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EVOKE/EVOKE+

Evoke and Evoke+: design of two large-scale, double-blind, placebo-controlled, phase 3 studies evaluating efficacy, safety, and tolerability of semaglutide in early-stage symptomatic Alzheimer's disease

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Year of Publication: 2025

Authors: Jeffrey L. Cummings, Alireza Atri, Howard H. Feldman, ..., Philip Scheltens

Journal: Alzheimer's Research & Therapy

Citation: Alzheimers Res Ther 2025;17:14

Link: https://doi.org/10.1186/s13195-024-01666-7

PDF: https://alzres.biomedcentral.com/counter...195-024-01666-7

Clinical Question

Does oral semaglutide, a GLP-1 receptor agonist with potential anti-inflammatory and neuroprotective effects, slow cognitive and functional decline in early-stage symptomatic Alzheimer's disease (MCI or mild dementia) with biomarker-confirmed amyloid pathology?

Bottom Line

Design paper for two identical phase 3 trials investigating semaglutide as a novel disease-modifying therapy targeting neuroinflammation and other non-amyloid pathways in early AD. This represents the first large-scale evaluation of a GLP-1RA in AD. Results expected September 2025, with 52-week extension to October 2026.

        Major Points
        Two identical phase 3 randomized, double-blind, placebo-controlled trials (evoke and evoke+) with planned N=1840 each
First large-scale trials of GLP-1 receptor agonist for disease modification in AD
Novel mechanism targeting neuroinflammation, vascular integrity, and neuroprotection rather than direct amyloid clearance
Oral once-daily dosing offers convenience advantage over IV anti-amyloid antibodies
156-week treatment period (104-week main phase + 52-week blinded extension)
Primary endpoint is CDR-SB change at 104 weeks
evoke+ allows enrollment of patients with significant small vessel pathology (ARWMC >2 and/or >1 lacunar infarct)
Participants can continue or initiate standard AD medications including anti-amyloid antibodies during trial
CSF sub-study (N=210) will assess neuroinflammation, neurodegeneration, BBB integrity, and AD biomarkers
Plasma biomarkers (NfL, p-tau181, GFAP, hs-CRP) collected from all participants
8-week dose escalation (3 mg → 7 mg → 14 mg) to minimize GI adverse events
Flexible dosing allows dose reduction and treatment pauses for tolerability
Up to 30% of population may have type 2 diabetes
Enrollment from 40 countries and 566 centers to ensure diverse population
Expected 80% MCI and 20% mild AD dementia at enrollment

      

Design

Study Type: Phase 3 randomized, double-blind, placebo-controlled, parallel-group trials (two identical trials)

Blinding: Double-blind; participants and investigators remain blinded throughout main phase and 52-week extension; interactive web response system for blind-breaking if needed for safety

Sample Size: 3680

Centers: 566

Follow-up Duration: 156 weeks total (104-week main phase + 52-week extension) plus 5-week follow-up

Inclusion Criteria

Male or female aged 55-85 years
MCI or mild dementia due to AD per NIA-AA 2018 criteria
MCI: CDR global score 0.5 with CDR domain score ≥0.5 in at least one of three ADL categories (personal care, home and hobbies, community affairs)
Mild AD dementia: CDR global score 1.0
Amyloid abnormalities confirmed by PET (visual read) or CSF Aβ1-42 or CSF Aβ1-42/Aβ1-40 (historical data up to 2 years accepted)
RBANS delayed memory index score ≤85
MMSE score ≥22
For evoke+: participants with significant small vessel pathology eligible (ARWMC >2 and/or >1 lacunar infarct)
Stable dose of approved AD medications for ≥3 months before screening (if applicable)

Exclusion Criteria

Neurologic disorders other than AD (Parkinson's, Lewy body, FTD, Huntington's)
Clinically relevant or unstable psychiatric disorder
MRI/CT scan with clinically significant structural CNS disease (large vessel infarcts >10 mm, prior macrohemorrhage >1 cm³, vascular malformations, cortical hemosiderosis, aneurisms, tumors, normal pressure hydrocephalus)
For evoke only: ARWMC=3 (excluded)
Current or previous GLP-1RA treatment within 90 days
Regular anticholinergic medications (>2 doses/week) within 4 weeks
Anti-parkinsonian, anticonvulsant, or neuroleptic medications within 3 months
Regular benzodiazepines, sedatives, morphine, or narcotic analgesics
Stimulant medications within 4 weeks
Medical marijuana, cannabis, or CBD
Type 1 diabetes mellitus
Personal or first-degree relative history of MEN2 or medullary thyroid carcinoma
Uncontrolled diabetic retinopathy or maculopathy
Malignancy within 5 years (except non-melanoma skin cancer, in situ carcinomas)
End-stage renal disease or dialysis
MI, stroke, hospitalization for unstable angina or TIA within 90 days
NYHA Class IV heart failure
Pregnancy or breastfeeding

Arms

Field	Oral semaglutide	Control
Intervention	Once-daily oral semaglutide, titrated to 3–14 mg over 8 weeks	Matching oral placebo once daily
Duration	156 weeks (104-week core + 52-week extension)	156 weeks

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Change in CDR-SB score from baseline to week 104	Primary	Not yet available (design paper)	Not yet available (design paper)

Criticisms

Design paper only - efficacy and safety not yet demonstrated in AD population
Semaglutide may have limited BBB penetration; effects may be indirect/peripheral
No prior phase 1/2 trial of semaglutide specifically in AD population
Rationale based primarily on epidemiologic data and preclinical studies
Participants can initiate anti-amyloid antibodies during trial, which may confound results
Implementation across 40 countries and 50 languages presents logistical challenges
May have higher screening failure in non-White populations affecting representativeness
Weight loss could be problematic in some elderly AD patients
Use of concurrent AD medications was not a stratification factor
Long trial duration (156 weeks) may lead to significant dropout

Funding

Novo Nordisk A/S

Based on: EVOKE/EVOKE+ (Alzheimer's Research & Therapy, 2025)