Clinical Trial to Evaluate the Potential Efficacy and Safety of Human Umbilical Cord Blood and Plasma

Study Overview
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Brief Summary
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This study aims to carry out a safety evaluation of human cord blood and frozen plasma as treatment for pre-frailty , to assess whether the treatment can prevent and improve the aging process, and to identify useful clinical markers of frailty. The study is a randomized, double-blinded and placebo-controlled pilot clinical Trial conducted at CHA clinical trial institute.

Detailed Description
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Assessment criteria for the study include (1) clinical indicators-weight loss, a decrease in physical activity, weak grip strength, depression; (2) Short Physical Performance Battery(SPPB); (3) SF-36; (4)cardiac output; (4)biomarkers for oxidative stress, inflammation and immune response; (5) methylation; (6) mitochondria DNA copy number; (7) growth factors; (8) antioxidant capacity; (9) hormone assay; (10) genome assay; (11) metabolite; (12) safety of intravenous administration. Participants will be randomly assigned to three experimental groups and one control group in a ratio of 1:1:1:1. At second visit, the participants will be administered with experimental and placebo agents. Follow-up visits are expected to be at 7 days, 1 and 6 months after the first treatment. Sixth visit is the completion of it. Primary end points are defined as severe clinical abnormalities, which could be observed until 1 month after administration of blood-derived products, including death, pulmonary embolism, stroke, respiratory stress and hospitalization due to abnormal findings in laboratory tests.

Official Title
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A Randomized, Double-blinded and Placebo-controlled Pilot Clinical Trial to Evaluate the Potential Efficacy and Safety of Human Umbilical Cord Blood and Plasma by Clinical Markers of Frailty in Adult Who Defined Pre-Frailty

Conditions
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Aging

Intervention / Treatment
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* Other: Fresh cord blood(experimental group A)
* Other: Frozen cord blood(experimental group B)
* Other: Frozen plasma(experimental group C)
* Other: Placebo group


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of pre-frailty One or two scores in Simple FRAIL questionnaire Aged 55 or over Willing and able to be hospitalized according to the research plan Able to participate in our research during 12 months For women, they must be diagnosed with menopause or infertility Exclusion Criteria: Diagnosis of being irreversible disabled Dementia or cognitive impairment clinically relevant to it Unable to perform tasks required for analysis of primary end point Scheduled to receive organ transplantation Hemoglobin < 8 g/dl; white blood cells count <3000/mm3; absolute Neutrophil count < 500/dl; Thrombocyte count <80,000/mm3; , AST/ALT or ALP > 3 times the normal level Hemoglobin >17g/dl for male and >16 g/dl for female Diagnosis of cancer within 5 years or having the possibility to contract cancer Anticancer chemotherapy and radiation therapy History (within 6 months) of acute diseases such as myocardial infarction, unstable angina, stroke, bone fracture Hormone therapy within 6 months Recent and current use of Immunosuppressive drug or HIV patients History of hospitalization due to infectious disease such as pneumonia within one year Previous (within one months) or current participants in other clinical trials Severe kidney (eGFR< 30) and heart failure (Class III/IV) Any participants who, in the opinion of the investigators, are considered to have safety problems and/or not to perform tasks successfully History of drug or alcohol abuse Chronic Hepatitis B or C: history taking Known or suspected pregnancy (Women must be subjected to pregnancy test) Hypersensitive to dimethyl sulfoxide(DMSO)

Ages Eligible for Study
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Minimum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fresh cord blood(experimental group A)<br>16 males and 16 females are assigned to the experimental group A. Dropout is 20 percent in each gender. | Other: Fresh cord blood(experimental group A)<br>* Cord blood is administered through intravenous at CHA clinical trail institute. Chlorpheniramine maleate at the concentration of 0.6ml/10kg is administered prior to the treatment.<br>|
| Experimental: Frozen cord blood(experimental group B)<br>16 males and 16 females are assigned to the experimental group B. Dropout is 20 percent in each gender. | Other: Frozen cord blood(experimental group B)<br>* Cord blood is administered through intravenous at CHA clinical trail institute. Chlorpheniramine maleate at the concentration of 0.6ml/10kg is administered<br>|
| Experimental: Frozen plasma(experimental group C)<br>16 males and 16 females are assigned to the experimental group C. Dropout is 20 percent in each gender. | Other: Frozen plasma(experimental group C)<br>* Cord blood is administered through intravenous at CHA clinical trail institute. Chlorpheniramine maleate at the concentration of 0.6ml/10kg is administered<br>|
| Placebo Comparator: Placebo group<br>16 males and 16 females are assigned to the Placebo group. Dropout is 20 percent in each gender. Total participants are 64 in males and 64 in females. | Other: Placebo group<br>* A placebo agent is administered through intravenous at CHA clinical trail institute. It should be certain that when administered, participants are not aware of which treatments are preformed.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in scores of Short Physical Performance Battery (SPPB) as a measure of efficacy for anti-aging effects | The investigators will assess changes in scores from baseline at 7 days after transplantation. After normality test, either unpaired t-test or wilcoxon rank sum test will be conducted. | 7 days after transplantation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hand grip strength (in kg) as a measure of efficacy for anti-aging effects | The test is scheduled to be conducted at the day of transplantation and at 1 week , 1 month, 6 months after the treatments. After normality test on the average difference, either unpaired t-test or wilcoxon rank sum test will be conducted for statistical analysis. The followings are diagnosis criteria for frailty based on hand grip strength(in kg): Male equal or less than 18 kg for the participants with BMI (body mass index)≤21.89 equal or less than 23 kg for the participants with 22.02 <BMI≤23.63 equal or less than 21.5 kg for the participants with 23.67<BMI≤24.63 equal or less than 25 kg for the participants with BMI>24.88 Female equal or less than 12.2 kg for the participants with BMI (body mass index)≤22.52 equal or less than 13 kg for the participants with 22.53<BMI ≤24.23 equal or less than 14.5 kg for the participants with 24.24<BMI ≤26.44 equal or less than 13 k | 6 months period after transplantation | 
| SF_36(The Short Form (36) Health Survey) as a measure of improvement in the quality of life | The test is scheduled to be conducted at the day of transplantation (2nd visit) and at 1 week (3rd visit), 1 month (4th visit), 6 months (5th visit) after the treatments. The investigators will assess changes compared to baseline which will be measured at the day of transplantation. After normality test on the average difference, either unpaired t-test or wilcoxon rank sum test will be conducted for statistical analysis. | 6 months period after transplantation | 
| Biomarkers for oxidative stress and inflammation as a measure of efficacy for anti-aging effects | The test is scheduled to be conducted at the day of transplantation (2nd visit) and at 1 week (3rd visit), 1 month (4th visit), 6 months (5th visit) after the treatments. Changes in biomarkers such as CRP, IL-1,6, IL-10, LIF, D-dimer, fibrinogen, TNF-α, CBC with differential, malondialdehyde, 4-hydroxynonenal will be assessed. After normality test on the average difference, either unpaired t-test or wilcoxon rank sum test will be conducted for statistical analysis. | 6 months period after transplantation | 
| Biomarkers for immune response as a measure of efficacy for anti-aging effects | The test is scheduled to be conducted at the day of transplantation (2nd visit) and at 1 week (3rd visit), 1 month (4th visit), 6 months (5th visit) after the treatments. The investigators will assess changes of the immune-related biomarkers compared to baseline which will be measured at the day of transplantation. After normality test on the average difference, either unpaired t-test or wilcoxon rank sum test will be conducted for statistical analysis. Followings are immune markers to be tested -Eotaxin, FGF-2,Flt-3 Ligand ,Fractalkine,G-CSF, GM-CSF, GRO, IFNa2, IFNr, IL-1a, IL-1b, IL-1ra, IL-2, IL-3, IL-4 ,IL-5 ,IL-6 ,IL-7, IL-8, IL-9, IL-10, IL-12(p40), IL-12(p70), IL-13, IL-15, IL-17, IP-10, MCP-1, MCP-3, MDC, MIP-1a, MIP-1b, PDGF-AA, PDGF-AB/BB, RANTES, sCD40L, sIL-2Ra TGFa, TNFa,TNFb, VEGF | 6 months period after transplantation | 
| Adrenal cortical hormone levels as a measure of efficacy for anti-aging effects | The test is scheduled to be conducted at the day of transplantation (2nd visit) and at 1 week (3rd visit), 1 month (4th visit), 6 months (5th visit) after the treatments. The investigators will assess changes in hormone levels compared to baseline which will be measured at the day of transplantation. After normality test on the average difference, either unpaired t-test or wilcoxon rank sum test will be conducted for statistical analysis. | Up to 6 months after transplantation | 
| Telomere length as a measure of efficacy for anti-aging effects | The test is scheduled to be conducted at the day of transplantation (2nd visit) and at 1 week (3rd visit), 1 month (4th visit), 6 months (5th visit) after the treatments. Whether the treatments protect telomere from shortening will be investigated through the comparison analysis. After normality test on the average difference, either unpaired t-test or wilcoxon rank sum test will be conducted for statistical analysis. | 6 months period after transplantation | 
| Body composition as a measure of efficacy for anti-aging effects | The test is scheduled to be conducted at the day of transplantation (2nd visit) and at 1 week (3rd visit), 1 month (4th visit), 6 months (5th visit) after the treatments. The investigators will assess changes of body composition compared to baseline which will be measured at the day of transplantation. After normality test on the average difference, either unpaired t-test or wilcoxon rank sum test will be conducted for statistical analysis. | 6 months period after transplantation | 
| Aging-related genetic and epigenetic markers as a measure of efficacy for anti-aging effects | The test is scheduled to be conducted at the day of transplantation (2nd visit) and at 1 week (3rd visit), 1 month (4th visit), 6 months (5th visit) after the treatments. The investigators will assess changes of aging-related genetic markes (e.g ELOVL2. ) compared to baseline which will be measured at the day of transplantation. After normality test on the average difference, either unpaired t-test or wilcoxon rank sum test will be conducted for statistical analysis. | 6 months period after transplantation | 
| mitochondria DNA copy number as a measure of efficacy for anti-aging effects | The test is scheduled to be conducted at the day of transplantation (2nd visit) and at 1 week (3rd visit), 1 month (4th visit), 6 months (5th visit) after the treatments. Mitochondria DNA copy number of participants will be compared among the treatment groups. After normality test on the average difference, either unpaired t-test or wilcoxon rank sum test will be conducted for statistical analysis. | 6 months period after transplantation | 
| Aging-related growth factors(GDF11, GDF15, Myostatin) as a measure of efficacy for anti-aging effects | The test is scheduled to be conducted at the day of transplantation (2nd visit) and at 1 week (3rd visit), 1 month (4th visit), 6 months (5th visit) after the treatments. The investigators will assess changes compared to baseline which will be measured at the day of transplantation. The factors will be compared among the treatment groups. After normality test on the average difference, either unpaired t-test or wilcoxon rank sum test will be conducted for statistical analysis. | 6 months period after transplantation | 
| DNA damage extent (8-hydroxyguanine level) as a measure of efficacy for anti-aging effects | The test is scheduled to be conducted at the day of transplantation (2nd visit) and at 1 week (3rd visit), 1 month (4th visit), 6 months (5th visit) after the treatments. The investigators will assess changes of 8-hydroxyguanine in white blood compared to baseline which will be measured at the day of transplantation. After normality test on the average difference, either unpaired t-test or wilcoxon rank sum test will be conducted for statistical analysis. | 6 months period after transplantation | 
| Changes in scores of Short Physical Performance Battery (SPPB) as a measure of efficacy for anti-aging effects | The test is scheduled to be conducted at the day of transplantation (2nd visit) and at 1 week (3rd visit), 1 month (4th visit), 6 months (5th visit) after the treatments. The investigators will assess changes in scores compared to baseline which will be measured at the day of transplantation. After normality test on the average difference, either unpaired t-test or wilcoxon rank sum test will be conducted for statistical analysis. | 6 months period after transplantation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Frailty, Umbilical cord blood, Plasma, Randomized trial, Double-blinded trial, Placebo-controlled trial