Improving Cerebral Blood Flow and Cognition in Patients With Cerebral Small Vessel Disease. The ETLAS-2 Trial

Study Overview
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Brief Summary
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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.

Detailed Description
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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

Official Title
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Improving Cerebral Blood Flow and Cognition in Patients With Cerebral Small Vessel Disease. The ETLAS-2 Trial

Conditions
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Cerebral Small Vessel Diseases, Stroke, Ischemic

Intervention / Treatment
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* Drug: Tadalafil 20 MG
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Exclusion Criteria: 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

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tadalafil<br>Oral tadalafil (20 mg) capsules once daily for three months. | Drug: Tadalafil 20 MG<br>* Daily dose of oral over-encapsulated tadalafil tablets (20 mg) for three months.<br>|
| Placebo Comparator: Placebo<br>Oral placebo capsules once daily for three months. | Drug: Placebo<br>* Daily dose of oral over-encapsulated placebo tablets for three months.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility of treatment defined as proportion of participants achieving full target dose of tadalafil/placebo. | 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. | From baseline to three months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MRI - Cerebral Blood Flow | Change in cerebral blood flow measured with arterial spin labeling (ASL) during a sensory hand stimulus. | From baseline to three months. | 
| MRI - Neurovascular reactivity and perfusion | Change in neurovascular reactivity, coupling, and cerebral blood flow/perfusion measured with BOLD/ASL during a visual stimulation with and without a carbon dioxide vascular challenge. | From baseline to three months. | 
| MRI - Neurovascular reactivity | Change in neurovascular reactivity measured with blood-oxygen-level dependent (BOLD) during a sensory hand stimulus. | From baseline to three months. | 
| MRI - Blood Brain Barrier | Change in blood brain barrier measured with diffusion-prepared (DP)-ASL MRI. | From baseline to three months. | 
| MRI - STRIVE criteria | Relative changes (%) in STRIVE assessment, including new strokes, white matter hyperintensity, cerebral microbleeds, enlarged perivascular space, atrophy, and lacunes. | From baseline to three months. | 
| Montreal Cognitive Assessment | Change in Montreal Cognitive Assessment (MoCA) score. Score range 0-30. Higher scores mean a better outcome. | From baseline to three months. | 
| Symbol Digit Modalities Test | Change in Symbol Digit Modalities Test (SDMT) score. Score range 0-110. Higher scores mean a better outcome. | From baseline to three months. | 
| Dementia Assessment by Rapid Test | Change in Dementia Assessment by Rapid Test - DART score. Score range 0-50. Higher scores mean a better outcome. | From baseline to three months. | 
| Trail Making Test A | Change in time to perform Trail Making Test A. Quicker time means a better outcome. | From baseline to three months. | 
| Trail Making Test B | Change in time to perform Trail Making Test B. Quicker time means a better outcome. | From baseline to three months. | 
| Digit Span Forward | Change Digit Span Forward test score. Score range 0-16. Higher scores mean a better outcome. | From baseline to three months. | 
| Digit Span Backward | Change Digit Span Backward test score. Score range 0-16. Higher scores mean a better outcome. | From baseline to three months. | 
| Digit Span Arrangement | Change Digit Span Arrangement test score. Score range 0-16. Higher scores mean a better outcome. | From baseline to three months. | 
| WAIS Letter Number Sequence | Change Letter Number sequence test score. Score range 0-30. Higher scores mean a better outcome. | From baseline to three months. | 
| Word mobilising test - F, S, A, and animals | Change word mobilising test score. Higher scores mean a better outcome. | From baseline to three months. | 
| Cambridge Neuropsychological Test Automated Battery - Spatial Working Memory | Change in spatial working memory score. | From baseline to three months. | 
| Cambridge Neuropsychological Test Automated Battery - Motor Screening | Change in motor screening score. | From baseline to three months. | 
| Cambridge Neuropsychological Test Automated Battery - Rapid Visual Information processing | Change in rapid visual information processing score. | From baseline to three months. | 
| Cambridge Neuropsychological Test Automated Battery - Paired Associates Learning Task | Change in paired associates learning task score. | From baseline to three months. | 
| Cambridge Neuropsychological Test Automated Battery - One-Touch Stockings of Cambridge | Change in One-Touch Stockings of Cambridge score. | From baseline to three months. | 
| Cambridge Neuropsychological Test Automated Battery - Reaction Time | Change in reaction time score. | From baseline to three months. | 
| Short Informant Questionnaire on Cognitive Decline in the Elderly - IQCODE | Change in short IQCODE score. Score range 1-5. A score of 3 means that the subject is rated on average as 'no change'. | From baseline to three months. | 
| Becks Depression Inventory - BDD | Change in BDD score. Score range 0-63. Higher score means increased risk of depression. | From baseline to three months. | 
| Fatigue Severity Scale - FSS | Change in FSS score. Score range 0-7. Higher score means increased fatigue severity. | From baseline to three months. | 
| WHO-5 Well-Beeing Index | Change in WHO-5 score. Score range 0-100. Higher score means better quality of life. | From baseline to three months. | 
| Vascular- and inflammatory biomarkers: vascular cell adhesion molecule (VCAM-1) | Changes in vascular cell adhesion molecule (VCAM-1) (unit pg/ml). | From baseline to three months. | 
| Vascular- and inflammatory biomarkers: intercellular adhesion molecule-1 (ICAM-1) | Changes in intercellular adhesion molecule-1 (ICAM-1) (unit pg/ml). | From baseline to three months. | 
| Vascular- and inflammatory biomarkers: interleukin-6 (IL-6) | Changes in interleukin-6 (IL-6) (unit pg/ml). | From baseline to three months. | 
| Vascular- and inflammatory biomarkers: tumour necrosis factor alpha (TNF-α) | Changes in tumour necrosis factor alpha (TNF-α) (unit pg/ml). | From baseline to three months. | 
| Vascular- and inflammatory biomarkers: interleukin 1beta (IL-1β) | Changes in interleukin 1beta (IL-1β) (unit pg/ml). | From baseline to three months. | 
| Vascular- and inflammatory biomarkers: E-selectin | Changes in E-selectin (unit pg/ml). | From baseline to three months. | 
| Vascular- and inflammatory biomarkers: vascular endothelial growth factor (VEGF) | Changes in vascular endothelial growth factor (VEGF) (unit pg/ml). | From baseline to three months. | 
| Vascular- and inflammatory biomarkers: specific micro RNA | Changes in specific micro RNA associated to vascular disease. | From baseline to three months. | 
| Death, ischemic and hemorrhagic event, and dementia | Difference in composite measure of death, any ischemic event, hemorrhagic event or dementia per patient registry after three and five years respectively from end of trial. | From baseline to five years. | 
| Blood pressure | Change in both systolic and diastolic blood pressure (unit mmHg). | From baseline to three months. | 
| Heart rate | Change in heart rate (unit beats per minute). | From baseline to three months. | 
| Adverse events | Difference in adverse events between groups. | From baseline to three months. |