Clinical trial NCT05365672: Clinical Trial With Donor Modified Immune Cells in Living Donor Kidney Transplantation
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
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
Lead sponsor: TolerogenixX GmbH
Sponsor class: INDUSTRY
Collaborators: name: FGK Clinical Research GmbH
First posted: 2022-05-09
Enrollment: 126
Sex: ALL
Minimum age (years): 18
Maximum age (years): 69
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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, except active infections that, in the investigator's opinion, do not affect patient safety (e.g., foot fungus, nail fungus, or common warts)
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 (including assessment of the suitability of the veins for leukapheresis by the investigator)

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, except active infections that, in the investigator's opinion, do not affect patient safety (e.g., foot fungus, nail fungus, or common warts)
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

Primary outcomes:
measure: No acute rejection, graft loss, graft dysfunction
timeFrame: On day 367 post investigational medicinal product application
measure: No development of de novo donor-specific HLA- antibodies
timeFrame: Between day 0 and day 367 post investigational medicinal product application
measure: Induction of regulatory B cells (Breg) to ≥3%
timeFrame: On day 367 post investigational medicinal product application
measure: Patient on tacrolimus therapy with ≤720 mg EC-MPS and no corticosteroids
timeFrame: Between days 277 and 367 post investigational medicinal product application
Secondary outcomes:
measure: Key secondary: Number of patient-relevant infections during the first year after transplantation
timeFrame: On day 367 post investigational medicinal product application
measure: Key secondary: Biopsy proven acute rejection, graft loss, graft dysfunction, or death
timeFrame: On day 367 post investigational medicinal product application
measure: Number of Adverse Events (AEs) including serious AEs and AEs of special interest
timeFrame: From screening through study completion, 3 years estimated.
measure: Frequency of local or systemic reactions as result of MIC application
timeFrame: From day 0 through study completion, 3 years estimated.
measure: Monitoring of patient survival
timeFrame: On Visit Days 187 and 367 post investigational medicinal product application
measure: Monitoring of graft kidney survival
timeFrame: On Visit days 187 and 367 post investigational medicinal product application
measure: Incidence of biopsy-proven acute rejections and time to first rejection (>Banff Borderline)
timeFrame: On Visit Days 97 and 142 post investigational medicinal product application
measure: Molecular scores in molecular microscope diagnostic system (MMDx)
timeFrame: On Visit Day 367 post investigational medicinal product application
measure: Percentage of patients who achieved tacrolimus and EC-MPS dual therapy or tacrolimus monotherapy
timeFrame: On day 367 post investigational medicinal product application
measure: Amount of donor-specific HLA antibodies (DSA)
timeFrame: On Visit Days 6, 187 and 367 post investigational medicinal product application
measure: Occurrence of delayed function of the kidney graft after transplantation
timeFrame: On Visit Day 37 post investigational medicinal product application
measure: Assessment of estimated Glomerular Filtration Rate (eGFR) [CKD-EPI])
timeFrame: From screening through study completion, 3 years estimated.
measure: Assessment of the incidence of cytomegalovirus (CMV) reactivation (CMV-DNA ≥1,000 copies/mL)
timeFrame: From screening through study completion, 3 years estimated.
measure: Assessment of the incidence of BK virus replication ≥10,000 copies/mL
timeFrame: From screening through study completion, 3 years estimated.
measure: Assessment of the incidence of BK virus associated nephropathy
timeFrame: From screening through study completion, 3 years estimated.
measure: Assessment of the incidence of hospital readmissions after transplant surgery
timeFrame: On days 5, 7, 37, 97, 142, 187, 277, 367, month 24, 36 post investigational medicinal product application
measure: Assessment of days in hospital, on intensive care and hours on mechanical ventilation upon re-admission
timeFrame: On day -14 to -7 and 367 post investigational medicinal product application
measure: Change in quality of life as assessed by questionnaire
timeFrame: Between day -14 to -7 and 367 post investigational medicinal product application
measure: Incidence of new-onset diabetes mellitus after transplantation
timeFrame: From day 0 through study completion, 3 years estimated.
measure: Determination of therapeutic intensity score (TIS) based on blood pressure on Visit Day 367 compared to Baseline
timeFrame: On day -14 to -7 and 367 post investigational medicinal product application
measure: Breg percentage
timeFrame: On day 367 post investigational medicinal product application
measure: Anti-donor T cell response to the donor
timeFrame: From day 0 through study completion, 3 years estimated.
measure: Cumulative steroid dose during the first year after treatment
timeFrame: On day 367 post investigational medicinal product application
Other outcomes:
Locations:
city: Berlin
country: Germany
facility: Medizinische Klinik mit Schwerpunkt Nephrologie und Internistische Intensivmedizin Charité - Universitätsmedizin Berlin
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf, Universitäres Transplantations Centrum
city: Heidelberg
country: Germany
facility: Innere Medizin V; Klinik für Hämatologie, Onkologie, Rheumatologie; Universitätsklinikum Heidelberg
city: Heidelberg
country: Germany
facility: Medizinische Klinik, Innere Medizin X Nephrologie - Nierenzentrum Universitätsklinikum Heidelberg
city: Munich
country: Germany
facility: Transplantationszentrum München; Ludwig-Maximilians-Universität
city: Munich
country: Germany
facility: Klinikum rechts der Isar, Abteilung Nephrologie, Technische Universität München
city: Münster
country: Germany
facility: Universitätsklinikum Münster, Transplantationsnephrologie
city: Stuttgart
country: Germany
facility: Klinik für Nieren-, Hochdruck- und Autoimmunerkrankungen; Transplantationszentrum Stuttgart
Study officials:
affiliation: University Hospital Heidelberg
name: Christian Morath, Prof.Dr.med.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.