The main purpose of this study is to evaluate the safety and tolerance of umbilical cord mesenchymal stem cells (UCMSCs) in patients with decompensated alcoholic cirrhosis, and to provide dose basis for subsequent clinical study design. We will also explore the possible mechanism of UCMSCs in the treatment of decompensated alcoholic cirrhosis (DAC).
This study adopted a single-center, single-arm, single-dose combined multiple-dose administration, and dose-escalation clinical trial design to evaluate the safety, tolerability and preliminary effectiveness of UCMSCs in the treatment of patients with decompensated liver cirrhosis. Patients were recruited into three different dose groups, and 12 subjects were enrolled in each group. The subjects of each group will receive 0.5×10\^6 cells/kg, 1.0×10\^6 cells/kg, and 2.0×10\^6 cells/kg respectively. According to the principle of dose escalation, subjects preset to low-dose will receive the administration first. Each group will receive only one corresponding dose for safety and tolerability check. The subjects will be observed for 21 days after the initial dose due to limited proliferation or differentiation potential and relatively low immunogenicity of mesenchymal stem cell products. The safety measures will be discussed by the Data Safety and Monitoring Board (DSMB) to determine whether subjects who have received a single dose will proceed with subsequent injections. Once all subjects in the lower-dose group have completed the initial administration and observed for 21 days. The DSMB will decided whether to proceed with the next-dose group. All subjects will receive routine drug treatment during the study. Primary endpoint: incidence and severity of cell therapy related adverse events from the beginning of treatment to the end of the follow-up. Secondary end point of the study includes: the change in Model For End-Stage Liver Disease (MELD) score of the subjects from baseline, at 1, 3, 6 and 12 months after the last administration; the overall survival rate at the 12th month after the last administration; Changes in liver function compared with baseline at 1, 3, 6 and 12 months after the last administration; changes of child Pugh score compared with baseline at 1, 3, 6 and 12 months after the last administration; and the change of Karnofsky Performance Status Scale (KPS) score from baseline at 1, 3, 6 and 12 months after the last administration.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Enrollment
36
Patients will receive the conventional therapy plus low dose UCMSCs treatment (0.5×10\^6 UCMSCs/kg body)
Patients will receive conventional therapy plus medium dose UCMSCs treatment (1×10\^6 UCMSCs/kg body)
Patients will receive conventional therapy plus high dose UCMSCs treatment (2×10\^6 UCMSCs/kg body)
Yantai Yuhuangding Hospital
Yantai, Shandong, China
RECRUITINGSeverity and incidence of adverse events (SIAE) on the 3rd day after the first administration
According to the evaluation criteria of common adverse events (CTCAE v5.0), any AE occurred in all subjects during the clinical study, including abnormalities in clinical symptoms and vital signs and abnormalities in laboratory examination was observed.
Time frame: The 3rd day after the first administration
1 week SIAE after the first administration
According to the evaluation criteria of common adverse events (CTCAE v5.0), any AE occurred in all subjects during the clinical study, including abnormalities in clinical symptoms and vital signs and abnormalities in laboratory examination was observed.
Time frame: 1 week after the first administration
3 weeks SIAE after the first administration
According to the evaluation criteria of common adverse events (CTCAE v5.0), any AE occurred in all subjects during the clinical study, including abnormalities in clinical symptoms and vital signs and abnormalities in laboratory examination was observed.
Time frame: 3 week after the first administration
3 week SIAE after the the second administration
According to the evaluation criteria of common adverse events (CTCAE v5.0), any AE occurred in all subjects during the clinical study, including abnormalities in clinical symptoms and vital signs and abnormalities in laboratory examination was observed.
Time frame: 3 weeks after the the second administration
1 month SIAE after the last administration
According to the evaluation criteria of common adverse events (CTCAE v5.0), any AE occurred in all subjects during the clinical study, including abnormalities in clinical symptoms and vital signs and abnormalities in laboratory examination was observed.
Time frame: 1 month after the last administration
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3 months SIAE after the last administration
According to the evaluation criteria of common adverse events (CTCAE v5.0), any AE occurred in all subjects during the clinical study, including abnormalities in clinical symptoms and vital signs and abnormalities in laboratory examination was observed.
Time frame: 3 months after the last administration
6 months SIAE after the last administration
According to the evaluation criteria of common adverse events (CTCAE v5.0), any AE occurred in all subjects during the clinical study, including abnormalities in clinical symptoms and vital signs and abnormalities in laboratory examination was observed.
