Butylphthalide, as a well-known neuroprotective medication, is a family of compounds initially isolated from the seeds of Apium graveolens Linn, of which active ingredient is dl-3-N-butylphthalide (dl-NBP). With the significant effects of reducing the cerebral ischemic damage and eventually improving patients' clinical outcomes, by the potential mechanisms of promoting microcirculation, as well as releasing oxidative stress, mitochondrial dysfunction and poststroke inflammation, dl-NBP has been widely applied in acute ischemic stroke as an anti-ischemic drug in China since 2002. While with the evolution of using iv. recombinant tissue plasminogen activator（rtPA ）and mechanical thrombectomy in acute ischemic stroke（AIS）patients, it is still undefined whether combination therapy with dl-NBP could enhance the curative effect. The primary purpose of this trial is to evaluate the recovery of neurological deficits in AIS patients who receive iv-rtPA and/or mechanical thrombectomy with the a 3-month regimen of Butylphthalide and Sodium Chloride Injection 100ml twice/day in the initial 14 days and Butylphthalide Soft Capsules 0.2g triple/day for the rest 15th to 90th day therapy versus a 3-month regimen of Butylphthalide Placebo Injection 100ml twice/day in the initial 14 days and followed by Butylphthalide Placebo Soft Capsules 0.2g triple/day for the rest 15th to 90th day therapy.
This trial is a prospective, randomized, double-blinded, placebo parallel controlled, multiple-center trial. A total of approximately 1200 patients (Age≥18years) within 6 hours of symptom onset of acute ischemic stroke, who shows NIHSS from 4-25 points and intend to be treated with iv-rtPA and/or mechanical thrombectomy will be enrolled. Patients fulfilling all of the inclusion criteria and none of the exclusion criteria will be randomized 1:1 into two groups after offering informed content, meanwhile the first injection will be within 6 hours from stroke onset : 1) one group will receive Butylphthalide and Sodium Chloride Injection 100ml twice/day in the initial 14 days, then take Butylphthalide Soft Capsules 0.2g triple/day for the rest 15th to 90th day therapy; 2) the other group will receive Butylphthalide Placebo Injection 100ml twice/day in the initial 14 days and then take Butylphthalide Placebo Soft Capsules 0.2g triple/day for the rest 15th to 90th day therapy. The primary objective is to explore whether the dl-NBP can improve the proportion of patients with a favorable outcome after receiving iv-rtPA and/or mechanical thrombectomy. The study consists of four visits including the day of randomization, 2 days after the first injection, 14 days when the injection therapy is done, and 30, 60 and 90 days when the oral therapy is finished. Demographic information, symptoms and signs, laboratory test, neuro-imaging assessment neurological function rating scale will be recorded during the program. The favorable outcome based on the 90-day modified Rankin Scale score was adjusted for baseline stroke severity, which was defined as a modified Rankin Scale score of 0 in patients with a baseline NIHSS core of 4 to 7, a modified Rankin Scale score of 0 to 1 in patients with a baseline NIHSS score of 8 to 14, and a modified Rankin Scale score of 0 to 2 in patients with a baseline NIHSS score of 15 to 25. The trial is anticipated to last from June 2018 to December 2022 with 1200 subjects recruited form 36 centers in China. All the related investigative organization and individuals will obey the Declaration of Helsinki and Chinese Good Clinical Practice standard. A Data and Safety Monitoring Board (DSMB) will regularly monitor safety during the study. The trial has been approved by Institutional Review Board (IRB) and Ethics Committee(EC) in Being Tiantan hospital, Capital Medical University.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
1,216
This group will receive a 3-month regimen of Butylphthalide and Sodium Chloride Injection 100ml twice/day in the initial 14 days and Butylphthalide Soft Capsules 0.2g triple/day for the rest Day 15 to Day 90.
This group will receive a 3-month regimen of Butylphthalide Placebo Injection 100ml twice/day in the initial 14 days and Butylphthalide Placebo Soft Capsules 0.2g triple/day for the rest Day 15 to Day 90.
Beijing Tiantan Hospital
Beijing, Beijing Municipality, China
Favorable outcome
A modified Rankin Scale score of 0 in patients with a baseline NIHSS core of 4 to 7, a modified Rankin Scale score of 0 to 1 in patients with a baseline NIHSS score of 8 to 14, and a modified Rankin Scale score of 0 to 2 in patients with a baseline NIHSS score of 15 to 25.
Time frame: 90 days
Neurological recovery
The difference value of the NIHSS between Day 14/Day 90 and the baseline
Time frame: 90 days
Cerebral infarction volume
Cerebral infarction volume at the Day 14 of the therapy
Time frame: 14 days
Recanalization rate
Recanalization rate at the first 24 hours during the therapy
Time frame: 24 hours
Symptomatic intracranial hemorrhage
The percentage of symptomatic intracranial hemorrhage.
Time frame: 24 hours
Recurrent stroke
New symptomatic vascular events (ischemic or hemorrhage) .
Time frame: 90 days
Recurrent ischemic stroke
Recurrent symptomatic ischemic stroke events
Time frame: 90 days
Any vascular complications
The quantity of patients who has complications with vascular events (recurrent symptomatic ischemic stroke, myocardiac infarction, vascular death)
Time frame: 90 days
EuroQol-5-Dimensions Scale（EQ-5D）questionnaire for measuring generic health status
Generic health status evaluated by EQ-5D questionnaire at the end of the therapy，which consists of two components：EuroQol-5-Dimensions Scale（EQ-5D）for health state description and Visual analogue scale（VAS）for self-evaluation. EQ-5D descriptive system covers five dimensions including mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has three response levels (no problem, some problems, and severe problems). The EQ-5D descriptive system generates 243 health states, each of which was assigned a utility score ranging from -0.59 to 1.00 (full health). While the EQ-5D also includes a 20-cm vertical VAS, with 0 and 100 representing worst and best imaginable health states, respectively. We classified the EQ-VAS scores into four groups, namely\<65 (bad), 65 to 79 (fair), 80 to 89 (good), and 90 to 100 (excellent).
Time frame: 90 days
Cognitive function evaluated by the Mini-mental State Examination（MMSE）
Cognitive function evaluated by the Mini-mental State Examination（MMSE）at the end of the treatment，which effected by age and education experience. Cognitive impairment is diagnosed when MMSE ≤17 for illiteracy，MMSE ≤20 for those who take less than 6-years primary education，MMSE ≤24 for those have at least a middle school education.
Time frame: 90 days
Cognitive function evaluated by the Montreal Cognitive Assessment（MoCA）
Cognitive function evaluated by the Montreal Cognitive Assessment（MoCA） Scales at the end of the treatment, while taking MoCA \<26 as cognitive impairment. Further more, when patient has a education experiment less than 12 years, investigator should give him or her one more score.
Time frame: 90 days
Favorable outcome
A modified Rankin Scale score of 0 in patients with a baseline NIHSS core of 4 to 7, a modified Rankin Scale score of 0 to 1 in patients with a baseline NIHSS score of 8 to 14, and a modified Rankin Scale score of 0 to 2 in patients with a baseline NIHSS score of 15 to 25.
Time frame: 14 days
Neurological recovery
The difference value of the NIHSS between Day 14/Day 90 and the baseline
Time frame: 14 days
Severity Adverse Event
The percentage of the Severity Adverse Events within the 14 days of the therapy.
Time frame: 90 days
Symptomatic intracranial hemorrhage
The percentage of symptomatic intracranial hemorrhage.
Time frame: 90 days
Total mortality
All deaths reported post-randomization will be recorded and adjudicated. Deaths will be subclassified by the adjudication committee as cardiovascular or non-cardiovascular.
Time frame: 90 days
Adverse Events
The percentage of the Adverse Events during the therapy.
Time frame: 90 days
Severity Adverse Event
The percentage of the Severity Adverse Events within the 14 days of the therapy.
Time frame: 14 days
Total mortality
All deaths reported post-randomization will be recorded and adjudicated. Deaths will be subclassified by the adjudication committee as cardiovascular or non-cardiovascular.
Time frame: 14 days
Adverse Events
The percentage of the Adverse Events during the therapy.
Time frame: 14 days
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