A Research Study Investigating Semaglutide in People With Early Alzheimer's Disease (EVOKE Plus)

Study Overview
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Brief Summary
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This study is done to find out whether the medicine, semaglutide, has a positive effect on early Alzheimer's disease. Participants will either get semaglutide or placebo (a dummy medicine which does not contain any study medicine) - which treatment participants get is decided by an equal chance. The study will last for up to 173 weeks (about 3 years and 4 months). Participants will have 17 clinic visits and 1 phone call with the study doctor. The study includes various tests and scans. At 10 of the clinic visits participants will have blood samples taken. Participants must have a study partner, who is willing to take part in the study. Women cannot take part if pregnant, breastfeeding or plan to become pregnant during the study period. A cerebrospinal fluid (CSF) sub-study will be performed as a part of the study. The sub-study will be performed on a selection of sites based on their experience with CSF sampling and willingness to participate in this sub-study. The endpoints related to this sub-study are exploratory only.

Official Title
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A Randomised Double-blind Placebo-controlled Clinical Trial Investigating the Effect and Safety of Oral Semaglutide in Subjects With Early Alzheimer´s Disease (EVOKE Plus)

Conditions
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Early Alzheimer´s Disease

Intervention / Treatment
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* Drug: Semaglutide
* Drug: Placebo (semaglutide)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, aged 55-85 years (both inclusive) at the time of signing informed consent. MCI (mild cognitive impairment) or mild dementia of the Alzheimer's type according to the NIA-AA (National Institute of Aging-Alzheimer's Association) 2018 criteria. CDR (Clinical Dementia Rating) 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 RBANS (Repeatable Battery for the Assessment of Neuropsychological Status) delayed memory index score of below or equal to 85 MMSE (Mini-Mental State Examination) greater than or equal to 22 Amyloid positivity established with either amyloid PET (positron emission tomography), CSF (cerebrospinal fluid) Aβ1-42 or CSF Aβ1-42/Aβ1-40. If receiving an approved Alzheimer's disease treatment (such as acetylcholinesterase inhibitors, memantine or aducanumab) 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. Exclusion Criteria: Brain MRI (or CT) scan suggestive of clinically significant structural CNS (central nervous system) disease confirmed by central read (e.g. cerebral large-vessel disease [large vessel (cortical) infarcts greater than10 mm in diameter], prior macro-haemorrhage [greater than1 cm^3], cerebral vascular malformations, cortical hemosiderosis, intracranial aneurism(s), intracranial tumours, changes suggestive of normal pressure hydrocephalus). Brain MRI (magnetic resonance imaging) (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 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, HIV (human immunodeficiency virus), 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.

