Efficacy and Safety of Levetiracetam in Preventing Seizures in Adults with Down Syndrome and Alzheimer's Disease: A Phase III Randomized, Double-Blind Study
- Trial ID
- 2024-516148-24-00
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this phase III, randomized, double-blinded study is to evaluate the **efficacy** of **levetiracetam** as a preventive measure for bilateral tonic-clonic seizures over a period of 96 weeks in adults with Alzheimer's disease associated with Down syndrome. This is clinically relevant as it aims to address seizure management in a population with dual diagnoses, potentially improving quality of life and reducing seizure-related complications.
Secondary objectives include:
- Quantifying the time to the first bilateral tonic-clonic seizure between groups (levetiracetam vs. placebo).
- Evaluating the incidence of mortality between groups (levetiracetam vs. placebo).
- Studying changes in biomarkers related to Alzheimer's disease, including functional changes (CAMDEX-DS), cognitive changes (CAMCOG, mCRT), plasma biomarkers (217-pTau, NfL), brain structure (cortical thickness, hippocampal volume, gray matter volume), and epileptiform activity (EEG).
- Assessing safety through the incidence of adverse events and serious adverse events in the levetiracetam vs. placebo groups.
Participants
The clinical trial involves a study population comprising adults diagnosed with **Down syndrome** and symptomatic **Alzheimer's Disease**. The participants are both male and female, aged over 40 years, reflecting the age at which cognitive decline due to Alzheimer's is more prevalent in this population. The trial includes individuals with varying levels of intellectual disability, as determined by specific neuropsychological assessments. Participants are required to have a willing and able caregiver who maintains daily contact and can assist in adhering to the study regimen, which includes biannual in-person visits. The trial population is considered vulnerable, given the dual diagnosis of Down syndrome and Alzheimer's Disease. The sponsor has not provided the total number of participants involved in the study. Participants must have stable concurrent treatment for Alzheimer's Disease, approved by the European Medicines Agency, for a specified period before the trial. The selection criteria ensure that subjects and their caregivers can provide informed consent and comply with the study requirements.
Plans and Procedures
The clinical trial is a **randomized**, **double-blind**, placebo-controlled study designed to evaluate the efficacy and safety of **levetiracetam** in preventing bilateral tonic-clonic seizures in adults with **Alzheimer's Disease** associated with **Down syndrome**. The trial is set to span a duration of 96 weeks, with an estimated recruitment start date of January 31, 2025, and an estimated end date of April 30, 2028. Participants will be randomly assigned to receive either levetiracetam or a placebo, with the primary endpoint being the number of subjects who do not develop a bilateral tonic-clonic epileptic seizure during the study period.
The sequence of study visits includes an initial inclusion (screening) visit, where eligibility criteria are assessed, followed by biannual follow-up visits to monitor the participants' health status and treatment adherence. The end-of-study visit will occur at the conclusion of the 96-week period, where final assessments will be conducted. Participants are expected to be involved in the study for the entire duration unless conditions arise that necessitate early termination, such as the development of a bilateral tonic-clonic epileptic seizure, non-compliance with the study protocol, or withdrawal of consent.
Inclusion criteria require participants to be over 40 years of age, diagnosed with Down syndrome and symptomatic Alzheimer's Disease, and have a willing and able caregiver. Exclusion criteria are not explicitly detailed in the provided data. The study will assess both primary and secondary endpoints, including time to first seizure, all-cause mortality, and various biomarkers related to Alzheimer's Disease. Safety assessments will include monitoring adverse events, vital signs, and routine laboratory evaluations. The trial aims to provide valuable insights into the potential of levetiracetam as a preventive treatment for seizures in this specific patient population.
Treatment
The clinical trial involves the administration of **Levetiracetam NORMON 250 mg** film-coated tablets, which contain the active substance **levetiracetam**. This medication is administered orally. The maximum daily dose is 500 mg, with a total maximum dose of 500 mg over a treatment period of up to 4 weeks. The pharmaceutical form is a film-coated tablet, and the product is manufactured by Laboratorios Normon, S.A. The active substance is of chemical origin, and the product is authorized in Spain under the marketing authorization number 75040.
Another experimental treatment in the trial is **Levetiracetam NORMON 500 mg** film-coated tablets, also containing the active substance **levetiracetam**. This medication is similarly administered orally. The maximum daily dose for this formulation is 1000 mg, with a total maximum dose of 1000 mg over a treatment period of up to 4 weeks. The pharmaceutical form remains a film-coated tablet, produced by the same manufacturer, Laboratorios Normon, S.A., and is authorized in Spain with the marketing authorization number 75042.
The trial also includes a placebo control, consisting of **PLACEBO LEVETIRACETAM 250 mg** and **PLACEBO LEVETIRACETAM 500 mg**. These placebo treatments are designed to match the experimental medications in appearance and administration route but do not contain the active substance **levetiracetam**. The placebo is used to maintain the double-blind nature of the study, ensuring unbiased assessment of the efficacy and safety of the active treatments.
Efficacy
The efficacy of **levetiracetam** in preventing bilateral tonic-clonic seizures in adults with Alzheimer's disease associated with Down syndrome will be assessed through a series of primary and secondary endpoints over a 96-week period. The primary efficacy endpoint is the number (percentage) of subjects who do not develop a bilateral tonic-clonic epileptic seizure during the study. A non-responder, or treatment failure, is defined as any subject who develops such a seizure during the study.
Secondary efficacy endpoints include the time to the first bilateral tonic-clonic epileptic seizure, all-cause mortality, and various Alzheimer's disease-related biomarkers. These biomarkers encompass cognitive assessments using the CAMCOG-DS and mCRT, plasma concentrations of 217-pTau and NfL, and neuroimaging biomarkers obtained through MRI, which will measure volumetric changes in subcortical gray matter regions and cortical thickness. Additionally, electroencephalography (EEG) will be used to detect graphoelements with irritative characteristics, such as spike-wave and polyspike-wave patterns.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Diagnosed with Down Syndrome (DS), either with a karyotype or a compatible typical phenotype.
- 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
- 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
- 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
- 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).
- Participation in another clinical trial within 3 months of screening.
- Hypersensitivity to the active ingredient, other pyrrolidone derivatives, or any of the excipients
- 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.
- Pregnant and breastfeeding patients
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Spain | Recruiting | 31 Jan 2025 | 120 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Levetiracetam NORMON 250 mg comprimidos recubiertos con película EFG | Test | COMPRIMIDOS RECUBIERTOS CON PELÍCULA | ORAL | 500 | 4 | PRD408467 |
PLACEBO LEVETIRACETAM 250 mg | Placebo | N/A | — | — | — | N/A |
Levetiracetam NORMON 500 mg comprimidos recubiertos con película EFG | Test | COMPRIMIDOS RECUBIERTOS CON PELÍCULA | ORAL | 1000 | 4 | PRD408468 |
PLACEBO LEVETIRACETAM 500 mg | Placebo | N/A | — | — | — | N/A |