Effects of Danhong Injection on 90‐Day Functional Outcome in Acute Ischemic Stroke: An Adaptive, Multicenter, Randomized, Double‐Blind, Placebo‐Controlled Phase IV Trial

ABSTRACT Therapeutic options for neurological recovery remain limited in acute ischemic stroke (AIS) patients ineligible for thrombolysis, and while multitarget drugs like Danhong injection ( DHI ) demonstrate efficacy, their polypharmacological mechanisms remain understood. In this trial including 1505 thrombolysis‐ineligible AIS patients with anterior‐circulation and blood stasis syndrome (NCT01677208), 14‐day treatment with DHI ( n = 1002) versus placebo ( n = 503) demonstrated superior 90‐day outcomes (modified Rankin scale [mRS] score ≤1: 64.57 vs. 59.24%; adjusted odds ratio 1.43, 95%CI 1.10–1.86, p = 0.007), particularly in females and hypertensive patients, and no significant between‐group differences in any serious adverse events (all p > 0.05). In the exploratory RNA‐sequencing substudy of 39 patients (24 DHI , 15 placebo), we identified 19 differentially expressed modules, including two paired targeted modules “ HBG2 ” and “ TMEM108 ,” whose topological features showed opposite correlations with the primary clinical outcome (δmRS at Day 90). Furthermore, a combination effect model was introduced to describe the time‐dependent joint association of these modules with outcome (combination effect score: −0.729 at Day 0, 0.227 at Day 14, and 1 at Day 90). These findings demonstrate DHI may be a favorable treatment option for thrombolysis‐ineligible AIS patients and provide a proposed analytical framework for future, independently validated studies of multitarget drug actions in complex diseases.