Mesenchymal Stromal Cell Therapy in Renal Recipients (MSCs)

Autologous Bone Marrow Derived Mesenchymal Stromal Cell Therapy in Combination With Everolimus to Preserve Renal Structure and Function in Renal Recipients

This study will test the hypothesis that MSCs in combination with Everolimus facilitate Tacrolimus withdrawal, reduce fibrosis and decrease the incidence of opportunistic infections compared to standard tacrolimus dose.

Study Overview

• Status: Unknown
• Conditions: Fibrosis; Renal Transplant Rejection
• Intervention / Treatment: Drug: Mesenchymal Stromal Cells

Detailed Description

Kidney transplantation has improved survival and quality of life for patients with end-stage renal disease. Despite excellent short-term results, long-term survival of transplanted kidneys has not improved accordingly in the last decades. Calcineurin inhibitors (CNI) have been the cornerstone of immunosuppressive therapy for many years, due to their efficacy in preventing acute rejection. However, CNI have nephrotoxic side effects that can directly contribute to renal dysfunction and compromise long-term outcomes. Consequently there is a strong interest in immunosuppressive (IS) regimens that maintain efficacy for the prevention of acute rejection, whilst reducing nephrotoxicity.

In this perspective the combination of mesenchymal stromal cells (MSCs) with a mTor inhibitor (Everolimus (Certican®)) might be an optimal strategy to facilitate CNI (tacrolimus) withdrawal. MSCs have IS properties and roles in tissue repair and everolimus is a proliferation signal inhibitor with potent immunosuppressant effects. In experimental studies the combination of mTor inhibitor and MSCs was shown to attenuate alloimmune responses and to promote allograft tolerance.

In total 70 de novo renal recipients, 18-75 years of ages will be recruited from the transplant clinics of the LUMC. Thirty five of these patients will be included in the Certican/ and MSC group and 35 patients in the Certican/ standard dose tacrolimus group. Patients of the MSC treated groups will receive two doses of autologous BM derived MSCs IV, 7 days apart, 6 and 7 weeks after transplantation in combination with Certican® (1.5 mg b.i.d.). At the time of the second MSC infusion tacrolimus will be withdrawn in 2 weeks (after 1 week dose of tacrolimus will be halved, after 2 weeks stopped). Patients in the control group will receive Certican® (1.5 mg b.i.d.) and standard dose tacrolimus (through levels 6-8 ng/ml after 6 weeks).

Primary goal is evaluate whether concentration-controlled Certican® with MSCs compared to Certican® with standard tacrolimus in renal transplant recipients reduces fibrosis by quantitative Sirius Red scoring.

• Study Type: Interventional
• Enrollment (Actual): 70
• Phase: Phase 2

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 deceased, living-unrelated or non-HLA identical living related donor > 50 years of age.
• Panel Reactive Antibodies (PRA) ≤ 10%.
• 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 first 6 weeks after transplantation.
• 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.
• Patients who have had a previous BM transplant.
• 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 TB 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 TB, 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).
• Contraindications to undergo a BM biopsy.
• Patients who are recipients of ABO incompatible transplants.
• Cold ischemia time >30 hrs.
• 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: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Mesenchymal Stromal Cells + Everolimus; Intervention: two doses of autologous bone marrow (BM) derived Mesenchymal Stromal Cells IV, 7 days apart, 6 and 7 weeks after transplantation in combination with Certican® (1.5mg/day). Doses of MSCs will be 1-2x10^6 million MSCs per/kg body weight. At the time of the second MSC infusion tacrolimus will be withdrawn in 2 weeks (after 1 week dose of tacrolimus wil be halved, after 2 weeks stopped)	Drug: Mesenchymal Stromal Cells; Two doses of autologous bone marrow (BM) derived MSCs IV, 7 days apart, 6 and 7 weeks after transplantation. Doses of MSCs will be 1-2x10^6 million MSCs per/kg body weight; Other Names: Bone marrow derived mesenchymal stromal cells
No Intervention: Everolimus + Tacrolimus; Patients in the control group will receive Certican® (1.5 mg b.i.d.) and standard dose tacrolimus (through levels 6-8 ng/ml after 6 weeks).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Fibrosis by quantitative Sirius Red scoring of MSC treated and untreated groups	at 6 months compared to 4 weeks post transplant

Secondary Outcome Measures

Outcome Measure	Time Frame
Number of participants with adverse events	6 months
Renal function and proteinuria	6 months
Number of participants with CMV and BK infection an other opportunistic infections between groups	6 months
composite end point efficacy failure (biopsy proven acute rejection, graft loss or death)	6 months
Presence of donor specific antibodies and immunologic monitoring	6 months
Progression of subclinical cardiovascular disease in the different treatment groups bij assessing echocardiographic parameters	6 months

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, de Fijter JW, Roelofs H, Bajema IM, de Vries DK, Schaapherder AF, Claas FH, van Miert PP, Roelen DL, van Kooten C, Fibbe WE, Rabelink TJ. Autologous bone marrow-derived mesenchymal stromal cells for the treatment of allograft rejection after renal transplantation: results of a phase I study. Stem Cells Transl Med. 2013 Feb;2(2):107-11. doi: 10.5966/sctm.2012-0114. Epub 2013 Jan 24.
• Reinders ME, Bank JR, Dreyer GJ, Roelofs H, Heidt S, Roelen DL, Al Huurman V, Lindeman J, van Kooten C, Claas FH, Fibbe WE, Rabelink TJ, de Fijter JW. Autologous bone marrow derived mesenchymal stromal cell therapy in combination with everolimus to preserve renal structure and function in renal transplant recipients. J Transl Med. 2014 Dec 10;12:331. doi: 10.1186/s12967-014-0331-x.

Study record dates

Study Major Dates

• Study Start: March 1, 2014
• Primary Completion (Actual): January 1, 2020
• Study Completion (Anticipated): January 1, 2022

Study Registration Dates

• First Submitted: February 5, 2014
• First Submitted That Met QC Criteria: February 6, 2014
• First Posted (Estimate): February 7, 2014

Study Record Updates

• Last Update Posted (Actual): September 17, 2020
• Last Update Submitted That Met QC Criteria: September 15, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Keywords: Fibrosis; Allograft rejection; Mesenchymal Stromal Cells
• Additional Relevant MeSH Terms: Pathologic Processes; Fibrosis
• Other Study ID Numbers: NL43712.000.13; 2013-000819-25 (EudraCT Number)