- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT05173896
Improving Cerebral Blood Flow and Cognition in Patients With Cerebral Small Vessel Disease. The ETLAS-2 Trial (ETLAS2)
Study Overview
Status
Conditions
Intervention / Treatment
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
Study Type
Enrollment (Estimated)
Phase
- Phase 2
Contacts and Locations
Study Contact
- Name: Christina Kruuse, MD, Prof
- Phone Number: +4538681233
- Email: christina.kruuse@regionh.dk
Study Contact Backup
- Name: Joakim Ölmestig, MD
- Phone Number: +4538686553
- Email: joakim.nils.erik.krogh.oelmestig@regionh.dk
Study Locations
-
-
-
Herlev, Denmark, 2730
- Recruiting
- Department of Neurology, Herlev Gentofte Hospital
-
Contact:
- Christina Kruuse, MD, Prof
- Phone Number: +4538681233
-
Contact:
- Joakim Ölmestig, MD
- Phone Number: +4538686553
-
Principal Investigator:
- Christina Kruuse, MD, Prof.
-
Sub-Investigator:
- Joakim Ölmestig, MD
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Hvidovre, Denmark, 2650
- Not yet recruiting
- Danish Research Centre for Magnetic Resonance
-
Contact:
- Hartwig R Siebner, MD, Prof
- Phone Number: +4538626541
- Email: hartwig.roman.siebner@regionh.dk
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Sub-Investigator:
- Hartwig R Siebner, MD, Prof
-
Contact:
- Esben T Petersen, Ass. Prof
- Phone Number: +4538623326
- Email: esbentp@drcmr.dk
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Sub-Investigator:
- Esben T Petersen, Ass. Prof
-
Sub-Investigator:
- Kristian Mortensen, MSc, PhD
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- 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.
Exclusion Criteria:
- 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
- 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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Prevention
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Tadalafil
Oral tadalafil (20 mg) capsules once daily for three months.
|
Daily dose of oral over-encapsulated tadalafil tablets (20 mg) for three months.
|
Placebo Comparator: Placebo
Oral placebo capsules once daily for three months.
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Daily dose of oral over-encapsulated placebo tablets for three months.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Feasibility of treatment defined as proportion of participants achieving full target dose of tadalafil/placebo.
Time Frame: From baseline to three months.
|
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 Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
MRI - Cerebral Blood Flow
Time Frame: From baseline to three months.
|
Change in cerebral blood flow measured with arterial spin labeling (ASL) during a sensory hand stimulus.
|
From baseline to three months.
|
MRI - Neurovascular reactivity and perfusion
Time Frame: From baseline to three months.
|
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.
|
MRI - Neurovascular reactivity
Time Frame: From baseline to three months.
|
Change in neurovascular reactivity measured with blood-oxygen-level dependent (BOLD) during a sensory hand stimulus.
|
From baseline to three months.
|
MRI - Blood Brain Barrier
Time Frame: From baseline to three months.
|
Change in blood brain barrier measured with diffusion-prepared (DP)-ASL MRI.
|
From baseline to three months.
|
MRI - STRIVE criteria
Time Frame: From baseline to three months.
|
Relative changes (%) in STRIVE assessment, including new strokes, white matter hyperintensity, cerebral microbleeds, enlarged perivascular space, atrophy, and lacunes.
|
From baseline to three months.
|
Montreal Cognitive Assessment
Time Frame: From baseline to three months.
|
Change in Montreal Cognitive Assessment (MoCA) score.
Score range 0-30.
Higher scores mean a better outcome.
|
From baseline to three months.
|
Symbol Digit Modalities Test
Time Frame: From baseline to three months.
|
Change in Symbol Digit Modalities Test (SDMT) score.
Score range 0-110.
Higher scores mean a better outcome.
|
From baseline to three months.
|
Dementia Assessment by Rapid Test
Time Frame: From baseline to three months.
|
Change in Dementia Assessment by Rapid Test - DART score.
Score range 0-50.
Higher scores mean a better outcome.
|
From baseline to three months.
|
Trail Making Test A
Time Frame: From baseline to three months.
|
Change in time to perform Trail Making Test A. Quicker time means a better outcome.
|
From baseline to three months.
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Trail Making Test B
Time Frame: From baseline to three months.
|
Change in time to perform Trail Making Test B. Quicker time means a better outcome.
|
From baseline to three months.
|
Digit Span Forward
Time Frame: From baseline to three months.
|
Change Digit Span Forward test score.
Score range 0-16.
Higher scores mean a better outcome.
|
From baseline to three months.
|
Digit Span Backward
Time Frame: From baseline to three months.
|
Change Digit Span Backward test score.
Score range 0-16.
Higher scores mean a better outcome.
|
From baseline to three months.
|
Digit Span Arrangement
Time Frame: From baseline to three months.
|
Change Digit Span Arrangement test score.
Score range 0-16.
Higher scores mean a better outcome.
|
From baseline to three months.
|
WAIS Letter Number Sequence
Time Frame: From baseline to three months.
|
Change Letter Number sequence test score.
Score range 0-30.
