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 |
Blagi kogitivni poremećaj (MCI) ili blaga demencija, oboje Alzheimerovog tipa |
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E.1.1.1 | Medical condition in easily understood language |
Early Alzheimer's disease |
Raniji stadij Alzheimerove bolesti |
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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. |
Potvrditi superiornost oralnog semaglutida u odnosu na placebo u kognitivnim sposobnostima i funkcioniranju ispitanika s blagim kognitivnim poremećajem (MCI) ili blagom demencijom, oboje Alzheimerovog tipa. |
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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 |
Usporediti učinak oralnog semaglutida u odnosu na placebo kod ispitanika s blagim kognitivnim poremećajem ili blagom demencijom, oboje Alzheimerovog tipa, na: - progresiju do demencije kod ispitanika s blagim kognitivnim poremećajem (MCI) - neuropsihijatrijske simptome - sigurnost i podnošljivost - kvalitetu života
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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 |
-Muškarci i žene u dobi od 55 do 85 godina u vrijeme potpisivanja Informiranog pristanka -Blagi kognitivni poremećaj (MCI) ili blaga demencija koje su tip Alzheimerove bolesti sukladno NIA-AA 2018 kriteriju -CDR globalni rezultat od 0,5 i CDR od 0,5 ili više u najmanje jednoj od tri instrumentalnih aktivnosti kategorija svakodnevnog života (osobna njega, dom i hobiji, poslovi unutar zajednice) ili CDR globalni rezultat od 1,0 -RBANS indeks rezultat odgođenog pamćenja ≤ 85 -MMSE ≥ 22 -Pozitivan test na amiloid utvrđen amiloidnim PET skenom ili CSF Aβ1-42 -Ako se ispitanik liječi odobrenim lijekom za Alzheimerovu bolest (inhibitori acetilkolinesteraze ili memantin), doza mora biti stabilna najmanje 3 mjeseca prije probira i ne bi se trebala mijenjati tijekom ispitivanja, osim zbog medicinskih razloga.
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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. |
-Sken magnetske rezonance (MR) ili kompjuteririrane tomografije (CT) ukazuje na prisutnost bolesti središnjeg živčanog sustava (SŽS) što povrđuju prisutne klinički značajne strukturne promjene u SŽS (npr. cerebralna ‚large vessel‘ bolest (kortikalni infarkti > 10 mm u promjeru), prethodno makrokrvarenje (>1 cm3), malformacije cerebralnih krvnih žila, kortikalna hemosideroza, intrakranijalna aneurizma(e) , intrakranijalni tumori, promjene sugeriraju hidrocefalus pod pritiskom) -MR (ili CT) sken mozga sugerira strateški infarkt definiran kao obostrani talamički lakunarni infarkt i pojedinačni paramedijanski talamični infarkti -Dokazi o relevantnim neurološkom poremećaju koji nije blagi kognitivni poremećaj(MCI) ili blaga demencija Alzheimerovog tipa prilikom probira, uključujući, ali ne i ograničavajući se na Parkinsonovu bolest, Lewyevu bolest, frontalnu temporalnu demenciju bilo koje vrste, Hungttinovu bolest, amiotrofična lateralna skleroza, multipla skleroza, sistemski eritemski lupus, progresivna supranuklearna paraliza, neurosifilis, humani imunodeficijentni virus (HIV), teškoće u učenju, intelektualni invaliditet, hipoksično cerebralno oštećenje ili značajne traume glave s gubitkom svijesti koje su dovele do trajnih kognitivnih deficita - Dokazi o klinički važnom ili nestabilnom psihijatrijskom poremećaju temeljeno na kriterijima u dijagnostičkom i statističkom priručniku za mentalne poremećaje (DSM-5) uključujući šizofreniju, bipolarni poremećaj ili drugi psihotični poremećaj. Ispitanik s dijagnozom velike depresije koji nije imao epizoda u posljednja 24 mjeseca prije probira te se smatra da je u remisiji ili ispitanik čija je depresija pod kontrolom, može se uključiti u ispitivanje prema odluci ispitivača.
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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 |
Promjena u CDR-SB (Change in the Clinical Dementia Rating – Sum of Boxes) rezultatu |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
From baseline (week 0) to week 104 |
Od početka ispitivanja (tjedan 0) do 104. tjedna |
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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. Promjena u ADCS-ADLMCI (Alzheimer’s Disease Cooperative Study Activities of Daily Living Scale for MCI) rezultatu za blagi kognitivni poremećaj (MCI) 2. Vrijeme progresije do demencije (Globalni CDR ≥ 1,0) kod ispitanika s blagim kognitivnim poremećajem (MCI) (Globalni CDR = 0,5) na početku ispitivanja 3. Promjena u ADAS-Cog-13 (13-item Alzheimer’s Disease Assessment Scale – Cognitive Subscale) rezultatu 4. Promjena u MoCA (Montreal Cognitive Assessment) rezultatu 5. Promjena u ADCOMS (Alzheimer’s Disease Composite Score) rezultatu 6. Promjena u MMSE (Mini-Mental State Examination) rezultatu 7. Promjena u NPI (10-item Neuropsychiatrics Inventory) rezultatu 8. Vrijeme progresije bolesti temeljeno na globalnom CDR rezultatu 9. Broj neželjenih događaja proizašlih iz primjene lijeka (TEAEs) 10. Promjena razine visoko osjetljivog C-reaktivnog proteina 11. Vrijeme do prve pojave velikog štetnog kardiovaskularnog događaja (MACE) koji obuhvaća moždani udar bez smrtnog ishoda 12. Vrijeme do prve pojave moždanog udara 13. Promjena u EQ-5D-5L rezultatu faze produženja 14. Promjena u CDR-SB rezultatu 15. Promjena ukupnog rezultata u ADCS-ADL-MCI 16. Vrijeme progresije do demencije (Globalni CDR ≥ 1,0) kod ispitanika s blagim kognitivnim poremećajem (MCI) (Globalni CDR = 0,5) na početku ispitivanja
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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 od početka ispitivanja (tjedan 0) do 104. tjedna 14.-16. od početka ispitivanja (tjedan 0) do 156. tjedna
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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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
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 |