Mesenchymal Stem Cells Under Basiliximab/Low Dose RATG to Induce Renal Transplant Tolerance

NCT00752479 | Terminated Phase 1

• 2 other identifiers: MSC KTX2009-012350-20
• Study Type: interventional
• Target: 4
• Locations: 1 country
• Sites: 1

Brief Summary

This a pilot, explorative study to define the safety and biological/mechanistic effect of the systemic intravenous infusion of syngeneic ex-vivo expanded MSCs in living-related kidney transplant recipients (one or two HLA haplotype mismatches) under basiliximab/low-dose RATG induction therapy and maintenance immunosuppressive drugs with the ultimate objective to test the feasibility of safely achieving graft tolerance in a subsequent efficacy pilot study. Specific objectives To compare changes in the immunophenotype and ex-vivo T-cell functional tests from samples of peripheral blood and measurement in the urine of messenger RNA for FoxP3,in kidney transplant recipients given or not syngeneic (from the recipient) MSC infusion under basiliximab/low-dose RATG induction therapy and maintenance immunosuppressive treatment with low-dose cyclosporine (CsA) plus low-dose mycophenolate mofetil (MMF). This will assess at different time up to 12 months post transplant. In addition the safety profile of MSC infusion will be investigated. We have planned to start with the safety and biological/mechanistic study in 6 living-related kidney transplant recipients. Three patients will receive ex-vivo expanded syngeneic MSC infusion (2x106 MSCs per kilogram body weight) at the time of kidney transplant, and 3 additional patients no cells (controls), both under the cover of induction therapy with basiliximab and low-dose RATG, and maintenance immunosuppression with low-dose CsA and MMF. Randomization to MSC or no cell infusion will be performed at the time the recipient will sign the informed consent to participate to the study. Should this biological/mechanistic ex vivo studies document that MSC infusion allows the development of an immune microenvironment permissive to graft tolerance, a pilot efficacy study to achieve operational tolerance after complete withdrawal of maintenance immunosuppressive therapy will follow. In this additional pilot explorative efficacy study all consecutive patients will be included and followed until the first episode of rejection (if any) will occur or 29 consecutive patients have successfully withdrawn the immunosuppressive therapy. This has been estimated according to the Simon's two-stage minimax design.

Conditions

Kidney Transplant

Keywords

living; related

Outcome Measures

Primary Outcomes (1)

• Assessing the percentage of inhibition of memory T cell response and/or naive T cell response, the induction of donor-reactive T cell anergy and the appearance in the peripheral blood of regulatory T cells.

  at 12 months post-kidney transplant

Secondary Outcomes (1)

• Safety parameters related to MSC infusion, graft function, graft rejection

  at 12 months post-kidney transplant

Study Arms (2)

1

EXPERIMENTAL

Biological: Mesenchymal stem cells infusion, Basiliximab,Methylprednisolone,RATG ,Cyclosporine ,Mycophenolate mofetil

2

ACTIVE COMPARATOR

Drug: Basiliximab, Methylprednisolone,RATG,Cyclosporine,Mycophenolate mofetil

Interventions

Mesenchymal stem cells infusion, Basiliximab,Methylprednisolone,RATG ,Cyclosporine ,Mycophenolate mofetil BIOLOGICAL

Cell therapy Mesenchymal cells infusion. Induction therapy: Basiliximab (20 mg i.v.day 0 and day 4 post-tx). Low dose RATG (0.5 mg/kg/day i.v. day 0-6 post-tx). Methylprednisolone (500 mg to 25 mg from day 0 to 6 post-tx. Then stop). Maintenance therapy: Cyclosporine (from day 0: dose according to target trough blood level). Mycophenolate mofetil (750 mg b.i.d. from day 1 post-tx).

1

Basiliximab, Methylprednisolone,RATG,Cyclosporine,Mycophenolate mofetil DRUG

Routine immunosuppressive therapy Induction therapy: Basiliximab (20 mg i.v.day 0 and day 4 post-tx). Low dose RATG (0.5 mg/kg/day i.v. day 0-6 post-tx). Methylprednisolone (500 mg to 25 mg from day 0 to 6 post-tx. Then stop). Maintenance therapy: Cyclosporine (from day 0: dose according to target trough blood level). Mycophenolate mofetil (750 mg b.i.d. from day 1 post-tx).

2

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male and female patients
• Aged 18 or older
• Non-HLA identical with the donor (one or two haplotype mismatches)
• First kidney transplant
• Capable of understanding the purpose and risk of the study
• Written informed consent

You may not qualify if:

• MSC donor positive for HIV-1, HIV-2, HBV, HCV, Syphilis.
• Specific contraindication to MSC infusion
• Any clinical relevant condition that might affect study participation and/or study results
• Pregnant women and nursing mothers
• Unwillingness or inability to follow study protocol in the investigator's opinion

Sponsors & Collaborators

• Mario Negri Institute for Pharmacological Research: lead

Study Sites (1)

Nephrology Unit

Bergamo, BG, 24128, Italy

Location

Related Publications (3)

• Perico N, Casiraghi F, Todeschini M, Cortinovis M, Gotti E, Portalupi V, Mister M, Gaspari F, Villa A, Fiori S, Introna M, Longhi E, Remuzzi G. Long-Term Clinical and Immunological Profile of Kidney Transplant Patients Given Mesenchymal Stromal Cell Immunotherapy. Front Immunol. 2018 Jun 14;9:1359. doi: 10.3389/fimmu.2018.01359. eCollection 2018.

  PMID: 29963053 DERIVED

• Perico N, Casiraghi F, Gotti E, Introna M, Todeschini M, Cavinato RA, Capelli C, Rambaldi A, Cassis P, Rizzo P, Cortinovis M, Noris M, Remuzzi G. Mesenchymal stromal cells and kidney transplantation: pretransplant infusion protects from graft dysfunction while fostering immunoregulation. Transpl Int. 2013 Sep;26(9):867-78. doi: 10.1111/tri.12132. Epub 2013 Jun 6.

  PMID: 23738760 DERIVED

• Perico N, Casiraghi F, Introna M, Gotti E, Todeschini M, Cavinato RA, Capelli C, Rambaldi A, Cassis P, Rizzo P, Cortinovis M, Marasa M, Golay J, Noris M, Remuzzi G. Autologous mesenchymal stromal cells and kidney transplantation: a pilot study of safety and clinical feasibility. Clin J Am Soc Nephrol. 2011 Feb;6(2):412-22. doi: 10.2215/CJN.04950610. Epub 2010 Oct 7.

  PMID: 20930086 DERIVED

MeSH Terms

Interventions

Basiliximab; Mycophenolic Acid

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Caproates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids; Lipids

Study Officials

• Giuseppe Remuzzi, MD

  Department of Immunology and Clinical Transplantation / Mario Negri Institute for Pharmacological Research and Ospedali Riuniti BG

  STUDY CHAIR

• Norberto Perico, MD

  Mario Negri Institute for Pharmacological Research, Ranica BG

  PRINCIPAL INVESTIGATOR

• Marina Noris, CH Ph

  Mario Negri Institute for Pharmacological Research, Ranica BG

  PRINCIPAL INVESTIGATOR

• Martino Introna, MD

  Cell and Gene therapy Laboratory "G. Lanzani" BG

  PRINCIPAL INVESTIGATOR

• Alessandro Rambaldi, MD

  Hematology Unit - Ospedali Riuniti BG

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 23, 2008
• First Posted: September 15, 2008
• Study Start: May 1, 2008
• Primary Completion: July 1, 2013
• Study Completion: December 1, 2013
• Last Updated: December 4, 2023

Record last verified: 2015-04

Locations

IT (1)