Efficacy and Safety of Allogeneic Human Bone Marrow Mesenchymal Stem Cells for the Treatment of Patients With Acute-on-chronic Liver Failure
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 90
- 试验地点
- 1
- 主要终点
- Phase I: Incidence of CG-BM1-related dose-limiting toxicity (DLT) events
研究概览
简要总结
The goal of this clinical trial is to learn if CG-BM1 Allogeneic Human Bone Marrow Mesenchymal Stem Cell Injection (hereinafter referred to as CG-BM1) can treat acute-on-chronic liver failure (ACLF) patients. Main purposes of this clinical trial are:
- To evaluate the safety and tolerability of CG-BM1 for the treatment of adult patients with ACLF.
- To observe the preliminary effectiveness of CG-BM1 in treating adult ACLF patients, and to provide a basis for subsequent clinical trial protocol design.
详细描述
CG-BM1 is a bone marrow mesenchymal stem cell product independently developed by Guangzhou Cellgenes Biotechnology Co., Ltd. The active ingredient of CG-BM1 is human bone marrow mesenchymal stem cell, which is derived from bone marrow donated by healthy adults and prepared into stem cell injection under aseptic conditions. CG-BM1 is the first bone marrow mesenchymal stem cell (BMSC) therapeutic drug for the treatment of ACLF in China. Preclinical data showed that CG-BM1 has the ability to immunomodulate, inhibit the secretion of pro-inflammatory factors by immune cells, and up-regulate the level of anti-inflammatory factors, which can significantly improve the liver function, reduce the inflammatory response, and reverse hepatic fibrosis in ACLF animal models, and the results of the study suggest that it is safe and effective, supporting its further clinical development. The purpose of this study was to evaluate the safety and tolerability of CG-BM1 for the treatment of patients with ACLF, as well as to evaluate the preliminary efficacy of CG-BM1 for the treatment of patients with ACLF.
The study was divided into 2 phases, the first with an open-labeled, dose-escalation design; the second with a multicenter, randomized, double-blind, placebo-controlled design. Phase I: Patients was divided into three dose groups using a traditional "3+3" design. 3-6 subjects were enrolled in each dose. Phase II: Multiple-dose, randomized, double-blind, placebo-controlled trial. Based on the results of the phase I trial, two dose groups were selected for phase II.
A total of 90 subjects were enrolled and randomized 1:1:1. The experiment group received CG-BM1 + conventional treatment regimen, and the control group received placebo + conventional treatment regimen.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Inclusion Criteria:
- •Voluntarily participate in the clinical study. The patient or legal guardian fully understands and is informed about the study and signs an informed consent form. Willing to follow and be able to complete all trial procedures.
- •Age ≥18 years old, male or female.
- •Diagnostic criteria in accordance with the Guidelines for Diagnosis and Treatment of Liver Failure (2018 edition) issued by the Liver Failure and Artificial Liver Group of the Infectious Diseases Branch of the Chinese Medical Association and the Liver Disease Branch of the Chinese Medical Association Diagnostic criteria, specific indicators include 1) Suffering from the basis of chronic liver disease; 2) Serum TBIL 171 μ mol/l or mean daily rise ≥17.1 μmol/L; 3) Meeting any of the following three: i. Having a bleeding tendency; ii. Comorbid hepatic encephalopathy; iii. Comorbid hepatorenal syndrome.
- •The cause of liver failure is unlimited.
- •Model for End Stage Liver Disease (MELD) score under
- •No conception (or conception of sexual partner) during the study period (from signing of informed consent to the last visit) and within 6 months after the last cell infusion; and childbearing, or breastfeeding potential, including:
- •Female subject with persistent spontaneous menopause >12 months or who have undergone sterilization (e.g., tubal ligation or bilateral oophorectomy or hysterectomy).
