Multiple System Atrophy - Cerebellar Subtype (MSA-C)
Conditions
Keywords
Multiple system atrophy
Brief summary
This is a single-center, prospective, randomized, open-label, blinded outcome assessment (PROBE) study. At the end of the PROBE study, patients who have completed the study may opt to enter the open-label extension (OLE) study. The objective of the study is to evaluate the safety, tolerability and potential preliminary efficacy of ALT001 in the treatment of patients with multiple system atrophy-cerebellar type (MSA-C).
Detailed description
Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by a blend of autonomic dysfunction, Parkinson's syndrome, and cerebellar syndrome. The incidence of MSA ranges from 1.9 to 4.9 per 100,000 individuals, with an average age of onset of 56.2 years. Among individuals aged 50 years and older, the prevalence stands at 3.0 per 100,000. The mean age of MSA onset is 56.2 years, and the median survival ranges from 6.2 to 7.5 years. The MSA-C subtype is associated with a poorer prognosis due to its predominant involvement of the cerebellum and brainstem. In patients with MSA-C, gait and balance disturbances manifest early, leading to nearly 50% of patients requiring a walking aid or physical assistance for ambulation within three years of motor symptom onset. Within five years, 60% of patients become wheelchair-dependent, and after six to eight years, most are completely bedridden, severely impacting their quality of life. Treating MSA-C, a rare neurodegenerative condition, remains a significant challenge. Current symptomatic and supportive therapies fall short of meeting the treatment requirements of MSA-C patients. Furthermore, potential adverse effects and disease progression factors restrict the use of certain drugs, highlighting the critical need for the development of disease-modifying or neuroprotective agents to decelerate disease advancement. "ALT001, a nerve repair protein created by Darwin Origin (Hubei) Biopharmaceutical Co.LTD, is derived from cellular exosomes, a set of specific microenvironmental protein polymers secreted by stem cells under emergency conditions. It boasts selective assembly, targeted delivery, highly efficient tissue repair, exceptional safety, chemical stability, and convenient storage. Previous basic research has indicated ALT001's potential for promoting endogenous neural tissue repair, exhibiting significant neuroprotective and neurorestorative effects in animal models. Therefore, building upon the ongoing study in patients with the MSA-parkinsonian subtype, this project further initiates a single-center, prospective, randomized, open-label, blinded endpoint evaluation (PROBE) study, followed by an open-label extension (OLE) study, specifically targeting patients with the MSA-C subtype. The objectives are to evaluate the safety, tolerability, and potential preliminary efficacy of ALT001 in treating MSA-C patients. This study aims to recruit 20 MSA-C subtype patients aged between 30 and 75 years. The visit content at each stage of this study includes vital signs, neurological examination, laboratory tests (such as routine blood test, blood biochemical examination, coagulation test, etc.), imaging examinations (such as MRI, bladder ultrasound), neurological assessments (such as unified multiple system atrophy rating scale \[UMSARS\], composite autonomic symptom score \[COMPASS\], scale for the assessment and rating of ataxia\[SARA\], quick MSA quality of life questionnaire \[MSA-QoL\], mini-mental state examination \[MMSE\]), and cerebrospinal fluid collection. Different stages of the study focus on monitoring patients' concomitant medications, adverse events, and serious adverse events. Detailed follow-up is conducted at the end of each treatment period, with face-to-face visits at specific time points. Additionally, researchers are required to promptly report and manage events when patients develop new neurological symptoms or suspicious events. The follow-up content of the study includes treatment and follow-up assessments at multiple stages. Initially, comprehensive physical examinations, laboratory tests (including blood, urine tests, etc.), multidimensional scoring assessments (such as UMSARS, COMPASS, SARA, MSA-QoL), and brain examinations through imaging techniques such as 3T MRI are performed on subjects at baseline. Subsequently, subjects enter three treatment periods and follow-up stages lasting a total of 90 days, with daily monitoring of vital signs, cerebrospinal fluid collection, laboratory tests, and adverse event documentation in each stage. Follow-up during the Open-Label Extension (OLE) phase (from day 90 to day 165 post-randomization) continues monitoring of vital signs, laboratory tests, and adverse event recording. At the follow-up visits on day 90, day 180, and day 360, comprehensive physical examinations, laboratory tests, gait analysis, bladder ultrasound, MRI, and repeat UMSARS, COMPASS, SARA, MSA-QoL scoring are conducted. Additionally, if patients experience new neurological symptoms or suspicious events, additional visits will be carried out, and researchers are required to submit and interpret relevant data within 72 hours of the event occurrence.The protocol of this study has been approved by the Ethics Committee of Beijing Tiantan Hospital. All participants will provide written informed consents before entering the study.
