This is a multicenter, randomized, double-blind, placebo-controlled, dose-escalation trial. The goal of this clinical trial is to evaluate the safety and preliminary efficacy of nasal drop exosomes derived from human umbilical cord blood mesenchymal stem cells (hUC-MSC-sEV-001) in amyotrophic lateral sclerosis.
This is a multicenter, randomized, double-blind, placebo-controlled, dose-escalation trial. The study will consist of two parts: Part 1 will be a dose-escalation study, and Part 2 will be an expanded safety study based on the findings from Part 1. A traditional 3+3 dose-escalation design will be implemented in Part 1. Cohort 1 will receive low-dose; Cohort 2 will receive middle-dose; and Cohort 3 will receive high-dose. (Cohort 1 to Cohort 3 will receive a dose of 1 mL per nostril, administered once daily, twice a week, for a total of two weeks.) If no dose-limiting toxicities (DLTs) are observed for 2 weeks after the administration of the first nasal drop, a new cohort will be enrolled at the next planned dose level. If DLTs are observed in one participant in the cohort, an additional three participants will be treated at the same dose level. Dose escalation will be stopped if DLTs are observed in more than 33% of the participants. In Part 2, 20 subjects will be randomized in a 1:1 ratio \[exosome (n=10) or exosome placebo (n=10)\]. The dose level will be determined by the primary researcher based on the findings from Part 1.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
38
Exosomes derived from human umbilical cord blood mesenchymal stem cells for nasal drop (administered once daily, twice a week, for a total of two weeks, based on the recommended dose during the dose-escalation phase).
Xuanwu Hospital ,Capital Medical University
Beijing, Beijing Municipality, China
RECRUITINGNumber of participants who experienced dose-limiting Toxicities (DLTs)
DLTs related to hUC-MSC-sEV-001 include adverse events of grade 3 or higher (including significant clinical laboratory findings) that are possibly, likely, or definitely related to the study drug, accompanied by clinical symptoms and requiring medical treatment within 14 days of administration. Adverse events are graded according to the Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE 5.0).
Time frame: 24 hours, 4±1 Weeks
Incidence of severe adverse events
The proportion of patients who experienced severe adverse events.
Time frame: 4±1 Weeks
Change from baseline in ALS functional rating scale - revised
The ALSFRS-R is rating scale (ratings 0 = can't do, to 4 = normal ability) used to determine participants' assessment of their capability and independence in 12 functional activities. This is a validated scale, both in person and by phone, which provides a total score from four sub-scores which assess speech and swallowing (bulbar function), use of upper extremities (cervical function), gait and turning in bed (lumbar function), and breathing (respiratory function). Total scores range from 0 (most impaired) to 48 (normal ability).
Time frame: 4±1 Weeks, 12±1 Weeks, 24±1 Weeks
Change from baseline in forced vital capacity to predicted value ratio (FVC% pred)
Spirometry is a physiological test that measures how an individual inhales or exhales volumes of air as a function of time. The primary signal measured in spirometry may be volume or flow. The forced vital capacity (FVC) is the maximal volume of air exhaled with maximally forced effort from a maximal inspiration.
Time frame: 4±1 Weeks, 24±1 Weeks
Time to event (death, tracheostomy, and permanent assisted mechanical ventilation)
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The number of time-to-event outcomes.
Time frame: up to 24 Weeks
Change from baseline in the Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40).
ALSAQ-40 score ranges from 0 to 160 points, and higher scores indicate better quality of life.
Time frame: 4±1 Weeks, 12±1 Weeks, 24±1 Weeks
Change from baseline in the Edinburgh Cognitive and Behavioral ALS Screen (ECAS).
ECAS determine cognitive and behavioral changes of patients suffering from Amyotrophic Lateral Sclerosis. With ECAS, ALS-specific (fluency, executive functions and social cognition, language; minimum score = 0, maximum score = 100) and ALS-nonspecific (memory, visuospatial functions; minimum score = 0, maximum score = 36) functions can be analyzed to enable the distinction from other diseases with cognitive and behavioral impairments.
Time frame: 12±1 Weeks, 24±1 Weeks
Change from baseline in the Neurophysiological Index (NI) and Compound Muscle Action Potential (CMAP) score.
The NI is derived from the CMAP, the DML and the F-wave frequency (CMAP amplitude/DML) x F frequency %), representing aspects of the effects of denervation and reinnervation, of degeneration of the terminal part of the motor axons, and of the excitability of anterior horn cells. The negative amplitudes of the CMAP for motor nerve conduction in the median and ulnar nerves in the upper extremities as well as the peroneal and tibial nerves in the lower extremities of ALS patients were recorded (median nerve-wrist, ulnar-wrist, peroneal-ankle, tibial-ankle). These nerves were scored based on the decrease in the amplitudes of each nerve CMAP- 0 (CMAP\> =\[X-2s\]), 1 (50% \[X-2s\] \< CMAP \< \[X-2s\]), 2 (30% \[X-2s\] \< CMAP \< 50% \[X-2s\]), 3 (CMAP \< =30% \[X-2s\]), respectively. The values of X and S for different nerves and different patient age groups, which were applied in the electrophysiology examination room.
Time frame: 12±1 weeks
Change from baseline in the Rasch Overall ALS Disability Scale (ROADS).
ROADS score ranges from 0 to 56 points, and higher scores indicate better basic daily function.
Time frame: 4±1 Weeks, 12±1 Weeks, 24±1 Weeks
Change from baseline in the Medical Research Council (MRC) Scale.
MRC ranges from 0 to V grades, and higher grades indicate higher muscle strength.
Time frame: 4±1 Weeks, 12±1 Weeks, 24±1 Weeks
Change from baseline in the the Lower Motor Neuro Scale(LMNS).
LMNS was calculated using the score proposed by Devine et al. that assign a separate LMN score for each limb, ranging from 0 (no involvement) to 3 (significant, severe involvement), based on the Medical Research Council and muscle wasting.
Time frame: 4±1 Weeks, 12±1 Weeks, 24±1 Weeks