- •Non-menopausal female subject with a negative serum pregnancy test within 7 days prior to the first cellular infusion. Sign an informed consent and willingness to use one of the following effective methods of contraception, including intrauterine device (IUD), tubal ligation, double barrier method (condom, vaginal diaphragm, spermicide) and spermicide for the male partner, but does not include oral contraceptives, for a period of 6 months after the last cellular infusion.
- •Male subjects who are willing to use one or more effective methods of contraception, including vasectomy, double-barrier methods, use of the pill by the female partner, intrauterine devices or tubal ligation from the time of the first infusion until 6 months after the last infusion.
- •Male or non-menopausal female subjects who do not have, or are willing to not have sexual intercourse during the study and for 6 months after the last cell infusion.
排除标准
- •Be allergic to known components of the drug (the main component of the product is bone marrow mesenchymal stem cells, excipients include dimethyl sulfoxide, human albumin) or other history of severe allergy.
- •Patients with severe infections such as septic shock.
- •Patients with gastrointestinal bleeding at the time of screening.
- •Hepatic encephalopathy grade
- •Concurrent failure of 3 or more organs (liver failure defined as TBiL ≥12 mg/dl, renal failure defined as creatinine ≥2.0 mg/dl, coagulation failure defined as INR ≥2.5, cerebral failure defined as hepatic encephalopathy grades 3-4, circulatory failure defined by use of vasoactive drugs, and respiratory failure was defined as PaO2 /FiO2 ≤200 or SpO2 /FiO2 ≤214 or mechanical ventilation)
- •Pregnancy or breastfeeding.
- •Previous history of malignant tumors.
- •Imaging suggestive of intrahepatic nodular space-occupying lesions.
- •A history of immunodeficiency, including HIV-positive, or other acquired or congenital immunodeficiency diseases.
- •Patients with previous liver transplantation.
- •Deep vein thrombosis at screening or history of pulmonary embolism within 3 months prior to screening.
- •Patients with pulmonary hypertension.
- •History of myocardial infarction within 6 months.
- •Previous stem cell therapy.
- •Participation in another interventional clinical trial within 3 months or 5 half-lives (for experimental drug interventions only, whichever is longer) prior to infusion.
- •Any other factors that, in the judgment of the investigator, make the subject inappropriate for participation in this trial.
- •Inclusion Criteria:
- •Inclusion Criteria:
- •Voluntarily participate in the clinical study. The patient or legal guardian fully understands and is informed about the study and signs an informed consent form. Willing to follow and be able to complete all trial procedures.
- •Age ≥18 years old, male or female.
- •Diagnostic criteria in accordance with the Guidelines for Diagnosis and Treatment of Liver Failure (2018 edition) issued by the Liver Failure and Artificial Liver Group of the Infectious Diseases Branch of the Chinese Medical Association and the Liver Disease Branch of the Chinese Medical Association Diagnostic criteria, specific indicators include 1) Suffering from the basis of chronic liver disease; 2) Serum TBIL 171 μ mol/l or mean daily rise ≥17.1 μmol/L; 3) Meeting any of the following three: i. Having a bleeding tendency; ii. Comorbid hepatic encephalopathy; iii. Comorbid hepatorenal syndrome.
- •The cause of liver failure is Hepatitis B.
- •Model for End Stage Liver Disease (MELD) score under
- •No conception (or conception of sexual partner) during the study period (from signing of informed consent to the last visit) and within 6 months after the last cell infusion; and childbearing, or breastfeeding potential, including:
- •Female subject with persistent spontaneous menopause >12 months or who have undergone sterilization (e.g., tubal ligation or bilateral oophorectomy or hysterectomy).
- •Non-menopausal female subject with a negative serum pregnancy test within 7 days prior to the first cellular infusion. Sign an informed consent and willingness to use one of the following effective methods of contraception, including intrauterine device (IUD), tubal ligation, double barrier method (condom, vaginal diaphragm, spermicide) and spermicide for the male partner, but does not include oral contraceptives, for a period of 6 months after the last cellular infusion.
- •Male subjects who are willing to use one or more effective methods of contraception, including vasectomy, double-barrier methods, use of the pill by the female partner, intrauterine devices or tubal ligation from the time of the first infusion until 6 months after the last infusion.
- •Male or non-menopausal female subjects who do not have, or are willing to not have sexual intercourse during the study and for 6 months after the last cell infusion.
- •Exclusion Criteria:
- •Be allergic to known components of the drug (the main component of the product is bone marrow mesenchymal stem cells, excipients include dimethyl sulfoxide, human albumin) or other history of severe allergy.
- •Patients with severe infections such as septic shock.
- •Patients with gastrointestinal bleeding at the time of screening.
- •Hepatic encephalopathy grade
- •Concurrent failure of 3 or more organs (liver failure defined as TBiL ≥12 mg/dl, renal failure defined as creatinine ≥2.0 mg/dl, coagulation failure defined as INR ≥2.5, cerebral failure defined as hepatic encephalopathy grades 3-4, circulatory failure defined by use of vasoactive drugs, and respiratory failure was defined as PaO2 /FiO2 ≤200 or SpO2 /FiO2 ≤214 or mechanical ventilation)
- •Pregnancy or breastfeeding.
- •Previous history of malignant tumors.
- •Imaging suggestive of intrahepatic solid nodal space-occupying lesions and which the investigator determines may compromise subject safety.
- •Received artificial liver therapy within 7 days prior to first dose.
- •A history of immunodeficiency, including HIV-positive, or other acquired or congenital immunodeficiency diseases.
- •Patients with previous liver transplantation.
- •Deep vein thrombosis at screening or history of pulmonary embolism within 3 months prior to screening.
- •Patients with pulmonary hypertension.
- •History of myocardial infarction within 6 months.
- •Previous stem cell therapy.
- •Participation in another interventional clinical trial within 3 months or 5 half-lives (for experimental drug interventions only, whichever is longer) prior to infusion.
- •Any other factors that, in the judgment of the investigator, make the subject inappropriate for participation in this trial.
研究组 & 干预措施
Phase 2: Placebo Control
The control group received placebo + conventional treatment. Placebo was solubilizer of CG-BM1. Conventional treatment included hepatoprotection, antiviral therapy or other etiologic treatments, supplementation of plasma and albumin, supplementation of coagulation factors, treatment of complications, and nutritional support.
干预措施: Solvent of CG-BM1 (Drug)
Phase 1: Low Dose Group
The trial group with a low dose (1.0×10^6 cells/kg) will first enroll one subject, who will be infused with single dose CG-BM1 and then observed for at least 28 days. The clinical data of the first subject will be reviewed by the SRC.
- If the first subject in the low-dose trial group experiences DLT, enrollment will be suspended. After discussion, recommendations will be made. If the trial is to continue, two additional subjects will be enrolled for observation. If no DLT occurs, the dose trial group will need to enroll three more subjects.
- If the first subject in the dose trial group does not experience DLT after 28 days, - the remaining two subjects in that dose trial group will be enrolled.
Once all subjects in the dose trial group have completed the infusion and have been observed for 28 days, the clinical data of all subjects will be submitted to the SRC. After a comprehensive evaluation, the SRC will provide recommendations for dose escalation.
干预措施: Bone marrow mesenchymal stem cells (low dose) (Drug)
Phase 1: Medium Dose Group
The trial group with a low dose (2.0×10^6 cells/kg) will first enroll one subject, who will be infused with single dose CG-BM1 and then observed for at least 28 days. The clinical data of the first subject will be reviewed by the SRC.
- If the first subject in the low-dose trial group experiences DLT, enrollment will be suspended. After discussion, recommendations will be made. If the trial is to continue, two additional subjects will be enrolled for observation. If no DLT occurs, the dose trial group will need to enroll three more subjects.
- If the first subject in the dose trial group does not experience DLT after 28 days, - the remaining two subjects in that dose trial group will be enrolled.
Once all subjects in the dose trial group have completed the infusion and have been observed for 28 days, the clinical data of all subjects will be submitted to the SRC. After a comprehensive evaluation, the SRC will provide recommendations for dose escalation.
干预措施: Bone marrow mesenchymal stem cells (medium dose) (Drug)
Phase 2: Low Dose Group
Patients in low dose group receive CG-BM1 + conventional treatment. Administration procedure of CG-BM1 is 1.0×10^6 cells/kg CG-BM1 once a week for a total of 4 administrations.
干预措施: Bone marrow mesenchymal stem cells (low dose) (Drug)
Phase 2: Medium Dose Group
Patients in medium dose group receive CG-BM1 + conventional treatment. Administration procedure of CG-BM1 is 2.0×10^6 cells/kg CG-BM1 once a week for a total of 4 administrations.
干预措施: Bone marrow mesenchymal stem cells (medium dose) (Drug)
Phase 1: High Dose Group
The trial group with a low dose (4.0×10^6 cells/kg) will first enroll one subject, who will be infused with single dose CG-BM1 and then observed for at least 28 days. The clinical data of the first subject will be reviewed by the SRC.
- If the first subject in the low-dose trial group experiences DLT, enrollment will be suspended. After discussion, recommendations will be made. If the trial is to continue, two additional subjects will be enrolled for observation. If no DLT occurs, the dose trial group will need to enroll three more subjects.
- If the first subject in the dose trial group does not experience DLT after 28 days, - the remaining two subjects in that dose trial group will be enrolled.
Once all subjects in the dose trial group have completed the infusion and have been observed for 28 days, the clinical data of all subjects will be submitted to the SRC. After a comprehensive evaluation, the SRC will provide recommendations for dose escalation.
干预措施: Bone marrow mesenchymal stem cells (high dose) (Drug)
结局指标
主要结局
Phase I: Incidence of CG-BM1-related dose-limiting toxicity (DLT) events
时间窗: From first dose to 180 days after the first dose.
Incidence of CG-BM1-related DLT events.
Phase I: Adverse event related to CG-BM1 treatment
时间窗: From first dose to 180 days after the first dose.
Any adverse event related to CG-BM1 treatment that occurred during the study period.
Phase II: Liver transplant-free survival
时间窗: 90 day after the first dose.
90-day liver transplant-free survival.
次要结局
- Phase I: Liver transplant-free survival(28 day, 90 day, and 180 days after the first dose.)
- Phase I: Changes of aspartate aminotransferase (AST)(Pre-treatment, 3 days, 7 days, 14 days, 21 days, 28 days, 90 days after the first dose.)
- Phase I: Changes of alanine aminotransferase (ALT)(Pre-treatment, 3 days, 7 days, 14 days, 21 days, 28 days, 90 days after the first dose.)
- Phase I: Changes of albumin(Pre-treatment, 3 days, 7 days, 14 days, 21 days, 28 days, 90 days after the first dose.)
- Phase I: Changes of alkaline phosphatase (ALP)(Pre-treatment, 3 days, 7 days, 14 days, 21 days, 28 days, 90 days after the first dose.)
- Phase I: Changes of γ-glutamyl transpeptidase (GGT)(Pre-treatment, 3 days, 7 days, 14 days, 21 days, 28 days, 90 days after the first dose.)
- Phase I: Changes of total bilirubin (TBil)(Pre-treatment, 3 days, 7 days, 14 days, 21 days, 28 days, 90 days after the first dose.)
- Phase I: Changes of international normalized ratio (INR)(Pre-treatment, 3 days, 7 days, 14 days, 21 days, 28 days, 90 days after the first dose.)
