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Mesenchymal Stromal Cell Therapy in Renal Recipients (MSCs)

Primary Purpose

Renal Transplant Rejection, Fibrosis

Status
Unknown status
Phase
Phase 2
Locations
Netherlands
Study Type
Interventional
Intervention
Mesenchymal Stromal Cells
Sponsored by
Leiden University Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Renal Transplant Rejection focused on measuring Mesenchymal Stromal Cells, Allograft rejection, Fibrosis

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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).

Sites / Locations

  • Leiden University Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

No Intervention

Arm Label

Mesenchymal Stromal Cells + Everolimus

Everolimus + Tacrolimus

Arm Description

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)

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).

Outcomes

Primary Outcome Measures

Fibrosis by quantitative Sirius Red scoring of MSC treated and untreated groups

Secondary Outcome Measures

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

Full Information

First Posted
February 5, 2014
Last Updated
September 15, 2020
Sponsor
Leiden University Medical Center
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1. Study Identification

Unique Protocol Identification Number
NCT02057965
Brief Title
Mesenchymal Stromal Cell Therapy in Renal Recipients
Acronym
MSCs
Official Title
Autologous Bone Marrow Derived Mesenchymal Stromal Cell Therapy in Combination With Everolimus to Preserve Renal Structure and Function in Renal Recipients
Study Type
Interventional

2. Study Status

Record Verification Date
September 2020
Overall Recruitment Status
Unknown status
Study Start Date
March 2014 (undefined)
Primary Completion Date
January 2020 (Actual)
Study Completion Date
January 2022 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Leiden University Medical Center

4. Oversight

Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Renal Transplant Rejection, Fibrosis
Keywords
Mesenchymal Stromal Cells, Allograft rejection, Fibrosis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
70 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Mesenchymal Stromal Cells + Everolimus
Arm Type
Active Comparator
Arm Description
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)
Arm Title
Everolimus + Tacrolimus
Arm Type
No Intervention
Arm Description
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).
Intervention Type
Drug
Intervention Name(s)
Mesenchymal Stromal Cells
Other Intervention Name(s)
Bone marrow derived mesenchymal stromal cells
Intervention Description
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
Primary Outcome Measure Information:
Title
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 Measure Information:
Title
Renal function and proteinuria
Time Frame
6 months
Title
Number of participants with CMV and BK infection an other opportunistic infections between groups
Time Frame
6 months
Title
Number of participants with adverse events
Time Frame
6 months
Title
composite end point efficacy failure (biopsy proven acute rejection, graft loss or death)
Time Frame
6 months
Title
Presence of donor specific antibodies and immunologic monitoring
Time Frame
6 months
Title
Progression of subclinical cardiovascular disease in the different treatment groups bij assessing echocardiographic parameters
Time Frame
6 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
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 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).
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Marlies EJ Reinders, MD/PhD
Organizational Affiliation
Leiden University Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Leiden University Medical Center
City
Leiden
ZIP/Postal Code
2333 ZA
Country
Netherlands

12. IPD Sharing Statement

Citations:
PubMed Identifier
23349326
Citation
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.
Results Reference
result
PubMed Identifier
25491391
Citation
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.
Results Reference
derived

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Mesenchymal Stromal Cell Therapy in Renal Recipients

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