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    Summary
    EudraCT Number:2018-004739-58
    Sponsor's Protocol Code Number:BAN2401-G000-301
    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:2021-01-29
    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 number2018-004739-58
    A.3Full title of the trial
    A Placebo-Controlled, Double-Blind, Parallel-Group, 18-Month Study With an Open-Label Extension Phase to Confirm Safety and Efficacy of BAN2401 in Subjects With Early Alzheimer's Disease
    Studio di 18 mesi, in doppio cieco, a gruppi paralleli, controllato con placebo, con una fase di estensione in aperto per confermare la sicurezza e l'efficacia di BAN2401 in soggetti affetti da morbo di Alzheimer precoce
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 3 clinical study to investigate the effects of BAN2401 in patients with Early Alzheimer's Disease
    Studio di fase 3 per studiare gli effetti di BAN2401 in pazienti affetti da morbo di Alzheimer precoce
    A.3.2Name or abbreviated title of the trial where available
    na
    na
    A.4.1Sponsor's protocol code numberBAN2401-G000-301
    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 SponsorEISAI LIMITED
    B.1.3.4CountryUnited Kingdom
    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 supportEisai Limited
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationEisai Limited
    B.5.2Functional name of contact pointMedical Information
    B.5.3 Address:
    B.5.3.1Street AddressMosquito Way
    B.5.3.2Town/ cityHatfield
    B.5.3.3Post codeAL10 9SN
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number00448456761400
    B.5.5Fax number00448456761486
    B.5.6E-mailLMedInfo@eisai.net
    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 nameBAN2401
    D.3.2Product code [na]
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.1CAS number 1260393-98-3
    D.3.9.2Current sponsor codeBAN2401
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    D.3.11.13.1Other medicinal product typeAnticorpo monoclonale
    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 placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's disease dementia
    Lieve deficit cognitivo dovuto a malattia di Alzheimer o demenza di Alzheimer lieve
    E.1.1.1Medical condition in easily understood language
    Mild cognitive impairment or mild dementia caused by Alzheimer's disease which results in progressive memory loss, reasoning, language and other mental abilities.
    Lieve deficit cognitivo o demenza lieve causata dal morbo di Alzheimer che si traduce in perdita progressiva di memoria, ragionamento, linguaggio e altre abilità mentali.
    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 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10074616
    E.1.2Term Prodromal Alzheimer's disease
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Core
    • To evaluate the efficacy of BAN2401 in subjects with early Alzheimer’s disease (EAD) by determining the superiority of BAN2401 compared with placebo on the change from baseline in the Clinical Dementia Rating–Sum of Boxes (CDR SB) at 18 months of treatment

    Extension
    • To evaluate the long term safety and tolerability of BAN2401 in subjects with EAD in the Extension Phase
    • To evaluate whether the long-term effects of BAN2401 as measured by the CDR-SB at the end of the Core Study is maintained over time in the Extension Phase
    Studio Principale

    • Valutare l’efficacia di BAN2401 nei soggetti affetti da morbo di Alzheimer in fase iniziale (EAD), dimostrando la superiorità di BAN2401 rispetto al placebo in base alle variazioni della scala Clinical Dementia Rating–Sum of Boxes (CDR SB) intercorse tra il Basale e il mese 18 di trattamento

    Fase di estensione
    • Valutare la sicurezza e la tollerabilità a lungo termine di BAN2401 nei soggetti affetti da EAD durante la Fase di Estensione
    • Valutare se gli effetti a lungo termine di BAN2401 misurati mediante CDR SB al termine dello Studio Principale siano mantenuti nel tempo nella Fase di Estensione
    E.2.2Secondary objectives of the trial
    Key Secondary Objective
    • To determine that BAN2401 is superior to placebo in reducing brain amyloid levels as measured by amyloid positron emission tomography (PET) at 18 months of treatment in subjects with EAD
    • To evaluate the efficacy of BAN2401 in subjects with EAD by determining the superiority of BAN2401 compared with placebo on the change from baseline in the Alzheimer’s disease (AD) composite score (ADCOMS) at 18 months of treatment
    • To evaluate the efficacy of BAN2401 in subjects with EAD by determining the superiority of BAN2401 compared with placebo on the change from baseline in the AD Assessment Scale–Cognitive Subscale14 (ADAS-cog14) at 18 months of treatment

