Fingolimod for the Abrogation of Interstitial Fibrosis and Tubular Atrophy Following Kidney Transplantation

NCT05285878 | Enrolling By Invitation Phase 2 FDA Drug

• 2 other identifiers: PRO00022269U1111-1226-4680
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Interstitial Fibrosis; Kidney Transplant; Complications; Kidney Transplant Rejection; Kidney Transplant Failure and Rejection; Kidney Transplant Failure; Kidney Failure, Chronic; Graft Rejection

Keywords

Fingolimod Hydrochloride; Kidney Transplantation; Glomerular Filtration Rate; Kidney; Fibrosis; Immunosuppression Therapy; TOR Serine-Threonine Kinases; Graft Survival; Transplantation; Transplant Recipients; Organ Transplant; Tubular Atrophy; Interstitial Fibrosis and Tubular Atrophy

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (13)

• Fraction of Renal Cortical Volume Occupied by Interstitium

  Baseline, 3 months after kidney transplant, 1 year after kidney transplant

• MCP1 Biomarker

  Baseline, 90 days, and 1 year after the first dose of fingolimod or placebo

• Procollagen 3 Peptide Biomarker

  Baseline, 90 days, and 1 year after the first dose of fingolimod or placebo

• BMP-7 Protein Biomarker

  Baseline, 90 days, and 1 year after the first dose of fingolimod or placebo

• TGF-beta Biomarker

  Baseline, 90 days, and 1 year after the first dose of fingolimod or placebo

Study Arms (2)

Placebo

PLACEBO COMPARATOR

Participants will take a placebo capsule daily for 3 months. Placebo will be methylcellulose encapsulated into an opaque closed gelatin capsule for blinding. Capsules will be placed in a labeled bottle, with the contents only identifiable by a code on the package label and only the compounding pharmacy and the unblinded pharmacist at Houston Methodist Investigational Drug Service will know the code definition.

Drug: Placebo

Fingolimod

ACTIVE COMPARATOR

Participants will take a 0.5 mg fingolimod capsule each day for 3 months. The fingolimod capsule will be placed inside an opaque closed gelatin capsule without transformation of the manufacteror's fingolimod capsule. The fingolimod blinded product and the placebo capsule will be identical in size, color, appearance, and weight.

Drug: Fingolimod

Interventions

Fingolimod DRUG

0.5 mg daily

Also known as: GILENYA®, FTY720

Fingolimod

Placebo DRUG

0.5 mg daily

Also known as: methylcellulose

Placebo

Eligibility Criteria

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

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• The Methodist Hospital Research Institute: lead

Study Sites (1)

Houston Methodist Research Institute

Houston, Texas, 77030, United States

Location

Related Publications (33)

• Gilenya [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2019.

  BACKGROUND

• 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.

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• 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.

  PMID: 28052609 BACKGROUND

• 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.

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• 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.

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• OPTN/SRTR Annual Data Report - 2011. 2011; https://srtr.transplant.hrsa.gov/annual_reports/2011/Default.aspx. Accessed July 29, 2020.

  BACKGROUND

• Vanhove T, Goldschmeding R, Kuypers D. Kidney Fibrosis: Origins and Interventions. Transplantation. 2017 Apr;101(4):713-726. doi: 10.1097/TP.0000000000001608.

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• 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.

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• 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.

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• 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.

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• 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.

  PMID: 23308016 BACKGROUND

• 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.

  PMID: 11912269 BACKGROUND

• 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.

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• 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.

  PMID: 15102874 BACKGROUND

• 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.

  PMID: 14767029 BACKGROUND

• 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.

  PMID: 14557756 BACKGROUND

• 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.

  PMID: 15917949 BACKGROUND

• 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.

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• 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.

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• 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.

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• 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.

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• 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.

  PMID: 29885441 BACKGROUND

• 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.

  PMID: 30005970 BACKGROUND

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  BACKGROUND

• 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.

  PMID: 12814476 BACKGROUND

MeSH Terms

Conditions

Pulmonary Fibrosis; Rejection, Psychology; Kidney Failure, Chronic; Fibrosis

Interventions

Fingolimod Hydrochloride; Methylcellulose

Condition Hierarchy (Ancestors)

Lung Diseases, Interstitial; Lung Diseases; Respiratory Tract Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Social Behavior; Behavior; 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

Intervention Hierarchy (Ancestors)

Sphingosine; Amino Alcohols; Alcohols; Organic Chemicals; Propylene Glycols; Glycols; Amines; Cellulose; Glucans; Polysaccharides; Carbohydrates

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, CARE PROVIDER
• Masking Details: Participants and the study team will be blinded as to the assignment until the database is locked. Only the investigational pharmacist will know the study assignment.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Chair, Department of Surgery

Model Details: Phase 2, Randomized, Placebo-Controlled Study

Study Record Dates

• First Submitted: March 8, 2022
• First Posted: March 18, 2022
• Study Start: July 28, 2022
• Primary Completion (Estimated): June 1, 2027
• Study Completion (Estimated): December 1, 2027
• Last Updated: March 14, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)