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Improving Cerebral Blood Flow and Cognition in Patients With Cerebral Small Vessel Disease. The ETLAS-2 Trial (ETLAS2)

Primary Purpose

Cerebral Small Vessel Diseases, Stroke, Ischemic

Status
Recruiting
Phase
Phase 2
Locations
Denmark
Study Type
Interventional
Intervention
Tadalafil 20 MG
Placebo
Sponsored by
Christina Kruuse
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Cerebral Small Vessel Diseases

Eligibility Criteria

50 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Department of Neurology, Herlev Gentofte HospitalRecruiting
  • Danish Research Centre for Magnetic Resonance

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Tadalafil

Placebo

Arm Description

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

Oral placebo capsules once daily for three months.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

MRI - Cerebral Blood Flow
Change in cerebral blood flow measured with arterial spin labeling (ASL) during a sensory hand stimulus.
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.
MRI - Neurovascular reactivity
Change in neurovascular reactivity measured with blood-oxygen-level dependent (BOLD) during a sensory hand stimulus.
MRI - Blood Brain Barrier
Change in blood brain barrier measured with diffusion-prepared (DP)-ASL MRI.
MRI - STRIVE criteria
Relative changes (%) in STRIVE assessment, including new strokes, white matter hyperintensity, cerebral microbleeds, enlarged perivascular space, atrophy, and lacunes.
Montreal Cognitive Assessment
Change in Montreal Cognitive Assessment (MoCA) score. Score range 0-30. Higher scores mean a better outcome.
Symbol Digit Modalities Test
Change in Symbol Digit Modalities Test (SDMT) score. Score range 0-110. Higher scores mean a better outcome.
Dementia Assessment by Rapid Test
Change in Dementia Assessment by Rapid Test - DART score. Score range 0-50. Higher scores mean a better outcome.
Trail Making Test A
Change in time to perform Trail Making Test A. Quicker time means a better outcome.
Trail Making Test B
Change in time to perform Trail Making Test B. Quicker time means a better outcome.
Digit Span Forward
Change Digit Span Forward test score. Score range 0-16. Higher scores mean a better outcome.
Digit Span Backward
Change Digit Span Backward test score. Score range 0-16. Higher scores mean a better outcome.
Digit Span Arrangement
Change Digit Span Arrangement test score. Score range 0-16. Higher scores mean a better outcome.
WAIS Letter Number Sequence
Change Letter Number sequence test score. Score range 0-30. Higher scores mean a better outcome.
Word mobilising test - F, S, A, and animals
Change word mobilising test score. Higher scores mean a better outcome.
Cambridge Neuropsychological Test Automated Battery - Spatial Working Memory
Change in spatial working memory score.
Cambridge Neuropsychological Test Automated Battery - Motor Screening
Change in motor screening score.
Cambridge Neuropsychological Test Automated Battery - Rapid Visual Information processing
Change in rapid visual information processing score.
Cambridge Neuropsychological Test Automated Battery - Paired Associates Learning Task
Change in paired associates learning task score.
Cambridge Neuropsychological Test Automated Battery - One-Touch Stockings of Cambridge
Change in One-Touch Stockings of Cambridge score.
Cambridge Neuropsychological Test Automated Battery - Reaction Time
Change in reaction time score.
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'.
Becks Depression Inventory - BDD
Change in BDD score. Score range 0-63. Higher score means increased risk of depression.
Fatigue Severity Scale - FSS
Change in FSS score. Score range 0-7. Higher score means increased fatigue severity.
WHO-5 Well-Beeing Index
Change in WHO-5 score. Score range 0-100. Higher score means better quality of life.
Vascular- and inflammatory biomarkers: vascular cell adhesion molecule (VCAM-1)
Changes in vascular cell adhesion molecule (VCAM-1) (unit pg/ml).
Vascular- and inflammatory biomarkers: intercellular adhesion molecule-1 (ICAM-1)
Changes in intercellular adhesion molecule-1 (ICAM-1) (unit pg/ml).
Vascular- and inflammatory biomarkers: interleukin-6 (IL-6)
Changes in interleukin-6 (IL-6) (unit pg/ml).
Vascular- and inflammatory biomarkers: tumour necrosis factor alpha (TNF-α)
Changes in tumour necrosis factor alpha (TNF-α) (unit pg/ml).
Vascular- and inflammatory biomarkers: interleukin 1beta (IL-1β)
Changes in interleukin 1beta (IL-1β) (unit pg/ml).
Vascular- and inflammatory biomarkers: E-selectin
Changes in E-selectin (unit pg/ml).
Vascular- and inflammatory biomarkers: vascular endothelial growth factor (VEGF)
Changes in vascular endothelial growth factor (VEGF) (unit pg/ml).
Vascular- and inflammatory biomarkers: specific micro RNA
Changes in specific micro RNA associated to vascular disease.
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.
Blood pressure
Change in both systolic and diastolic blood pressure (unit mmHg).
Heart rate
Change in heart rate (unit beats per minute).
Adverse events
Difference in adverse events between groups.

