Research

JAMA Neurology | Original Investigation

Efficacy and Safety of Butylphthalide in Patients

With Acute Ischemic Stroke
A Randomized Clinical Trial
Anxin Wang, PhD; Baixue Jia, MD; Xuelei Zhang, MD; Xiaochuan Huo, MD; Jianhuang Chen, BS; Liqiang Gui, MD;
Yefeng Cai, PhD; Zaiyu Guo, PhD; Yuqing Han, MS; Zhaolong Peng, BS; Ping Jing, MS; Yongjun Chen, PhD;
Yan Liu, MS; Yong Yang, MS; Fengyun Wang, BS; Zengqiang Sun, PhD; Tong Li, MS; Hongxia Sun, MS;
Haicheng Yuan, MS; Hongmin Shao, BS; Lianbo Gao, MS; Peipei Zhang, BS; Feng Wang, MD; Xiangyang Cao, MS;
Wanchao Shi, PhD; Changmao Li, BS; Jianwen Yang, MD; Hong Zhang, BS; Feng Wang, PhD; Jianzhong Deng, BS;
Yanjie Liu, MD; Weisheng Deng, BS; Cunfeng Song, PhD; Huisheng Chen, MD; Li He, PhD; Hongdong Zhao, MD;
Xianfeng Li, BS; Hong Yang, MS; Zhiming Zhou, PhD; Yilong Wang, MD, PhD; Zhongrong Miao, MD, PhD;
for the BAST Investigators

Visual Abstract
IMPORTANCE DL-3-n-butylphthalide (NBP) is a drug for treating acute ischemic stroke and Supplemental content
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 Author Affiliations: Author
affiliations are listed at the end of this
intravenous thrombolysis and/or endovascular treatment, NBP was associated with a higher
article.
proportion of patients achieving a favorable functional outcome at 90 days compared with
Group Information: A full list of the
placebo. BAST Investigators appears in
Supplement 3.
TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03539445
Corresponding Authors: Yilong
Wang, MD, PhD (yilong528@aliyun.
com), and Zhongrong Miao, MD, PhD
(zhongrongm@163.com),
Department of Neurology,
Beijing Tiantan Hospital, Capital
Medical University, No. 119, South 4th
JAMA Neurol. doi:10.1001/jamaneurol.2023.1871 Ring West Rd, Fengtai District,
Published online June 26, 2023. Beijing 100070, China.

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 Research Original Investigation
S
troke is one of the most common causes of mortality
worldwide and is a leading cause of disability.1 Reper-
fusion is a proven approach, and neuroprotection is
a promising additional approach to treat ischemic stroke. Al-
though reperfusion therapy has been recommended as a stan-
dard treatment strategy for ischemic stroke, 2-6 approxi-
mately half of patients failed to benefit from timely initiation
of acute reperfusion therapy.3,6-8 Therefore, neuroprotective
drugs and recovery strategies are urgently needed in clinical
practice. Cerebroprotection or brain cytoprotection is a po-
tential treatment to break the ceiling effect of reperfusion
therapy through salvage, recovery, or regeneration of struc-
ture 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 mecha-
nism of action of NBP is unknown, preclinical data from mul-
tiple models showed that NBP could act on multiple links of
cerebral ischemia pathology and play a protective role on ce-
rebral infarction through anti-inflammation, antioxidation,
anti-apoptosis, and microcirculation protection.11-16 Several
randomized clinical trials also reported the potential benefit
of NBP in patients with ischemic stroke; however, the find-
ings needed to be interpreted with caution due to the study
design and the methodology.17-19 It is worth noting that the
Stroke Treatment Academic Industry Roundtable X (STAIR X)
consortium consensus recommended that new cytoprotec-
tive 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 reper-
fusion.
The Butylphthalide for Acute Ischemic Stroke Patients
Receiving Intravenous Thrombolysis or Endovascular Treat-
ment (BAST) trial was to investigate whether treatment with
NBP adjunctive to reperfusion therapy of intravenous throm-
bolysis and/or endovascular treatment could improve the func-
tional outcome in patients with acute ischemic stroke com-
pared 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 intrave-
nous 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 Supple-
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Efficacy and Safety of Butylphthalide in Patients With Acute Ischemic Stroke
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.
ment 2. The BAST trial design is in compliance with the Dec-
laration of Helsinki and was approved by the ethics commit-
tee at Beijing Tiantan Hospital and at each participating site.
Written informed consent for participation in the trial was pro-
vided by the patients or their legal representative.
The steering committee was responsible for the design and
supervision of the trial, the development of and amend-
ments to the protocol, and the interpretation of the data as well
as for ensuring the integrity of the data, analysis, and presen-
tation 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, adju-
dicated the primary and secondary efficacy outcomes and
bleeding events. An independent data and safety monitoring
committee monitored the progress of the trial, with regular as-
sessment 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 Phar-
maceutical 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 is-
chemic 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 intra-
venous recombinant tissue plasminogen activator (rt-PA) or en-
dovascular 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 con-
firmed by preoperational computed tomography scan; were
diagnosed with intracranial hemorrhagic diseases (eg, intra-
cranial hemorrhage, subarachnoid hemorrhage); already used
NBP or any drugs containing NBP between onset and random-
ization; appeared with dysphagia before randomization; had
jamaneurology.com
 Efficacy and Safety of Butylphthalide in Patients With Acute Ischemic Stroke
a history of coagulation disorders, hemorrhagic diathesis, neu-
tropenia, 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 ran-
domly 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 as-
signed a random serial number based on their time of enroll-
ment 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 along-
side standard intravenous thrombolysis and/or endovascular
treatment. The dose of NBP was decided based on unpub-
lished data of the phase II trial (eTable 2 in Supplement 2). Pa-
tients 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 con-
tinue the injections for 10 to 14 days according to length of hos-
pitalization. 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 admin-
istration, which was checked by researchers. The steering
committee made recommendations for concomitant medica-
tions. All secondary preventive strategies, including antithrom-
bosis and management of risk factors, were followed accord-
ing 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 defi-
cit 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 se-
curity 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 pa-
tients 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 differ-
ence 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 hemor-
rhage within the first 24 hours as defined by the criteria of the
Heidelberg bleeding classification24; recurrent symptomatic
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Original Investigation Research
ischemic stroke and vascular events within 90 days; any vas-
cular complications due to vascular events (recurrent symp-
tomatic ischemic stroke, myocardial infarction, or vascular
death) within 90 days; and the proportion of patients with
a favorable functional outcome at 14 days. Additionally, fa-
vorable 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 sys-
tem or organ, a life-threatening condition, or death. The sec-
ondary outcomes included symptomatic intracranial hemor-
rhage 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 se-
rious 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 butylphtha-
lide group and 50% in the placebo group with a 2-side signifi-
cance level of .05 and an overall dropout rate of 10%. Two
formal interim analyses were conducted to determine over-
whelming efficacy or futility when 50% and 75% of partici-
pants had completed follow-up. The stopping rule for over-
whelming efficacy was defined with the use of O’Brien-
Fleming boundaries on the binary outcome of the 90-day
favorable functional outcome, with corresponding signifi-
cance 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 signifi-
cance 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 de-
scriptive statistics as appropriate. Missing data on the pri-
mary outcome were handled using the last observation car-
ried 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 ef-
fect, and odds ratios (ORs) and 95% CIs are reported. A simi-
lar approach was used for the secondary outcomes of symp-
tomatic 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 propor-
tional 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 esti-
mated by analysis of covariance.
(Reprinted) JAMA Neurology Published online June 26, 2023 E3
 Research Original Investigation Efficacy and Safety of Butylphthalide in Patients With Acute Ischemic Stroke

Figure 1. Flowchart of the Study

1236 Patients with ischemic stroke

assessed for eligibility

20 Excluded
18 Did not meet inclusion criteria or
met exclusion criteria
2 Declined to participate

1216 Randomized

607 Received butylphthalide and 609 Received placebo and were

were included in the intention- included in the intention-to-
to-treat population treat population

106 Excluded 100 Excluded

68 Had premature permanent 71 Had premature permanent
drug discontinuation drug discontinuation
26 Had adverse event or severe 27 Had adverse event or severe
adverse event adverse event
42 Had other reasons 44 Had other reasons
17 Needed prohibited 13 Were enrolled inappropriately
concomitant medications 8 Did not start within 6 h from
13 Were enrolled inappropriately symptom onset
7 Did not start within 6 h from 4 Did not receive rt-PA and
symptom onset endovascular treatment
5 Did not receive rt-PA and 1 Had baseline NIHSS score <4
endovascular treatment or >25
1 Had chronic hepatopathy or 9 Needed prohibited
liver or kidney dysfunction concomitant medications
8 Were lost to follow-up 7 Were lost to follow-up

501 Included in the 509 Included in the

per-protocol population per-protocol population

NIHSS indicates National Institute of Health Stroke Scale; rt-PA, recombinant tissue plasminogen activator.

Because the statistical analysis plan did not include a pro-
vision for correcting the widths of confidence intervals for mul-
tiple comparisons, secondary and other outcomes are pre-
sented 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).
According to Oxfordshire Community Stroke Project classifi-
cation, 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 pro-
hibited medications taken during the treatment period are
reported in eTables 3 and 4 in Supplement 2.

Primary and Secondary Outcomes

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 meet-
ing 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 butylph-
thalide 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).
The randomized groups had similar baseline characteris-
tics (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%).
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 dif-
ference 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 differ-
ences 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 analy-
sis were consistent with the primary intention-to-treat analy-
sis (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.

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 Efficacy and Safety of Butylphthalide in Patients With Acute Ischemic Stroke Original Investigation Research

Safety Outcomes Table 1. Baseline Characteristics

Serious adverse events within 90 days occurred in 61 pa-
tients (10.0%) in the butylphthalide group, and 73 patients No. (%)
Butylphthalide Placebo
(12.0%) in the placebo group (HR, 0.85; 95% CI, 0.60-1.20) Characteristic (n = 607) (n = 609)
(Table 2). Symptomatic intracranial hemorrhage within 90 days Age, median (IQR), y 66 (56-72) 66 (57-74)
occurred in 24 patients (4.0%) in the butylphthalide group and Gender
in 31 patients (5.1%) in the placebo group. The incidence of Men 412 (67.9) 415 (68.1)
death was 6.6% (40 of 607) in the butylphthalide group com- Women 195 (32.1) 194 (31.9)
pared with 6.9% (42 of 609) in the placebo group. The per- Body mass index, median (IQR)a 24.2 (22.0-26.4) 24.2 (21.9-26.7)
centage of adverse events was 23.1% (140 of 607 patients) in Blood pressure, median (IQR),
the butylphthalide group and 24.5% (149 of 609 patients) mm Hg
in the placebo group. Other safety outcomes are presented in Systolic 149.5 150.0
(138.0-163.5) (136.0-163.0)
Table 2 and in eTable 7 in Supplement 2. 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)
Discussion
Hypercholesterolemia 29.0 (4.8) 20 (3.3)
In this clinical trial, NBP was associated with a higher propor- Diabetes 131 (21.6) 113 (18.6)
tion of patients achieving a favorable functional outcome at Heart disease 144 (23.7) 147 (24.1)
90 days compared with placebo in patients with acute ische- mRS score prior to onset
mic stroke receiving reperfusion therapy of intravenous throm- 0 563 (92.8) 573 (94.1)
bolysis and/or endovascular treatment. Additionally, the in- 1 44 (7.2) 36 (5.9)
cidence of adverse events did not differ between the NBP and ASPECTS score, median (IQR) 9 (8-10) 9 (8-10)
placebo groups. NIHSS score, median (IQR) 8 (5-12) 8 (5-12)
Numerous clinical trials targeting neuroprotection drugs Stroke category
have been conducted and failed to demonstrate a significant ben- Mild (NIHSS score of 4-7) 262 (43.2) 283 (46.5)
efit of neuroprotective drugs for patients with stroke, such as Moderate (NIHSS score 246 (40.5) 226 (37.1)
the NXY-059,25,26 albumin,27 uric acid,28 magnesium sulfate,29 of 8-14)
Severe (NIHSS score 99 (16.3) 100 (16.4)
and natalizumab.30 However, several effective neuroprotective of 15-25)
drugs were reported in recent clinical trials. The Treatment of Revascularization treatment,
Acute Ischemic Stroke with Edaravone Dexborneol (TASTE) No./total No. (%)
trial,9 for instance, found that 90-day good functional outcomes Intravenous rt-PA treatment 417/601 (69.4) 420/604 (69.5)

