LEvetiracetam to Prevent Seizures in Symptomatic Alzheimer's Disease in Adults With Down Syndrome (LESS-AD)

A Phase III, Randomized, Double-blinded Study of the Efficacy and Safety of LEvetiracetam to Prevent Seizures in Symptomatic Alzheimer's Disease in Adults With Down Syndrome (the LESS-AD Trial).

The purpose of this study is to evaluate whether levetiracetam can prevent epileptic seizures in patients with Alzheimer's disease associated with Down syndrome. It will also analyze whether it can delay the neurodegeneration associated with this disease.

Patients will be randomly assigned to one of two groups: one group will receive the active drug (levetiracetam), and the other will receive a placebo.

Both groups will receive the treatment for 96 weeks. Each patient will participate for a total of 2 years and 5 months.

Study Overview

• Status: Recruiting
• Conditions: Epilepsy; Alzheimer Disease; Seizures; Down Syndrome; Alzheimer Dementia; Down Syndrome (Trisomy 21); Alzheimer Disease (AD); Alzheimer Dementia (AD); Down Syndrome (DS); Alzheimer Blood Biomarkers
• Intervention / Treatment: Drug: Placebo; Drug: Levetiracetam 500mg

Detailed Description

This study is a clinical trial that will examine the efficacy and safety of a medication called levetiracetam in people with Down syndrome and Alzheimer's disease.

Adults with Down syndrome have a high risk of developing Alzheimer's disease. Epilepsy frequently coexists in these patients, and is associated with a worse clinical outcome. The early dysfunction of inhibitory interneuronal circuits, found in epilepsy, contributes to cognitive decline in Alzheimer's disease patients. Modifying this abnormal activity with levetiracetam could have potential benefits in the treatment of Alzheimer's disease, beyond its benefits on epileptic seizures' control and interictal epileptic activity recorded on EEG. Levetiracetam is a widely used drug with a proven safety profile, with more than 20 years of commercialization. This trial will evaluate the preventive benefit on the development of epileptic seizures in Alzheimer's disease associated with Down syndrome and, secondarily, its effect on cognitive decline and Alzheimer's disease markers. If the described benefits of levetiracetam use are independent of its antiepileptic effect, it could be a drug with a potential disease-modifying effect in Alzheimer's disease.

Primary objective:

To evaluate the efficacy of levetiracetam as a preventive measure for bilateral tonic-clonic seizures at 96 weeks in adults with Alzheimer's disease associated with Down syndrome.

Secondary objectives:

1. To quantify the time to the first bilateral tonic-clonic seizure between groups (levetiracetam vs. placebo).
2. To evaluate the incidence of mortality between groups (levetiracetam vs. placebo).

3. To study changes in biomarkers related to Alzheimer's disease:

   1. Functional changes (CAMDEX-DS)
   2. Cognitive changes (CAMCOG, mCRT)
   3. Plasma biomarkers (217-pTau, NfL)
   4. Brain structure (cortical thickness, hippocampal volume, gray matter volume)
   5. Epileptiform activity (EEG)
4. Safety: Incidence of adverse events and serious adverse events in the LEV vs. placebo groups.

A total of 120 participants will be included (60 per group).

The dose of levetiracetam to be used in this clinical trial is 1000 mg/day (two doses of 500mg each 12 hours) orally. During the first 4 weeks of the treatment period, LEV, treatment will be administered 500mg/d (250mg/12h) to facilitate the compliance. During the last 4 weeks of the treatment period, LEV will be administered 500mg/d (250mg/12h) to enable a gradual withdrawal.

Participants in placebo arm will receive placebo 1 capsule/12h during the 96 weeks of the treatment period.

The patients will have a total of 12 medical visits during their participation in the study. In those visits the following medical procedures will be carried out:

• Neuropsychological evaluation
• Blood analysis
• Magnetic resonance imaging (MRI)
• Electroencephalogram (EEG)

This study not only aims to improve the health and quality of life of people with Down syndrome but also to advance our general understanding of Alzheimer's disease, which could benefit more patients in the future.

