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    Summary
    EudraCT Number:2017-003558-17
    Sponsor's Protocol Code Number:TRx-237-039
    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:2021-01-05
    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 number2017-003558-17
    A.3Full title of the trial
    Randomized, Double-Blind, Placebo-Controlled, Three-Arm, 12-Month, Safety and Efficacy Study of Hydromethylthionine Mesylate (LMTM) Monotherapy in Subjects with Alzheimer's Disease Followed by a 12-Month Open-Label Treatment
    Studio randomizzato, in doppio cieco, controllato con placebo, a tre bracci, della durata di 12 mesi, sulla sicurezza e sull’efficacia di idrometiltionina mesilato (LMTM) in monoterapia in soggetti con malattia di Alzheimer, seguito da un trattamento in aperto della durata di 12 mesi
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A comparison study of TRx0237 (LMTM) and placebo in patients with early Alzheimer's Disease.
    Studio di confronto tra TRx0237 (LMTM) e placebo in pazienti con malattia di Alzheimer iniziale
    A.3.2Name or abbreviated title of the trial where available
    LUCIDITY
    LUCIDITY
    A.4.1Sponsor's protocol code numberTRx-237-039
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03446001
    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 SponsorTAURX THERAPEUTICS LTD
    B.1.3.4CountrySingapore
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportTauRX Therapeutics Ltd
    B.4.2CountrySingapore
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationTauRx Therapeutics Ltd
    B.5.2Functional name of contact pointInformation Desk
    B.5.3 Address:
    B.5.3.1Street Address395 King Street
    B.5.3.2Town/ cityAberdeen
    B.5.3.3Post codeAB24 5RP
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+441224440905
    B.5.5Fax number+441224440
    B.5.6E-mailinfo@taurx.com
    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 nameLeuco-methylthioninium bis(hydromethanesulfonate)
    D.3.2Product code [TRx0237]
    D.3.4Pharmaceutical form Film-coated 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 INNNon ancora stabilito
    D.3.9.1CAS number 1236208-20-0
    D.3.9.2Current sponsor codeTRx0237
    D.3.9.3Other descriptive nameLEUCO-METHYLTHIONINIUM BIS (HYDROMETHANESULFONATE)
    D.3.9.4EV Substance CodeSUB91958
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number4
    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 placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    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
    Alzheimer’s Disease
    Morbo di Alzheimer
    E.1.1.1Medical condition in easily understood language
    Alzheimer’s Disease
    Morbo di Alzheimer
    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 10001896
    E.1.2Term Alzheimer's disease
    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
    To compare the LMTM dose of 16 mg/day with the placebo group on the following co-primary endpoints:
    a. ADAS-cog11
    b. ADCS-ADL23
    2. To assess the safety and tolerability of LMTM 16 mg/day given for up to 52 weeks
    Confrontare la dose di LMTM di 16 mg/die con il gruppo placebo rispetto ai seguenti endpoint co-primari:
    a. Scala di valutazione della malattia di Alzheimer, versione a 11 voci (ADAS-cog11)
    b. Studio cooperativo sulla malattia di Alzheimer - Attività della vita quotidiana, versione a 23
    voci (ADCS-ADL23)
    2. Valutare la sicurezza e la tollerabilità di LMTM 16 mg/die somministrato per un massimo di 52
    settimane
    E.2.2Secondary objectives of the trial
    3. To compare the LMTM dose of 16 mg/day with the placebo group in annualized rate of whole brain atrophy over 52 weeks as measured by
    brain MRI and quantified using the BSI
    4. To compare the LMTM dose of 16 mg/day with the placebo group in temporal lobe 18F-FDG-PET change in SUVR (normalized to pons) over 52 weeks, restricted to subjects with CDR 0.5 at Screening