    For all other objectives see protocol.
    Obiettivi secondari chiave
    • Dimostrare che BAN2401 è superiore al placebo nel ridurre i livelli di amiloide cerebrale misurati mediante tomografia a emissione di positroni (PET) per l’amiloide eseguita a 18 mesi di trattamento nei soggetti affetti da EAD
    • Valutare l’efficacia di BAN2401 nei soggetti affetti da EAD dimostrando la superiorità di BAN2401 rispetto al placebo in base alle variazioni dell’ADCOMS [Punteggio Composito per il Morbo di Alzheimer (AD)] osservate a 18 mesi di trattamento rispetto al Basale
    • Valutare l’efficacia di BAN2401 nei soggetti affetti da EAD dimostrando la superiorità di BAN2401 rispetto al placebo in base alle variazioni dell’ADAS-cog14 (Scala per la Valutazione dell’AD – Sottoscala Cognitiva 14) osservate a 18 mesi di trattamento rispetto al Basale

    Per tutti gli altri obiettivi, fare riferimento 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

    Other types of substudies
    Specify title, date and version of each substudy with relative objectives: There will be 3 longitiudinal substudies: amyloid PET, CSF biomarker assessments, and tau PET. Participation in these substudies is optional and will require specific consent that will not affect enrollment or treatment in the main study. Subjects may participate in 1 or more substudies. However, the longitudinal tau PET will be offered only to subjects who 1) enroll at sites able to participate (based on the site’s geographical location or proximity to the tau PET ligand manufacturing sites), 2) have an amyloid positive study-specific PET scan at baseline, 3) consent to participate in the longitudinal amyloid PET substudy, and 4) have a tau positive study-specific PET scan at baseline. For any given subject participating in the imaging substudies (amyloid PET and/or tau PET), the same PET tracer must be used at the baseline and postbaseline assessments.
    Longitudinal amyloid PET assesments will be conducted at 3, 6, 12, and 18 months of treatment in consenting subjects from participating countries to demonstrate target engagement and to assess amyloid clearance for BAN2401. Longitudinal CSF assessments will be performed at 12 and 18 months of treatment for soluble biomarker analysis (eg, Aß[1-42], neurogranin, NFL, t-tau, and p-tau) in consenting subjects in participating countries to assess effects on indicators of disease pathology.
    Longitudinal tau PET assessments will be performed at 13 and 18 months of treatment using a sponsor-supplied tau PET imaging agent. For subjects who discontinue early from the study drug, an early termination amyloid PET scan will be performed only if the preceding amyloid PET assessment was performed 3 or more months prior to the early termination visit. The medical monitor must be consulted before an early termination tau PET scan is performed.

