Clinical Trial With Donor Modified Immune Cells in Living Donor Kidney Transplantation

NCT05365672 | Recruiting Phase 2 DMC

• 1 other identifier: TOL-2
• Study Type: interventional
• Target: 126
• Locations: 1 country
• Sites: 8

Brief Summary

In this clinical trial the investigational medicinal product MIC is to be examined for its efficacy and safety in patients with living kidney transplantation. For this purpose the patients participating in the clinical trial and their associated kidney donors are randomly assigned to one of three treatment groups during the screening procedure. For the production of the investigational medicinal product MIC for the patients in the MIC therapy group mononuclear cells of the peripheral blood are obtained from the donors in a leukapheresis procedure. In the subsequent treatment phase, the patients in the MIC therapy group receive MIC as a weight-adjusted single dose administered intravenously. As part of the 12-month follow-up phase the kidney transplant and the corresponding immunosuppressive therapy will take place seven days later. Patients in the control group will receive a conventional standard immunosuppressive regimen without prior administration of the investigational medicinal product MIC after kidney transplantation. All patients taking part in this clinical trial are followed up for one year after kidney transplantation with regard to the efficacy and safety of MIC in regular visits at their study site. As the investigational medicinal product is an advanced therapy medicinal product (ATMP) all subjects will be monitored for a further 2 years after the end of the follow-up phase of the clinical trial. A total of 63 transplant pairs, consisting of donor and transplant recipient, are to be included in the clinical trial. The 63 patients will be randomized 2:1 to be treated with MIC (MIC group) or without MIC (control group). Additionally, low immunosuppression or minimal immunosuppression treatments will be used in the patients in the MIC group.

Conditions

Kidney Transplantation

Keywords

living donor kidney transplantation; TOL-2; modified immune cells; MIC; mitomycin C; peripheral blood mononuclear cells; PBMC; kidney donor; TolerogenixX; tolerance; immunosuppression; donor-specific unresponsiveness; EudraCT No. 2021-000561-33

Outcome Measures

Primary Outcomes (4)

• No acute rejection, graft loss, graft dysfunction

  Proportion of patients who achieve an operational tolerance-like phenotype compared to standard of care therapy defined on Visit Day 367 as fulfilling four criteria that are evaluated: Criterium 1.: No acute rejection (biopsy-proven as \>Banff Borderline or clinically suspected rejection according to evaluation of adjudication committee), graft loss, graft dysfunction (eGFR \<30 mL/min), or death on Visit Day 367

  On day 367 post investigational medicinal product application

• No development of de novo donor-specific HLA- antibodies

  Proportion of patients who achieve an operational tolerance-like phenotype compared to standard of care therapy defined on Visit Day 367 as fulfilling four criteria that are evaluated: Criterium 2.: No development of donor-specific HLA antibodies (DSA ≤1,000 MFI; values \>1,000 MFI after Visit Day 6 has to be confirmed by second measurement after 4 weeks) until Visit Day 367 as measured by Luminex single antigen test

  Between day 0 and day 367 post investigational medicinal product application

• Induction of regulatory B cells (Breg) to ≥3%

  Proportion of patients who achieve an operational tolerance-like phenotype compared to standard of care therapy defined on Visit Day 367 as fulfilling four criteria that are evaluated: Criterium 3.: Induction of Breg ≥3% measured on Visit Day 367 (patient has to be infection-free at timepoint of measurement)

  On day 367 post investigational medicinal product application

• Patient on tacrolimus therapy with ≤720 mg EC-MPS and no corticosteroids

  Proportion of patients who achieve an operational tolerance-like phenotype compared to standard of care therapy defined on Visit Day 367 as fulfilling four criteria that are evaluated: Criterium 4.: Patient on tacrolimus therapy with ≤720 mg EC-MPS and no corticosteroids (as well as no other immunosuppressive drug) on Visit Day 277 and remaining on this therapy until Visit Day 367

  Between days 277 and 367 post investigational medicinal product application

Secondary Outcomes (23)

• Key secondary: Number of patient-relevant infections during the first year after transplantation

  On day 367 post investigational medicinal product application

• Key secondary: Biopsy proven acute rejection, graft loss, graft dysfunction, or death

  On day 367 post investigational medicinal product application

• Number of Adverse Events (AEs) including serious AEs and AEs of special interest

  From screening through study completion, 3 years estimated.

