Key Points
Question
Does DL-3-n-butylphthalide (NBP) improve the functional outcome in patients with acute ischemic stroke receiving reperfusion therapy of intravenous thrombolysis and/or endovascular treatment?
Findings
In this randomized clinical trial including 1216 patients randomized to NBP or placebo, the proportion of patients achieving a favorable outcome based on the 90-day modified Rankin Scale score was significantly higher in the butylphthalide group compared with the placebo group (344 of 607 [56.7%] vs 258 of 609 [44.0%]). The rate of serious adverse events was similar between the 2 groups.
Meaning
In this trial, NBP was associated with a higher proportion of patients achieving a favorable functional outcome at 90 days compared with placebo among patients with acute ischemic stroke receiving intravenous thrombolysis and/or endovascular treatment.
This randomized clinical trial assesses the efficacy and safety of DL-3-n-butylphthalide in patients with acute ischemic stroke receiving reperfusion therapy of intravenous thrombolysis and/or endovascular treatment.
Abstract
Importance
DL-3-n-butylphthalide (NBP) is a drug for treating acute ischemic stroke and may play a neuroprotective role by acting on multiple active targets. The efficacy of NBP in patients with acute ischemic stroke receiving reperfusion therapy remains unknown.
Objective
To assess the efficacy and safety of NBP in patients with acute ischemic stroke receiving reperfusion therapy of intravenous thrombolysis and/or endovascular treatment.
Design, Setting, and Participants
This multicenter, double-blind, placebo-controlled, parallel randomized clinical trial was conducted in 59 centers in China with 90-day follow-up. Of 1236 patients with acute ischemic stroke, 1216 patients 18 years and older diagnosed with acute ischemic stroke with a National Institutes of Health Stroke Scale score ranging from 4 to 25 who could start the trial drug within 6 hours from symptom onset and received either intravenous recombinant tissue plasminogen activator (rt-PA) or endovascular treatment or intravenous rt-PA bridging to endovascular treatment were enrolled, after excluding 20 patients who declined to participate or did not meet eligibility criteria. Data were collected from July 1, 2018, to May 22, 2022.
Interventions
Within 6 hours after symptom onset, patients were randomized to receive NBP or placebo in a 1:1 ratio.
Main Outcomes and Measures
The primary efficacy outcome was the proportion of patients with a favorable outcome based on 90-day modified Rankin Scale score (a global stroke disability scale ranging from 0 [no symptoms or completely recovered] to 6 [death]) thresholds of 0 to 2 points, depending on baseline stroke severity.
Results
Of 1216 enrolled patients, 827 (68.0%) were men, and the median (IQR) age was 66 (56-72) years. A total of 607 were randomly assigned to the butylphthalide group and 609 to the placebo group. A favorable functional outcome at 90 days occurred in 344 patients (56.7%) in the butylphthalide group and 268 patients (44.0%) in the placebo group (odds ratio, 1.70; 95% CI, 1.35-2.14; P < .001). Serious adverse events within 90 days occurred in 61 patients (10.1%) in the butylphthalide group and 73 patients (12.0%) in the placebo group.
Conclusions and Relevance
Among patients with acute ischemic stroke receiving intravenous thrombolysis and/or endovascular treatment, NBP was associated with a higher proportion of patients achieving a favorable functional outcome at 90 days compared with placebo.
Trial Registration
ClinicalTrials.gov Identifier: NCT03539445
Introduction
Stroke is one of the most common causes of mortality worldwide and is a leading cause of disability.1 Reperfusion is a proven approach, and neuroprotection is a promising additional approach to treat ischemic stroke. Although reperfusion therapy has been recommended as a standard treatment strategy for ischemic stroke,2,3,4,5,6 approximately half of patients failed to benefit from timely initiation of acute reperfusion therapy.3,6,7,8 Therefore, neuroprotective drugs and recovery strategies are urgently needed in clinical practice. Cerebroprotection or brain cytoprotection is a potential treatment to break the ceiling effect of reperfusion therapy through salvage, recovery, or regeneration of structure and function of neurons and other supporting cells in the central neurological system. Several neuroprotective drugs used in clinical trials, such as edaravone dexborneol9 and nerinetide,10 suggested that neuroprotection in human stroke might be possible and promising.
DL-3-n-butylphthalide (NBP) is a synthesized compound that was originally extracted from seeds of Apium graveolens (Chinese celery). Although the specific molecular mechanism of action of NBP is unknown, preclinical data from multiple models showed that NBP could act on multiple links of cerebral ischemia pathology and play a protective role on cerebral infarction through anti-inflammation, antioxidation, anti-apoptosis, and microcirculation protection.11,12,13,14,15,16 Several randomized clinical trials also reported the potential benefit of NBP in patients with ischemic stroke; however, the findings needed to be interpreted with caution due to the study design and the methodology.17,18,19 It is worth noting that the Stroke Treatment Academic Industry Roundtable X (STAIR X) consortium consensus recommended that new cytoprotective agents needed to work synergistically with thrombolysis and thrombectomy, and future clinical trials should make reperfusion therapy as an inclusion criterion.20 However, to our knowledge, none of previous studies on NBP included patients receiving reperfusion therapy, leaving a knowledge gap of whether NBP works better synergistically with reperfusion.
The Butylphthalide for Acute Ischemic Stroke Patients Receiving Intravenous Thrombolysis or Endovascular Treatment (BAST) trial was to investigate whether treatment with NBP adjunctive to reperfusion therapy of intravenous thrombolysis and/or endovascular treatment could improve the functional outcome in patients with acute ischemic stroke compared with placebo.
Methods
Trial Design
The BAST trial was a multicenter, double-blind, placebo-controlled, parallel-group randomized clinical trial involving patients with acute ischemic stroke who received intravenous thrombolysis and/or endovascular treatment. Details of the trial rationale, design, and methods have been published previously21 and can be found in Supplement 1. Information on the statistical analysis plan, trial leadership, committees, sites, and investigators are provided in eAppendix 1 in Supplement 2. The BAST trial design is in compliance with the Declaration of Helsinki and was approved by the ethics committee at Beijing Tiantan Hospital and at each participating site. Written informed consent for participation in the trial was provided by the patients or their legal representative.
The steering committee was responsible for the design and supervision of the trial, the development of and amendments to the protocol, and the interpretation of the data as well as for ensuring the integrity of the data, analysis, and presentation of results and the fidelity of the trial to the protocol. An independent clinical event adjudication committee, whose members were unaware of the trial group assignments, adjudicated the primary and secondary efficacy outcomes and bleeding events. An independent data and safety monitoring committee monitored the progress of the trial, with regular assessment of safety outcomes, overall trial integrity, and trial conduct (eAppendix 2 in Supplement 2). The trial drugs and placebos were produced and provided by Shijiazhuang Pharmaceutical Group dl-3-butylphthalide Pharmaceutical.
Trial Patients
The trial was conducted at 59 centers across China. Eligibility criteria included age 18 years and older; diagnosis of acute ischemic stroke with a National Institutes of Health Stroke Scale (NIHSS) score ranging from 4 to 25; able to start the trial drug within 6 hours from symptom onset; receipt of either intravenous recombinant tissue plasminogen activator (rt-PA) or endovascular treatment (including intra-arterial thrombolysis and mechanical thrombectomy) or intravenous rt-PA bridging endovascular treatment; and signed informed consent.
Patients were not eligible if they had a modified Rankin Scale (mRS) score greater than 1 at randomization (premorbid historical assessment); had an Alberta Stroke Program Early Computed Tomography Score (ASPECT) score of 6 or less confirmed by preoperational computed tomography scan; were diagnosed with intracranial hemorrhagic diseases (eg, intracranial hemorrhage, subarachnoid hemorrhage); already used NBP or any drugs containing NBP between onset and randomization; appeared with dysphagia before randomization; had a history of coagulation disorders, hemorrhagic diathesis, neutropenia, or thrombocytopenia; chronic hepatopathy; or liver or kidney dysfunction. Additional information and exclusion criteria are provided in the protocol (Supplement 1) and in eTable 1 in Supplement 2.
Randomization and Blinding
Within 6 hours after symptom onset, eligible patients were randomly assigned in a 1:1 ratio to the butylphthalide or placebo group using a central stratified block randomization method. The randomization was stratified by site. Patients were assigned a random serial number based on their time of enrollment and provided with the corresponding medicines, which are masked beforehand. Both researchers and patients were masked to the treatment.
Intervention
Patients received adjunctive NBP or placebo treatment alongside standard intravenous thrombolysis and/or endovascular treatment. The dose of NBP was decided based on unpublished data of the phase II trial (eTable 2 in Supplement 2). Patients in the butylphthalide group received NBP and a 100-mL sodium chloride injection twice daily in the first 14 days and soft 0.2-g capsules of NBP 3 times daily for the next 76 days. The placebo group received a 100-mL placebo injection twice daily in the first 14 days and soft 0.2-g placebo capsules 3 times daily for the next 76 days. Patients were recommended to continue the injections for 10 to 14 days according to length of hospitalization. Each injection lasted for at least 50 minutes and was administered 6 hours apart. Patients were asked to take the capsules daily before meals and record medication administration, which was checked by researchers. The steering committee made recommendations for concomitant medications. All secondary preventive strategies, including antithrombosis and management of risk factors, were followed according to guidelines. However, neuroprotective medications, such as human urinary kallindinogenase, edaravone, and any ginkgo-containing injections, were prohibited.
Outcomes
The previous primary outcome, recovery of neurological deficit at 90 days, was changed shortly after the beginning of the trial, with cautious consideration of peer reviews during the publication of the protocol and comments from the data security monitoring board as well as the previous literature.22 The current primary efficacy outcome was the proportion of patients with a favorable functional outcome at 90 days after randomization, which was defined as an mRS score of 0 in patients with a baseline NIHSS score of 4 to 7; an mRS score of 0 to 1 in patients with a baseline NIHSS score of 8 to 14; and an mRS score of 0 to 2 in patients with a baseline NIHSS score of 15 to 25.22,23
The secondary efficacy outcomes included the difference in NIHSS score change from baseline to 14 days and from baseline to 90 days; cerebral infarction volume at 14 days; the percentage of patients with symptomatic intracranial hemorrhage within the first 24 hours as defined by the criteria of the Heidelberg bleeding classification24; recurrent symptomatic ischemic stroke and vascular events within 90 days; any vascular complications due to vascular events (recurrent symptomatic ischemic stroke, myocardial infarction, or vascular death) within 90 days; and the proportion of patients with a favorable functional outcome at 14 days. Additionally, favorable outcome was also redefined as an mRS score of 0 to 2 from a clinical perspective.
