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

Stroke, Ischemic Clinical Trial

— ETLAS2  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05173896
• Other study ID #: H-20031301
• Secondary ID: 2020-002329-27
• Status: Recruiting
• Phase: Phase 2
• Start date: May 31, 2022
• Est. completion date: December 2029

Study information

• Verified date: February 2024
• Source: Herlev Hospital
• Contact: Christina Kruuse, MD, Prof
• Phone: +4538681233
• Email: christina.kruuse[@]regionh.dk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 100
• Est. completion date: December 2029
• Est. primary completion date: December 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 50 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Cerebral Small Vessel Diseases
• Ischemic Stroke
• Stroke, Ischemic

Intervention

Drug:
• Tadalafil 20 MG
Daily dose of oral over-encapsulated tadalafil tablets (20 mg) for three months.
• Placebo
Daily dose of oral over-encapsulated placebo tablets for three months.

Locations

Country	Name	City	State
Denmark	Department of Neurology, Herlev Gentofte Hospital	Herlev
Denmark	Danish Research Centre for Magnetic Resonance	Hvidovre

Sponsors (7)

Lead Sponsor	Collaborator
Christina Kruuse	Bispebjerg Hospital, Danish Research Centre for Magnetic Resonance, Hillerod Hospital, Denmark, Rigshospitalet, Denmark, The Novo Nordic Foundation, University of Copenhagen

Country where clinical trial is conducted

Denmark, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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.
Secondary	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.
Secondary	MRI - Neurovascular reactivity	Change in neurovascular reactivity measured with blood-oxygen-level dependent (BOLD) during a sensory hand stimulus.	From baseline to three months.
Secondary	MRI - Blood Brain Barrier	Change in blood brain barrier measured with diffusion-prepared (DP)-ASL MRI.	From baseline to three months.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	Trail Making Test A	Change in time to perform Trail Making Test A. Quicker time means a better outcome.	From baseline to three months.
Secondary	Trail Making Test B	Change in time to perform Trail Making Test B. Quicker time means a better outcome.	From baseline to three months.
Secondary	Digit Span Forward	Change Digit Span Forward test score. Score range 0-16. Higher scores mean a better outcome.	From baseline to three months.
Secondary	Digit Span Backward	Change Digit Span Backward test score. Score range 0-16. Higher scores mean a better outcome.	From baseline to three months.
Secondary	Digit Span Arrangement	Change Digit Span Arrangement test score. Score range 0-16. Higher scores mean a better outcome.	From baseline to three months.
Secondary	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.
Secondary	Word mobilising test - F, S, A, and animals	Change word mobilising test score. Higher scores mean a better outcome.	From baseline to three months.
Secondary	Cambridge Neuropsychological Test Automated Battery - Spatial Working Memory	Change in spatial working memory score.	From baseline to three months.
Secondary	Cambridge Neuropsychological Test Automated Battery - Motor Screening	Change in motor screening score.	From baseline to three months.
Secondary	Cambridge Neuropsychological Test Automated Battery - Rapid Visual Information processing	Change in rapid visual information processing score.	From baseline to three months.
Secondary	Cambridge Neuropsychological Test Automated Battery - Paired Associates Learning Task	Change in paired associates learning task score.	From baseline to three months.
Secondary	Cambridge Neuropsychological Test Automated Battery - One-Touch Stockings of Cambridge	Change in One-Touch Stockings of Cambridge score.	From baseline to three months.
Secondary	Cambridge Neuropsychological Test Automated Battery - Reaction Time	Change in reaction time score.	From baseline to three months.
Secondary	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.
Secondary	Becks Depression Inventory - BDD	Change in BDD score. Score range 0-63. Higher score means increased risk of depression.	From baseline to three months.
Secondary	Fatigue Severity Scale - FSS	Change in FSS score. Score range 0-7. Higher score means increased fatigue severity.	From baseline to three months.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	Vascular- and inflammatory biomarkers: interleukin-6 (IL-6)	Changes in interleukin-6 (IL-6) (unit pg/ml).	From baseline to three months.
Secondary	Vascular- and inflammatory biomarkers: tumour necrosis factor alpha (TNF-a)	Changes in tumour necrosis factor alpha (TNF-a) (unit pg/ml).	From baseline to three months.
Secondary	Vascular- and inflammatory biomarkers: interleukin 1beta (IL-1ß)	Changes in interleukin 1beta (IL-1ß) (unit pg/ml).	From baseline to three months.
Secondary	Vascular- and inflammatory biomarkers: E-selectin	Changes in E-selectin (unit pg/ml).	From baseline to three months.
Secondary	Vascular- and inflammatory biomarkers: vascular endothelial growth factor (VEGF)	Changes in vascular endothelial growth factor (VEGF) (unit pg/ml).	From baseline to three months.
Secondary	Vascular- and inflammatory biomarkers: specific micro RNA	Changes in specific micro RNA associated to vascular disease.	From baseline to three months.
Secondary	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.
Secondary	Blood pressure	Change in both systolic and diastolic blood pressure (unit mmHg).	From baseline to three months.
Secondary	Heart rate	Change in heart rate (unit beats per minute).	From baseline to three months.
Secondary	Adverse events	Difference in adverse events between groups.	From baseline to three months.