Interventions
DRUGALT001
Intrathecal administration combined with intravenous administration of ALT001 was given to each MSA patient in the intervention group, with intrathecal administration on days 1, 31 and 61 and intravenous administration on days 2 to 14, 32 to 44±3 and 62 to 74±5, and treatment was given once a day. intrathecal administration: 8 mL sodium chloride injection + ALT001 (130 μg/branch) for intrathecal administration, which was completed in about 5 minutes; intravenous administration: ALT001 (130 μg/branch) was dissolved in 100 ml sodium chloride injection, which was completed in about 30-40 minutes. After completion of the above treatments and 90±7 days of follow-up, all subjects entered the OLE study phase. During this period, all participants were given the option of continuing to receive 3 phases (on Days 91 to 104±7, Days 121 to 134±7, and Days 151 to 164±7) of intravenous ALT001 administration (14 consecutive days of ALT001 130 μg qd i.v. in each phase).
Sponsors
yilong Wang
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
30 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* 1\. Age between 30 and 75 years inclusive, either sex; * 2\. Clinically established or clinically probable MSA-C as defined by the 2022 MDS diagnostic criteria for multiple system atrophy; * 3\. Duration of MSA-C-related motor symptoms, including ataxia, no longer than 5 years; * 4\. Score ≤ 3 on Item 14 of the Unified Multiple System Atrophy Rating Scale (UMSARS) Part II (motor examination); * 5\. Estimated life expectancy ≥ 1 year as assessed by the investigator; * 6\. Voluntary participation in this study and provision of written informed consent
Exclusion criteria
* 1\. Presence of other diseases that may cause ataxia at screening (e.g., infectious diseases, immune-mediated diseases, tumors, paraneoplastic conditions, hereditary disorders, trauma, nutritional deficiencies, toxic exposure, or other neurodegenerative diseases); * 2\. Dementia indicated by the Mini-Mental State Examination (MMSE) at enrollment (score ≤17 for illiterate individuals, ≤20 for primary school education, or ≤24 for junior high school or above) or a prior definitive diagnosis of dementia; * 3\. Evidence of other central nervous system pathologies on brain MRI at screening suggesting a diagnosis of neurodegenerative diseases other than MSA; or other significant pathological findings on brain MRI at screening, including but not limited to: cerebral hemorrhage, acute cerebral infarction, aneurysm, vascular malformation, infectious lesions, brain tumors, or other space-occupying lesions (meningiomas or arachnoid cysts with a maximum diameter \<1 cm do not require exclusion); * 4\. Presence of immune-mediated diseases that are inadequately controlled or require treatment with biologic agents; * 5\. Known history of allergies to biologic agents, such as proteins or cell-based products; * 6\. Receipt of any vaccination within the past 1 month; * 7\. Patients with a prior definitive diagnosis of malignancy or those currently receiving anti-tumor drug therapy; * 8\. Patients with a prior definitive diagnosis of epilepsy or those currently taking anti-epileptic drugs; * 9\. Presence of lumbar spine diseases or deformities, or other contraindications to lumbar puncture; * 10\. Coagulation abnormalities at enrollment (e.g., platelet count \<100 × 10⁹/L; prothrombin time \[PT\] \>3 seconds), a prior diagnosis of coagulation disorders such as hemophilia, or current use of two or more antiplatelet agents; * 11\. Contraindications to MRI (e.g., claustrophobia, implanted cardiac pacemaker, or ferromagnetic metal); * 12\. Concurrent severe hepatic insufficiency, renal insufficiency, or severe cardiac insufficiency (severe hepatic insufficiency defined as ALT ≥1.5 times the upper limit of normal or AST ≥1.5 times the upper limit of normal; severe renal insufficiency defined as serum creatinine \[CRE\] ≥1.5 times the upper limit of normal or estimated glomerular filtration rate \[eGFR\] \<40 mL/min/1.73 m²; severe cardiac insufficiency defined as NYHA class 3-4), or any significant abnormalities on physical examination, vital signs, laboratory tests, or electrocardiogram that, in the investigator's opinion, require further examination or treatment, or may interfere with the study procedures or safety; * 13\. Active hepatitis B infection (positive for hepatitis B surface antigen, recurrent/persistent ALT elevation, positive serum HBV DNA, or serum HBV DNA \>2 × 10⁵ IU/mL); * 14\. Positive for hepatitis C virus antibody or a history of positive test results; * 15\. Positive for HIV or a history of positive test results; * 16\. Patients with a history of alcohol or substance abuse, or alcohol or substance dependence within the past 2 years; * 17\. Diagnosis of psychiatric disorders, severe anxiety, severe depression, or obvious suicidal ideation according to DSM-V diagnostic criteria; * 18\. Patients who are pregnant, lactating, or have the potential to become pregnant, or those planning a pregnancy; * 19\. Current participation in other interventional trials or use of other investigational biologic agents, drugs, or devices, or use of other investigational drugs within the past 1 month or within 5 half-lives of the drug; * 20\. Inability to comply with follow-up assessments due to other reasons; * 21\. Patients deemed by the investigator to be unsuitable for participation in this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The incidence of investigator-reported adverse events (AEs) and serious adverse events (SAEs) | Day 90±7 after randomization | The incidence of investigator-reported adverse events (AEs) and serious adverse events (SAEs) |
| The incidence of changes in clinical laboratory test parameters, changes in vital signs, neurological examination abnormalities and ECG abnormalities | Day 90±7 after randomization | Laboratory tests include: routine blood test, coagulation test, blood biochemical examination, urinalysis (note that abnormal changes in laboratory test results may need to be reviewed to further determine and assess their relevance to the study). Vital signs include: abnormal body temperature (≥38℃ or ≤35℃), blood pressure (systolic blood pressure ≥180mmHg or \<90mmHg), respiration (\>24 beats/min and other rhythm abnormalities), and heart rate (\>100 beats/min or \<60 beats/min). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in the unified multiple system atrophy rating scale (UMSARS) part scores, sum of part 1 and 2 scores | Day 15, 45±3, 75±5, 90±7, 180±14, and 360±14 after randomization | The Unified Multiple System Atrophy Rating Scale (UMSARS) comprises four sections. Part I is the "Historical Review," consisting of 12 items that evaluate impairment in activities of daily living as reported by the patient. Each item is scored from a minimum of 0 points (normal) to a maximum of 4 points (severe disability), resulting in a total score range for this section of 0 to 48. Part II is the "Motor Examination," which assesses motor impairment based on clinical examination. It contains 14 items, each also scored from a minimum of 0 (normal) to a maximum of 4 (severe disability), yielding a total score range of 0 to 56. Part III is the "Autonomic Examination." Part IV is the "Global Disability Scale," a single-item scale used to assess the patient's overall level of disability, with scores ranging from a minimum of 1 (completely independent) to a maximum of 5 (totally bedridden). |
| Changes in the scale for the assessment and rating of ataxia (SARA) | Day 15, 45±3, 75±5, 90±7, 180±14, and 360±14 after randomization | The Scale for the Assessment and Rating of Ataxia (SARA) is a semi-quantitative clinical instrument designed to quantify the severity of cerebellar ataxia, with total scores ranging from 0 (no ataxia) to 40 (most severe ataxia). The scale comprises eight items that reflect progressively increasing functional impairment, assessing gait (0-8 points), stance (0-6 points), sitting (0-4 points), speech disturbance (0-6 points), finger chase (0-4 points), nose-finger test (0-4 points), fast alternating hand movements (0-4 points), and heel-knee-shin slide (0-4 points). For the upper and lower limb items, both sides are assessed separately, and the mean score is calculated for inclusion in the total score. SARA demonstrates good reliability and validity and is commonly used in clinical practice to evaluate the severity of ataxia and monitor disease progression. |
| Changes in the composite autonomic symptom score (COMPASS) scores | Day 15, 45±3, 75±5, 90±7, 180±14, and 360±14 after randomization | The Composite Autonomic Symptom Score (COMPASS) is a revised version of the 169-item Autonomic Symptom Profile assessing 11 domains of autonomic function, to the 31-item COMPASS, now assessing six domains: orthostatic hypotension (maximum score 10), vasomotor (maximum score 6), secretomotor (maximum score 7), gastrointestinal (maximum score 28), bladder (maximum score 9), and pupillomotor functions (maximum score 15). Scores from each component are recorded and a weighted total score is calculated. Higher scores on this scale indicate more severe clinical symptoms related to autonomic dysfunction. It is a validated, easy-to-use self-assessment instrument designed for clinical autonomic research and practice. |
| Changes in the incidence of orthostatic hypotension | Day 15, 45±3, 75±5, 90±7, 180±14, and 360±14 after randomization | Changes in the incidence of orthostatic hypotension in patients on days 15, 45±3, 75±5, 90±7, 180±14, and 360±14 after randomization as measured by recumbent-upright blood pressure monitoring/24-hour ambulatory blood pressure monitoring/head-upright tilt test. |
| Changes in quick MSA quality of life questionnaire (MSA-QoL) | Day 90±7, 180±14, and 360±14 after randomization | The Quick MSA Quality of Life questionnaire (Quick MSA-QoL) is a concise, patient-reported outcome measure derived and validated from the original 40-item MSA-QoL scale. It is designed to reduce the completion burden for patients with multiple system atrophy (MSA) while enhancing data quality. This unidimensional scale comprises 15 items covering core domains, including motor function, non-motor symptoms, and emotional/social functioning. Each item offers five response options: no problem, mild problem, moderate problem, severe problem, and extreme problem. The total score of the scale ranges from 0 (minimum) to 60 (maximum). A higher total score indicates greater impairment in health-related quality of life. |
| Changes in immunological indices (lymphocyte subpopulation) | Day 15, 30±3, 45±3, 60±5, 75±5, 105±7, 135±7, and 165±7 after randomization | Changes in immunological indices (lymphocyte subpopulation) on days 15, 30±3, 45±3, 60±5, 75±5, 105±7, 135±7, and 165±7 after randomization. Lymphocyte subsets include CD3+%, CD3+CD4+%, and CD3+CD8+%, among others. |
| Variation of three-dimensional gait analysis parameters under multitasking | Day 90±7, 180±14, and 360±14 after randomization | Changes in three-dimensional gait analysis parameters under multitasking in patients on day 90±7, 180±14, and 360±14 after randomization. The main content of three-dimensional gait analysis is gait speed (m/s). The gait speed of participants was measured using a three-dimensional gait analyzer at various follow-up time points. |
Countries
China
Contacts
CONTACTWeiqi Chen
CONTACTYahui Zhu
PRINCIPAL_INVESTIGATORYilong Wang
Beijing Tiantan Hospital, Capital Medical University, Beijing, China
PRINCIPAL_INVESTIGATORTao Feng
Beijing Tiantan Hospital, Capital Medical University, Beijing, China
Outcome results
None listed