MSC-Exosome Therapy for Frontotemporal Dementia

Comparatore placebo: Placebo Comparator

Participants randomized to the placebo group will receive intranasal spray of normal saline (0.9% sodium chloride), 1 mL per administration, twice weekly for 24 consecutive weeks. The placebo is identical in appearance, packaging, and administration procedure to the active investigational product to maintain blinding.

Altro: Placebo Comparator (0.9% NaCl)

Participants randomized to the placebo group will receive intranasal spray of normal saline (0.9% sodium chloride), 1 mL per administration, twice weekly for 24 consecutive weeks. The placebo is identical in appearance, packaging, and administration procedure to the active investigational product to maintain blinding.

Sperimentale: Low-Dose Exosome Group

Participants randomized to the low-dose group will receive intranasal spray of human umbilical cord mesenchymal stem cell-derived exosomes (MSC-Exos), 1 mL per administration containing 24 × 10⁹ particles, twice weekly for 24 consecutive weeks.

Biologico: Umbilical Cord Mesenchymal Stem Cell-Derived Exosomes （Low-Dose）

Participants randomized to the low-dose group will receive intranasal spray of human umbilical cord mesenchymal stem cell-derived exosomes (MSC-Exos), 1 mL per administration containing 24 × 10⁹ particles, twice weekly for 24 consecutive weeks.

Sperimentale: High-Dose MSC-Exosome

Participants randomized to the high-dose group will receive intranasal spray of human umbilical cord mesenchymal stem cell-derived exosomes (MSC-Exos), 1 mL per administration containing 24 × 10⁹ particles, three times weekly for 24 consecutive weeks. Enrollment in this arm will only begin after the first 3 participants in the low-dose arm complete the 4-week safety lead-in and 21-day safety observation period without dose-limiting toxicity or serious adverse events.

Biologico: Umbilical Cord Mesenchymal Stem Cell-Derived Exosomes （High-Dose）

Participants randomized to the high-dose group will receive intranasal spray of human umbilical cord mesenchymal stem cell-derived exosomes (MSC-Exos), 1 mL per administration containing 24 × 10⁹ particles, three times weekly (e.g., Monday, Wednesday, Friday) for 24 consecutive weeks. Enrollment in this arm will only begin after the first 3 participants in the low-dose arm complete the 4-week safety lead-in and 21-day safety observation period without dose-limiting toxicity or serious adverse events.

Clinical Efficacy: Change in CDR plus NACC FTLD Score

Change from baseline in the Clinical Dementia Rating (CDR®) Dementia Staging Instrument plus the National Alzheimer's Coordinating Center Frontotemporal Lobar Degeneration (NACC FTLD) module total score at Week 24.

Scale Range: Minimum = 0, Maximum = 30

Interpretation: A higher score indicates worse cognitive and behavioral function; a decrease (negative change) from baseline indicates improvement.

Safety and Tolerability: Incidence of Adverse Events

Number of participants with treatment-emergent adverse events (AE), serious adverse events (SAE), adverse drug reactions (ADR), and serious adverse drug reactions (SADR), including assessment of causality and severity. Adverse events include local nasal reactions (e.g., epistaxis, nasal congestion, rhinorrhea, cough, pharyngeal discomfort, sneezing, nasal dryness) and systemic reactions (e.g., rash, pruritus, facial/eyelid swelling, dyspnea, chest tightness, fever, chills). Severity graded as mild, moderate, or severe.

Change in Global Cognition: MMSE Score

Change from baseline in Mini-Mental State Examination (MMSE) total score. Range: 0-30, with higher scores indicating better cognitive function.

Change in Global Cognition: MoCA Score

Change from baseline in Montreal Cognitive Assessment (MoCA) Basic Version total score. Range: 0-30, with higher scores indicating better cognitive function.

Change in Language Function: BNT Score

Change from baseline in Boston Naming Test (BNT) total score, measuring confrontation naming ability.

Unabbreviated Scale Title: Boston Naming Test (BNT)

Scale Range: Minimum = 0, Maximum = 60

Interpretation: Higher scores indicate better language function; an increase (positive change) from baseline indicates improvement.

Change in Language Function: Semantic Fluency Test

Change from baseline in the number of animals named per minute on the Semantic Fluency Test, measuring verbal fluency and lexical access.

Unabbreviated Scale Title: Semantic Fluency Test (Animal Naming)

Scale Range: Minimum = 0, Maximum = no fixed upper limit (typical range in healthy adults: 12-25; in FTD patients: 0-15)

*Note: The test is scored as the number of unique, correct animal names produced within 60 seconds. While theoretically open-ended, practical scores rarely exceed 30-40.*

Interpretation: Higher scores indicate better verbal fluency and language function; an increase (positive change) from baseline indicates improvement.

