Ki Tae Suk, Soon Koo Baik, et al.
[Stage 2 Cirrhosis] Safety and Efficacy of Hepatic Artery Injection of Autologous Bone Marrow-Derived Mesenchymal Stem Cells in Patients with Alcoholic Cirrhosis (Phase 2 Clinical Trial)
Study Summary
Seventy-two patients with alcoholic cirrhosis who had abstained from alcohol for at least six months received one or two injections of mesenchymal stem cells cultured from their own bone marrow into the hepatic artery. Six months later, the degree of liver fibrosis decreased by 25% in the single-dose group and by 37% in the double-dose group; the only treatment-related adverse event was one case of fever. However, increasing the number of administrations to two did not improve the results, and the study used an open-label design without a placebo control group. |
Study Results
Patients with alcoholic cirrhosis received mesenchymal stem cells cultured from their own bone marrow via hepatic artery injection. The primary endpoint was the collagen area ratio (the proportion of hardened fibrous tissue in the liver), measured by biopsy after 6 months.
The collagen area ratio decreased by 25% in the single-dose group (from 19.5% to 14.5%) and by 37% in the double-dose group (from 21.1% to 13.2%) (P < 0.001). The control group showed no change at 17.5%, and there was no difference between the two treatment groups (P = 0.329). The Child-Pugh score (a measure of liver function) also decreased from 7.6 to 6.3 in the single-dose group (P = 0.035) and from 7.8 to 6.8 in the twice-daily dose group (P = 0.003). The MELD score remained unchanged in all three groups.
There was no difference in the incidence of adverse events among the three groups. The only treatment-related adverse event was one case of fever in the twice-daily group, which resolved after hospitalization. Serious adverse events occurred in 8 cases in the control group, 5 cases in the single-dose group, and 9 cases in the twice-dose group; there were no cell-related tumors.
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Figure. Changes in collagen area ratio in the control group and the single- and double-dose groups (pre-treatment → 6 months)
Study Design
This was a randomized, open-label Phase 2 trial conducted at 12 tertiary general hospitals in Korea from January 2013 to November 2015 (NCT01875081). The study included patients aged 20–70 years with Child-Pugh grades B or C who had been diagnosed via biopsy and had abstained from alcohol for at least 6 months. Of the 81 patients screened, 72 were randomized into the control group (24 patients), the single-dose group (22 patients), and the two-dose group (26 patients); 55 patients were included in the primary endpoint analysis.
The control group received only standard treatment without cell infusion. Secondary endpoints included liver function tests and Child-Pugh and MELD scores. Biopsies were performed twice—at enrollment and at the 6-month mark—and adverse events were monitored in 68 participants for up to 12 months.
Cells Used and Administration Method
Autologous bone marrow-derived mesenchymal stem cells—that is, the patients’ own cells—were used. After local anesthesia, 10–20 mL of bone marrow was harvested from the posterior iliac crest and cultured in a GMP facility for one month to 4–5 passages. The release criteria were a viability rate exceeding 70%, negative for microbial contamination, at least 85% positive for CD73 and CD105, and less than 3% positive for CD14, CD34, and CD45.
The dosage consisted of 5 × 10⁷ cells per administration in a 10 mL solution. A catheter inserted into the femoral artery was advanced to the hepatic artery, and the solution was then infused. The single-dose group received the infusion on day 30 (±7 days) after bone marrow collection, while the two-dose group received infusions on days 30 and 60.
Discussion
This study demonstrates that intra-arterial administration of mesenchymal stem cells into the hepatic artery reduces liver fibrosis and lowers the Child-Pugh score in patients with alcoholic cirrhosis who are abstaining from alcohol. The researchers noted that a single administration appears to be sufficient, and that the lack of change in MELD scores may be due to the patients’ initially low baseline score of 5.2.
There are also clear limitations. The study used an open-label design without a placebo control group, and 17 of the 72 randomly assigned patients were subsequently excluded, so only patients who underwent two biopsies were included in the analysis. The researchers cited the inability to elucidate the mechanism behind the reduction in fibrosis as a limitation and stated that the impact on survival and prognosis must be confirmed in a subsequent Phase 3 study. This study was conducted with research funding from the Korea Health Industry Development Institute under the Ministry of Health and Welfare, and the cells used for administration were manufactured by Pamicell.
