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    Summary
    EudraCT Number:2021-004565-13
    Sponsor's Protocol Code Number:GR-2018-12366771
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2022-09-06
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2021-004565-13
    A.3Full title of the trial
    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.
    Ambroxolo come trattamento modificante la malattia per ridurre il rischio di deterioramento cognitivo nella malattia di Parkinson associata a mutazione del gene GBA. Uno studio multicentrico, randomizzato, in doppio cieco, controllato con placebo, di fase 2.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of the mucolytic Ambroxol to slow down the progression of Parkinson's disease associated with the mutation of the GBA1 gene, performed in 3 Italian centers, compared with an inert drug (placebo) with random assignment.
    Studio del mucolitico Ambroxolo per rallentare la progressione della malattia di Parkinson associata alla mutazione del gene GBA1, effettuato in 3 centri clinici italiani, a confronto con un farmaco inerte (placebo) ad assegnazione casuale (random).
    A.3.2Name or abbreviated title of the trial where available
    High-dose Ambroxol as a disease-modifying treatment for Parkinson' disease
    Ambroxolo ad alta dose come terapia neuroprotettiva nella malattia di Parkinson
    A.4.1Sponsor's protocol code numberGR-2018-12366771
    A.5.4Other Identifiers
    Name:Project Code Ministry of HealthyNumber:GR-2018-12366771
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorFONDAZIONE IRCCS ISTITUTO NEUROLOGICO CARLO BESTA
    B.1.3.4CountryItaly
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMinistero della Salute
    B.4.2CountryItaly
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationFondazione IRCCS Istituto Neurologico Carlo Besta
    B.5.2Functional name of contact pointDipartimento Ricerca e Sviluppo Cli
    B.5.3 Address:
    B.5.3.1Street Addressvia Celoria 11
    B.5.3.2Town/ cityMilano
    B.5.3.3Post code20133
    B.5.3.4CountryItaly
    B.5.4Telephone number0223942020
    B.5.5Fax number0223942113
    B.5.6E-mailcrc@istituto-besta.it
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameAmbroxol hydrochloride
    D.3.2Product code [18683-91-5]
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAMBROXOL CLORIDRATO
    D.3.9.1CAS number 23828-92-4
    D.3.9.2Current sponsor code23828-92-4
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Parkinson's disease associated to mutation on the GBA1 gene
    Malattia di Parkinson con mutazione del gene GBA1
    E.1.1.1Medical condition in easily understood language
    Parkinson's disease
    Malattia di Parkinson
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10042832
    E.1.2Term Syndrome Parkinson's
    E.1.2System Organ Class 100000004852
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Provide preliminary evidence of the clinical efficacy of high-dose oral Ambroxol on the progression of cognitive dysfunction, using the outcome of the Montreal Cognitive Assessment (MoCA) test (primary endpoint) and of motor and non-motor symptoms (secondary endpoints) in the intermediate phase of PD associated to GBA1 mutation. As co-primary endpoint, in addition to changes in MoCA test scores, the frequency of conversion from normal cognitive functions (PD-N) to minor cognitive impairment (PD-MCI) and from PD-MCI to Parkinson-Dementia (PD-D) will also be calculated (Litvan et al., Mov Disord 2012;27(3):349-56).
    Fornire una prova preliminare dell'efficacia clinica di Ambroxolo orale ad alte dosi sulla progressione della disfunzione cognitiva, utilizzando come outcome di misura il risultato al test Montreal Cognitive Assessment (MoCA) (endpoint primario) ed una batteria estensiva di test neuropsicologici, nonché la valutazione di sintomi motori e non-motori (endpoint secondari) nella fase intermedia di GBA-PD. Come endpoint co-primario, in aggiunta ai cambiamenti nei punteggi del test MoCA, verrà calcolata anche la frequenza di conversione da funzioni cognitive normali (PD-N) a deficit cognitivo minore (PD-MCI) e da PD-MCI a Parkinson-Demenza (PD-D) (Litvan et al., Mov Disord 2012;27(3):349-56).
