Improving Cerebral Blood Flow and Cognition in Patients with Cerebral Small Vessel Disease. the ETLAS-2 Trial
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 100
- 试验地点
- 2
- 主要终点
- Feasibility of treatment defined as proportion of participants achieving full target dose of tadalafil/placebo.
研究概览
简要总结
In a randomized controlled trial the feasibility and effect of three months treatment with daily tadalafil, on cerebral blood flow/reactivity and cognition, is investigated in patients with cerebral small vessel disease.
详细描述
Cerebral small vessel disease is a progressive brain and blood vessel disease for which there currently is no effective treatment. The disease associates with 25 % of all stroke and 30 % of all dementia cases and imposes a major and increasing health burden worldwide. In this trial the investigator suggest a new promising solution to this problem.
Patients with cerebral small vessel disease, who experience stroke or vascular dementia, may show reduced brain perfusion or altered neurovascular reactivity. The investigator has previously shown that a single dose of tadalafil (20 mg), shortly increased blood supply to the brain in patients with cerebral small vessel disease. This holds promise for new effective treatment targets. The investigator test if patients find three months daily intake of tadalafil (20 mg) feasible, and if it alters cerebral perfusion, neurovascular reactivity, and cognition, including memory and planning ability. The trial will help identify new treatment targets to reduce the number of patients with stroke, stroke sequelae, and vascular dementia.
This trial is divided into one main study and three sub studies:
- Main study
- Dynamical MRI sub study
- Cognitive sub study
- Biomarker sub study
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)
入排标准
- 年龄范围
- 50 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •MRI/computed tomography (CT) evidence of small vessel occlusion stroke(s)/lacunar stroke(s) (involving ≤2 cm in the acute phase and ≤1.5cm in the late phase) and/or confluent deep white matter hyperintensities (≥ grade 2 on Fazekas's scale).
- •Clinical evidence of cerebral small vessel disease can be: a) small vessel occlusion stroke (lacunar stroke) syndrome with symptoms lasting > 24 hours, occurring < 5 years ago; OR b) transient ischemic attack (TIA) with symptoms lasting < 24 hours AND with MR-DWI imaging performed acutely showing small vessel occlusion stroke, occurring < 5 years ago; OR c) TIA with symptoms lasting < 24 hours AND no acute MRI-DWI lesion but MRI/CT evidence of CSVD with old small vessel occlusion stroke(s) (involving ≤1.5cm) and/or confluent deep white matter hyperintensities (≥ grade 2 on Fazekas's scale).
- •Age ≥ 50 years.
排除标准
- •Known diagnosis of dementia, medically treated dementia, or under investigation for dementia
- •Pregnancy or nursing
- •Women of childbearing age not taking contraception
- •Known cortical infarction (> 1.5 cm maximum diameter)
- •Known carotid artery stenosis ≥ 50 % with Doppler ultrasound, CT angiography, or MRI angiography diagnosed within the last five years
- •Known carotid or vertebral dissection as a cause of stroke
- •Stroke after carotid or heart surgery
- •Known hypercoagulable disease
- •Systolic BP < 90 and/or diastolic BP < 50
- •Known severe renal impairment (eGFR < 30ml/min)
- •Known severe hepatic impairment (Child-Pugh > B)
- •History of non-arthritic anterior ischemic optic neuropathy
- •Concomitant use of PDE5 inhibitors e.g. sildenafil, tadalafil, and vardenafil during trial period
- •Patients receiving nicorandil and nitrates e.g. isosorbide mononitrate, isosorbide dinitrate, glyceryl trinitrate
- •History of acute myocardial infarction in the last three months before trial intervention
- •Body weight > 130kg
- •Known cardiac failure (NYHA ≥ II)
- •Known persistent or paroxysmal atrial fibrillation/flutter
- •History of "sick sinus syndrome" or other supraventricular cardiac conduction conditions such as sinoatrial or atrioventricular block (2nd of 3rd degree)
- •Other known cardiogenic cause of stroke
- •Contraindication to CO2 challenge, eg severe respiratory disease
- •MRI not tolerated or contraindicated
- •Known monogenic causes of stroke i.e. CADASIL
- •Unable to provide informed consent
- •The participant does not wish to be informed about results from the MRI
研究组 & 干预措施
Tadalafil
Oral tadalafil (20 mg) capsules once daily for three months.
