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

Phase 2Active Not RecruitingNCT05173896

Christina Kruuse100 enrolled

Overview

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

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

PREVENTION

Masking

QUADRUPLE

Enrollment

100

Conditions

Cerebral Small Vessel Diseases Stroke, Ischemic

Interventions

Tadalafil 20 MGDRUG

Daily dose of oral over-encapsulated tadalafil tablets (20 mg) for three months.

PlaceboDRUG

Daily dose of oral over-encapsulated placebo tablets for three months.

Eligibility

Sex: ALLMin age: 50 Years

Medical Language ↔ Plain English

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

Locations (2)

Department of Neurology, Herlev Gentofte Hospital

Herlev, Denmark

Danish Research Centre for Magnetic Resonance

Hvidovre, Denmark

Outcomes

Primary Outcomes

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.