Mesenchymal Stromal Cell Therapy in Renal Recipients (MSCs)

• ClinicalTrials.gov Identifier: NCT02057965
• Recruitment Status: Recruiting
• First Posted: February 7, 2014
• Last Update Posted: August 14, 2019
• Sponsor: Leiden University Medical Center
• Information provided by (Responsible Party): M.E. J. Reinders, Leiden University Medical Center

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Renal Transplant Rejection; Fibrosis	Drug: Mesenchymal Stromal Cells	Phase 2

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 At the time of the second MSC infusion tacrolimus will be withdrawn in 2 weeks (after 1 week dose of tacrolimus will be halved, after 2 weeks stopped).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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 70 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Autologous Bone Marrow Derived Mesenchymal Stromal Cell Therapy in Combination With Everolimus to Preserve Renal Structure and Function in Renal Recipients
• Study Start Date: March 2014
• Estimated Primary Completion Date: January 2020
• Estimated Study Completion Date: January 2020

Arms and Interventions

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 Name: 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).

Outcome Measures

Primary Outcome Measures :

1. Fibrosis by quantitative Sirius Red scoring of MSC treated and untreated groups [ Time Frame: at 6 months compared to 4 weeks post transplant ]

Secondary Outcome Measures :

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

Eligibility Criteria

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

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 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).

Contacts and Locations

Contacts

Contact: Marlies EJ Reinders, MD/PhD; m.e.j.reinders@lumc.nl

Locations

Netherlands

Leiden University Medical Center; Recruiting

Leiden, Netherlands, 2333 ZA

Principal Investigator: Marlies EJ Reinders, MD/PhD

Sponsors and Collaborators

Leiden University Medical Center

Investigators

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

More Information

Publications of Results:

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: M.E. J. Reinders, MD/PhD, Leiden University Medical Center
• ClinicalTrials.gov Identifier: NCT02057965
• Other Study ID Numbers: NL43712.000.13; 2013-000819-25 ( EudraCT Number )
• First Posted: February 7, 2014
• Last Update Posted: August 14, 2019
• Last Verified: August 2019

Keywords provided by M.E. J. Reinders, Leiden University Medical Center:

Mesenchymal Stromal Cells; Allograft rejection; Fibrosis

Additional relevant MeSH terms:

Fibrosis; Pathologic Processes