- Phase I: Changes in liver stiffness measurement (LSM) values(Pre-treatment, 14 days, 28 days, 60 days, 90 days after the first dose.)
- Phase I: Changes of 15-minute retention rate obtained by indocyanine green (ICG) retention test(Pre-treatment, 7 days, 14 days, 28 days, 60 days, 90 days after the first dose.)
- Phase I: Complication rate(180 days after the first dose.)
- Phase I: Changes in chronic liver failure consortium organ failure score (CLIF-C OFs)(Pre-treatment, 3 days, 7 days, 14 days, 28 days, 60 days, 90 days after the first dose.)
- Phase I: Changes in Model for end-stage liver disease (MELD) score(Pre-treatment, 3 days, 7 days, 14 days, 28 days, 60 days, 90 days after the first dose.)
- Phase I: Anti-human histocompatibility antigen antibody (HLA-Ab) positivity rate(Pre-treatment, 28 days, 60 days after the first dose.)
- Phase I: Serum Interleukin-6 (IL-6) levels(Pre-treatment, 3 days, 7 days, 14 days, 21 days, 28 days after the first dose.)
- Phase I: Serum tumor necrosis factor-α (TNF-α) levels(Pre-treatment, 3 days, 7 days, 14 days, 21 days, 28 days after the first dose.)
- Phase II: Adverse event related to CG-BM1 treatment(From first dose to 180 days after the first dose.)
- Phase II: Liver transplant-free survival(28 days, 180 days after the first dose.)
- Phase II: Changes in Model for end-stage liver disease (MELD) score(Pre-treatment, 28 days, 60 days, 90 days, 180 days after the first dose.)
- Phase II: Changes in chronic liver failure consortium organ failure score (CLIF-C OFs)(Pre-treatment, 28 days, 60 days, 90 days, 180 days after the first dose.)
- Phase II: Complication rate(180 days after the first dose.)
- Phase II: Changes of aspartate aminotransferase (AST)(Pre-treatment, 28 days, 60 days, 90 days, 180 days after the first dose.)
- Phase II: Changes of alanine aminotransferase (ALT)(Pre-treatment, 28 days, 60 days, 90 days, 180 days after the first dose.)
- Phase II: Changes of albumin(Pre-treatment, 28 days, 60 days, 90 days, 180 days after the first dose.)
- Phase II: Changes of alkaline phosphatase (ALP)(Pre-treatment, 28 days, 60 days, 90 days, 180 days after the first dose.)
- Phase II: Changes of γ-glutamyl transpeptidase (GGT)(Pre-treatment, 28 days, 60 days, 90 days, 180 days after the first dose.)
- Phase II: Changes of total bilirubin (TBil)(Pre-treatment, 28 days, 60 days, 90 days, 180 days after the first dose.)
- Phase II: Changes of international normalized ratio (INR)(Pre-treatment, 28 days, 60 days, 90 days, 180 days after the first dose.)
- Phase II: Changes in liver stiffness measurement (LSM) values(Pre-treatment, 28 days, 60 days, 90 days, 180 days after the first dose.)
- Phase II: Changes of 15-minute retention rate obtained by indocyanine green (ICG) retention test(Pre-treatment, 28 days, 60 days, 90 days, 180 days after the first dose.)
- Phase II: Anti-human histocompatibility antigen antibody (HLA-Ab) positivity rate(Pre-treatment, 28 days, 90 days after the first dose.)
- Phase II: Serum Interleukin-6 (IL-6) levels(Pre-treatment, 28 days, 60 days, 90 days, 180 days after the first dose.)
- Phase II: Serum tumor necrosis factor-α (TNF-α) levels(Pre-treatment, 28 days, 60 days, 90 days, 180 days after the first dose.)
- Phase II: Serum hepatocyte growth factor (HGF) levels(Pre-treatment, 28 days, 60 days, 90 days, 180 days after the first dose.)
研究者
Lin Bingliang
professor
Sun Yat-sen University