Atherosclerotic Ischemic Disease Clinical Trial
Official title:
Peripheral Blood Autologous CD34+ Cell Transplantation Promotes Angiogenesis in Elderly Patients With Atherosclerotic Ischemia: Study Protocol for a Prospective, Single-center, Open-label, Randomized, Controlled, Clinical Trial
To verify angiogenesis in elderly patients with atherosclerotic ischemia after peripheral blood autologous CD34+ cell transplantation.
History and current related studies Arteriosclerosis obliterans is a kind of arterial lumen
stenosis and occlusive disease, which is caused by the continuous expansion of arterial
atherosclerosis and secondary thrombosis. Clinical manifestations are local skin temperature
reduction, intermittent claudication, rest pain, ulcers difficult to heal, and gangrene
infection.Some patients require amputation or even it is life-threatening. Arteriosclerosis
obliterans of lower limbs are commonly treated by surgical treatment, endovascular treatment
and non-surgical treatment, but the effect is not very satisfactory.
For the treatment of arteriosclerosis obliterans, stem cell transplantation has achieved
great progress in angiogenesis and collateral circulation. There are two main mechanisms of
stem cells involved in angiogenesis: (1) Promoting differentiation and maturation of new
blood vessels by homing and integration in the damaged vascular plexus; (2) Promoting
angiogenesis in ischemic tissue by paracrine of vascular endothelial growth factor (VEGF).In
recent years, because of the discovery of endothelial progenitor cells in peripheral blood,
the concept of angiogenesis has been renewed. Transplantation of endothelial progenitor
cells and bone marrow cells for angiogenesis has become the focus of research. Endothelial
progenitor cell and bone marrow cell transplantation have been used to promote angiogenesis
in ischemic tissue in order to treat limb ischemia.
Bone marrow stem cell mobilization is used to promote the replication of bone marrow stem
cells, so as to increase the number of endothelial progenitor cells in peripheral blood,
i.e., the number of stem cells homing to ischemic tissue, and finally accelerating the speed
and magnitude of angiogenesis. Fujisaki et al. have confirmed that bone marrow cell
mobilizers can significantly stimulate bone marrow hematopoiesis and increase the number of
peripheral blood stem cells.Bone marrow cell mobilizer-recombinant human granulocyte colony
stimulating factor (rhG-CSF) are used to mobilize bone marrow stem cells to peripheral
blood, and to increase the number of peripheral blood stem cells, especially endothelial
progenitor cells, so as to treat ischemic diseases using transplanted autologous stem cells,
which is called autologous stem cell transplantation. Nevertheless, in animal and human
experiments, the proliferation potential and influencing factors of mobilized bone marrow
stem cells and peripheral blood endothelial progenitor cells in ischemic tissue require
further investigations.
Autologous stem cell transplantation is to transplant stem cells in muscles of ischemic
limb, so that new capillaries improve and restore lower limb blood flow, aiming to treat
lower limb ischemia. Endothelial progenitor cells and hematopoietic stem cells are thought
to come from a common ancestor, and called blood vessel stem cells. They express immature
stem cell markers CD34 and CD133. Endothelial progenitor cells migrated from bone marrow to
peripheral blood will gradually lose CD133, and the disappearance of CD34 is relatively
slow. A large number of basic and clinical studies have confirmed that the transplantation
of CD34+ cells can promote angiogenesis in ischemic limbs of experimental animals (partial
patients).
Adverse events
1. To record adverse events, including fever, infection, lower limb pain and ulcers,
during follow-up at out-patient clinic.
2. If severe adverse events occur, investigators will report details, including the date
of occurrence and measures taken to treat the adverse events, to the principle
investigator and the institutional review board within 24 hours.
Data collection, management, analysis, open access
1. Data collection: Case report forms will be collected and processed using Epidata
software (Epidata Association, Odense, Denmark), collated, and then recorded
electronically using a double-data entry strategy.
2. Data management: The locked electronic database will be accessible and locked only by
the project manager. This arrangement will not be altered. The Qingdao No. 9 People's
Hospital, China will preserve all of the data regarding this trial.
3. Data analysis: A professional statistician will statistically analyze the electronic
database and will create an outcome analysis report that will be submitted to the lead
researchers. An independent data monitoring committee will supervise and manage the
trial data, ensuring a scientific and stringent trial that yields accurate and complete
data.
4. Data open access: Anonymized trial data will be published at www.figshare.com.
Statistical analysis
1. Statistical analysis will be performed using SPSS 19.0 software (IBM, Armonk, NY, USA)
and will follow the intention-to-treat principle.
2. Normally distributed measurement data will be expressed as means, standard deviation,
minimums and maximums. Non-normally distributed measurement data will be expressed as
the lower quartile (q1), median and upper quartiles (q3). Count data will be expressed
as a percentage.
3. Kolmogorov-Smirnov test will be used to determine normality of measurement data. If
data obey the normal distribution, ABI, number of microvessels in the lower limb
muscles and number of VEGF-immunoreactive cells will be compared with two-sample t-test
between the two groups. Intragroup difference of above indicators will be compared
using paired t-test before and 6 months after transplantation. If data do not obey the
normal distribution, intergroup and intragroup data will be compared using Mann Whitney
U test and Wilcoxon signed-rank test. The incidence of adverse reactions will be
compared with Fisher's exact probability test between the two groups 6 months after
transplantation.
4. The significance level will be α = 0.05.
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