Efficacy and Safety of BMSCs (CG-BM1) for ACLF Patients

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.

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.

Eligibility Criteria:
Phase I:

Inclusion Criteria:

1. 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.
2. Age ≥18 years old, male or female.
3. 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.
4. The cause of liver failure is unlimited.
5. Model for End Stage Liver Disease (MELD) score under 30.
6. 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:

1. 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.
2. Patients with severe infections such as septic shock.
3. Patients with gastrointestinal bleeding at the time of screening.
4. Hepatic encephalopathy grade 4.
5. 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)
6. Pregnancy or breastfeeding.
7. Previous history of malignant tumors.
8. Imaging suggestive of intrahepatic nodular space-occupying lesions.
9. A history of immunodeficiency, including HIV-positive, or other acquired or congenital immunodeficiency diseases.
10. Patients with previous liver transplantation.
11. Deep vein thrombosis at screening or history of pulmonary embolism within 3 months prior to screening.
12. Patients with pulmonary hypertension.
13. History of myocardial infarction within 6 months.
14. Previous stem cell therapy.
15. Participation in another interventional clinical trial within 3 months or 5 half-lives (for experimental drug interventions only, whichever is longer) prior to infusion.
16. Any other factors that, in the judgment of the investigator, make the subject inappropriate for participation in this trial.

Phase II:

Inclusion Criteria:

Inclusion Criteria:

1. 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.
2. Age ≥18 years old, male or female.
3. 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.
4. The cause of liver failure is Hepatitis B.
5. Model for End Stage Liver Disease (MELD) score under 30.
6. 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:

1. 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.
2. Patients with severe infections such as septic shock.
3. Patients with gastrointestinal bleeding at the time of screening.
4. Hepatic encephalopathy grade 4.
5. 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)
6. Pregnancy or breastfeeding.
7. Previous history of malignant tumors.
8. Imaging suggestive of intrahepatic solid nodal space-occupying lesions and which the investigator determines may compromise subject safety.
9. Received artificial liver therapy within 7 days prior to first dose.
10. A history of immunodeficiency, including HIV-positive, or other acquired or congenital immunodeficiency diseases.
11. Patients with previous liver transplantation.
12. Deep vein thrombosis at screening or history of pulmonary embolism within 3 months prior to screening.
13. Patients with pulmonary hypertension.
14. History of myocardial infarction within 6 months.
15. Previous stem cell therapy.
16. Participation in another interventional clinical trial within 3 months or 5 half-lives (for experimental drug interventions only, whichever is longer) prior to infusion.
17. Any other factors that, in the judgment of the investigator, make the subject inappropriate for participation in this trial.