Primary: 1 to test the safety and feasibility of autologous MSC therapy in HLA-DR mismatched patients with SCR in the renal biopsy 4 weeks after renal transplantation.Secondary1 To assess histologic changes before and after MSC treatment.2 To…
ID
Source
Brief title
Condition
- Other condition
- Renal disorders (excl nephropathies)
Synonym
Health condition
aandoeningen na niertransplantatie
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
1 Safety: rate of (serious) adverse events in the study population using the
World Health Organization (WHO) criteria.
2 Feasibility: determination of the number of expanded MSCs in relation to the
amount of BM collected, number of passages required and time to reach study
target doses.
Secondary outcome
1 Presence of late acute rejection in the 6 month biopsy compared with the 4
week biopsy.
2 Sirius red staining for renal cortical matrix accumulation in the 6 month
biopsy compared with the 4 week biopsy.
3 Immunologic response (immunologic properties of peripheral blood T cells
before and after MSC infusion) after 6 months.
Background summary
Kidney transplantation has improved survival and quality of life for patients
with end-stage organ failure. Despite dramatic improvements in short-term
survival, long-term survival of renal allografts has changed little during the
past decade. Recently, it has been demonstrated that chronic lesions originate
already very early after transplantation and that SCR in protocol biopsies is a
risk factor for late graft loss. However the efficacy of high-dose
corticosteroids and other therapies for the treatment of SCR have been shown to
be inadequate. Thus, despite the availability of a range of available
medications there remains a need for therapeutic alternatives because patients
may not respond to existing therapeutic choices, they do not show an
improvement of the fibrosis reaction or an effect on long term survival, or
they may develop immunosuppression induced serious (sometimes fatal) side
effects and toxicities.
In recent years it has become evident that bone marrow (BM) derived mesenchymal
stem cells (MSCs) have potent immunomodulatory effects. MSCs are pluripotent
cells that can differentiate into several mesenchymal tissues, including
fibroblasts, osteoblasts, adipocytes and chondrocyte progenitors. MSCs have
potent immunosuppressive effects on T and B cells in vitro and in animal models
of chronic inflammation. Encouraging results have been obtained in patients
with steroid resistant acute and severe Graft versus Host Disease (GvHD). We
hypothesize that infusion of MSCs may similarly provide a novel treatment
option in the treatment of patients with allograft rejection with less side
effects than existing immunosuppressive therapies.
Study objective
Primary:
1 to test the safety and feasibility of autologous MSC therapy in HLA-DR
mismatched patients with SCR in the renal biopsy 4 weeks after renal
transplantation.
Secondary
1 To assess histologic changes before and after MSC treatment.
2 To evaluate the incidence of late acute rejection in the biopsy 24 weeks
after transplantation.
3 To evaluate renal function in de novo renal transplant recipients before and
after MSC infusion.
4 To study the immunologic properties of peripheral blood T cells before and
after MSC infusion.
Study design
Open label, non randomized, non blinded, prospective, single center, clinical
phase 1b study.
Intervention
MSC infusion: two doses of 1-2 miljon MSCs per kilogram body weight,
intravenously, 7 days apart.
Study burden and risks
Kidney transplantation has improved survival and quality of life for patients
with end-stage organ failure. Despite dramatic improvements in short-term
survival, long-term survival of renal allografts has changed little during the
past decade. Recently, it has been demonstrated that SCR in protocol biopsies
is a risk factor for late graft loss. However the efficacy of high-dose
corticosteroids and other therapies have been shown to be inadequate. Thus,
despite the availability of a range of available medications there remains a
need for therapeutic alternatives because patients may not respond to existing
therapeutic choices, they do not show an improvement of the fibrosis reaction
or an effect on long term survival, or they may develop immunosuppression
induced serious (sometimes fatal) side effects and toxicities.
Both autologous and allogenic MSC transplantation have been used clinically for
the treatment of a wide variety of diseases. In total 16 studies using MSCs to
treat more than 250 patients have been published and many more clinical phase I
to III trials are ongoing. We think that the results, which suggest beneficial
effect from MSC administration for patients with chronic inflammatory diseases,
and the expected limited possibility on adverse side effects, justify
participation in this study.
Albinusdreef 2
2333 ZA Leiden
NL
Albinusdreef 2
2333 ZA Leiden
NL
Listed location countries
Age
Inclusion criteria
1. Female or male, aged between 18 and 65 years.
2. Subject is willing to participate in the study and has signed the informed consent.
3. Recipents of a first kidney graft from a living HLA-DR mismatched donor (2 HLA-DR mismatches).
4. Subjects included in the study must have kidney biopsy proven SCR 4 weeks after transplantation.
5. Patients must be on triple immunosuppressive therapy of prednisone, CsA or tacrolimus and MMF according to current protocol.
6. Panel Reactive Antibodies (PRA) <= 5%.
7. Patients must be able to adhere to the study visit schedule and protocol requirements.
8. If female and of child-bearing age, subject must be non-pregnant, non-breastfeeding, and use adequate contraception.
9. Patients must be able to give informed consent and the consent must be obtained prior to any study procedure.
Exclusion criteria
1. Double organ transplant recipient.
2. Acute clinical rejection after transplantation.
3. Patients with evidence of active infection or abcesses 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 (e.g., herpes zoster [shingles], cytomegalovirus (CMV), Pneumocystis carinii (PCP), aspergillosis, histoplasmosis, or mycobacteria other than TB) 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. Contraindications to undergo a BM biopsy.
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 | EUCTR2008-001300-23-NL |
| CCMO | NL21298.000.08 |