Full Information

First Posted
November 16, 2021
Last Updated
June 8, 2022
Sponsor
Christina Kruuse
Collaborators
Danish Research Centre for Magnetic Resonance, Bispebjerg Hospital, Rigshospitalet, Denmark, Hillerod Hospital, Denmark, University of Copenhagen, The Novo Nordic Foundation
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1. Study Identification

Unique Protocol Identification Number
NCT05173896
Brief Title
Improving Cerebral Blood Flow and Cognition in Patients With Cerebral Small Vessel Disease. The ETLAS-2 Trial
Acronym
ETLAS2
Official Title
Improving Cerebral Blood Flow and Cognition in Patients With Cerebral Small Vessel Disease. The ETLAS-2 Trial
Study Type
Interventional

2. Study Status

Record Verification Date
June 2022
Overall Recruitment Status
Recruiting
Study Start Date
May 31, 2022 (Actual)
Primary Completion Date
December 2024 (Anticipated)
Study Completion Date
December 2029 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Christina Kruuse
Collaborators
Danish Research Centre for Magnetic Resonance, Bispebjerg Hospital, Rigshospitalet, Denmark, Hillerod Hospital, Denmark, University of Copenhagen, The Novo Nordic Foundation

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cerebral Small Vessel Diseases, Stroke, Ischemic

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
100 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Tadalafil
Arm Type
Experimental
Arm Description
Oral tadalafil (20 mg) capsules once daily for three months.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Oral placebo capsules once daily for three months.
Intervention Type
Drug
Intervention Name(s)
Tadalafil 20 MG
Intervention Description
Daily dose of oral over-encapsulated tadalafil tablets (20 mg) for three months.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Daily dose of oral over-encapsulated placebo tablets for three months.
Primary Outcome Measure Information:
Title
Feasibility of treatment defined as proportion of participants achieving full target dose of tadalafil/placebo.
Description
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.
Time Frame
From baseline to three months.
Secondary Outcome Measure Information:
Title
MRI - Cerebral Blood Flow
Description
Change in cerebral blood flow measured with arterial spin labeling (ASL) during a sensory hand stimulus.
Time Frame
From baseline to three months.
Title
MRI - Neurovascular reactivity and perfusion
Description
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.
Time Frame
From baseline to three months.
Title
MRI - Neurovascular reactivity
Description
Change in neurovascular reactivity measured with blood-oxygen-level dependent (BOLD) during a sensory hand stimulus.
Time Frame
From baseline to three months.
Title
MRI - Blood Brain Barrier
Description
Change in blood brain barrier measured with diffusion-prepared (DP)-ASL MRI.
Time Frame
From baseline to three months.
Title
MRI - STRIVE criteria
Description
Relative changes (%) in STRIVE assessment, including new strokes, white matter hyperintensity, cerebral microbleeds, enlarged perivascular space, atrophy, and lacunes.
Time Frame
From baseline to three months.
Title
Montreal Cognitive Assessment
Description
Change in Montreal Cognitive Assessment (MoCA) score. Score range 0-30. Higher scores mean a better outcome.
Time Frame
From baseline to three months.
Title
Symbol Digit Modalities Test
Description
Change in Symbol Digit Modalities Test (SDMT) score. Score range 0-110. Higher scores mean a better outcome.
Time Frame
From baseline to three months.
Title
Dementia Assessment by Rapid Test
Description
Change in Dementia Assessment by Rapid Test - DART score. Score range 0-50. Higher scores mean a better outcome.
Time Frame
From baseline to three months.
Title
Trail Making Test A
Description
Change in time to perform Trail Making Test A. Quicker time means a better outcome.
Time Frame
From baseline to three months.
Title
Trail Making Test B
Description
Change in time to perform Trail Making Test B. Quicker time means a better outcome.
Time Frame
From baseline to three months.
Title
Digit Span Forward
Description
Change Digit Span Forward test score. Score range 0-16. Higher scores mean a better outcome.
Time Frame
From baseline to three months.
Title
Digit Span Backward
Description
Change Digit Span Backward test score. Score range 0-16. Higher scores mean a better outcome.
Time Frame
From baseline to three months.
Title
Digit Span Arrangement
Description
Change Digit Span Arrangement test score. Score range 0-16. Higher scores mean a better outcome.
Time Frame
From baseline to three months.
Title
WAIS Letter Number Sequence
Description
Change Letter Number sequence test score. Score range 0-30. Higher scores mean a better outcome.
Time Frame
From baseline to three months.
Title
Word mobilising test - F, S, A, and animals
Description
Change word mobilising test score. Higher scores mean a better outcome.
Time Frame
From baseline to three months.
Title
Cambridge Neuropsychological Test Automated Battery - Spatial Working Memory
Description
Change in spatial working memory score.
Time Frame
From baseline to three months.
Title
Cambridge Neuropsychological Test Automated Battery - Motor Screening
Description
Change in motor screening score.
Time Frame
From baseline to three months.
Title
Cambridge Neuropsychological Test Automated Battery - Rapid Visual Information processing
Description
Change in rapid visual information processing score.
Time Frame
From baseline to three months.
Title
Cambridge Neuropsychological Test Automated Battery - Paired Associates Learning Task
Description
Change in paired associates learning task score.
Time Frame
From baseline to three months.
Title
Cambridge Neuropsychological Test Automated Battery - One-Touch Stockings of Cambridge
Description
Change in One-Touch Stockings of Cambridge score.
Time Frame
From baseline to three months.
Title
Cambridge Neuropsychological Test Automated Battery - Reaction Time
Description
Change in reaction time score.
Time Frame
From baseline to three months.
Title
Short Informant Questionnaire on Cognitive Decline in the Elderly - IQCODE
Description
Change in short IQCODE score. Score range 1-5. A score of 3 means that the subject is rated on average as 'no change'.
Time Frame
From baseline to three months.
Title
Becks Depression Inventory - BDD
Description
Change in BDD score. Score range 0-63. Higher score means increased risk of depression.
Time Frame
From baseline to three months.
Title
Fatigue Severity Scale - FSS
Description
Change in FSS score. Score range 0-7. Higher score means increased fatigue severity.
Time Frame
From baseline to three months.
Title
WHO-5 Well-Beeing Index
Description
Change in WHO-5 score. Score range 0-100. Higher score means better quality of life.
Time Frame
From baseline to three months.
Title
Vascular- and inflammatory biomarkers: vascular cell adhesion molecule (VCAM-1)
Description
Changes in vascular cell adhesion molecule (VCAM-1) (unit pg/ml).
Time Frame
From baseline to three months.
Title
Vascular- and inflammatory biomarkers: intercellular adhesion molecule-1 (ICAM-1)
Description
Changes in intercellular adhesion molecule-1 (ICAM-1) (unit pg/ml).
Time Frame
From baseline to three months.
Title
Vascular- and inflammatory biomarkers: interleukin-6 (IL-6)
Description
Changes in interleukin-6 (IL-6) (unit pg/ml).
Time Frame
From baseline to three months.
Title
Vascular- and inflammatory biomarkers: tumour necrosis factor alpha (TNF-α)
Description
Changes in tumour necrosis factor alpha (TNF-α) (unit pg/ml).
Time Frame
From baseline to three months.
Title
Vascular- and inflammatory biomarkers: interleukin 1beta (IL-1β)
Description
Changes in interleukin 1beta (IL-1β) (unit pg/ml).
Time Frame
From baseline to three months.
Title
Vascular- and inflammatory biomarkers: E-selectin
Description
Changes in E-selectin (unit pg/ml).
Time Frame
From baseline to three months.
Title
Vascular- and inflammatory biomarkers: vascular endothelial growth factor (VEGF)
Description
Changes in vascular endothelial growth factor (VEGF) (unit pg/ml).
Time Frame
From baseline to three months.
Title
Vascular- and inflammatory biomarkers: specific micro RNA
Description
Changes in specific micro RNA associated to vascular disease.
Time Frame
From baseline to three months.
Title
Death, ischemic and hemorrhagic event, and dementia
Description
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.
Time Frame
From baseline to five years.
Title
Blood pressure
Description
Change in both systolic and diastolic blood pressure (unit mmHg).
Time Frame
From baseline to three months.
Title
Heart rate
Description
Change in heart rate (unit beats per minute).
Time Frame
From baseline to three months.
Title
Adverse events
Description
Difference in adverse events between groups.
Time Frame
From baseline to three months.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
50 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Christina Kruuse, MD, Prof
Phone
+4538681233
Email
christina.kruuse@regionh.dk
First Name & Middle Initial & Last Name or Official Title & Degree
Joakim Ölmestig, MD
Phone
+4538686553
Email
joakim.nils.erik.krogh.oelmestig@regionh.dk
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Christina Kruuse, MD, Prof
Organizational Affiliation
Herlev Gentofte Hospital, Department of Neurology
Official's Role
Principal Investigator
Facility Information:
Facility Name
Department of Neurology, Herlev Gentofte Hospital
City
Herlev
ZIP/Postal Code
2730
Country
Denmark
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Christina Kruuse, MD, Prof
Phone
+4538681233
First Name & Middle Initial & Last Name & Degree
Joakim Ölmestig, MD
Phone
+4538686553
First Name & Middle Initial & Last Name & Degree
Christina Kruuse, MD, Prof.
First Name & Middle Initial & Last Name & Degree
Joakim Ölmestig, MD
Facility Name
Danish Research Centre for Magnetic Resonance
City
Hvidovre
ZIP/Postal Code
2650
Country
Denmark
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Hartwig R Siebner, MD, Prof
Phone
+4538626541
Email
hartwig.roman.siebner@regionh.dk
First Name & Middle Initial & Last Name & Degree
Esben T Petersen, Ass. Prof
Phone
+4538623326
Email
esbentp@drcmr.dk
First Name & Middle Initial & Last Name & Degree
Hartwig R Siebner, MD, Prof
First Name & Middle Initial & Last Name & Degree
Esben T Petersen, Ass. Prof
First Name & Middle Initial & Last Name & Degree
Kristian Mortensen, MSc, PhD

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
IPD can be accessed upon reasonable request and after evaluation from the investigator.

Learn more about this trial

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

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