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: María Carmona Iragui, Doctor; Phone Number: +34 93 556 59 56; Email: mcarmonai@santpau.cat
• Study Contact Backup: Name: Diego Real de Asúa Cruzat, Doctor; Email: diego.realdeasua@salud.madrid.org

Study Locations

• Spain
  • Madrid, Spain, 28006
    • Not yet recruiting
    • Hospital La Princesa
    • Contact: Diego Real de Asúa Cruzat, Doctor; Phone Number: +34 915 20 22 00; Email: diego.realdeasua@salud.madrid.org
  • Andalusia
    • Granada, Andalusia, Spain, 18014
      • Not yet recruiting
      • Hospital Virgen de las Nieves
      • Contact: Joaquín Escobar Sevilla, Doctor; Phone Number: +34 958 02 00 00; Email: escobarsevillaj@gmail.com
  • Basque Country
    • Donostia / San Sebastian, Basque Country, Spain, 20009
      • Not yet recruiting
      • Fundacion CITA ALZHEIMER
      • Contact: Miren Altuna Azkargorta, Doctor; Phone Number: +34 943 02 17 92; Email: maltuna@cita-alzheimer.org
  • Cantabria
    • Santander, Cantabria, Spain, 39008
      • Not yet recruiting
      • Hospital Universitario Marques de Valdecilla
      • Contact: Eloy Rodríguez Rodríguez, Doctor; Phone Number: +34 942 20 25 20; Email: eloymrod@gmail.com
  • Catalonia
    • Barcelona, Catalonia, Spain, 08041
      • Recruiting
      • Hospital de la Santa Creu i Sant Pau
      • Contact: Maria Carmona Iragui, Doctor; Phone Number: +34 935565986; Email: mcarmonai@santpau.cat

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosed with Down Syndrome (DS), either with a karyotype or a compatible typical phenotype.
• Age over 40 years at time of screening.
• Symptomatic Alzheimer's Disease (AD) dementia, based on change in functionality and neuropsychological tests' results. Different cut-off points will be established to diagnose dementia depending on the level of intellectual disability of the individual, according to previous experience (Benejam et al; 2020): in adults with mild intellectual disability, a CAMCOG-DS score of 80 and an mCRT score of 29 will be chosen, whereas values of 56 and 28, respectively, will be used in subjects with moderate intellectual disability. Doubtful cases (e.g., with compromised functionality, but without alteration in the neuropsychological assessment) or those unable to complete the evaluation will be categorized by consensus among expert clinicians, using all available clinical information.
• Willing and able caregiver who has daily contact with the study subject.
• Subjects and caregivers must be able to comply with the prescribed regimen of study treatment throughout the course of the study and meet a minimum required time commitment of biannual in-person visits.
• Any concurrent treatment for AD approved by the European Medicines Agency (EMA) must be stable for at least 30 days prior to screening and at least 60 days prior to study day 1. Other medications (except for those listed under exclusion criteria) are allowed as long as the dose is stable for 30 days prior to screening.
• Subjects and/or their caregivers must be able to provide their consent before participating in any study-related procedures.

Exclusion Criteria:

• Cognitive changes attributable to causes other than AD (for example, but not limited to, uncorrected visual or hearing deficit, severe, untreated sleep apnea or uncontrolled thyroid disorders).
• Previous history of adult-onset epileptic seizures (over 18 years old).
• Treatment with any kind of antiepileptic drugs, benzodiazepines, narcotics.
• Significant comorbidities or analytical abnormalities, such as:
• Any unstable and/or clinically significant medical condition likely to hamper the evaluation of safety and/or efficacy of the study (eg, moderate and/or severe untreated obstructive sleep apnea, clinically significant reduction in serum B12 or folate levels, clinically significant abnormalities of thyroid function, stroke, or other cerebrovascular conditions), as per investigator's judgement.
• Severe renal dysfunction (creatinine clearance < 30 mL/min), which would affect serum levetiracetam levels, or any other medical condition which is determined by the investigators to potentially create an undue risk for an adverse effect.
• Concomitant or past history psychiatric or neurologic disorder other than those considered to be related to AD (eg, head injury with loss of consciousness, symptomatic stroke, Parkinson's disease, severe carotid occlusive disease, transient ischemic attacks [TIAs]).
• Significant risk of suicide, defined using the C-SSRS as the subject answering "yes" to suicidal ideation questions 4 or 5 or answering "yes" to suicidal behavior within the past 12 months.
• Deviations from normal values for hematologic parameters, liver function tests, and other biochemical measures, judged to be clinically significant by the investigator.
• Participation in another clinical trial within 3 months of screening.
• Hypersensitivity to the active ingredient, other pyrrolidone derivatives, or any of the excipients
• Pregnant and breastfeeding patients

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Levetiracetam 500 mg/12h; Tablets for twice daily administration for 96 weeks. During the first 4 weeks of the treatment period, LEV, treatment will be administered 500mg/d (250mg/12h) to facilitate the compliance. During the last 4 weeks of the treatment period, LEV will be administered 500mg/d (250mg/12h) to enable a gradual withdrawal.	Drug: Levetiracetam 500mg; Use of Levetiracetam to prevent Seizures in Symptomatic Alzheimer's Disease in adults with Down syndrome (the LESS-AD trial)
Placebo Comparator: Placebo; Tablets for twice daily administration for 96 weeks.	Drug: Placebo; Comparator

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy of Levetiracetam as a preventive treatment for epileptic seizures in adults with Alzheimer's disease associated with Down syndrome.	Number (percentage) of subjects who do not develop a bilateral tonic-clonic epileptic seizure during the study treatment phase (96 weeks).	From enrollment to the end of treatment at 96 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to first bilateral tonic-clonic epileptic seizure	Baseline (randomization) to first adjudicated epileptic seizure or censoring, up to 96 weeks.	days
All-cause mortality	All-cause mortality (number and percentage) - Time Frame: Baseline (randomization) to study completion, up to 96 weeks.; Alzheimer-related mortality (number and percentage) - Time Frame: Baseline (randomization) to study completion, up to 96 weeks.	percentage
Time to death	Baseline (randomization) to death or censoring, up to 96 weeks.	days
Cognition	CAMCOG-DS (total score): change from baseline and week 96. Change from baseline visit in the CAMCOG-DS total score. Missing visits will be handled per the statistical analysis plan.	CAMCOG-DS: change from baseline and week 96.
Plasma biomarkers -217p-tau	Plasma pTau-217-change (pg/mL) from baseline and week 96. Change from baseline in plasma pTau-217 concentration, quantified using the same laboratory and assay throughout the study.	Change from baseline and week 96
Plasma biomarkers- NfL	Plasma Neurofilament light (NfL) (pg/mL) - Change from Baseline. Change from Baseline in plasma NfL concentration.	At week 96
Neuroimaging GMV	Subcortical gray matter volume - change from Baseline (by region). Change from Baseline in volume (mm³) for 12 subcortical gray matter regions (left/right: amygdala, caudate, nucleus accumbens, pallidum, putamen, thalamus). Each region will be reported separately.	At week 96
Neuroimaging- HV	Hippocampal volume (mm3)- Change from Baseline (left and right). Change from Baseline in hippocampal volume for the left and right hemispheres. Each hemisphere will be reported separately.	Change at week 96
Neuroimaging- LVV	Lateral ventricle volume (mm3) - Change from Baseline (left and right). Change from Baseline in lateral ventricle volume for the left and right hemispheres. Each hemisphere will be reported separately.	Week 96
Neuroimaging CTh	Cortical thickness (mm) - Change from Baseline (by region). Change from Baseline in cortical thickness (mm) for 34 left-hemispheric and 34 right-hemispheric cortical regions. Each region will be reported separately.	Week 96
Electroencephalography (EEG)	Presence of epileptiform/irritative graphoelements. Proportion of participants showing irritative graphoelements (spike-wave, polyspike-wave, sharp waves, focal or generalized slowing) per standardized EEG reading.	At week 96.
EEG- band power	EEG band power (µV²/Hz) - Change from Baseline. Change from Baseline in mean band power (δ, θ, α, β, γ) computed with a prespecified processing pipeline.	At week 96
EEG sync	EEG synchronization/coherence (unitless index (0-1)) - Change from Baseline (by band). Change from Baseline in synchronization/coherence indices by frequency band (dimensionless 0-1) across predefined electrode pairs.	At week 96
Safety of Levetiracetam	The primary endpoints are number, type, frequency, and intensity of AEs evaluated until the end of treatment and assessment of tolerability during the medical visit, physical and neurological examination, vital signs, brain MRI assessment, suicidality (as measured with the C-SSRS), routine hematology and biochemistry evaluation in blood.	From enrollment to the end of treatment at 96 weeks
Incidence of adverse events (AEs)	Proportion (%) of participants: with ≥1 treatment-emergent adverse events (TEAEs); with TEAEs considered related to the treatment by the investigator; with ≥1 serious adverse events (SAEs) after first dose of treatment; who discontinue the study due to AEs	At week 96
AEs- TEAE rate	TEAE rate- Rate of TEAEs per participant-year of exposure.	Up to week 36
Maximum AE severity	Proportion of participants with at least one TEAE of maximum severity mild, moderate, or severe (% reported by category).	At week 96
AEs- Dose interruptions	Dose interruptions due to AEs. Proportion of participants with ≥1 levetiracetam dose interruption or reduction attributable to AEs.	At week 96.
Vital signs- BP	Systolic and diastolic blood pressure (mmHg)- Change from Baseline in systolic and diastolic blood pressure.	At week 96
Vital signs- HR	Heart rate. Change from Baseline in resting heart rate (bpm).	At week 96
Physical examination	Clinically significant abnormalities on physical/neurological exam. Proportion of participants with new or worsening clinically significant findings on physical or neurological examination.	Week 96
Brain MRI safety	Clinically significant new MRI findings. Proportion of participants with new clinically significant MRI findings (e.g., edema, hemorrhage) vs Baseline.	At week 96
Suicidality (C-SSRS)	Suicidal ideation or behavior (C-SSRS). Proportion of participants with any positive suicidal ideation or behavior signal on the C-SSRS.	Week 96
Laboratory safety	Treatment-emergent hematology and biochemistry abnormalities: Proportion of participants with ≥1 treatment-emergent hematology abnormality meeting predefined thresholds (e.g., CTCAE grade ≥2).; Proportion of participants with ≥1 treatment-emergent biochemistry abnormality meeting predefined thresholds (e.g., CTCAE grade ≥2).	At week 96

Collaborators and Investigators

• Sponsor: Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau
• Collaborators: Fundación de Investigación Biomédica - Hospital Universitario de La Princesa; Hospital Universitario Marqués de Valdecilla; University Hospital Virgen de las Nieves; Fundación CITA Alzheimer

Study record dates

Study Major Dates

• Study Start (Estimated): December 22, 2025
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): July 1, 2028

Study Registration Dates

• First Submitted: October 2, 2025
• First Submitted That Met QC Criteria: November 14, 2025
• First Posted (Estimated): November 18, 2025

Study Record Updates

• Last Update Posted (Estimated): January 12, 2026
• Last Update Submitted That Met QC Criteria: January 8, 2026
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: dementia; epilepsy; prevention; Alzheimer; Down syndrome; phase III; randomized; placebo-controlled; double-blind; epileptic seizures; levetiracetam; NfL; Alzheimer's disease markers; bilateral tonic-clonic seizure; 217-pTau
• Additional Relevant MeSH Terms: Neurologic Manifestations; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Genetic Diseases, Inborn; Neurobehavioral Manifestations; Neurocognitive Disorders; Tauopathies; Neurodegenerative Diseases; Congenital Abnormalities; Abnormalities, Multiple; Epilepsy, Generalized; Intellectual Disability; Chromosome Disorders; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Alzheimer Disease; Dementia; Epilepsy; Seizures; Down Syndrome; Epilepsy, Tonic-Clonic; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Acids, Acyclic; Carboxylic Acids; Amides; Pyrrolidines; Acetamides; Acetates; Pyrrolidinones; Levetiracetam
• Other Study ID Numbers: IIBSP-LEV-2024-86; 2024-516148-24-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No