干预措施: Tadalafil 20 MG (Drug)
Placebo
Oral placebo capsules once daily for three months.
干预措施: Placebo (Drug)
结局指标
主要结局
Feasibility of treatment defined as proportion of participants achieving full target dose of tadalafil/placebo.
时间窗: From baseline to three months.
Number of participants achieving full target dose of tadalafil/placebo by end of three months trial period. Outcome will be assessed by a structured questionnaire with tablet count.
次要结局
- MRI - Neurovascular reactivity and perfusion(From baseline to three months.)
- MRI - Cerebral Blood Flow(From baseline to three months.)
- MRI - Blood Brain Barrier(From baseline to three months.)
- Symbol Digit Modalities Test(From baseline to three months.)
- Dementia Assessment by Rapid Test(From baseline to three months.)
- Trail Making Test A(From baseline to three months.)
- Digit Span Backward(From baseline to three months.)
- Word mobilising test - F, S, A, and animals(From baseline to three months.)
- Cambridge Neuropsychological Test Automated Battery - Paired Associates Learning Task(From baseline to three months.)
- Cambridge Neuropsychological Test Automated Battery - One-Touch Stockings of Cambridge(From baseline to three months.)
- Trail Making Test B(From baseline to three months.)
- Digit Span Forward(From baseline to three months.)
- Vascular- and inflammatory biomarkers: intercellular adhesion molecule-1 (ICAM-1)(From baseline to three months.)
- Vascular- and inflammatory biomarkers: interleukin 1beta (IL-1β)(From baseline to three months.)
- Vascular- and inflammatory biomarkers: specific micro RNA(From baseline to three months.)
- Blood pressure(From baseline to three months.)
- Adverse events(From baseline to three months.)
- MRI - Neurovascular reactivity(From baseline to three months.)
- Montreal Cognitive Assessment(From baseline to three months.)
- WAIS Letter Number Sequence(From baseline to three months.)
- Cambridge Neuropsychological Test Automated Battery - Reaction Time(From baseline to three months.)
- Fatigue Severity Scale - FSS(From baseline to three months.)
- Vascular- and inflammatory biomarkers: vascular cell adhesion molecule (VCAM-1)(From baseline to three months.)
- MRI - STRIVE criteria(From baseline to three months.)
- Cambridge Neuropsychological Test Automated Battery - Spatial Working Memory(From baseline to three months.)
- Cambridge Neuropsychological Test Automated Battery - Rapid Visual Information processing(From baseline to three months.)
- Vascular- and inflammatory biomarkers: tumour necrosis factor alpha (TNF-α)(From baseline to three months.)
- Vascular- and inflammatory biomarkers: E-selectin(From baseline to three months.)
- Digit Span Arrangement(From baseline to three months.)
- Cambridge Neuropsychological Test Automated Battery - Motor Screening(From baseline to three months.)
- Becks Depression Inventory - BDD(From baseline to three months.)
- Death, ischemic and hemorrhagic event, and dementia(From baseline to five years.)
- Heart rate(From baseline to three months.)
- Short Informant Questionnaire on Cognitive Decline in the Elderly - IQCODE(From baseline to three months.)
- WHO-5 Well-Beeing Index(From baseline to three months.)
- Vascular- and inflammatory biomarkers: interleukin-6 (IL-6)(From baseline to three months.)
- Vascular- and inflammatory biomarkers: vascular endothelial growth factor (VEGF)(From baseline to three months.)
研究者
Christina Kruuse
MD, Ph.D., DMSc, Professor in Neurology
Herlev Hospital