Mesenchymal Stem Cells for Age-Related Frailty (MESCAFY)

A Pilot Study of Mesenchymal Stem Cells as Novel Therapy for Age-Related Frailty in Veterans

Frailty is a health state related to the aging process in which multiple body systems gradually lose their built-in reserves. It is a medical condition of reduced function in older adults which is associated with increased risks of adverse outcomes such as falls, disability, admission to hospital, or need for long-term care. Currently, there is no specific medical treatment of frailty. Mesenchymal stem cells (MSCs) are undifferentiated cells that self-replicated, and some may change into a particular cell type. These cells go to areas of injury due to signals released by injured cells. Upon reaching, the target tissue, MSCs repair injury by releasing growth factors and immune modulators to assist in the body's repair process. This initial study will assess the practicability of using MSCs for age-related frailty and provide information for planning a future full study of MSCs for maximizing Veteran's functional independence.

Study Overview

• Status: Withdrawn
• Conditions: Frailty
• Intervention / Treatment: Drug: Mesenchymal Stem Cells (MSCs)

Detailed Description

Frailty is an aging-related syndrome of impaired physiologic reserve and function across multiple organs, leading to increased vulnerability for adverse health outcomes. Frailty is associated with an increased risk for falls, disability, hospitalization, and mortality. Given the rapid growth in the aging population, the prevalence of frailty will continue to increase. In fact, Veterans receiving care at Veterans Health Administration are a high risk population for onset of frailty due to being predominantly older associated with a larger proportion of minorities, lower socioeconomic and educational status, higher prevalence of comorbidities, and higher rates of unemployment. Frailty now affects at least 3 of every 10 U.S. Veterans aged 65 years and older and is strongly associated with mortality. It is increasingly being recognized that frailty may be an appropriate target for intervention to reduce disability and dependence in older adults. However, there are no specific medical or biologic treatments that ameliorate or reverse frailty. Conversely, stem cell depletion is a key mechanism for age-related frailty. There is a strong link between frailty, inflammation, and the impaired ability to repair tissue injury due to decreases in endogenous stem cell production. Accordingly, a cell-based, regenerative treatment strategy i.e., allogenic bone-marrow derived mesenchymal stem cell (MSC) therapy may represent a novel therapy for aging frailty. MSCs migrate into the site of injury and home to the affected tissue, where they act to reduce inflammation and promote cellular repair. The advantages of MSCs as a therapeutic strategy for age-related frailty include availability, ease of isolation and expansion, multilineage differentiation and immunosuppression, free from ethical issues, and limited replicative lifespan. In this 6-month pilot study, the investigators will assess 1) the feasibility of MSC therapy in age-related frailty as it relates to functional improvement and 2) develop/refine MSC therapy as a new intervention in older Veterans with frailty, and thus provide preliminary participant response to inform a future trial.

• Study Type: Interventional
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Dennis T Villareal, MD; Phone Number: (713) 794-7151; Email: Dennis.Villareal@va.gov

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030-4211
      • Michael E. DeBakey VA Medical Center, Houston, TX

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 65 years to 85 years (OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age 65 - 85 years and living in the community
• Modified Physical Performance Test score of 18 to 31
• Clinical Frailty Scale score of 5 or 6
• 6-minute walk distance of >200m and <400m
• Willing to provide informed consent

Exclusion Criteria:

• Failure to provide informed consent
• Major cardiopulmonary disease (e.g., recent MI, unstable angina, stroke) or unstable disease (e.g. NYHA Class II or IV congestive heart failure, severe pulmonary disease requiring steroid pills or the use of supplemental oxygen
• Severe neuromuscular disease (e.g., multiple sclerosis, Parkinson's disease, Amyotrophic lateral sclerosis)
• Renal impairment as defined by an estimated glomerular filtration rate (eGFR or less than 30 ml/min/1.73 m2)
• Other significant co-morbid disease (e.g., severe psychiatric disorder [e.g. bipolar, schizophrenia], excess alcohol use (>14 drinks per week)
• Uncontrolled hypertension (BP>160/90 mm Hg)
• Significant cognitive impairment, defined as a known diagnosis of dementia or positive screening test for dementia using the Mini-Mental State Exam (i.e., MMSE score <24)
• Poorly controlled diabetes (HbA1c >8.5%)
• History of malignancy during the past 5 years (except non-melanoma skin cancers)
• Have autoimmune disease (e.g., Rheumatoid arthritis, systemic lupus erythematosus)
• Be using chronic immunosuppressant therapy such as high-dose corticosteroids or TNF-alpha antagonists (prednisone use at doses of < 5 mg daily is allowed)
• Test positive for hepatitis B virus - If the subject tests positive for anti-hepatitis B core antigen (HBc) or anti-HBs, they must be currently receiving treatment for Hepatitis B prior to infusion and remain on treatment throughout the study
• Test positive for Hepatitis C virus, HIV1/2, or syphilis
• Have any clinically important screening laboratory values, including hemoglobin <10.0 g/dL, WBC <2.500/ul or platelet count<100,000/ul, AST or ALT > 3 times the upper limit of normal, INR>1.3 not due to reversible cause (e.g., warfarin)
• Treatment with another investigational drug or other intervention within three months
• A history or current evidence of any condition, laboratory abnormality, or other circumstance that might confound the interpretation of the results

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Group 1; Peripheral IV Infusion of 100 million MSCs at baseline and repeated at three months	Drug: Mesenchymal Stem Cells (MSCs); The MSCs are recovered from bone marrows of healthy donors. Each donor is carefully screened for pathogens to assure the product is safe. The MSCs are strictly compliant with FDA standards under Current Good Manufacturing Practice (cGMP) regulations.
EXPERIMENTAL: Group 2; Peripheral IV Infusion of 100 million MSCs at baseline and peripheral IV infusion of placebo at three months	Drug: Mesenchymal Stem Cells (MSCs); The MSCs are recovered from bone marrows of healthy donors. Each donor is carefully screened for pathogens to assure the product is safe. The MSCs are strictly compliant with FDA standards under Current Good Manufacturing Practice (cGMP) regulations.
PLACEBO_COMPARATOR: Group 3; Peripheral IV infusion of placebo at baseline and repeated at three months	Drug: Mesenchymal Stem Cells (MSCs); The MSCs are recovered from bone marrows of healthy donors. Each donor is carefully screened for pathogens to assure the product is safe. The MSCs are strictly compliant with FDA standards under Current Good Manufacturing Practice (cGMP) regulations.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adherence	Percent of study visits attended	Through study completion at 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recruitment	Number of participants recruited	Through study completion at 6 months
Modified Physical Performance Test	Includes seven standardized tests (walking 15.2 m, putting and removing a coat, picking up a penny, standing up from a chair, lifting a book, climbing one flight of stairs, and progressive romberg test) plus two additional tasks (going up and down four flights of stairs and making a 360-degree turn). Perfect score is 36	Change from baseline to 6 months
6-Minute Walk Test	A performance based measure of functional exercise capacity.	Change from baseline to 6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
4-minute walk gait speed	Time needed to walk 4 meters at the usual pace will be measured	Change from baseline to 6 months
Activities of daily living (ADL) and instrumental ADL	Assessed using the physical function subscale of the Functional Status Questionnaire	Change from baseline to 6 months
High-Sensitivity C-reactive protein	Marker of chronic inflammation - measured by immunoturbidimetric assay	Change from baseline to 6 months
Knee extensor strength	as evaluated using a Biodex System 3 dynamometer	Change from baseline to 6 months
Soluble tumor necrosis factor receptor 1 (sTNF)	Measured in serum using enzyme-linked immunoabsorbent assay	Change from baseline to 6 months
Interleukin-6	Measured in serum using enzyme-linked immunoabsorbent assay	Change from baseline to 6 months
Bone mineral density of the lumbar spine and hip	Measured using dual-energy x-ray absorptiometry	Change from baseline to 6 months
Lean body mass	Measured by dual-energy x-ray absorptiometry	Change from baseline to 6 months
Visceral fat mass	Measured by dual-energy x-ray absorptiometry (DXA)	Change from baseline to 6 months
Bone microarchitecture	Measured by High-resolution peripheral computed tomography (HR-pQCT) at wrist and distal radius	Change from baseline to 6 months
Bone strength	Measured using micro-finite element analyses of HR-pQCT	Change from baseline to 6 months
Trabecular bone score	A textual parameter that provides an index of trabecular microarchitecture	Change from baseline to 6 months
Cognition	Using the Composite Age-Adjusted Scale Score from the National Institute of Health Toolbox Cognition Battery.	Change from baseline to 6 months
Quality of Life	Using the Physical a nd Mental component subscale of the Medical Outcomes Study SF-36	Change from baseline to 6 months
Body fat	Measured using dual-energy x-ray absorptiometry	Change from baseline to 6 months
Grip strength	Evaluated with a Jamar Handheld dynamometer	Change from baseline to 6 months
Adverse Events	Number of non-serious and serious adverse events	Through study completion at 6 months
Short Physical Performance Battery	Objective assessment tool for evaluating lower extremity function	Change from baseline to 6 months
Lipoprotein levels	Measured using automated enzymatic/colorimetric assays	Change from baseline to 6 months

Collaborators and Investigators

• Sponsor: VA Office of Research and Development
• Collaborators: Baylor College of Medicine; Michael E. DeBakey VA Medical Center

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 31, 2023
• Primary Completion (ACTUAL): January 31, 2023
• Study Completion (ACTUAL): January 31, 2023

Study Registration Dates

• First Submitted: March 8, 2022
• First Submitted That Met QC Criteria: March 16, 2022
• First Posted (ACTUAL): March 17, 2022

Study Record Updates

• Last Update Posted (ACTUAL): February 6, 2023
• Last Update Submitted That Met QC Criteria: February 2, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: Physical Function; Aging; Mesenchymal Stem Cells; Sarcopenia; Osteoporosis; Frailty; Cognitive Function
• Additional Relevant MeSH Terms: Pathologic Processes; Frailty
• Other Study ID Numbers: E4096-P

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: MEDVAMC will not provide unrestricted, open public access to large scale health related datasets because of re-identification concerns and the obligation to protect Veterans' private information. However, controlled public access will be provided to the greatest extent possible under specific DUAs or other written agreements, and open access will be provided to the final datasets underlying peer-reviewed publications (aggregated data that can be released with privacy and confidentiality risks).

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes