Overview
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.
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:
- To quantify the time to the first bilateral tonic-clonic seizure between groups (levetiracetam vs. placebo).
- To evaluate the incidence of mortality between groups (levetiracetam vs. placebo).
- To study changes in biomarkers related to Alzheimer's disease:
- Functional changes (CAMDEX-DS)
- Cognitive changes (CAMCOG, mCRT)
- Plasma biomarkers (217-pTau, NfL)
- Brain structure (cortical thickness, hippocampal volume, gray matter volume)
- Epileptiform activity (EEG)
- 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.
Eligibility
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