nephrotoxicity. Lancet. 2001 Mar 17;357(9259):856-7. — View Citation

Chancharoenthana W, Leelahavanichkul A, Wattanatorn S, Avihingsanon Y, Praditpornsilpa K, Eiam-Ong S, Townamchai N. Alteration of urinary neutrophil gelatinase-associated lipocalin as a predictor of tacrolimus-induced chronic renal allograft fibrosis in tacrolimus dose adjustments following kidney transplantation. PLoS One. 2018 Dec 21;13(12):e0209708. doi: 10.1371/journal.pone.0209708. eCollection 2018. Erratum in: PLoS One. 2019 Feb 22;14(2):e0213009. — View Citation

Cosio FG, Amer H, Grande JP, Larson TS, Stegall MD, Griffin MD. Comparison of low versus high tacrolimus levels in kidney transplantation: assessment of efficacy by protocol biopsies. Transplantation. 2007 Feb 27;83(4):411-6. — View Citation

Myers BD, Ross J, Newton L, Luetscher J, Perlroth M. Cyclosporine-associated chronic nephropathy. N Engl J Med. 1984 Sep 13;311(11):699-705. — View Citation

Naesens M, Kuypers DR, Sarwal M. Calcineurin inhibitor nephrotoxicity. Clin J Am Soc Nephrol. 2009 Feb;4(2):481-508. doi: 10.2215/CJN.04800908. Review. — View Citation

Ojo AO, Held PJ, Port FK, Wolfe RA, Leichtman AB, Young EW, Arndorfer J, Christensen L, Merion RM. Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med. 2003 Sep 4;349(10):931-40. — View Citation

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. — View Citation

Tsuchimoto A, Shinke H, Uesugi M, Kikuchi M, Hashimoto E, Sato T, Ogura Y, Hata K, Fujimoto Y, Kaido T, Kishimoto J, Yanagita M, Matsubara K, Uemoto S, Masuda S. Urinary neutrophil gelatinase-associated lipocalin: a useful biomarker for tacrolimus-induced acute kidney injury in liver transplant patients. PLoS One. 2014 Oct 20;9(10):e110527. doi: 10.1371/journal.pone.0110527. eCollection 2014. — View Citation

Vaidya VS, Ozer JS, Dieterle F, Collings FB, Ramirez V, Troth S, Muniappa N, Thudium D, Gerhold D, Holder DJ, Bobadilla NA, Marrer E, Perentes E, Cordier A, Vonderscher J, Maurer G, Goering PL, Sistare FD, Bonventre JV. Kidney injury molecule-1 outperforms traditional biomarkers of kidney injury in preclinical biomarker qualification studies. Nat Biotechnol. 2010 May;28(5):478-85. doi: 10.1038/nbt.1623. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Urinary neutrophil gelatinase-associated lipocalin (NGAL)	Change in Urinary NGAL level (ng/mL)	4 weeks
Secondary	Estimated Glomerular Filtration Rate (eGFR)	Change in eGRF level by the Creatinine-Cystatin C CKD-EPI equation (mL/min/1.73m2)	4 weeks
Secondary	Microalbuminuria	Change in Urine albumin-creatinine ratio	4 weeks
Secondary	CYP3A5 expressor category	CYP3A5 genotyping to determine expressor category	Baseline
Secondary	Heart transplant rejection	The rate of rejection as defined as treated rejection within the last 30 days for any grade>1R, AMR, or acute graft dysfunction (LVEF drop greater than 10%)	1 year
Secondary	Cardiac allograft vasculopathy	The rate of cardiac allograft vasculopathy based on coronary angiography with or without IVUS and right heart catheterization hemodynamics	1 year
Secondary	Blood pressure	Change in blood pressure (mmHg)	1 year
Secondary	Serum glucose	Change in serum glucose levels (mg/dL)	1 year
Secondary	LDL Cholesterol	Change in LDL cholesterol level (mg/dL)	1 year