Clinical trial NCT05173896: Improving Cerebral Blood Flow and Cognition in Patients with Cerebral Small Vessel Disease. the ETLAS-2 Trial
Official title: Improving Cerebral Blood Flow and Cognition in Patients with Cerebral Small Vessel Disease. the ETLAS-2 Trial
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Cerebral Small Vessel Diseases
Stroke, Ischemic
Lead sponsor: Herlev Hospital
Sponsor class: OTHER
Collaborators: name: Danish Research Centre for Magnetic Resonance
name: Bispebjerg Hospital
name: Rigshospitalet, Denmark
name: University of Copenhagen
name: The Novo Nordic Foundation
name: North Zealand Hospital, Denmark
First posted: 2021-12-30
Enrollment: 100
Sex: ALL
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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: 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

Primary outcomes:
measure: Feasibility of treatment defined as proportion of participants achieving full target dose of tadalafil/placebo.
timeFrame: From baseline to three months.
Secondary outcomes:
measure: MRI - Cerebral Blood Flow
timeFrame: From baseline to three months.
measure: MRI - Neurovascular reactivity and perfusion
timeFrame: From baseline to three months.
measure: MRI - Neurovascular reactivity
timeFrame: From baseline to three months.
measure: MRI - Blood Brain Barrier
timeFrame: From baseline to three months.
measure: MRI - STRIVE criteria
timeFrame: From baseline to three months.
measure: Montreal Cognitive Assessment
timeFrame: From baseline to three months.
measure: Symbol Digit Modalities Test
timeFrame: From baseline to three months.
measure: Dementia Assessment by Rapid Test
timeFrame: From baseline to three months.
measure: Trail Making Test A
timeFrame: From baseline to three months.
measure: Trail Making Test B
timeFrame: From baseline to three months.
measure: Digit Span Forward
timeFrame: From baseline to three months.
measure: Digit Span Backward
timeFrame: From baseline to three months.
measure: Digit Span Arrangement
timeFrame: From baseline to three months.
measure: WAIS Letter Number Sequence
timeFrame: From baseline to three months.
measure: Word mobilising test - F, S, A, and animals
timeFrame: From baseline to three months.
measure: Cambridge Neuropsychological Test Automated Battery - Spatial Working Memory
timeFrame: From baseline to three months.
measure: Cambridge Neuropsychological Test Automated Battery - Motor Screening
timeFrame: From baseline to three months.
measure: Cambridge Neuropsychological Test Automated Battery - Rapid Visual Information processing
timeFrame: From baseline to three months.
measure: Cambridge Neuropsychological Test Automated Battery - Paired Associates Learning Task
timeFrame: From baseline to three months.
measure: Cambridge Neuropsychological Test Automated Battery - One-Touch Stockings of Cambridge
timeFrame: From baseline to three months.
measure: Cambridge Neuropsychological Test Automated Battery - Reaction Time
timeFrame: From baseline to three months.
measure: Short Informant Questionnaire on Cognitive Decline in the Elderly - IQCODE
timeFrame: From baseline to three months.
measure: Becks Depression Inventory - BDD
timeFrame: From baseline to three months.
measure: Fatigue Severity Scale - FSS
timeFrame: From baseline to three months.
measure: WHO-5 Well-Beeing Index
timeFrame: From baseline to three months.
measure: Vascular- and inflammatory biomarkers: vascular cell adhesion molecule (VCAM-1)
timeFrame: From baseline to three months.
measure: Vascular- and inflammatory biomarkers: intercellular adhesion molecule-1 (ICAM-1)
timeFrame: From baseline to three months.
measure: Vascular- and inflammatory biomarkers: interleukin-6 (IL-6)
timeFrame: From baseline to three months.
measure: Vascular- and inflammatory biomarkers: tumour necrosis factor alpha (TNF-α)
timeFrame: From baseline to three months.
measure: Vascular- and inflammatory biomarkers: interleukin 1beta (IL-1β)
timeFrame: From baseline to three months.
measure: Vascular- and inflammatory biomarkers: E-selectin
timeFrame: From baseline to three months.
measure: Vascular- and inflammatory biomarkers: vascular endothelial growth factor (VEGF)
timeFrame: From baseline to three months.
measure: Vascular- and inflammatory biomarkers: specific micro RNA
timeFrame: From baseline to three months.
measure: Death, ischemic and hemorrhagic event, and dementia
timeFrame: From baseline to five years.
measure: Blood pressure
timeFrame: From baseline to three months.
measure: Heart rate
timeFrame: From baseline to three months.
measure: Adverse events
timeFrame: From baseline to three months.
Other outcomes:
Locations:
city: Herlev
country: Denmark
facility: Department of Neurology, Herlev Gentofte Hospital
city: Hvidovre
country: Denmark
facility: Danish Research Centre for Magnetic Resonance
Study officials:
affiliation: Herlev Gentofte Hospital, Department of Neurology
name: Christina Kruuse, MD, Prof
role: PRINCIPAL_INVESTIGATOR
References: