Clinical trial NCT05631847: Direct Endovascular Treatment Versus Bridging Treatment In Basilar Artery Occlusive Stroke
Official title: Endovascular Treatment With Or Without Intravenous Alteplase In Acute Ischemic Stroke Of Basilar Artery Occlusion: A Multicenter, Prospective, Randomized Controlled Trial (BEST-BAO)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Acute Ischemic Stroke
Basilar Artery Occlusion
Thrombosis
Alteplase
Endovascular Treatment
Keywords: Endovascular treatment
Alteplase
Acute ischemic stroke
Basilar artery occlusion
Intravenous thrombosis
Lead sponsor: Sichuan Academy of Medical Sciences
Sponsor class: OTHER
Collaborators: name: Sichuan Provincial People's Hospital
First posted: 2022-11-30
Enrollment: 340
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Currently, both intravenous thrombolysis (IVT) followed by endovascular treatment (EVT) and EVT alone are widely used for the treatment of acute ischemic stroke (AIS) caused by basilar artery occlusion (BAO) (AIS-BAO), but no direct comparison of their efficacy and safety was reported. Only a limited number of cohort and registry studies have preliminarily compared the two strategies in the treatment of AIS-BAO, with results generally indicating that IVT followed by EVT was slightly superior to EVT alone. However, these findings are generally limited by small sample sizes, heterogeneous inclusion and exclusion criteria, different endpoint definitions, and distinct study designs, leading to inconsistent conclusions. Therefore, this study plans to conduct a multicentre, prospective, open-label, blinded endpoint evaluation, randomized controlled trial comparing the efficacy and safety of IVT followed by EVT and EVT alone in the treatment of patients with AIS-BAO who are eligible for both treatment strategies within 4.5 hours of symptom onset. This study intends to include patients with AIS due to BAO fulfilling the following inclusion criteria: patients with AIS caused by BAO confirmed by CTA/MRA/DSA; IVT can be started within 4.5 hours after symptoms onset; Age ≥ 18 years old; NIHSS score ≥ 6.

The primary endpoint of the study is the proportion of patients achieving mRS ≤ 2 at 90±14 days after stroke onset.

Detailed description: Stroke is a leading cause of death and disability in China, with acute ischemic stroke (AIS) accounting for approximately 85% of all acute strokes. Among these, large vessel occlusion-related AIS (AIS-LVO) represents about 20% of cases. Posterior circulation infarction, which occur in the vertebrobasilar artery territory, comprise 20-25% of all ischemic strokes. Although less common than anterior circulation ischemic strokes, posterior circulation infarctions-particularly AIS caused by basilar artery occlusion (AIS-BAO)-often present with severe symptoms and poor outcomes. Due to the heterogeneity of initial symptoms and diagnostic challenges, AIS-BAO frequently results in poor prognoses, posing significant challenges in clinical diagnosis and treatment.

The safety and efficacy of intravenous thrombolysis (IVT) with recombinant tissue plasminogen activator (rtPA) within 4.5 hours of symptom onset in AIS have been confirmed by numerous randomized controlled trials (RCTs). However, the heterogeneous presentation of posterior circulation AIS, the difficulty in clinical recognition compared to anterior circulation AIS, and the severe neurological deficits-especially the high mortality rate of AIS-BAO-pose various limitations on IVT. Endovascular treatment (EVT), including thrombectomy techniques, has substantially reduced the mortality and disability rates of patients with AIS-LVO. The key to treating AIS-BAO is recanalizing the acutely occluded basilar artery and rescuing the ischemic penumbra. Large RCTs have demonstrated that early EVT achieves better clinical outcomes in anterior circulation AIS-LVO patients eligible for mechanical thrombectomy compared to IVT alone.

In recent years, while multiple large RCTs have confirmed the efficacy of EVT for anterior circulation AIS-LVO, evidence for EVT in posterior circulation AIS-LVO remains limited. The BEST trial enrolled AIS patients with vertebrobasilar artery occlusion within 8 hours of symptom onset to compare EVT plus standard medical treatment versus medical treatment alone. The results showed that the combination group achieved better outcomes at 90 days, with no significant difference in mortality or symptomatic intracranial hemorrhage (sICH) rates compared to the medical treatment-only group. Similarly, the BASICS trial, an international multicenter RCT, enrolled 300 AIS-BAO patients within 6 hours of symptom onset and compared EVT combined with standard medical treatment to standard medical treatment alone. This study found no significant differences between the two groups in good functional outcomes, sICH, or mortality.

Recently, two studies focusing on thrombectomy for AIS-BAO reported promising results. The BAOCHE study randomized AIS-BAO patients who presented 6-24 hours after symptom onset into a thrombectomy plus standard medical treatment group or a standard medical treatment-only group. The primary endpoint was the proportion of patients with modified Rankin Scale (mRS) scores of 0-3 at 90 days. A total of 217 patients (110 in the combination group, 107 in the medical treatment group) were enrolled, and the results demonstrated that thrombectomy performed within 6-24 hours led to better functional outcomes at 90 days. The ATTENTION study, another RCT conducted across 36 stroke centers in China, enrolled AIS-BAO patients within 12 hours of symptom onset. Patients were randomized 2:1 to thrombectomy plus optimal medical treatment or optimal medical treatment alone. The primary outcome was the proportion of patients achieving an mRS score of 0-3 at 90 days, and 340 patients (226 in the combination group, 114 in the medical treatment group) were enrolled. The results showed that thrombectomy within 12 hours significantly improved functional outcomes. Both studies demonstrated that thrombectomy combined with medical treatment yielded better outcomes than medical treatment alone for AIS-BAO. However, questions remain regarding the optimal timing, treatment modalities, bridging strategies, and anesthesia options for EVT in posterior circulation AIS. Further exploration is required to rapidly identify posterior circulation strokes and select appropriate EVT strategies based on clinical indications.

Clinically, the morbidity and mortality of posterior circulation AIS-LVO exceed 80%. AIS-BAO, in particular, is a neurological emergency with extremely high mortality if untreated, significantly affecting patients' quality of life and imposing substantial medical and financial burdens on families and society. IVT remains the most effective ultra-early treatment for AIS within 6 hours of onset. However, the adoption of IVT for posterior circulation AIS is lower than that for anterior circulation AIS, potentially due to delays in diagnosis or missed diagnoses caused by the heterogeneity of AIS-BAO symptoms. Among AIS patients receiving IVT, posterior circulation strokes (PCS) account for about 5-19%. Studies comparing the efficacy and safety of IVT in PCS and anterior circulation strokes (ACS) have found that while the risk of hemorrhagic complications is halved for PCS, functional outcomes are similar, but mortality is higher. Clinically, IVT can be used as standalone therapy for AIS-BAO or as a prelude to EVT. Which approach better improves AIS-BAO outcomes remains uncertain.

To date, most studies on IVT with EVT have focused on anterior circulation AIS. Both IVT and EVT are time-dependent treatments for AIS, with EVT success hinging on prompt initiation and optimization of processes to reduce door-to-puncture time (DTP). The SKIP trial found no significant difference in the time from randomization to femoral artery puncture between only EVT and IVT with EVT. Similarly, the DEVT trial, conducted in China, also reported no difference in this time interval between the two groups. A meta-analysis of 38 observational studies including 11,798 AIS-LVO patients (56% of whom underwent IVT with EVT) also confirmed no significant difference in EVT procedural time between the two groups. For anterior circulation AIS-LVO, four recent RCTs showed mixed results. DIRECT-MT and DEVT demonstrated that only EVT was non-inferior to IVT with EVT in terms of good functional outcomes at 90 days, while SKIP and MR CLEAN-IV did not confirm non-inferiority. Thus, EVT alone requires further robust evidence\[17, 18\]. Regarding safety, all four RCTs confirmed that IVT with EVT does not increase sICH rates. Additionally, the aforementioned meta-analysis\[16\] confirmed that IVT with EVT does not increase sICH risk. SKIP, DIRECT-MT, and DEVT further showed no significant difference in mortality between the two groups. However, the meta-analysis suggested that IVT with EVT significantly reduces 90-day mortality compared to only EVT. A real-world study also found that IVT with EVT was independently associated with lower 90-day mortality compared to only EVT.

Does IVT before EVT achieve higher recanalization rates? A retrospective study including 93 AIS patients with middle cerebral artery occlusion showed that IVT with EVT resulted in a higher proportion of reperfusion within 1 hour of femoral artery puncture compared to only EVT. Moreover, IVT with EVT achieved significantly higher rates of successful reperfusion (mTICI ≥ 2b). The DIRECT-MT study found that IVT with EVT caused fewer new infarctions from thrombus fragmentation than only EVT. Similarly, post-hoc analyses of the ESCAPE trial demonstrated that IVT with EVT significantly reduced new infarct risk compared to only EVT. Another study of 57 patients with M1 segment occlusions reported that IVT with EVT often required fewer thrombectomy passes to achieve recanalization compared to only EVT.

