| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Living donor kidney transplantation |
|
| E.1.1.1 | Medical condition in easily understood language |
| Transplantation of kidney from living donors |
|
| E.1.1.2 | Therapeutic area | Body processes [G] - Immune system processes [G12] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10023438 |
| E.1.2 | Term | Kidney transplant |
| E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main 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.2.2 | Secondary 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.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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.4 | Principal 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.5.1 | Primary 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.5.1.1 | Timepoint(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.5.2 | Secondary 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.5.2.1 | Timepoint(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.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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