The primary safety outcome was serious adverse events occurred within 90 days, which included any event resulting in prolonged hospital time, permanent damage to the body system or organ, a life-threatening condition, or death. The secondary outcomes included symptomatic intracranial hemorrhage defined according to Heidelberg bleeding classification within 90 days,24 all-cause mortality within 14 days and 90 days, adverse events within 14 days and 90 days, and serious adverse events within 14 days.
Statistical Analysis
We determined that a total of 1200 patients would provide 90% power to detect a 60% rate of a favorable functional outcome at 90 days (based on adjusted mRS score) in the butylphthalide group and 50% in the placebo group with a 2-side significance level of .05 and an overall dropout rate of 10%. Two formal interim analyses were conducted to determine overwhelming efficacy or futility when 50% and 75% of participants had completed follow-up. The stopping rule for overwhelming efficacy was defined with the use of O’Brien-Fleming boundaries on the binary outcome of the 90-day favorable functional outcome, with corresponding significance levels of .003, .018, and .044. The independent data and safety monitoring committee recommended pursuit the study after 2 protocol-specified interim analyses were performed. A 2-sided P value less than .044 indicated statistical significance for the primary outcome after accounting for interim analyses.
Data analyses were carried out in the intention-to-treat population, defined as all randomized patients. Baseline data are presented according to treatment assignment, with descriptive statistics as appropriate. Missing data on the primary outcome were handled using the last observation carried forward method and multiple imputation, respectively. The primary efficacy outcome was assessed with the use of a logistic regression, with the trial centers set as a random effect, and odds ratios (ORs) and 95% CIs are reported. A similar approach was used for the secondary outcomes of symptomatic intracranial hemorrhage within the first 24 hours, favorable mRS score at 14 days, and the dichotomous results in the exploratory analysis. Changes in NIHSS score and the cerebral infarction volume were analyzed using Wilcoxon rank sum tests to compare the median change in response across treatment groups, and the Hodges-Lehmann method was used to calculate median differences. Recurrent symptomatic stroke, symptomatic ischemic stroke, combined vascular events, and all the safety outcomes were analyzed using a Cox proportional hazards model, and hazard ratios (HRs) were reported. NIHSS score on day 90 was calculated for each group, and the mean difference between the treatment groups were estimated by analysis of covariance.
Because the statistical analysis plan did not include a provision for correcting the widths of confidence intervals for multiple comparisons, secondary and other outcomes are presented as point estimates with unadjusted 95% CIs, from which no clinical inferences can be made. Statistical analyses were performed with SAS software version 9.4 (SAS Institute).
Results
Baseline Characteristics
Between July 1, 2018, and May 22, 2022, 1236 patients with acute ischemic stroke were screened, of which 20 patients who declined to participate or did not meet eligibility criteria were excluded. Consequently, a total of 1216 patients meeting the eligibility criteria were enrolled, of whom 827 (68.0%) were men, and the median (IQR) age was 66 (56-72) years. A total of 607 were randomly assigned to the butylphthalide group and 609 to the placebo group. Among the treated patients, 1010 (501 in the butylphthalide group and 509 in the placebo group) did not have major violations of the study protocol and were therefore included in the per-protocol analysis (Figure 1).
Figure 1. Flowchart of the Study.
NIHSS indicates National Institute of Health Stroke Scale; rt-PA, recombinant tissue plasminogen activator.
The randomized groups had similar baseline characteristics (Table 1). A total of 1136 patients (93.4%) had an mRS score of 0, and 545 (44.8%) had mild stroke (NIHSS score of 4 to 7). Intravenous rt-PA treatment was used in 838 patients (68.3%). According to Oxfordshire Community Stroke Project classification, total anterior circulation infarcts were observed in 337 patients (27.7%), partial anterior circulation infarcts in 650 (53.4%), posterior circulation infarcts in 152 (12.5%), and lacunar infarcts in 77 (6.3%). Concomitant treatment and prohibited medications taken during the treatment period are reported in eTables 3 and 4 in Supplement 2.
Table 1. Baseline Characteristics.