Higher scores mean a better outcome.
|
From baseline to three months.
|
Word mobilising test - F, S, A, and animals
Time Frame: From baseline to three months.
|
Change word mobilising test score.
Higher scores mean a better outcome.
|
From baseline to three months.
|
Cambridge Neuropsychological Test Automated Battery - Spatial Working Memory
Time Frame: From baseline to three months.
|
Change in spatial working memory score.
|
From baseline to three months.
|
Cambridge Neuropsychological Test Automated Battery - Motor Screening
Time Frame: From baseline to three months.
|
Change in motor screening score.
|
From baseline to three months.
|
Cambridge Neuropsychological Test Automated Battery - Rapid Visual Information processing
Time Frame: From baseline to three months.
|
Change in rapid visual information processing score.
|
From baseline to three months.
|
Cambridge Neuropsychological Test Automated Battery - Paired Associates Learning Task
Time Frame: From baseline to three months.
|
Change in paired associates learning task score.
|
From baseline to three months.
|
Cambridge Neuropsychological Test Automated Battery - One-Touch Stockings of Cambridge
Time Frame: From baseline to three months.
|
Change in One-Touch Stockings of Cambridge score.
|
From baseline to three months.
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Cambridge Neuropsychological Test Automated Battery - Reaction Time
Time Frame: From baseline to three months.
|
Change in reaction time score.
|
From baseline to three months.
|
Short Informant Questionnaire on Cognitive Decline in the Elderly - IQCODE
Time Frame: From baseline to three months.
|
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.
|
Becks Depression Inventory - BDD
Time Frame: From baseline to three months.
|
Change in BDD score.
Score range 0-63.
Higher score means increased risk of depression.
|
From baseline to three months.
|
Fatigue Severity Scale - FSS
Time Frame: From baseline to three months.
|
Change in FSS score.
Score range 0-7.
Higher score means increased fatigue severity.
|
From baseline to three months.
|
WHO-5 Well-Beeing Index
Time Frame: From baseline to three months.
|
Change in WHO-5 score.
Score range 0-100.
Higher score means better quality of life.
|
From baseline to three months.
|
Vascular- and inflammatory biomarkers: vascular cell adhesion molecule (VCAM-1)
Time Frame: From baseline to three months.
|
Changes in vascular cell adhesion molecule (VCAM-1) (unit pg/ml).
|
From baseline to three months.
|
Vascular- and inflammatory biomarkers: intercellular adhesion molecule-1 (ICAM-1)
Time Frame: From baseline to three months.
|
Changes in intercellular adhesion molecule-1 (ICAM-1) (unit pg/ml).
|
From baseline to three months.
|
Vascular- and inflammatory biomarkers: interleukin-6 (IL-6)
Time Frame: From baseline to three months.
|
Changes in interleukin-6 (IL-6) (unit pg/ml).
|
From baseline to three months.
|
Vascular- and inflammatory biomarkers: tumour necrosis factor alpha (TNF-α)
Time Frame: From baseline to three months.
|
Changes in tumour necrosis factor alpha (TNF-α) (unit pg/ml).
|
From baseline to three months.
|
Vascular- and inflammatory biomarkers: interleukin 1beta (IL-1β)
Time Frame: From baseline to three months.
|
Changes in interleukin 1beta (IL-1β) (unit pg/ml).
|
From baseline to three months.
|
Vascular- and inflammatory biomarkers: E-selectin
Time Frame: From baseline to three months.
|
Changes in E-selectin (unit pg/ml).
|
From baseline to three months.
|
Vascular- and inflammatory biomarkers: vascular endothelial growth factor (VEGF)
Time Frame: From baseline to three months.
|
Changes in vascular endothelial growth factor (VEGF) (unit pg/ml).
|
From baseline to three months.
|
Vascular- and inflammatory biomarkers: specific micro RNA
Time Frame: From baseline to three months.
|
Changes in specific micro RNA associated to vascular disease.
|
From baseline to three months.
|
Death, ischemic and hemorrhagic event, and dementia
Time Frame: From baseline to five years.
|
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.
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Blood pressure
Time Frame: From baseline to three months.
|
Change in both systolic and diastolic blood pressure (unit mmHg).
|
From baseline to three months.
|
Heart rate
Time Frame: From baseline to three months.
|
Change in heart rate (unit beats per minute).
|
From baseline to three months.
|
Adverse events
Time Frame: From baseline to three months.
|
Difference in adverse events between groups.
|
From baseline to three months.
|
Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Christina Kruuse, MD, Prof, Herlev Gentofte Hospital, Department of Neurology
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Estimated)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Cardiovascular Diseases
- Vascular Diseases
- Cerebrovascular Disorders
- Brain Diseases
- Central Nervous System Diseases
- Nervous System Diseases
- Stroke
- Ischemic Stroke
- Cerebral Small Vessel Diseases
- Molecular Mechanisms of Pharmacological Action
- Vasodilator Agents
- Urological Agents
- Enzyme Inhibitors
- Phosphodiesterase Inhibitors
- Phosphodiesterase 5 Inhibitors
- Tadalafil
Other Study ID Numbers
- H-20031301
- 2020-002329-27 (EudraCT Number)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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