Parkinson DiseasePhase 2AMBITIOUSNCT05287503

Ambroxol as a Disease-modifying Treatment in GBA-PD

A Phase 2 study testing Ambroxol Hydrochloride in people with Parkinson Disease and GBA Gene Mutation, run by Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta at 3 sites in Italy.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

Search all trials

Trial summary

Who is it for?: Ages 21 to 80 years
Conditions the study is for: Parkinson Disease, GBA Gene Mutation
What is being tested?: Ambroxol Hydrochloride
Type of treatment: Pill or oral medicine
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 65 participants
Where: 3 sitesItaly
Study dates: 9 Mar 2022to 20 Dec 2024
Phase: Phase 2
Are there results?: None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 21 to 80 years
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

Age 21-80 years
Diagnosis of idiopathic PD
Duration of motor symptoms >5 years
Heterozygous carrier of a GBA1 mutation.
Capable of complying with all study procedures, including fasting lumbar puncture
All male and female participants of childbearing age must agree with their partners to use double barrier birth control or total abstinence during study participation and for 2 weeks after the last dose of study drug.

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Male participants who have received bilateral vasectomy are permanently sterile.
A woman can participate if she is of:
Non-childbearing potential
Women of childbearing potential must have a negative pregnancy test at the screening visit and use accepted contraceptive methods defined as highly effective.

Who cannot join

Secondary and primary atypical parkinsonism
Diagnosis of Parkinson-Dementia (MDS Level II criteria) or other conditions that result in inability to understand and sign the informed consent
Hoehn \& Yahr stage ≥ 4/5 in the medication-ON condition
Deep Brain Stimulation
Any clinically significant or unstable medical condition, which, in the opinion of the principal investigator or the clinician delegated by the principal investigator, may put the participant at risk when participating in the study (e.g. previous gastric/duodenal peptic ulcer, chronic obstructive pulmonary disease, severe liver or kidney changes, major cardiovascular event (e.g. myocardial infarction, decompensated congestive heart failure, pulmonary embolism occurring within 6 months prior to the screening visit), neoplastic diseases).
Bronchial asthma

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Abnormalities that could preclude safe completion of the spinal cord in the investigator's opinion, including: treatment with anticoagulants; severe abnormalities or malformations of the lower spine or other spinal disorders; bleeding diathesis (e.g. clinically significant coagulopathies or thrombocytopenia); hypersensitivity to lidocaine.
Pregnant or breastfeeding women.
All participants of childbearing age who disagree to use double barrier or abstinence birth control while participating in the study and for 2 weeks after the last dose of study drug;
Known hypersensitivity to the active substance Ambroxol or to any of its excipients.

Trial locations and contacts

3 sites in 1 country.

Italy3 sites

Fondazione IRCCS Istituto Neurologico Carlo Besta
Milan, 20133
University of Campania "Luigi Vanvitelli"
Naples
IRCCS National Neurological Institute "C. Mondino" Foundation
Pavia, 27100

Other trials in Italy

About this study

Official title: Ambroxol as a Disease-modifying Treatment to Reduce the Risk of Cognitive Impairment in GBA-associated Parkinson's Disease. A Multicenter, Randomized, Double-blind, Placebo-controlled, Phase 2 Trial

The present multicenter, randomized, double-blind, placebo-controlled clinical trial will investigate whether the prolonged administration of high-dose oral Ambroxol over 52 weeks is safe, tolerable, able to change Glucocerebrosidase enzyme activity and alpha-synuclein levels in the central nervous system and, ultimately, to reduce the progression of cognitive decline and motor disability in 60 individuals with Parkinson's disease with mutations of the glucocerebrosidase gene (GBA1; OMIM 606463).

Participants will undergo clinical, biomarker blood and cerebrospinal fluid analysis, neuropsychological, neuroimaging assessment throughout the course of the study.

