Background Frailty is an age-related syndrome characterized by reduced physiological reserve, decreased stress tolerance and multisystem functional decline in the elderly, which markedly increases the risks of falls, hospitalization, functional impairment and all-cause mortality. Chronic low-grade inflammation, immune senescence, oxidative stress and abnormal protein modification are key mechanisms underlying the development and progression of frailty. Current mainstream interventions including nutritional support and physical exercise yield limited efficacy for moderate to severe frailty, and targeted therapies against biological aging mechanisms are still lacking.Objective To evaluate the efficacy and safety of plasma exchange combined with human albumin (ALB), with or without intravenous immunoglobulin (IVIg), in the treatment of frailty, and to preliminarily explore the potential mechanisms of the combined therapy.Methods This is a prospective, randomized, exploratory clinical trial. A total of 34 participants with a FRAIL scale score ≥ 1 will be enrolled and randomly assigned at a 1:1 ratio into two groups, with 17 cases in each group: the plasma exchange plus ALB group and the plasma exchange plus ALB plus IVIg group. The study consists of a screening phase, a 5-month treatment phase with six intervention sessions, and follow-up visits at 1, 3 and 6 months after the final treatment. Frailty status, physical function, laboratory parameters, inflammatory levels and albumin modification will be dynamically assessed throughout the trial, and adverse events will be recorded.Results The trial has not yet been initiated. It is expected that the within-group and between-group comparisons will clarify the therapeutic effects and long-term stability of the two regimens, as well as their safety profiles. Changes in biomarkers will help illustrate the potential molecular mechanisms of plasma purification combined with functional protein supplementation for frailty.Conclusion Plasma exchange combined with ALB (with or without IVIg) can exert multi-target intervention on frailty by eliminating aging-related toxic factors and restoring plasma and immune homeostasis. The findings of this study will provide preliminary clinical evidence and theoretical basis for novel biological therapeutic strategies for frailty.
Frailty is a common age-related clinical syndrome characterized by progressive decline in physiological reserve, reduced stress tolerance, and multisystem functional impairment in older adults. It significantly increases the risk of adverse outcomes including falls, hospitalizations, functional dependence, and all-cause mortality. Chronic low-grade inflammation, immune senescence, oxidative stress, and abnormal protein modification are considered key biological mechanisms driving the onset and progression of frailty. Current mainstream interventions, such as nutritional support and physical exercise, have shown only limited efficacy in moderate to severe frailty, and targeted biological therapies for frailty remain lacking. This study aims to evaluate the efficacy and safety of plasma exchange combined with human albumin (ALB), with or without adjunctive intravenous immunoglobulin (IVIg), in the treatment of frailty, and to preliminarily explore the potential mechanisms underlying the combined therapy. This is a prospective, randomized, exploratory clinical trial. A total of 34 participants with a FRAIL scale score of ≥ 1 will be enrolled and randomly assigned at a 1:1 ratio into two groups (17 participants in each group): the plasma exchange plus human albumin group (ALB group) and the plasma exchange plus human albumin plus intravenous immunoglobulin group (ALB + IVIg group). The study is divided into three phases: a screening phase, a treatment phase, and a follow-up phase. The screening phase will be conducted within 7 days prior to the first treatment. Eligible subjects will sign an informed consent form and complete a comprehensive baseline assessment, including frailty status evaluation, physical function testing, routine laboratory and imaging examinations, frailty-related biomarker detection, albumin (ALB) modification profiling, and inflammatory marker testing to confirm eligibility. The treatment phase will last for 5 months, consisting of a total of 6 treatment sessions administered monthly. Systemic assessments will be performed at each visit, including frailty status evaluation, physical function testing, routine pre-treatment examinations, frailty-related biomarker detection, ALB modification profiling, and inflammatory marker testing, to monitor treatment response and safety. Blood samples for complete blood count and coagulation function will be collected within 1 hour after the first plasma exchange session. All participants will receive plasma exchange with 5% human albumin solution as the replacement fluid, according to the study protocol. Subjects in the ALB + IVIg group will additionally receive intravenous immunoglobulin (IVIg) immediately after each plasma exchange session. Adverse events will be recorded throughout the study. Follow-up visits will be conducted at 1, 3, and 6 months after the final treatment session. All assessments and laboratory tests will be repeated to evaluate the long-term efficacy, safety, and sustained effects of the interventions. This trial has not yet been initiated. It is expected that within-group and between-group comparisons will clarify the therapeutic effects and long-term stability of the two regimens, as well as their safety profiles. Changes in frailty-related biomarkers, inflammatory markers, and albumin modification patterns will help to illustrate the potential molecular mechanisms of plasma exchange combined with functional protein supplementation for frailty. It is hypothesized that plasma exchange combined with ALB (with or without IVIg) may exert multi-targeted intervention on frailty by eliminating aging-related toxic factors and restoring plasma and immune homeostasis. The findings of this study will provide preliminary clinical evidence and a theoretical basis for novel biological therapeutic strategies for frailty.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
34
Plasma exchange procedure, target exchange volume 50±5 mL/kg per session, flow rate 40-60 mL/min, administered once monthly for 6 cycles.
Equal-volume 5% human albumin solution used as replacement fluid during plasma exchange.
IVIg administered at a fixed dose of 2.5 g per subject, infused immediately after each plasma exchange session.
Institute of Hematology & Blood Diseases Hospital, China
Tianjin, Tianjin Municipality, China
Efficacy rate of frailty intervention at 1 month after the last treatment
Calculation formula: \[(Baseline score - Follow-up score at 1 month after the last treatment) / Baseline score\] × 100%. This rate represents the degree of improvement in patients' frailty status following intervention.
Time frame: 1 month after the last treatment
Efficacy rate of frailty intervention assessed by FRAIL Scale
The efficacy rate of frailty intervention calculated based on the FRAIL Scale (Fatigue, Resistance, Ambulation, Illnesses, Loss of weight). The scale ranges from 0 (no frailty) to 5 (severe frailty); higher scores indicate worse frailty status. Efficacy rate = (Baseline score - Score at follow-up) / Baseline score × 100%.
Time frame: Baseline, 4 week, 8 week, 12 week, 16 week, 20 week, 24 week, 28 week, and 32 week after enrollment
Strand specificity of frailty-related cfDNA and therapeutic response to plasma exchange
Assess strand specificity of frailty-related circulating cell-free DNA and evaluate its predictive value for plasma exchange treatment response.
Time frame: Baseline, 1 month and 6 months after the last treatment
Clonal hematopoiesis gene mutation dynamics and correlation with frailty
Observe clonal hematopoiesis-associated gene mutation and clonal evolution at baseline, 1 month and 6 months post last treatment; explore the correlation between clonal hematopoiesis features and frailty status.
Time frame: Baseline, 4 week,24 week, 28 week, and 32 week after enrollment
BCR clonotype characteristics
Analysis of BCR clonotype derived from identical BCR high-throughput sequencing assay. Assessments are performed at baseline, 1 month and 6 months after the last treatment.
Time frame: Baseline, 1 month and 6 months after the last treatment
BCR V/J gene usage bias
Analysis of BCR V/J gene usage bias derived from identical BCR high-throughput sequencing assay. Assessments are performed at baseline, 1 month and 6 months after the last treatment.
Time frame: Baseline, 1 month and 6 months after the last treatment
BCR diversity index
Analysis of BCR diversity index derived from identical BCR high-throughput sequencing assay. Assessments are performed at baseline, 1 month and 6 months after the last treatment.
Time frame: Baseline, 1 month and 6 months after the last treatment
Frequency of senescence-associated antigen-specific B cell clones
Analysis of senescence-associated antigen-specific B cell clones derived from identical BCR high-throughput sequencing assay. Assessments are performed at baseline, 1 month and 6 months after the last treatment.
Time frame: Baseline, 1 month and 6 months after the last treatment
TCR clonotype characteristics
Analysis of TCR clonotype derived from a single unified TCR high-throughput sequencing assay. Assessments are performed at baseline, 1 month and 6 months after the last treatment.
Time frame: Baseline, 1 month and 6 months after the last treatment
TCR diversity index
Analysis of TCR diversity index derived from a single unified TCR high-throughput sequencing assay. Assessments are performed at baseline, 1 month and 6 months after the last treatment.