    Altre tipologie di sottostudi
    specificare il titolo, la data e la versione di ogni sottostudio con i relativi obiettivi: Saranno effettuati 3 sottostudi longitudinali: PET per l’amiloide, valutazioni dei biomarcatori nell’LCR e PET per la tau. La partecipazione a questi sottostudi è facoltativa e richiederà un consenso specifico che non influenzerà l’arruolamento o il trattamento nello Studio Principale. I soggetti possono partecipare a 1 o più sottostudi. Il sottostudio longitudinale con PET per la tau sarà comunque proposto soltanto ai soggetti che 1) vengono arruolati presso i centri in grado di partecipare (secondo la posizione geografica dei centri o la loro vicinanza ai siti di produzione del ligando della tau per PET), 2) presentano al basale una scansione PET positiva per l’amiloide studio specifica, 3) hanno acconsentito a partecipare al sottostudio longitudinale con PET per amiloide e 4) presentano al basale una scansione PET positiva per tau studio specifica. In un determinato soggetto che partecipa ai sottostudi di imaging (PET per amiloide e/o per tau) deve essere utilizzato lo stesso tracciante per PET alle valutazioni basali e postbasali.
    Le valutazioni longitudinali mediante PET per amiloide saranno eseguite a 3, 6, 12 e 18 mesi di trattamento in soggetti consenzienti selezionati nei paesi partecipanti per dimostrare il coinvolgimento delle molecole bersaglio e per valutare la clearance dell’amiloide per BAN2401. Saranno effettuate valutazioni longitudinali dell’LCR a 12 e 18 mesi di trattamento per analizzare i biomarcatori solubili (per es., Aß[1-42], neurogranina, NFL, t-tau e p-tau) in soggetti consenzienti selezionati nei paesi partecipanti per valutare gli effetti sugli indicatori della patologia. (come modificato dall’Emendamento 01)
    Le valutazioni longitudinali mediante PET per tau saranno effettuate a 13 e 18 mesi di trattamento servendosi di un tracciante per scansioni PET per tau fornito dallo sponsor. Nei soggetti che interrompono anticipatamente il farmaco in studio, una scansione PET per amiloide di Interruzione Anticipata sarà eseguita soltanto se la precedente valutazione mediante PET per amiloide è stata effettuata 3 o più mesi prima della Visita di Interruzione Anticipata. Il medical monitor deve essere consultato prima che venga effettuata una scansione PET per tau di Interruzione Anticipata.
    E.3Principal inclusion criteria
    Diagnosis
    MCI due to AD–intermediate likelihood:
    1. Meet the National Institute of Aging–Alzheimer’s Association (NIA-AA) core clinical criteria for MCI due to AD–intermediate likelihood.
    2. Have a global CDR score of 0.5 and a CDR Memory Box score of 0.5 or greater at Screening and Baseline.
    3. Report a history of subjective memory decline with gradual onset and slow progression over the last 1 year before Screening; must be corroborated by an informant.
    Mild AD dementia:
    4. Meet the NIA-AA core clinical criteria for probable AD dementia.
    5. Have a global CDR score of 0.5 to 1.0 and a CDR Memory Box score of 0.5 or greater at Screening and Baseline.
    Key Inclusion Criteria that must be met by all subjects:
    6. Objective impairment in episodic memory as indicated by at least 1 standard deviation below age-adjusted mean in the WMS-IV LMII, as follows:
    a. =15 for age 50 to 64 years
    b. =12 for age 65 to 69 years
    c. =11 for age 70 to 74 years
    d. =9 for age 75 to 79 years
    e. =7 for age 80 to 90 years
    7. Positive biomarker for brain amyloid pathology as indicated by at least 1 of the following:
    a. PET assessment of imaging agent uptake into brain. Note: amyloid PET screens will be performed according to local regulatory guidelines and thus may be restricted for those subjects who are not suitable for lumbar puncture (LP) to obtain CSF for testing of eligibility.
    b. CSF assessment of t-tau/Aß[1-42]
    NOTE1: Subjects who are on anticoagulant therapy may not participate in CSF assessments. NOTE2: Subjects may consent to both the PET and CSF assessments, but to confirm eligibility, a positive amyloid result is needed in only 1 of the 2 procedures (ie, the subject will be eligible even if 1 of the 2 results does not meet its eligibility criterion). Subjects who consent to amyloid PET or CSF at Screening for the purposes of eligibility are not required to participate in the amyloid PET, tau PET, or CSF longitudinal substudies. Use of a historical amyloid positive PET (conducted within 12 months before the planned date of randomization) is acceptable for determination of eligibility provided the subject had not participated in any clinical studies involving anti-amyloid therapies subsequent to the PET assessment. Historical PET will not suffice for the baseline assessment if the subject wishes to consent to the amyloid PET longitudinal substudy. The historical imaging data must be made available to the sponsor to confirm amyloid positivity.
    8. Male or female subjects aged =50 and =90 years, at the time of informed consent.
    9. MMSE score greater than or equal to 22 at Screening and Baseline and less than or equal to 30 at Screening and Baseline.
    10. Body mass index (BMI) greater than 17 and less than 35 at Screening.

    Extension Phase:
    1. Subjects who have completed the Core Study.
    2. Have a BMI greater than 17 and less than 35.
    3. Must continue to have a study partner who is willing and able to provide follow-up information on the subject throughout the course of the Extension Phase. The study partner must provide separate written informed consent for the Extension Phase. Study partners must continue to participate in person for visits where clinical assessment of CDR (global and CDR-SB), EQ-5D-5L, QOL-AD, ADCS MCI-ADL, and Zarit Burden Interview take place.
    4. Provide written informed consent for the Extension Phase. If a subject lacks capacity to consent in the investigator's opinion, the subject's assent should be obtained, if required and in accordance with local laws, regulations and customs, plus the written informed consent of a legal representative should be obtained (capacity to consent and definition of legal representative should be determined in accordance with applicable local laws and regulations). In countries where local laws, regulations, and customs do not permit subjects who lack capacity to consent to participate in this study (eg, Germany and Spain), they will not be enrolled.
    See protocol for full list.
    Diagnosi
    MCI dovuto a probabilità intermedia di AD:
    1. Risponde ai principali criteri clinici del National Institute of Aging–Alzheimer’s Association (NIA-AA) relativi all’MCI dovuto a probabilità intermedia di AD.
    2. Presenta un punteggio globale di 0,5 alla scala CDR e un punteggio di 0,5 o maggiore alla scala CDR Memory Box allo Screening e al Basale.
    3. Riferisce un’anamnesi di declino soggettivo della memoria con insorgenza graduale e progressione lenta nell’arco dell’anno precedente lo Screening; la dichiarazione deve essere confermata da una persona informata.
    Demenza da AD lieve:
    4. Risponde ai principali criteri clinici NIA-AA relativi alla demenza da probabile AD.
    5. Presenta un punteggio globale da 0,5 a 1,0 alla scala CDR e un punteggio di 0,5 o maggiore alla scala CDR Memory Box allo Screening e al Basale.
    Principali Criteri di Inclusione ai quali tutti i soggetti dovranno rispondere:
    6. Deterioramento oggettivo della memoria episodica, come indicato da almeno una deviazione standard al di sotto della media corretta per età nella WMS-IV LMII, corrispondente ai seguenti parametri:
    a. =15 per i soggetti di età compresa tra i 50 e i 64 anni
    b. =12 per i soggetti di età compresa tra i 65 e i 69 anni
    c. =11 per i soggetti di età compresa tra i 70 e i 74 anni
    d. =9 per i soggetti di età compresa tra i 75 e i 79 anni
    e. =7 per i soggetti di età compresa tra gli80 e i 90 anni
    7. Biomarcatori positivi per la patologia da amiloide cerebrale, come indicato da almeno 1 dei seguenti parametri:
    a. Valutazione PET dell’assorbimento del tracciante nel cervello. N.B.: le scansioni PET per amiloide saranno eseguite in conformità con le linee guida locali di regolamentazione e potranno perciò essere limitate per i soggetti che non risultino idonei alla puntura lombare (LP) necessaria per ottenere il LCR richiesto per verificare l’idoneità.
    b. Analisi del LCR per la proteina t-tau/Aß[1-42]
    N.B. 1: i soggetti in terapia con anticoagulanti non potranno partecipare alle valutazioni del LCR. (come modificato dall’Emendamento 05)
    N.B.2: i soggetti potranno autorizzare sia la valutazione PET, sia quella delLCR, ma per confermare l’idoneità sarà necessario un risultato positivo per l’amiloide in una sola delle due procedure (cioè, il soggetto risulterà idoneo anche se uno dei due risultati non risponderà al relativo criterio di idoneità). I soggetti che autorizzeranno la valutazione PET per amiloide o quella delLCR allo Screening a scopo di verifica dell’idoneità, non saranno obbligati a partecipare ai sottostudi longitudinali con PET per amiloide, PET per tau o LCR. Per stabilire l’idoneità sarà accettato l’uso di una PET positiva per amiloide precedentemente eseguita (durante i 12 mesi precedenti la data fissata per la randomizzazione), a condizione che il soggetto non abbia partecipato a studi clinici che comportano l’uso di terapie anti amiloide dopo la valutazione mediante PET. La PET precedentemente eseguitanon sarà sufficiente per la valutazione basale nel caso in cui il soggetto intenda acconsentire a partecipare al sottostudio longitudinale con PET per amiloide. I dati di imaging precedentemente eseguiti dovranno essere messi a disposizione dello sponsor, per confermare la positività per l’amiloide. (come modificato dall’Emendamento 01)
    8. Soggetti di sesso maschile o femminile di età compresa tra =50 e =90 anni al momento del consenso informato.
    9. Punteggio MMSE superiore o pari a 22 allo Screening e al Basale e inferiore o pari a 30 allo Screening e al Basale.
    10. Indice di massa corporea (BMI) superiore a 17 e inferiore a 35 allo Screening.

