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

Phase 3

Active, not recruiting

• Conditions: Early Alzheimer´s Disease
• Interventions: Drug: Semaglutide; Drug: Placebo (semaglutide)

• Registration Number: NCT04777409
• Lead Sponsor: Novo Nordisk A/S

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2021-02-26
• Study First Submitted QC: 2021-02-26
• Study First Posted: 2021-03-02
• Study Start: 2021-05-18
• Status Verified: 2025-06
• Last Update Submitted: 2025-06-24
• Last Update Posted: 2025-06-25
• Primary Completion: 2025-09-19
• Study Completion: 2026-10-06

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 1840

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 study unless medically necessary.

Exclusion Criteria

• Brain Magnetic resonance imaging (MRI) (or Computed Tomography (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 than (>) 10 milimeter (mm) in diameter], prior macro-haemorrhage [greater than 1 cubic centimetre (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 participant 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 study per investigator's judgement.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Oral semaglutide	Semaglutide	Participants are given oral semaglutide once daily
Placebo (semaglutide)	Placebo (semaglutide)	Participants are given oral placebo once daily

Primary Outcome Measures

Name	Time	Method
Change in the Clinical Dementia Rating - Sum of Boxes (CDR-SB) score	From baseline (week 0) to week 104	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.

Secondary Outcome Measures

Name	Time	Method
Main Phase: Change in the 13-item Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog-13) score	From baseline (week 0) to week 104	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.
Extension Phase: Change in the 13-item Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog-13) score	From baseline (week 0) to week 156	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.
Main Phase: Change in the Montreal Cognitive Assessment (MoCA) score	From baseline (week 0) to week 104	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.
Extension Phase: Change in the Montreal Cognitive Assessment (MoCA) score	From baseline (week 0) to week 156	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.
Main Phase: Change in the Alzheimer's Disease Composite Score (ADCOMS)	From baseline (week 0) to week 104	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.
Extension Phase: Change in the Alzheimer's Disease Composite Score (ADCOMS)	From baseline (week 0) to week 156	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.
Main Phase: Change in the Mini-Mental State Examination (MMSE) score	From baseline (week 0) to week 104	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.
Extension Phase: Change in the Mini-Mental State Examination (MMSE) score	From baseline (week 0) to week 156	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.
Main Phase: Change in the 10-item Neuropsychiatric Inventory (NPI) score	From baseline (week 0) to week 104	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.
Extension Phase: Change in the 10-item Neuropsychiatric Inventory (NPI) score	From baseline (week 0) to week 156	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.
Main Phase: Change in high sensitivity C-reactive protein level	From baseline (week 0) to week 104	Ratio to baseline
Extension Phase: Change in high sensitivity C-reactive protein level	From baseline (week 0) to week 156	Ratio to baseline
Main Phase: Number of treatment emergent adverse events (TEAEs)	From baseline (week 0) up to week 156	Number of events
Extension Phase: Number of treatment emergent adverse events (TEAEs)	From baseline (week 0) to week 156	Number of events
Main Phase: Time to first occurrence of major adverse cardiovascular event (MACE) comprising non-fatal myocardial infarction, non-fatal stroke and allcause death	From baseline (week 0) to week 104	Week(s)
Extension Phase: Time to first occurrence of major adverse cardiovascular event (MACE) comprising non-fatal myocardial infarction, non-fatal stroke and allcause death	From baseline (week 0) to week 156	Week(s)
Extension Phase: Time to first occurrence of stroke	From baseline (week 0) to week 156	Weeks
Main Phase: Change in the EQ-5D-5L (proxy version) index score	From baseline (week 0) to week 104	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.
Extension Phase: Change in the EQ-5D-5L (proxy version) index score	From baseline (week 0) to week 156	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.
Extension phase: Change in the CDR-SB score	From baseline (week 0) to week 156	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.
Main Phase: Change in the 24-item Alzheimer's Disease Cooperative Study Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-ADL-MCI) score	From baseline (week 0) to week 104	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.
Extension phase: Change in the ADCS-ADL-MCI score	From baseline (week 0) to week 156	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.
Main Phase: Time to progression to Clinical Dementia Rating (CDR) global score greater than or equal to (≥)1.0 among patients with CDR global score equal to (=) 0.5 at baseline	From baseline (week 0) up to week 156	Week(s)
Extension Phase: Time to progression to Clinical Dementia Rating (CDR) global score greater than or equal to (≥)1.0 among patients with CDR global score equal to (=) 0.5 at baseline	From baseline (week 0) to week 156	Week(s)
Main Phase: Time to progression in disease stage based on CDR global score	From baseline (week 0) up to week 156	Week(s)
Extension Phase: Time to progression in disease stage based on CDR global score	From baseline (week 0) to week 156	Week(s)
Main Phase: Change in the composite Z-score based on the three outcome measures CDR-SB, ADCS-ADL-MCI, and ADAS-Cog-13	From baseline (week 0) to week 104	Score
Extension Phase: Change in the composite Z-score based on the three outcome measures CDR-SB, ADCS-ADL-MCI, and ADAS-Cog-13	From baseline (week 0) to week 156	Score
Main Phase: Time to first occurrence of stroke	From baseline (week 0) to week 104	Weeks

Trial Locations

Locations (385)

Banner Alzheimer's Institute; 🇺🇸 Phoenix, Arizona, United States

Banner Sun Health Research Institute; 🇺🇸 Sun City, Arizona, United States

Advanced Research Center, Inc.; 🇺🇸 Anaheim, California, United States

Torrance Clin Res Inst, Inc.; 🇺🇸 Lomita, California, United States

ASCLEPES Research Centers,; 🇺🇸 Long Beach, California, United States

Well Care Medical Center; 🇺🇸 Panorama City, California, United States

Cedars-Sinai Medical Center; 🇺🇸 Pasadena, California, United States

Sharp Neurocog Res Ctr; 🇺🇸 San Diego, California, United States

Syrentis Clinical Research; 🇺🇸 Santa Ana, California, United States

Calfornia Neurosc Resrch Med; 🇺🇸 Sherman Oaks, California, United States

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