favored the edaravone dexborneol group vs edaravone group Endovascular treatment or 184/601 (30.6) 184/604 (30.5)
bridging
in patients with acute ischemic stroke. Similarly, the Efficacy Successful reperfusionb,c 160 (87.0) 168 (91.3)
and Safety of Nerinetide of the Treatment of Acute Ischemic Clot locationc
Stroke (ESCAPE-NA1) trial10 observed a possible treatment ef- Internal carotid artery 41 (22.3) 47 (25.5)
fect of nerinetide in the post hoc subgroup of patients who were Middle cerebral artery 110 (59.8) 115 (62.5)
not treated with alteplase. Anterior cerebral artery 3 (1.6) 1 (0.5)
With respect to our trial, we found that NBP, as another Vertebral artery 7 (3.8) 4 (2.2)
neuroprotective drug, was associated with a higher propor- Posterior cerebral artery 4 (2.2) 0
tion of a favorable functional outcome at 90 days compared Basilar artery 19 (10.3) 17 (9.2)
with placebo in patients with acute ischemic stroke receiving Onset to drug administration, 254 (203-310) 261 (209-310)
reperfusion therapy of intravenous thrombolysis and/or en- median (IQR), min
dovascular treatment. In the present era of stroke treatment, OCSP subtype

highly successful reperfusion therapies, including thromboly- TACI 171 (28.2) 166 (27.3)

sis and thrombectomy, give new opportunities to restudy and PACI 321 (52.9) 329 (54.0)

repurpose previous neuroprotective agents.20 Combined with POCI 76 (12.5) 76 (12.5)

reperfusion therapies, NBP may help to target the tissue and
slow down the conversion of ischemic penumbra into ische-
mic core before reperfusion31 and ameliorate deleterious con-
sequences 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 har-
ness a more favorable time window to entry into play of plas-
tic 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
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.
a
Calculated as weight in kilograms divided by height in meters squared.
b
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.
c
Data were only available for 368 patients receiving endovascular treatment.

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 Research Original Investigation Efficacy and Safety of Butylphthalide in Patients With Acute Ischemic Stroke

Table 2. Efficacy and Safety Outcomesa

No. (%)
Butylphthalide Placebo P
Outcome (n = 607) (n = 609) Effect size (95% CI) value
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 −6 (−10 to −4) −5 (−9 to −3) Median difference, −1.00 .03
to day 90, median (IQR) (−1.00 to 0)
Cerebral infarction volume on day 14, 2.8 (0.7 to 16.9) 3.7 (1.0 to 18.2) Median difference, −0.23 .18
median (IQR), mLb (−0.71 to 0.11)
Symptomatic intracranial hemorrhage 8 (1.3) 7 (1.1) OR, 1.17 (0.42 to 3.24) .77
within the first 24 h
Recurrent symptomatic stroke 56 (9.2) 54 (8.9) HR, 1.04 (0.71 to 1.52) .84
within 90 d Abbreviations: AE, adverse event;
Recurrent symptomatic ischemic 34 (5.6) 23 (3.8) HR, 1.53 (0.90 to 2.61) .12 HR, hazard ratio; mRS, modified
stroke within 90 d Rankin Scale; NIHSS, National
Combined vascular events 67 (11.0) 68 (11.2) HR, 0.99 (0.71 to 1.39) .97 Institute of Health stroke scale;
within 90 d OR, odds ratio; SAE, serious adverse
Favorable mRS score on day 14 213 (35.1) 194 (31.9) OR, 1.17 (0.92 to 1.49) .20 event.
a
Changes of NIHSS score from baseline −5 (−7 to-2) −4 (−8 to −2) Median difference, 0 .53 Favorable functional outcome was
to day 14, median (IQR) (−1.00 to 0) defined as an mRS score of 0 in
mRS score of 0-2 on day 90 461 (76.0) 424 (69.6) OR, 1.39 (1.08 to 1.80) .01 patients with a baseline NIHSS score
Primary safety outcome of 4 to 7; an mRS score of 0 to 1 in
patients with a baseline NIHSS score
SAE within 90 d 61 (10.0) 73 (12.0) HR, 0.85 (0.60 to 1.20) .35
of 8 to 14; and an mRS score of 0 to
Secondary safety outcome 2 in patients with a baseline NIHSS
Symptomatic intracranial hemorrhage 24 (4.0) 31 (5.1) HR, 0.76 (0.44 to 1.31) .32 score of 15 to 25.
within 90 d b
The number of patients with
Death within 90 d 40 (6.6) 42 (6.9) HR, 0.98 (0.63 to 1.51) .92
missing data was similar in the
AE within 90 d 140 (23.1) 149 (24.5) HR, 0.95 (0.75 to 1.20) .65 2 treatment groups; missing data on
SAE within 14 d 49 (8.1) 46 (7.6) HR, 1.08 (0.72 to 1.61) .72 cerebral infarction volume on day 14
Death within 14 d 25 (4.1) 18 (3.0) HR, 1.37 (0.75 to 2.51) .31 occurred in 119 patients in the
butylphthalide group and 136
AE within 14 d 117 (19.3) 131 (21.5) HR, 0.90 (0.70 to 1.16) .41
patients in the placebo group.

Figure 2. Distribution of 90-Day Modified Rankin Scale (mRS) Score by Treatment Group
and Baseline Stroke Severity

mRS score at 90 d
0 1 2 3 4 5 6
Overall 2.0
Butylphthalide (n = 607) 36.1 29.7 10.2 7.6 7.9 6.6

Placebo (n = 609) 31.0 27.1 11.5 10.3 9.7 6.9 The mRS is a global stroke disability
3.5 scale with scores ranging from 0 (no
Mild (NIHSS score of 4-7) 3.0
0.4 symptoms or completely recovered)
Butylphthalide (n = 262) 52.7 27.1 8.8 6.9 1.2
2.1 to 6 (death). The diagonal line
Placebo (n = 283) 38.9 33.6 11.3 7.4 5.0 1.8 between the 2 study groups indicates
the dichotomization of a favorable
Moderate (NIHSS score of 8-14) 2.0 functional outcome in each severity
Butylphthalide (n = 246) 27.2 36.2 9.4 9.4 8.5 7.3 stratum. Favorable functional
Placebo (n = 226) 29.2 23.0 12.8 12.0 12.4 4.0 6.6 outcome was defined as an mRS
score of 0 in patients with a baseline
Severe (NIHSS score of 15-25) National Institutes of Health Stroke
Butylphthalide (n = 99) 14.1 20.2 16.2 5.1 19.2 6.1 19.2 Scale (NIHSS) score of 4 to 7; an mRS
score of 0 to 1 in patients with a
Placebo (n = 100) 13.0 18.0 9.0 15.0 17.0 6.0 22.0
baseline NIHSS score of 8 to 14; and
0 20 40 60 80 100 an mRS score of 0 to 2 in patients
Patients, % with a baseline NIHSS score of 15
to 25.

the ischemic cascade progress of brain ischemia involves many
pathways simultaneously and might interact with each other.
Hence, the combination treatments targeting several path-
ways of ischemic injury may have advantages over single-
pathway strategies. NBP is reported to be associated with mul-
tifunctional 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 oxida-
tive 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

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 Efficacy and Safety of Butylphthalide in Patients With Acute Ischemic Stroke Original Investigation Research

Figure 3. Odds Ratio for the Primary Outcome in Prespecified Subgroups

Placebo Butylphthalide
Patients, Events, No. (%) Odds ratio better better
Characteristic No. Butylphthalide Placebo (95% CI)
Overall 1216 344 (56.7) 268 (44.0) 1.70 (1.35-2.14)
Age, y
<60 400 128 (63.1) 107 (54.3) 1.40 (0.92-2.13)
≥60 816 216 (53.8) 161 (39.1) 1.80 (1.35-2.41)
Sex
Male 827 244 (59.2) 175 (42.2) 2.03 (1.53-2.70)
Female 389 100 (51.3) 93 (47.9) 1.15 (0.75-1.76)
NIHSS score at baseline
Mild (NIHSS score of 4-7) 545 138 (52.7) 110 (38.9) 1.83 (1.27-2.65)
Moderate (NIHSS score of 8-14) 472 156 (63.4) 118 (52.2) 1.61 (1.09-2.38)
Severe (NIHSS score of 15-25) 199 50 (50.5) 40 (40.0) 1.52 (0.82-2.82)
Hypertension
No 520 156 (60.9) 125 (47.4) 1.71 (1.19-2.45)
Yes 696 188 (53.6) 143 (41.5) 1.60 (1.17-2.18)
Diabetes
No 972 285 (59.9) 229 (46.2) 1.75 (1.35-2.27)
Yes 244 59 (45.0) 39 (34.5) 1.49 (0.86-2.58)
OCSP
TACI 337 95 (55.6) 64 (38.6) 2.08 (1.28-3.36)
PACI 650 188 (58.6) 151 (45.9) 1.64 (1.20-2.26)
POCI 152 44 (57.9) 39 (51.3) 1.46 (0.71-2.99)
LACI 77 17 (43.6) 14 (36.8) 2.31 (0.80-6.69)
Treatment methods
Intravenous rt-PA 837 235 (56.4) 177 (42.1) 1.76 (1.32-2.33)
EVT and bridging 368 108 (58.7) 90 (48.9) 1.48 (0.96-2.27)

0 1 2 3 4 5 6
Odds ratio (95% CI)

EVT indicates endovascular treatment; LACI, lacunar infarcts; NIHSS, National rt-PA, recombinant tissue plasminogen activator; TACI, total anterior circulation
Institute of Health Stroke Scale; OCSP, Oxfordshire Community Stroke Project; infarcts.
PACI, partial anterior circulation infarcts; POCI, posterior circulation infarcts;

of new capillaries in the ischemic area.35 Additionally, NBP could
facilitate the collateral circulation, increase the number of mi-
crovessels, rebuild the microcirculation in the ischemic area,
maintain the structure and form of micro-vessels, and en-
hance 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 clini-
cal trials reported that the risk of liver-related adverse events
was higher in the NBP arm than in the control arm.17-19 In con-
trast, 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 compa-
rable, including hepatobiliary disorders and symptomatic in-
tracranial hemorrhage within 90 days. In accordance with the
previous clinical study, NBP was safe both used as mono-
therapy and combined therapy with standard treatments.38
Limitations
This study has several limitations. First, the percentage of pa-
tients 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 ische-
mic 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 sympto-
matic 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 pro-
cess. Fifth, this trial was conducted in China, and the find-
ings may not be generalizable to other populations. The effi-
cacy 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 throm-
bolysis and/or endovascular treatment showed that use of NBP
was efficacious in improving functional outcome at 90 days
without increased adverse events.

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 Research Original Investigation
ARTICLE INFORMATION
Accepted for Publication: April 7, 2023.
Published Online: June 26, 2023.
doi:10.1001/jamaneurol.2023.1871
Author Affiliations: Department of Neurology,
Beijing Tiantan Hospital, Capital Medical University,
Beijing, China (A. Wang, Jia, X. Zhang, Huo,
Y. Wang, Miao); China National Clinical Research
Center for Neurological Diseases, Beijing Tiantan
Hospital, Capital Medical University, Beijing, China
(A. Wang, Jia, X. Zhang, Huo, Y. Wang, Miao);
Center of Stroke, Beijing Institute for Brain
Disorders, Capital Medical University, Beijing, China
(X. Zhang); Department of Neurology, Liuyang Jili
Hospital, Hunan, China (J. Chen); Department of
Interventional Neuroradiology, Langfang
Changzheng Hospital, Hebei, China (Gui);
Department of Neurology, Traditional Chinese
Medicine Hospital of Guangdong Province,
Guangdong, China (Cai); Department of
Neurosurgery, Tianjin TEDA Hospital, Tianjin, China
(Guo); Department of Neurology, Tianjin Xiqing
Hospital, Tianjin, China (Han); Department of
Neurosurgery, Nanyang Nanshi Hospital, Henan,
China (Peng); Department of Neurology, Central
Hospital of Wuhan, Hubei, China (Jing);
Department of Neurology, University of South
China Affiliated Nanhua Hospital, Huna, China
(Y. Chen); Department of Neurology, Jingjiang
People's Hospital, Jiangsu, China (Yan Liu);
Department of Neurology, Jilin Qianwei Hospital,
Jilin, China (Y. Yang); Department of Neurology,
Liaocheng Brain Hospital, Shandong, China
(Fengyun Wang); Department of Neurology, Zibo
Municipal Hospital, Shandong, China (Z. Sun);
Department of Neurology, The Second People's
Hospital of Nanning, Guangxi, China (T. Li);
Department of Neurology, Jilin Province People's
Hospital, Jilin, China (H. Sun); Department of
Neurology, Qingdao Central Hospital, Shandong,
China (Yuan); Department of Neurology, Tangshan
Fengrun District People's Hospital, Tangshan, China
(Shao); Department of Neurology, The Fourth
Affiliated Hospital of China Medical University,
Liaoning, China (Gao); Department of Neurology,
People's Hospital of Nanpi, Hebei, China (P. Zhang);
Department of Neurology, The Affiliated Wuxi
People’s Hospital of Nanjing Medical University,
Jiangsu, China (Feng Wang); Department of
Neurology, The Affiliated Huai’an Hospital of
Xuzhou Medical University and The Second
People’s Hospital of Huai’an, Jiangsu, China (Cao);
Department of Neurosurgery, Peking University
BinHai Hospital, Tianjin, China (Shi); Department of
Neurology, Loudi Central Hospital, Hunan, China
(C. Li); Department of Interventional
Neuroradiology, The People's Hospital of Hunan
Province, Hunan, China (J. Yang); Department of
Neurology, General Hospital of Fushun Mining
Bureau of Liaoning Health Industry Group,
Liaoning, China (H. Zhang); Department of
Neurology, Shanghai Seventh People's Hospital,
Shanghai, China (Feng Wang); Department of
Neurology, Anyang District Hospital, Henan, China
(J. Deng); Department of Neurology, Shenzhen
Hospital of Southern Medical University, Shenzhen,
China (Yanjie Liu); Department of Neurology,
Meizhou People's Hospital, Guangdong, China
(W. Deng); Department of Interventional
