EVOKE/EVOKE+
Objective
Semaglutide – To evaluate the efficacy and safety of once-daily oral semaglutide versus placebo in individuals with early-stage symptomatic Alzheimer's disease.
Study Summary
• Targets neuroinflammation, vascular dysfunction, and other non-amyloid pathways
• Global trial in 40 countries; ongoing with results expected 2025–2026
Intervention
Randomized, double-blind, placebo-controlled, phase 3 trials with identical design. Patients receive 3–14 mg oral semaglutide once daily (escalated over 8 weeks) or placebo for 156 weeks (104-week core phase + 52-week extension). Trial includes CSF and biomarker substudy. Participants allowed to remain on stable doses of approved Alzheimer's medications.
Inclusion Criteria
Adults 55–85 years with MCI or mild AD (CDR global 0.5–1.0), MMSE ≥22, RBANS delayed memory ≤85, and confirmed amyloid positivity by PET or CSF. EVOKE+ includes participants with small vessel disease. Exclusion criteria include neurologic disorders other than AD, recent use of GLP-1RAs, or unstable psychiatric or systemic medical conditions.
Study Design
Arms: Semaglutide vs. Placebo
Patients per Arm: Planned ~1840 per trial, 1:1 randomization
Outcome
• Secondary: Change in ADCS-ADL-MCI, MMSE, MoCA, ADAS-Cog-13, ADCOMS, and NPI scores; time to progression to dementia for MCI subgroup
• Exploratory: Plasma biomarkers (NfL, p-tau181, GFAP, hs-CRP) and CSF markers (sTREM2, neurogranin, IL-6, YKL-40, etc.)
• Safety: Common adverse events include GI symptoms; semaglutide generally well tolerated with flexible dosing and pauses
• Imaging: MRI or CT allowed; hippocampal atrophy assessed
• Trial allows continued use of cholinesterase inhibitors and anti-amyloid antibodies during participation
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
Study 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
- Follow-up
- 156 weeks total (104-week main phase + 52-week extension) plus 5-week follow-up
- Centers
- 566
Primary Outcome
Definition: Change in CDR-SB score from baseline to week 104
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| Not yet available (design paper) | Not yet available (design paper) | - |
Limitations & 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
Citation
Alzheimers Res Ther 2025;17:14