Allogeneic Mesenchymal Stromal Cell Therapy in Renal Transplant Recipients (Neptune)

Safety of Allogeneic Bone Marrow Derived Mesenchymal Stromal Cell Therapy in Renal Transplant Recipients

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.

Study Overview

• Status: Completed
• Conditions: Rejection; Graft Loss
• Intervention / Treatment: Drug: mesenchymal stromal cells

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.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 1

Contacts and Locations

Study Locations

• Netherlands
  • Leiden, Netherlands, 2333 ZA
    • Leiden University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: mesenchymal stromal cells; allogeneic mesenchymal stromal cell infusion	Drug: mesenchymal stromal cells; 2 doses of 1-2x10^6 allogeneic bone marrow derives MSCs IV per/kg body weight at weeks 25 and 26 after transplantation; Other Names: MSC; bone marrow derived mesenchymal stromal cells

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
biopsy proven acute rejection / graft loss	12 months after transplantation

Secondary Outcome Measures

Outcome Measure	Time Frame
Comparison of fibrosis by quantitative Sirius Red scoring	Before MSC infusion (week 24 after transplantation) and 6 months after MSC infusion (week 52 after transplantation)
Serious adverse events	12 months after transplantation
Renal function measured by cGFR (MDRD formula) and iohexol clearance	week 24 after transplantation (before MSC infusion) and 52 after transplantation
CMV, BK infection (viremia, disease and syndrome; and subtypes of BK viremia) and other opportunistic infections	from baseline up to 26 weeks after MSC treatment
Development of de novo donor specific antibodies (DSA) and immunological responses	at baseline, week 24 after transplantation (before MSC treatment) up to week 26 after MSC treatment

Collaborators and Investigators

• Sponsor: Leiden University Medical Center
• Investigators: Principal Investigator: Marlies EJ Reinders, MD/PhD, Leiden University Medical Center

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2015
• Primary Completion (Actual): November 1, 2018
• Study Completion (Actual): November 1, 2018

Study Registration Dates

• First Submitted: March 3, 2015
• First Submitted That Met QC Criteria: March 6, 2015
• First Posted (Estimate): March 12, 2015

Study Record Updates

• Last Update Posted (Actual): July 2, 2019
• Last Update Submitted That Met QC Criteria: June 30, 2019
• Last Verified: June 1, 2019

More Information

Terms related to this study

• Keywords: Rejection; Mesenchymal Stromal Cells
• Other Study ID Numbers: NL4724400013; 2013-005407-14 (EudraCT Number)