Perfusion by Arterial Spin Labelling Following Single Dose Tadalafil in Small Vessel Disease (PASTIS) Trial
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 55
- 试验地点
- 1
- 主要终点
- change in deep brain blood flow as measured by MRI-Arterial Spin Labelling
研究概览
简要总结
Could Tadalafil improve blood flow in deep brain tissue and potentially improve cognitive function in patients with cerebral small vessel disease
详细描述
Cerebral small vessel disease (SVD) is the primary cause of vascular cognitive impairment (VCI), which in its most severe form manifests as vascular dementia (VaD). SVD is a fibrous thickening of small penetrating arteries in deep brain nuclei (basal ganglia, thalami) and subcortical white matter.Clinical studies suggest that pure VCI/VaD contributes approximately 8-15% of dementia in older people Reduced CBF is well established in VCI. Improved blood flow in the vasculature of the deep white and grey matter is therefore an attractive mechanism for slowing the pathology of VCI and is a valuable biomarker for an initial proof of concept study.
To increase the likelihood of success in a full scale clinical trial of tadalafil in VCI, this study will test the effects of single dose tadalafil on cerebral blood flow in subjects with SVD using ASL-MRI. A strict definition of SVD will be used that combines clinical and MRI criteria.
Phosphodiesterase-5 (PDE5) specifically degrades cGMP within cells; limiting activation of protein kinase G. Guanylyl cyclase enzymes generate cGMP, downstream from NOS-nitric oxide signalling.
PDE5 inhibitors in SVD. PDE5 blockade is a plausible strategy to improve local cerebral blood flow (CBF), in the deep brain areas afflicted by SVD. By augmenting the NO-cGMP-PKG pathway, PDE5i drugs are expected to be vaso-relaxant in small artery myocytes.
In patients with pulmonary hypertension sildenafil improved cerebral vascular reactivity in response to hypercapnic challenge, indicative of an improvement in neurovascular coupling. Similar increased reactivity was recorded 60 min after administration of sildenafil in ED patients. By contrast, healthy volunteers showed no change in MCA blood flow following sildenafil, similar to healthy rodents, where vasodilation occurred only at high concentrations of drug. Overall it appears that PDE5i may have little effect on "healthy" cerebral arteries in rodents and humans.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Prevention
- 盲法
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 55 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Radiological evidence of cerebral small vessel disease defined as: MRI evidence of lacunar infarct(s) (≤ 1.5 cm maximum diameter) and/or confluent deep white matter leukoaraiosis (≥ grade 2 on Fazekas scale)
- •Clinical evidence of cerebral small vessel disease can be:
- •lacunar stroke syndrome with symptoms lasting >24 hours, occurring at least 6 months previously; OR:
- •transient ischaemic attack lasting < 24 hours with limb weakness, hemi-sensory loss or dysarthria at least 6 months previously AND with MRI DWI performed acutely showing lacunar infarction, OR if MRI is not performed within 10 days of TIA, a lacunar infarction in an anatomically appropriate position is demonstrated on a subsequent MRI
- •Age ≥ 55 years.
- •Imaging of the carotid arteries with Doppler ultrasound, CT angiography or MR angiography in the previous 12 months, demonstrating < 70% stenosis in both internal carotid arteries
排除标准
- •Known diagnosis of dementia
- •Cortical infarction (>1.5 cm maximum diameter)
- •Systolic BP <90 and/or diastolic BP < 50
- •Creatinine Clearance<50ml/min
- •Severe hepatic impairment
- •History of Lactose intolerance
- •Concomitant use of PDE5 inhibitors e.g. sildenafil, tadalafil, vardenafil.
- •Concomitant use of alpha-blockers e.g. alfuzosin, doxazosin, indoramin, prazosin, tamsulosin, and terazosin can all increase the risk of postural hypotension.
- •Participants receiving nicorandil and nitrates e.g. isosorbide mononitrate, isosorbide dinitrate, glyceryl trinitrate
- •weight > 130kg
- •11 Uncontrolled cardiac failure
- •Persistent or paroxysmal atrial fibrillation
- •History of gastric ulceration
- •History of 'sick sinus syndrome' or other supraventricular cardiac conduction conditions such as sinoatrial or atrioventricular block
- •Uncontrolled COPD
- •Stroke or TIA within the last 6 months
- •MRI not tolerated or contra-indicated : MRI exclusion criteria -Participant has a cardiac pacemaker; recent surgery; vascular clips; metal implants or joint replacements; have had metal fragments in their eyes; has ever worked on a lathe; has shrapnel from a war injury; possibility of pregnancy
- •Known monogenic causes of stroke e.g.. CADASIL
- •19 Unable to provide informed consent
- •enrolled in another CTIMP study
研究组 & 干预措施
Active Treatment
Tadalafil 20mg Capsule Stat single dose 2 x MRI scans (pre and post dose) Neuropsychological tests pre and post IMP dose Cognitive functioning prior to 1st MRI scan of that visit
干预措施: Tadalafil (Drug)
Active Treatment
Tadalafil 20mg Capsule Stat single dose 2 x MRI scans (pre and post dose) Neuropsychological tests pre and post IMP dose Cognitive functioning prior to 1st MRI scan of that visit
干预措施: Cognitive functioning tests (Behavioral)
Active Treatment
Tadalafil 20mg Capsule Stat single dose 2 x MRI scans (pre and post dose) Neuropsychological tests pre and post IMP dose Cognitive functioning prior to 1st MRI scan of that visit
干预措施: Neuropsychological tests (Behavioral)
Active Treatment
Tadalafil 20mg Capsule Stat single dose 2 x MRI scans (pre and post dose) Neuropsychological tests pre and post IMP dose Cognitive functioning prior to 1st MRI scan of that visit
干预措施: MRI Scan - Arterial Spin Labelling (Other)
Control
Matched placebo Capsule Stat single dose 2 x MRI scans (pre and post dose) Neuropsychological tests pre and post IMP dose Cognitive functioning prior to 1st MRI scan of that visit
干预措施: Placebo (Drug)
Control
Matched placebo Capsule Stat single dose 2 x MRI scans (pre and post dose) Neuropsychological tests pre and post IMP dose Cognitive functioning prior to 1st MRI scan of that visit
干预措施: Cognitive functioning tests (Behavioral)
Control
Matched placebo Capsule Stat single dose 2 x MRI scans (pre and post dose) Neuropsychological tests pre and post IMP dose Cognitive functioning prior to 1st MRI scan of that visit
干预措施: Neuropsychological tests (Behavioral)
Control
Matched placebo Capsule Stat single dose 2 x MRI scans (pre and post dose) Neuropsychological tests pre and post IMP dose Cognitive functioning prior to 1st MRI scan of that visit
干预措施: MRI Scan - Arterial Spin Labelling (Other)
结局指标
主要结局
change in deep brain blood flow as measured by MRI-Arterial Spin Labelling
时间窗: 3-5 hours following IMP dosing
次要结局
- Change in regional CBF in cortical grey matter areas Plasma [drug concentration] dependence of deep CBF as measured by MRI ASL Changes in neuropsychological parameters including attention in Neuro attention and cognitive speed(3-5 hours following IMP dosing)