Neuroradiology, Liaocheng Third People's Hospital,
Shandong, China (Song); Department of Neurology,
E8 JAMA Neurology Published online June 26, 2023 (Reprinted)
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Efficacy and Safety of Butylphthalide in Patients With Acute Ischemic Stroke
General Hospital of Northern Theatre Command,
Liaoning, China (H. Chen); Department of
Neurology, West China Hospital of Sichuan
University, Sichuan, China (He); Department of
Neurology, Nanjing First Hospital, Nanjing Medical
University, Jiangsu, China (Zhao); Department of
Neurology, The First People’s Hospital of Nanning
City, Guangxi, China (X. Li); Department of
Neurology, The Fourth Affiliated Hospital of
Guangxi Medical University, Guangxi, China
(H. Yang); Department of Neurology, Yijishan
Hospital of Wannan Medical College, Anhui,
China (Zhou).
Author Contributions: Drs Y. Wang and Miao had
full access to all of the data in the study and take
responsibility for the integrity of the data and the
accuracy of the data analysis. Drs A. Wang, Jia,
and X. Zhang contributed equally to this work.
Study concept and design: Jia, X. Zhang, Y. Wang,
Miao.
Acquisition, analysis, or interpretation of data:
A. Wang, Jia, X. Zhang, Huo, J. Chen, Gui, Cai, Guo,
Han, Peng, Jing, Y. Chen, Yan Liu, Y. Yang, Feng-Yun
Wang, T. Li, H. Sun, Yuan, Shao, Gao, P. Zhang, Feng
Wang, Cao, Shi, C. Li, J. Yang, H. Zhang, Feng Wang,
J. Deng, Yajie Liu, W. Deng, Song, H. Chen, He,
Zhao, X. Li, H. Yang, Zhou, Y. Wang, Miao.
Drafting of the manuscript: A. Wang, Jia, X. Zhang,
H. Chen, Miao.
Critical revision of the manuscript for important
intellectual content: A. Wang, Jia, Huo, J. Chen, Gui,
Cai, Guo, Han, Peng, Jing, Y. Chen, Yan Liu, Y. Yang,
Feng-Yun Wang, T. Li, H. Sun, Yuan, Shao, Gao,
P. Zhang, Feng Wang, Cao, Shi, C. Li, J. Yang, H.
Zhang, Feng Wang, J. Deng, Yajie Liu, W. Deng,
Song, He, Zhao, X. Li, H. Yang, Zhou, Y. Wang, Miao.
Statistical analysis: A. Wang.
Obtained funding: Y. Wang, Miao.
Administrative, technical, or material support:
A. Wang, Jia, X. Zhang, Huo, J. Chen, Gui, Cai, Guo,
Han, Peng, Jing, Y. Chen, Yan Liu, Y. Yang, Feng-Yun
Wang, T. Li, H. Sun, Yuan, Shao, Gao, P. Zhang, Feng
Wang, Cao, Shi, C. Li, J. Yang, H. Zhang, Feng Wang,
J. Deng, Yajie Liu, W. Deng, Song, He, Zhao, X. Li,
H. Yang, Zhou, Y. Wang, Miao.
Study supervision: X. Zhang, Y. Wang, Miao.
Conflict of Interest Disclosures: None disclosed.
Funding/Support: The study was supported by
grants from the National Key Technology Research
and Development Program of the Ministry of
Science and Technology of the People’s Republic
of China (grant 2016YFC1301501) and Shijiazhuang
Pharmaceutical Group dl-3-butylphthalide
Pharmaceutical.
Role of the Funder/Sponsor: The funders had no
role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review,
or approval of the manuscript; and decision to
submit the manuscript for publication.
Group Information: A full list of the BAST
Investigators appears in Supplement 3.
Data Sharing Statement: See Supplement 4.
Additional Contributions: We thank all study
participants, their relatives, the members
of the survey teams at the 59 centers of the
BAST study.
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