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
试验速览
- 阶段
- 1 期
- 入组人数
- 7
- 试验地点
- 2
- 主要终点
- Number of participants with MYSTEP-score grade 3 and grade 2 (toxicity of MSC infusion)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 8 Weeks 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Written informed consent (patients, both parents and / or legal guardian)
- •age ≥ 8 weeks and ≤ 18 years
- •undergoing living donor liver transplantation for chronic terminal liver failure
- •Body weight > 5kg
排除标准
- •No suitability of the living-donor
- •Pregnant or breastfeeding
- •If appropriate: no use of adequate contraception
- •Acute liver failure; highly urgent transplantations
- •Receiving any form of solid organ retransplantation
- •Multi-Organ-Transplantations
- •Active autoimmune disease
- •Pre-existing renal failure with eGFR < 50 ml/min/1.73 m2 or requiring hemodialysis
- •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.
- •History of pulmonary embolism
- •Pulmonary hypertension and / or right ventricular load in echocardiography
- •Cardiac function: left ventricular shortening fraction (FS) < 25%
- •Clinically significant systemic infections
- •Critical care treatment like mechanical ventilation, dialysis or vasopressor agents.
- •HIV seropositive, HTLV seropositive, Hepatitis B/C seropositive
- •Hepato-biliary malignancies or history of any extra-hepatic malignancy
- •Thrombophilia
- •Budd-Chiari syndrome
- •Pre-existent thrombosis of portal vein
- •Doppler-sonographic evidence for relevant porto-systemic shunts, like persistent Ductus Venosus
- •Cold ischemia time > 90 min
- •Known abuse for drugs or alcohol
- •Known allergy to DMSO
研究组 & 干预措施
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
干预措施: Mesenchymal Stem Cells (Biological)
结局指标
主要结局
Number of participants with MYSTEP-score grade 3 and grade 2 (toxicity of MSC infusion)
时间窗: 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)
时间窗: 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
时间窗: Two years
Graft function after liver transplantation, measured by aminotransferase and gamma glutamyl transferase activity, bilirubin, albumin and INR.
次要结局
- Individual need for immunosuppressive medication(Two years)
- Time to first biopsy-proven acute rejection (BPAR)(Two years)
- Immune monitoring: donor-specific antibodies (DSA)(Two years)
- Patient and graft survival at 1 and 2 years after liver transplantation(up to Two years)
研究者
PD Dr. Ekkehard Sturm (MD, PhD)
Head of Pediatric Gastroenterology and Hepatology
University Hospital Tuebingen