An Interventional, Single Arm, Multicenter, Phase I/IIa Clinical Trial to Investigate the Efficacy and Safety of Allo-APZ2-ACLF for the Treatment of Acute-on-Chronic Liver Failure (ACLF)
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 5
- 试验地点
- 10
- 主要终点
- Change of Model for End-Stage Liver Disease (MELD) score at Week 24 or last available post-baseline measurement if the Week 24 score is missing.
研究概览
简要总结
This is an interventional, single arm, multicenter, phase I/IIa clinical trial. The study objective is to investigate the efficacy and safety of three i.v. doses of the investigational medicinal product (IMP) allo-APZ2-ACLF for the treatment of acute-on-chronic liver failure (ACLF). The allogeneic IMP allo-APZ2-ACLF contains skin-derived ABCB5-positive mesenchymal stem cells isolated from skin tissue of healthy donors and stored in a donor cell bank.
详细描述
This is an interventional, phase I/IIa clinical trial to investigate the efficacy (by changes in Model for End-Stage Liver Disease [MELD] score) and safety (by monitoring adverse events) of the IMP in patients with acute-on-chronic liver failure grade 2 and 3. The allogeneic IMP allo-APZ2-ACLF contains skin-derived ABCB5-positive mesenchymal stem cells isolated from skin tissue of healthy donors and stored in a donor cell bank.
The clinical trial will be conducted in Germany and will consist of a screening, treatment and efficacy follow-up period, and a safety follow-up period.The total duration is planned to be about 3 years including the follow-up period.
The planned sample size is up to 18 treated patients. 2 x 10e6 cells/kg, each at Day 0, Day 5 (±1) and Day 13 (±1), will be administrated into peripheral vein (arm) by use of a perfusor. allo-APZ2-ACLF will be in a concentration of 1 x 10e7 cells/mL in HRG-solution. In patients which require dialysis, the IMP application has to be performed at least 3 hours after end of dialysis. This is necessary to ensure that cells and secreted molecules are not cleared from the system by the dialysis.
Patients will be followed up for 24 weeks with clinic visits at Weeks 3, 4, 8, 12, 16, 20 and 24 after IMP application. Further safety follow-ups will be scheduled as home interviews via telephone at Months 15 and 24. If necessary (at the discretion of the investigator), safety follow-ups at Months 15 and 24 can also be carried out as an on-site visit.
The first six patients will be enrolled into the clinical trial consecutively with an interval of 2 weeks between the third IMP-application of the first patient and the enrolment of the second patient, etc. During this period the patient receives all three applications and immediate severe adverse effects (allergic reactions, SIRS) that could occur after treatment would be reported before treatment start of the next patient.
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
- 20 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female patients, aged 20 to 75 years;
- •Diagnosed ACLF of grade 2 or 3 according to EASL-CLIF definition;
- •Patients are not eligible for liver transplant (confirmed by transplantation board);
- •Histology result of liver biopsy not older than 4 weeks before screening;
- •Women of childbearing potential must have a negative blood pregnancy test at screening;
- •Women of childbearing potential and fertile men, and their partners must be willing to use highly effective contraceptive methods during the course of the clinical trial;
- •Written informed consent from patient, legal or authorized representative or a confirmation of justification of trial participation by an independent medical consultant. In case of confirmation by the independent medical consultant, a deferred informed consent from patient, legal or authorized representative has to be given.
