Cerebral blood flow and cognition after three months tadalafil treatment in small vessel disease (ETLAS-2): study protocol for a randomized controlled trial.

Abstract

Background: Targeted treatment is highly warranted for cerebral small vessel disease, a causal factor of one in four strokes and a major contributor to vascular dementia. Patients with cerebral small vessel disease have impaired cerebral blood flow and vessel reactivity. Tadalafil is a specific phosphodiesterase 5 inhibitor shown to improve vascular reactivity in the brain. Methods: The ETLAS-2 trial is a phase 2 double-blind, randomized placebo-controlled, parallel trial with feasibility of tadalafil as the primary outcome. The trial aims to include 100 patients with small vessel occlusion stroke or transitory ischemic attacks and signs of cerebral small vessel disease more than six months before administration of study medication. Patients are treated for three months with tadalafil 20 mg or placebo daily and undergo magnetic resonance imaging (MRI) to evaluate changes in small vessel disease according to the Standards for ReportIng Vascular changes on nEuroimaging (STRIVE) criteria as well as cerebral blood flow, cerebrovascular reactivity, and neurovascular coupling in a functional MRI sub-study. The investigation includes comprehensive cognitive testing using paper-pencil tests and Cambridge Neuropsychological Test Automated Battery (CANTAB)-tests in a cognitive sub-study. Discussion: The ETLAS-2 trial tests the feasibility of long-term treatment with tadalafil and explores vascular and cognitive effects in cerebral small vessel disease in trial sub-studies. The study aims to propose a new treatment target and improve the understanding of small vessel disease. Currently, 64 patients have been included and the trial is estimated to be completed in year 2024. Trial registration: The trial is registered at clinicaltrials.gov (NCT05173896).