Ambroxol as a Disease-modifying Treatment in GBA-PD

NCT ID: NCT05287503

Last Updated: 2025-08-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 65 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-03-09
• Study Completion Date: 2024-12-20

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.

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Ambroxol

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

Group Type: EXPERIMENTAL

Ambroxol Hydrochloride

Intervention Type: 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.

Placebo

Excipients

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Excipients

Interventions

Ambroxol Hydrochloride

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.

Intervention Type: DRUG

Placebo

Excipients

Intervention Type: DRUG

Other Intervention Names

Ambroxol

Eligibility Criteria

Inclusion Criteria

1. Age 21-80 years

2. Diagnosis of idiopathic PD

3. Duration of motor symptoms >5 years

4. Heterozygous carrier of a GBA1 mutation.

5. Capable of complying with all study procedures, including fasting lumbar puncture

6. 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:

1. Non-childbearing potential

2. Women of childbearing potential must have a negative pregnancy test at the screening visit and use accepted contraceptive methods defined as highly effective.

Exclusion Criteria

1. Secondary and primary atypical parkinsonism

2. Diagnosis of Parkinson-Dementia (MDS Level II criteria) or other conditions that result in inability to understand and sign the informed consent

3. Hoehn & Yahr stage ≥ 4/5 in the medication-ON condition

4. Deep Brain Stimulation

5. 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).

6. Bronchial asthma

7. 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.

8. Pregnant or breastfeeding women.

9. 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;

10. Known hypersensitivity to the active substance Ambroxol or to any of its excipients.

• Minimum Eligible Age: 21 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

IRCCS National Neurological Institute "C. Mondino" Foundation

OTHER

Sponsor Role: collaborator

University of Campania Luigi Vanvitelli

OTHER

Sponsor Role: collaborator

Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Roberto Cilia

Role: PRINCIPAL_INVESTIGATOR

Fondazione IRCCS Istituto Neurologico Carlo Besta

Locations

Fondazione IRCCS Istituto Neurologico Carlo Besta

Milan, , Italy

University of Campania "Luigi Vanvitelli"

Naples, , Italy

IRCCS National Neurological Institute "C. Mondino" Foundation

Pavia, , Italy

Countries

Italy

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Other Identifiers

2021-004565-13

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

GR-2018-12366771

Identifier Type: -

Identifier Source: org_study_id