Clinical trial NCT02957552: Safety and Tolerance of Immunomodulating Therapy With Donor-specific MSC in Pediatric Living-Donor Liver Transplantation
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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
Conditions: Pediatric Liver Transplantation
Lead sponsor: University Hospital Tuebingen
Sponsor class: OTHER
First posted: 2016-11-06
Enrollment: 7
Sex: ALL
Minimum age (years): 8
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Number of participants with MYSTEP-score grade 3 and grade 2 (toxicity of MSC infusion)
timeFrame: 28 days
measure: Number of participants with occurrence of any severe adverse events (SAE)
timeFrame: Two years
measure: Graft function after liver transplantation - Number of participants with abnormal liver tests
timeFrame: Two years
Secondary outcomes:
measure: Individual need for immunosuppressive medication
timeFrame: Two years
measure: Time to first biopsy-proven acute rejection (BPAR)
timeFrame: Two years
measure: Immune monitoring: donor-specific antibodies (DSA)
timeFrame: Two years
measure: Patient and graft survival at 1 and 2 years after liver transplantation
timeFrame: up to Two years
Other outcomes:
Locations:
city: Tuebingen
country: Germany
facility: University Children's Hospital
Study officials:
affiliation: University Hospital Tuebingen, Germany; Dept. for Pediatric Gastroenterology and Hepatology
name: Ekkehard Sturm, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: