Safety and Tolerance of Immunomodulating Therapy With Donor-specific MSC in Pediatric Living-Donor Liver Transplantation (MYSTEP1)
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|ClinicalTrials.gov Identifier: NCT02957552|
Recruitment Status : Recruiting
First Posted : November 7, 2016
Last Update Posted : November 14, 2018
Since the introduction of calcineurin-based immunosuppression, patient and graft survival in pediatric liver transplantation (LT) improved significantly. However, in contrast, calcineurin inhibitor (CNI) toxicity leads to significant morbidity and impairs quality of life for recipients. Moreover, CNI cannot prevent long-term allograft inflammation and fibrosis.
Mesenchymal stem (stromal) cells (MSC) have potent immunomodulatory properties potentially promoting allograft tolerance and ameliorating toxicity of exposure to high dose CNI. Previous trials for non-solid organ transplant indications have shown an excellent safety profile of intravenous MSC application. The MYSTEP1 trial aims to investigate safety and benefits portal and intravenous MSC infusion in pediatric LT.
|Condition or disease||Intervention/treatment||Phase|
|Pediatric Liver Transplantation||Biological: Mesenchymal Stem Cells||Phase 1|
Background: Calcineurin inhibitors (CNI) have significantly improved patient and graft survival in pediatric liver transplantation (pLT). However, CNI toxicity leads to significant morbidity. Moreover, CNIs cannot prevent long-term allograft injury.
Mesenchymal stem (stromal) cells (MSC) have potent immunomodulatory properties, which may promote allograft tolerance and ameliorate toxicity of high-dose CNI. The MYSTEP1 trial aims to investigate safety and feasibility of donor-derived MSCs in pLT.
Methods/Design: 7 to 10 children undergoing living-donor pLT will be included in this open-label, prospective pilot trial. A dose of 1 × 106 MSCs/kg body weight will be given at two time points: first by intraportal infusion intraoperatively and second by intravenous infusion on postoperative day 2. In addition, participants will receive standard immunosuppressive treatment. Our primary objective is to assess the safety of intraportal and intravenous MSC infusion in pLT recipients. Our secondary objective is to evaluate efficacy of MSC treatment as measured by the individual need for immunosuppression and the incidence of biopsy-proven acute rejection. We will perform detailed immune monitoring to investigate immunomodulatory effects.
Discussion: Our study will provide information on the safety of donor-derived MSCs in pediatric living-donor liver transplantation and their effect on immunomodulation and graft survival.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||7 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Safety and Tolerance of Immunomodulating Therapy With Donor-specific Mesenchymal Stem Cells in Pediatric Living-Donor Liver Transplantation, a 24-month, Non-randomized, Open-label, Prospective, Single-center Pilot Trial|
|Actual Study Start Date :||March 10, 2017|
|Estimated Primary Completion Date :||December 2019|
|Estimated Study Completion Date :||December 2021|
Experimental: Treatment with Mesenchymal Stem Cells
Two doses of 1 x 10^6 MSCs/kg body weight:
Standard immunosuppressive treatment consisting of steroids, basiliximab and tacrolimus according to the center's pediatric liver transplantation protocol
Biological: Mesenchymal Stem Cells
Donor-specific, bone marrow derived mesenchymal stem (stromal) cells
- Number of participants with MYSTEP-score grade 3 and grade 2 (toxicity of MSC infusion) [ Time Frame: 28 days ]In order to evaluate and quantifiy acute clinical complications related to MSC infusion, the investigators defined the MYSTEP score, a specific pediatric infusional toxicity scoring system (adapted from MiSOT-I score). The score focusses on description of intraportal, pulmonary and systemic toxicity. For each of these three modalities, degrees of severity between 0 (no treatment emergent adverse event) and 3 (severe treatment emergent adverse event) have been defined.
- Number of participants with occurrence of any severe adverse events (SAE) [ Time Frame: Two years ]A particular focus will be on viral infections and reactivation (ADV, HCMV, EBV, Hepatitis B, Hepatitis C and Hepatitis E), bacterial or fungal infections.
- Graft function after liver transplantation - Number of participants with abnormal liver tests [ Time Frame: Two years ]Graft function after liver transplantation, measured by aminotransferase and gamma glutamyl transferase activity, bilirubin, albumin and INR.
- Individual need for immunosuppressive medication [ Time Frame: Two years ]measured by tacrolimus trough levels [ng/ml] and prednisolon dosage [mg/kgBW/day]. Tapering of tacrolimus and steroids will be performed according to a step-wise tapering protocol after day 180.
- Time to first biopsy-proven acute rejection (BPAR) [ Time Frame: Two years ]Protocol liver biopsy will be performed on day 180 post LT. Additional biopsies will be taken whenever clinically necessary.
- Immune monitoring: donor-specific antibodies (DSA) [ Time Frame: Two years ][Participants with positive DSA]
- Patient and graft survival at 1 and 2 years after liver transplantation [ Time Frame: up to Two years ][Death, Re-Transplantation]
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02957552
|Contact: Steffen Hartleif, MD||+49-7071-29-0 ext firstname.lastname@example.org|
|University Children's Hospital||Recruiting|
|Tuebingen, Germany, 72076|
|Contact: Steffen Hartleif, MD +497071-29 ext 84711 email@example.com|
|Principal Investigator:||Ekkehard Sturm, MD, PhD||University Hospital Tuebingen, Germany; Dept. for Pediatric Gastroenterology and Hepatology|