Diabetes Mellitus Foot Ulcer Clinical Trial
Official title:
Clinical Study of Adipose-derived Stem Cells in the Treatment of Diabetic Foot
1. Program Name: Clinical Study on Treatment of Diabetic Foot with Autologous Adipose Stem
Cells
2. Bidding Unit: Tenth People's Hospital Affiliated to Tongji University
3. Study subjects: diabetic foot patients
4. OBJECTIVE: To establish an autologous adipose stem cell therapy for diabetic foot and
evaluate its clinical safety and efficacy.
5. Study Design: Randomized Controlled Clinical Study
6. Target number of cases: 60
7. Main evaluation indicators: ulcer healing and amputation, calculating ulcer healing rate
= total wound healing cases / total ulcer cases in this group; amputation rate =
amputation cases / total cases in this group.
8. Secondary evaluation indicators: ankle-brachial index (ABI), Ruthford classification,
painless walking time Wong-Baker Faces pain score, transcutaneous partial pressure of
oxygen (TcPO2), laser Doppler flowmetry, multi-slice spiral CT angiography (CTA)
research design: A randomized controlled trial was designed. According to the established
inclusion criteria/exclusion criteria, the subjects were randomly divided into two groups by
random number table. Each group received Mesenchymal Stem Cells(MSCs)from fat sources and
conventional diabetic foot treatment according to the estimated results of sample size. A
randomized controlled study was conducted with three blinds. The subjects were blind, the
interventions were blind, and the evaluators were blind. Subjects were randomly grouped and
assisted by coordinators. Follow-up was carried out at 5 time points 7 days, 1, 3, 6 and 12
months after operation to evaluate the pain and functional changes of the subjects, and to
evaluate the safety and effectiveness.
Subject inclusion, exclusion criteria and allocation methods entry criteria and exclusion
criteria will be executed.
Method of allocation and grouping:
A randomized controlled study was conducted with three blinds. The subjects were blind, the
interventions were blind, and the evaluators were blind. Subjects were randomly grouped and
assisted by coordinators. After receiving the random number, the test specimens and
injections are marked by the research number rather than the names of the subjects.
Injections of stem cells or saline are randomly determined by the computer system and will
not be disclosed to the subjects. Subject groups would not inform the interveners that each
injection was prepared by an assistant and the syringe was covered with black cloth. The
operator and the participants would not know which drug was injected. The evaluation is done
by a third party and the grouping will not be disclosed to the evaluator.After preliminary
screening of qualified subjects, after signing the informed consent and verifying the
entry/exclusion criteria by the research unit, and confirming that they meet the selection
criteria, according to the results of the random system, the distribution of subjects is
strictly carried out according to the random results.Subject Entry Records: Researchers
should fill in the corresponding record forms according to the order of
participants'enrollment, including the screening form, the identification form and the record
form of participants' enrollment. All research-related test sheets need to be attached to the
original record sheet kept by the researcher. The original record table is also the original
record of this study which is monitored according to Good Clinical Practice(GCP)principle.
Number of cases required:
To test the effectiveness of stem cell therapy in the treatment of lower limb ischemic
necrosis in diabetic patients, the subjects were randomly divided into stem cell treatment
group and control group. Both groups received routine treatment, while the stem cell
treatment group would receive stem cell therapy. According to the results of Lu Debin et al.,
the effective rate of stem cell therapy for ischemic necrosis of lower limbs in diabetic
patients can reach 83.3%, while the effective rate in control group is 45%. In this study,
two-sided test will be used, taking alpha = 0.05, beta = 0.1, and calculating the sample size
according to the following formula .N=(Ualpha+Ubeta)22P(1-P)/(P1-P)2 N is the sample size
required for each treatment group. In this study, the sample size was divided into two
groups, and the sample size of each group was the same.
Ualpha and Ubeta are the standard normal deviations corresponding to alpha and beta
respectively. Looking at the quantile table of normal distribution, we can see that
Ualpha(0.05)=1.65, Ubeta(0.1)=1.28.
P 0 and P 1 represent the effective rates of the control group and the stem cell treatment
group respectively. In this study, P 0 = 45%, P 1 = 83.3%; P = (P 0 + P 1) / 2 = (0.45 +
0.8333) / 2 = 0.6416, The above parameters and numerical values are introduced into the
formula calculation.
N=(1.65+1.28)2*2*0.6416(1-0.6416)/(0.833-0.45)2=26.8732≈27 There were 54 patients in the two
groups. Considering that some patients might withdraw from the study, the original sample
size was added to 10% of the sample size, and the final sample size of the study was 60.
Use, dosage, time and course of treatment of stem cell preparations:
1. Stem cell preparation: stem cells derived from autologous fat.
2. Usage: Lower extremity muscle injection. Adipose stem cell transplantation anesthesia
was performed by lumbar anesthesia; purified adipose stem cells were injected
intramuscularly into lower extremities at intervals of 3 cm, which could be injected at
about 50 points, 0.5 ml stem cell suspension at each point, about 1 x 106 cells, 25
points in lower extremities, 25 points in sole and well-being, and the total number of
transplanted cells was about 1 x 108; (At the same time, the ulcer with infection was
debrided and about 1 ml cell suspension was retained.) Subcutaneous injection of ulcer
at the base and around the ulcer was performed, i.e. local injection of wound surface.
3. dose: The cells (1 x 108 cells) were mixed in 25 mL saline.
4. course of treatment: one-time intramuscular injection.
Criteria for discontinuation and termination of clinical research:
1. Research discontinuation 1.1 Subjects voluntarily withdraw from the study at any time
without affecting further treatment.
1.2 The following adverse events occurred (mainly referring to National Cancer Institute
Common Terminology Criteria for Adverse Events (NCI-CTCAE) ).(1) fever, syncope,
sweating, vomiting and other systemic symptoms with unknown causes; (2) dysfunction of
gastrointestinal tract with unknown causes, loss of appetite, nausea, abdominal
distention, constipation or diarrhea; (3) headache, fatigue, unexplained muscle pain,
discomfort and changes in sleep; Mental symptoms such as anxiety, irritability,
unexplained visual impairment, muscle tremor, dysuria, etc. Local manifestations such as
skin macula, erythema, etc. Local pain aggravation or reduced range of activity, _Acute
poisoning symptoms or death.
1.3 Researchers believe that there are serious violations of research programs or
incorrect grouping.
1.4 Researchers believe that there are safety problems in the research program. 1.5
subjects were not interviewed. If participants discontinue treatment in advance, the
cause of discontinuation must be documented in the Case report form (CRF), but follow-up
is required until the end of the study and the study form is filled in.
2. Endpoint of the study 2.1 Severe treatment-related adverse events occurred between the
end of treatment and the end of follow-up.
2.2 At the end of the follow-up, compared with the control group, ulcer healing, limb salvage
rate, Ruthford grade, painless walking time, ankle-brachial index (ABI), transcutaneous
partial pressure of oxygen (TcPO2), laboratory examination and vascular magnetic resonance
imaging (MRA) improved significantly, indicating the effectiveness (with statistical
differences): Criteria for evaluating efficacy
Compared with the control group, the ulcer healing rate, limb salvage rate, lower limb
vascular ultrasound, ankle-brachial index (ABI), percutaneous partial pressure of oxygen
(TcPO2), multi-slice spiral CT angiography (CTA), Rutherford grading, Wong-Baker Faces pain
score of the subjects improved significantly compared with the control group, indicating the
effectiveness (with statistical differences):
Main Evaluation Indicators:
1.Ulcer healing and amputation were calculated. Ulcer healing rate = number of complete wound
healing cases / total number of ulcers in this group; amputation rate = number of amputations
/ total number of cases in this group.
2 Secondary Observation Indicators Lower extremity vascular ultrasound, ankle brachial index
(ABI), percutaneous partial pressure of oxygen (TcPO2), multi-slice spiral CT angiography
(CTA), Rutherford classification, Wong-Baker Faces pain score.
Recording requirements of adverse events and reporting methods and handling measures of
serious adverse events Formulate detailed and standardized "Risk Management Mechanisms and
Damage Event Processing Measures for Stem Cell Clinical Research" before the start of the
experiment. All the subjects who received lower limb muscle injection of stem cells will
become effective population for safety analysis. Researchers will faithfully record the side
effects and adverse events of the subjects and analyze the causes.
1. Adverse events are defined as adverse and unexpected medical events during treatment and
follow-up, including: (1) systemic symptoms such as fever, syncope, sweating and
vomiting with unknown causes; (2) gastrointestinal dysfunction with unknown causes,
anorexia, nausea, abdominal distention, constipation or diarrhea; and (3) headache,
fatigue, unexplained muscle pain, No. Suitability and changes in sleep, etc. (4) Mental
symptoms such as unexplained anxiety, restlessness and restlessness; (5) Visual
impairment, muscle tremor, dysuria, etc. (5) Local manifestations such as skin macula
and erythema; (5) Local pain aggravation or reduced range of activity; and (5) Acute
poisoning symptoms or death.
2. Severe adverse events (SAEs) are defined as events requiring hospitalization, prolonging
hospitalization, disability, impacting work ability, life-threatening or
death-threatening, congenital malformations, etc. The severity of adverse events must be
recorded and graded according to CTCAE criteria. The relationship between SAEs and
treatment should be evaluated according to the following definitions. (1) Irrelevant:
There is evidence that the cause of adverse events is not intra-articular injection
therapy (such as past conditions, potential diseases, complications); 2) related:
adverse events are time-related with intra-articular injection of drugs and known or
suspected that intramuscular injection of drugs in lower extremities can cause the
adverse events; 3) unable to assess. Adverse events are required to be recorded in the
Case report form(CRF) related sections, which need to be described as: start and end
dates; adverse event outcomes; whether they lead to withdrawal from the study; whether
they are related to lower extremity intramuscular drug injections; and whether they are
serious adverse events.
Reporting of Serious Adverse Events
Reporting time limit:
Within 24 hours of Observers'knowledge of the time of serious adverse events. Reporting mode
Telephone or fax, and fill in the Record Form of Serious Adverse Events and send it to the
main researchers, declaration units, ethics committees and the State Food and Drug
Administration
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