Ambroxol as a Disease-modifying Treatment in GBA-PD (AMBITIOUS)

September 8, 2023 updated by: Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta

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.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

65

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

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

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

19 years to 78 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: 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
Drug: 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.
Other Names:
  • Ambroxol
Placebo Comparator: Placebo
Excipients
Drug: Placebo
Excipients

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
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)
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
baseline and week 52

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Incidence of treatment-related adverse events and drop-outs
Time Frame: Day 1-372
Assessment of any treatment-related adverse events and drop-outs throughout the whole study period
Day 1-372
Change from baseline in Parkinson Disease Cognitive Functional Rating Scale (PD-CFRS)
Time Frame: baseline and week 52

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.
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
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.
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
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.
baseline, week 26 and week 52
Change from baseline in Hoehn and Yahr stage
Time Frame: baseline, week 26 and week 52
This is a 5-points staging of Parkinson's disease. The higher the stage the worse the motor disability
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

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.
baseline and week 52
Penetration of Ambroxol into the cerebrospinal fluid
Time Frame: week 26 and week 52
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)
week 26 and week 52
Changes in Cerebrospinal Fluid biomarkers of neurodegeneration
Time Frame: baseline and week 52
Quantify the effects of Ambroxol on biomarkers of neurodegeneration
baseline and week 52
Changes in functional connectivity at rest using brain magnetic resonance imaging
Time Frame: baseline and week 52
Imaging biomarker of neurodegeneration
baseline and week 52

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

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

Collaborators

University of Campania "Luigi Vanvitelli"
IRCCS National Neurological Institute "C. Mondino" Foundation

Investigators

  • Principal Investigator: Roberto Cilia, Fondazione IRCCS Istituto Neurologico Carlo Besta

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 15, 2022

Primary Completion (Estimated)

December 15, 2024

Study Completion (Estimated)

December 15, 2024

Study Registration Dates

First Submitted

January 28, 2022

First Submitted That Met QC Criteria

March 10, 2022

First Posted (Actual)

March 18, 2022

Study Record Updates

Last Update Posted (Actual)

September 11, 2023

Last Update Submitted That Met QC Criteria

September 8, 2023

Last Verified

September 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • GR-2018-12366771
  • 2021-004565-13 (EudraCT Number)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

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.

IPD Sharing 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.

IPD Sharing 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)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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