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

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.

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

Eligibility Criteria:
Inclusion Criteria:

1. 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).
2. 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).
3. Age ≥ 50 years.

Exclusion Criteria:

1. Known diagnosis of dementia, medically treated dementia, or under investigation for dementia
2. Pregnancy or nursing
3. Women of childbearing age not taking contraception
4. Known cortical infarction (\> 1.5 cm maximum diameter)
5. Known carotid artery stenosis ≥ 50 % with Doppler ultrasound, CT angiography, or MRI angiography diagnosed within the last five years
6. Known carotid or vertebral dissection as a cause of stroke
7. Stroke after carotid or heart surgery
8. Known hypercoagulable disease
9. Systolic BP \< 90 and/or diastolic BP \< 50
10. Known severe renal impairment (eGFR \< 30ml/min)
11. Known severe hepatic impairment (Child-Pugh \> B)
12. History of non-arthritic anterior ischemic optic neuropathy
13. Concomitant use of PDE5 inhibitors e.g. sildenafil, tadalafil, and vardenafil during trial period
14. Patients receiving nicorandil and nitrates e.g. isosorbide mononitrate, isosorbide dinitrate, glyceryl trinitrate
15. History of acute myocardial infarction in the last three months before trial intervention
16. Body weight \> 130kg
17. Known cardiac failure (NYHA ≥ II)
18. Known persistent or paroxysmal atrial fibrillation/flutter
19. History of "sick sinus syndrome" or other supraventricular cardiac conduction conditions such as sinoatrial or atrioventricular block (2nd of 3rd degree)
20. Other known cardiogenic cause of stroke
21. Contraindication to CO2 challenge, eg severe respiratory disease
22. MRI not tolerated or contraindicated
23. Known monogenic causes of stroke i.e. CADASIL
24. Unable to provide informed consent
25. The participant does not wish to be informed about results from the MRI