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

NCT05173896 | Active Not Recruiting Phase 2 DMC

• 2 other identifiers: H-200313012020-002329-27
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 2

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.

Conditions

Cerebral Small Vessel Diseases; Stroke, Ischemic

Outcome Measures

Primary Outcomes (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.

  From baseline to three months.

Secondary Outcomes (37)

• MRI - Cerebral Blood Flow

  From baseline to three months.

• MRI - Neurovascular reactivity and perfusion

  From baseline to three months.

• MRI - Neurovascular reactivity

  From baseline to three months.

• MRI - Blood Brain Barrier

  From baseline to three months.

• MRI - STRIVE criteria

  From baseline to three months.

Study Arms (2)

Tadalafil

EXPERIMENTAL

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

Drug: Tadalafil 20 MG

Placebo

PLACEBO COMPARATOR

Oral placebo capsules once daily for three months.

Drug: Placebo

Interventions

Tadalafil 20 MG DRUG

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

Tadalafil

Placebo DRUG

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

Placebo

Eligibility Criteria

• Age: 50 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Christina Kruuse: lead
• Danish Research Centre for Magnetic Resonance: collaborator
• Bispebjerg Hospital: collaborator
• Rigshospitalet, Denmark: collaborator
• University of Copenhagen: collaborator
• The Novo Nordic Foundation: collaborator
• Nordsjaellands Hospital: collaborator

Study Sites (2)

Department of Neurology, Herlev Gentofte Hospital

Herlev, 2730, Denmark

Location

Danish Research Centre for Magnetic Resonance

Hvidovre, 2650, Denmark

Location

Related Publications (3)

• 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.

  PMID: 41332889 DERIVED

• 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.

  PMID: 40718899 DERIVED

• 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.

  PMID: 39210472 DERIVED

MeSH Terms

Conditions

Cerebral Small Vessel Diseases; Ischemic Stroke

Interventions

Tadalafil

Condition Hierarchy (Ancestors)

Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Stroke

Intervention Hierarchy (Ancestors)

Carbolines; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Indole Alkaloids; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds, 3-Ring

Study Officials

• Christina Kruuse, MD, Prof

  Herlev Gentofte Hospital, Department of Neurology

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: MD, Ph.D., DMSc, Professor in Neurology

Study Record Dates

• First Submitted: November 16, 2021
• First Posted: December 30, 2021
• Study Start: May 31, 2022
• Primary Completion: September 23, 2024
• Study Completion (Estimated): December 1, 2029
• Last Updated: December 9, 2024

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will share

Locations

DK (2)