    Fase di estensione:
    1. Completare lo Studio Principale.
    2. Indice di massa corporea superiore a 17 e inferiore a 35.

    Per la lista completa consultare il protocollo.
    E.4Principal exclusion criteria
    Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive beta-human chorionic gonadotropin [ß-hCG] or human chorionic gonadotropin [hCG] test with a
    minimum sensitivity of 25 IU/L or equivalent units of ß-hCG [or hCG]). A separate baseline assessment is required if a negative Screening pregnancy test was obtained more than 72 hours before the first dose of study drug.
    2. Females of childbearing potential who:
    ¿ Within 28 days before study entry, did not use a highly effective method of contraception, which includes any of the following:
    o total abstinence (if it is their preferred and usual lifestyle)
    o an intrauterine device or intrauterine hormone-releasing system (IUS)
    o a contraceptive implant
    o an oral contraceptive (with additional barrier method) (Subject must be on a stable dose of the same oral contraceptive product for at least 28 days before dosing and throughout the study and for 28 days after study drug discontinuation.)
    o have a vasectomized partner with confirmed azoospermia.
    ¿ Do not agree to use a highly effective method of contraception (as described above) throughout the entire study period and for 28 days after study drug discontinuation.
    ¿ For sites outside of the EU, it is permissible that if a highly effective method of contraception is not appropriate or acceptable to the subject, then the subject must agree to use a medically acceptable method of contraception, ie, double-barrier methods of contraception such as latex or synthetic condom plus diaphragm or cervical/vault cap with spermicide.
    NOTE: All females will be considered to be of childbearing potential unless they are postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age group, and without other known or suspected cause) or have been sterilized surgically (ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing).
    3. Any neurological condition that may be contributing to cognitive impairment above and beyond that caused by the subject’s AD.
    4. History of transient ischemic attacks (TIA), stroke, or seizures within 12 months of Screening.
    5. Any psychiatric diagnosis or symptoms, (eg, hallucinations, major depression, or delusions) that could interfere with study procedures in the subject.
    6. Geriatric Depression Scale (GDS) score greater than or equal to 8 at Screening.
    7. Contraindications to MRI scanning, including cardiac pacemaker/defibrillator, ferromagnetic metal implants (eg, in skull and cardiac devices other than those approved as safe for use in MRI scanners).
    8. Evidence of other clinically significant lesions on brain MRI at Screening that could indicate a dementia diagnosis other than AD.

    Extension Phase:
    1. Subjects who discontinued early from the Core Study.