| Characteristic | No. (%) | |
|---|---|---|
| Butylphthalide (n = 607) | Placebo (n = 609) | |
| Age, median (IQR), y | 66 (56-72) | 66 (57-74) |
| Gender | ||
| Men | 412 (67.9) | 415 (68.1) |
| Women | 195 (32.1) | 194 (31.9) |
| Body mass index, median (IQR)a | 24.2 (22.0-26.4) | 24.2 (21.9-26.7) |
| Blood pressure, median (IQR), mm Hg | ||
| Systolic | 149.5 (138.0-163.5) | 150.0 (136.0-163.0) |
| Diastolic | 87.0 (80.0-95.0) | 86.0 (79.0-95.0) |
| Medical history | ||
| Stroke | 138 (22.7) | 133 (21.8) |
| Hypertension | 351 (57.8) | 345 (56.7) |
| Hypercholesterolemia | 29.0 (4.8) | 20 (3.3) |
| Diabetes | 131 (21.6) | 113 (18.6) |
| Heart disease | 144 (23.7) | 147 (24.1) |
| mRS score prior to onset | ||
| 0 | 563 (92.8) | 573 (94.1) |
| 1 | 44 (7.2) | 36 (5.9) |
| ASPECTS score, median (IQR) | 9 (8-10) | 9 (8-10) |
| NIHSS score, median (IQR) | 8 (5-12) | 8 (5-12) |
| Stroke category | ||
| Mild (NIHSS score of 4-7) | 262 (43.2) | 283 (46.5) |
| Moderate (NIHSS score of 8-14) | 246 (40.5) | 226 (37.1) |
| Severe (NIHSS score of 15-25) | 99 (16.3) | 100 (16.4) |
| Revascularization treatment, No./total No. (%) | ||
| Intravenous rt-PA treatment | 417/601 (69.4) | 420/604 (69.5) |
| Endovascular treatment or bridging | 184/601 (30.6) | 184/604 (30.5) |
| Successful reperfusionb,c | 160 (87.0) | 168 (91.3) |
| Clot locationc | ||
| Internal carotid artery | 41 (22.3) | 47 (25.5) |
| Middle cerebral artery | 110 (59.8) | 115 (62.5) |
| Anterior cerebral artery | 3 (1.6) | 1 (0.5) |
| Vertebral artery | 7 (3.8) | 4 (2.2) |
| Posterior cerebral artery | 4 (2.2) | 0 |
| Basilar artery | 19 (10.3) | 17 (9.2) |
| Onset to drug administration, median (IQR), min | 254 (203-310) | 261 (209-310) |
| OCSP subtype | ||
| TACI | 171 (28.2) | 166 (27.3) |
| PACI | 321 (52.9) | 329 (54.0) |
| POCI | 76 (12.5) | 76 (12.5) |
| LACI | 39 (6.4) | 38 (6.2) |
Abbreviations: ASPECTS, Alberta Stroke Program Early Computed Tomography Score; LACI, lacunar infarcts; mRS, modified Rankin Scale; NIHSS, National Institute of Health Stroke Scale; OCSP, Oxfordshire Community Stroke Project; PACI, partial anterior circulation infarcts; POCI, posterior circulation infarcts; rt-PA, recombinant tissue plasminogen activator; TACI, total anterior circulation infarcts.
Calculated as weight in kilograms divided by height in meters squared.
Reperfusion status was evaluated according to the modified Thrombolysis In Cerebral Infarction scale, and successful reperfusion was defined as an modified Thrombolysis In Cerebral Infarction score of 2b to 3.
Data were only available for 368 patients receiving endovascular treatment.
Primary and Secondary Outcomes
A favorable functional outcome at 90 days occurred in 344 patients (56.7%) in the butylphthalide group and 268 patients (44.0%) in the placebo group (OR, 1.70; 95% CI, 1.35-2.14; P < .001) (Table 2). Figure 2 illustrates the distribution of 90-day mRS scores in the overall patients and by baseline stroke severity. With respect to secondary outcomes, the difference between the groups in the NIHSS score changed from baseline to 90 days was −1.00 points (95% CI, −1.00 to 0; P = .03). There were no significant between-group differences in other prespecified secondary efficacy outcomes. Additionally, a higher proportion of mRS scores of 0 to 2 on day 90 was observed in the NBP group (HR, 1.39; 95% CI, 1.08-1.80; P = .01) (Table 2). Results of the per-protocol analysis were consistent with the primary intention-to-treat analysis (eTable 5 in Supplement 2), and the exploratory analysis yielded similar results (eTable 6 in Supplement 2). The results of subgroup analyses for the primary outcome are shown in Figure 3.
Table 2. Efficacy and Safety Outcomesa.
| Outcome | No. (%) | Effect size (95% CI) | P value | |
|---|---|---|---|---|
| Butylphthalide (n = 607) | Placebo (n = 609) | |||
| Primary outcome | ||||
| Favorable mRS score on day 90 | 344 (56.7) | 268 (44.0) | OR, 1.70 (1.35 to 2.14) | <.001 |
| Secondary outcomes | ||||
| Changes of NIHSS score from baseline to day 90, median (IQR) | −6 (−10 to −4) | −5 (−9 to −3) | Median difference, −1.00 (−1.00 to 0) | .03 |
| Cerebral infarction volume on day 14, median (IQR), mLb | 2.8 (0.7 to 16.9) | 3.7 (1.0 to 18.2) | Median difference, −0.23 (−0.71 to 0.11) | .18 |
| Symptomatic intracranial hemorrhage within the first 24 h | 8 (1.3) | 7 (1.1) | OR, 1.17 (0.42 to 3.24) | .77 |
| Recurrent symptomatic stroke within 90 d | 56 (9.2) | 54 (8.9) | HR, 1.04 (0.71 to 1.52) | .84 |
| Recurrent symptomatic ischemic stroke within 90 d | 34 (5.6) | 23 (3.8) | HR, 1.53 (0.90 to 2.61) | .12 |
| Combined vascular events within 90 d | 67 (11.0) | 68 (11.2) | HR, 0.99 (0.71 to 1.39) | .97 |
| Favorable mRS score on day 14 | 213 (35.1) | 194 (31.9) | OR, 1.17 (0.92 to 1.49) | .20 |
| Changes of NIHSS score from baseline to day 14, median (IQR) | −5 (−7 to-2) | −4 (−8 to −2) | Median difference, 0 (−1.00 to 0) | .53 |
| mRS score of 0-2 on day 90 | 461 (76.0) | 424 (69.6) | OR, 1.39 (1.08 to 1.80) | .01 |
| Primary safety outcome | ||||
| SAE within 90 d | 61 (10.0) | 73 (12.0) | HR, 0.85 (0.60 to 1.20) | .35 |
| Secondary safety outcome | ||||
| Symptomatic intracranial hemorrhage within 90 d | 24 (4.0) | 31 (5.1) | HR, 0.76 (0.44 to 1.31) | .32 |
| Death within 90 d | 40 (6.6) | 42 (6.9) | HR, 0.98 (0.63 to 1.51) | .92 |
| AE within 90 d | 140 (23.1) | 149 (24.5) | HR, 0.95 (0.75 to 1.20) | .65 |
| SAE within 14 d | 49 (8.1) | 46 (7.6) | HR, 1.08 (0.72 to 1.61) | .72 |
| Death within 14 d | 25 (4.1) | 18 (3.0) | HR, 1.37 (0.75 to 2.51) | .31 |
| AE within 14 d | 117 (19.3) | 131 (21.5) | HR, 0.90 (0.70 to 1.16) | .41 |
Abbreviations: AE, adverse event; HR, hazard ratio; mRS, modified Rankin Scale; NIHSS, National Institute of Health stroke scale; OR, odds ratio; SAE, serious adverse event.
Favorable functional outcome was defined as an mRS score of 0 in patients with a baseline NIHSS score of 4 to 7; an mRS score of 0 to 1 in patients with a baseline NIHSS score of 8 to 14; and an mRS score of 0 to 2 in patients with a baseline NIHSS score of 15 to 25.
The number of patients with missing data was similar in the 2 treatment groups; missing data on cerebral infarction volume on day 14 occurred in 119 patients in the butylphthalide group and 136 patients in the placebo group.
Figure 2. Distribution of 90-Day Modified Rankin Scale (mRS) Score by Treatment Group and Baseline Stroke Severity.
The mRS is a global stroke disability scale with scores ranging from 0 (no symptoms or completely recovered) to 6 (death). The diagonal line between the 2 study groups indicates the dichotomization of a favorable functional outcome in each severity stratum. Favorable functional outcome was defined as an mRS score of 0 in patients with a baseline National Institutes of Health Stroke Scale (NIHSS) score of 4 to 7; an mRS score of 0 to 1 in patients with a baseline NIHSS score of 8 to 14; and an mRS score of 0 to 2 in patients with a baseline NIHSS score of 15 to 25.
Figure 3. Odds Ratio for the Primary Outcome in Prespecified Subgroups.
EVT indicates endovascular treatment; LACI, lacunar infarcts; NIHSS, National Institute of Health Stroke Scale; OCSP, Oxfordshire Community Stroke Project; PACI, partial anterior circulation infarcts; POCI, posterior circulation infarcts; rt-PA, recombinant tissue plasminogen activator; TACI, total anterior circulation infarcts.
Safety Outcomes
Serious adverse events within 90 days occurred in 61 patients (10.0%) in the butylphthalide group, and 73 patients (12.0%) in the placebo group (HR, 0.85; 95% CI, 0.60-1.20) (Table 2). Symptomatic intracranial hemorrhage within 90 days occurred in 24 patients (4.0%) in the butylphthalide group and in 31 patients (5.1%) in the placebo group. The incidence of death was 6.6% (40 of 607) in the butylphthalide group compared with 6.9% (42 of 609) in the placebo group. The percentage of adverse events was 23.1% (140 of 607 patients) in the butylphthalide group and 24.5% (149 of 609 patients) in the placebo group. Other safety outcomes are presented in Table 2 and in eTable 7 in Supplement 2.
Discussion
In this clinical trial, NBP was associated with a higher proportion of patients achieving a favorable functional outcome at 90 days compared with placebo in patients with acute ischemic stroke receiving reperfusion therapy of intravenous thrombolysis and/or endovascular treatment. Additionally, the incidence of adverse events did not differ between the NBP and placebo groups.
Numerous clinical trials targeting neuroprotection drugs have been conducted and failed to demonstrate a significant benefit of neuroprotective drugs for patients with stroke, such as the NXY-059,25,26 albumin,27 uric acid,28 magnesium sulfate,29 and natalizumab.30 However, several effective neuroprotective drugs were reported in recent clinical trials. The Treatment of Acute Ischemic Stroke with Edaravone Dexborneol (TASTE) trial,9 for instance, found that 90-day good functional outcomes favored the edaravone dexborneol group vs edaravone group in patients with acute ischemic stroke. Similarly, the Efficacy and Safety of Nerinetide of the Treatment of Acute Ischemic Stroke (ESCAPE-NA1) trial10 observed a possible treatment effect of nerinetide in the post hoc subgroup of patients who were not treated with alteplase.
With respect to our trial, we found that NBP, as another neuroprotective drug, was associated with a higher proportion of a favorable functional outcome at 90 days compared with placebo in patients with acute ischemic stroke receiving reperfusion therapy of intravenous thrombolysis and/or endovascular treatment. In the present era of stroke treatment, highly successful reperfusion therapies, including thrombolysis and thrombectomy, give new opportunities to restudy and repurpose previous neuroprotective agents.20 Combined with reperfusion therapies, NBP may help to target the tissue and slow down the conversion of ischemic penumbra into ischemic core before reperfusion31 and ameliorate deleterious consequences after reperfusion (ie, reperfusion injury and blood-brain barrier disruption). NBP in our trial was used within 6 hours after symptom onset; this early intervention can harness a more favorable time window to entry into play of plastic capacities of brain, which may have a potential protective role from neurological impairments.32
Plausible reasons underlying the inconsistent findings between our studies and previously failed studies may be that the ischemic cascade progress of brain ischemia involves many pathways simultaneously and might interact with each other. Hence, the combination treatments targeting several pathways of ischemic injury may have advantages over single-pathway strategies. NBP is reported to be associated with multifunctional cytoprotective pathways by addressing different pathophysiological functions in the ischemia. Evidence from in-vivo or ex-vivo studies have found that NBP could inhibit the inflammatory response with inhibited expression of pro-inflammatory cytokines,33 decrease ischemia-induced oxidative impairment and neuron apoptosis after focal cerebral ischemia,34 improve microcirculation by upregulating the expression of vascular endothelial growth factor, promote the formation of new blood vessels, and increase the number of new capillaries in the ischemic area.35 Additionally, NBP could facilitate the collateral circulation, increase the number of microvessels, rebuild the microcirculation in the ischemic area, maintain the structure and form of micro-vessels, and enhance perfusion to the ischemic area.36 In animal models, NBP could also diminish the cerebral infarct zone and improve brain edema in the rates of middle cerebral artery occlusion.34
For safety outcomes, a meta-analysis of clinical trials found that the most frequent events were elevated transaminase, rash, and gastrointestinal discomfort.37 Several previous clinical trials reported that the risk of liver-related adverse events was higher in the NBP arm than in the control arm.17,18,19 In contrast, several other adverse effects, which affected mainly the digestive system, occurred with similar incidence in the NBP and control arms.38 In our study, the incidence of adverse events in the NBP group and the placebo group were comparable, including hepatobiliary disorders and symptomatic intracranial hemorrhage within 90 days. In accordance with the previous clinical study, NBP was safe both used as monotherapy and combined therapy with standard treatments.38
Limitations
This study has several limitations. First, the percentage of patients receiving endovascular treatment is small, which is mainly attributed to the high cost of endovascular treatment as well as the strict 6-hour time window from onset to drug administration. The low rate of endovascular treatment may limit generalizability of the findings in other populations with higher rates. Second, the BAST trial was designed in a specific ischemic stroke population in which patients were selected for intravenous thrombolysis and/or endovascular treatment, and the results might not be generalized to all patients with ischemic stroke. Third, our study enrolled a substantial number of patients with a relatively low NIHSS score (mild stroke), which resulted in a relatively lower rate of mortality and symptomatic intracranial hemorrhage in our study. Fourth, since we used blocks of 4 in the method of randomization, the small block size might increase the risk of predictable allocation process. Fifth, this trial was conducted in China, and the findings may not be generalizable to other populations. The efficacy of NBP should be further investigated in other populations.
Conclusions
In summary, our trial involving patients with acute ischemic stroke receiving reperfusion therapy of intravenous thrombolysis and/or endovascular treatment showed that use of NBP was efficacious in improving functional outcome at 90 days without increased adverse events.
Trial Protocol
eAppendix 1. Clinical Sites and Number of Patients Enrollment
eAppendix 2. Summary of Deliberations by the BAST DSMB
eTable 1. Inclusion and Exclusion Criteria
eTable 2. NIHSS Score Change From Baseline to Day 21
eTable 3. Concomitant Treatment Within 90 Days
eTable 4. Concomitant Prohibited Medication Used Within 90 Days
eTable 5. Primary and Secondary Outcomes in Per-Protocol Population
eTable 6. Exploratory Analysis
eTable 7. Safety Outcomes Recorded During 90 Days of Follow-up
Group Information. BAST Investigators
Data Sharing Statement
References
- 1.GBD 2016 Neurology Collaborators . Global, regional, and national burden of neurological disorders, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2019;18(5):459-480. doi: 10.1016/S1474-4422(18)30499-X [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Hacke W, Donnan G, Fieschi C, et al. ; ATLANTIS Trials Investigators; ECASS Trials Investigators; NINDS rt-PA Study Group Investigators . Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet. 2004;363(9411):768-774. doi: 10.1016/S0140-6736(04)15692-4 [DOI] [PubMed] [Google Scholar]
- 3.Goyal M, Menon BK, van Zwam WH, et al. ; HERMES collaborators . Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Lancet. 2016;387(10029):1723-1731. doi: 10.1016/S0140-6736(16)00163-X [DOI] [PubMed] [Google Scholar]
- 4.Powers WJ, Rabinstein AA, Ackerson T, et al. ; American Heart Association Stroke Council . 2018 Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2018;49(3):e46-e110. doi: 10.1161/STR.0000000000000158 [DOI] [PubMed] [Google Scholar]
- 5.Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2019;50(12):e344-e418. doi: 10.1161/STR.0000000000000211 [DOI] [PubMed] [Google Scholar]
- 6.Jovin TG, Nogueira RG, Lansberg MG, et al. Thrombectomy for anterior circulation stroke beyond 6 h from time last known well (AURORA): a systematic review and individual patient data meta-analysis. Lancet. 2022;399(10321):249-258. doi: 10.1016/S0140-6736(21)01341-6 [DOI] [PubMed] [Google Scholar]
- 7.National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group . Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333(24):1581-1587. doi: 10.1056/NEJM199512143332401 [DOI] [PubMed] [Google Scholar]
- 8.Hacke W, Kaste M, Bluhmki E, et al. ; ECASS Investigators . Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359(13):1317-1329. doi: 10.1056/NEJMoa0804656 [DOI] [PubMed] [Google Scholar]
- 9.Xu J, Wang A, Meng X, et al. ; TASTE Trial Investigators . Edaravone dexborneol versus edaravone alone for the treatment of acute ischemic stroke: a phase III, randomized, double-blind, comparative trial. Stroke. 2021;52(3):772-780. doi: 10.1161/STROKEAHA.120.031197 [DOI] [PubMed] [Google Scholar]
- 10.Hill MD, Goyal M, Menon BK, et al. ; ESCAPE-NA1 Investigators . Efficacy and safety of nerinetide for the treatment of acute ischaemic stroke (ESCAPE-NA1): a multicentre, double-blind, randomised controlled trial. Lancet. 2020;395(10227):878-887. doi: 10.1016/S0140-6736(20)30258-0 [DOI] [PubMed] [Google Scholar]
- 11.Chang Q, Wang XL. Effects of chiral 3-n-butylphthalide on apoptosis induced by transient focal cerebral ischemia in rats. Acta Pharmacol Sin. 2003;24(8):796-804. [PubMed] [Google Scholar]
- 12.Zhang Y, Wang L, Li J, Wang XL. 2-(1-Hydroxypentyl)-benzoate increases cerebral blood flow and reduces infarct volume in rats model of transient focal cerebral ischemia. J Pharmacol Exp Ther. 2006;317(3):973-979. doi: 10.1124/jpet.105.098517 [DOI] [PubMed] [Google Scholar]
- 13.Bi M, Zhang M, Guo D, et al. N-butylphthalide alleviates blood-brain barrier impairment in rats exposed to carbon monoxide. Front Pharmacol. 2016;7:394. doi: 10.3389/fphar.2016.00394 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Zhang C, Cui L, He W, Zhang X, Liu H. DL-3-n-butylphthalide promotes neurite outgrowth of primary cortical neurons by Sonic Hedgehog signaling via upregulating Gap43. Exp Cell Res. 2021;398(2):112420. doi: 10.1016/j.yexcr.2020.112420 [DOI] [PubMed] [Google Scholar]
- 15.Liu X, Liu R, Fu D, et al. DL-3-n-butylphthalide inhibits neuroinflammation by stimulating foxp3 and Ki-67 in an ischemic stroke model. Aging (Albany NY). 2021;13(3):3763-3778. doi: 10.18632/aging.202338 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Xue LX, Zhang T, Zhao YW, Geng Z, Chen JJ, Chen H. Efficacy and safety comparison of DL-3-n-butylphthalide and cerebrolysin: effects on neurological and behavioral outcomes in acute ischemic stroke. Exp Ther Med. 2016;11(5):2015-2020. doi: 10.3892/etm.2016.3139 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Cui LY, Zhu YC, Gao S, et al. Ninety-day administration of DL-3-n-butylphthalide for acute ischemic stroke: a randomized, double-blind trial. Chin Med J (Engl). 2013;126(18):3405-3410. [PubMed] [Google Scholar]
- 18.Zhang C, Zhao S, Zang Y, et al. The efficacy and safety of Dl-3n-butylphthalide on progressive cerebral infarction: a randomized controlled STROBE study. Medicine (Baltimore). 2017;96(30):e7257. doi: 10.1097/MD.0000000000007257 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Zhao H, Yun W, Zhang Q, et al. Mobilization of circulating endothelial progenitor cells by DL-3-n-butylphthalide in acute ischemic stroke patients. J Stroke Cerebrovasc Dis. 2016;25(4):752-760. doi: 10.1016/j.jstrokecerebrovasdis.2015.11.018 [DOI] [PubMed] [Google Scholar]
- 20.Savitz SI, Baron JC, Fisher MSX; STAIR X Consortium . Stroke Treatment Academic Industry Roundtable X: brain cytoprotection therapies in the reperfusion era. Stroke. 2019;50(4):1026-1031. doi: 10.1161/STROKEAHA.118.023927 [DOI] [PubMed] [Google Scholar]
