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

Pediatric Liver Transplantation Clinical Trial

— MYSTEP1  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02957552
• Other study ID #: MYSTEP1
• Secondary ID: 2014-003561-15
• Status: Recruiting
• Phase: Phase 1
• Start date: March 10, 2017
• Est. completion date: December 2021

Study information

• Verified date: November 2018
• Source: University Hospital Tuebingen
• Contact: Steffen Hartleif, MD
• Phone: +49-7071-29-0
• Email: steffen.hartleif[@]med.uni-tuebingen.de
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 7
• Est. completion date: December 2021
• Est. primary completion date: December 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 8 Weeks to 18 Years

Eligibility

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

Related Conditions & MeSH terms

• Pediatric Liver Transplantation

Intervention

Biological:
• Mesenchymal Stem Cells
Donor-specific, bone marrow derived mesenchymal stem (stromal) cells

Locations

Country	Name	City	State
Germany	University Children's Hospital	Tuebingen

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital Tuebingen

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of participants with MYSTEP-score grade 3 and grade 2 (toxicity of MSC infusion)	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.	28 days
Primary	Number of participants with occurrence of any severe adverse events (SAE)	A particular focus will be on viral infections and reactivation (ADV, HCMV, EBV, Hepatitis B, Hepatitis C and Hepatitis E), bacterial or fungal infections.	Two years
Primary	Graft function after liver transplantation - Number of participants with abnormal liver tests	Graft function after liver transplantation, measured by aminotransferase and gamma glutamyl transferase activity, bilirubin, albumin and INR.	Two years
Secondary	Individual need for immunosuppressive medication	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.	Two years
Secondary	Time to first biopsy-proven acute rejection (BPAR)	Protocol liver biopsy will be performed on day 180 post LT. Additional biopsies will be taken whenever clinically necessary.	Two years
Secondary	Immune monitoring: donor-specific antibodies (DSA)	[Participants with positive DSA]	Two years
Secondary	Patient and graft survival at 1 and 2 years after liver transplantation	[Death, Re-Transplantation]	up to Two years