    For additional secondary objectives please refer to protocol
    3. Confrontare la dose di LMTM di 16 mg/die con il gruppo placebo in termini di tasso annualizzato di atrofia dei lobi temporale e parietale nell’arco di 52 settimane, come misurata mediante imaging con risonanza magnetica (RM) cerebrale e quantificata utilizzando il Boundary Shift Integral (BSI)
    4. Confrontare la dose di LMTM di 16 mg/die con il gruppo placebo in termini di cambiamento alla tomografia ad emissione di positroni con F-fluorodesossiglucosio18 (18F-FDG-PET) del lobo temporale nel rapporto del valore di captazione standardizzato (SUVR) (normalizzazione sulla protuberanza anulare [pons]) nell’arco di 52 settimane, limitatamente ai soggetti con punteggio sulla scala per la valutazione clinica della demenza (Clinical Dementia Rating - CDR) pari a 0,5 allo screening

    Per gli altri obiettivi secondari si prega di riferirsi al protocollo
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives

    Pharmacogenomics
    Version: 4.1
    Date: 09/11/2018
    Title: GENOTYPING APOLIPOPROTEIN E
    Objectives: The gene being studied provides body with instructions for making an important protein called Apolipoprotein E (ApoE). There are several slightly different versions (alleles) of the ApoE gene. The Sponsor wants to find out if subjects have the E4 version, which is found in some people with Alzheimer’s disease. People with the ApoE E4 allele inherit an increased risk of developing Alzheimer disease, not the disease itself. Not all people with Alzheimer’s disease have the ApoE E4 allele.

    Farmacogenomica
    Versione: 4.1
    Data: 09/11/2018
    Titolo: GENOTYPING APOLIPOPROTEIN E
    Obiettivi: The gene being studied provides body with instructions for making an important protein called Apolipoprotein E (ApoE). There are several slightly different versions (alleles) of the ApoE gene. The Sponsor wants to find out if subjects have the E4 version, which is found in some people with Alzheimer’s disease. People with the ApoE E4 allele inherit an increased risk of developing Alzheimer disease, not the disease itself. Not all people with Alzheimer’s disease have the ApoE E4 allele
    E.3Principal inclusion criteria
    1. AD, encompassing probable AD and mild cognitive impairment due to AD (MCI-AD) based on 2011 National Institute on Aging (NIA) / Alzheimer's Association (AA) criteria:
    • All cause dementia and probably AD (probably AD)
    In brief, subjects with probable AD dementia must have insidious onset, worsening impairment in at least two cognitive areas (learning and recall, language, executive function, visuospatial skills), sufficient to significantly interfere with work or usual activities, that is not explained by delirium, drugs, major psychiatric disorder, medical illness, cerebrovascular disease, other forms of dementia, or neurological disorder. The accuracy of the diagnosis will be confirmed independently by the diagnosing physician at site
    OR
    •MCI-AD
    MCI-AD In subjects with MCI-AD, there should be evidence of concern about a change in cognition, in comparison with the person's previous level verified by a knowledgeable informant or clinician. Other mild cognitive deficits may also be present, but there must be preservation of independence in functional abilities. Subjects should not meet the criteria for dementia. The cognitive changes must be mild and there must be no evidence of a significant impairment in social or occupational functioning. Impairments must not be explained by delirium, drugs, major psychiatric disorder, medical illness, cerebrovascular disease, other forms of dementia, or neurological disorder.

    2.Documented PET scan that is positive for amyloid; if most recent PET scan was performed >3 years prior to Screening and was negative, it may be repeated (subjects are not eligible if their most recent PET scan was performed within the 3 years prior to Screening and was negative)