Read the detailed description

Glucocerebrosidase (GCase) is a lysosomal enzyme encoded by the GBA1 beta-glucosylceramidase gene (GBA). Heterozygous GBA mutations are recognized as the most frequent genetic risk factor for Parkinson's disease (PD),with an overall carrier frequency of about 10% in PD. Heterozygous carriers of GBA mutations are at increased odds for developing PD and even higher for PD Dementia and Dementia with Lewy Bodies. In GBA carriers, PD usually occurs at earlier age at onset, higher risk for dementia, visual hallucinations, autonomic dysfunction and faster progression of motor symptoms than noncarriers, culminating in an overall reduced survival.

GBA1 mutations reduce the enzymatic function of GCase, ultimately promoting the toxic accumulation of alpha-synuclein (alpha-syn) fibrils throughout the central nervous system. The toxic conversion of physiological alpha-syn conformers by glycosphingolipids should be reversible at a stage prior to incorporation into fibrils. Therefore, the use of agents able to enhance GCase activity might hold a therapeutic potential. Ambroxol is a metabolite of bromhexine which has been used for over 30 years as an over-the-counter mucolytic, with an excellent safety profile with few side effects. The brain penetrance of Ambroxol in vivo and its ability to increase GCase activity and reduce alpha-syn levels has been consistently confirmed in several in vitro and in vivo studies, but only at a higher dose (1.2 g/day in humans).

The investigators hypothesize that the greatest impact of Ambroxol as a disease-modifying agent will be on cognitive performance, because it is the clinical feature that showed the greatest difference between PD carriers vs. non-carriers.

Sixty patients diagnosed with PD and carriers of GBA mutations will be recruited and randomly allocated to either Ambroxol 1.2 g/day or Placebo. Galenic formulation of Ambroxol 200 mg per tablet and similar Placebo tablets have been manufactured ad hoc and their use in this study has been authorized by the Italian Medicines Agency (AIFA; Provvedimento 2021-004565-13 SC23119).

The investigators will administer clinical and cognitive assessments to determine if there is any difference in the progression of cognitive dysfunction (primary endpoint) as well as other motor and non-motor features between the two treatment arms.

Pharmacokinetics (Ambroxol drug levels) and pharmacodynamics (GCase enzyme activity) of the experimental drug in blood and cerebrospinal fluid samples will be measured as well as neurodegeneration biomarkers in the cerebrospinal fluid (alpha-synuclein, Tau, phospho-Tau and beta amyloid-42) at baseline and after the intake of oral Ambroxol for 12 months.

Conditions: Parkinson Disease, GBA Gene Mutation
Being tested: Ambroxol Hydrochloride, Placebo
Keywords: Parkinson disease, glucocerebrosidase, GBA, ambroxol, placebo, disease-modifying, randomized clinical trial
Medical subject headings: Parkinson Disease

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Ambroxol HydrochlorideDrug
Also called Ambroxol
Drug Ambroxol hydrochloride 200 mg plus excipients. The manufacturing process of the 200 mg Ambroxol hydrochloride tablets will be performed by wet granulation, drying, mixing and compression to the target final weight.
PlaceboDrug
Excipients

Study groups in NCT05287503
Study group	Role	What they receive
Ambroxol	Experimental	Ambroxol hydrochloride 200 mg tablets Dose: 1.2 g daily Escalation scheme: Day 1 - 5 200 mg 200 mg once a day Day 6 - 10 400 mg 200 mg twice a day Day 11 - 15 600 mg 200 mg three times a day Day 16 - 20 800 mg 400 mg twice a day Day 21 - 25 1000 mg 400 mg + 200 mg + 400 mg a day Day 26 - 365 1200 mg 400 mg three times a day Receives: Drug: Ambroxol Hydrochloride
Placebo	Placebo comparator	Excipients Receives: Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

Change from baseline in Montreal Cognitive Assessment score
This 30-point test investigates global cognitive functions and it has been recommended for the assessment of Parkinson's dementia. The lower the score the worse the cognitive functions.
Measured: baseline and week 52
Change from baseline in conversion rate from normal cognitive function (PD-N) to mild cognitive impairment (PD-MCI) and from PD-N or PD-MCI to Parkinson-Dementia (PD-D)
Rate of conversion from normal cognitive status to MCI or from MCI to overt dementia over the 52-week treatment period
Measured: baseline and week 52

