Mesenchymal Stem/Stromal Cell Therapy in the Treatment of Frailty

Study Overview
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Brief Summary
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This trial is to investigate the safety and potential therapeutic efficacy of allogeneic administration of umbilical cord-derived MSCs (UC-MSCs) in combination with standard frailty treatment in Vietnam

Detailed Description
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Frailty, a specific condition of increased vulnerability and reduced general health associated with aging in elderly people, is an emerging global burden requiring major implications for clinical practice and public health. The lack of standardized definition and treatment of the disease resulted in the increasing number of elders diagnosed with frailty. Recently, preclinical and clinical studies support the safety of mesenchymal stem/stromal cells (MSCs) in the treatment of frailty. However, no comprehensive study has been conducted to access the interrelationship between frailty conditions and the effects of MSC-based therapy. To fill this knowledge gap, the aim of the trial is to investigate the safety and potential therapeutic efficacy of allogeneic administration of umbilical cord-derived MSCs (UC-MSCs) in combination with standard frailty treatment in Vietnam. Moreover, this study describes the rationale, study design, methodologies, and analysis strategy currently employed in stem cell research and clinical study. This randomized case-control phase I/II trial is conducted at Vinmec Times City International Hospital, Hanoi, Vietnam between July 2021 and November 2022. In this trial, 44 patients will be enrolled and randomized into a UC-MSC administration group and control group. Both groups will receive the standard frailty treatment and supplementary medication. The UC-MSC group will receive two doses of thawed UC-MSC product at 1.5x10^6 cells/kg of patient body's weight with an intervention interval of three months. The primary outcome measures will include the incidence of prespecified administration-associated adverse events (AEs) and serious adverse events (SAEs). The potential efficacy will be evaluated based on the improvement in frailty conditions (including physical examination, patient-reported outcomes, quality of life, immune markers of frailty, metabolism analysis, and cytokine markers from patient's plasma). The clinical evaluation will be conducted at baseline and 1-, 3-, 6- and 9-months post-intervention. This clinical trial and stem cell analysis associated with patients' sampling at different timepoints seeks to identify and characterize the potential effects of UC-MSCs on the improvement of frailty based on stem cell quality, cytokines/growth factors secretion profiles of UC-MSCs, cellular senescence, and metabolic analysis of patient's CD3+ cells. The ultimate results of the study will be essential for evaluating the utility of UC-MSC therapy for the treatment of frailty and mechanism underlying these effects providing the fundamental knowledge for designing and implementing research strategy of future studies

Official Title
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Clinical Study of Mesenchymal Stem/Stromal Cell Therapy in Frailty: a Proposed Experimental Design for Therapeutic and Mechanism Investigation

Conditions
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Frailty

Intervention / Treatment
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* Biological: Umbilical Cord Mesenchymal Stem Cells transplantation
* Drug: standard frailty treatment and supplementary medication


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must show signs of frailty apart from a concomitant condition as assessed by the investigator with a frailty score >=3 using the Fried Phenotype Scale. They showed the signs of frailty based on physician assessment, apart from a concomitant condition, by a score between 3 and 6 as denoted by the Canadian Study on Health Aging. Must provide written informed consent. Exclusion Criteria: Score of less than or equal to 20 on the Mini-Mental State Examination (MMSE) Active listing (or expected future listing) for transplant of any organ. Clinically important abnormal screening laboratory values, including but not limited to: hemoglobin <8 g/dl, white blood cell count <3000/mm3, platelets<80,000/mm3, alkaline phosphatase > 3 times the upper limit of normal, total bilirubin > 1.5 mg/dl. Serious comorbid illness that, in the opinion of the investigator, may compromise the safety or compliance of the patient or preclude successful completion of the study. Including, but not limited to HIV, advanced liver or renal failure, class II/III/IV congestive heart failure, myocardial infarction, unstable angina, or cardiac revascularization within the last six months, or severe obstructive ventilator defect, COPD with GOLD D, ischemic stroke with NIHSS <5, type II diabetes with HbA1C >8.5% Any other condition that, in the opinion of the investigator, may compromise the safety or compliance of the patient or preclude successful completion of the study. Be an organ transplant recipient. Have a clinical history of malignancy within 5 years (i.e., patients with prior malignancy must be disease-free for 5 years), except curatively treated basal cell carcinoma, squamous cell carcinoma, melanoma in situ or cervical carcinoma if recurrence occurs. Have a non-pulmonary condition that limits lifespan to < 1 year.

Ages Eligible for Study
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Minimum Age: 60 Years
Maximum Age: 85 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (UC-MSC trasnplatation)<br>1.5 x 10^6 umbilical Cord Mesenchymal Stem Cells per body kg will transplant via the intravenous at baseline, and the second transplantation will be performed 3 months after the first transplantation and combination with standard frailty treatment and supplementary medication | Biological: Umbilical Cord Mesenchymal Stem Cells transplantation<br>* Patients assigned to UC-MSC administration groups will receive two administrations at a dose of 1.5 million cells/kg patient body weight via the IV route with a 3-month intervening interval<br>Drug: standard frailty treatment and supplementary medication<br>* Hightamine (Hankook Korus Pharm, Korea), Total calcium (Nugale Pharmaceutical, Canada), Bioflex (Ausbiomed, Australia)<br>|
| Other: control arm<br>standard frailty treatment and supplementary medication | Drug: standard frailty treatment and supplementary medication<br>* Hightamine (Hankook Korus Pharm, Korea), Total calcium (Nugale Pharmaceutical, Canada), Bioflex (Ausbiomed, Australia)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events and serious adverse events | To assess safety, the number of AEs or SAEs during stem cell administration (72 h) at 1 months, 3 months, 6 months and 9 months after discharge will be evaluated | up to the 9-month period following treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reduced activities | Reduced activities using Community Healthy Activities Model Program for Seniors questionnaire | up to the 9-month period following treatment | 
| Slowing of mobility | slowing of mobility using 6-minute walk test | up to the 9-month period following treatment | 
| reduction of handgrip strength | reduction of handgrip strength using dynamometer | up to the 9-month period following treatment | 
| exhaustion | exhaustion using multidimensional fatigue inventory questionnaire | up to the 9-month period following treatment | 
| the level of pain in the knee | the level of pain in the knee using Western Ontario and McMaster Universities Osteoarthritis Index | up to the 9-month period following treatment | 
| respiratory function | respiratory function using FEV1/FVC | up to the 9-month period following treatment | 
| Quality of Life | Quality of Life using Short Form 36 items | up to the 9-month period following treatment | 
| patients' inflammation | information of patients' inflammation response to umbilical cord-derived mesenchymal stem/stromal cells administration | up to the 9-month period following treatment | 
| patients' immune | information of patients' immune response to umbilical cord-derived mesenchymal stem/stromal cells administration | up to the 9-month period following treatment | 
| immunoregulatory properties of umbilical cord-derived mesenchymal stem/stromal cells | Evaluation of immunoregulatory properties of umbilical cord-derived mesenchymal stem/stromal cells | up to the 9-month period following treatment | 
| Cellular senescence | Measurement of cellular senescence using qPCR will be conducted in CD3+ cell population to access the expression of cyclin-dependent kinase inhibitor 2A (CDKN2A) gene, a specific biomarker indicated the cellular senescence | up to the 9-month period following treatment | 
| metabolic profiles of CD3+ cells | metabolic profiles of CD3+ cells via Seahorse XF Cell Mito Stress Test Kit and Seahorse XF Cell Glycolysis Stress Test Kit (Agilent Technologies) | up to the 9-month period following treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Frailty, umbilical cord mesenchymal stem cells