Tadalafil Treatment in Patients With Cerebral Small Vessel Disease: The ETLAS-2 Randomized Clinical Trial
Bibliographic record
Abstract
BACKGROUND: White matter hyperintensities and reduced cerebral blood flow are hallmarks of cerebral small vessel disease (CSVD). We tested the feasibility of daily treatment with the vasoactive drug tadalafil in patients with CSVD and its effects on cognition and imaging markers of CSVD. METHODS: The ETLAS-2 trial (Effect of Tadalafil in Lacunar Stroke) was a randomized, placebo-controlled, double-blind, parallel phase II trial testing 3 months of daily tadalafil 20 mg versus placebo in patients with CSVD and previous stroke or transient ischemic attack. Participants were included from the Capital Region of Denmark from 2022 to 2024. Outcomes were assessed at baseline and after 3 months. A binary logistic regression model with the treatment group as a covariate was used to calculate the primary outcome of feasibility (≥90% study drug compliance). Secondary outcomes included the Montreal Cognitive Assessment, magnetic resonance imaging markers of CSVD (Standards for Reporting Vascular Changes on Neuroimaging criteria), blood pressure, and adverse events. RESULTS: We included 76 participants (20 female, mean age, 68.0±8.9 years). Seventy-one initiated treatment, and 26 of 38 participants with tadalafil were ≥90% compliant versus 31 of 33 with placebo (odds ratio, 0.13 [95% CI, 0.03–0.69]; P =0.030). There was a female preponderance in tadalafil dropouts, with 46% of females stopping treatment, compared with only 16% of males. Adverse events occurred in 76% of participants with tadalafil versus 36% with placebo (odds ratio, 5.49 [95% CI, 1.81–18.07]; P =0.001). A trend toward lower white matter hyperintensity volume at follow-up was observed in the tadalafil group in the unadjusted per-protocol analysis (relative change, 0.939 [95% CI, 0.881–1.001]; P =0.054). No differences were observed in cognition, mental well-being, or blood pressure. CONCLUSIONS: In participants with CSVD, adherence to tadalafil was significantly lower than to placebo and did not meet the prespecified compliance threshold. We observed a nonsignificant reduction in white matter hyperintensity volume after tadalafil, which warrants larger and prolonged studies with reduced tadalafil doses to explore potential benefits in CSVD. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05173896.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".