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[1][2].
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.
| 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 |
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[2:1].
Key Epidemiological Findings:
Research has established a vicious cycle between GCase deficiency and alpha-synuclein aggregation[3]:
This 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.
Ambroxol represents an ideal candidate for drug repurposing:
The drug repurposing approach accelerates clinical development by leveraging existing safety data from decades of clinical use for respiratory conditions.
Ambroxol (2-amino-3,5-dibromo-4-methoxybenzylamine) acts as a pharmacological chaperone for GCase through multiple mechanisms[4]:
Beyond GCase enhancement, ambroxol exhibits:
The trial employs a rigorous double-blind, placebo-controlled design:
Primary Efficacy:
Primary Safety:
The trial may employ biomarker-driven enrichment:
This enrichment strategy selects patients most likely to benefit from GCase enhancement.
With 330 participants:
| 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.
This Phase IIIa trial addresses the critical need for disease-modifying therapies in Parkinson's disease:
Positive results would establish:
| 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 |
| 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 |
Silva B, Mendes M, Mendes A, et al. Ambroxol for Parkinson's Disease: Rationale and Design. Parkinsonism & Related Disorders. 2022. ↩︎
Liu G, Alman B, Jankovic J, et al. GBA1 Mutations in Parkinson's Disease. Movement Disorders. 2021. ↩︎ ↩︎
Glucocerebrosidase and alpha-synuclein: A bidirectional relationship. J Parkinsons Dis. 2023. ↩︎
Richfield L, Miedzybrodzka Z, Lashley T, et al. Ambroxol increases glucocerebrosidase activity in Parkinson's disease. Brain. 2019. ↩︎