E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Mild cognitive impairment (MCI) or mild dementia, both of the Alzheimer’s type |
Deterioro cognitivo leve (DCL) o demencia leve, ambos de tipo Alzheimer. |
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E.1.1.1 | Medical condition in easily understood language |
Early Alzheimer's disease |
Enfermedad de Alzheimer incipiente |
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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 |
To confirm the superiority of oral semaglutide versus placebo on the change in cognition and function in subjects with mild cognitive impairment (MCI) or mild dementia, both of the Alzheimer’s type. |
Confirmar la superioridad de semaglutida oral sobre placebo en cuanto a la variación de la función cognitiva en pacientes con deterioro cognitivo leve (DCL) o demencia leve, ambos de tipo Alzheimer. |
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E.2.2 | Secondary objectives of the trial |
To compare the effects of oral semaglutide versus placebo in subjects with MCI or mild dementia, both of the Alzheimer’s type, on: - progression to dementia among subjects with MCI at baseline - neuropsychiatric symptoms - safety and tolerability - quality of life |
Comparar los efectos de semaglutida oral con los de placebo en sujetos con DCL o demencia leve, ambos de tipo Alzheimer, sobre: -progresión a demencia en sujetos con DCL en el momento basal -síntomas neuropsiquiátricos -seguridad y tolerabilidad. -calidad de vida |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Male or female, aged 55-85 years (both inclusive) at the time of signing informed consent. - MCI or mild dementia of the Alzheimer’s type according to the National Institute of Aging-Alzheimer’s Association (NIA-AA) 2018 criteria. - Clinical Dementia Rating (CDR) global score of 0.5 and CDR of 0.5 or more in at least one of the three instrumental activities of daily living categories (personal care, home & hobbies, community affairs) Or CDR global score of 1.0 - Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) delayed memory index score of less than or equal to 85 - Mini-Mental State Examination (MMSE) greater than or equal to 22. - Amyloid positivity established with either amyloid positron emission tomography (PET) or cerebrospinal fluid (CSF) Aβ1-42. - If receiving an approved Alzheimer's disease treatment (such as acetylcholinesterase inhibitors or memantine) the dose must have been stable for at least 3 months prior to screening and should not be changed during the trial unless medically necessary |
-Varón o mujer de 55-85 años (ambos inclusive) en el momento de firmar el consentimiento informado. -DCL o demencia leve de tipo Alzheimer según los criterios del National Institute of Aging-Alzheimer's Association (NIA-AA) 2018. -Puntuación global de la calificación clínica de demencia (CDR) de 0,5 y de 0,5 o más en al menos una de las tres categorías de actividades instrumentales de la vida diaria (cuidados personales, hogar y aficiones, asuntos comunitarios) O Puntuación global de la CDR de 1,0 -Puntuación del índice de memoria diferida de la escala RBANS (Repeatable Battery for the Assessment of Neuropsychological Status) menor o igual a 85. -Puntuación MMSE (Mini-Mental State Examination) mayor o igual a 22. -Positividad para amiloide determinada mediante tomografía por emisisón de positrones (PET) para amiloide o Aβ1-42 en líquido cefalorraquídeo (LCR). -Si recibe un tratamiento aprobado para la enfermedad de Alzheimer (como inhibidores de la acetilcolinesterasa o memantina), la dosis deberá haberse mantenido estable durante al menos 3 meses antes de la selección y no podrá modificarse durante el ensayo a menos que sea médicamente necesario. |
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E.4 | Principal exclusion criteria |
- Brain magnetic resonance imaging (MRI) (or computerised tomography (CT)) scan suggestive of clinically significant structural central nervous system (CNS) disease confirmed by central read (e.g. cerebral large-vessel disease [large vessel (cortical) infarcts greater than 10 mm in diameter], prior macro-haemorrhage [ greater than 1 cm^3], cerebral vascular malformations, cortical hemosiderosis, intracranial aneurism(s), intracranial tumours, changes suggestive of normal pressure hydrocephalus). - Brain MRI (or CT) scan suggestive of strategic infarcts defined as bilateral thalamic lacunar infarcts and singular paramedian thalamic infarcts confirmed by central read. - Evidence of a relevant neurological disorder other than mild cognitive impairment (MCI) or mild dementia of the Alzheimer’s type at screening, including but not limited to Parkinson’s disease, Lewy body disease, frontotemporal dementia of any type, Huntington’s disease, amyotrophic lateral sclerosis, multiple sclerosis, systemic lupus erythematosus, progressive supranuclear palsy, neurosyphilis, human immunodeficiency virus (HIV), learning disability, intellectual disability, hypoxic cerebral damage, or significant head trauma with loss of consciousness that led to persistent cognitive deficits. - Evidence of a clinically relevant or unstable psychiatric disorder, based on Diagnostic and Statistical Manual of Mental Disorders (DSM–5) criteria, including schizophrenia or other psychotic disorder, or bipolar disorder. A subject with a history of major depression who has not had an episode in the last 24 months before the day of screening and is considered in remission or whose depression is controlled with treatment can be included in the trial per investigator’s judgement. |
-Resonancia Magnética (RM) (o tomografía computerizada (TC)) cerebral indicativa de enfermedad estructural del SNC clínicamente significativa confirmada por interpretación central (p. ej., enfermedad cerebral de grandes vasos [infartos de grandes vasos (corticales) mayores de 10 mm de diámetro], macrohemorragia previa [mayor de 1 cm3], malformaciones vasculares cerebrales, hemosiderosis cortical, aneurismas intracraneales, tumores intracraneales o alteraciones indicativas de hidrocefalia de presión normal). -RM (o TC) cerebral indicativa de infartos estratégicos definidos como infartos -lacunares talámicos bilaterales e infartos talámicos paramedianos singulares confirmados mediante interpretación central. -Signos de un trastorno neurológico importante distinto del deterioro cognitivo leve (DCL) o demencia leve de tipo Alzheimer en la selección como, entre otros, enfermedad de Parkinson, enfermedad de cuerpos de Lewy, demencia frontotemporal de cualquier tipo, enfermedad de Huntington, esclerosis lateral amiotrófica, esclerosis múltiple, lupus eritematoso sistémico, parálisis supranuclear progresiva, neurosífilis, infección por el VIH, discapacidad del aprendizaje, discapacidad intelectual, daño cerebral hipóxico o traumatismo craneoencefálico importante con pérdida de conciencia que origina déficit cognitivos persistentes. -Signos de un trastorno psiquiátrico clínicamente relevante o inestable, según los criterios del Manual diagnóstico y estadístico de los trastornos mentales (DSM–5), como esquizofrenia u otro trastorno psicótico o trastorno bipolar. Un paciente con antecedentes de depresión mayor que no haya tenido un episodio en los 24 meses previos al día de la selección y que se considere en remisión o cuya depresión esté controlada con tratamiento podrá ser incluido en el ensayo a criterio del investigador. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change in the Clinical Dementia Rating – Sum of Boxes (CDR-SB) score |
Variación de la puntuación Escala de valoración clínica de la demencia-suma de casillas (CDR-SB) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
From baseline (week 0) to week 104 |
Desde el momento basal (semana 0) hasta la semana 104 |
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E.5.2 | Secondary end point(s) |
1. Change in the Alzheimer’s Disease Cooperative Study Activities of Daily Living Scale for mild cognitive impairment (MCI) (ADCS-ADL-MCI) score 2. Time to progression to dementia (CDR global greater than or equal to 1.0) among subjects with MCI (CDR global equal to 0.5) at baseline 3. Change in the 13-item Alzheimer’s Disease Assessment Scale – Cognitive Subscale (ADAS-Cog-13) score 4. Change in the Montreal Cognitive Assessment (MoCA) score 5. Change in the Alzheimer’s Disease Composite Score (ADCOMS) 6. Change in the Mini-Mental State Examination (MMSE) score 7. Change in the 10-item Neuropsychiatric Inventory (NPI) score 8. Time to progression in disease stage based on global CDR score 9. Number of treatment emergent adverse events (TEAEs) 10. Change in high sensitivity C-reactive protein level 11. Time to first occurrence of major adverse cardiovascular event (MACE) comprising non-fatal myocardial infarction, non-fatal stroke and all-cause death 12. Time to first occurrence of stroke 13. Change in the EQ-5D-5L proxy score Extension phase 14. Change in the CDR-SB score 15. Change in the ADCS-ADL-MCI total score 16. Time to progression to dementia (CDR global greater than or equal to 1.0) among subjects with MCI (CDR global equal to 0.5) at baseline |
1.Variación de la puntuación de la Escala de actividades cotidianas del estudio cooperativo sobre la enfermedad de Alzheimer para el deterioro cognitivo leve (DCL) (ADCS-ADL-MCI). 2.Tiempo hasta la progresión a demencia (CDR global mayor o igual a 1,0) en los pacientes con DCL (CDR global igual a 0,5) en el momento basal. 3.Variación de la puntuación de la Escala de evaluación de la enfermedad de Alzheimer de 13 apartados – Subescala cognitiva (ADAS-Cog-13). 4.Variación de la puntuación en la Evaluación cognitiva de Montreal (MoCA). 5.Variación de la puntuación combinada de la enfermedad de Alzheimer (ADCOMS) 6.Variación de la puntuación del Miniexploración del estado mental (MMSE) 7.Variación de la puntuación del Inventario neuropsiquiátrico (NPI) de 10 apartados. 8.Tiempo hasta la progresión del estadio de la enfermedad según la puntuación global de la CDR 9.Número de acontecimientos adversos aparecidos durante el tratamiento (AAAT) 10.Variación de la concentración de proteína C reactiva de alta sensibilidad 11.Tiempo transcurrido hasta el primer episodio de acontecimiento adverso cardiovascular grave (MACE), que comprende infarto de miocardio no mortal, ictus no mortal y muerte por cualquier causa. 12.Tiempo hasta el primer episodio de ictus 13.Variación de la puntuación indirecta del EQ-5D-5L.
Fase de extensión 14.Change in the CDR-SB score 15.Variación de la puntuación total ADCS-ADL-MCI 16.Tiempo hasta la progresión a la demencia (CDR global mayor o igual a 1,0) en los pacientes con DCL (CDR global igual a 0,5) en el momento basal |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.-13 From baseline (week 0) to week 104 14.-16. From baseline (week 0) to week 156 |
1.-13 Desde el momento basal (semana 0) hasta la semana 104 14.-16. Desde el momento basal (semana 0) hasta la semana 156 |
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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 | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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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 | Yes |
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 | No |
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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 152 |
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 | No |
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 |
Australia |
Brazil |
Canada |
China |
Israel |
Japan |
Korea, Republic of |
Russian Federation |
Serbia |
South Africa |
Taiwan |
Turkey |
Ukraine |
United States |
Austria |
Belgium |
Bulgaria |
Croatia |
Denmark |
Finland |
France |
Germany |
Hungary |
Ireland |
Italy |
Netherlands |
Norway |
Poland |
Portugal |
Romania |
Slovakia |
Slovenia |
Spain |
Sweden |
Switzerland |
United Kingdom |
Czechia |
Argentina |
Greece |
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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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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 | 3 |
E.8.9.1 | In the Member State concerned days | 28 |
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 | 3 |
E.8.9.2 | In all countries concerned by the trial days | 28 |