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

An Open, Randomized-controlled, Multi-center Phase-II Clinical Trial of Individualized Immunosuppression With Intravenously Administered Donor Modified Immune Cells (MIC) Compared to Standard-of-care in Living Donor Kidney Transplantation

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.

Study Overview

• Status: Recruiting
• Conditions: Kidney Transplantation
• Intervention / Treatment: Biological: MIC; Other: Standard of Care

• Study Type: Interventional
• Enrollment (Estimated): 126
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Matthias Schaier, Prof.Dr.med.; Phone Number: +49 162 2638 005; Email: schaier@tolerogenixx.com

Study Locations

• Germany
  • Frankfurt, Germany, 60590
    • Not yet recruiting
    • Medizinische Klinik III: Kardiologie, Angiologie, Nephrologie; Funktionsbereich Nephrologie; Universitätsklinikum Frankfurt
  • Heidelberg, Germany, 69120
    • Recruiting
    • Innere Medizin V; Klinik für Hämatologie, Onkologie, Rheumatologie; Universitätsklinikum Heidelberg
  • Heidelberg, Germany, 69120
    • Recruiting
    • Nierenzentrum Heidelberg; Zentrum für Innere Medizin; Universitätsklinikum Heidelberg
  • Munich, Germany, 81377
    • Recruiting
    • Transplantationszentrum München; Ludwig-Maximilians-Universität
  • Stuttgart, Germany, 70174
    • Recruiting
    • Klinik für Nieren-, Hochdruck- und Autoimmunerkrankungen; Transplantationszentrum Stuttgart

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 69 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Donors:

1. Age ≥18 years and able to consent
2. Ability to understand the nature and scope of the clinical trial
3. Written consent form given prior to any trial-related procedures (including PBMC donation)

Patients:

1. 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
2. Age ≥18 years, <70 years
3. ABO-blood group identical or compatible with donor
4. First kidney transplantation
5. Complement dependent cytotoxicity (CDC)-panel reactive antibodies <20%
6. No detection of a donor-specific HLA-antibody in the Luminex-Assay (cutoff: mean fluorescence intensity [MFI] ≤1,000)
7. Negative CDC crossmatch with the donor
8. Negative PCR test result for severe acute respiratory syndrome coronavirus-2 (SARSCoV-2) at Screening
9. Patient's living donor gave written consent for trial participation
10. Ability to understand the nature and scope of the clinical trial
11. Written informed consent given prior to any trial-related procedures

12. Female patients of childbearing potential must:

    1. have a negative pregnancy test (blood) at Screening.
    2. either commit to true abstinence from heterosexual contact or agree to use, and be able to comply with, 2 highly effective measures of contraception control (failure rate less than 1% per year when used consistently and correctly) without interruption, during the trial participation. Patients who discontinue mycophenolic acid derivate during the trial participation can switch to 1 highly effective contraceptive method 6 weeks after the end of mycophenolic acid derivative treatment. Reliable methods for this trial are: combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable), intrauterine device, intrauterine hormone releasing system, bilateral tubal occlusion, sexual abstinence or vasectomized sexual partner. Abstinence from heterosexual contact is only accepted as true abstinence: when this is in line with the preferred and usual lifestyle of the patient. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods and withdrawal] is not an acceptable method of contraception.) Postmenopausal (no menses for at least 1 year without alternative medical cause) or surgically sterile female patients (tubal ligation, hysterectomy or bilateral oophorectomy) may be enrolled.
    3. agree to abstain from breast feeding during the trial participation.
13. Male patients must practice true abstinence or agree to use a condom during sexual contact with a pregnant woman or a woman of childbearing potential during the trial participation and for at least 90 days after the end of mycophenolic acid derivative treatment, even if he has undergone a successful vasectomy.

Exclusion Criteria:

Donors:

1. Pregnant or breastfeeding
2. Participation in an interventional clinical trial within 30 days prior to Screening or in observation period of a competing study
3. Severe psychiatric disease
4. Severe cardiovascular diseases (i.e., heart insufficiency of grade NYHA III or IV)
5. Severe neurological diseases
6. Severe liver or kidney diseases
7. Any acute or chronic disease that may put the donor at risk in case of cell donation by leukapheresis
8. Malignant neoplasms, except in situ carcinoma after complete removal
9. 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)
10. Active bacterial, mycotic or viral infection
11. 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)
12. Known transmissible spongiform encephalopathies
13. 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)
14. Autoimmune diseases requiring systemic immunosuppressive therapy
15. Allergies requiring systemic immunosuppressive therapy
16. Immunosuppressive therapy within 6 months prior screening
17. Known or suspected abuse of alcohol, drugs, or medicinal products
18. Unexplained night sweats, unexplained fever, unexplained weight loss, prolonged unexplained cough or diarrhea, unexplained skin lesions, lymph gland swelling or thrush
19. Dura mater and/or cornea grafts, allogeneic organ transplants, xenotransplants, pituitary hormones of human origin received
20. Stay of longer than 6 months in the United Kingdom between 1980 and 1996 and/or an operation and/or blood transfusion in the United Kingdom after 01-Jan-1980
21. Operations or other invasive interventions (e.g., endoscopies, biopsies, catheter applications, acupunctures [except acupuncture with sterile and/or disposable needles]) within 4 months prior to Screening
22. Any invasive exposure to blood (i.e., allogeneic blood components or plasma derivatives) or blood-contaminated injection needles or instruments, tattoos or piercings within 4 months prior to Screening
23. Positive PCR test result for SARS-CoV-2 at Screening
24. Hemoglobin <8.0 g/dL, thrombocytes <80,000/μL and/or leukocytes <3,000/μL
25. Known history of hypersensitivity to components used in the leukapheresis setting (i.e., components of the anticoagulant acid citrate dextrose solution)
26. Any finding or medical condition prohibiting the inclusion in the trial according to the judgment of the responsible leukapheresis physician

Patients:

1. Preexisting severe psychiatric disorder
2. Heart insufficiency of grade NYHA III or IV
3. Severe liver disease (aspartate aminotransferase or alanine aminotransferase or gamma glutamyl transpeptidase ≥3 x ULN)
4. Active infection of HIV, HBV, HCV, EBV or syphilis
5. Active bacterial, mycotic, or viral infection
6. Negative serological test result for antibodies specific for Epstein-Barr virus (EBV) antigens (Note: EBV negative patients can be included if the donor is confirmed EBV negative)
7. Malignant disease within 2 years prior to Screening, except basal cell carcinomas of the skin and in situ carcinomas
8. Immunosuppressive therapy (e.g., for the treatment of an auto-immune disease) within 6 months prior Screening
9. Preexisting vasculitis or collagenosis
10. Known presence of irregular antibodies in Coombs test
11. Vaccination within 4 weeks prior to Screening
12. Spleen removed
13. Known or suspected abuse of alcohol, drugs, or medicinal products
14. Pregnant or breastfeeding
15. Female patients who have a child with the donor or were pregnant from the donor due to possible sensitization
16. Known history of hypersensitivity to the cellular components or to any other constituent/excipient in the pharmaceutical formulation of MIC (e.g., components of the SSP+ buffer as electrolytes (sodium chloride, potassium chloride, magnesium), citrate and phosphate, traces of mitomycin C, human albumin, or EDTA)
17. Any finding or medical condition prohibiting the inclusion in the trial according to the judgment of the investigator
18. Participation in an interventional clinical trial within 30 days prior to Screening or in observation period of a competing study
19. Employees of the sponsor, or employees or relatives of the investigator

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: MIC with low immunosuppression; 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; Single intravenous infusion of 1.5x10exp8 MIC per kg of body weight
Experimental: MIC with minimal immunosuppression; 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; Single intravenous infusion of 1.5x10exp8 MIC per kg of body weight
Other: Standard of care immunosuppression for transplantation; 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; No application of the investigational medicinal product MIC

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Key secondary: Number of patient-relevant infections during the first year after transplantation	Safety evaluation of MIC treatment versus standard of care therapy is based on number of patient-relevant infections during the first year after transplantation. Patient-relevant infections are: Pneumonia, and/or complicated urinary tract infection, and/or sepsis from any cause, and/or opportunistic infection.	On day 367 post investigational medicinal product application
Number of Adverse Events (AEs) including serious AEs and AEs of special interest	Determine safety and efficacy of MIC treatment based on AE outcome	From screening through study completion, 3 years estimated.
Frequency of local or systemic reactions as result of MIC application	Determine safety and efficacy of MIC treatment based on further parameters other than comparison to standard of care therapy	From day 0 through study completion, 3 years estimated.
Monitoring of patient survival	Determine safety and efficacy of MIC treatment based on further parameters other than comparison to standard of care therapy: Monitoring for death of patient.	On Visit Days 187 and 367 post investigational medicinal product application
Monitoring of graft kidney survival	Determine safety and efficacy of MIC treatment based on further parameters other than comparison to standard of care therapy: Monitoring for death of grafted kidney.	On Visit days 187 and 367 post investigational medicinal product application
Incidence of biopsy-proven acute rejections and time to first rejection (>Banff Borderline)	Assessment is done according to Banff 2018 criteria and confirmed by a blinded central pathologist	On Visit Days 97 and 142 post investigational medicinal product application
Molecular scores in molecular microscope diagnostic system (MMDx)	Molecular biopsy analysis using MMDx will be done	On Visit Day 367 post investigational medicinal product application
Percentage of patients who achieved tacrolimus and EC-MPS dual therapy or tacrolimus monotherapy	Percentage of patients who achieved tacrolimus and EC-MPS dual therapy in the MIC Arm A or Control Arm or tacrolimus monotherapy in the MIC Arm B	On day 367 post investigational medicinal product application
Occurrence of delayed function of the kidney graft after transplantation	Defined as dialysis within the first week after transplantation, except for one dialysis for hyperkalemia	On Visit Day 37 post investigational medicinal product application
Assessment of estimated Glomerular Filtration Rate (eGFR) [CKD-EPI])	Measurement of eGFR according to chronic kidney disease epidemiology collaboration (CKD-EPI)	From screening through study completion, 3 years estimated.
Assessment of the incidence of cytomegalovirus (CMV) reactivation (CMV-DNA ≥1,000 copies/mL)	CMV amount will be measured as CMV-DNA copies/mL	From screening through study completion, 3 years estimated.
Assessment of the incidence of BK virus replication ≥10,000 copies/mL	BK virus amount will be measured as DNA copies/mL	From screening through study completion, 3 years estimated.
Assessment of the incidence of BK virus associated nephropathy	Nephropathy will be assessed using biopsy material	From screening through study completion, 3 years estimated.
Assessment of the incidence of hospital readmissions after transplant surgery	Assessment of the number of patients who had hospital readmissions after transplant surgery	On days 5, 7, 37, 97, 142, 187, 277, 367, month 24, 36 post investigational medicinal product application
Assessment of days in hospital, on intensive care and hours on mechanical ventilation upon re-admission	Assessment of days in hospital, on intensive care and hours on mechanical ventilation (the treatment to help a person breathe when they find it difficult or are unable to breathe on their own) that patients needed upon hospital re-admission after transplant surgery	On day -14 to -7 and 367 post investigational medicinal product application
Change in quality of life as assessed by questionnaire	The SF-36 questionnaire with 36 questions will be used to assess the change in quality of life between screening and first year after treatment	Between day -14 to -7 and 367 post investigational medicinal product application
Incidence of new-onset diabetes mellitus after transplantation	Assessment of incidence of diabetes mellitus after transplantation by measuring fasting plasma glucose (≥7.0 mmol/L / 126 mg/dL) with no calorie intake for at least 8 hours	From day 0 through study completion, 3 years estimated.
Determination of therapeutic intensity score (TIS) based on blood pressure on Visit Day 367 compared to Baseline	Assessment of the TIS as a summary measure that accounts for the number and the relative doses of blood pressure medications for a patient by a blinded adjudication committee one year after treatment	On day -14 to -7 and 367 post investigational medicinal product application
Breg percentage	Assessment of the percentage of regulatory B cells of the white blood cell population measured from blood samples by Fluorecscence Activated Cell Sorting (FACS)	On day 367 post investigational medicinal product application
Anti-donor T cell response to the donor	Anti-donor T cell response will be assessed from blood samples using the mixed lymphocyte reaction in vitro assay	From day 0 through study completion, 3 years estimated.
Cumulative steroid dose during the first year after treatment	Assessment of the overall amount of steroids given to the patient as immunosuppressive treatment 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	Safety evaluation of MIC treatment versus standard of care therapy is also based on proportion of patients with acute rejection (biopsy-proven as >Banff Borderline or clinically suspected rejection according to evaluation of adjudication committee), graft loss, graft dysfunction, or death on Visit Day 367	On day 367 post investigational medicinal product application
Amount of donor-specific HLA antibodies (DSA)	DSA measurement (>1,000 MFI; confirmed by second measurement after 4 weeks for assessments after Day 6) will be done by blinded Luminex single antigen test	On Visit Days 6, 187 and 367 post investigational medicinal product application

Collaborators and Investigators

• Sponsor: TolerogenixX GmbH
• Collaborators: FGK Clinical Research GmbH
• Investigators: Principal Investigator: Christian Morath, Prof.Dr.med., University Hospital Heidelberg

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): May 4, 2022
• Primary Completion (Estimated): June 1, 2025
• Study Completion (Estimated): June 1, 2027

Study Registration Dates

• First Submitted: April 26, 2022
• First Submitted That Met QC Criteria: May 3, 2022
• First Posted (Actual): May 9, 2022

Study Record Updates

• Last Update Posted (Estimated): December 4, 2023
• Last Update Submitted That Met QC Criteria: November 28, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

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

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No