    See protocol for full list.
    1. Donne in fase di allattamento o in gravidanza allo Screening o al Basale (come verificato mediantetest della beta gonadotropina corionica umana [ß-hCG] o test dellagonadotropina corionica umana [hCG] con sensibilità minima di 25 UI/l o di unità equivalenti di ß-hCG [o hCG]). Se il test di gravidanza negativo allo Screening sarà stato ottenuto più di 72 ore prima della prima dose di farmaco in studio, sarà necessaria una valutazione basale a parte.
    2. Donne potenzialmente fertili che:
    • Non abbiano utilizzato un metodo anticoncezionale ad alta efficacia durante i 28 giorni precedenti l’arruolamento nello studio. Si considerano altamente efficaci i seguenti metodi:
    • astinenza totale (ove coincida con lo stile di vita preferito e abitualmente praticato)
    • dispositivo intrauterino o sistema intrauterino a rilascio ormonale (IUS)
    • impianto anticoncezionale
    • contraccettivo orale (associato a metodo di barriera) (i soggetti dovranno assumere una dose stabile dello stesso contraccettivo orale da almeno 28 giorni prima del dosaggio, per tutta la durata dello studio e per i 28 giorni successivi all’interruzione del farmaco in studio.)
    • vasectomia del partner con azoospermia confermata.
    • Non accettino di utilizzare un metodo anticoncezionale ad alta efficacia (come precedentemente descritto) per l’intero periodo di studio e per i 28 giorni successivi all’interruzione del farmaco in studio.
    • Per i centri che non hanno sede nell’UE, è consentito che, ove un metodo anticoncezionale ad alta efficacia non sia adeguato o accettabile per il soggetto, quest’ultimo garantisca di utilizzare un metodo anticoncezionale medicalmente accettabile, cioè metodi anticoncezionali di doppia barriera come preservativo in lattice o sintetico associato a diaframma o a cappuccio/coppetta cervicale con spermicida.
    N.B.: tutte le donne saranno considerate potenzialmente fertili a meno che non siano in fase di post-menopausa (amenorrea da almeno 12 mesi consecutivi, fascia di età adeguata e assenza di altre cause note o sospette) o non siano state sterilizzate mediante intervento chirurgico (legatura bilaterale delle tube, isterectomia totale o ooforectomia bilaterale, in ogni caso con intervento chirurgico avvenuto almeno 1 mese prima del dosaggio).
    3. Presenza di qualsiasi condizione neurologica che possa contribuire al deterioramento cognitivo a prescindere da quello provocato dall’AD.
    4. Anamnesi di attacco ischemico transitorio (TIA), ictus o convulsioni durante i 12 mesi precedenti lo Screening.
    5. Qualsiasi diagnosi o sintomo psichiatrico (per es., allucinazioni, depressione maggiore o deliri) in grado di interferire con le procedure di studio richieste al soggetto.
    6. Punteggio alla Scala della Depressione Geriatrica (GDS) superiore o pari a 8 allo Screening.
    7. Controindicazioni alla scansione RMI, ivi compresi pacemaker/defibrillatore cardiaco e impianti metallici ferromagnetici (per es., dispositivi cranici e cardiaci diversi da quelli approvati come sicuri in caso di scansione RMI).
    8. Evidenza alla RMI cerebrale di Screening di altre lesioni clinicamente significative che potrebbero indicare una diagnosi di demenza diversa dall’AD.

    Fase di estensione:
    1. Trattamento dello Studio Principale interrotto anticipatamente.

    Per la lista completa consultare il protocollo.
    E.5 End points
    E.5.1Primary end point(s)
    Core
    • Change from baseline in the CDR-SB at 18 months .

    Extension
    • Safety assessments will be based on medical review of AE reports and the results of vital sign measurements, ECG, physical examinations, clinical laboratory tests, ADA test results, and any relevant test of cognitive function to evaluate decline. Additionally, MRI assessments of microhemorrhage, vasogenic edema, and other clinically significant abnormalities will be evaluated.
    • Change from Core Study baseline in CDR-SB
    Studio Principale
    • Variazione della scala CDR-SB a 18 mesi rispetto al Basale

    Fase di Estensione
    • Le valutazioni di sicurezza si baseranno sulla revisione medica dei rapporti sugli AE e dei risultati della misurazione di parametri vitali, ECG, esame obiettivo, analisi cliniche di laboratorio, risultati delle analisi degli ADA e di tutti gli appositi test per valutare il declino della funzione cognitiva. Saranno valutate inoltre le scansioni RMI per microemorragie, edema vasogenico e altre anomalie clinicamente significative.
    • Variazione di CDR SB rispetto al basale dello Studio Principale.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Core
    •18 months
    Studio Principale
    •18 mesi
    E.5.2Secondary end point(s)
    Key secondary endpoints:
    • Change from baseline in amyloid PET standard uptake value ratio (SUVR) composite at 18 months for brain amyloid levels
    • Change from baseline in ADCOMS at 18 months
    • Change from baseline in ADAS-cog14 at 18 months; Other Secondary Endpoints
    • Rate of change over time (mean slope) based on CDR-SB score over 18 months
    • Correlation between changes in CDR-SB and changes in amyloid PET SUVR composite for brain amyloid levels
    • Time to worsening of global CDR scores at 18 months, eg, the worsening of global CDR score is defined as an increase from baseline by at least 0.5 points on the global CDR scale on 2 consecutive scheduled visits at which global CDR is undertaken
    • Change from baseline in MMSE at 18 months
    • Incidence of AEs and changes in vital signs, ECGs, laboratory safety tests, suicidality assessments, and MRI safety parameters
    • Population PK parameters of BAN2401 in serum, including but not limited, to AUC, Cav
    Endpoint Secondari Chiave:
    • Variazione del rapporto SUV composito (standard uptake value ratio) della PET per amiloide a 18 mesi rispetto al Basale per i livelli di amiloide cerebrale
    • Variazione della scala ADCOMS a 18 mesi rispetto al Basale
    • Variazione della scala ADAS-cog14 a 18 mesi rispetto al Basale; Altri Endpoint Secondari
    • Tasso di variazione nel tempo (pendenza media) in base al punteggio CDR-SB nell’arco di 18 mesi
    • Correlazione tra le variazioni della scala CDR-SB e le variazioni del rapporto SUV composito della PET per l’amiloide per i livelli di amiloide cerebrale
    • Tempo di peggioramento del punteggio CDR globale a 18 mesi (si definisce peggioramento del punteggio CDR globale un aumento rispetto al Basale di almeno 0,5 punti nella scala CDR globale per 2 visite programmate consecutive durante le quali sia stata somministrata la scala CDR globale)
    • Variazione della scala MMSE a 18 mesi rispetto al Basale
    • Incidenza di AE e variazioni di parametri vitali, ECG, analisi di laboratorio di sicurezza, valutazioni della suicidalità e parametri di sicurezza all’RMI
    • Parametri sierici di BAN2401 nella popolazione PK, ivi compresi, ma non esclusivamente AUC e Cav
    E.5.2.1Timepoint(s) of evaluation of this end point
    Core
    •18 months; Core
    •18 months
    Studio Principale
    •18 mesi; Studio Principale
    •18 mesi
    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 Yes
    E.6.7Pharmacodynamic Yes
    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) No
    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 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 concerned13
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA44
    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
    Canada
    China
    France
    Germany
    Italy
    Japan
    Korea, Republic of
    Russian Federation
    Spain
    Sweden
    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
    LVLS
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months0
    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: 310
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 1256
    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 state61
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 307
    F.4.2.2In the whole clinical trial 1566
    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 have completed Visit 42 (Week 79) have the option to participate in the Extension Phase. Those who choose not to participate in the Extension will complete the 3-month Follow-up Visits after their last dose of study drug in the study. Subjects who discontinue the study or study drug must comply with the Early Termination Visit (within 7 days after the last dose of study drug) and the Follow-up Visit (3 months after the last dose of study drug).
    I soggetti che completeranno la visita 42 (settimana 79) avranno la possibilità di partecipare alla fase di estensione. Coloro che scelgono di non partecipare all'estensione completeranno le visite di follow-up 3 mesi dopo l'ultima dose di farmaco. I soggetti che interrompono lo studio o il trattamento devono attenersi alla Visita di Interruzione anticipata (entro 7 giorni dall'ultima dose del farmaco) e alla Visita di follow-up (3 mesi dopo l'ultima dose del farmaco).
    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 Decision2019-07-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-06-03
    P. End of Trial
    P.End of Trial StatusOngoing
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