The Design and Rationale of a Phase 2b, Randomized, Double-Blinded, and Placebo-Controlled Trial to Evaluate the Safety and Efficacy of Lomecel-B in Older Adults with Frailty

Background: Frailty in older adults is a rapidly growing unmet medical need. It is an aging-related syndrome characterized by physical decline leading to higher risk of adverse health outcomes. OBJECTIVES: To evaluate the efficacy of Lomecel-B, an allogeneic medicinal signaling cell (MSC) formulation, in older adults with frailty. DESIGN: This multicenter, randomized, parallel-arm, double-blinded, and placebo-controlled phase 2b trial is designed to evaluate dose-range effects of Lomecel-B for frailty on physical functioning, patient-reported outcomes (PROs), frailty status, and biomarkers. SETTING: Eight enrolling clinical research centers, including the Miami Veterans Affairs Medical Center. PARTICIPANTS: Target enrollment is 150 subjects aged 70-85 years of any race, ethnicity, or gender. Enrollment criteria include a Clinical Frailty Score of 5 (“mild”) or 6 (“moderate”), a 6MWT of 200-400 m, and serum tumor necrosis factor-alpha (TNF-α) ≥2.5 pg/mL. INTERVENTION: A single intravenous infusion of Lomecel-B (25, 50, 100, or 200 million cells) or placebo (N=30/arm). Patients are followed for 365 days for safety, and the efficacy assessments performed at 90, 180, and 270 days. MEASUREMENTS: The primary endpoint is change in 6MWT in the Lomecel-B-treated arms versus placebo at 180 days post-infusion. Secondary and exploratory endpoints include change in: 6MWT and other physical function measures at all time points; PROs; frailty status; cognitive status; and an inflammatory biomarkers panel. A pre-specified sub-study examines vascular/endothelial biomarkers. Safety is evaluated throughout the trial. RESULTS: The trial is conducted under a Food and Drug Administration Investigational New Drug (IND), with Institutional Review Board approval, and monitoring by an NIH-appointed independent Data Safety Monitoring Board. CONCLUSION: This clinical trial investigates the use of a regenerative medicine strategy for frailty in older adults. The results will further the understanding of the potential for Lomecel-B in the geriatric condition of frailty.

Frailty in Caregivers and Its Relationship with Psychological Stress and Resilience: A Cross-Sectional Study Based on the Deficit Accumulation Model

Background: Studies increasingly suggest that chronic exposure to psychological stress can lead to health deterioration and accelerated ageing, thus possibly contributing to the development of frailty. Recent approaches based on the deficit accumulation model measure frailty on a continuous grading through the “Frailty Index” (FI), i.e. a macroscopic indicator of biological senescence and functional status. OBJECTIVES: The study aimed at testing the relationship of FI with caregiving, psychological stress, and psychological resilience. DESIGN: Cross-sectional study, with case-control and correlational analyses. PARTICIPANTS: Caregivers of patients with dementia (n=64), i.e. individuals a priori considered to be exposed to prolonged psychosocial stressors, and matched controls (n=64) were enrolled. MEASUREMENTS: The two groups were compared using a 38-item FI condensing biological, clinical, and functional assessments. Within caregivers, the association of FI with Perceived Stress Scale (PSS) and Brief Resilience Scale (BRS) was tested. RESULTS: Caregivers had higher FI than controls (F=8.308, p=0.005). FI was associated directly with PSS (r=0.660, p<0.001) and inversely with BRS (r=-0.637, p<0.001). Findings remained significant after adjusting for certain confounding variables, after excluding from the FI the conditions directly related to psychological stress, and when the analyses were performed separately among participants older and younger than 65 years. CONCLUSIONS: The results provide insight on the relationship of frailty with caregiving, psychological stress, and resilience, with potential implications for the clinical management of individuals exposed to chronic emotional strain.

Vitamin D Supplementation Is Associated with a Reduction in Self-Reported Falls among Older Adults with Previous Fall History – Feasibility Study

Background: Vitamin D insufficiency contributes to muscle weakness and a higher risk of falls in older adults. Objectives: This study explored the impact of vitamin D supplementation on self-reported falls and physical function in older adults with low vitamin D levels and a recent fall history. Materials and Methods: Twenty-five older adults ≥ 70 years with two or more falls during the past year, low vitamin D blood levels (≥10 ng/ml and < 30 ng/mL), and slow gait speed (1.2 m/s) participated in a 6-month vitamin D supplementation (800 IU/day) study. A modified version of the Morse Fall Scale questionnaire was used to assess frequency of falls over one-year prior to study enrollment. Functional outcomes (short physical performance battery, handgrip strength, gait Timed Up and Go, and six-minute walk), and vitamin D levels were assessed at baseline and 6-month follow-up. Results: Based on diaries and pill counts, participants were generally adherent to the intervention (6 of 7 days per week). Supplementation with 800 IU/day of vitamin D for 6 months increased blood vitamin D levels from 23.25±4.8 ng/ml to 29.13±6.9 ng/ml (p<0.001). Self-reported number of falls decreased from an average of 3.76 ± 2.2 falls in one-year to 0.76 ± 1.4 falls (p <0.0001) over the 6-month intervention. No changes in functional outcome measures were observed. Conclusions: Vitamin D supplementation at the currently recommended dose of 800 IU/day increased blood vitamin D levels and reduced frequency of falls in older adults with low vitamin D levels and a recent fall history.