Change in Neuropsychiatric Symptoms: NPI Score

Change from baseline in Neuropsychiatric Inventory (NPI) total score, assessing behavioral and psychiatric symptoms in dementia.

Unabbreviated Scale Title: Neuropsychiatric Inventory (NPI)

Scale Range: Minimum = 0, Maximum = 144

Note: The NPI assesses 12 domains (e.g., delusions, hallucinations, agitation, depression, anxiety, apathy, disinhibition, irritability, motor disturbances, sleep disturbances, appetite changes, and aberrant motor behavior). Each domain is scored as frequency (1-4) × severity (1-3), for a maximum of 12 per domain.

Interpretation: Lower scores indicate fewer or less severe neuropsychiatric symptoms; a decrease (negative change) from baseline indicates improvement.

Change in Neuropsychiatric Symptoms: FBI Score

Change from baseline in Frontal Behavior Inventory (FBI) total score, measuring behavioral symptoms associated with frontotemporal dysfunction.

Unabbreviated Scale Title: Frontal Behavior Inventory (FBI)

Scale Range: Minimum = 0, Maximum = 72

*Note: The FBI assesses 24 items (each scored 0-3), covering negative symptoms (e.g., apathy, indifference, loss of insight) and positive/disinhibited symptoms (e.g., impulsivity, perseveration, irritability, poor judgment).*

Interpretation: Lower scores indicate fewer or less severe frontal behavioral symptoms; a decrease (negative change) from baseline indicates improvement.

Change in Executive Function: FAB Score

Change from baseline in Frontal Assessment Battery (FAB) total score, assessing executive functions including conceptualization, mental flexibility, motor programming, sensitivity to interference, inhibitory control, and environmental autonomy.

Unabbreviated Scale Title: Frontal Assessment Battery (FAB)

Scale Range: Minimum = 0, Maximum = 18

Note: The FAB consists of 6 subtests, each scored from 0 to 3.

Interpretation: Higher scores indicate better executive function; an increase (positive change) from baseline indicates improvement.

Change in Daily Function and Behavior: ADL Score

Change from baseline in Activities of Daily Living (ADL) scale total score, measuring the participant's ability to perform daily living activities.

Unabbreviated Scale Title: Barthel Index of Activities of Daily Living (or specify the actual scale used, e.g., Katz Index of Independence in Activities of Daily Living, Lawton Instrumental Activities of Daily Living Scale)

Scale Range (Barthel Index): Minimum = 0, Maximum = 100

Note: The Barthel Index assesses 10 items (e.g., feeding, bathing, grooming, dressing, bowel and bladder control, toilet use, transfers, mobility, stair climbing). Alternative ADL scales may have different ranges (e.g., Katz Index: 0-6).

Interpretation: Lower scores indicate worse functional status (greater dependence); higher scores indicate better functional status (greater independence). Please confirm - the provided description states "Lower scores indicate better functional status," which is atypical for most ADL scales. Usually, higher scores = better fun

Change in Brain Structure: Regional Brain Volume

Change from baseline in regional brain volume, assessed by structural magnetic resonance imaging (MRI), to evaluate the effect of intranasal exosome treatment on brain structure in FTD patients.

Units of Measure: Cubic millimeters (mm³) or percentage change from baseline in specific regions of interest (e.g., frontal lobe, temporal lobe, hippocampus)

Interpretation: Specific regional volume changes will be analyzed exploratory. Direction of improvement is not predefined for this exploratory outcome.

Change in Brain Function: Resting-State Functional Connectivity

Change from baseline in resting-state functional connectivity, assessed by functional magnetic resonance imaging (fMRI), to evaluate the effect of intranasal exosome treatment on brain function in FTD patients.

Units of Measure: Correlation coefficient (z-scored or Fisher-transformed correlation values between predefined brain networks or regions of interest)

Interpretation: Changes in functional connectivity will be analyzed exploratory. Direction of improvement is not predefined for this exploratory outcome.

Change in Plasma Biomarker: Neurofilament Light Chain (NfL)

Exploratory outcome: Change from baseline in plasma levels of neurofilament light chain (NfL), a biomarker of axonal injury associated with frontotemporal dementia pathophysiology.

Units of Measure: Picograms per milliliter (pg/mL)

Interpretation: Higher levels indicate greater axonal injury; a decrease (negative change) from baseline may suggest improvement (reduced neuronal damage). This is an exploratory outcome.

Change in Plasma Biomarker: Tau Proteins

Exploratory outcome: Change from baseline in plasma levels of tau proteins (e.g., total tau, phosphorylated tau), biomarkers associated with frontotemporal dementia pathophysiology.

Units of Measure: Picograms per milliliter (pg/mL) - please confirm based on assay used

Interpretation: Higher levels may indicate greater neurodegeneration; a decrease (negative change) from baseline may suggest improvement. This is an exploratory outcome.