Kidney Failure, Chronic Clinical Trial
Official title:
A Phase 2, Randomized, Placebo-Controlled Study to Evaluate Fingolimod for the Abrogation of Interstitial Fibrosis and Tubular Atrophy Following Kidney Transplantation
Verified date | January 2023 |
Source | The Methodist Hospital Research Institute |
Contact | n/a |
Is FDA regulated | No |
Health authority | |
Study type | Interventional |
This is a randomized, double-blind, placebo-controlled trial in de novo kidney transplant patients to determine if the addition of fingolimod (brand name Gilenya®, candidate name- FTY720) on the background of standard immunosuppression will prevent expansion of the interstitial compartment of the transplanted kidney. Interstitial expansion is the precursor of interstitial fibrosis and graft loss. The study will test the hypothesis that abgrogating the fibrogenic effects of both the RhoA and mTOR pathways with fingolimod will reduce structural damage in transplanted kidneys and possible subsequent transplant failure.
Status | Enrolling by invitation |
Enrollment | 20 |
Est. completion date | September 15, 2025 |
Est. primary completion date | January 15, 2025 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 18 Years to 65 Years |
Eligibility | Inclusion Criteria: - Provision of signed and dated informed consent form - Stated willingness to comply with all study procedures and availability for the duration of the study - Receiving a first or second kidney transplant - Male or female, aged =18 to =65 - Women of child bearing potential who have a negative serum pregnancy test prior to treatment - Women of child bearing potential (including perimenopausal women who have had a menstrual period within the previous 1 year) who agree to use 2 forms of effective birth control regimen (at least one of which is a barrier method) throughout the study period and for 6 weeks following the end of the study or the last dose of mycophenolic acid, whichever comes first. - Panel of reactive antibodies <50% - Able to take oral medication - Agreement to adhere to Lifestyle Considerations throughout study duration: refraining from the consumption of grapefruit or grapefruit juice and stopping any anticoagulation therapy, including ASA, one week prior and one week post kidney biopsy procedure Exclusion Criteria: - Transplantation of any organ other than kidney - History or presence of second degree AV block, third degree AV block, symptomatic bradycardia, or an arrhythmia requiring current treatment with Class Ia or III antiarrhythmic drugs. - Heart rate <60 beats per minute - Presence of an increased QTc interval > 500 ms on screening ECG. - Presence of a cardiac pacemaker. - History of any major cardiac events, including heart attack within the last six months of enrollment, unstable angina, congestive heart failure, or any severe cardiac disease as determined by investigator - Known macular degeneration - Diagnosed with any significant coagulopathy or medical condition requiring long-term systemic anticoagulation after transplantation, which would interfere with obtaining biopies. - Diagnosed with chronic immune system disease - Diagnosed with acute pulmonary disease - Diagnosed with severe liver disease, including abnormal liver enzymes or total bilirubin greater than three times upper limit of normal. - Diagnosed with any past or present malignancies except squamous or basal cell carcinoma of the skin excised at least two years prior to randomization. - Diagnosed with active acute or chronic infection, or febrile illness within two weeks prior to randomization. - Recent history of strokes in the preceding 6 months - Use of ketoconazole for more than 2 weeks - Use of any investigational drug during the 4 weeks prior to enrolling in this study - Women of child bearing potential who are breastfeeding - Women of childbearing potential not practicing reliable methods of contraception. Reliable methods for contraception include surgical sterilization (hysterectomy, bilateral tubal ligation), double-barrier method (such as condom and diaphragm). To be considered as post-menopausal and not of childbearing potential, female participants must have experienced 12 consecutive months of amenorrhea. - Known allergic reactions to components of Gilenya®, specifically fingolimod, gelatin, magnesium stearate, mannitol, titanium dioxide, and/or yellow iron oxide - Presence of any medical or psychosocial condition, which the investigator believes, would hinder adherence to the study requirements. |
Country | Name | City | State |
---|---|---|---|
United States | Houston Methodist Research Institute | Houston | Texas |
Lead Sponsor | Collaborator |
---|---|
The Methodist Hospital Research Institute |
United States,
Bohler T, Waiser J, Schuetz M, Neumayer HH, Budde K. FTY720 exerts differential effects on CD4+ and CD8+ T-lymphocyte subpopulations expressing chemokine and adhesion receptors. Nephrol Dial Transplant. 2004 Mar;19(3):702-13. doi: 10.1093/ndt/gfg599. — View Citation
Budde K, L Schmouder R, Nashan B, Brunkhorst R, W Lucker P, Mayer T, Brookman L, Nedelman J, Skerjanec A, Bohler T, Neumayer HH. Pharmacodynamics of single doses of the novel immunosuppressant FTY720 in stable renal transplant patients. Am J Transplant. 2003 Jul;3(7):846-54. doi: 10.1034/j.1600-6143.2003.00130.x. — View Citation
Budde K, Schmouder RL, Brunkhorst R, Nashan B, Lucker PW, Mayer T, Choudhury S, Skerjanec A, Kraus G, Neumayer HH. First human trial of FTY720, a novel immunomodulator, in stable renal transplant patients. J Am Soc Nephrol. 2002 Apr;13(4):1073-1083. doi: 10.1681/ASN.V1341073. — View Citation
Chen W, Chen S, Chen W, Li XC, Ghobrial RM, Kloc M. Screening RhoA/ROCK inhibitors for the ability to prevent chronic rejection of mouse cardiac allografts. Transpl Immunol. 2018 Oct;50:15-25. doi: 10.1016/j.trim.2018.06.002. Epub 2018 Jun 6. — View Citation
Chen W, Chen W, Li XC, Ghobrial RM, Kloc M. Coinhibition of mTORC1/mTORC2 and RhoA/ROCK pathways prevents chronic rejection of rat cardiac allografts. Transplant Reports. 2018;3(4):21-28.
