Clinical trial NCT01560845: ABMSC Infusion Through Hepatic Artery in Portal Hypertension Surgery for the Treatment of Liver Cirrhosis
Official title: Autologous Bone Marrow Stem Cells Infusion Through Hepatic Artery in Open Abdominal Portal Hypertension Surgery for the Treatment of Liver Cirrhosis: a Prospective, Non-randomized, Controlled Study
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
PHASE3
Conditions: Liver Cirrhosis
Portal Hypertension
Hepatic Decompensation
Surgery
Keywords: autologous bone marrow stem cells
portal hypertension
surgery
liver cirrhosis
Lead sponsor: Wenzhou Medical University
Sponsor class: OTHER
First posted: 2012-03-22
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: In recent years, the safety and efficacy of autologous bone marrow stem cells infusion (ABMSCi) therapy were confirmed. The investigators attempted to infuse autologous bone marrow stem cells (ABMSC) through inserting a catheter into right gastric artery as far as proper hepatic artery after finishing open abdominal portal hypertension surgery. The present study was designed to treat bleeding from esophageal varices and hypersplenism and hopefully to improve the liver function as well.

Detailed description: 1. ABMSC mobilization and harvest

   * For harvesting more ABMSC, ABMSC mobilization was induced by rhG-CSF (Gran○R), administered subcutaneously at a dose of 300μg daily for three consecutive days before open abdominal portal hypertension surgery.
   * Bone marrow (160-200ml) of the patients was harvested from both posterior superior iliac according to standard procedures under local anaesthesia and was collected in a plastic bag containing heparin.
2. Open abdominal portal hypertension surgery

   - Immediately after the harvest of ABMSC, the modified Sugiura procedure was performed for the patients who were assigned to the study group. The same surgical procedure was also performed for the control group (without harvest of ABMSC and ABMSC infusion).
3. ABMSC separation and infusion

   * While performing the portal hypertension surgery, ABMSC was separated and purified in a class 10,000 clean laboratory. After fat and bony particles were removed by filtration, collected cells were moved to a cell-processing device. We used the reagent kit (\[Patent Number\] ZL 2006 1 0106875.5; \[Number of Criteria Applicable\] YZB/NING YIN 0008-2008; \[Researcher and Developer\] Wealthlin Science \& Technology Inc., Canada; \[Producer\] Ningxia Zhonglianda Biotech Co., Ltd.). The reagents adopt the method of negative cells collection. Take the cells which intended to remove as target cells, and carry out the removal step-by-step. On the basis of this method, red blood cells, blood platelets, blood plasma will be completely removed with part of white cells and lymphocytes being remarkably removed as well while all the stem cells / progenitor cells are being well retained.
   * The nucleated cell (white blood cell) count of final ABMSC was measured by an automated complete blood count instrument and flow cytometry analysis. The number of mononuclear cells was counted manually under a microscope by Wright-Giemsa stain method. CD34 positive cells were determined by flow cytometry analysis.
   * The time of ABMSC separation and purification was 2.5-3 hours which had to be completed before the conclusion of portal hypertension surgery (3-3.5 hours). ABMSC was added to 10 ml saline and well mixed by shaking the vial gently. Before incision closure, the right gastric artery or right gastroepiploic artery was selected and a catheter was inserted. The catheter was pushed to reach the proper hepatic artery. The diameter of the catheter is 1.4mm, it is thin enough to easily been inserted to right gastric artery or right gastroepiploic artery (central venous catheterization, REF product NO.ES-04218, Arrow International, Inc.). The mixture of saline and AMBC was infused into hepatic artery at uniform speed for about two minutes. The catheter was removed after the ABMSCi. The puncture point of the right gastric artery was repaired using blood vessel suture or transfixed.
4. Statistical analysis - Categorical data are presented as absolute values and percentages, whereas continuous data are summarized as mean and Standard Deviation. Statistical analysis was performed using t-test for paired or unpaired samples. Time courses of measurements of liver function parameters were analyzed by repeated-measures ANOVA. The analyses were performed using the SPSS 15.0 statistical package (SPSS Inc., Chicago, IL, USA). All statistical analyses were based on two-tailed hypothesis tests with a significance level of p\< 0.05.

Eligibility criteria: Inclusion Criteria:

1. Advanced liver cirrhosis after hepatitis B resulted in bleeding from esophageal varices and hypersplenism, and needed open abdominal portal hypertension surgery;
2. Endoscopy evidence of showing severe gastric and esophageal varices;
3. Severe hypersplenism （white blood cells (WBC) \<3×109/L and platelet (PLT) \<100×109/L）;
4. Active bone marrow hyperplasia showed by bone marrow biopsy before surgery;
5. Age between 18 and 60 years;
6. Plasma albumin \<35g/L, or mild ascites;

Exclusion Criteria:

1. Enlisted for liver transplantation
2. Diagnosis of hepatocellular carcinoma or other cancers
3. Other severe medical disease, and acute infection.

Primary outcomes:
measure: Child-pugh score
timeFrame: 1 month after treament
Secondary outcomes:
measure: Incidence of complications
timeFrame: within the first week after treatment
measure: Mortality
timeFrame: 1week, 1 month, 3 month, 6 month, 1 year and 2 year
measure: blood test (hypersplenism)
timeFrame: whinin 7 days before treatment, 1 week,1,3, 6 and 12 months after treatment
measure: liver volume calculated by CT
timeFrame: whinin 7 days before treatment, 1 month and a year after treatment
measure: Indocyanine green (ICG) retention (clearance)
timeFrame: whinin 7 days before treatment, 1 week,1,3, 6 and 12 months after treatment
measure: blood biochemistry
timeFrame: whinin 7 days before treatment, 1 week,1,3, 6 and 12 months after treatment
Other outcomes:
Locations:
city: Wenzhou
country: China
facility: the First Affiliated Hospital of Wenzhou Medical College
state: Zhejiang
Study officials:
affiliation: First Affiliated Hospital of Wenzhou Medical University
name: qiyu zhang, MD
role: STUDY_CHAIR
References:
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citation: Terai S, Ishikawa T, Omori K, Aoyama K, Marumoto Y, Urata Y, Yokoyama Y, Uchida K, Yamasaki T, Fujii Y, Okita K, Sakaida I. Improved liver function in patients with liver cirrhosis after autologous bone marrow cell infusion therapy. Stem Cells. 2006 Oct;24(10):2292-8. doi: 10.1634/stemcells.2005-0542. Epub 2006 Jun 15.