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Parkinson DiseasePhase 1/2NCT06193421

High-Dose Ambroxol in GBA1-Related Parkinson

A Phase 1/2 study testing Ambroxol Hydrochloride in people with Parkinson Disease and GBA Gene Mutation, run by Agyany Pharma LTD at 1 site in Israel.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
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Trial summary

Parkinson's disease (PD), affecting 10 million people globally, lacks a cure, and current therapies only manage symptoms. A link between Gaucher disease (GD) and PD, particularly in carriers of glucocerebrosidase (GBA1) mutations, has sparked interest in developing new drugs. Read more about this study

Who is it for?
Ages 30 to 70 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?
No, everyone receives an active treatment
How many people
40 participants
Where
1 siteIsrael
Study dates
24 Oct 2023to 30 Apr 2025
Phase
Phase 1/2
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 30 to 70 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • For inclusion into the trial, subjects are required to fulfill all of the following criteria:
  • Newly diagnosed PD patients:
  • Individuals who exclusively carry at least one single GBA1 variant without any additional genetic variants.
  • Confirmed diagnosis of PD, by a movement disorder specialist, according to MDS PD criteria, within a maximum of three years from the date of diagnosis, coupled with the following conditions:
  • Hoehn and Yahr staged between I-II, inclusive.
  • No motor fluctuations or L-dopa induced dyskinesia.
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  • Stable anti-PD medications for ≥ 4 weeks:
  • Subjects can take PD medications including NMDA glutamate antagonists, monoamine oxidase B (MAO-B) inhibitors, dopamine agonists, and L-Dopa.
  • Male or female, age 30-70 years; however, if female:
  • must be using contraception measures if of childbearing potential.
  • must not be lactating.
  • Complying with study protocol.

Who cannot join

  • Eligible subjects may not have any of the following exclusion criteria:
  • Presence of any medical, emotional, behavioral, or psychological condition that in the judgment of the Investigator would interfere with the subject's compliance with the requirements of the study (such as clinical depression).
  • Any other disorder that may interfere with the results of the efficacy endpoints.
  • Currently taking another investigational drug for any condition.
  • Use of dopaminergic treatment under these conditions:
  • L-Dopa equivalent daily dose > 400mg
Show all 12Show fewer
  • L-Dopa daily dose > 300mg
  • L-Dopa equivalent and L-Dopa daily dose has been changed in the past 4 weeks prior to screening visit.
  • Medical history of psychosis.
  • Exposure to ambroxol in the last 24 months prior to screening and/or history of adverse events to ambroxol.
  • Exposure to dopamine receptor blocking agents, lithium, cinnarizine, amiodarone or valproic acid in the last 12 months prior to screening.
  • Pregnancy or lactation; female subjects of a childbearing age who are unwilling to use contraceptive measures.

Trial locations and contacts

1 site in 1 country.

Majdolen Istaiti, MBA contact

+972526659995

joleen.istaiti@agyany-pharmaceuticals.com

Israel1 site, 1 recruiting

  • Shaare Zedek Medical Center

    Jerusalem, 9103102

    Michal Becker-Cohen, MSc, +972504606310, michalbc@szmc.org.il

    Shoshana Revel-Vilk, MD

    Recruiting

Other trials in Israel

About this study

Official title: An Open-Label Pilot Study for Assessing the Safety and Efficacy of High-Dose Ambroxol (HDA) in Newly Diagnosed GBA1 Parkinson Disease (PD)

Parkinson's disease (PD), affecting 10 million people globally, lacks a cure, and current therapies only manage symptoms. A link between Gaucher disease (GD) and PD, particularly in carriers of glucocerebrosidase (GBA1) mutations, has sparked interest in developing new drugs. Despite pharmaceutical companies focusing on formulations, progress is slow. Agyany, with decades of experience in GD research, plans clinical trials using existing generic drugs for GBA-related PD and idiopathic PD. Their approach targets the misfolded enzyme glucocerebrosidase with pharmacological chaperons, inspired by success in GD using ambroxol. The strategy aims to provide a quicker path to novel therapeutic options for PD.

Read the detailed description

Parkinson disease (PD) is the second most common neurodegenerative disease affecting around 10 million people worldwide. It is a debilitating disorder that despite many years and billions of dollars research - there is still no cure and none of the therapeutic options truly reverse its manifestations. The realization that the relationship between Gaucher disease (GD) - the rare lysosomal storage disease - and PD, also exists in carriers of the disease (with a mono-allele mutation in glucocerebrosidase (GBA1)) has led to several attempts to develop new drugs not just for GBA-related PD, but also for PD at large. However, heretofore all pharmaceutical companies have focused on finding new formulations, mostly based on what Agyany believe is not targeting the underlying pathology, but in any case, will require several years before new drugs will reach the market. With the background of three decades working at the world's largest center for GD at Shaare Zedek Medical Center in Jerusalem, and with a different understanding of the pathological processes leading to PD among a significant number of GD patients and carriers, Agyany plans to begin clinical trials in newly diagnosed PD patients using existing generic drugs that would enable a short path for introducing novel therapeutic approach to GBA-related PD and potentially also for so called idiopathic PD (when no genetic cause is known).

