Clinical trial NCT02387151: Allogeneic Mesenchymal Stromal Cell Therapy in Renal Transplant Recipients
Official title: Safety of Allogeneic Bone Marrow Derived Mesenchymal Stromal Cell Therapy in Renal Transplant Recipients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Rejection
Graft Loss
Keywords: Mesenchymal Stromal Cells
Rejection
Lead sponsor: Leiden University Medical Center
Sponsor class: OTHER
First posted: 2015-03-12
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This study will test 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.

Detailed description: 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.

A promising novel therapeutic immunosuppressive option in the treatment of renal recipients with a profound effect on the fibrosis reaction is the clinical application of mesenchymal stromal cells (MSCs). Allogeneic MSCs offer the advantage of availability for clinical use without the delay required for expansion.

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.

MSCs are infused at a time point when immune suppression is lowered and the kidney is at increased risk for developing immune mediated injury. In addition, a large amount of the kidneys already has signs of fibrosis at this time point and MSCs might reduce the fibrosis which so importantly affects long term survival. MSCs will have no Human Leucocyte Antigen (HLA) sharing with the mismatches of the donor and the recipient should have no antibodies directed to the MSCs to reduce the anti-donor immune respons risk.

Eligibility criteria: Inclusion Criteria:

* 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.
* Recipients of a first kidney graft from a living-unrelated or non-HLA identical living related donor.
* Panel Reactive Antibodies (PRA) ≤ 50%.
* Patients must be able to adhere to the study visit schedule and protocol requirements.
* If female and of child-bearing age, subject must be non-pregnant, non-breastfeeding, and use adequate contraception.

Exclusion Criteria:

* Double organ transplant recipient.
* Biopsy proven acute rejection (according to the Banff criteria) in the 4 weeks before MSC infusion.
* Patients with evidence of active infection or abscesses (with the exception of an uncomplicated urinary tract infection) before MSC infusion.
* Patients suffering from hepatic failure.
* Patients suffering from an active autoimmune disease.
* A psychiatric, addictive or any disorder that compromises ability to give truly informed consent for participation in this study.
* Use of any investigational drug after transplantation.
* Documented HIV infection, active hepatitis B, hepatitis C or tuberculosis according to current transplantation inclusion criteria.
* 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 tuberculosis, BK) after transplantation.
* 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
* Known recent substance abuse (drug or alcohol).
* Patients who are recipients of ABO incompatible transplants.
* 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).

Primary outcomes:
measure: biopsy proven acute rejection / graft loss
timeFrame: 12 months after transplantation
Secondary outcomes:
measure: Comparison of fibrosis by quantitative Sirius Red scoring
timeFrame: Before MSC infusion (week 24 after transplantation) and 6 months after MSC infusion (week 52 after transplantation)
measure: Serious adverse events
timeFrame: 12 months after transplantation
measure: Renal function measured by cGFR (MDRD formula) and iohexol clearance
timeFrame: week 24 after transplantation (before MSC infusion) and 52 after transplantation
measure: CMV, BK infection (viremia, disease and syndrome; and subtypes of BK viremia) and other opportunistic infections
timeFrame: from baseline up to 26 weeks after MSC treatment
measure: Development of de novo donor specific antibodies (DSA) and immunological responses
timeFrame: at baseline, week 24 after transplantation (before MSC treatment) up to week 26 after MSC treatment
Other outcomes:
Locations:
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
Study officials:
affiliation: Leiden University Medical Center
name: Marlies EJ Reinders, MD/PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Reinders ME, Dreyer GJ, Bank JR, Roelofs H, Heidt S, Roelen DL, Zandvliet ML, Huurman VA, Fibbe WE, van Kooten C, Claas FH, Rabelink TJ, de Fijter JW. Safety of allogeneic bone marrow derived mesenchymal stromal cell therapy in renal transplant recipients: the neptune study. J Transl Med. 2015 Nov 4;13:344. doi: 10.1186/s12967-015-0700-0.