• Frequency of local or systemic reactions as result of MIC application

  From day 0 through study completion, 3 years estimated.

• Monitoring of patient survival

  On Visit Days 187 and 367 post investigational medicinal product application

Study Arms (3)

MIC with low immunosuppression

EXPERIMENTAL

Patients in MIC Arm A receive the investigational medicinal product MIC plus immunosuppression consisting of tacrolimus, mycophenolic acid derivative and corticosteroids (without IL-2 receptor antibody induction therapy). Tacrolimus dose will be gradually reduced to 4-8 μg/L at Day 183 and the corticosteroid treatment will be stopped at Day 92 after gradual dose reduction.

Biological: MIC

MIC with minimal immunosuppression

EXPERIMENTAL

Patients in MIC Arm B receive the investigational medicinal product MIC plus immunosuppression consisting of tacrolimus, mycophenolic acid derivative and corticosteroids (without IL-2 receptor antibody induction therapy). Tacrolimus dose will be gradually reduced to 4-8 μg/L at Day 183 and the corticosteroid treatment will be stopped at Day 92 after gradual dose reduction. The mycophenolic acid derivative will be stopped between Days 141 and 182.

Biological: MIC

Standard of care immunosuppression for transplantation

OTHER

Patients of the Control Arm receive standard of care immunosuppression for kidney transplantations according to the Efficacy Limiting Toxicity Elimination (ELITE) symphony scheme (interleukin \[IL\]-2 receptor antibody induction therapy, tacrolimus, mycophenolic acid derivative and corticosteroids) without the investigational medicinal product MIC.

Other: Standard of Care

Interventions

MIC BIOLOGICAL

Single intravenous infusion of 1.5x10exp8 MIC per kg of body weight

MIC with low immunosuppression; MIC with minimal immunosuppression

Standard of Care OTHER

No application of the investigational medicinal product MIC

Standard of care immunosuppression for transplantation

Eligibility Criteria

• Age: 18 Years - 69 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Donors:
• Age ≥18 years and able to consent
• Ability to understand the nature and scope of the clinical trial
• Written consent form given prior to any trial-related procedures (including PBMC donation)
• Patients:
• Patient with CKD in stage 5 (e.g., estimated glomerular filtration rate \[eGFR\] \<15 mL/min and/or on renal replacement therapy), who are in preparation for kidney transplantation from a live donor
• Age ≥18 years, \<70 years
• ABO-blood group identical or compatible with donor
• First kidney transplantation
• Complement dependent cytotoxicity (CDC)-panel reactive antibodies \<20%
• No detection of a donor-specific HLA-antibody in the Luminex-Assay (cutoff: mean fluorescence intensity \[MFI\] ≤1,000)
• Negative CDC crossmatch with the donor
• Negative PCR test result for severe acute respiratory syndrome coronavirus-2 (SARSCoV-2) at Screening
• Patient's living donor gave written consent for trial participation
• Ability to understand the nature and scope of the clinical trial

You may not qualify if:

• Donors:
• Pregnant or breastfeeding
• Participation in an interventional clinical trial within 30 days prior to Screening or in observation period of a competing study
• Severe psychiatric disease
• Severe cardiovascular diseases (i.e., heart insufficiency of grade NYHA III or IV)
• Severe neurological diseases
• Severe liver or kidney diseases
• Any acute or chronic disease that may put the donor at risk in case of cell donation by leukapheresis
• Malignant neoplasms, except in situ carcinoma after complete removal
• Known infections or exposures to human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis E virus, West Nile virus (WNV; testing only required during WNV season \[June 1st to November 30th of a year\]), gonorrhea or syphilis, with the risk of transmission of infection (Note: If tested positive for EBV immunoglobulin \[Ig\]M, an EBV PCR test has to be performed for confirmation)
• Active bacterial, mycotic or viral infection, except active infections that, in the investigator's opinion, do not affect patient safety (e.g., foot fungus, nail fungus, or common warts)
• Known malaria infection; known infection of tuberculosis, Q fever, Salmonella typhi and paratyphi, or osteomyelitis (if not medically documented to have been cured for 2 years); known toxoplasmosis (except if symptom free for 6 months); after completion of treatment for rheumatic fever (except if treatment was completed for 2 years)
• Known transmissible spongiform encephalopathies
• Known protozoonosis (babesiosis, trypanosomiasis \[e.g., chagas\], leishmaniosis), known chronic bacterial infections as brucellosis, rickettsiosis, leprosy, relapsing fever, melioidosis, tularemia (except after assured healing according to documented medical assessment)
• Autoimmune diseases requiring systemic immunosuppressive therapy

Sponsors & Collaborators

• TolerogenixX GmbH: lead
• FGK Clinical Research GmbH: collaborator

Study Sites (8)

Medizinische Klinik mit Schwerpunkt Nephrologie und Internistische Intensivmedizin Charité - Universitätsmedizin Berlin

Berlin, 13353, Germany

NOT YET RECRUITING

Universitätsklinikum Hamburg-Eppendorf, Universitäres Transplantations Centrum

Hamburg, 20246, Germany

RECRUITING

Innere Medizin V; Klinik für Hämatologie, Onkologie, Rheumatologie; Universitätsklinikum Heidelberg

Heidelberg, 69120, Germany

RECRUITING

Medizinische Klinik, Innere Medizin X Nephrologie - Nierenzentrum Universitätsklinikum Heidelberg

Heidelberg, 69120, Germany

RECRUITING

Transplantationszentrum München; Ludwig-Maximilians-Universität

Munich, 81377, Germany

RECRUITING

Klinikum rechts der Isar, Abteilung Nephrologie, Technische Universität München

Munich, 81675, Germany

NOT YET RECRUITING

Universitätsklinikum Münster, Transplantationsnephrologie

Münster, 48149, Germany

RECRUITING

Klinik für Nieren-, Hochdruck- und Autoimmunerkrankungen; Transplantationszentrum Stuttgart

Stuttgart, 70174, Germany

RECRUITING

Related Publications (1)

• Morath C, Schmitt A, Schmitt M, Wang L, Kleist C, Opelz G, Susal C, Tran TH, Scherer S, Schwenger V, Kemmner S, Fischereder M, Stangl M, Hauser IA, Sommerer C, Nusshag C, Kalble F, Speer C, Benning L, Bischofs C, Sauer S, Schubert ML, Kunz A, Huckelhoven-Krauss A, Neuber B, Mehrabi A, Schwab C, Waldherr R, Sander A, Busch C, Czock D, Bohmig GA, Reiser J, Roers A, Muller-Tidow C, Terness P, Zeier M, Daniel V, Schaier M. Individualised immunosuppression with intravenously administered donor-derived modified immune cells compared with standard of care in living donor kidney transplantation (TOL-2 Study): protocol for a multicentre, open-label, phase II, randomised controlled trial. BMJ Open. 2022 Nov 11;12(11):e066128. doi: 10.1136/bmjopen-2022-066128.

  PMID: 36368749 DERIVED

MeSH Terms

Interventions

Standard of Care

Intervention Hierarchy (Ancestors)

Quality Indicators, Health Care; Quality of Health Care; Health Services Administration; Health Care Quality, Access, and Evaluation

Study Officials

• Christian Morath, Prof.Dr.med.

  University Hospital Heidelberg

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Matthias Schaier, Prof.Dr.med.

CONTACT

+49 162 2638 005; schaier@tolerogenixx.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 26, 2022
• First Posted: May 9, 2022
• Study Start: May 4, 2022
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2028
• Last Updated: April 11, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will not share

Locations

DE (8)