Clinical trial NCT05287503: Ambroxol as a Disease-modifying Treatment in GBA-PD
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Parkinson Disease
GBA Gene Mutation
Keywords: Parkinson disease
glucocerebrosidase
GBA
ambroxol
placebo
disease-modifying
randomized clinical trial
Lead sponsor: Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta
Sponsor class: OTHER
Collaborators: name: IRCCS National Neurological Institute "C. Mondino" Foundation
name: University of Campania Luigi Vanvitelli
First posted: 2022-03-18
Enrollment: 65
Sex: ALL
Minimum age (years): 21
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Multicenter, Randomized, Double-blind, Placebo controlled, Parallel-group trial
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Change from baseline in Montreal Cognitive Assessment score
timeFrame: baseline and week 52
measure: 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)
timeFrame: baseline and week 52
Secondary outcomes:
measure: Incidence of treatment-related adverse events and drop-outs
timeFrame: Day 1-372
measure: Change from baseline in Parkinson Disease Cognitive Functional Rating Scale (PD-CFRS)
timeFrame: baseline and week 52
measure: Change from baseline in Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part II
timeFrame: baseline, week 26 and week 52
measure: Change from baseline in Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III
timeFrame: baseline, week 26 and week 52
measure: Change from baseline in Hoehn and Yahr stage
timeFrame: baseline, week 26 and week 52
measure: Change from baseline in glucocerebrosidase enzyme activity in blood leucocytes and cerebrospinal fluid
timeFrame: baseline and week 52
measure: Penetration of Ambroxol into the cerebrospinal fluid
timeFrame: week 26 and week 52
measure: Changes in Cerebrospinal Fluid biomarkers of neurodegeneration
timeFrame: baseline and week 52
measure: Changes in functional connectivity at rest using brain magnetic resonance imaging
timeFrame: baseline and week 52
Other outcomes:
Locations:
city: Milan
country: Italy
facility: Fondazione IRCCS Istituto Neurologico Carlo Besta
city: Naples
country: Italy
facility: University of Campania "Luigi Vanvitelli"
city: Pavia
country: Italy
facility: IRCCS National Neurological Institute "C. Mondino" Foundation
Study officials:
affiliation: Fondazione IRCCS Istituto Neurologico Carlo Besta
name: Roberto Cilia
role: PRINCIPAL_INVESTIGATOR
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