Chen W, Ghobrial RM, Li XC, Kloc M. Inhibition of RhoA and mTORC2/Rictor by Fingolimod (FTY720) induces p21-activated kinase 1, PAK-1 and amplifies podosomes in mouse peritoneal macrophages. Immunobiology. 2018 Nov;223(11):634-647. doi: 10.1016/j.imbio.2018.07.009. Epub 2018 Jul 7. — View Citation
CONSORT Group. CONSORT Transparent reporting of trials. 2010; http://www.consort-statement.org/consort-2010. Accessed July 29, 2020.
Cosio FG, Grande JP, Larson TS, Gloor JM, Velosa JA, Textor SC, Griffin MD, Stegall MD. Kidney allograft fibrosis and atrophy early after living donor transplantation. Am J Transplant. 2005 May;5(5):1130-6. doi: 10.1111/j.1600-6143.2005.00811.x. — View Citation
Fioretto P, Steffes MW, Sutherland DE, Mauer M. Sequential renal biopsies in insulin-dependent diabetic patients: structural factors associated with clinical progression. Kidney Int. 1995 Dec;48(6):1929-35. doi: 10.1038/ki.1995.493. — View Citation
Gilenya [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2019.
Hart A, Smith JM, Skeans MA, Gustafson SK, Stewart DE, Cherikh WS, Wainright JL, Kucheryavaya A, Woodbury M, Snyder JJ, Kasiske BL, Israni AK. OPTN/SRTR 2015 Annual Data Report: Kidney. Am J Transplant. 2017 Jan;17 Suppl 1(Suppl 1):21-116. doi: 10.1111/ajt.14124. — View Citation
Hart A, Smith JM, Skeans MA, Gustafson SK, Wilk AR, Castro S, Robinson A, Wainright JL, Snyder JJ, Kasiske BL, Israni AK. OPTN/SRTR 2017 Annual Data Report: Kidney. Am J Transplant. 2019 Feb;19 Suppl 2:19-123. doi: 10.1111/ajt.15274. — View Citation
Hoitsma AJ, Woodle ES, Abramowicz D, Proot P, Vanrenterghem Y; FTY720 Phase II Transplant Study Group. FTY720 combined with tacrolimus in de novo renal transplantation: 1-year, multicenter, open-label randomized study. Nephrol Dial Transplant. 2011 Nov;26(11):3802-5. doi: 10.1093/ndt/gfr503. Epub 2011 Sep 12. — View Citation
Ibrahim HN, Jackson S, Connaire J, Matas A, Ney A, Najafian B, West A, Lentsch N, Ericksen J, Bodner J, Kasiske B, Mauer M. Angiotensin II blockade in kidney transplant recipients. J Am Soc Nephrol. 2013 Feb;24(2):320-7. doi: 10.1681/ASN.2012080777. Epub 2013 Jan 10. — View Citation
Kahan BD, Karlix JL, Ferguson RM, Leichtman AB, Mulgaonkar S, Gonwa TA, Skerjanec A, Schmouder RL, Chodoff L. Pharmacodynamics, pharmacokinetics, and safety of multiple doses of FTY720 in stable renal transplant patients: a multicenter, randomized, placebo-controlled, phase I study. Transplantation. 2003 Oct 15;76(7):1079-84. doi: 10.1097/01.TP.0000084822.01372.AC. — View Citation
Kappos L, Antel J, Comi G, Montalban X, O'Connor P, Polman CH, Haas T, Korn AA, Karlsson G, Radue EW; FTY720 D2201 Study Group. Oral fingolimod (FTY720) for relapsing multiple sclerosis. N Engl J Med. 2006 Sep 14;355(11):1124-40. doi: 10.1056/NEJMoa052643. — View Citation
Kovarik JM, Schmouder R, Barilla D, Riviere GJ, Wang Y, Hunt T. Multiple-dose FTY720: tolerability, pharmacokinetics, and lymphocyte responses in healthy subjects. J Clin Pharmacol. 2004 May;44(5):532-7. doi: 10.1177/0091270004264165. — View Citation
Kovarik JM, Schmouder R, Barilla D, Wang Y, Kraus G. Single-dose FTY720 pharmacokinetics, food effect, and pharmacological responses in healthy subjects. Br J Clin Pharmacol. 2004 May;57(5):586-91. doi: 10.1111/j.1365-2125.2003.02065.x. — View Citation
Matas AJ, Smith JM, Skeans MA, Thompson B, Gustafson SK, Stewart DE, Cherikh WS, Wainright JL, Boyle G, Snyder JJ, Israni AK, Kasiske BL. OPTN/SRTR 2013 Annual Data Report: kidney. Am J Transplant. 2015 Jan;15 Suppl 2:1-34. doi: 10.1111/ajt.13195. — View Citation
Meng XM, Nikolic-Paterson DJ, Lan HY. Inflammatory processes in renal fibrosis. Nat Rev Nephrol. 2014 Sep;10(9):493-503. doi: 10.1038/nrneph.2014.114. Epub 2014 Jul 1. — View Citation
Mulgaonkar S, Tedesco H, Oppenheimer F, Walker R, Kunzendorf U, Russ G, Knoflach A, Patel Y, Ferguson R; FTYA121 study group. FTY720/cyclosporine regimens in de novo renal transplantation: a 1-year dose-finding study. Am J Transplant. 2006 Aug;6(8):1848-57. doi: 10.1111/j.1600-6143.2006.01404.x. Epub 2006 Jun 12. Erratum In: Am J Transplant. 2006 Dec;6(12):3044. — View Citation
Naesens M, Kuypers DR, De Vusser K, Vanrenterghem Y, Evenepoel P, Claes K, Bammens B, Meijers B, Lerut E. Chronic histological damage in early indication biopsies is an independent risk factor for late renal allograft failure. Am J Transplant. 2013 Jan;13(1):86-99. doi: 10.1111/j.1600-6143.2012.04304.x. Epub 2012 Nov 8. — View Citation
Nankivell BJ, Borrows RJ, Fung CL, O'Connell PJ, Allen RD, Chapman JR. The natural history of chronic allograft nephropathy. N Engl J Med. 2003 Dec 11;349(24):2326-33. doi: 10.1056/NEJMoa020009. — View Citation
Nankivell BJ, Chapman JR. Chronic allograft nephropathy: current concepts and future directions. Transplantation. 2006 Mar 15;81(5):643-54. doi: 10.1097/01.tp.0000190423.82154.01. — View Citation
Nankivell BJ, Fenton-Lee CA, Kuypers DR, Cheung E, Allen RD, O'Connell PJ, Chapman JR. Effect of histological damage on long-term kidney transplant outcome. Transplantation. 2001 Feb 27;71(4):515-23. doi: 10.1097/00007890-200102270-00006. — View Citation
OPTN/SRTR Annual Data Report - 2011. 2011; https://srtr.transplant.hrsa.gov/annual_reports/2011/Default.aspx. Accessed July 29, 2020.
