To study whether MCA-derived MSC therapy is safe and effective in allowing tacrolimus reduction after kidney transplantation.Secondary Objective(s): To assess the effect of MCA-derived MSC therapy and subsequent tacrolimus reduction on renal…
ID
Source
Brief title
Condition
- Renal disorders (excl nephropathies)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary end point is the incidence of BPAR/graft loss after MCA-derived MSC
treatment
Secondary outcome
- Renal function by calculated GFR , eGFR (CKD-EPI formula) and iohexol
clearance
- CMV and BK infection (viremia, disease and syndrome and subtype of BK).
- Donor specific HLA sensitization by luminex before and after MSC infusions
- Immune monitoring before and after MSC treatment
- Incidence and severity of reported SAEs and AEs at 12 months
Background summary
Kidney transplantation has improved survival and quality of life for patients
with end-stage renal disease. However, despite advances in immunosuppressive
therapy, long- term allograft survival outcomes have not improved over the last
decade. There is a clear need for therapeutic alternatives because 1) patients
may not respond to existing therapeutic choices, 2) they do not show an
improvement of the fibrosis reaction 3) they do not show an effect on long term
survival, 4) they may develop immunosuppression induced serious (sometimes
fatal) side effects and toxicities. LUMC has conducted 3 trials using
bone-marrow derived mesenchymal stromal cells (BM-MSC) showing both safety and
efficacy of their use in the setting of kidney transplantation.
MSC isolation and culture from both autologous and allogeneic sources is being
hampered by cellular heterogeneity and replicative senescence. Generation of
MSC from induced pluripotent stem cells (iPSC) so called MCA-derived MSC may
circumvent these limitations. MCA-derived MSC have recently been tested in
clinical trials and found to be safe and more cost effective than traditional
MSC. Given the benefits of MCA-derived MSC we propose to test whether
MCA-derived MSC are safe in the setting of kidney transplantation in a clinical
study. The TRITON study in which MSC therapy was shown to allow withdrawal of
the nephrotoxic calcineurin inhibitor tacrolimus, will form the backbone for
this clinical trial in which 16 patients will receive MCA-derived MSC combined
with tacrolimus reduction to study safety and immunological efficacy of
MCA-derived MSC therapy.
Study objective
To study whether MCA-derived MSC therapy is safe and effective in allowing
tacrolimus reduction after kidney transplantation.
Secondary Objective(s):
To assess the effect of MCA-derived MSC therapy and subsequent tacrolimus
reduction on renal function, the occurrence of opportunistic infections, the
development of de novo donor specific antibodies
Study design
A non-randomized, open-label, non-blinded, prospective, single-center clinical
phase I/IIb study to investigate whether MCA-derived MSC are safe by assessing
the incidence of adverse events and BPAR/graft loss after MCA-derived MSC
treatment.
Intervention
All patients will receive steroids according to the LUMC protocol and induction
treatment with basiliximab at day 0 and 4 (20 mg intravenously). Patients will
receive either 1 or 2 doses of 2x10^6 (+/- 10%) MCA-derived MSC/kg - the first
at week 6 and the second at week 7 after transplantation.
Study burden and risks
Visits to the hospital: 14 visits of which 4 are extra above standard visits
(including 1 or 2 MSC infusions); during 2 visits an Iohexol clearance will be
done, which consists of 4 extra blood samples, during 2 hours, which will be
done by using a peripheral venous catheter. All other blood samples will be
combined with the routine blood samples. In total an extra 576 ml of blood will
be taken during the course of 12 months; risks MSC infusion are considered low
(possibly infections and sensitization).
Different from the previous MSC studies, we will not perform potentially
harmful protocol kidney biopsies, as our previous trials did not show reduction
in quantitative fibrosis scoring during the study period (fibrosis was overall
low at these timepoints).
Albinusdreef 2
Leiden 2333ZA
NL
Albinusdreef 2
Leiden 2333ZA
NL
Listed location countries
Age
Inclusion criteria
1. Female or male, aged between 18 and 75 years.
2. Subject is willing to participate in the study, must be able to give
informed consent
and the consent must be obtained prior to any study procedure.
3. Recipients of a first kidney graft from a living-unrelated or non-HLA
identical living related donor.
If a donor is > 50 years of age, recipient must be >25 years of age.
4. Panel Reactive Antibodies (PRA) <= 10%.
5. No HLA repeated mismatch between MCA-derived MSC and the HLA mismatch
between kidney graft and recipient.
6. Patients must be able to adhere to the study visit schedule and protocol
requirements.
7. If female and of child-bearing age, subject must be non-pregnant,
non-breastfeeding,
and use adequate contraception.
Exclusion criteria
1. Double organ transplant recipient.
2. Biopsy proven acute rejection (according to the Banff criteria) in the first
6 weeks after
transplantation.
3. Patients with evidence of active infection or abscesses (with the exception
of an
uncomplicated urinary tract infection) before MSC infusion.
4. Patients suffering from hepatic failure.
5. Patients suffering from an active autoimmune disease.
6. Patients who have had a previous BM transplant.
7. A psychiatric, addictive or any disorder that compromises ability to give
truly informed
consent for participation in this study.
8. Use of any investigational drug after transplantation.
9. Documented HIV infection, active hepatitis B, hepatitis C or TB according to
current transplantation inclusion criteria.
10. Subjects who currently have an active opportunistic infection at the time
of MCA-derived MSC infusion (e.g., herpes zoster [shingles], cytomegalovirus
(CMV), Pneumocystis carinii (PCP), aspergillosis, histoplasmosis, or
mycobacteria other than TB, BK) after transplantation.
11. Malignancy (including lymphoproliferative disease) within the past 2-5
years (except for squamous or basal cell carcinoma of the skin that has been
treated with no evidence of recurrence) according to current transplantation
inclusion criteria.
12. Known recent substance abuse (drug or alcohol).
13. Patients who are recipients of ABO incompatible transplants.
14. Cold ischemia time >30 hrs.
15.Patients with severe total hypercholesterolemia (>7.5 mmol/L) or total
hypertriglyceridemia (>5.6 mmol/L) (patients on lipid lowering treatment with
controlled hyperlipidemia are acceptable).
16. Repeated HLA mismatch present between the MCA-derived MSC and the
mismatches between donor and kidney graft
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2022-004168-11-NL |
| CCMO | NL83484.000.22 |