The LESS-AD trial: A study on the use of levetiracetam to prevent seizures in adults with Down syndrome and Alzheimer's disease.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fundacio Institut De Recerca De L'Hospital De La Santa Creu I Sant Pau

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10], Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Therapeutics [E02], Phenomena and Processes [G] - Genetic Phenomena [G05]

Trial duration

16 Dec 2025 → ongoing

Decision date (initial)

2025-05-06

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

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 4

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

Conditions and MedDRA coding

Down syndrome

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Diagnosed with Down Syndrome (DS), either with a karyotype or a compatible typical phenotype.
2. 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.
3. Willing and able caregiver who has daily contact with the study subject.
4. 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
5. 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
6. Age over 40 years at time of screening. This age cutoff has been selected because the beginning of cognitive decline attributable to AD in the study population is exceptional below this age
7. Subjects and/or their caregivers must be able to provide their consent before participating in any study-related procedures. A thorough description of the informed consent process can be found under section 12.2. Participants’ Informed Consent Process.

Exclusion criteria 12

1. 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).
2. Participation in another clinical trial within 3 months of screening.
3. Hypersensitivity to the active ingredient, other pyrrolidone derivatives, or any of the excipients
4. Previous history of adult-onset epileptic seizures (over 18 years old).
5. Treatment with any kind of antiepileptic drugs, benzodiazepines, narcotics.
6. Significant comorbidities or analytical abnormalities, such as:
7. 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.
8. 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
9. 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]).
10. 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
11. Deviations from normal values for hematologic parameters, liver function tests, and other biochemical measures, judged to be clinically significant by the investigator.
12. Pregnant and breastfeeding patients

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Efficacy: Number (percentage) of subjects who do not develop a bilateral tonic-clonic epileptic seizure during the study (96 weeks). Therefore, a non-responder, or treatment failure, is defined as any subject who develops a bilateral tonic-clonic epileptic seizure during the study.

Secondary endpoints 7

1. Time to first bilateral tonic-clonic epileptic seizure (days)
2. All-cause mortality: - Number (percentage) of patients dying from any cause during the study. - Number (percentage) of patients dying due to AD complications during the study. - Time to death (days).
3. AD-related biomarkers: - Cognition: The neuropsychological assessment will include the CAMCOG-DS, mCRT
4. Plasma biomarkers: plasma concentrations of 217-pTau and NfL (pg/mL).
5. Neuroimaging biomarkers (MRI): Volumetric measures extracted for 12 subcortical gray matter regions (six left and six right, including the amygdala, caudate nucleus accumbens, pallidum, putamen, and thalamus), the left and right hippocampi, and the left and right lateral ventricles. Cortical thickness measure extracted for 34 left-hemispheric gray matter regions, and 34 right hemispheric gray matter regions (Whelan et al, Brain 2018).
6. Electroencephalography (EEG): Appearance of graphoelements with irritative characteristics: spike-wave, polyspike-wave, acute wave and spike or focal and generalized slowing of the activity, power spectrum analysis and synchronization by bands.
7. - Safety: 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.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Placebo 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fundacio Institut De Recerca De L'Hospital De La Santa Creu I Sant Pau

Sponsor organisation

Fundacio Institut De Recerca De L'Hospital De La Santa Creu I Sant Pau

Address

Calle Sant Quinti 77-79

City

Barcelona

Postcode

08041

Country

Spain

Scientific contact point

Organisation

Fundacio Institut De Recerca De L'Hospital De La Santa Creu I Sant Pau

Contact name

Alejandra Espinosa

Public contact point

Organisation

Fundacio Institut De Recerca De L'Hospital De La Santa Creu I Sant Pau

Contact name

Alejandra Espinosa

Locations

1 EU/EEA country · 5 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 16 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications