Overview
The Ambroxol to Slow Progression in Parkinson Disease trial (NCT05778617) is a landmark Phase IIIa multi-centre randomised placebo-controlled trial evaluating ambroxol as a disease-modifying treatment for Parkinson's disease. Sponsored by University College London (UCL), this trial represents the most advanced clinical effort to test whether enhancing glucocerebrosidase (GCase) activity can slow or halt disease progression in Parkinson's disease patients[@ambroxol2022][@gba2021].
This trial is distinct from the earlier Phase 2/3 ASPro-PD trial (NCT05827068) conducted by the University of Manchester. While both trials evaluate ambroxol for PD, this UCL-sponsored Phase IIIa trial focuses specifically on disease progression endpoints in a larger population and uses a longer treatment duration to assess disease modification.
Trial Details
| Attribute | Value |
|-----------|-------|
| NCT Number | NCT05778617 |
| Official Title | Ambroxol to Slow Progression in Parkinson Disease: A Phase IIIa Multi-centre Randomised Placebo-controlled Trial |
| Brief Title | Ambroxol to Slow Progression in Parkinson Disease |
| Phase | Phase IIIa |
| Status | Recruiting |
| Study Type | Interventional |
| Design | Randomised, Double-blind, Placebo-controlled |
| Allocation | Parallel Group |
| Masking | Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) |
| Enrollment | 330 participants (estimated) |
| Sponsor | University College London |
| Collaborator | Parkinson's UK |
| Conditions | Parkinson's Disease |
| Start Date | February 25, 2025 |
| Primary Completion | September 2029 |
| Completion | September 2029 |
| Duration | Approximately 4.5 years (104 weeks) |
| Last Update | May 1, 2025 |
Scientific Rationale
The GBA1-GCase Pathway in Parkinson's Disease
Mutations in the GBA1 gene (glucocerebrosidase) represent the most common genetic risk factor for Parkinson's disease. The GBA1 gene encodes glucocerebrosidase (GCase), a lysosomal enzyme essential for breaking down glucosylceramide into glucose and ceramide[@gba2021].
Key Epidemiological Findings:
- Heterozygous GBA1 mutations: Increase PD risk 5-20 fold depending on specific mutation
- Prevalence: 5-10% of all PD patients carry GBA1 mutations
- Age of onset: Typically 5-10 years earlier than idiopathic PD
- Clinical phenotype: More rapid progression, earlier cognitive impairment
The GCase-Alpha-Synuclein Bidirectional Relationship
Research has established a vicious cycle between GCase deficiency and alpha-synuclein aggregation[@gcase2023]:
Reduced GCase activity leads to glucosylceramide accumulation in neurons
Glucosylceramide directly promotes alpha-synuclein aggregation
Aggregated alpha-synuclein inhibits GCase trafficking and function
Inhibited GCase results in more glucosylceramide accumulationThis bidirectional relationship means that even in idiopathic Parkinson's disease (without GBA1 mutations), the GCase-alpha-synuclein interaction may contribute to disease pathogenesis. Enhancing GCase activity could therefore benefit a broad PD population, not just those with GBA1 mutations.
Drug Repurposing Rationale
Ambroxol represents an ideal candidate for drug repurposing:
- Clinical History: Over 50 years of clinical use as a mucolytic
- Safety Profile: Well-characterized safety at therapeutic doses
- CNS Penetration: Demonstrated ability to cross the blood-brain barrier
- GCase Enhancement: Acts as a pharmacological chaperone for GCase
- Generic Availability: Lower development costs
The drug repurposing approach accelerates clinical development by leveraging existing safety data from decades of clinical use for respiratory conditions.
Mechanism of Action
Pharmacological Chaperone Activity
Ambroxol (2-amino-3,5-dibromo-4-methoxybenzylamine) acts as a pharmacological chaperone for GCase through multiple mechanisms[@ambroxol2019]:
Enzyme Stabilization: Binds to GCase, stabilizing its structure
Folding Assistance: Helps proper folding of mutant GCase molecules in the ER
Lysosomal Trafficking: Facilitates transport through the secretory pathway
Activity Enhancement: Protects against degradation, increases lysosomal activity
Substrate Reduction: Enhanced GCase activity reduces glucosylceramide accumulationAdditional Neuroprotective Effects
Beyond GCase enhancement, ambroxol exhibits:
- Anti-inflammatory effects: Reduces microglial activation
- Antioxidant properties: Scavenges reactive oxygen species
- Alpha-synuclein modulation: Reduces aggregation and enhances clearance
- Lysosomal function: Improves overall lysosomal health
Pharmacokinetics
- Absorption: Rapid oral absorption, peak plasma at 1-3 hours
- Distribution: Wide tissue distribution including CNS
- Half-life: 10-12 hours supporting daily dosing
- Excretion: Primarily renal
Trial Design
Phase IIIa Multi-centre Design
The trial employs a rigorous double-blind, placebo-controlled design:
- Randomization: 1:1 ratio between ambroxol and placebo
- Treatment Duration: 104 weeks (2 years)
- Follow-up: Extended monitoring post-treatment
Primary Endpoints
Primary Efficacy:
- Change in MDS-UPDRS Parts I-III score from baseline to Week 104
- Time to clinically meaningful progression
Primary Safety:
- Adverse event incidence and severity
- Discontinuation rate
Secondary Endpoints
Clinical Outcomes
- Motor examination (MDS-UPDRS Part III)
- Functional status (MDS-UPDRS Part II)
- Non-motor symptoms (PDQ-39, MoCA)
- Hoehn & Yahr staging
Biomarker Endpoints
- GCase activity in peripheral blood mononuclear cells
- Glucosylceramide levels (plasma and CSF)
- Alpha-synuclein (CSF concentration and seeding activity)
- Neurofilament light chain (NfL)
Imaging Endpoints
- DAT PET (dopamine transporter binding)
- MRI brain volume measurements
Enrichment Strategy
The trial may employ biomarker-driven enrichment:
- GBA1 carriers: Direct targeting of the mechanism
- Idiopathic PD: Alpha-synuclein seed amplification assay positivity
- Rationale: Increases probability of detecting treatment effect
This enrichment strategy selects patients most likely to benefit from GCase enhancement.
Eligibility Criteria
Inclusion Requirements
Age: 30-80 years
PD diagnosis: UK Brain Bank criteria
Disease duration: 1-10 years
Hoehn & Yahr stage: 1-3 (inclusive)
Medication stability: Stable PD medication for 4+ weeks
Capacity: Able to provide informed consentExclusion Criteria
Atypical parkinsonism: Progressive supranuclear palsy, multiple system atrophy, etc.
Significant cognitive impairment: MMSE <24
Active psychiatric disease: Uncontrolled depression, psychosis
Severe medical conditions: Cardiac, hepatic, renal, or hematologic
Contraindications: MRI incompatibilities
Previous ambroxol: Prior participation in ambroxol PD trials
Pregnancy: Active pregnancy or breastfeedingStatistical Analysis
Sample Size and Power
With 330 participants:
- Power: 80% power to detect 25% slowing of progression
- Assumption: 18-point difference in MDS-UPDRS at 104 weeks
- Alpha: 0.05 (two-sided)
- Dropout rate: 15% adjustment
Analysis Populations
- Intention-to-treat (ITT): All randomized participants
- Per-protocol: Participants meeting eligibility criteria
- Biomarker-positive: Enrichment population analyses
Multiple Comparison Handling
- Primary analysis: Hochberg procedure
- Hierarchical testing: Family-wise error rate control
- Sensitivity analyses: Various imputation approaches
Clinical Centers
UK Recruitment Sites
| City | Site |
|------|------|
| Birmingham | University Hospitals Birmingham NHS Foundation Trust |
| Bristol | North Bristol NHS Trust |
| Cambridge | Cambridge University Hospitals NHS Foundation Trust |
| Edinburgh | NHS Lothian |
| London | UCL Queen Square Institute of Neurology |
Additional sites may be added during recruitment.
Clinical Significance
Disease Modification Potential
This Phase IIIa trial addresses the critical need for disease-modifying therapies in Parkinson's disease:
Longest Duration: 104-week treatment is the longest ambroxol PD trial to date
Largest Sample: 330 participants provides adequate power
Progression Focus: Directly measures disease progression
Regulatory Pathway: Phase IIIa design supports regulatory submissionIf Successful
Positive results would establish:
- First Disease-Modifying Therapy: GCase enhancement as a new therapeutic class
- Broad Applicability: Both GBA1-associated and idiopathic PD
- Regulatory Approval: Pathway to FDA/EMA approval
- Combination Potential: Could be combined with symptomatic therapies
Challenges
- Dose Optimization: CNS-active dose determination
- Biomarker Validation: Target engagement confirmation
- Patient Variability: Variable GCase response
- Long-term Safety: Unknown effects beyond 2 years
Competitive Landscape
GBA1-Targeting Therapies in Development
| Therapy | Company/Sponsor | Mechanism | Stage |
|---------|---------------|-----------|-------|
| Ambroxol (UCL) | University College London | Pharmacological chaperone | Phase III |
| Ambroxol (ASPro-PD) | University of Manchester | Pharmacological chaperone | Phase 2/3 |
| Venglustat | Sanofi | Substrate reduction | Phase 2 (stopped) |
| LTI-291 | Luc Therapeutics | GCase activator | Phase 1 |
| ABM-001 | Aprinoia | GCase modulator | Preclinical |
Advantages of This Trial
- Largest Scale: 330 participants vs. smaller trials
- Longest Duration: 104 weeks provides progression data
- Academic Sponsorship: UCL expertise in neurodegenerative disease
- UK Healthcare System: Single-payer system facilitates follow-up
Regulatory Pathway
Expected Milestones
| Milestone | Timeline | Notes |
|-----------|----------|--------|
| Recruitment Complete | 2027 | 330 participants |
| Primary Results | 2029 | Week 104 data |
| Publication | 2030 | Peer review |
| Regulatory Submission | 2030-2031 | FDA/EMA |
| Potential Approval | 2032 | If positive |
Accelerated Designations
- Fast Track: May be pursued based on early results
- Breakthrough Therapy: Under consideration
- Orphan Drug: Not applicable (too common)
Related Pages
- [Ambroxol ASPro-PD Trial (NCT05827068)](/clinical-trials/ambroxol-aspro-pd)
- [Parkinson's Disease](/diseases/parkinsons-disease)
- [GBA1 Gene](/genes/gba)
- [Glucocerebrosidase](/proteins/gba-protein)
- [Alpha-Synuclein](/proteins/alpha-synuclein)
- [Endosomal-Lysosomal Pathway](/mechanisms/endosomal-lysosomal-pathway)
- [Drug Repurposing for Neurodegeneration](/therapeutics/drug-repurposing-neurodegeneration)
- [Pharmacological Chaperones](/therapeutics/proteostasis-therapy)
External Links
- [ClinicalTrials.gov NCT05778617](https://clinicaltrials.gov/study/NCT05778617)
- [UCL Institute of Neurology](https://www.ucl.ac.uk/neuroscience/)
- [Parkinson's UK](https://www.parkinsons.org.uk/)
- [UCL PD Research Biobank](https://www.ucl.ac.uk/parkinsons/)
References
[Richfield et al., Ambroxol increases glucocerebrosidase activity in Parkinson's disease (2019)](https://doi.org/10.1093/brain/awz093)
[Silva et al., Ambroxol for Parkinson's Disease: Rationale and Design (2022)](https://doi.org/10.1016/j.parkreldis.2022.10.012)
[Sriram et al., Ambroxol in Parkinson's disease: 12-month results (2024)](https://doi.org/10.1002/mds.29767)
[Liu et al., GBA1 Mutations in Parkinson's Disease (2021)](https://doi.org/10.1002/mds.28979)
[Glucocerebrosidase and alpha-synuclein: A bidirectional relationship (2023)](https://doi.org/10.3233/JPD-230123)
[Silva et al., Pharmacological chaperones for neurodegenerative diseases (2024)](https://doi.org/10.1038/s41573-024-00567-8)