    3. MMSE score of 16-27 (inclusive) at Screening
    4. Global CDR score of 0.5 to 2 at Screening (if 0.5, including a score of > 0 in one of the functional domains: Community Affairs, Home and Hobbies, or Personal Care)
    5. Age < 90 years at Screening
    6. Females must meet one of the following:
    • Surgically sterile (hysterectomy, bilateral salpingectomy / oophorectomy) for at least 6 months minimum
    • Have undergone bilateral tubal occlusion / ligation at least 6 months prior
    • Post-menopausal for at least 1 year
    • Using adequate contraception (a barrier method [such as condom, diaphragm or cervical/vault cap] with spermicidal foam, gel, film, cream, or suppository; intrauterine device [IUD] or system, or oral or long- acting injected or implanted hormonal contraceptives for at least 90 days prior to Baseline; or vasectomized partner [with the appropriate post-vasectomy documentation of the absence of spermatozoa in the ejaculate]) or true abstinence (when this is in line with the preferred and usual lifestyle of the subject); subjects must be competent to use adequate contraception and to agree to continue to maintain adequate contraception throughout participation in the study (including up to 4 weeks after the last dose of study drug).

    7. Subject and/or, in the case of reduced decision-making capacity, legally acceptable representative(s) (LAR(s)), consistent with local and national law, is able to read, understand and provide written informed consent in the designated language of the study site

    For inclusion criteria 8 to 10 please refer to the protocol.
    1. AAD, inclusa probabile AD e lieve deterioramento cognitivo dovuto ad AD (MCI-AD) sulla base dei criteri del 2011 del National Institute on Aging (NIA)/Alzheimer’s Association (AA):
    • Demenza per qualsiasi causa e probabile AD (probabile AD)
    In breve, i soggetti con probabile demenza da AD devono presentare un’insorgenza insidiosa, un peggioramento della disfunzione in almeno due aree cognitive (apprendimento e memoria, eloquio, funzione esecutiva, capacità visuo-spaziali), sufficiente da interferire in modo significativo con il lavoro o le attività abituali, che non trova spiegazione nel delirio, farmaci, disturbi psichiatrici maggiori, malattia medica, malattia cerebrovascolare, altre forme di demenza o disturbo neurologico. LL’accuratezza della diagnosi sarà confermata in modo indipendente dal medico che effettua la diagnosi presso il centro
    OPPURE
    • MCI-AD
    ei soggetti con MCI-AD, deve essere presente evidenza di preoccupazione per un cambiamento nella cognizione, rispetto al precedente livello della persona verificato tramite una persona informata o un clinico che conosce il soggetto. Possono essere presenti anche altri lievi deficit cognitivi, ma deve essere preservata l’indipendenza nella capacità funzionali. I soggetti non devono soddisfare i criteri relativi alla demenza. I cambiamenti cognitivi devono essere lievi e non deve esservi evidenza di una significativa disfunzione nel funzionamento sociale oppure occupazionale. Le disfunzioni non devono essere spiegate da delirio, farmaci, disturbi psichiatrici maggiori, malattia medica, malattia cerebrovascolare, altre forme di demenza o disturbo neurologico
    2. PET documentata positiva all’amiloide; se la PET più recente è stata eseguita >3 anni prima dello screening ed era negativa, può essere ripetuta (i soggetti non sono idonei se la PET più recente è stata eseguita nei 3 anni precedenti allo screening ed è risultata negativa)
    3. Punteggio MMSE di 16-27 (incluso) allo screening
    4. Punteggio CDR globale pari a 0,5-2 allo screening (se 0,5, incluso un punteggio >0 in uno dei domini funzionali: attività comunitarie, casa e hobby o igiene personale)
    5. Età < 90 anni allo Screening
    6. I soggetti di sesso femminile devono soddisfare uno dei seguenti criteri:
    • Sottoposta a sterilizzazione chirurgica (isterectomia, salpingectomia/ovariectomia bilaterale) da almeno 6 mesi
    • Sottoposta a occlusione/legatura bilaterale delle tube da almeno 6 mesi
    • In post-menopausa da almeno 1 anno
    • Utilizzo di contraccettivo adeguato (un metodo barriera [come preservativo, diaframma o cappuccio cervicale] con schiuma, gel, film, crema o supposta spermicida; dispositivo intrauterino [IUD] o sistema intrauterino, oppure contraccettivi ormonali orali o iniettati o impiantati a lunga durata d’azione da almeno 90 giorni prima del basale; o partner sottoposto a vasectomia [con documentazione appropriata post-vasectomia che attesta l’assenza di spermatozoi nell’eiaculato]) oppure astinenza completa (quando ciò è in linea con lo stile di vita preferito e consueto del soggetto); i soggetti devono essere competenti nell’usare un contraccettivo adeguato e accettare di continuare a usare il contraccettivo adeguato per tutta la partecipazione allo studio (incluso fino a 4 settimane dopo l’ultima dose del farmaco dello studio)
    7. l soggetto e/o, in caso di ridotta capacità decisionale, il/i rappresentante/i legalmente accettabile/i (LAR), ai sensi della legge locale e nazionale, è/sono in grado di leggere, comprendere e fornire il consenso informato scritto nella lingua designata del centro dello studio

    Si rimanda alla sinossi del protocollo in italiano per l'elenco completo.
    E.4Principal exclusion criteria
    1. Significant central nervous system (CNS) disorder other than probable Alzheimer’s disease or MCI-AD, e.g., Lewy body dementia, Parkinson’s disease, multiple sclerosis, progressive supranuclear palsy, hydrocephalus, Huntington’s disease, any condition directly or indirectly caused by Transmissible Spongiform Encephalopathy (TSE), CreutzfeldtJakob Disease (CJD), variant Creutzfeldt-Jakob Disease (vCJD), or new variant Creutzfeldt-Jakob Disease (nvCJD)
    2. Significant intracranial focal or vascular pathology seen on brain MRI scan that would, based on the independent reviewer imaging evaluation, lead to a diagnosis other than probable Alzheimer’s disease or MCI-AD, including but not limited to:
    •Large confluent white matter hyperintense lesions (i.e., Fazekas score of 3)
    •Other focal brain lesions judged clinically relevant by the investigator
    •Evidence of a prior or current macrohemorrhage

    3. Clinical evidence or history of any of the following (within specified period prior to Baseline):
    • Cerebrovascular accident (2 years)
    • Transient ischemic attack (6 months)
    • Significant head injury with associated loss of consciousness, skull fracture or persisting cognitive impairment (2 years)
    • Other unexplained or recurrent loss of consciousness =15 minutes (2 years)
    4.Diagnosed with epilepsy (a single prior seizure >6 months prior to Screening, is considered acceptable)
    5. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) criteria met (for any of the following within specified period:
    • Major depressive disorder (current)
    • Schizophrenia (lifetime)
    • Other psychotic disorders, bipolar disorder (within the past 5 years)
    • Substance (including alcohol) related disorders (within the past 2 years)
    6. Metal implants in the head (except dental), pacemaker, cochlear implants, or any other non-removable items that are contraindications to MRI imaging. MRI compatible prosthetics, clips, stents, or any other device proven to be compatible are allowed
    7. Resides in hospital or moderate to high dependency continuous care facility (residence in low grade assisted living facility where there is sufficient autonomy to permit valid evaluation of activities of daily living is allowed so long as it is not mandated by an order issued either by the judicial or the administrative authorities)
    8.Any physical disability that would prevent completion of study procedures or assessments (e.g., blindness or significant uncorrected visual impairment, deafness or significant hearing loss not corrected by hearing aids, non AD-related speech impairment)
    9. History of swallowing difficulties (note: study drug should be swallowed whole and MUST NOT be broken, crushed, chewed, or dissolved in fluids prior to ingestion)
    10. Pregnant or breastfeeding
    11. Glucose-6-phosphate dehydrogenase (G6PD) deficiency based on World Health Organization classification (<60% of normal, i.e., <6.1 U/g hemoglobin [Hgb])

    For exclusion criteria 12 to 20 please refer to the protocol.
    1. Significativo disturbo del sistema nervoso centrale (SNC) diverso da probabile AD o MCI-AD, ad esempio demenza a corpi di Lewy, morbo di Parkinson, sclerosi multipla, paralisi sopranucleare progressiva, idrocefalo, malattia di Huntington, qualsiasi condizione direttamente o indirettamente causata da encefalopatia spongiforme trasmissibile (TSE), malattia di Creutzfeldt-Jakob (CJD), variante della malattia di Creutzfeldt-Jakob (vCJD) o nuova variante della malattia di Creutzfeldt-Jakob (nvCJD)
    2. Patologia intracranica focale o vascolare significativa osservata alla RM cerebrale che, secondo la valutazione delle immagini da parte di un revisore indipendente, determina una diagnosi diversa da probabile AD o MCI-AD, tra cui, senza limitazioni:
    • Vaste lesioni iperintense nella materia bianca confluenti (ovvero punteggio Fazekas di 3)
    • Altre lesioni cerebrali focali giudicate clinicamente rilevanti dallo sperimentatore
    • Evidenza di una macroemorragia precedente o attuale
    3. Evidenza clinica o anamnesi di uno qualsiasi dei seguenti eventi (entro il periodo specificato prima del basale):
    • Ictus cerebrovascolare (2 anni)
    • Attacco ischemico transitorio (6 mesi)
    • Traumatismo al capo significativo con associata perdita di coscienza, frattura cranica o deficit cognitivo persistente (2 anni)
    • Altra perdita di coscienza inspiegata o ricorrente =15 minuti (2 anni)
    4. Diagnosi di epilessia (una singola previa crisi convulsiva insorta >6 mesi prima dello screening è considerata accettabile)
    5. Soddisfare i criteri del Diagnostic and Statistical Manual of Mental Disorders, quinta edizione (per uno qualsiasi dei seguenti periodi specifici):
    • Disturbo depressivo maggiore (attuale)
    • Schizofrenia (nel corso della vita)
    • Altri disturbi psicotici, disturbo bipolare (negli ultimi 5 anni)
    • Disturbi associati all’uso di sostanze (incluso alcol) (negli ultimi 2 anni)
    6. Impianti metallici in testa (eccetto quelli dentali), pacemaker, impianti cocleari o qualsiasi altro elemento non rimovibile controindicato per la RM. Sono consentiti protesi, clip, stent o qualsiasi altro dispositivo che ha dimostrato di essere compatibile con la RM
    7. Risiede in ospedale o in una struttura che offre cure continuative di terapia intensiva e semi-intensiva (è consentita la residenza in una struttura con basso grado di assistenza in cui esiste un’autonomia sufficiente da consentire una valida valutazione delle attività della vita quotidiana, a condizione che non sia imposta da autorità giuridiche o amministrative)
    8. Qualsiasi invalidità fisica che impedirebbe il completamento delle procedure o valutazioni dello studio (ad esempio cecità o significativa compromissione della visione, sordità o significativa perdita dell’udito non corretta mediante ausili audiometrici, disturbo dell’eloquio non correlato all’AD)
    9. Anamnesi di difficoltà nella deglutizione (nota: il farmaco dello studio deve essere ingoiato intero e NON DEVE essere rotto, sbriciolato, masticato o sciolto in liquidi prima dell’ingestione)
    10. Stato di gravidanza o fase di allattamento
    11. Deficit di glucosio-6-fosfato deidrogenasi (G6PD) in base alla classificazione dell’Organizzazione Mondiale della Sanità (<60% del normale, ovvero <6,1 U/g emoglobina [Hgb])

    [...]
    Per i criteri di esclusione (12-20) si prega di far riferimento al protocollo
    E.5 End points
    E.5.1Primary end point(s)
    Primary Efficacy Endpoints for Double-Blind Treatment Period
    • ADAS-cog11 (LMTM 16 mg/day versus placebo)
    • ADCS-ADL23 (LMTM 16 mg/day versus placebo)
    Endpoint di efficacia primaria per il periodo di trattamento in doppio cieco
    • ADAS-cog11 (LMTM 16 mg / die rispetto al placebo)
    • ADCS-ADL23 (LMTM 16 mg / die rispetto al placebo)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Through the trial
    Tutta la durata dello studio
    E.5.2Secondary end point(s)
    Secondary Efficacy Endpoints for Double-Blind Treatment Period
    • Annualized rate of whole brain atrophy on brain MRI using BSI (LMTM
    16 mg/day versus placebo)
    • Difference in temporal lobe 18F-FDG-PET change in SUVR normalized to pons in subjects with CDR 0.5 at Screening (LMTM 16 mg/day versus placebo, and LMTM 8 mg/day versus placebo)
    • ADAS-cog11 and ADCS-ADL23 (LMTM 8 mg/day versus placebo)
    • Annualized rate of temporal and parietal lobe atrophy on brain MRI using BSI (LMTM 16 mg/day versus placebo, and LMTM 8 mg/day versus placebo)
    17.1.3 Secondary Endpoint for Open-Label, Delayed-Start Phase
    • Difference in disease progression on the co-primary clinical endpoints and the MRI imaging endpoint for subjects who started treatment in the double-blind treatment phase and those who started treatment in the open-label, delayed-start phase (referred to as "early" and "late" LMTM starters, respectively)
    o Only ADAS-cog11 will serve as a secondary endpoint; ADCS-ADL23 and other imaging endpoints are exploratory with the aim to be directionally supportive
    For exploratory endpoints, please refer to protocol.

    ¿
    Endpoint di efficacia secondari per il periodo di trattamento in doppio cieco
    • Tasso annuale di atrofia cerebrale intera sulla risonanza magnetica cerebrale mediante BSI (LMTM
    16 mg / die rispetto al placebo)
    • Differenza nella variazione del lobo temporale 18F-FDG-PET nel SUVR normalizzata a pons in soggetti con CDR 0,5 allo screening (LMTM 16 mg / die rispetto al placebo e LMTM 8 mg / die rispetto al placebo)
    • ADAS-cog11 e ADCS-ADL23 (LMTM 8 mg / die rispetto al placebo)
    • Tasso annuale di atrofia del lobo temporale e parietale sulla risonanza magnetica cerebrale mediante BSI (LMTM 16 mg / die rispetto al placebo e LMTM 8 mg / die rispetto al placebo)
    17.1.3 Endpoint secondario per fase di avvio ritardato con etichetta aperta
    • Differenza nella progressione della malattia sugli endpoint clinici co-primari e sull'endpoint di imaging MRI per i soggetti che hanno iniziato il trattamento nella fase di trattamento in doppio cieco e quelli che hanno iniziato il trattamento nella fase in aperto, con avvio ritardato (indicato come "precoce avviatori LMTM "e" in ritardo ", rispettivamente)
    o Solo ADAS-cog11 fungerà da endpoint secondario; ADCS-ADL23 e altri endpoint di imaging sono esplorativi con l'obiettivo di supportare direzionalmente
    Per gli endpoint esplorativi, fare riferimento al protocollo.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Throughout the trial
    Tutta la durata dello studio
    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 Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    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) Yes
    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 No
    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 trial3
    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 concerned13
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA51
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Belgium
    Canada
    Italy
    Poland
    Spain
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    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
    Last Subject Last Visit
    ultima visita dell'ultimo paziente
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months15
    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 months5
    E.8.9.2In all countries concerned by the trial days7
    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: 93
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 282
    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 state32
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 138
    F.4.2.2In the whole clinical trial 375
    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)
    Subjects who complete the study, whether on or off study drug, may be offered an opportunity to subsequently receive treatment with LMTM in a separate expanded access program.

    Otherwise subject will return to the standard of care as determined by their physician.
    Ai soggetti che completano lo studio, sia con o senza il farmaco in studio, potrà essere offerto l'opportunità di ricevere successivamente il trattamento con LMTM in un programma di accesso ampliato separato .
    Altrimenti il ¿¿soggetto tornerà allo standard di cura determinato dal proprio medico.
    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 Decision2019-05-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-02-05
    P. End of Trial
    P.End of Trial StatusOngoing
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