E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Alzheimer’s Disease |
Morbo di Alzheimer |
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E.1.1.1 | Medical condition in easily understood language |
Alzheimer’s Disease |
Morbo di Alzheimer |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10001896 |
E.1.2 | Term | Alzheimer's disease |
E.1.2 | System Organ Class | 100000004852 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Efficacy:evaluate crenezumab 60 mg/kg compared with placebo when admin. by IV infusion q4w over 100 wks as measured(final outcome assessment at Wk 105,4 wks after the final dose)Change from baseline on CDR-sum of boxes Safety:evaluate the safety of crenezumab compared with placebo in patients with prodromal to mild AD on the basis of the follow. endpoints •Nature,frequency,severity and timing of adverse events and serious adverse events •Physical and neurologic examinations,vital signs,blood tests,ECGs,Columbia Suicide Severity Rating Scale,Non-serious adverse events of special interest, specific. pneumonia •Adverse events,as assessed by magnetic resonance imaging:amyloid related imaging abnormalities edema/effusion,amyloid related imaging abnormalities hemosiderin deposition •The immunogenic potential of crenezumab through measurement of antibodies directed against crenezumab and other components of the drug product,assessment of their relationship with other outcome measures
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Efficacia:la valutazione di crenezumab 60 mg/kg rispetto al placebo, quando somministrato per infusione endovenosa (EV) ogni 4 settimane (q4w) per 100 settimane (valutazione esiti globali in 105,4 settimane dopo la dose finale), misurata con il seguente endpoint primario: Esiti globali, valutati in base alla scala CDR. Sicurezza:valutazione della sicurezza di crenezumab rispetto al placebo in pazienti affetti da AD da prodromica a lieve, sulla base dei seguenti endpoint:-Natura, frequenza, grado e tempi degli eventi avversi e degli eventi avversi seri- Esami fisici e neurologici, segni vitali, esami del sangue, ECG, scala Columbia-Suicide Severity Rating Scale; Eventi avversi di speciale interesse, nello specifico la polmonite- Eventi avversi valutati con la risonanza magnetica (RM): anomalie di imaging correlate all'amiloide-edema/versamento e anomalie di imaging correlate all'amiloide-depositi di emosiderina- Potenziale immunogeno di crenezumab attraverso la misurazione di anticorpi |
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E.2.2 | Secondary objectives of the trial |
Efficacy: secondary efficacy objective for this study is to evaluate the benefits of crenezumab versus placebo administered to patients by IV infusion over 100 weeks through assessment of the following endpoints •Cognition, as measured by the ADAS-Cog (subscale) 13 (ADAS Cog 13) •Effect on severity of dementia, assessed using the CDR-Global Score (CDR GS) •Effect on cognition, assessed using the MMSE, ADAS-COG12 •Effect on function, assessed using the ADCS-ADL instrumental subscale (ADCS iADL) and ADCS-ADL total score •Effect on behavioral and neuropsychological symptoms of AD, assessed using the Neuropsychiatric Inventory Questionnaire (NPI-Q) •Effect of crenezumab on health-related quality of life (QoL), assessed using the Quality of Life-Alzheimer’s Disease scale, caregiver burden, assessed using the Zarit Caregiver Interview for Alzheimer’s Disease scale and on health outcomes in patient and caregiver as measured by EQ-5D
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Efficacia: obiettivo secondario di efficacia di questo studio è quello di valutare i benefici di crenezumab rispetto al placebo somministrato ai pazienti per infusione endovenosa per più di 100 settimane attraverso la valutazione dei seguenti endpoint • La cognizione, misurata dal ADAS- Cog- 13 (ADAS Cog 13)• Effetto sulla gravità della demenza, valutata mediante il punteggio di CDR -Global (CDR GS)• Effetti sulla cognizione , valutata utilizzando il MMSE , ADAS- COG12 • effetto sulla funzione , valutata utilizzando la sottoscala ADCS - ADL strumentali ( ADCS IADL ) e punteggio totale ADCS - ADL• effetto sui sintomi comportamentali e neuropsicologici di AD, valutata utilizzando il questionario Neuropsychiatric Inventory ( NPI - Q ) • Effetto della crenezumab sulla salute legati alla qualità della vita (QoL), valutata utilizzando la Quality of Life-AD scale, impatto nei caregiver, valutata usando l'intervista Zarit Caregiver e sulla salute nei pazienti e nei caregiver, misurata con EQ5D |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full 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: ECG SUBSTUDY (v.1 8Oct2015); CONCORDANCE SUBSTUDY (v.1 9Nov2015); PET LONGITUDINAL SUBSTUDY (v.1 9Nov2015); CSF LONGITUDINAL SUBSTUDY (v.1 9Nov2015); RESEACH SUBSTUDY (v.1 18Sep2015), associated with the Main Study
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Altre tipologie di sottostudi specificare il titolo, la data e la versione di ogni sottostudio con i relativi obiettivi: SOTTOSTUDIO ECG (v.1 8Oct2015); SOTTOSTUDIO SULLA CONCORDANZA CSF-PET (v.1 9Nov2015); SOTTOSTUDIO LONGITUDINALE SULLA PET (v.1 9Nov2015); SOTTOSTUDIO LONGITUDINALE SUL CSF (v.1 9Nov2015); SOTTOSTUDIO DI RICERCA (v.1 18Sep2015), associati allo Studio Principale
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E.3 | Principal inclusion criteria |
• Must meet all of the following clinical criteria for MCI due to AD or mild AD and must have: • A Clinical Dementia Rating (CDR)-Global Score of 0.5 or 1.0 • Objective evidence of cognitive impairment at screening • An MMSE score between 22 and 30 (inclusive) • Must have confirmed amyloid pathology consistent with AD (by PET scan or CSF measurement) • Must consent genotyping for apolipoprotein E (ApoE) • If using drugs to treat symptoms related to AD, doses must be stable for at least 3 months prior to screening • Must have a reliable study partner or caregiver
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• Deve soddisfare tutti i seguenti criteri clinici per MCI (derioramento cognitivo lieve) a causa di AD o AD lieve e deve avere : • Un punteggio globale di Clinical Dementia Rating (CDR) di 0,5 o 1,0 • L'obiettiva evidenza di deterioramento cognitivo allo screening • Un punteggio MMSE tra 22 e 30 ( compreso) • Deve avere una patologia amiloide confermata in linea con AD ( da PET o di misura CSF ) • Deve acconsentire alla genotipizzazione per apolipoproteina E ( ApoE ) • Se si utilizzano farmaci per il trattamento dei sintomi legati alla dC , le dosi devono essere stabili per almeno 3 mesi prima dello screening • Deve avere un partner di studio o caregiver affidabili |
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E.4 | Principal exclusion criteria |
• Any medical or neurological condition (other than Alzheimer's Disease) that might result in cognitive impairment. • Have had a stroke resulting in clinical symptoms within 2 years or Transient Ischemic Attack (TIA) within 6 months • History of serious psychiatric illness or untreated major depressive disorder • History of unstable angina, myocardial infarction, advanced chronic heart failure within 2 years prior to screening • Have human immunodeficiency virus (HIV) infection • Relevant brain hemorrhage or cerebrovascular abnormalities • Any contraindications to brain magnetic resonance imaging (MRI) scans • Alcohol or substance abuse in past 2 years • Anti-coagulation medications within 3 months of screening – antiplatelet therapies including clopidogrel are permitted.
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• Qualsiasi condizione medica o neurologica ( diverse dalla malattia di Alzheimer) che potrebbero causare deterioramento cognitivo . • ha avuto un ictus con conseguenti sintomi clinici entro 2 anni o un attacco ischemico transitorio (TIA) entro 6 mesi • storia di malattia psichiatrica grave o disturbo depressivo significativo non trattati • Storia di angina instabile ,infarto del miocardio , insufficienza cardiaca cronica avanzata entro 2 anni prima dello screening • Avere infezione da virus dell'immunodeficienza umana (HIV) • rilevanti emorragie cerebrali o anomalie cerebrovascolari • eventuali controindicazioni per imaging del cervello alla risonanza magnetica ( MRI) • abuso di alcool o di sostanze negli ultimi 2 anni • sono consentiti farmaci anticoaugulanti entro 3 mesi di screening - e terapie antiaggreganti incluso il clopidogrel |
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E.5 End points |
E.5.1 | Primary end point(s) |
To evaluate crenezumab 60 mg/kg compared with placebo when administered by IV infusion q4w over 100 weeks as measured by the following primary endpoint (final outcome assessment at Week 105, 4 weeks after the final dose): Global outcomes, as assessed by the CDR SB |
Valutare crenezumab 60 mg / kg rispetto al placebo quando somministrato per infusione endovenosa q4w per un periodo di trattamento di 100 settimane , come misurato dal seguente endpoint primario ( valutazione finale alla Settimana 105 , 4 settimane dopo la dose finale ) : i risultati globali , come valutato dal CDR SB
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Change from baseline at week 105 |
Cambiamento dal basale alla settimana 105
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E.5.2 | Secondary end point(s) |
To evaluate the benefits of crenezumab versus placebo administered to patients by IV infusion q4w over 100 weeks through assessment of the following endpoints: Effect on cognition, as measured by the ADAS-Cog (subscale) 13 (ADAS Cog 13) |
Valutare i benefici di crenezumab rispetto al placebo somministrato ai pazienti per infusione endovenosa q4w per un periodi di trattamento di 100 settimane attraverso la valutazione dei seguenti endpoint : Effetto sulla cognizione , come misurato dal ADAS- Cog ( sottoscala ) 13 ( ADAS Cog 13 ) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Change from baseline at week 105 |
Cambiamento dal basale alla settimana 105 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
PET Ligando (florbetapir F18) |
PET Ligand (florbetapir F18) |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 119 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial 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
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last patient, last visit (LPLV) occurs or the date at which the last data point required for safety analyses or safety follow up is received for the last patient, whichever occurs later. LPLV for the double blind treatment period is expected to occur 153 weeks after the last patient is enrolled (i.e., 52 weeks after the last dosing visit at week 101) |
si verifica all'ultima visita dell'ultimo ( LPLV ) o alla data in cui l'ultimo punto di dati necessari per le analisi di sicurezza o la sicurezza di follow-up è ricevuto per l'ultimo paziente , a seconda di quale si verifica in seguito . LPLV per il periodo di trattamento in doppio cieco dovrebbe avvenire 153 settimane dopo l' ultimo paziente è iscritto ( cioè 52 settimane dopo l'ultima visita di dosaggio alla settimana 101 ) |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |