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    The EU Clinical Trials Register currently displays   43974   clinical trials with a EudraCT protocol, of which   7312   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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    Summary
    EudraCT Number:2021-000561-33
    Sponsor's Protocol Code Number:TOL-2
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-07-08
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - PEI
    A.2EudraCT number2021-000561-33
    A.3Full title of the trial
    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
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A non blinded phase-II study with 3 randomized patient groups of individualized suppression of the patient's immune system with donor modified immune cells (MIC) compared to standard-of-care in kidney transplantation from living donors
    A.4.1Sponsor's protocol code numberTOL-2
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorTolerogenixX GmbH
    B.1.3.4CountryGermany
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportTolerogenixX GmbH
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationTolerogenixX GmbH
    B.5.2Functional name of contact pointCEO
    B.5.3 Address:
    B.5.3.1Street AddressIm Neuenheimer Feld 162
    B.5.3.2Town/ cityHeidelberg
    B.5.3.3Post code69120
    B.5.3.4CountryGermany
    B.5.4Telephone number+491622638 005
    B.5.5Fax number+496221911 2229
    B.5.6E-mailschaier@tolerogenixx.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameMIC
    D.3.4Pharmaceutical form Suspension for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.3Other descriptive nameAllogeneic peripheral blood mononuclear cells incubated in vitro with mitomycin C
    D.3.9.4EV Substance CodeSUB203787
    D.3.10 Strength
    D.3.10.1Concentration unit million organisms/ml million organisms/millilitre
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number50 to 200
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Yes
    D.3.11.3.1Somatic cell therapy medicinal product Yes
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Living donor kidney transplantation
    E.1.1.1Medical condition in easily understood language
    Transplantation of kidney from living donors
    E.1.1.2Therapeutic area Body processes [G] - Immune system processes [G12]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10023438
    E.1.2Term Kidney transplant
    E.1.2System Organ Class 10042613 - Surgical and medical procedures
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Primary:
    Determine efficacy of MIC treatment in terms of achieving an operational tolerance-like phenotype compared to the SoC therapy
    E.2.2Secondary objectives of the trial
    Key-secondary:
    Determine safety of MIC treatment versus SoC therapy based on number of patient-relevant infections as well as efficacy in terms of biopsy proven acute rejection, graft loss, graft dysfunction, or death

    Secondary:
    Determine safety and efficacy of MIC treatment based on further parameters

    Other:
    Determine safety and efficacy of MIC treatment based on other parameters
    E.2.3Trial contains a sub-study No
    E.3Principal 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 [GFR] <15 mL/min and/or on renal replacement therapy), who are in preparation for kidney transplantation from a live donor
    2. Age ≥18 years, <75 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 (SARS-CoV-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:
    a. have a negative pregnancy test (blood) at Screening.
    b. 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.
    c. 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 trial participationmycophenolic acid derivative treatment, even if he has undergone a successful vasectomy.
    E.4Principal 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
    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. deleted
    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
    E.5 End points
    E.5.1Primary end point(s)
    Proportion of patients who achieve an operational tolerance-like phenotype defined on Visit Day 367 as fulfilling all of the following criteria:
    • 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
    •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
    • Induction of Breg ≥3% measured on Visit Day 367 (patient has to be infection-free at time-point of measurement)
    • 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
    E.5.1.1Timepoint(s) of evaluation of this end point
    • On day 367
    • On day 0, 6, 37, 97,142, 187, 277, 367
    • On day 367
    • At day 277 and day 367
    E.5.2Secondary end point(s)
    Key secondary:
    • Number of patient-relevant infections during the first year after transplantation
    • 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

    Secondary:
    • AEs including serious AEs and AEs of special interest
    • Frequency of local or systemic reactions as result of MIC application
    • Patient-, graft and death-censored graft survival
    • Incidence of biopsy-proven acute rejections and time to first rejection (>Banff Borderline) according to Banff 2018 criteria and confirmed by a blinded central pathologist
    • Molecular scores in molecular microscope diagnostic system (MMDx) reading on Visit Day 367
    • Percentage of patients who achieved tacrolimus and EC-MPS dual therapy (MIC Arm A, Control Arm) or tacrolimus monotherapy (MIC Arm B) on Visit Day 367
    • Development of donor-specific HLA-antibodies (>1,000 MFI; confirmed by second measurement after 4 weeks for assessments after Day 6) until
    Visit Days 6, 187 and 367, as measured by Luminex single antigen test
    • 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
    • eGFR (according to chronic kidney disease epidemiology collaboration [CKD-EPI])
    • Incidence of CMV reactivation (CMV-DNA ≥1,000 copies/mL)
    • Incidence of BK virus replication ≥1,000 copies/mL
    • Incidence of BK virus associated nephropathy
    • Incidence of hospital readmissions after transplant surgery
    • Days in hospital, on intensive care (ICU)/intermediate care (IMC) and hours on mechanical ventilation upon re-admission
    • Change of quality of life (SF-36) on Visit Day 367 compared to Baseline
    • Incidence of new-onset diabetes mellitus after transplantation (fasting plasma glucose ≥7.0 mmol/L / 126 mg/dL with no calorie intake for at least 8 hours)
    • Therapeutic intensity score and blood pressure on Visit Day 367 compared to Baseline
    • Breg percentage
    • Anti-donor T cell response to the donor
    • Cumulative steroid dose until Visit Day 367
    E.5.2.1Timepoint(s) of evaluation of this end point
    Key secondary:
    • On day 367
    • On day 367

    Secondary:
    • On each single visit
    • On each single visit
    • On day 187 and 367
    • On day 97 and day 142
    • On day 367
    • On day 367
    • On day 6, 187 and 367
    • On day 37
    • On each single visit
    • On each single visit
    • On each single visit
    • On each single visit
    • On day 5, 7, 37, 97, 142, 187, 277, 367, month 24, 36
    • On day 14 to -7, 367
    • On day 14 to -7, 367
    • On each single visit
    • On day 14 to -7, 367
    • On day 367
    • On each single visit except screening
    • On day 367
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned7
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 86
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 40
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers Yes
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state126
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2022-02-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-03-08
    P. End of Trial
    P.End of Trial StatusOngoing
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