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
Aperçu de l'étude
Statut
Les conditions
Intervention / Traitement
Description détaillée
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 At the time of the second MSC infusion tacrolimus will be withdrawn in 2 weeks (after 1 week dose of tacrolimus will be halved, after 2 weeks stopped).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.
Type d'étude
Inscription (Réel)
Phase
- Phase 2
Contacts et emplacements
Lieux d'étude
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Leiden, Pays-Bas, 2333 ZA
- Leiden University Medical Center
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Critères de participation
Critère d'éligibilité
Âges éligibles pour étudier
Accepte les volontaires sains
Sexes éligibles pour l'étude
La 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).
Plan d'étude
Comment l'étude est-elle conçue ?
Détails de conception
- Objectif principal: Traitement
- Répartition: Randomisé
- Modèle interventionnel: Affectation parallèle
- Masquage: Aucun (étiquette ouverte)
Armes et Interventions
Groupe de participants / Bras |
Intervention / Traitement |
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Comparateur actif: 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) |
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
Autres noms:
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Aucune 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).
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Que mesure l'étude ?
Principaux critères de jugement
Mesure des résultats |
Délai |
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Fibrosis by quantitative Sirius Red scoring of MSC treated and untreated groups
Délai: at 6 months compared to 4 weeks post transplant
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at 6 months compared to 4 weeks post transplant
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Mesures de résultats secondaires
Mesure des résultats |
Délai |
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Nombre de participants avec événements indésirables
Délai: 6 mois
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6 mois
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Renal function and proteinuria
Délai: 6 months
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6 months
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Number of participants with CMV and BK infection an other opportunistic infections between groups
Délai: 6 months
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6 months
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composite end point efficacy failure (biopsy proven acute rejection, graft loss or death)
Délai: 6 months
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6 months
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Presence of donor specific antibodies and immunologic monitoring
Délai: 6 months
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6 months
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Progression of subclinical cardiovascular disease in the different treatment groups bij assessing echocardiographic parameters
Délai: 6 months
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6 months
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Collaborateurs et enquêteurs
Parrainer
Les enquêteurs
- Chercheur principal: Marlies EJ Reinders, MD/PhD, Leiden University Medical Center
Publications et liens utiles
Publications générales
- 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.
Dates d'enregistrement des études
Dates principales de l'étude
Début de l'étude
Achèvement primaire (Réel)
Achèvement de l'étude (Anticipé)
Dates d'inscription aux études
Première soumission
Première soumission répondant aux critères de contrôle qualité
Première publication (Estimation)
Mises à jour des dossiers d'étude
Dernière mise à jour publiée (Réel)
Dernière mise à jour soumise répondant aux critères de contrôle qualité
Dernière vérification
Plus d'information
Termes liés à cette étude
Termes MeSH pertinents supplémentaires
Autres numéros d'identification d'étude
- NL43712.000.13
- 2013-000819-25 (Numéro EudraCT)
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