排除标准
- •Patients without cirrhosis;
- •Patients with ACLF grade 1 according to EASL-CLIF definition;
- •Patient with septic shock;
- •Patients with known hepatopulmonal syndrome (HPS);
- •Patients with known pulmonary embolism that needs anticoagulative treatment;
- •Patients with pre-existing lung disease with necessity of respiratory support;
- •Active malignancy or history of malignancy within 5 years prior to trial entry;
- •Known infection with human immunodeficiency virus (HIV˗1, HIV-2);
- •Any known allergies to components of the IMP;
- •Current or previous (within 30 days of enrolment) treatment with another IMP, or participation and/or under follow-up in another clinical trial;
- •Patients anticipated to be unwilling or unable to comply with the requirements of the protocol;
- •Evidence of any other medical conditions (such as psychiatric illness, physical examination, or laboratory findings) that may interfere with the planned treatment, affect the patient's compliance, or place the patient at high risk of complications related to the treatment;
- •Pregnant or nursing women;
- •Employees of the sponsor, or employees or relatives of the investigator.
结局指标
主要结局
Change of Model for End-Stage Liver Disease (MELD) score at Week 24 or last available post-baseline measurement if the Week 24 score is missing.
时间窗: Week 24, or last available post-baseline measurement of Days 5 (±1) or 13 (±1) or Weeks 3, 4, 8, 12, 16 or 20 if the Week 24 measurement is missing [LOCF].
Model for End-Stage Liver Disease (MELD) score for assessing the severity of chronic liver disease is measured as absolute change to baseline score at Week 24 or last available post-baseline measurement if the Week 24 score is missing.
Assessment of adverse event (AE) occurrence
时间窗: Between Screening and Month 24
All AEs occurring during the clinical trial will be registered, documented and evaluated.
次要结局
- Vital signs at Week 24: Heart rate(Week 24)
- Complications of ACLF (hepatorenal syndrome [HRS], variceal bleeding, ascites, hepatic encephalopathy [HE], spontaneous bacterial peritonitis [SBP])(Between Screening and Week 24)
- Time to respiratory failure after first IMP administration until Week 24(Between Day 0 (after first IMP administration) and Week 24)
- Vital signs at Week 24: Body temperature(Week 24)
- Change of Child-Pugh-Score at Weeks 3, 4, 8, 12, 16, 20 and 24(Weeks 3, 4, 8, 12, 16, 20 and 24)
- Infections (proven infection necessitating systemic use of antibiotics)(Between Screening and Month 24)
- Changes in the profile of 80 different immunomodulatory cytokines at Weeks 3, 4, 8, 12, 16, 20 and 24(Weeks 3, 4, 8, 12, 16, 20 and 24)
- Change of MELD score at Weeks 3, 4, 8, 12, 16 and 20(Weeks 3, 4, 8, 12, 16 and 20)
- Overall survival time until Week 24(Between Screening and Week 24)
- Transient elastography assessment at Weeks 4, 12 and 24(Weeks 4, 12 and 24)
- Change of levels of C-reactive protein in serum at Weeks 3, 4, 8, 12, 16, 20 and 24(Weeks 3, 4, 8, 12, 16, 20 and 24)
- Duration of initial intensive care stay(Between Screening and Week 24)
- Coagulation parameter "INR" at Week 24(Week 24)
- Vital signs at Week 24: Respiratory rate(Week 24)
- Coagulation parameter "factor V" at Week 24(Week 24)
- Change of CLIF-C ACLF score at Weeks 3, 4, 8, 12, 16, 20 and 24(Weeks 3, 4, 8, 12, 16, 20 and 24)
- Changes in dialytic treatment until Week 24(Between Screening and Week 24)
- Liver Function Test (ALT, AST, AP, Albumin, Bilirubin, GGT) at Weeks 3, 4, 8, 12, 16, 20 and 24(Weeks 3, 4, 8, 12, 16, 20 and 24)
- Duration of the initial hospital stay(Between Screening and Week 24)
- Hematological laboratory parameters at Week 24(Week 24)
- Clinical chemistry parameters at Week 24(Week 24)
- Optional: Evaluation of liver biopsy (necrosis quantification)(Between Week 8 and Week 24)
- Physical examination at Week 24(Week 24)
- Vital signs at Week 24: Blood pressure(Week 24)
- Overall survival at Week 24 and at Month 24(Week 24, Month 24)