Background <p>Despite advances in embolization techniques and neurocritical care, patients with severe aneurysmal subarachnoid hemorrhage (SaSAH) continue to face substantial risk of morbidity and long-term disability. The presence of subarachnoid blood and its breakdown products significantly contributes to secondary brain injury and subsequent complications. Although the EARLYDRAIN trial demonstrated a benefit from lumbar drainage in clearing blood, this method alone is insufficient to remove clots located above the fourth ventricle. Urokinase, a fibrinolytic agent, offers a potential means to enhance clot clearance. However, the combined strategy of lumbar drainage plus intrathecal urokinase (LD-ITUK) has not yet been rigorously evaluated.</p> Methods/design <p>This is an investigator-initiated, multicenter, prospective, randomized, double-blind, placebo-controlled superiority trial. It aims to compare the efficacy of LD-ITUK against lumbar drainage alone (with intrathecal saline) in patients with SaSAH, when added to standard care. A total of 424 eligible patients will be randomized in a 1:1 ratio to receive either the intervention (LD-ITUK) or the control treatment (lumbar drainage plus intrathecal saline). Eligible participants are adults with a first-episode aSAH, clinically graded as Hunt-Hess III to V, whose ruptured aneurysm has been secured via surgical clipping or endovascular coiling within 48&#xa0;h after onset. The primary outcome is the proportion of patients achieving a favorable functional outcome, defined as a modified Rankin Scale (mRS) score of 0 to 2 at 180&#xa0;days after onset, as adjudicated by an independent Outcome Adjudication Committee (OAC) blinded to treatment allocation.</p> Discussion <p>This trial will determine whether the LD-ITUK method could improve the long-term functional outcomes compared to the current standard treatment in patients with SaSAH.</p> Trial registration <p>ClinicalTrials.gov NCT06284642. Registered 28 February 2024</p>