To study whether selected allogeneic bone marrow derived MSCs are safe by assessing the composite end point Biopsy Proven Acute Rejection (BPAR)/ graft loss at 12 months
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 safety by assessing the composite end point of
BPAR/graft loss after MSC treatment.
Secondary outcome
Comparison of fibrosis by quantitative Sirius Red scoring at 52 weeks compared
to 24 weeks post-transplant; de novo HLA antibody development by luminex
(including C1q binding) before and after MSC infusions; renal function measured
by cGFR (MDRD formula); CMV and BK infection (viremia, disease and syndrome and
subtype of BK) and other opportunistic infections; immune monitoring after MSC
treatment
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. Thus 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. A promising novel therapeutic immunosuppressive option
in the treatment of renal recipients with a profound effect on the fibrosis
reaction and fewer side effects than existing immunosuppressive therapies is
the clinical application of mesenchymal stromal cells (MSCs). In contrast to
most current pharmacological agents that target only a single
pathophysiological pathway, MSCs potentially affect immunologic, inflammatory,
vascular and regenerative pathways, which provide an exciting opportunity for
further research. In vitro studies imply that MSCs may play a role in
modulation of immune responses and beneficial immunomodulatory effects of MSCs
have been shown in models of experimental allo- and autoimmune disorders,
including allograft rejection. After human renal transplantation, first results
demonstrate safety, feasibility and an indication for immunosuppressive
capacities of autologous bone marrow derived MSCs. In renal recipients, MSCs
might play roles in the treatment of allograft rejection and fibrosis, and in
calcineurin minimization and induction protocols. As MSCs are immunoprivileged,
both autologous and allogeneic therapies are possible, but most studies have
used autologous cells. Allogeneic MSCs offer the advantage of availability for
clinical use without the delay required for expansion. This is of major
importance in the case of indications where treatment is needed without delay,
for example in allograft rejection of the transplanted organ. Although it is
believed that allo MSCs are immune privileged, they could possibly elicit an
anti-donor immune response, which may increase the incidence of rejection/
graft loss and impact the allograft survival on the long term. These safety
issues should be studied before further studies are planned with allogeneic
MSCs in the transplant setting.
Study objective
To study whether selected allogeneic bone marrow derived MSCs are safe by
assessing the composite end point Biopsy Proven Acute Rejection (BPAR)/ graft
loss at 12 months
Study design
Open label, non randomized, non blinded, prospective, single centre clinical
phase Ib study
Intervention
Patients will receive two doses of allogeneic BM derived MSCs IV, 7 days apart,
25 and 26 weeks after transplantation^ (^time point of protocol biopsy and
further reduction of immune suppression). The criteria of allogeneic MSCs are:
no HLA sharing with the kidney donor; the recipient should have no antibodies
directed to the MSCs. Doses of MSCs will be 1x-2 million MSCs per/kg body
weight.
Study burden and risks
Renal biopsy (1 extra biopsy associated with participation); visits to the
hospital (1 extra hospital stay for the renal biopsy), 15 visits, 3 extra above
standard visits (2 for MSC infusion); 15 blood samples, 25 ml each time of
which 2 blood samples are extra for study patients, others performed in all
transplantation patients), in total 360 ml blood; risks MSC infusion (possibly
infections and sensitization).
Albinusdreef 2
Leiden 2300 RC
NL
Albinusdreef 2
Leiden 2300 RC
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.
4.Panel Reactive Antibodies (PRA) <= 50%.
5.Patients must be able to adhere to the study visit schedule and protocol requirements.
6.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 4 weeks before MSC infusion.
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. A psychiatric, addictive or any disorder that compromises ability to give truly informed consent for participation in this study.
7. Use of any investigational drug after transplantation.
8. Documented HIV infection, active hepatitis B, hepatitis C or TB according to current transplantation inclusion criteria.
9. Subjects who currently an active opportunistic infection at the time of MSC infusion (e.g., herpes zoster [shingles], cytomegalovirus (CMV), Pneumocystis carinii (PCP), aspergillosis, histoplasmosis, or mycobacteria other than TB, BK) after transplantation.
10. 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.
11. Known recent substance abuse (drug or alcohol).
12. Patients who are recipients of ABO incompatible transplants.
13. Patients with severe total hypercholesterolemia (>7.5 mmol/L) or total hypertriglyceridemia (>5.6 mmol/L) (lipid lowering treatment with controlled hyperlipidemia is acceptable).*
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 | EUCTR2013-005407-14-NL |
| CCMO | NL47244.000.13 |