Park SI, Felipe CR, Machado PG, Garcia R, Skerjanec A, Schmouder R, Tedesco-Silva H Jr, Medina-Pestana JO. Pharmacokinetic/pharmacodynamic relationships of FTY720 in kidney transplant recipients. Braz J Med Biol Res. 2005 May;38(5):683-94. doi: 10.1590/S0100-879X2005000500005. Epub 2005 May 25. — View Citation
Salvadori M, Budde K, Charpentier B, Klempnauer J, Nashan B, Pallardo LM, Eris J, Schena FP, Eisenberger U, Rostaing L, Hmissi A, Aradhye S; FTY720 0124 Study Group. FTY720 versus MMF with cyclosporine in de novo renal transplantation: a 1-year, randomized controlled trial in Europe and Australasia. Am J Transplant. 2006 Dec;6(12):2912-21. doi: 10.1111/j.1600-6143.2006.01552.x. — View Citation
Sis B, Einecke G, Chang J, Hidalgo LG, Mengel M, Kaplan B, Halloran PF. Cluster analysis of lesions in nonselected kidney transplant biopsies: microcirculation changes, tubulointerstitial inflammation and scarring. Am J Transplant. 2010 Feb;10(2):421-30. doi: 10.1111/j.1600-6143.2009.02938.x. Epub 2010 Jan 6. — View Citation
Skerjanec A, Tedesco H, Neumayer HH, Cole E, Budde K, Hsu CH, Schmouder R. FTY720, a novel immunomodulator in de novo kidney transplant patients: pharmacokinetics and exposure-response relationship. J Clin Pharmacol. 2005 Nov;45(11):1268-78. doi: 10.1177/0091270005279799. — View Citation
Tedesco-Silva H, Lorber MI, Foster CE, Sollinger HW, Mendez R, Carvalho DB, Shapiro R, Rajagopalan PR, Mayer H, Slade J, Kahan BD; FTY720A2202 clinical study group. FTY720 and everolimus in de novo renal transplant patients at risk for delayed graft function: results of an exploratory one-yr multicenter study. Clin Transplant. 2009 Sep-Oct;23(5):589-99. doi: 10.1111/j.1399-0012.2009.01070.x. Epub 2009 Aug 27. — View Citation
Tedesco-Silva H, Szakaly P, Shoker A, Sommerer C, Yoshimura N, Schena FP, Cremer M, Hmissi A, Mayer H, Lang P; FTY720 2218 Clinical Study Group. FTY720 versus mycophenolate mofetil in de novo renal transplantation: six-month results of a double-blind study. Transplantation. 2007 Oct 15;84(7):885-92. doi: 10.1097/01.tp.0000281385.26500.3b. — View Citation
Vanhove T, Goldschmeding R, Kuypers D. Kidney Fibrosis: Origins and Interventions. Transplantation. 2017 Apr;101(4):713-726. doi: 10.1097/TP.0000000000001608. — View Citation
* Note: There are 33 references in all — Click here to view all references
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | Emergent and Adverse Events | The difference in the proportion of cumulative treatment-emergent (TE) adverse events (AE) determined to be = grade 3 severity that occur during 12 months from the first dose of FTY720 compared to the placebo group. | Baseline (day of kidney transplant surgery); 3, 14, 30, 90, 180, 270, and 365 days after starting study drug or placebo | |
Secondary | Fraction of Renal Cortical Volume Occupied by Interstitium | A doubling of the fraction of renal cortical volume occupied by interstitium (VvInt/cortex) compared to the baseline biopsy in participants taking 0.5mg/day fingolimod (experimental group) or placebo (control group) for 3 months | Baseline, 3 months after kidney transplant, 1 year after kidney transplant | |
Secondary | MCP1 Biomarker | Measurement of Monocyte Chemoattractant Protein-1 | Baseline, 90 days, and 1 year after the first dose of fingolimod or placebo | |
Secondary | Procollagen 3 Peptide Biomarker | Measurement of Procollagen 3 Peptide | Baseline, 90 days, and 1 year after the first dose of fingolimod or placebo | |
Secondary | BMP-7 Protein Biomarker | Measurement of Bone Morphogenetic Protein 7 | Baseline, 90 days, and 1 year after the first dose of fingolimod or placebo | |
Secondary | TGF-beta Biomarker | Measurement of Transforming Growth Factor beta | Baseline, 90 days, and 1 year after the first dose of fingolimod or placebo | |
Secondary | RhoA of Blood Monocytes | Measurement of Ras homolog family member A protein | Baseline, 90 days, and 1 year after the first dose of fingolimod or placebo | |
Secondary | RICTOR Biomarker | Measurement of RPTOR Independent Companion Of MTOR Complex 2 | Baseline, 90 days, and 1 year after the first dose of fingolimod or placebo | |
Secondary | Urinary Albumin:Creatinine Ratio | The ratio of albumin to creatinine in a urine sample from the patient | Baseline; 3, 14, 30, 90, 180, 270, and 365 days after starting study drug or placebo | |
Secondary | Change in Estimated Glomerular Filtration Rate | Estimated glomerular filtration rate relative to the baseline value or previous endpoints | Baseline; 3, 14, 30, 90, 180, 270, and 365 days after starting study drug or placebo | |
Secondary | Causes of End-Stage Renal Disease | Recording the cause of end-stage renal disease, if it develops | Up to 1 year after taking the first dose of the study drug or placebo | |
Secondary | Biopsy-Proven Acute Rejection | Biopsy-proven acute rejection as diagnosed by a qualified pathologist | Baseline, 3 months after kidney transplant, 1 year after kidney transplant | |
Secondary | Patient Survival | Whether the patient is deceased or alive | Baseline; 3, 14, 30, 90, 180, 270, and 365 days after starting study drug or placebo | |
Secondary | Graft Survival | Whether the patient required a new kidney graft or the patient is deceased | Baseline; 3, 14, 30, 90, 180, 270, and 365 days after starting study drug or placebo |
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