- 21.Zhang X, Wang A, Zhang JY, et al. ; BAST study Investigators . Efficacy and safety of butylphthalide for patients who had acute ischaemic stroke receiving intravenous thrombolysis or endovascular treatment (BAST trial): study protocol for a randomised placebo-controlled trial. BMJ Open. 2021;11(5):e045559. doi: 10.1136/bmjopen-2020-045559 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Johnston KC, Bruno A, Pauls Q, et al. ; Neurological Emergencies Treatment Trials Network and the SHINE Trial Investigators . Intensive vs standard treatment of hyperglycemia and functional outcome in patients with acute ischemic stroke: the SHINE randomized clinical trial. JAMA. 2019;322(4):326-335. doi: 10.1001/jama.2019.9346 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Adams HP Jr, Leclerc JR, Bluhmki E, Clarke W, Hansen MD, Hacke W. Measuring outcomes as a function of baseline severity of ischemic stroke. Cerebrovasc Dis. 2004;18(2):124-129. doi: 10.1159/000079260 [DOI] [PubMed] [Google Scholar]
- 24.von Kummer R, Broderick JP, Campbell BC, et al. The Heidelberg bleeding classification: classification of bleeding events after ischemic stroke and reperfusion therapy. Stroke. 2015;46(10):2981-2986. doi: 10.1161/STROKEAHA.115.010049 [DOI] [PubMed] [Google Scholar]
- 25.Shuaib A, Lees KR, Lyden P, et al. ; SAINT II Trial Investigators . NXY-059 for the treatment of acute ischemic stroke. N Engl J Med. 2007;357(6):562-571. doi: 10.1056/NEJMoa070240 [DOI] [PubMed] [Google Scholar]
- 26.Lees KR, Zivin JA, Ashwood T, et al. ; Stroke-Acute Ischemic NXY Treatment (SAINT I) Trial Investigators . NXY-059 for acute ischemic stroke. N Engl J Med. 2006;354(6):588-600. doi: 10.1056/NEJMoa052980 [DOI] [PubMed] [Google Scholar]
- 27.Martin RH, Yeatts SD, Hill MD, Moy CS, Ginsberg MD, Palesch YY; ALIAS Parts 1 and 2 and NETT Investigators . ALIAS (Albumin in Acute Ischemic Stroke) trials: analysis of the combined data from parts 1 and 2. Stroke. 2016;47(9):2355-2359. doi: 10.1161/STROKEAHA.116.012825 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Chamorro A, Amaro S, Castellanos M, et al. ; URICO-ICTUS Investigators . Safety and efficacy of uric acid in patients with acute stroke (URICO-ICTUS): a randomised, double-blind phase 2b/3 trial. Lancet Neurol. 2014;13(5):453-460. doi: 10.1016/S1474-4422(14)70054-7 [DOI] [PubMed] [Google Scholar]
- 29.Saver JL, Starkman S, Eckstein M, et al. ; FAST-MAG Investigators and Coordinators . Prehospital use of magnesium sulfate as neuroprotection in acute stroke. N Engl J Med. 2015;372(6):528-536. doi: 10.1056/NEJMoa1408827 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Elkins J, Veltkamp R, Montaner J, et al. Safety and efficacy of natalizumab in patients with acute ischaemic stroke (ACTION): a randomised, placebo-controlled, double-blind phase 2 trial. Lancet Neurol. 2017;16(3):217-226. doi: 10.1016/S1474-4422(16)30357-X [DOI] [PubMed] [Google Scholar]
- 31.Fisher M, Saver JL. Future directions of acute ischaemic stroke therapy. Lancet Neurol. 2015;14(7):758-767. doi: 10.1016/S1474-4422(15)00054-X [DOI] [PubMed] [Google Scholar]
- 32.Investigators ET; ENOS Trial Investigators . Efficacy of nitric oxide, with or without continuing antihypertensive treatment, for management of high blood pressure in acute stroke (ENOS): a partial-factorial randomised controlled trial. Lancet. 2015;385(9968):617-628. doi: 10.1016/S0140-6736(14)61121-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Yang M, Dang R, Xu P, et al. DL-3-n-butylphthalide improves lipopolysaccharide-induced depressive-like behavior in rats: involvement of Nrf2 and NF-κB pathways. Psychopharmacology (Berl). 2018;235(9):2573-2585. doi: 10.1007/s00213-018-4949-x [DOI] [PubMed] [Google Scholar]
- 34.Zheng B, Zhou Y, Zhang H, et al. DL-3-n-butylphthalide prevents the disruption of blood-spinal cord barrier via inhibiting endoplasmic reticulum stress following spinal cord injury. Int J Biol Sci. 2017;13(12):1520-1531. doi: 10.7150/ijbs.21107 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Chen XQ, Qiu K, Liu H, He Q, Bai JH, Lu W. Application and prospects of butylphthalide for the treatment of neurologic diseases. Chin Med J (Engl). 2019;132(12):1467-1477. doi: 10.1097/CM9.0000000000000289 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Tan Z, Zhao Y, Yang W, He S, Ding Y, Xu A. Efficacy and safety of adherence to DL-3-n-butylphthalide treatment in patients with non-disabling minor stroke and TIA—analysis from a nationwide, multicenter registry. Front Neurol. 2021;12:720664. doi: 10.3389/fneur.2021.720664 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Wang H, Ye K, Li D, Liu Y, Wang D. DL-3-n-butylphthalide for acute ischemic stroke: an updated systematic review and meta-analysis of randomized controlled trials. Front Pharmacol. 2022;13:963118. doi: 10.3389/fphar.2022.963118 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Xu ZQ, Zhou Y, Shao BZ, Zhang JJ, Liu C. A systematic review of neuroprotective efficacy and safety of DL-3-n-butylphthalide in ischemic stroke. Am J Chin Med. 2019;47(3):507-525. doi: 10.1142/S0192415X19500265 [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial Protocol
eAppendix 1. Clinical Sites and Number of Patients Enrollment
eAppendix 2. Summary of Deliberations by the BAST DSMB
eTable 1. Inclusion and Exclusion Criteria
eTable 2. NIHSS Score Change From Baseline to Day 21
eTable 3. Concomitant Treatment Within 90 Days
eTable 4. Concomitant Prohibited Medication Used Within 90 Days
eTable 5. Primary and Secondary Outcomes in Per-Protocol Population
eTable 6. Exploratory Analysis
eTable 7. Safety Outcomes Recorded During 90 Days of Follow-up
Group Information. BAST Investigators
Data Sharing Statement