Drug Combo Tied to Functional Improvement After Stroke

Abu Dhabi, UAE — In the latest multicenter randomized trial testing a combination of edaravone and dexborneol for the treatment of acute stroke, the proportion of patients with complete or near complete function at 90 days was improved significantly relative to placebo. 

The third in a series, this trial, like the previous two, showed that participants who received the experimental treatment “were more likely to achieve functional independence at 90 days without increased safety concerns,” said study investigator Chun-Juan Wang, MD, PhD, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.

The results of TASTE-2 were presented in a late-breaking session on October 24 at the 16th World Stroke Congress (WSC) 2024. 

Data From Three Key Trials

For the study, 1362 patients were randomly assigned to receive edaravone dexborneol or placebo within 24 hours of an acute stroke at 106 participating centers. The primary outcome assessed at 90 days was functional independence as defined by a modified Rankin Scale (mRS) score of 0 to 2.

Unlike in the previous two trials, all patients underwent endovascular thrombectomy (EVT). All three multicenter studies were conducted in China.

The primary endpoint was reached by 55.0% of participants in active treatment arm vs 49.6% of those in the placebo group, producing a 24% improvement in the odds ratio (OR) of achieving a functional recovery (OR, 1.24; P

Edaravone, which is an antioxidant but might have other neuroprotective activity, is currently approved for the treatment of amyotrophic lateral sclerosis. Bornel, the active ingredient of dexborneol, has been shown to downregulate anti-inflammatory factors in the experimental setting and might also have other neuroprotective properties. 

The combination of these active drugs in a single infusion was first evaluated in the TASTE-1 trial, which was published in 2021. In that phase 3 double-blind study, 1165 acute stroke patients were randomly assigned to receive edaravone dexborneol or edaravone alone within 48 hours of an acute stroke. The primary endpoint of mRS score ≤ 1 was achieved by 67.18% of those in the combination therapy arm vs 58.9% of those receiving dexborneol alone (OR, 1.42; P

A second large randomized trial, called TASTE-SL, was published in JAMA Neurology earlier this year. In this multicenter study, 914 acute stroke patients were assigned in a 1:1 fashion to sublingual edaravone dexborneol or matching placebo within 48 hours of symptom onset. The primary endpoint of mRS score ≤ 1 was achieved by 64.4% of those assigned to receive the combination therapy vs 54.7% of those receiving placebo (OR, 1.50; P = .003). 

TASTE-1 enrolled acute stroke patients with a median baseline National Institutes of Health Stroke Scale (NIHSS) score of 6. They did not receive reperfusion therapy. TASTE-SL enrolled patients with a median NIHSS score of 7 who did not undergo EVT. In TASTE-2, the median NIHSS score was 15, and EVT was an inclusion criterion.

When patients were stratified by specific functional mRS scores, there was a numerically higher proportion of patients achieving mRS score of 0 (22.1% vs 20.9%) and 1 (18.1% vs 17.4%) but the greatest between-group difference was seen for an mRS score of 2 (14.8% vs 11.3%). 

The advantage of edaravone dexborneol moved in the same direction across almost all subgroups evaluated. There were trends for greater benefit among those treated within 6 hours relative to later and in those who had hypertension, coronary artery disease, or a high NIHSS score (≥ 15) relative to those who did not.

The proportion of patients with adverse events (33.0% vs 32.3%) or serious adverse events (27.2% vs 25.7%) was slightly higher in the active treatment arm, but none of these adverse events were considered to be treatment related. 

The proportion of patients with intracranial hemorrhage within 36 hours was numerically lower in the active treatment arm (5.3% vs 6.5%). The all-cause mortality at 90 days was the same in both groups (16.5%). 

The effect size of edaravone dexborneol was smaller than that anticipated in the design of the trial, but Chun-Juan Wang, who presented these data along with the senior investigator, Yongjun Wang, MD, chief physician at her institution, said that the positive results from three randomized trials are mutually reinforcing. Conducted in a population with a higher NIHSS score, TASTE-2 supports broader application.

On the basis of these data, “edaravone dexborneol may serve as a concomitant agent with EVT or with intravenous thrombolysis,” Chun-Juan Wang said.

Additional Therapeutic Evidence 

By itself, edaravone has demonstrated a therapeutic effect in acute stroke in numerous trials, according to Mariana Fidalgo, MD, Centro Hospitalar de Vila Nova de Gaia/Espinho, Vila Nova De Gaia, Portugal. In a systemic review and meta-analysis that she published 2 years ago, based on 19 randomized controlled trials, the likelihood of a good (OR, 1.31; 95% CI, 1.06-1.67) or excellent (OR, 1.26, 95% CI, 1.04-1.54) outcome at 90 days was increased significantly.

“Edaravone was also associated with a lower risk of death compared to placebo or no therapy,” Fidalgo said, noting that these studies, like the TASTE trials, did not associate edaravone with an increased risk for intracranial hemorrhage or other serious adverse events.

Despite these data, edaravone with or without dexborneol has not received regulatory approval for the treatment of acute stroke, but Fidalgo, who was not involved in the TASTE trials, called an edaravone-based therapy given shortly after the onset of stroke “promising” for increasing the odds of functional recovery.

Marc Fisher, MD, professor of neurology at Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, noted that edaravone dexborneol has now demonstrated a statistically significant benefit for acute stroke in three large blinded multicenter trials. 

Fisher, who was the senior author on a review article published 2 years ago that suggested cytoprotective therapies are showing promise as adjuncts to acute stroke reperfusion therapies, acknowledged that the relative benefit of edaravone dexborneol has been modest across the three trials in which it was studied, but these data are “clinically meaningful for a drug that is safe.”

The study received funding from Simcere Pharmaceutical Group Limited. Chun-Juan Wang, Yongjun Wang, and Fidalgo report no relevant financial relationships. Fisher reports that he has been a consultant for Simcere.