Ambroxol as a Disease-modifying Treatment in GBA-PD

NCT05287503 | Completed Phase 2 DMC

• 2 other identifiers: GR-2018-123667712021-004565-13
• Study Type: interventional
• Target: 65
• Locations: 1 country
• Sites: 3

Brief Summary

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.

Conditions

Parkinson Disease; GBA Gene Mutation

Keywords

Parkinson disease; glucocerebrosidase; GBA; ambroxol; placebo; disease-modifying; randomized clinical trial

Outcome Measures

Primary Outcomes (2)

• 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.

  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

  baseline and week 52

Secondary Outcomes (9)

• Incidence of treatment-related adverse events and drop-outs

  Day 1-372

• Change from baseline in Parkinson Disease Cognitive Functional Rating Scale (PD-CFRS)

  baseline and week 52

• Change from baseline in Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part II

  baseline, week 26 and week 52

• Change from baseline in Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III

  baseline, week 26 and week 52

• Change from baseline in Hoehn and Yahr stage

  baseline, week 26 and week 52

Study Arms (2)

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

Drug: Ambroxol Hydrochloride

Placebo

PLACEBO COMPARATOR

Excipients

Drug: Placebo

Interventions

Ambroxol Hydrochloride DRUG

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.

Also known as: Ambroxol

Ambroxol

Placebo DRUG

Excipients

Placebo

Eligibility Criteria

• Age: 21 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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.

You may not qualify if:

• 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
• 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.

Sponsors & Collaborators

• Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta: lead
• IRCCS National Neurological Institute "C. Mondino" Foundation: collaborator
• University of Campania Luigi Vanvitelli: collaborator

Study Sites (3)

Fondazione IRCCS Istituto Neurologico Carlo Besta

Milan, 20133, Italy

Location

University of Campania "Luigi Vanvitelli"

Naples, Italy

Location

IRCCS National Neurological Institute "C. Mondino" Foundation

Pavia, 27100, Italy

Location

Related Publications (13)

• 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.

  PMID: 31930374 BACKGROUND

• 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.

  PMID: 27632223 BACKGROUND

• 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.

  PMID: 30589955 BACKGROUND

• 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.

  PMID: 24574503 BACKGROUND

• 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.

  PMID: 28295625 BACKGROUND

• 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.

  PMID: 27042680 BACKGROUND

• 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.

  PMID: 30738426 BACKGROUND

• 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.

  PMID: 23413260 BACKGROUND

• 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.

  PMID: 29290548 BACKGROUND

• 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.

  PMID: 25355820 BACKGROUND

• 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.

  PMID: 23773412 BACKGROUND

• 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.

  PMID: 19303930 BACKGROUND

• 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.

  PMID: 38027469 DERIVED

MeSH Terms

Conditions

Parkinson Disease

Interventions

Ambroxol

Condition Hierarchy (Ancestors)

Parkinsonian Disorders; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases

Intervention Hierarchy (Ancestors)

Bromhexine; Aniline Compounds; Amines; Organic Chemicals; Cyclohexylamines

Study Officials

• Roberto Cilia

  Fondazione IRCCS Istituto Neurologico Carlo Besta

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Double Blind
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Multicenter, Randomized, Double-blind, Placebo controlled, Parallel-group trial

Study Record Dates

• First Submitted: January 28, 2022
• First Posted: March 18, 2022
• Study Start: March 9, 2022
• Primary Completion: December 15, 2024
• Study Completion: December 20, 2024
• Last Updated: August 14, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will share
• Time Frame: Data requests can be submitted starting 9 months after article publication and the data will be made accessible for up to 24 months. Extensions will be considered on a case-by-case basis.
• Access Criteria: Access to trial individual participant data can be requested by qualified researchers engaging in independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan and execution of a Data Sharing Agreement. For more information or to submit a request, please contact the P.I. of the study (roberto.cilia@istituto-besta.it)

Locations

IT (3)