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

NCT ID: NCT02957552

Last Updated: 2018-11-14

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE1
• Total Enrollment: 7 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-03-10
• Study Completion Date: 2021-12-31

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.

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.

Conditions

Pediatric Liver Transplantation

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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

Group Type: EXPERIMENTAL

Mesenchymal Stem Cells

Intervention Type: BIOLOGICAL

Donor-specific, bone marrow derived mesenchymal stem (stromal) cells

Interventions

Mesenchymal Stem Cells

Donor-specific, bone marrow derived mesenchymal stem (stromal) cells

Intervention Type: BIOLOGICAL

Eligibility Criteria

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

• Minimum Eligible Age: 8 Weeks
• Maximum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University Hospital Tuebingen

OTHER

Sponsor Role: lead

Responsible Party

PD Dr. Ekkehard Sturm (MD, PhD)

Head of Pediatric Gastroenterology and Hepatology

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Ekkehard Sturm, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

University Hospital Tuebingen, Germany; Dept. for Pediatric Gastroenterology and Hepatology

Locations

University Children's Hospital

Tübingen, , Germany

Site Status: RECRUITING

Countries

Germany

Central Contacts

Steffen Hartleif, MD

Role: CONTACT

steffen.hartleif@med.uni-tuebingen.de

+49-7071-29-0 ext. 81339

Facility Contacts

Steffen Hartleif, MD

Role: primary

steffen.hartleif@med.uni-tuebingen.de

+497071-29 ext. 84711

Other Identifiers

2014-003561-15

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

MYSTEP1

Identifier Type: -

Identifier Source: org_study_id