Efficacy and Safety of Butylphthalide in the Treatment of Multiple System Atrophy (ENMSA)

Efficacy and Safety of Butylphthalide in the Treatment of Multiple System Atrophy（ENMSA）: A Multicenter, Randomised, Double-blinded, Placebo-controlled Trial

The present study aims to conduct a randomized controlled trial to evaluate the efficacy and safety of 3-n-Butylphthalide (NBP) in improving symptoms in patients with Multiple System Atrophy (MSA). The main questions it aims to answer are:

1. To evaluate whether NBP soft capsules, compared with placebo, alleviates the major clinical symptoms in patients with MSA.
2. Whether NBP application is safe to treat patients with MSA. In this trial, NBP will be compared with placebo (similar soft capsule without effective component of NBP) to demonstrate if NBP can alleviates MSA symptoms

Participants of ENMSA will:

1. Take NBP or Placebo three times a day for 6 months
2. Be served with clinical visit four times for follow-up and tests
3. Keep a diary of drug application and symptom changes

Study Overview

• Status: Not yet recruiting
• Conditions: Multiple System Atrophy
• Intervention / Treatment: Drug: 3-N-butylphthalide

• Study Type: Interventional
• Enrollment (Estimated): 150
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Jiali Pu, MD; Phone Number: +86 13989468062; Email: jialipu@zju.edu.cn

Study Locations

• China
  • Beijing, China
    • Affiliated Beijing Chaoyang Hospital of Capital Medical University
    • Contact: Chaodong Wang, MD
  • Guangxi
    • Nanning, Guangxi, China
      • The First Affiliated Hospital of Guangxi Medical University
      • Contact: Yousheng Xiao, MD
  • Zhejiang
    • Huzhou, Zhejiang, China
      • Huzhou Central Hospital
      • Contact: Ying Tan, MD
    • Jiaxing, Zhejiang, China
      • The Second Hospital of Jiaxing
      • Contact: Yanping Wang, MD
    • Ningbo, Zhejiang, China
      • Ningbo Second Hospital
      • Contact: Weinv Fan, MD
    • Taizhou, Zhejiang, China
      • Taizhou Hospital of Zhejiang Province
      • Contact: Suzhi Liu, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Meet a diagnosis for "clinically established MSA" according to the Movement Disorder Society (MDS) diagnostic criteria for multiple system atrophy revised in 2022, as assessed by a neurologist;
2. Patients aged between 30 and 80 years, within 5 years since the initial diagnosis of MSA, and with a life expectancy greater than 3 years;
3. Patients are not entirely dependent on a wheelchair or bedridden and are capable of cooperating with necessary assessments and examinations, including scale evaluations, magnetic resonance imaging (MRI), and PET-CT scans;
4. Patients must have been on a stable medication regimen (for a duration of at least one month) prior to the trial, which may include drugs for anti-Parkinson, anti-autonomic dysfunction, anti-anxiety/depression agents, and sleep aids

Exclusion Criteria:

1. Patients with a diagnosis confirmed by PET-CT or revised during follow-up to other diseases, such as idiopathic Parkinson's disease, progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies, or secondary parkinsonian syndromes.
2. Patients with a history of other major neurological disorders, including ischemic stroke, intracranial hemorrhage, epilepsy, encephalitis, or central nervous system demyelinating diseases;
3. Patients with a history of psychiatric disorders that may involve psychotic symptoms, such as schizophrenia, major depressive disorder, or dissociative -conversion disorders.
4. Patients with severe hepatic or renal impairment (alanine aminotransferase [ALT] or aspartate aminotransferase [AST] levels >2 xULN; Estimated creatinine clearance <30 mL/min;
5. Patients with a heamorrhage event within the past 3 months or a high bleeding risk;
6. Patients with a history of significant craniocerebral trauma or surgery;
7. Patients with severe cognitive impairment (Mini-Mental State Examination [MMSE] score <24);
8. Patients with a history of malignancy or autoimmune diseases;
9. Patients with dysphagia due to severe medullary dysfunction or esophageal disorders, or those unable to comply with medication administration for other reasons;
10. Patients who are pregnant, lactating, or planning a pregnancy within the next year.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: NBP treatment group; Participants in the NBP treatment group will receive NBP soft capsules (dosage form: 100 mg/capsule), two capsules per dose, three times daily (total daily dose of 600 mg). The whole treatment duration is six months, during which all patients will maintain their original medication unchanged.	Drug: 3-N-butylphthalide; 3-n-Butylphthalide (NBP), also known as celery seed oil extract, is a lipid-soluble compound isolated from celery seeds. NBP was approved by the China Food and Drug Administration (CFDA) in 2002 for the treatment of acute ischemic stroke. NBP has demonstrated significant improvement in motor deficits and exhibited neuroprotective effects in animal models of various neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). For NBP used in ENMSA trial, its dosage form is soft capsule, containing 100mg NBP per capsule. Application frequency will be three times a day, 2 capsules each time.
Placebo Comparator: Placebo control group; Participants in the Placebo control group will receive two Placebo soft capsules each time, three times daily (total daily dose of 600 mg). The whole application duration is six months, during which all patients will maintain their original medication unchanged.	Drug: 3-N-butylphthalide; 3-n-Butylphthalide (NBP), also known as celery seed oil extract, is a lipid-soluble compound isolated from celery seeds. NBP was approved by the China Food and Drug Administration (CFDA) in 2002 for the treatment of acute ischemic stroke. NBP has demonstrated significant improvement in motor deficits and exhibited neuroprotective effects in animal models of various neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). For NBP used in ENMSA trial, its dosage form is soft capsule, containing 100mg NBP per capsule. Application frequency will be three times a day, 2 capsules each time.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Main symptom control of MSA	Use sum score Movement Disorder Society-Unified Multiple System Atrophy Rating Scale(MDS-UMSARS; score range: 0-104; higher score means worse symptoms of MSA) part I+II to evaluate the effectiveness of main symptom control of MSA	Baseline; 1st, 3rd, 6th, 12th month after intervention initiation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall symptom control of MSA	Use sub score of Movement Disorder Society-Unified Multiple System Atrophy Rating Scale(MDS-UMSARS; score range: 0-104; higher score means worse symptoms of MSA) to evaluate the overall effectiveness of main symptom control of MSA	Baseline; 1st, 3rd, 6th, 12th month after intervention initiation
Autonomic function of MSA	Use Composite Autonomic Symptom Score 31 (COMPASS-31; score range: 0-100; higher score means worse autonomic symptoms of MSA) scale to evaluate autonomic symptoms of MSA	Baseline; 6th, 12th month after intervention initiation
Depressive symptom of MSA	Use Hamilton Depression Scale (HAMD; score range: 0-52; higher score means worse depressive symptoms of MSA) scale to evaluate depressive symptom of MSA	Baseline; 6th, 12th month after intervention initiation
Cognitive function of MSA	Use Mini-mental State Examination scale (MMSE; score range: 0-30; higher score means better cognitive function of MSA patients) to evaluate cognitive symptoms of MSA	Baseline; 6th, 12th month after intervention initiation
Life quality of MSA	Use Multiple System Atrophy-Quality of Life (MSA-QoL; score range: 0-160; higher score means worse life quality of MSA) scale to evaluate life quality of MSA patients	Baseline; 6th, 12th month after intervention initiation
Safety of Butylphthalide application in MSA patients	Monitoring the incidence of AE/SAE and MSA specific mortality rate during the trial	through study completion, an average of 1 year
Anxiety symptoms of MSA	Use Hamilton Anxiety scale (HAMA; score range: 0-56; higher score means worse anxiety symptoms of MSA) to evaluate anxiety symptoms of MSA	Baseline; 6th, 12th month after intervention initiation
Advanced Cognitive function of MSA	Use Montreal Cognitive Assessment (MoCA; score range: 0-30; higher score means better cognitive function of MSA) to evaluate cognitive symptoms of MSA	Baseline; 6th, 12th month after intervention initiation

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
α-Syn aggregates	Use blood sample collected from participents to evalute the α-Syn aggregates in blood	Baseline; 6th month after intervention initiation
Plasma Neuro-filament light chain	Use plasma sample collected from participents to evalute the NfL concentration in MSA patients	Baseline; 6th month after intervention initiation

Collaborators and Investigators

• Sponsor: Second Affiliated Hospital, School of Medicine, Zhejiang University
• Collaborators: Beijing Chao Yang Hospital; Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University; Ningbo No.2 Hospital; The Second Affiliated Hospital of Jiaxing University; First Affiliated Hospital of Guangxi Medical University; Huzhou Central Hospital
• Investigators: Principal Investigator: Jiali Pu, MD, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, China

Study record dates

Study Major Dates

• Study Start (Estimated): April 10, 2026
• Primary Completion (Estimated): April 10, 2027
• Study Completion (Estimated): October 10, 2027

Study Registration Dates

• First Submitted: March 26, 2026
• First Submitted That Met QC Criteria: April 2, 2026
• First Posted (Actual): April 9, 2026

Study Record Updates

• Last Update Posted (Actual): April 9, 2026
• Last Update Submitted That Met QC Criteria: April 2, 2026
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Keywords: multiple system atrophy; 3-n-butylphthalide
• Additional Relevant MeSH Terms: Synucleinopathies; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurodegenerative Diseases; Movement Disorders; Basal Ganglia Diseases; Primary Dysautonomias; Autonomic Nervous System Diseases; Multiple System Atrophy; 3-n-butylphthalide
• Other Study ID Numbers: 2025-1012

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Share IPD within 1 year after trail completion by public study protocol, CRF,Email Contact, etc.
• IPD Sharing Time Frame: 1 year after trial completion
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No