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

NCT ID: NCT05173896

Last Updated: 2024-12-09

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 100 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-05-31
• Study Completion Date: 2029-12-31

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

Conditions

Cerebral Small Vessel Diseases; Stroke, Ischemic

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: QUADRUPLE

Study Groups

Tadalafil

Oral tadalafil (20 mg) capsules once daily for three months.

Group Type: EXPERIMENTAL

Tadalafil 20 MG

Intervention Type: DRUG

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

Placebo

Oral placebo capsules once daily for three months.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

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

Interventions

Tadalafil 20 MG

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

Intervention Type: DRUG

Placebo

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

Intervention Type: DRUG

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

• Minimum Eligible Age: 50 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Danish Research Centre for Magnetic Resonance

OTHER

Sponsor Role: collaborator

Bispebjerg Hospital

OTHER

Sponsor Role: collaborator

Rigshospitalet, Denmark

OTHER

Sponsor Role: collaborator

University of Copenhagen

OTHER

Sponsor Role: collaborator

The Novo Nordic Foundation

OTHER

Sponsor Role: collaborator

Nordsjaellands Hospital

OTHER

Sponsor Role: collaborator

Christina Kruuse

OTHER

Sponsor Role: lead

Responsible Party

Christina Kruuse

MD, Ph.D., DMSc, Professor in Neurology

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Christina Kruuse, MD, Prof

Role: PRINCIPAL_INVESTIGATOR

Herlev Gentofte Hospital, Department of Neurology

Locations

Department of Neurology, Herlev Gentofte Hospital

Herlev, , Denmark

Danish Research Centre for Magnetic Resonance

Hvidovre, , Denmark

Countries

Denmark

References

Olmestig J, Mortensen KN, Thomas MB, Fagerlund B, Naveed N, Nordling MM, Nielsen MKK, Rasmussen BS, Christensen H, Iversen HK, Poulsen MB, Siebner HR, Kruuse C. Tadalafil Treatment in Patients With Cerebral Small Vessel Disease: The ETLAS-2 Randomized Clinical Trial. Stroke. 2025 Oct;56(10):2846-2857. doi: 10.1161/STROKEAHA.125.051602. Epub 2025 Jul 28.

Reference Type: DERIVED

PMID: 40718899 (View on PubMed)

Olmestig J, Mortensen KN, Fagerlund B, Naveed N, Nordling MM, Christensen H, Iversen HK, Poulsen MB, Siebner HR, Kruuse C. Cerebral blood flow and cognition after 3 months tadalafil treatment in small vessel disease (ETLAS-2): study protocol for a randomized controlled trial. Trials. 2024 Aug 29;25(1):570. doi: 10.1186/s13063-024-08402-4.

Reference Type: DERIVED

PMID: 39210472 (View on PubMed)

Other Identifiers

2020-002329-27

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

H-20031301

Identifier Type: -

Identifier Source: org_study_id