Performance of a Novel Handheld Bioelectrical Impedance Device for Assessing Muscle Mass in Older Inpatients

Objectives: To investigate practicality and repeatability of a handheld compared to a state-of-the-art multisegmental bioelectrical impedance analysis (BIA) device to facilitate screening of sarcopenia in older inpatients. Design and setting: Cross-sectional study in a geriatric rehabilitation hospital. Participants: 207 inpatients aged 70+. Measurements: In a first phase, appendicular skeletal muscle mass index (ASMI) was measured using the handheld Biody xpertZm II BIA device (n=100). In a second phase, ASMI was obtained using the multisegmental Biacorpus RX 4004M device (n=107). Repeatability of BIA devices was compared in subgroups of patients (handheld BIA device: n=36, multisegmental BIA device: n=46) by intra-class correlation (ICC) and Bland-Altman plots. Results: Overall, measurement failure was seen in 31 patients (31%) tested with the handheld BIA device compared to one patient (0.9%) using the multisegmental BIA device (p<0.001). Main reasons for measurement failure were inability of patients to adopt the position necessary to use the handheld BIA device and device failure. The mean difference of two ASMI measurements in the same patient was 0.32 (sd 0.85) using the handheld BIA device compared to 0.02 kg/m2 (sd 0.07) using the multisegmental device (adjusted mean difference between both groups -0.35, 95% confidence interval (CI) -0.61 to -0.09 kg/m2). Congruently, Bland-Altman plots showed poor agreement with the handheld compared to the multisegmental BIA device. Conclusion: The handheld BIA device is neither a practical nor reliable device for assessing muscle mass in older rehabilitation inpatients.

Mechanisms of Musculoskeletal Frailty in People Living with HIV

People over age 50 living with HIV experience frailty including functional declines and illnesses usually attributed to aging, more frequently and ten years earlier than people without HIV. As the number of people living with HIV over age 50 is expected to triple by the year 2040, those experiencing early frailty will continue to grow. This review synthesizes the known correlates and contributors to musculoskeletal frailty in people living with HIV. A conceptual model of musculoskeletal frailty in HIV that outlines chronic inflammation, altered energy metabolism, immune activation, and endocrine alterations as mechanisms associated with frailty development is presented. Additionally, the potential ability of aerobic exercise to modify the risk of frailty is highlighted as an important intervention.

Frailty among Older Adults and Its Distribution in England

Background: Information on the spatial distribution of the frail population is crucial to inform service planning in health and social care. Objectives: To estimate small-area frailty prevalence among older adults using survey data. To assess whether prevalence differs between urban, rural, coastal and inland areas of England. Design: Using data from the English Longitudinal Study of Ageing (ELSA), ordinal logistic regression was used to predict the probability of frailty, according to age, sex and area deprivation. Probabilities were applied to demographic and economic information in 2020 population projections to estimate the district-level prevalence of frailty. Results: The prevalence of frailty in adults aged 50+ (2020) in England was estimated to be 8.1 [95% CI 7.3-8.8]%. We found substantial geographic variation, with the prevalence of frailty varying by a factor of 4.0 [3.5-4.4] between the most and least frail areas. A higher prevalence of frailty was found for urban than rural areas, and coastal than inland areas. There are widespread geographic inequalities in healthy ageing in England, with older people in urban and coastal areas disproportionately frail relative to those in rural and inland areas. Conclusions: Interventions aimed at reducing inequalities in healthy ageing should be targeted at urban and coastal areas, where the greatest benefit may be achieved.

HEALTH STATUS AND LIFESTYLE HABITS OF VULNERABLE, COMMUNITY-DWELLING OLDER PEOPLE DURING THE COVID-19 LOCKDOWN

This study evaluated the health status and lifestyle habits of vulnerable, community-dwelling older adults during the first COVID-19 lockdown in Spain. A telephone assessment was carried out in 38 individuals (71% women), with a Barthel index ≥85 who were frail or had a high risk of falls. Data were compared with those from an assessment performed 9 months earlier. In the latter part of the lockdown, a high percentage of the studied individuals showed difficulties in walking up 10 steps and reported sleep problems (66%) and pain (74%). On the other hand, participants were not anxious/depressed (71%) and the majority did not report loneliness (60%). Compared to the earlier assessment, we identified a decline in functional capacity and worsening of nutritional status, but an increase in family support. Efforts should be made to implement intervention programs seeking to avoid accelerated decline under the current pandemic situation, and especially during possible new lockdowns.