Based on our understanding of the underlying mechanism of GBA1-related PD, on research done in animal models and on our own anecdotal experience, Agyany believe that pharmacological chaperons are the most reasonable therapeutic modality to achieve success. Since the misfolding of the mutant enzyme, glucocerebrosidase, is the same both in GBA1-related PD and GD, and that the ambroxol impact is the same as well, Agyany can extrapolate from the success of ambroxol to achieve reversibility of neuronopathic features (that heretofore were considered irreversible, and the best expectation was lack of deterioration), in neuronopathic GD (nGD), to potential success in GBA-related PD.

The plan is to first use generic formulations with a confirmed safety profile and repurpose their indication to PD.

Being tested
Ambroxol Hydrochloride
Keywords
GBA1-related Parkinson Disease, Parkinson Disease, Glucocerebrosidase, Ambroxol
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

    75mg slow release (SR), X16/day or 300mg X4/day oral capsules.

Study groups in NCT06193421
Study groupRoleWhat they receive
Ambroxol hydrochlorideExperimentalDaily administration of Ambroxol in newly diagnosed GBA1 PD.
Receives: Drug: Ambroxol Hydrochloride

What is being measured

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

  1. Number of Participants With Treatment-Emergent Adverse Events (TEAEs), and Treatment-Emergent Serious Adverse Events (TESAEs)

    The outcome measure involves the assessment of adverse events (AEs) experienced by study participants throughout the duration of the trial. Adverse events will be documented, and their severity will be graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5. This comprehensive evaluation aims to provide a clear understanding of the safety profile of the intervention by specifically measuring and reporting the incidence and severity of treatment-emergent adverse events.

    Measured: 12 months

  2. Number of Participants With Potentially Clinically Significant Laboratory Abnormalities: Hematology

    Criteria for potentially clinically significant abnormalities (PCSA): Hemoglobin: less than or equal to (<=) 115 grams per liter (g/L) (Male[M]) or <=95 g/L (Female[F]), greater than or equal to (>=) 185 g/L (M) or >=165 g/L (F), Decrease from baseline (DFB) >=20 g/L; Hematocrit: <=0.37 volume/volume (v/v) (M) or <=0.32 v/v (F), >=0.55 v/v (M) or >=0.5 v/v (F); Red blood cells (RBC): >=6 Tera/L; Platelets: less than (<) 100 Giga/L, >=700 Giga/L; White blood cells (WBC): <3.0 Giga/L (Non-Black [NB]) or <2.0 Giga/L (Black [B]), >=16.0 Giga/L; Neutrophils: <1.5 Giga/L (NB) or <1.0 Giga/L (B); Lymphocytes: <lower limit of normal (LLN), greater than (>) 4.0 Giga/L; Monocytes: <LLN, >0.7 Giga/L; Basophils: >0.1 Giga/L; Eosinophils: >0.5 Giga/L or >upper limit of normal (ULN) (if ULN >=0.5 Giga/L).

    Measured: 12 months

  3. Number of Participants With Potentially Clinically Significant Laboratory Abnormalities: Biochemistry (Metabolic, Electrolytes, Renal and Liver Function)

    Criteria for PCSA: Alanine Aminotransferase (ALT): >3 ULN, >5 ULN; Aspartate aminotransferase (AST): >3 ULN; Alkaline phosphatase: >1.5 ULN; Total Bilirubin: >1.5 ULN; ALT and Bilirubin: >3 ULN and >2 ULN; Direct Bilirubin and Bilirubin: >35% and >1.5 ULN.

    Criteria for PCSA: Creatinine: >=150 micromoles per liter (mcmol/L) (adults), >=30% change from baseline, >=100% change from baseline; Blood urea nitrogen: >=17 millimoles (mmol)/L.

    Criteria for PCSA: Glucose: <=3.9 mmol/L and <LLN; >=11.1 mmol/L (unfasted [unfas]) or >=7 mmol/L (fasted [fas]); Albumin: <=25 g/L.

    Criteria for PCSA: Sodium: <=129 mmol/L, >=160 mmol/L; Potassium: <3 mmol/L, >=5.5 mmol/L and Chloride: <80 mmol/L, >115 mmol/L.

    Measured: 12 months

  4. Number of Participants With Potentially Clinically Significant Vital Signs Abnormalities

    Criteria for PCSA: Systolic blood pressure (SBP) supine: <=95 millimeters of mercury (mmHg) and DFB >=20 mmHg; >=160 mmHg and increase from baseline (IFB) >=20 mmHg; Diastolic blood pressure (DBP) supine: <=45 mmHg and DFB >=10 mmHg; >=110 mmHg and IFB >=10 mmHg; SBP (Orthostatic): <=-20 mmHg; DBP (Orthostatic): <=-10 mmHg; Heart rate (HR) supine: <=50 beats per minute (bpm) and DFB >=20 bpm; >=120 bpm and IFB >=20 bpm; Weight: >=5% DFB; >=5% IFB.

    Measured: 12 months

  5. Number of Participants With Abnormal Physical Examination Findings

    Routine physical examinations will be conducted to assess participants for any physical manifestations of adverse effects or safety concerns.

    In the final report the number of participants with new abnormal physical examination findings will be reported.

    Measured: 12 months

Secondary outcomes (2)

  1. Number of Participants With Significant Change in Transcranial Ultrasonography (TCS) of Substantia Nigra Region

    Transcranial Ultrasonography detects the area of hyper-echogenicity in the region of substantia nigra (values greater than 0.2 cm square are considered abnormal.

    Improvement from baseline will be assessed and considered significant if greater than 15% from baseline.

    Measured: 12 months

  2. Difference of dopamine turnover rate measured by Fluoro-Dopa-PET in the putamen between baseline and after 12 months of treatment.

    Change from baseline to end of study (EOS) in F-DOPA imaging will be qualitative as assessed by independent expert in nuclear medicine in a central imaging center.

    Measured: 12 months

Timeline

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

  1. First posted5 Jan 2024
  2. Study start24 Oct 2023
  3. Primary completion27 Feb 2025 (estimated)
  4. Study completion30 Apr 2025 (estimated)

Resources

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 1/2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Model description
Open label single arm study using ambroxol in newly diagnosed patients with motor Parkinson's disease.
Masking
None (open label)
Enrolment
40 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT06193421
Sponsor's protocol ID
AGPI
Status last verified
Feb 2024
First submitted
7 Nov 2023
Last updated
8 Feb 2024
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No: There is no plan to share such data.

Publications

  • Zimran A, Altarescu G, Elstein D. Pilot study using ambroxol as a pharmacological chaperone in type 1 Gaucher disease. Blood Cells Mol Dis. 2013 Feb;50(2):134-7. doi: 10.1016/j.bcmd.2012.09.006. Epub 2012 Oct 22.

    PubMed 23085429

  • 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

  • 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

  • Becker-Cohen M, Zimran A, Dinur T, Tiomkin M, Cozma C, Rolfs A, Arkadir D, Shulman E, Manor O, Paltiel O, Yahalom G, Berg D, Revel-Vilk S. A Comprehensive Assessment of Qualitative and Quantitative Prodromal Parkinsonian Features in Carriers of Gaucher Disease-Identifying Those at the Greatest Risk. Int J Mol Sci. 2022 Oct 13;23(20):12211. doi: 10.3390/ijms232012211.

    PubMed 36293067

  • Hannaway N, Zarkali A, Leyland LA, Bremner F, Nicholas JM, Wagner SK, Roig M, Keane PA, Toosy A, Chataway J, Weil RS. Visual dysfunction is a better predictor than retinal thickness for dementia in Parkinson's disease. J Neurol Neurosurg Psychiatry. 2023 Sep;94(9):742-750. doi: 10.1136/jnnp-2023-331083. Epub 2023 Apr 20.

    PubMed 37080759

  • Giladi N, Alcalay RN, Cutter G, Gasser T, Gurevich T, Hoglinger GU, Marek K, Pacchetti C, Schapira AHV, Scherzer CR, Simuni T, Minini P, Sardi SP, Peterschmitt MJ. Safety and efficacy of venglustat in GBA1-associated Parkinson's disease: an international, multicentre, double-blind, randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2023 Aug;22(8):661-671. doi: 10.1016/S1474-4422(23)00205-3.

    PubMed 37479372

  • Julien C, Hache G, Dulac M, Dubrou C, Castelnovo G, Giordana C, Azulay JP, Fluchere F. The clinical meaning of levodopa equivalent daily dose in Parkinson's disease. Fundam Clin Pharmacol. 2021 Jun;35(3):620-630. doi: 10.1111/fcp.12646. Epub 2021 Feb 23.

    PubMed 33458868

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Ambroxol Hydrochloride in people with Parkinson Disease and GBA Gene Mutation, run by Agyany Pharma LTD at 1 site in Israel.

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 12 inclusion and 12 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: status not confirmed, as of the sponsor's last update on 8 Feb 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Israel. 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. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

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?

Results are not available in the source record.

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

Contact Majdolen Istaiti, MBA (+972526659995, joleen.istaiti@agyany-pharmaceuticals.com), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of Participants With Treatment-Emergent Adverse Events (TEAEs), and Treatment-Emergent Serious Adverse Events (TESAEs) (time frame: 12 months). The study lists 5 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 NCT06193421, which also lists 7 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 8 Feb 2024.

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