    E.2.2Secondary objectives of the trial
    To correlate clinical results at 52 weeks (assessment of cognitive features, motor and nonmotor symptoms, quality of life) with CSF markers of neurodegeneration (alpha-synuclein, Tau, phospho-Tau, beta-amyloid-42). Evaluate the safety and tolerability of oral Ambroxol at high doses. To correlate changes in clinical outcome measures with changes in GCase activity in the blood and cerebrospinal fluid (pharmacodynamics) based on Ambroxol levels in the blood and cerebrospinal fluid (pharmacokinetics) after 52 weeks of treatment, aiming (i) to confirm the blood-liquor penetration ratio of the bloodbrain barrier and (ii) to guide future phase 3 studies. To detect the subclinical neuroprotective effects of Ambroxol using brain Magnetic Resonance Imaging as surrogate biomarker of initial neuronal disorganization.
    Correlare i risultati clinici a 52 settimane con i marcatori liquorali di neurodegenerazione (alfa-sinucleina, Tau, fosfo-Tau, beta-amiloide-42). Valutare la sicurezza e la tollerabilità di Ambroxolo orale ad alte dosi. Correlare i cambiamenti nelle misure dell'outcome clinico con i cambiamenti dell'attività di GCase nel sangue e nel liquido cerebrospinale (farmacodinamica) in base ai livelli di Ambroxolo nel sangue e nel liquido cerebrospinale (farmacocinetica) dopo 52 settimane di trattamento, mirando (i) a confermare il rapporto sangue-liquor di penetrazione della barriera emato-encefalica e (ii) per guidare futuri studi di fase 3. Rilevare gli effetti neuroprotettivi subclinici di Ambroxolo utilizzando la Risonanza Magnetica cerebrale come biomarcatore
    surrogato di iniziale disorganizzazione neuronale.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Age 21-80 anni.
    - Diagnosis of Parkinson's disease
    - Duration of motor symptoms = 5 years
    - Heterozygous carrier of a GB1 mutation
    1) Età 21-80 anni.
    2) Diagnosi clinica di Malattia di Parkinson idiopatica
    3) Durata dei sintomi motori = 5 anni
    4) Portatore eterozigote di una mutazione nel gene GBA1
    E.4Principal exclusion criteria
    - Secondary and primary atypical Parkinsonism
    - Parkinson-Dementia MDS Criteria (21) (inability to express consent)
    - Hoehn & Yahr stage = 4/5 in Levodopa-ON condition
    - Deep brain stimulation (DBS)
    - Severe medical disorders, including past gastric / duodenal peptic ulcer, COPD, severe hepatic or renal dysfunction, bleeding diathesis or neoplastic diseases.
    - Women of childbearing age who do not accept a double anticonventional barrier.
    - Pregnancy or Breast-feeding.
    - Asthma
    - Known hypersensitivity to the active substance Ambroxol or to any of its excipients.
    - Parkinson-Demenza Criteri MDS (21) (incapacità di esprimere il proprio consenso)
    - Hoehn & Yahr stage = 4/5 in fase ON
    - Stimolazione cerebrale profonda (Deep Brain Stimulation, DBS)
    - Disturbi medici gravi, incluse pregressa ulcera peptica gastrica/duodenale, BPCO, gravi alterazioni epatiche o renali, diatesi emorragica o malattie neoplastiche.
    -Donne in età fertile che non accettino una doppia barriera anticoncenzionale
    - Donne in gravidanza o allattamento
    - Asma bronchiale
    - Ipersensibilità nota al principio attivo Ambroxolo o ad uno qualsiasi dei suoi eccipienti.
    E.5 End points
    E.5.1Primary end point(s)
    - change in the Montreal Cognitive Assessment (MoCA) score.
    - rate of conversion from normal cognition to either mild cognitive impairment or dementia.
    - cambiamento del punteggio al test Montreal Cognitive Assessment (MoCA).
    - frequenza di conversione da funzioni cognitive normali (PD-N) a deficit cognitivo minore (mild cognitive impairment, PD-MCI) e da PD-N o PDMCI a Parkinson-Demenza (PD-D).
    E.5.1.1Timepoint(s) of evaluation of this end point
    at baseline, week 26 and week 52 after the initiation of the experimental treatment
    al baseline, alla settimana 26 e alla settimana 52 dall'inizio del trattamento sperimentale
    E.5.2Secondary end point(s)
    (1) assessment of tolerability and safety (adverse events) of the IMP and drop-out frequency
    (2) changes in scores of scales and questionnaires used to assess cognitive functions and psychiatric features using extensive neuropsychological testing
    (3) changes in scores of scales/questionnaires assessing non-motor symptoms (using the Non-Motor Symptoms Scale, NMSS), autonomic dysfunction (using the COMPASS31), freezing of gait (using the FOG-Q) and sleep disturbances (using the RBD-questionnaire)
    (4) changes in scores of scales assessing motor features of PD (using MDS-UPDRS and Hoehn and Yahr stage)
    (5) changes in cortical thickness, cortical and subcortical volumes (3D T1-weighted images), white matter tract damage (diffusion tensor MRI), and resting state functional connectivity as assessed by brain MRI
    (6) changes in plasma levels of ambroxol and activity of glucocerebrosidase.
    (7) changes in CSF levels of ambroxol and activity of glucocerebrosidase.
    (8) changes in routine laboratory exams
    (9) changes in CSF levels of alpha-syn, Tau, phospho-Tau, beta amyloid-42.
    (1) Valutazione sicurezza e tollerabilità dell'IMP attraverso la raccolta sistematica di tutti gli eventi avversi (AEs) e la frequenza dei drop-out
    (2) Variazioni nei punteggi delle scale e dei questionari usati per valutare le funzioni cognitive e le caratteristiche psichiatriche usando una batteria di test neuropsicologici.
    (3) Variazioni nei punteggi delle scale/questionari che valutano sintomi non-motori e la qualità della vita: qualità della vita (39-item Parkinson’s disease Questionnaire, PDQ39); disfunzione autonomica (COMPASS31); Sintomi Non Motori (Non-Motor Symptoms Scale, NMSS); freezing of gait questionnaire (FOG-Q); RBD-questionnaire (RBDQ).
    (4) Variazioni nei punteggi delle scale che valutano sintomi e segni motori: MDS-UPDRS parti II e parte III; Stadio Hoehn & Yahr.
    (5) Variazioni nello spessore corticale, i volumi corticali e sottocorticali (immagini 3D T1-pesate), il danno del tratto della sostanza bianca (tensore di diffusione) e la connettività funzionale a riposo utilizzando la risonanza magnetica cerebrale
    (6) variazioni nei livelli plasmatici di Ambroxolo e nell'attività dell'enzima GCase.
    (7) variazioni nei livelli liquorali di Ambroxolo in compresse dopo 52 settimane di trattamento e nell'attività dell'enzima glucocerebrosidasi, mirando a (i) valutare il rapporto sangue-liquor di penetrazione della barriera emato-encefalica e (ii) guidare studi futuri di fase 3.
    (8) variazioni degli esami ematochimici di routine
    (9) variazioni dei livelli liquorali dei markers di neurodegenerazione (alfa-sinucleina, Tau, fosfo-Tau, beta-amiloide-42)
    E.5.2.1Timepoint(s) of evaluation of this end point
    (1) throughout the study using patient home diaries. Objective assessment at week 12, week 26, week 38, week 52 after the initiation of the experimental treatment.
    (2, 5, 7, 8, 9) at baseline and at week 52 after the initiation of the experimental treatment.
    (3, 4) at baseline, at week 26 and at week 52 after the initiation of the experimental treatment.
    (6) at baseline (for GCase only), at week 26 and at week 52 after the initiation of the experimental treatment.
    - Endpoints secondari 3,4: baseline, alla settimana 26 e alla settimana 52 dall’inizio del trattamento sperimentale.
    - Endpoint 1: durante tutto lo studio utilizzando i diari di casa del paziente. Valutazione oggettiva alla settimana 12, settimana 26, settimana 38, settimana 52 dopo l'inizio del trattamento sperimentale.
    - Endpoints 2, 5, 7, 8, 9: baseline e alla settimana 52 dall’inizio del trattamento sperimentale.
    - Endpoint 6: basale (solo per attività di GCase, non verrà invece dosato ambroxolo), alla settimana 26 e alla settimana 52 dopo l'inizio del trattamento sperimentale.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 35
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 25
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state60
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 60
    F.4.2.2In the whole clinical trial 60
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Follow-up of patients treated with ambroxol for adverse events (after unblinding)
    Monitoraggio di eventuale emergenza di eventi avversi a distanza
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2021-12-03
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-09-08
    P. End of Trial
    P.End of Trial StatusOngoing
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