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Safety and Tolerance of Immunomodulating Therapy With Donor-specific MSC in Pediatric Living-Donor Liver Transplantation (MYSTEP1)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT02957552
Recruitment Status : Recruiting
First Posted : November 6, 2016
Last Update Posted : November 14, 2018
Information provided by (Responsible Party):
PD Dr. Ekkehard Sturm (MD, PhD), University Hospital Tuebingen

Brief Summary:

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

Detailed Description:

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 7 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Treatment with Mesenchymal Stem Cells

Two doses of 1 x 10^6 MSCs/kg body weight:

  • first administration intraoperatively via intraportal infusion
  • second infusion via intravenous infusion on postoperative day 2 (+/- 1 day)

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

Primary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. Immune monitoring: donor-specific antibodies (DSA) [ Time Frame: Two years ]
    [Participants with positive DSA]

  4. Patient and graft survival at 1 and 2 years after liver transplantation [ Time Frame: up to Two years ]
    [Death, Re-Transplantation]

Information from the National Library of Medicine

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Ages Eligible for Study:   8 Weeks to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Written informed consent (patients, both parents and / or legal guardian)
  2. age ≥ 8 weeks and ≤ 18 years
  3. undergoing living donor liver transplantation for chronic terminal liver failure
  4. Body weight > 5kg

Exclusion Criteria:

  1. No suitability of the living-donor
  2. Pregnant or breastfeeding
  3. If appropriate: no use of adequate contraception
  4. Acute liver failure; highly urgent transplantations
  5. Receiving any form of solid organ retransplantation
  6. Multi-Organ-Transplantations
  7. Active autoimmune disease
  8. Pre-existing renal failure with eGFR < 50 ml/min/1.73 m2 or requiring hemodialysis
  9. Reduced pulmonary function (lung function test in children older than 6 years: FEV1 and FVC < 70% of age-appropriate norm) or clinical suspicion of pulmonary disease affecting patient's physical performance, requiring invasive or non-invasive mechanical ventilation.
  10. History of pulmonary embolism
  11. Pulmonary hypertension and / or right ventricular load in echocardiography
  12. Cardiac function: left ventricular shortening fraction (FS) < 25%
  13. Clinically significant systemic infections
  14. Critical care treatment like mechanical ventilation, dialysis or vasopressor agents.
  15. HIV seropositive, HTLV seropositive, Hepatitis B/C seropositive
  16. Hepato-biliary malignancies or history of any extra-hepatic malignancy
  17. Thrombophilia
  18. Budd-Chiari syndrome
  19. Pre-existent thrombosis of portal vein
  20. Doppler-sonographic evidence for relevant porto-systemic shunts, like persistent Ductus Venosus
  21. Cold ischemia time > 90 min
  22. Known abuse for drugs or alcohol
  23. Known allergy to DMSO

Information from the National Library of Medicine

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 identifier (NCT number): NCT02957552

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Contact: Steffen Hartleif, MD +49-7071-29-0 ext 81339

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University Children's Hospital Recruiting
Tuebingen, Germany, 72076
Contact: Steffen Hartleif, MD    +497071-29 ext 84711   
Sponsors and Collaborators
University Hospital Tuebingen
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Principal Investigator: Ekkehard Sturm, MD, PhD University Hospital Tuebingen, Germany; Dept. for Pediatric Gastroenterology and Hepatology
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Responsible Party: PD Dr. Ekkehard Sturm (MD, PhD), Head of Pediatric Gastroenterology and Hepatology, University Hospital Tuebingen Identifier: NCT02957552    
Other Study ID Numbers: MYSTEP1
2014-003561-15 ( EudraCT Number )
First Posted: November 6, 2016    Key Record Dates
Last Update Posted: November 14, 2018
Last Verified: November 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No