Time frame: 6 months after the last administration
12 months SIAE after the last administration
According to the evaluation criteria of common adverse events (CTCAE v5.0), any AE occurred in all subjects during the clinical study, including abnormalities in clinical symptoms and vital signs and abnormalities in laboratory examination was observed.
Time frame: 12 months after the last administration
24 months SIAE after the last administration
According to the evaluation criteria of common adverse events (CTCAE v5.0), any AE occurred in all subjects during the clinical study, including abnormalities in clinical symptoms and vital signs and abnormalities in laboratory examination was observed.
Time frame: 24 months after the last administration
Child-Pugh score (effectiveness evaluation index)
The Child-Pugh grading standard is a grading standard commonly used in clinical practice to quantitatively evaluate the liver reserve function of patients with liver cirrhosis. Grading: 5\~6 points for Grade A, 7\~9 points for Grade B and 10\~15 points for grade C; Note: For Primary Biliary Cirrhosis (PBC) or Primary Sclerosing Cholangitis (PSC): total bilirubin (umol/L): 17\~68 is 1 point, 68\~170 is 1 point, and \>170 is 1 point; The Child-Pugh grading standard has been widely recognized by clinicians, and provides a specific clinical reference for the selection of treatment options for patients with liver cirrhosis and has important clinical value.
Time frame: At baseline, 3, 7 and 21 days after the first administration, 21 days after the second administration (if any), and 1, 3, 6 and 12 months after the last administration.
Survival rate (effectiveness evaluation index)
Overall survival rate of participants in this study.
Time frame: 12 months after the last administration.
Liver function (effectiveness evaluation index)
Indicators: Alanine transaminase (AST), Alanine transaminase (ALT)
Time frame: Baseline, 3, 7, and 21 days after the first administration, 21 days after the second administration (if any), and 1, 3, 6, and 12 months after the last administration.
The Model for End-Stage Liver Disease (MELD) score (effectiveness evaluation index)
MELD is a numerical scale, ranging from 6 (less ill) to 40 (gravely ill), used for liver transplant candidates age 12 and older. It gives each person a 'score' (number) based on how urgently he or she needs a liver transplant within the next three months. The number is calculated by a formula using three routine lab test results: MELD score = 3.8×ln\[bilirubin (mg/dl)\] + 11.2×ln(INR) + 9.6×ln\[Scr(mg/dl)\] + 6.4×(Cause: Bile or alcoholic 0, other 1) Bilirubin (mg/dl) = Bilirubin (μmol/L)/17.1 Scr(mg/dl) = Scr(μmol/L)/88.4
Time frame: Baseline, 3, 7, and 21 days after the first administration, 21 days after the second administration (if any), and 1, 3, 6, and 12 months after the last administration.
KPS score (effectiveness evaluation index)
KPS score is the Karnofsky (Karen, KPS, percentile method) functional status scoring standard. The higher the score, the better the health status, and the more the patient able to tolerate the side effects of treatment, hence a better curative effect. It is generally believed that a Karnofsky score above 80 is independent, which means the patient is able to take care of himself. Karnofsky score between 50 to 70 stands for a semi-independent status, that is, the patient is semi-self-care. A score of 50 means the patients require help from others. Those with a score greater than 80 are in better postoperative state and have a longer survival period. The lower the score, the worse the health status. If the score is less than 60, many effective anti-tumor treatments cannot be implemented.
Time frame: Baseline, 3, 7, and 21 days after the first administration, 21 days after the second administration (if any), and 1, 3, 6, and 12 months after the last administration.
Detection of Blood Coagulation Index of PT (effectiveness evaluation index)
To test the blood coagulation index of Prothrombin time (PT);
Time frame: Baseline, 3, 7, and 21 days after the first administration, 21 days after the second administration (if any), and 1, 3, 6, and 12 months after the last administration.
Detection of Blood Coagulation Index of APTT (effectiveness evaluation index)
To test the blood coagulation index of activated partial thromboplastin time (APTT);
Time frame: Baseline, 3, 7, and 21 days after the first administration, 21 days after the second administration (if any), and 1, 3, 6, and 12 months after the last administration.
Detection of Blood Coagulation Index of TT (effectiveness evaluation index)
To test the blood coagulation index of thrombin time (TT);
Time frame: Baseline, 3, 7, and 21 days after the first administration, 21 days after the second administration (if any), and 1, 3, 6, and 12 months after the last administration.
Detection of Blood Coagulation Index of FIB (effectiveness evaluation index)
To test the blood coagulation index of fibrinogen (FIB);
Time frame: Baseline, 3, 7, and 21 days after the first administration, 21 days after the second administration (if any), and 1, 3, 6, and 12 months after the last administration.