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Cerebral Small Vessel DiseasesPhase 2ETLAS2NCT05173896

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

A Phase 2 study testing Tadalafil 20 MG in people with Cerebral Small Vessel Diseases and Stroke, Ischemic, run by Christina Kruuse at 2 sites in Denmark.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record
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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. Read more about this study

Who is it for?
Ages 50 years and older
What is being tested?
Tadalafil 20 MG
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
100 participants
Where
2 sitesDenmark
Study dates
31 May 2022to Dec 2029
Phase
Phase 2
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 50 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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).
  • 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).
  • Age ≥ 50 years.

Who cannot join

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

Trial locations and contacts

2 sites in 1 country.

Denmark2 sites
  • Department of Neurology, Herlev Gentofte Hospital

    Herlev, 2730

  • Danish Research Centre for Magnetic Resonance

    Hvidovre, 2650

Other trials in Denmark

About this study

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.

Read the 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
Being tested
Tadalafil 20 MG, Placebo
Medical subject headings
Cerebral Small Vessel Diseases, Ischemic Stroke

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • 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.

Study groups in NCT05173896
Study groupRoleWhat they receive
TadalafilExperimentalOral tadalafil (20 mg) capsules once daily for three months.
Receives: Drug: Tadalafil 20 MG
PlaceboPlacebo comparatorOral placebo capsules once daily for three months.
Receives: Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: From baseline to three months.

Secondary outcomes (37)
  1. MRI - Cerebral Blood Flow

    Change in cerebral blood flow measured with arterial spin labeling (ASL) during a sensory hand stimulus.

    Measured: From baseline to three months.

  2. 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.

    Measured: From baseline to three months.

  3. MRI - Neurovascular reactivity

    Change in neurovascular reactivity measured with blood-oxygen-level dependent (BOLD) during a sensory hand stimulus.

    Measured: From baseline to three months.

  4. MRI - Blood Brain Barrier

    Change in blood brain barrier measured with diffusion-prepared (DP)-ASL MRI.

    Measured: From baseline to three months.

  5. MRI - STRIVE criteria

    Relative changes (%) in STRIVE assessment, including new strokes, white matter hyperintensity, cerebral microbleeds, enlarged perivascular space, atrophy, and lacunes.

    Measured: From baseline to three months.

  6. Montreal Cognitive Assessment

    Change in Montreal Cognitive Assessment (MoCA) score. Score range 0-30. Higher scores mean a better outcome.

    Measured: From baseline to three months.

  7. Symbol Digit Modalities Test

    Change in Symbol Digit Modalities Test (SDMT) score. Score range 0-110. Higher scores mean a better outcome.

    Measured: From baseline to three months.

  8. Dementia Assessment by Rapid Test

    Change in Dementia Assessment by Rapid Test - DART score. Score range 0-50. Higher scores mean a better outcome.

    Measured: From baseline to three months.

  9. Trail Making Test A

    Change in time to perform Trail Making Test A. Quicker time means a better outcome.

    Measured: From baseline to three months.

  10. Trail Making Test B

    Change in time to perform Trail Making Test B. Quicker time means a better outcome.

    Measured: From baseline to three months.

  11. Digit Span Forward

    Change Digit Span Forward test score. Score range 0-16. Higher scores mean a better outcome.

    Measured: From baseline to three months.

  12. Digit Span Backward

    Change Digit Span Backward test score. Score range 0-16. Higher scores mean a better outcome.

    Measured: From baseline to three months.

  13. Digit Span Arrangement

    Change Digit Span Arrangement test score. Score range 0-16. Higher scores mean a better outcome.

    Measured: From baseline to three months.

  14. WAIS Letter Number Sequence

    Change Letter Number sequence test score. Score range 0-30. Higher scores mean a better outcome.

    Measured: From baseline to three months.

  15. Word mobilising test - F, S, A, and animals

    Change word mobilising test score. Higher scores mean a better outcome.

    Measured: From baseline to three months.

  16. Cambridge Neuropsychological Test Automated Battery - Spatial Working Memory

    Change in spatial working memory score.

    Measured: From baseline to three months.

  17. Cambridge Neuropsychological Test Automated Battery - Motor Screening

    Change in motor screening score.

    Measured: From baseline to three months.

  18. Cambridge Neuropsychological Test Automated Battery - Rapid Visual Information processing

    Change in rapid visual information processing score.

    Measured: From baseline to three months.

  19. Cambridge Neuropsychological Test Automated Battery - Paired Associates Learning Task

    Change in paired associates learning task score.

    Measured: From baseline to three months.

  20. Cambridge Neuropsychological Test Automated Battery - One-Touch Stockings of Cambridge

    Change in One-Touch Stockings of Cambridge score.

    Measured: From baseline to three months.

  21. Cambridge Neuropsychological Test Automated Battery - Reaction Time

    Change in reaction time score.

    Measured: From baseline to three months.

  22. 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'.

    Measured: From baseline to three months.

  23. Becks Depression Inventory - BDD

    Change in BDD score. Score range 0-63. Higher score means increased risk of depression.

    Measured: From baseline to three months.

  24. Fatigue Severity Scale - FSS

    Change in FSS score. Score range 0-7. Higher score means increased fatigue severity.

    Measured: From baseline to three months.

  25. WHO-5 Well-Beeing Index

    Change in WHO-5 score. Score range 0-100. Higher score means better quality of life.

    Measured: From baseline to three months.

  26. Vascular- and inflammatory biomarkers: vascular cell adhesion molecule (VCAM-1)

    Changes in vascular cell adhesion molecule (VCAM-1) (unit pg/ml).

    Measured: From baseline to three months.

  27. Vascular- and inflammatory biomarkers: intercellular adhesion molecule-1 (ICAM-1)

    Changes in intercellular adhesion molecule-1 (ICAM-1) (unit pg/ml).

    Measured: From baseline to three months.

  28. Vascular- and inflammatory biomarkers: interleukin-6 (IL-6)

    Changes in interleukin-6 (IL-6) (unit pg/ml).

    Measured: From baseline to three months.

  29. Vascular- and inflammatory biomarkers: tumour necrosis factor alpha (TNF-α)

    Changes in tumour necrosis factor alpha (TNF-α) (unit pg/ml).

    Measured: From baseline to three months.

  30. Vascular- and inflammatory biomarkers: interleukin 1beta (IL-1β)

    Changes in interleukin 1beta (IL-1β) (unit pg/ml).

    Measured: From baseline to three months.

  31. Vascular- and inflammatory biomarkers: E-selectin

    Changes in E-selectin (unit pg/ml).

    Measured: From baseline to three months.

  32. Vascular- and inflammatory biomarkers: vascular endothelial growth factor (VEGF)

    Changes in vascular endothelial growth factor (VEGF) (unit pg/ml).

    Measured: From baseline to three months.

  33. Vascular- and inflammatory biomarkers: specific micro RNA

    Changes in specific micro RNA associated to vascular disease.

    Measured: From baseline to three months.

  34. 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.

    Measured: From baseline to five years.

  35. Blood pressure

    Change in both systolic and diastolic blood pressure (unit mmHg).

    Measured: From baseline to three months.

  36. Heart rate

    Change in heart rate (unit beats per minute).

    Measured: From baseline to three months.

  37. Adverse events

    Difference in adverse events between groups.

    Measured: From baseline to three months.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted30 Dec 2021
  2. Study start31 May 2022
  3. Primary completion23 Sep 2024
  4. Study completionDec 2029 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Prevention
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
100 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05173896
Sponsor's protocol ID
H-20031301
Other IDs
2020-002329-27
Acronym
ETLAS2
Status last verified
Feb 2024
First submitted
16 Nov 2021
Last updated
9 Dec 2024
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Yes: IPD can be accessed upon reasonable request and after evaluation from the investigator.

Publications

  • Olmestig J, Mortensen KN, Thomas MB, Fagerlund B, Robbins TW, Naveed N, Nordling MM, Christensen H, Iversen HK, Poulsen MB, Siebner HR, Kruuse C. Cognitive outcomes after tadalafil treatment in patients with cerebral small vessel disease: ETLAS-2 sub-study. Cereb Circ Cogn Behav. 2025 Nov 11;9:100520. doi: 10.1016/j.cccb.2025.100520. eCollection 2025.

    PubMed 41332889
  • 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.

    PubMed 40718899
  • 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.

    PubMed 39210472

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Tadalafil 20 MG in people with Cerebral Small Vessel Diseases and Stroke, Ischemic, run by Christina Kruuse at 2 sites in Denmark.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 3 inclusion and 25 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: under way, not looking for participants, as of the sponsor's last update on 9 Dec 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in Denmark. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Feasibility of treatment defined as proportion of participants achieving full target dose of tadalafil/placebo. (time frame: From baseline to three months.). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05173896, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Dec 2024.

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