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Oral semaglutide 14 mg<br>Participants are given oral semaglutide once daily | Drug: Semaglutide<br>* Oral semaglutide once-daily, dose gradually increased to 14 mg. The study will last for up to 173 weeks<br>|
| Placebo Comparator: Placebo (semaglutide)<br>Participants are given oral placebo once daily | Drug: Placebo (semaglutide)<br>* Oral placebo (semaglutide) once-daily. The study will last for up to 173 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the Clinical Dementia Rating - Sum of Boxes (CDR-SB) score | Score on scale (0 to 18) Measures the impact of cognitive decline on daily function using the following six domains commonly affected in Alzheimer's disease: Cognitive domains: memory, orientation, and judgement and problem solving Function domains: community affairs, home and hobbies, and personal care Based on clinical information obtained from the subject and informant, an individual box score ranging from 0 to 3 is determined that represents none to severe impairment for each of the six domains. The CDR-Sum of Boxes (CDR-SB) score will be derived by adding the individual scores of the six domains at a given time point. The total CDR-SB score ranges from 0 to 18 with higher scores representing greater impairment. | From baseline (week 0) to week 104 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the Alzheimer's Disease Cooperative Study Activities of Daily Living Scale for MCI (ADCS-ADLMCI) score | Score on scale (0 to 53). An interview-based assessment of information provided by the study partner (informant). The total scores based on 18 items on the scale range from 0 to 53 with lower scores representing greater impairment. | From baseline (week 0) to week 104 | 
| 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 | Week(s) | From baseline (week 0) to week 104 | 
| Change in the 13-item Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog-13) score | Score on scale (0 to 85) Measures the severity of cognitive impairment in various domains including memory, language, orientation, praxis and executive function. The total scores on the scale range from 0 to 85 with higher scores representing greater impairment. | From baseline (week 0) to week 104 | 
| Change in the Montreal Cognitive Assessment (MoCA) score | Score on scale (0 to 30) The assessment includes 8 domains of cognitive function with total scores ranging from 0 to 30 and lower scores indicating greater impairment. | From baseline (week 0) to week 104 | 
| Change in the Alzheimer's Disease Composite Score (ADCOMS) | Score on scale (0 to 1.97) The ADCOMS is a composite clinical outcome comprising 4 items from the ADAS-Cog-13, 2 items from the MMSE and all 6 items from the CDR-SB.32 The total scores on the scale range from 0 to 1.97 with higher scores indicating greater impairment. | From baseline (week 0) to week 104 | 
| Change in the Mini-Mental State Examination (MMSE) score | Score on scale (0 to 30) The MMSE measures orientation, attention, memory, language and visuo-spatial function. The total scores on the scale range from 0 to 30 with lower scores indicating greater impairment. | From baseline (week 0) to week 104 | 
| Change in the 10-item Neuropsychiatric Inventory (NPI) score | 104 Score on scale (0 to 120) The 10-item scale assesses symptoms including delusions, hallucinations, agitation/aggression, dysphoria, anxiety, euphoria, apathy, disinhibition, irritability/lability and aberrant motor activity. For each domain the frequency (4-point scale) and severity (3-point scale) of symptoms is reported. The score for each domain is calculated by multiplying the frequency and severity score. The total 10-item NPI score is 0 to 120 with higher scores indicating a greater symptomatology. | From baseline (week 0) to week 104 | 
| Time to progression in disease stage based on global CDR score | Week(s) | From baseline (week 0) to week 104 | 
| Number of treatment emergent adverse events (TEAEs) | Number of events | From baseline (week 0) to week 104 | 
| Change in high sensitivity C-reactive protein level | Ratio | From baseline (week 0) to week 104 | 
| Time to first occurrence of major adverse cardiovascular event (MACE) comprising non-fatal myocardial infarction, non-fatal stroke and allcause death | Week(s) | From baseline (week 0) to week 104 | 
| Time to first occurrence of stroke | Weeks | From baseline (week 0) to week 104 | 
| Change in the EQ-5D-5L proxy score | Score The EQ-5D-5L descriptive system comprises mobility, self-care, usual activities, pain/discomfort and anxiety/depression with five response levels each (no problems, slight problems, moderate problems, severe problems, unable to /extreme problems). The EQ-5D-5L proxy version 1 (the study partner is asked to rate how he/she [the proxy] would rate the subject´s health) will be used in this trial. | From baseline (week 0) to week 104 | 
| Extension phase: Change in the CDR-SB score | Score on scale (0 to 18) Measures the impact of cognitive decline on daily function using the following six domains commonly affected in Alzheimer's disease: Cognitive domains: memory, orientation, and judgement and problem solving Function domains: community affairs, home and hobbies, and personal care Based on clinical information obtained from the subject and informant, an individual box score ranging from 0 to 3 is determined that represents none to severe impairment for each of the six domains. The CDR-Sum of Boxes (CDR-SB) score will be derived by adding the individual scores of the six domains at a given time point. The total CDR-SB score ranges from 0 to 18 with higher scores representing greater impairment. | From baseline (week 0) to week 156 | 
| Extension phase: Change in the ADCS-ADL-MCI score | Score on scale (0 to 53) An interview-based assessment of information provided by the study partner (informant). The total scores based on 18 items on the scale range from 0 to 53 with lower scores representing greater impairment. | From baseline (week 0) to week 156 | 
| Extension phase: 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 | Week(s) | From baseline (week 0) to week 156 |