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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

TolerogenixX GmbH

Participant type

Patients, Healthy volunteers

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Phenomena and Processes [G] - Immune system processes [G12]

Trial duration

3 May 2022 → ongoing

Decision date (initial)

2024-07-23

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

TolerogenixX GmbH

External identifiers

EU CT number

2024-513446-12-00

EudraCT number

2021-000561-33

WHO UTN

U1111-1309-8673

ClinicalTrials.gov

NCT05365672

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Prophylaxis

Determine efficacy of MIC treatment in terms of achieving an operational tolerance-like phenotype compared to the SoC therapy

Secondary objectives 2

1. 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
2. Secondary: Determine safety and efficacy of MIC treatment based on further parameters

Conditions and MedDRA coding

Living donor kidney transplantation

Regulatory references

Scientific advice from competent authorities

Paul-Ehrlich-Institut, Food And Drug Administration, European Medicines Agency

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 16

1. Donors: 1. Age ≥18 years and able to consent
2. Donors: 2. Ability to understand the nature and scope of the clinical trial
3. Donors: 3. Written consent form given prior to any trial-related procedures (including PBMC donation)
4. Patients: 1. Patient with CKD in stage 5 (e.g., estimated glomerular filtration rate [GFR] <15mL/min and/or on renal replacement therapy), who are in preparation for kidney transplantation from a live donor
5. Patients: 2. Age ≥18 years, <75 years
6. Patients: 3. ABO-blood group identical or compatible with donor
7. Patients: 4. First kidney transplantation
8. Patients: 5. Complement dependent cytotoxicity (CDC)-panel reactive antibodies <20%
9. Patients: 6. No detection of a donor-specific HLA-antibody in the Luminex-Assay (cutoff: mean fluorescence intensity [MFI] ≤1,000)
10. Patients: 7. Negative CDC crossmatch with the donor
11. Patients: 8. Negative PCR test result for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) at Screening
12. Patients: 9. Patient's living donor gave written consent for trial participation
13. Patients: 10. Ability to understand the nature and scope of the clinical trial
14. Patients: 11. Written informed consent given prior to any trial-related procedures
15. Patients: 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.
16. Patients: 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.

Exclusion criteria 44

1. Donors: 1. Pregnant or breastfeeding
2. Donors: 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)
3. Donors: 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)
4. Donors: 12. Known transmissible spongiform encephalopathies
5. Donors: 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)
6. Donors: 14. Autoimmune diseases requiring systemic immunosuppressive therapy
7. Donors: 15. Allergies requiring systemic immunosuppressive therapy
8. Donors: 16. Immunosuppressive therapy within 6 months prior screening
9. Donors: 17. Known or suspected abuse of alcohol, drugs, or medicinal products
10. Donors: 18. Unexplained night sweats, unexplained fever, unexplained weight loss, prolonged unexplained cough or diarrhea, unexplained skin lesions, lymph gland swelling or thrush
11. Donors: 19. Dura mater and/or cornea grafts, allogeneic organ transplants, xenotransplants, pituitary hormones of human origin received
12. Donors: 2. Participation in an interventional clinical trial within 30 days prior to Screening or in observation period of a competing study
13. Donors: 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
14. Donors: 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
15. Donors: 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
16. Donors: 23. Positive PCR test result for SARS-CoV-2 at Screening
17. Donors: 24. Hemoglobin <8.0 g/dL, thrombocytes <80,000/µL and/or leukocytes <3,000/µL
18. Donors: 25. Known history of hypersensitivity to components used in the leukapheresis setting (i.e., components of the anticoagulant acid citrate dextrose solution)
19. Donors: 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)
20. Patients: 1. Preexisting severe psychiatric disorder
21. Patients: 2. Heart insufficiency of grade NYHA III or IV
22. Patients: 3. Severe liver disease (aspartate aminotransferase or alanine aminotransferase or gamma glutamyl transpeptidase ≥3 x ULN)
23. Donors: 3. Severe psychiatric disease
24. Patients: 4. Active infection of HIV, HBV, HCV, EBV, or syphilis
25. Patients: 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)
26. Patients: 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)
27. Patients: 7. Malignant disease within 2 years prior to Screening, except basal cell carcinomas of the skin and in situ carcinomas
28. Patients: 8. Immunosuppressive therapy (e.g., for the treatment of an auto-immune disease) within 6 months prior Screening
29. Patients: 9. Preexisting vasculitis or collagenosis
30. Patients: 10. Known presence of irregular antibodies in Coombs test
31. Patients: 11. Vaccination within 4 weeks prior to Screening
32. Patients: 12. Spleen removed
33. Patients: 13. Known or suspected abuse of alcohol, drugs, or medicinal products
34. Donors: 4. Severe cardiovascular diseases (i.e., heart insufficiency of grade NYHA III or IV)
35. Patients: 14. Pregnant or breastfeeding
36. Patients: 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)
37. Patients: 17. Any finding or medical condition prohibiting the inclusion in the trial according to the judgment of the investigator
38. Patients: 18. Participation in an interventional clinical trial within 30 days prior to Screening or in observation period of a competing study
39. Patients: 19. Employees of the sponsor, or employees or relatives of the investigator
40. Donors: 5. Severe neurological diseases
41. Donors: 6. Severe liver or kidney diseases
42. Donors: 7. Any acute or chronic disease that may put the donor at risk in case of cell donation by leukapheresis
43. Donors: 8. Malignant neoplasms, except in situ carcinoma after complete removal
44. Donors: 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Proportion of patients who achieve an operational tolerance-like phenotype defined on Visit Day 367 as fulfilling all of the following criteria: 1. No acute rejection, graft loss, graft dysfunction or death; 2. No development of donor-specific HLA antibodies until Visit Day 367; 3. Induction of Breg ≥3% measured on Visit Day 367; 4. Patient on tacrolimus therapy with ≤720 mg ECMPS and no corticosteroids on Visit Day 277 and remaining on this therapy until Visit Day 367.

Secondary endpoints 22

1. Key secondary: Number of patient-relevant infections during the first year after transplantation
2. Key secondary: 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
3. AEs including serious AEs and AEs of special interest
4. Frequency of local or systemic reactions as result of MIC application
5. Patient-, graft and death-censored graft survival
6. Incidence of biopsy-proven acute rejections and time to first rejection (>Banff Borderline) according to current version Banff criteria and confirmed by a blinded central pathologist
7. Molecular scores in molecular microscope diagnostic system (MMDx) reading on Visit Day 367
8. 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
9. 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
10. 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
11. eGFR (according to chronic kidney disease epidemiology collaboration [CKD-EPI])
12. Incidence of CMV reactivation (CMV-DNA ≥1,000 copies/mL)
13. Incidence of BK virus replication ≥1,000 copies/mL
14. Incidence of BK virus associated nephropathy
15. Incidence of hospital readmissions after transplant surgery
16. Days in hospital, on intensive care (ICU)/intermediate care (IMC) and hours on mechanical ventilation upon re-admission
17. Change of quality of life (SF-36) on Visit Day 367 compared to Baseline
18. 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)
19. Therapeutic intensity score and blood pressure on Visit Day 367 compared to Baseline
20. Breg percentage
21. Anti-donor T cell response to the donor
22. Cumulative steroid dose until Visit Day 367

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

TolerogenixX GmbH

Sponsor organisation

TolerogenixX GmbH

Address

Im Neuenheimer Feld 162, Neuenheim Neuenheim

City

Heidelberg

Postcode

69120

Country

Germany

Scientific contact point

Organisation

TolerogenixX GmbH

Contact name

Information desk

Public contact point

Organisation

TolerogenixX GmbH

Contact name

Information desk

Third parties 10

Locations

1 EU/EEA country · 8 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 11 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications