Landmark 320 · Trial in people
AMBITIOUS: ambroxol in GBA carriers
No benefit for thinking in 65 gene carriers over a year. This is a preprint, not yet checked by other scientists.
In short
The first placebo-controlled ambroxol trial in people with Parkinson's and a GBA1 mutation found no slowing of cognitive decline over 52 weeks, in a preprint that has not yet been peer reviewed.
- What it is
- Trial in people
- Outcome
- Did not work
- When
- 2022–2026
- Size
- 65 people · Phase 2
- Approach
- Help cells clean up
- Research lane
- Lysosome & GBA
- Trial registry
- NCT05287503
- Last checked
- 19 Oct 2026
The research record
This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".
Who
Roberto Cilia, Fabiana Colucci, Micol Avenali and colleagues; sponsor Fondazione IRCCS Istituto Neurologico Carlo Besta (Milan), with the Mondino Institute (Pavia) and the University of Campania (Naples). Registered as NCT05287503.
What happened
- Design. Phase 2, randomised, double-blind, placebo-controlled. Adults aged 21 to 80, all carrying one faulty copy of the GBA1 gene, with motor symptoms for over 5 years. Ambroxol was stepped up to 1.2 g a day (about ten times a cough dose, see landmark 40) for 52 weeks. Planned size was 60; 65 were enrolled (33 on ambroxol, 32 on placebo, according to the preprint abstract).
- Main measure. Change in the Montreal Cognitive Assessment (MoCA) score at week 52, plus the rate of conversion to mild cognitive impairment or dementia.
- Dates. Registry start 9 March 2022; completed 20 December 2024; record last updated 14 August 2025, with no results posted (checked 19 Oct 2026).
- Result (preprint). MoCA change was -0.69 on ambroxol and +0.19 on placebo (difference -1.18, 95% CI -2.63 to 0.27, P = 0.053), based on 28 patients per arm. After adjusting for sex, disease duration and GBA1 variant type, the decline was worse on ambroxol (-1.05, P = 0.030). Levodopa dose was lower on ambroxol, and CSF amyloid-beta 42 was lower. The authors concluded ambroxol was well tolerated but showed no disease-modifying benefit.
- A 2026 systematic review confirms the results exist only as a non-peer-reviewed preprint and "did not show disease modification".
Why it moved us toward a cure
It is the first controlled test of the GCase-boosting idea (landmark 16) in carriers chosen by genotype (landmark 86). A negative or null result in the group most likely to respond is a caution for the 330-person Phase 3 (landmark 321), though AMBITIOUS tested cognition, not motor progression, and was small.
Outcome
Dead end on the evidence so far, pending peer review. The same drug was also null for cognition in Parkinson's dementia (landmark 40). Other GBA-directed drugs have also failed (landmark 69, 235).
Sources
- ClinicalTrials.gov NCT05287503 (API v2, read 19 Oct 2026)
- Cilia, Colucci, Avenali et al., AMBITIOUS preprint, SSRN 7064193 (the page blocked me; numbers are from the abstract as shown in a search result)
- AMBITIOUS protocol, BMJ Neurol Open 2023, DOI 10.1136/bmjno-2023-000535
- Lipiński et al., systematic review, Acta Neurol Belg 2026, DOI 10.1007/s13760-026-03202-w (via Europe PMC, PMID 42801449)
- Not yet verified: the preprint's full text and posting date; whether it has been submitted to or accepted by a journal; the full author list; motor outcomes.
How it connects
Built on
- tests Ambroxol: cough medicine to first Parkinson's trials · 2009
- builds on GBA mutation severity · 2015
Led to
None recorded.