Secondary outcomes (9)

Incidence of treatment-related adverse events and drop-outs
Assessment of any treatment-related adverse events and drop-outs throughout the whole study period
Measured: Day 1-372
Change from baseline in Parkinson Disease Cognitive Functional Rating Scale (PD-CFRS)
The PD-CFRS is a short questionnaire addressed to explore a wide range of functional aspects sensible to detect cognitive impairment in PD, minimizing the motor impact of the disease. The scale is administered to a knowledgeable informant in interview form by 12 items selected to cover the spectrum of instrumental cognitive changes seen in PD over the last two weeks before the evaluation (exploring for example whether or not the patient has had trouble in handling money, domestic economy, controlling drug treatment schedule, organizing daily activities, handling home electrical appliances, understanding how to use public transport, solving unforeseen events, explaining things he/she want to say, and handling the cell phone).
The score ranges from 0 to 24; the higher the score the worse the disability.
Measured: baseline and week 52
Change from baseline in Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part II
MDS-UPDRS is a multimodal scale assessing impairment and disability consisting of 4 parts. Part II assesses motor experiences of daily living (Range 0-52). It contains 13 questions completed by the participant. For each question a numeric score was assigned between 0-4, where 0 = Normal, 1 = Slight, 2 = Mild, 3 = Moderate, 4 = Severe.
Measured: baseline, week 26 and week 52
Change from baseline in Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III
Changes on a validated scale used to assess motor performance. MDS-UPDRS is a multimodal scale assessing impairment and disability consisting of 4 parts. Part III assesses the motor signs of PD and is administered by the rater (Range 0-132). Part III contains 33 scores based on 18 items. For each question a numeric score was assigned between 0-4, where 0 = Normal, 1 = Slight, 2 = Mild, 3 = Moderate, 4 = Severe.
Measured: baseline, week 26 and week 52
Change from baseline in Hoehn and Yahr stage
This is a 5-points staging of Parkinson's disease. The higher the stage the worse the motor disability
Measured: baseline, week 26 and week 52
Change from baseline in glucocerebrosidase enzyme activity in blood leucocytes and cerebrospinal fluid
Pharmacodynamic effects of Ambroxol will be measured through the change from baseline in glucocerebrosidase enzyme activity in blood leucocytes (nmol/mg/h) and cerebrospinal fluid (nmol/mL/h), using the substrate 4-methylumbelliferyl-β-D-glucopyranoside.
This outcome measure aims to investigate whether ambroxol oral administration is able to target the glucocerebrosidase pathway in PD and increase GCase enzyme activity in peripheral blood mononuclear cells and in the central nervous system.
Measured: baseline and week 52
Penetration of Ambroxol into the cerebrospinal fluid
Assess ambroxol cerebrospinal fluid penetration by measuring the ratio (expressed in %) between Ambroxol levels in blood serum (ng/mL) and in the cerebrospinal fluid (ng/ml)
Measured: week 26 and week 52
Changes in Cerebrospinal Fluid biomarkers of neurodegeneration
Quantify the effects of Ambroxol on biomarkers of neurodegeneration
Measured: baseline and week 52
Changes in functional connectivity at rest using brain magnetic resonance imaging
Imaging biomarker of neurodegeneration
Measured: baseline and week 52

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

9 Mar 202220 Dec 2024

First posted18 Mar 2022
Study start9 Mar 2022
Primary completion15 Dec 2024
Study completion20 Dec 2024

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Publications (13)Papers the sponsor has linked to this study.
Other trials for Parkinson DiseaseStudies of the same condition, open and under way.
More trials run by Fondazione I.R.C.C.S. Istituto Neurologico Carlo BestaThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 2
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Model description: Multicenter, Randomized, Double-blind, Placebo controlled, Parallel-group trial
Masking: Quadruple blind
Who is masked: Participant, Care provider, Investigator, Outcomes assessor
Enrolment: 65 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT05287503
Sponsor's protocol ID: GR-2018-12366771
Other IDs: 2021-004565-13
Acronym: AMBITIOUS
Status last verified: Aug 2025
First submitted: 28 Jan 2022
Last updated: 14 Aug 2025
Results posted: No
Data monitoring committee: Yes
FDA-regulated drug: No
FDA-regulated device: No
Individual data sharing: Yes: Data obtained through this study may be provided to qualified researchers with academic interest in GBA-associated Parkinson's disease. Data or samples shared will be coded, with no protected health information included. Approval of the request and execution of all applicable agreements (i.e. a material transfer agreement) are prerequisites to the sharing of data with the requesting party.

Publications

Mullin S, Smith L, Lee K, D'Souza G, Woodgate P, Elflein J, Hallqvist J, Toffoli M, Streeter A, Hosking J, Heywood WE, Khengar R, Campbell P, Hehir J, Cable S, Mills K, Zetterberg H, Limousin P, Libri V, Foltynie T, Schapira AHV. Ambroxol for the Treatment of Patients With Parkinson Disease With and Without Glucocerebrosidase Gene Mutations: A Nonrandomized, Noncontrolled Trial. JAMA Neurol. 2020 Apr 1;77(4):427-434. doi: 10.1001/jamaneurol.2019.4611.
PubMed 31930374
Cilia R, Tunesi S, Marotta G, Cereda E, Siri C, Tesei S, Zecchinelli AL, Canesi M, Mariani CB, Meucci N, Sacilotto G, Zini M, Barichella M, Magnani C, Duga S, Asselta R, Solda G, Seresini A, Seia M, Pezzoli G, Goldwurm S. Survival and dementia in GBA-associated Parkinson's disease: The mutation matters. Ann Neurol. 2016 Nov;80(5):662-673. doi: 10.1002/ana.24777. Epub 2016 Oct 3.
PubMed 27632223
Blandini F, Cilia R, Cerri S, Pezzoli G, Schapira AHV, Mullin S, Lanciego JL. Glucocerebrosidase mutations and synucleinopathies: Toward a model of precision medicine. Mov Disord. 2019 Jan;34(1):9-21. doi: 10.1002/mds.27583. Epub 2018 Dec 27.
PubMed 30589955
McNeill A, Magalhaes J, Shen C, Chau KY, Hughes D, Mehta A, Foltynie T, Cooper JM, Abramov AY, Gegg M, Schapira AH. Ambroxol improves lysosomal biochemistry in glucocerebrosidase mutation-linked Parkinson disease cells. Brain. 2014 May;137(Pt 5):1481-95. doi: 10.1093/brain/awu020. Epub 2014 Feb 25.
PubMed 24574503
Migdalska-Richards A, Ko WKD, Li Q, Bezard E, Schapira AHV. Oral ambroxol increases brain glucocerebrosidase activity in a nonhuman primate. Synapse. 2017 Jul;71(7):e21967. doi: 10.1002/syn.21967. Epub 2017 Mar 17.
PubMed 28295625
Narita A, Shirai K, Itamura S, Matsuda A, Ishihara A, Matsushita K, Fukuda C, Kubota N, Takayama R, Shigematsu H, Hayashi A, Kumada T, Yuge K, Watanabe Y, Kosugi S, Nishida H, Kimura Y, Endo Y, Higaki K, Nanba E, Nishimura Y, Tamasaki A, Togawa M, Saito Y, Maegaki Y, Ohno K, Suzuki Y. Ambroxol chaperone therapy for neuronopathic Gaucher disease: A pilot study. Ann Clin Transl Neurol. 2016 Feb 2;3(3):200-15. doi: 10.1002/acn3.292. eCollection 2016 Mar.
PubMed 27042680
Silveira CRA, MacKinley J, Coleman K, Li Z, Finger E, Bartha R, Morrow SA, Wells J, Borrie M, Tirona RG, Rupar CA, Zou G, Hegele RA, Mahuran D, MacDonald P, Jenkins ME, Jog M, Pasternak SH. Ambroxol as a novel disease-modifying treatment for Parkinson's disease dementia: protocol for a single-centre, randomized, double-blind, placebo-controlled trial. BMC Neurol. 2019 Feb 9;19(1):20. doi: 10.1186/s12883-019-1252-3.
PubMed 30738426
Winder-Rhodes SE, Evans JR, Ban M, Mason SL, Williams-Gray CH, Foltynie T, Duran R, Mencacci NE, Sawcer SJ, Barker RA. Glucocerebrosidase mutations influence the natural history of Parkinson's disease in a community-based incident cohort. Brain. 2013 Feb;136(Pt 2):392-9. doi: 10.1093/brain/aws318.
PubMed 23413260
Zunke F, Moise AC, Belur NR, Gelyana E, Stojkovska I, Dzaferbegovic H, Toker NJ, Jeon S, Fredriksen K, Mazzulli JR. Reversible Conformational Conversion of alpha-Synuclein into Toxic Assemblies by Glucosylceramide. Neuron. 2018 Jan 3;97(1):92-107.e10. doi: 10.1016/j.neuron.2017.12.012. Epub 2017 Dec 28.
PubMed 29290548
Shinotoh H, Tessitore A. Resting-state fMRI sheds light on neural substrates of cognitive decline in Parkinson disease. Neurology. 2014 Nov 25;83(22):2000-1. doi: 10.1212/WNL.0000000000001037. Epub 2014 Oct 29. No abstract available.
PubMed 25355820
Kulisevsky J, Fernandez de Bobadilla R, Pagonabarraga J, Martinez-Horta S, Campolongo A, Garcia-Sanchez C, Pascual-Sedano B, Ribosa-Nogue R, Villa-Bonomo C. Measuring functional impact of cognitive impairment: validation of the Parkinson's disease cognitive functional rating scale. Parkinsonism Relat Disord. 2013 Sep;19(9):812-7. doi: 10.1016/j.parkreldis.2013.05.007. Epub 2013 Jun 15.
PubMed 23773412
Parnetti L, Balducci C, Pierguidi L, De Carlo C, Peducci M, D'Amore C, Padiglioni C, Mastrocola S, Persichetti E, Paciotti S, Bellomo G, Tambasco N, Rossi A, Beccari T, Calabresi P. Cerebrospinal fluid beta-glucocerebrosidase activity is reduced in Dementia with Lewy Bodies. Neurobiol Dis. 2009 Jun;34(3):484-6. doi: 10.1016/j.nbd.2009.03.002. Epub 2009 Mar 20.
PubMed 19303930
Colucci F, Avenali M, De Micco R, Fusar Poli M, Cerri S, Stanziano M, Bacila A, Cuconato G, Franco V, Franciotta D, Ghezzi C, Gastaldi M, Elia AE, Romito L, Devigili G, Leta V, Garavaglia B, Golfre Andreasi N, Cazzaniga F, Reale C, Galandra C, Germani G, Mitrotti P, Ongari G, Palmieri I, Picascia M, Pichiecchio A, Verri M, Esposito F, Cirillo M, Di Nardo F, Aloisio S, Siciliano M, Prioni S, Amami P, Piacentini S, Bruzzone MG, Grisoli M, Moda F, Eleopra R, Tessitore A, Valente EM, Cilia R. Ambroxol as a disease-modifying treatment to reduce the risk of cognitive impairment in GBA-associated Parkinson's disease: a multicentre, randomised, double-blind, placebo-controlled, phase II trial. The AMBITIOUS study protocol. BMJ Neurol Open. 2023 Nov 24;5(2):e000535. doi: 10.1136/bmjno-2023-000535. eCollection 2023.
PubMed 38027469

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

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Study at a glance

From the registry record, last updated by the sponsor on 14 Aug 2025. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Ambroxol as a Disease-modifying Treatment to Reduce the Risk of Cognitive Impairment in GBA-associated Parkinson's Disease. A Multicenter, Randomized, Double-blind, Placebo-controlled, Phase 2 Trial
ClinicalTrials.gov ID: NCT05287503
Acronym / sponsor ID: AMBITIOUS / GR-2018-12366771
Conditions: Parkinson Disease, GBA Gene Mutation
Keywords: Parkinson disease, glucocerebrosidase, GBA, ambroxol, placebo, disease-modifying, randomized clinical trial
Phase: Phase 2
Study type: Interventional
Recruitment status: Completed
Enrolment: 65 participants (actual)
Lead sponsor: Fondazione I.R.C.C.S. Istituto Neurologico Carlo BestaUniversity, hospital or other
Collaborators: IRCCS National Neurological Institute "C. Mondino" Foundation, University of Campania Luigi Vanvitelli
Study start: 9 Mar 2022 (actual)
Primary completion: 15 Dec 2024 (actual)
Study completion: 20 Dec 2024 (actual)
First posted: 18 Mar 2022 (actual)
Results: Not posted in the source record

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Participants will undergo clinical, biomarker blood and cerebrospinal fluid analysis, neuropsychological, neuroimaging assessment throughout the course of the study.

Detailed description

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Quadruple blind (participant, care provider, investigator, outcomes assessor)
Number of arms: 2
Model description: Multicenter, Randomized, Double-blind, Placebo controlled, Parallel-group trial

Arm	Type	Receives
Ambroxol	Experimental	Drug: Ambroxol HydrochlorideAmbroxol hydrochloride 200 mg tablets Dose: 1.2 g daily Escalation scheme: Day 1 - 5 200 mg 200 mg once a day Day 6 - 10 400 mg 200 mg twice a day Day 11 - 15 600 mg 200 mg three times a day Day 16 - 20 800 mg 400 mg twice a day Day 21 - 25 1000 mg 400 mg + 200 mg + 400 mg a day Day 26 - 365 1200 mg 400 mg three times a day
Placebo	Placebo comparator	Drug: PlaceboExcipients

Who may qualify

Ages: 21 to 80 years
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (10 listed)

Age 21-80 years
Diagnosis of idiopathic PD
Duration of motor symptoms >5 years
Heterozygous carrier of a GBA1 mutation.
Capable of complying with all study procedures, including fasting lumbar puncture

Key exclusion criteria (10 listed)

Secondary and primary atypical parkinsonism
Diagnosis of Parkinson-Dementia (MDS Level II criteria) or other conditions that result in inability to understand and sign the informed consent
Hoehn \& Yahr stage ≥ 4/5 in the medication-ON condition
Deep Brain Stimulation
Any clinically significant or unstable medical condition, which, in the opinion of the principal investigator or the clinician delegated by the principal investigator, may put the participant at risk when participating in the study (e.g. previous gastric/duodenal peptic ulcer, chronic obstructive pulmonary disease, severe liver or kidney changes, major cardiovascular event (e.g. myocardial infarction, decompensated congestive heart failure, pulmonary embolism occurring within 6 months prior to the screening visit), neoplastic diseases).

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
Ambroxol HydrochlorideAlso: AmbroxolDrug Ambroxol hydrochloride 200 mg plus excipients. The manufacturing process of the 200 mg Ambroxol hydrochloride tablets will be performed by wet granulation, drying, mixing and compression to the target final weight.	Drug	Ambroxol
PlaceboExcipients	Drug	Placebo

Primary outcome

Change from baseline in Montreal Cognitive Assessment score
Time frame: baseline and week 52
This 30-point test investigates global cognitive functions and it has been recommended for the assessment of Parkinson's dementia. The lower the score the worse the cognitive functions.
Change from baseline in conversion rate from normal cognitive function (PD-N) to mild cognitive impairment (PD-MCI) and from PD-N or PD-MCI to Parkinson-Dementia (PD-D)
Time frame: baseline and week 52
Rate of conversion from normal cognitive status to MCI or from MCI to overt dementia over the 52-week treatment period

9 secondary outcomes

Incidence of treatment-related adverse events and drop-outs
Time frame: Day 1-372
Change from baseline in Parkinson Disease Cognitive Functional Rating Scale (PD-CFRS)
Time frame: baseline and week 52
Change from baseline in Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part II
Time frame: baseline, week 26 and week 52
Change from baseline in Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III
Time frame: baseline, week 26 and week 52
Change from baseline in Hoehn and Yahr stage
Time frame: baseline, week 26 and week 52
Change from baseline in glucocerebrosidase enzyme activity in blood leucocytes and cerebrospinal fluid
Time frame: baseline and week 52
Penetration of Ambroxol into the cerebrospinal fluid
Time frame: week 26 and week 52
Changes in Cerebrospinal Fluid biomarkers of neurodegeneration
Time frame: baseline and week 52
Changes in functional connectivity at rest using brain magnetic resonance imaging
Time frame: baseline and week 52

Results and safety

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 14 Aug 2025.
Background: PubMed 31930374Mullin S, Smith L, Lee K, D'Souza G, Woodgate P, Elflein J, Hallqvist J, Toffoli M, Streeter A, Hosking J, Heywood WE, Khengar R, Campbell P, Hehir J, Cable S, Mills K, Zetterberg H, Limousin P, Libri V, Foltynie T, Schapira AHV. Ambroxol for the Treatment of Patients With Parkinson Disease With and Without Glucocerebrosidase Gene Mutations: A Nonrandomized, Noncontrolled Trial. JAMA Neurol. 2020 Apr 1;77(4):427-434. doi: 10.1001/jamaneurol.2019.4611.
Background: PubMed 27632223Cilia R, Tunesi S, Marotta G, Cereda E, Siri C, Tesei S, Zecchinelli AL, Canesi M, Mariani CB, Meucci N, Sacilotto G, Zini M, Barichella M, Magnani C, Duga S, Asselta R, Solda G, Seresini A, Seia M, Pezzoli G, Goldwurm S. Survival and dementia in GBA-associated Parkinson's disease: The mutation matters. Ann Neurol. 2016 Nov;80(5):662-673. doi: 10.1002/ana.24777. Epub 2016 Oct 3.
Background: PubMed 30589955Blandini F, Cilia R, Cerri S, Pezzoli G, Schapira AHV, Mullin S, Lanciego JL. Glucocerebrosidase mutations and synucleinopathies: Toward a model of precision medicine. Mov Disord. 2019 Jan;34(1):9-21. doi: 10.1002/mds.27583. Epub 2018 Dec 27.
Background: PubMed 24574503McNeill A, Magalhaes J, Shen C, Chau KY, Hughes D, Mehta A, Foltynie T, Cooper JM, Abramov AY, Gegg M, Schapira AH. Ambroxol improves lysosomal biochemistry in glucocerebrosidase mutation-linked Parkinson disease cells. Brain. 2014 May;137(Pt 5):1481-95. doi: 10.1093/brain/awu020. Epub 2014 Feb 25.
Background: PubMed 28295625Migdalska-Richards A, Ko WKD, Li Q, Bezard E, Schapira AHV. Oral ambroxol increases brain glucocerebrosidase activity in a nonhuman primate. Synapse. 2017 Jul;71(7):e21967. doi: 10.1002/syn.21967. Epub 2017 Mar 17.
Background: PubMed 27042680Narita A, Shirai K, Itamura S, Matsuda A, Ishihara A, Matsushita K, Fukuda C, Kubota N, Takayama R, Shigematsu H, Hayashi A, Kumada T, Yuge K, Watanabe Y, Kosugi S, Nishida H, Kimura Y, Endo Y, Higaki K, Nanba E, Nishimura Y, Tamasaki A, Togawa M, Saito Y, Maegaki Y, Ohno K, Suzuki Y. Ambroxol chaperone therapy for neuronopathic Gaucher disease: A pilot study. Ann Clin Transl Neurol. 2016 Feb 2;3(3):200-15. doi: 10.1002/acn3.292. eCollection 2016 Mar.
Background: PubMed 30738426Silveira CRA, MacKinley J, Coleman K, Li Z, Finger E, Bartha R, Morrow SA, Wells J, Borrie M, Tirona RG, Rupar CA, Zou G, Hegele RA, Mahuran D, MacDonald P, Jenkins ME, Jog M, Pasternak SH. Ambroxol as a novel disease-modifying treatment for Parkinson's disease dementia: protocol for a single-centre, randomized, double-blind, placebo-controlled trial. BMC Neurol. 2019 Feb 9;19(1):20. doi: 10.1186/s12883-019-1252-3.
Background: PubMed 23413260Winder-Rhodes SE, Evans JR, Ban M, Mason SL, Williams-Gray CH, Foltynie T, Duran R, Mencacci NE, Sawcer SJ, Barker RA. Glucocerebrosidase mutations influence the natural history of Parkinson's disease in a community-based incident cohort. Brain. 2013 Feb;136(Pt 2):392-9. doi: 10.1093/brain/aws318.
Background: PubMed 29290548Zunke F, Moise AC, Belur NR, Gelyana E, Stojkovska I, Dzaferbegovic H, Toker NJ, Jeon S, Fredriksen K, Mazzulli JR. Reversible Conformational Conversion of alpha-Synuclein into Toxic Assemblies by Glucosylceramide. Neuron. 2018 Jan 3;97(1):92-107.e10. doi: 10.1016/j.neuron.2017.12.012. Epub 2017 Dec 28.
Background: PubMed 25355820Shinotoh H, Tessitore A. Resting-state fMRI sheds light on neural substrates of cognitive decline in Parkinson disease. Neurology. 2014 Nov 25;83(22):2000-1. doi: 10.1212/WNL.0000000000001037. Epub 2014 Oct 29. No abstract available.
Background: PubMed 23773412Kulisevsky J, Fernandez de Bobadilla R, Pagonabarraga J, Martinez-Horta S, Campolongo A, Garcia-Sanchez C, Pascual-Sedano B, Ribosa-Nogue R, Villa-Bonomo C. Measuring functional impact of cognitive impairment: validation of the Parkinson's disease cognitive functional rating scale. Parkinsonism Relat Disord. 2013 Sep;19(9):812-7. doi: 10.1016/j.parkreldis.2013.05.007. Epub 2013 Jun 15.
Background: PubMed 19303930Parnetti L, Balducci C, Pierguidi L, De Carlo C, Peducci M, D'Amore C, Padiglioni C, Mastrocola S, Persichetti E, Paciotti S, Bellomo G, Tambasco N, Rossi A, Beccari T, Calabresi P. Cerebrospinal fluid beta-glucocerebrosidase activity is reduced in Dementia with Lewy Bodies. Neurobiol Dis. 2009 Jun;34(3):484-6. doi: 10.1016/j.nbd.2009.03.002. Epub 2009 Mar 20.
Individual participant dataSharing planned: Yes. Data obtained through this study may be provided to qualified researchers with academic interest in GBA-associated Parkinson's disease. Data or samples shared will be coded, with no protected health information included. Approval of the request and execution of all applicable agreements (i.e. a material transfer agreement) are prerequisites to the sharing of data with the requesting party.

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Roberto Cilia principal investigator

Fondazione IRCCS Istituto Neurologico Carlo Besta

3 sites in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Ambroxol Hydrochloride in people with Parkinson Disease and GBA Gene Mutation, run by Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta at 3 sites in Italy.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 10 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 14 Aug 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change from baseline in Montreal Cognitive Assessment score (time frame: baseline and week 52). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05287503, which also lists 13 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Aug 2025.