Time frame: Baseline, 1 month and 6 months after the last treatment
TCR V/J gene usage bias
Analysis of TCR V/J gene usage bias derived from a single unified TCR high-throughput sequencing assay. Assessments are performed at baseline, 1 month and 6 months after the last treatment.
Time frame: Baseline, 1 month and 6 months after the last treatment
Frequency of senescence-associated antigen-specific T cell clones
Analysis of senescence-associated antigen-specific T cell clones derived from a single unified TCR high-throughput sequencing assay. Assessments are performed at baseline, 1 month and 6 months after the last treatment.
Time frame: Baseline, 1 month and 6 months after the last treatment
Between-group differences in frailty scale score: ALB group vs ALB+IVIg group
Compare the changes of frailty scale score between albumin monotherapy group and albumin combined with IVIg group.
Time frame: Baseline, 4 week, 8 week, 12 week, 16 week, 20 week, 24 week, 28 week, and 32 week after enrollment
Baseline changes of serum ALB modification at 1 month after last treatment
Evaluate the alterations of serum albumin subtypes including oxidation, glycation, nitration, sulfenylation, cysteinylation, cysteinylation combined with glycation versus baseline.
Time frame: 1 month after the last treatment
Changes from baseline in senescence-related indicators at 1 month after last treatment
Detect plasma proteome and glycoproteome related to senescence, including SASP, serum inflammatory factors and epigenetic senescence clock, and analyze their changes compared with baseline.
Time frame: 1 month after the last treatment
Changes from baseline in Tilburg Frailty Indicator (TFI) scores
To evaluate the changes of Tilburg Frailty Indicator (TFI) score compared with baseline at each follow-up time point.
Time frame: Baseline, 4 week, 8 week, 12 week, 16 week, 20 week, 24 week, 28 week, and 32 week after enrollment
Changes from baseline in Fried Frailty Phenotype Scale scores
To evaluate the change of Fried Frailty Phenotype Scale score compared with baseline. This is one single outcome indicator (scale score) assessed repeatedly at multiple planned follow-up time points, not multiple distinct outcome measures.This represents one continuous outcome (Frailty Phenotype score) assessed longitudinally at multiple prespecified time points.
Time frame: Baseline, 4 week, 8 week, 12 week, 16 week, 20 week, 24 week, 28 week, and 32 week after enrollment
Changes from baseline in physical and mental health questionnaire scores
Assess changes from baseline in EQ-5D, PROMIS-29, Generalized Anxiety Disorder (GAD) scale, Patient Health Questionnaire (PHQ), Pittsburgh Sleep Quality Index (PSQI).
Time frame: Baseline, 4 week, 8 week, 12 week, 16 week, 20 week, 24 week, 28 week, and 32 week after enrollment
Short Physical Performance Battery (SPPB) score
To evaluate patients' physical function using the Short Physical Performance Battery (SPPB). This single continuous scale outcome will be repeatedly assessed at multiple scheduled follow-up time points.
Time frame: Baseline, 4 week, 8 week, 12 week, 16 week, 20 week, 24 week, 28 week, and 32 week after enrollment
Changes in gene mutation frequency and its correlation with immune cell subsets
Analyze the shift of gene mutation frequency before and after treatment, and explore the correlation between mutation frequency and immune cell profiles.
Time frame: Baseline, 1 month and 6 months after the last treatment
Changes from baseline in CRP
Detect serum CRP, and calculate their changes compared with baseline at predefined visits.
Time frame: Baseline, 4 week, 24 week, 28 week, and 32 week after enrollment
Changes from baseline in ESR levels
Detect serum erythrocyte sedimentation rate (ESR) , and calculate their changes compared with baseline at predefined visits.
Time frame: Baseline, 4 week, 24 week, 28 week, and 32 week after enrollment
Changes from baseline in ferritin levels
To assess changes in serum ferritin concentration relative to baseline.
Time frame: Baseline, 4 week, 24 week, 28 week, and 32 week after enrollment
Incidence of adverse events during treatment
The incidence rate of all adverse events occurring during the treatment period will be calculated. Focused adverse events include catheter-related infections, hypersensitivity reactions, thrombosis, and other related adverse events.
Time frame: From initiation of the first treatment through 6-month after completion of all study treatments, assessed up to 12 months
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