Abstract

Importance

Sublingual edaravone dexborneol, which can rapidly diffuse and be absorbed through the oral mucosa after sublingual exposure, is a multitarget brain cytoprotection composed of antioxidant and anti-inflammatory ingredients edaravone and dexborneol.

Objective

To investigate the efficacy and safety of sublingual edaravone dexborneol on 90-day functional outcome in patients with acute ischemic stroke (AIS).

Design, Setting, and Participants

This was a double-blind, placebo-controlled, multicenter, parallel-group, phase 3 randomized clinical trial conducted from June 28, 2021, to August 10, 2022, with 90-day follow-up. Participants were recruited from 33 centers in China. Patients randomly assigned to treatment groups were aged 18 to 80 years and had a National Institutes of Health Stroke Scale score between 6 and 20, a total motor deficit score of the upper and lower limbs of 2 or greater, a clinically diagnosed AIS symptom within 48 hours, and a modified Rankin Scale (mRS) score of 1 or less before stroke. Patients who did not meet the eligibility criteria or declined to participate were excluded.

Intervention

Patients were assigned, in a 1:1 ratio, to receive sublingual edaravone dexborneol (edaravone, 30 mg; dexborneol, 6 mg) or placebo (edaravone, 0 mg; dexborneol, 60 μg) twice daily for 14 days and were followed up until 90 days.

Main Outcomes and Measures

The primary efficacy outcome was the proportion of patients with mRS score of 1 or less on day 90 after randomization.

Results

Of 956 patients, 42 were excluded. A total of 914 patients (median [IQR] age, 64.0 [56.0-70.0] years; 608 male [66.5%]) were randomly allocated to the edaravone dexborneol group (450 [49.2%]) or placebo group (464 [50.8%]). The edaravone dexborneol group showed a significantly higher proportion of patients experiencing good functional outcomes on day 90 after randomization compared with the placebo group (290 [64.4%] vs 254 [54.7%]; risk difference, 9.70%; 95% CI, 3.37%-16.03%; odds ratio, 1.50; 95% CI, 1.15-1.95, P = .003). The rate of adverse events was similar between the 2 groups (89.8% [405 of 450] vs 90.1% [418 of 464]).

Conclusions and Relevance

Among patients with AIS within 48 hours, sublingual edaravone dexborneol could improve the proportion of those achieving a favorable functional outcome at 90 days compared with placebo.

Trial Registration

ClinicalTrials.gov Identifier: NCT04950920

Key Points

Question  Does sublingual edaravone dexborneol improve functional outcome in patients with acute ischemic stroke?

Findings In this randomized clinical trial including 914 patients who received sublingual edaravone dexborneol or placebo, the proportion of patients achieving a favorable outcome defined as a 90-day modified Rankin Scale score of 1 or less was 64.4% in the sublingual edaravone dexborneol group, which was significantly higher than 54.7% in the placebo group. The rate of adverse events was similar between the 2 groups.

Meaning  Sublingual edaravone dexborneol, as a fast-acting and convenient agent, could improve the proportion of patients who achieve good clinical outcomes at 90 days compared with placebo among patients with acute ischemic stroke.

요약

소개

설하투여형 에다라본 덱스보르네올(Sublingual edaravone dexborneol)은 구강 점막을 통해 빠르게 확산되고 흡수될 수 있는 다중 표적 뇌 세포 보호제(multitarget brain cytoprotection)이며, 항산화 및 항염증 성분인 에다라본과 덱스보르네올로 이루어져 있다. 이 연구는 급성 허혈성 뇌졸중(AIS) 환자의 치료 90일 이후의 기능적 결과(functional outcome)에 대한 설하 에다라본 덱스보르네올의 효능과 안전성을 조사하기 위해 진행되었다.

방법

이 연구는 2021년 6월 28일부터 2022년 8월 10일까지 실시된 이중 맹검, 위약 대조, 다기관, 3상 무작위 임상 시험으로, 90일 추적 관찰이 이루어졌다. 중국의 33개 센터에서 참여자가 모집되었으며, 환자들은 설하 에다라본 덱스보르네올(에다라본 30 mg; 덱스보르네올 6 mg) 또는 위약(에다라본 0 mg; 덱스보르네올 60 μg)을 1:1 비율로 무작위 배정받아 14일 동안 하루 두 번 투여받고 90일까지 추적 관찰되었다.

주요 효능 결과(primary efficacy outcome)는 무작위 배정 후 90일째의 mRS 점수가 1 이하인 환자의 비율로 설정하였다.

결과

1. 에다라본 덱스보르네올 그룹은 위약 그룹에 비해 무작위 배정 후 90일째에 좋은 기능적 결과를 경험한 환자의 비율이 유의미하게 높았다. (290 [64.4%] vs 254 [54.7%]; risk difference, 9.70%; 95% CI, 3.37%-16.03%; odds ratio, 1.50; 95% CI, 1.15-1.95, P = .003)

2. 두 그룹 간의 이상 반응 발생률은 비슷했다. (89.8% [405 of 450] vs 90.1% [418 of 464])

결론 및 의의

AIS 발병 48시간 이내의 환자들에서 설하 에다라본 덱스보르네올은 위약에 비해 90일 후에 유리한 기능적 결과를 달성하는 환자의 비율을 개선할 수 있었다.

설하 에다라본 덱스보르네올은 빠르게 작용하고 투여하기 편리한 약제로, 급성 허혈성 뇌졸중 환자들에서 좋은 임상 결과를 달성하는 비율을 개선할 수 있을 것으로 기대된다.