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).
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- 入组人数
- 120
- 试验地点
- 5
- 主要终点
- Efficacy of Levetiracetam as a preventive treatment for epileptic seizures in adults with Alzheimer's disease associated with Down syndrome.
研究概览
简要总结
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.
详细描述
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:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Clinical Research Associate, Project Manager, Data Manager
入排标准
- 年龄范围
- 40 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
- •Other medications (except for those listed under
排除标准
- •) 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
研究组 & 干预措施
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.
干预措施: Levetiracetam 500mg (Drug)
Placebo
Tablets for twice daily administration for 96 weeks.
干预措施: Placebo (Drug)
结局指标
主要结局
Efficacy of Levetiracetam as a preventive treatment for epileptic seizures in adults with Alzheimer's disease associated with Down syndrome.
时间窗: From enrollment to the end of treatment at 96 weeks
Number (percentage) of subjects who do not develop a bilateral tonic-clonic epileptic seizure during the study treatment phase (96 weeks).
次要结局
- Time to first bilateral tonic-clonic epileptic seizure(days)
- All-cause mortality(percentage)
- Time to death(days)
- Cognition(CAMCOG-DS: change from baseline and week 96.)
- Plasma biomarkers -217p-tau(Change from baseline and week 96)
- Plasma biomarkers- NfL(At week 96)
- AEs- TEAE rate(Up to week 36)
- Neuroimaging GMV(At week 96)
- Neuroimaging- HV(Change at week 96)
- Neuroimaging- LVV(Week 96)
- Neuroimaging CTh(Week 96)
- Electroencephalography (EEG)(At week 96.)
- EEG- band power(At week 96)
- EEG sync(At week 96)
- Safety of Levetiracetam(From enrollment to the end of treatment at 96 weeks)
- Incidence of adverse events (AEs)(At week 96)
- Maximum AE severity(At week 96)
- AEs- Dose interruptions(At week 96.)
- Vital signs- BP(At week 96)
- Vital signs- HR(At week 96)
- Physical examination(Week 96)
- Brain MRI safety(At week 96)
- Suicidality (C-SSRS)(Week 96)
- Laboratory safety(At week 96)