Sublingual Acute Stroke Neuroprotectant Dazzles in Phase III Trial

For acute ischemic stroke within 48 hours of onset, the novel sublingual combination of edaravone (Radicava) with dexborneol appeared to dramatically improve functional outcomes in the phase III TASTE-SL trial from China.

The chance of a good functional outcome as marked by a modified Rankin Scale (mRS) score of 0-1 on day 90 was 50% improved with the neuroprotectant compared with placebo (64.4% vs 54.7%, OR 1.50, 95% CI 1.15-1.95, P=0.003), reported Dongsheng Fan, MD, of Peking University Third Hospital in Beijing, and colleagues in JAMA Neurology.

Adverse events (AEs) occurred in most patients in both groups; serious AEs were uncommon and balanced between the two.

“This is a remarkable result, and given that edaravone dexborneol is low cost, simple to administer (even in patients who are unconscious, disabled, or dysphagic), and readily available in China, it has major potential practice implications,” said Craig S. Anderson, PhD, and Lili Song, MD, PhD, both of the George Institute for Global Health in Sydney.

In an accompanying editorial, they acknowledged the “litany of failed neuroprotection trials in acute ischemic stroke” over after several decades of considerable investment but noted a “clear rationale” for adjuvant stroke treatment in the endovascular treatment era.

“Many patients have poor access to reperfusion therapy and, even when they do have it, do not have a satisfactory recovery despite achieving a good technical result of recanalization of an occluded vessel. Moreover, in showing the benefits of endovascular therapy within a 6- to 24-hour onset-to-treatment time window in patients with a large ischemic lesion, recent trials have also challenged understanding about how viable vs dead neuronal tissue is defined on brain imaging,” they wrote.

Edaravone is a low-molecular-weight drug that appears to protect neurons, glia, and vascular endothelial cells against oxidative stress and inflammation. It is FDA approved for amyotrophic lateral sclerosis. The combination with dexborneol, a component of proprietary Chinese medicine, “is believed to offer a synergistic action,” the editorialists noted.

However, they pointed out some serious concerns with the results: “To begin with, the size of the observed treatment effect … is much higher than would be expected of a neuroprotective agent. Because approximately half of the patients commenced the treatment at 24 hours or longer after symptom onset, this size of benefit is equivalent to that seen with intravenous thrombolysis initiated within the first few hours of an acute ischemic stroke. Therefore, the results challenge our understanding of the ‘time is brain’ concept of the evolving ischemic penumbra and are contrary to the neutral results of the ESCAPE-NA1 trial, and most recently ESCAPE-NEXT … which evaluated nerinetide, a highly promising drug that attenuates excitotoxic cell death.”

The editorialists suggested chance could be at play in TASTE-SL, which was powered at 80% rather than a more conventional 90% and did not show benefits of edaravone dexborneol in any secondary endpoints, including early neurological impairment in NIH Stroke Scale (NIHSS) scores between baseline and 14 and 30 days.

“It is unfortunate that no ancillary measures of health-related quality of life were collected during follow-up to allow a broader appraisal of the recovery of patients,” Anderson and Song lamented.

The researchers, though, chalked the nonsignificant secondary endpoint results up to the substantial number of mild strokes in the trial, with an average NIHSS score of 7.

The trial included 914 patients, ages 18-80 years, who had an NIHSS score of 6-20; a total motor deficit score of the upper and lower limbs of 2 or greater; clinically diagnosed acute ischemic stroke symptoms within 48 hours; and a pre-stroke mRS score of 1 or less.

They were randomly assigned to sublingual edaravone dexborneol (30 and 6 mg, respectively) or placebo comprised of inert dexborneol (60 μg, to simulate the taste of the active drug) twice daily for 14 days.

Limitations included exclusion of a patient who got endovascular thrombectomy and enrollment of only persons of Chinese ethnicity.

The editorialists also pointed to another limitation: “Just before being unblinded to the data toward the end of the study, the steering committee made the decision to use a complex approach to addressing missing primary outcome data in the primary analysis rather than a more conventional complete case analysis of the primary outcome. This included using the last observation carried forward or assigning a worse-case variable (6 for death) in patients with a missing outcome. Given that missingness (loss to follow-up) is invariably not lost at random, this could have influenced the result. Inevitably, this did not occur as they were readily confirmed in secondary imputation, covariate-adjusted, and subsequent complete case analyses.”

They also raised the specter of conflicts of interest, as the study authors included employees of three pharmaceutical companies, “including the one that sponsored the study and would naturally have an interest in the trial outcome.”

Furthermore, Anderson and Song added to the call for replication of the results in other regions of the world.

“Because maximizing access to reperfusion treatment is at the forefront of modern stroke services, and disease and social reasons for delayed presentation after symptom onset differ across regions, the TASTE-SL results are promising but less relevant to contemporary clinical practice outside of China,” they wrote. “However, they provide a clear justification for further evaluations of edaravone dexborneol in other populations, and for individual patient data meta-analysis to be undertaken to determine the totality of the evidence.”

“The performance bar is set high, but the benefits offered by safe treatments with only modest effects in reducing the burden of acute ischemic stroke worldwide are considerable,” Anderson and Song stated.