Combination therapy combines the rapidity of IVT with the high recanalization rates of EVT, theoretically offering better outcomes than only EVT. However, most of these studies focus on anterior circulation stroke treatment. To date, no large-scale RCTs have specifically evaluated EVT with or without prior IVT for AIS-BAO. Therefore, we plan to conduct a multicenter, prospective, randomized controlled study to assess the impact of different EVT strategies on outcomes in AIS-BAO.

The primary objective of this trial is to compare the efficacy and safety of IVT followed by EVT versus EVT alone in patients with AIS caused by BAO who are eligible for both treatment strategies within 4.5 hours after symptom onset.

The secondary objectives include assessing the effects of the two treatment strategies on neurological function (assessed by National Institutes of Health Stroke Scale \[NIHSS\] score), activities of daily living (assessed by Barthel Index \[BI\] score), quality of life (assessed by EQ-5D-5L score), cerebrovascular reperfusion (assessed by eTICI), cerebrovascular recanalization (assessed by mAOL), infarct size (assessed by PC-ASPECTS and quantitative imaging detection), mortality, and the incidence of symptomatic intracranial hemorrhage (sICH).

This is a multicentre, prospective, open-label, blinded endpoint evaluation, randomized controlled clinical trial (PROBE design). Based on published observational studies, this trial will first validate the superiority of IVT followed by EVT compared with EVT alone. However, given the limited prior evidence and the current findings from anterior circulation stroke studies, this trial will also validate the non-inferiority of EVT compared with IVT followed by EVT alone if the efficacy of the two treatment strategies is found to be comparable.

An interim analysis is scheduled after one-third of the sample size completes follow-up for the primary endpoint. The primary purpose of the interim analysis is to allow for sample size re-estimation. The data and safety monitoring board (DSMB) will calculate the conditional power based on the current data and provide recommendations to the BEST-BAO research team regarding potential sample size adjustments.

The trial will be conducted at nationally recognized stroke centers and is expected to last for 3 years.

Eligibility criteria: Inclusion criteria:

1. A clinical diagnosis of AIS.
2. Caused by BAO confirmed by CTA, MRA, or DSA. (BAO is defined as the absence of visualization of the basilar artery on CTA, MRA or DSA. Bilateral vertebral artery occlusions or occlusion of a unilateral vertebral artery that is the sole supplier of the basilar artery, even in the presence of patent basilar artery, will be considered de facto BAO.)
3. CT or MRI ruling out intracranial hemorrhage,
4. Eligible for IVT and EVT (within 4.5 hours of symptom onset). (Symptoms onset is defined as point in time the patient was last seen well \[at baseline\] if patients are unable to provide a reliable history or the point in time when symptoms have started if patients can provide a reliable history. Symptoms onset includes diplopia, midline ataxia, visual loss, sensory or motor deficits, and conscious disturbance. Isolated vertigo \[not accompanied by dysarthria, motor weakness, sensory symptoms, double vision, depressed level of consciousness\] is not considered onset of symptoms.)
5. NIHSS score ≥ 6.
6. Age ≥ 18 years.
7. Signed informed consent by the patient or legal representative.

Exclusion criteria:

1. mRS score \> 2 before this stroke.
2. Any contraindication to IVT as per the 2019 AHA/ASA guidelines for early management of AIS:

1) Blood pressure \> 185/110 mmHg and cannot be controlled by standard medication, 2) Blood glucose \< 50mg/dL (2.8 mmol/L) or \> 400mg/dL (22.2 mmol/L), 3) Had a cerebral infarction in the previous 6 weeks with residual neurological deficit or signs of recent infarction on neuroimaging, 4) Severe head trauma in the previous 3 months, 5) Major surgery or severe trauma in the previous 2 weeks, 6) Gastrointestinal or urinary bleeding in the previous 3 weeks, 7) previous intracranial hemorrhage, 8) Using anticoagulants and International normalized ratio (INR) \> 1.7, 9) Known platelet count \< 100 × 109/L, 10) treatment with direct thrombin or factor X inhibitors, 11) Heparin treatment in the previous 48 hours with the activated partial thromboplastin time (APTT) exceeding the upper limit of normal.

(3) Pregnancy, breastfeeding, or intention to conceive during the study period. (4) Other conditions deemed unsuitable by the investigator.

Primary outcomes:
measure: Proportion of patients achieving mRS ≤ 2.
timeFrame: At 90±14 days after stroke onset.
Secondary outcomes:
measure: Proportions of patients with mRS = 0 or 1.
timeFrame: At 90±14 days after stroke onset.
measure: Proportions of patients with mRS = 0-3.
timeFrame: At 90±14 days after stroke onset
measure: The mRS score.
timeFrame: At 90±14 days after stroke onset
measure: NIHSS (the National Institutes of Health Stroke Scale) score
timeFrame: At 18-24 hours after procedure, 24-74 hours after procedure, and 5-7 days after stroke onset and their changes from baseline.
measure: Proportions of patients with a NIHSS score = 0 or 1, a NIHSS score = 0-2, a NIHSS score improvement ≥ 4 points, and a NIHSS score improvement ≥ 8 points.
timeFrame: At 18-24 hours after procedure, 24-74 hours after procedure, and 5-7 days after stroke onset.
measure: Glasgow Coma Scale
timeFrame: At 18-24 hours after procedure, 24-74 hours after procedure, and 5-7 days after stroke onset and their changes from baseline.
measure: BI score and the proportion with BI = 95-100.
timeFrame: At 30±7 and 90±14 days after stroke onset
measure: EQ-5D-5L (the European Quality of Life 5-Dimension 5-Level) score
timeFrame: At 90±14 days after after stroke onset.
measure: eTICI (Extended Treatment In Cerebral Ischemia) score and successful reperfusion rates.
timeFrame: Before and after EVT.
measure: mAOL score and recanalization rates
timeFrame: At 24-72 hours after procedure.
measure: PC-ASPECTS score
timeFrame: At 24-72 hours after procedure and 5-7 days after stroke onset.
measure: Lesion volume.
timeFrame: At 24-72 hours after procedure and 5-7 days after stroke onset.
measure: All-cause mortality
timeFrame: Within 7, 30±7, and 90±14 days after stroke onset.
measure: Proportions of patients with intracranial hemorrhage and symptomatic intracranial hemorrhage
timeFrame: At 24-72 hours after procedure and 5-7 days after stroke onset.
measure: New regional cerebral embolisms.
timeFrame: During EVT.
measure: Proportions of patients with new cerebral infarction
timeFrame: At 24-72 hours after procedure and 5-7 days after stroke onset.
measure: EVT procedure-related complications.
timeFrame: Within 90±14 days after stroke onset.
Other outcomes:
measure: Other serious adverse events.
timeFrame: Within 90±14 days after stroke onset.
Locations:
city: Chongqing
country: China
facility: Banan Hospital Affiliated to Chongqing Medical University
state: Chongqing
city: Chongqing
country: China
facility: Chongqing Sanbo Chang'an Hospital
state: Chongqing
city: Chongqing
country: China
facility: Chongqing University Affiliated S Central Hospital
state: Chongqing
city: Chongqing
country: China
facility: Chongqing University Medical University Affiliated Yongchuan Hospital
state: Chongqing
city: Chongqing
country: China
facility: Chongqing Yongchuan District People's Hospital
state: Chongqing
city: Chongqing
country: China
facility: Hechuan District People's Hospital
state: Chongqing
city: Chongqing
country: China
facility: Liangping District People's Hospital
state: Chongqing
city: Chongqing
country: China
facility: The First People's Hospital of Liangjiang New Area
state: Chongqing
city: Zhangzhou
country: China
facility: Zhangzhou Hospital
state: Fujian
city: Guangzhou
country: China
facility: The Fifth People's Hospital Affiliated to Southern Medical University
state: Guangdong
city: Maoming
country: China
facility: Maoming County Traditional Chinese Medicine Hospital
state: Guangdong
city: Shaoguan
country: China
facility: Yuebei People's Hospital
state: Guangdong
city: Yulin
country: China
facility: Yulin First People's Hospital
state: Guangxi
city: Kaili
country: China
facility: Qiandongnan Miao and Dong Autonomous Prefecture People's Hospital
state: Guizhou
city: Anyang
country: China
facility: Anyang People's Hospital
state: Henan
city: Jiaozuo
country: China
facility: Jiaozuo Second People's Hospital
state: Henan
city: Luoyang
country: China
facility: Luoyang Central Hospital
state: Henan
city: Nanyang
country: China
facility: Nanyang Central Hospital
state: Henan
city: Nanyang
country: China
facility: Nanyang Nanshi Hospital
state: Henan
city: Puyang
country: China
facility: Puyang Oilfield General Hospital
state: Henan
city: Xinxiang
country: China
facility: Xinxiang Central Hospital
state: Henan
city: Zhengzhou
country: China
facility: Zhengzhou Central Hospital
state: Henan
city: Zhoukou
country: China
facility: Zhoukou Central Hospital
state: Henan
city: Zhumadian
country: China
facility: Zhumadian Central Hospital
state: Henan
city: Xiangyang
country: China
facility: Xiangyang Central Hospital
state: Hubei
city: Changde
country: China
facility: Changde First People's Hospital
state: Hunan
city: Chenzhou
country: China
facility: Chenzhou First People's Hospital
state: Hunan
city: Xiangtan
country: China
facility: Xiangtan Central Hospital
state: Hunan
city: Huaian
country: China
facility: Huai'an First People's Hospital
state: Jiangsu
city: Jingjiang
country: China
facility: Jingjiang People's Hospital
state: Jiangsu
city: Suqian
country: China
facility: The First People's Hospital of Suqian City
state: Jiangsu
city: Taizhou
country: China
facility: Taizhou People's Hospital
state: Jiangsu
city: Xuzhou
country: China
facility: Xuzhou Medical University Affiliated Hospital
state: Jiangsu
city: Yancheng
country: China
facility: Yancheng First People's Hospital
state: Jiangsu
city: Changchun
country: China
facility: Jilin University Sino Japanese Friendship Hospital
state: Jilin
city: Jilin
country: China
facility: The First Hospital of Jilin University
state: Jilin
city: Tieling
country: China
facility: Tieling Central Hospital
state: Liaoning
city: Yingkou
country: China
facility: Yingkou Central Hospital
state: Liaoning
city: Heze
country: China
facility: Heze Municipal Hospital
state: Shandong
city: Liaocheng
country: China
facility: Liaocheng Second People's Hospital
state: Shandong
city: Linyi
country: China
facility: Linyi Traditional Chinese Medicine Hospital
state: Shandong
city: Rizhao
country: China
facility: Rizhao Traditional Chinese Medicine Hospital
state: Shandong
city: Taian
country: China
facility: The Second Affiliated Hospital of Shandong First Medical University
state: Shandong
city: Bazhong
country: China
facility: Bazhong Central Hospital
state: Sichuan
city: Chengde
country: China
facility: Chengdu Third People's Hospital
state: Sichuan
city: Chengdu
country: China
facility: Sichuan Third People's Hospital
state: Sichuan
city: Chengdu
country: China
facility: West China Hospital of Sichuan University
state: Sichuan
city: Chengdu
country: China
facility: Affiliated Hospital of Chengdu Medical College
state: Sichuan
city: Chengdu
country: China
facility: Chengdu Fifth People's Hospital
state: Sichuan
city: Chengdu
country: China
facility: Chengdu First People's Hospital
state: Sichuan
city: Chengdu
country: China
facility: Chengdu Second People's Hospital
state: Sichuan
city: Chengdu
country: China
facility: Chongzhou People's Hospital
state: Sichuan
city: Chengdu
country: China
facility: Dayi County People's Hospital
state: Sichuan
city: Chengdu
country: China
facility: Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital
state: Sichuan
city: Chengdu
country: China
facility: Western Theater General Hospital
state: Sichuan
city: Deyang
country: China
facility: Deyang People's Hospital
state: Sichuan
city: Guang'an
country: China
facility: Guang'an Central Hospital
state: Sichuan
city: Guanghan
country: China
facility: Guanghan People's Hospital
state: Sichuan
city: Guangyuan
country: China
facility: Guangyuan Central Hospital
state: Sichuan
city: Guangyuan
country: China
facility: Guangyuan First People's Hospital
state: Sichuan
city: Jintang
country: China
facility: Jintang County People's Hospital
state: Sichuan
city: Leshan
country: China
facility: Leshan People's Hospital
state: Sichuan
city: Luzhou
country: China
facility: Affiliated Hospital of Southwest Medical University
state: Sichuan
city: Luzhou
country: China
facility: Affiliated Traditional Chinese Medicine Hospital of Southwest Hospital Medical University
state: Sichuan
city: Meishan
country: China
facility: Meishan Cardiovascular and Cerebrovascular Disease Hospital
state: Sichuan
city: Meishan
country: China
facility: Meishan Second People's Hospital
state: Sichuan
city: Meishan
country: China
facility: Meishan Traditional Chinese Medicine Hospital
state: Sichuan
city: Mianyang
country: China
facility: Mianyang 404 Hospital
state: Sichuan
city: Mianyang
country: China
facility: Mianyang Central Hospital
state: Sichuan
city: Mianyang
country: China
facility: Mianyang Third People's Hospital
state: Sichuan
city: Nanchong
country: China
facility: Affiliated Hospital of North Sichuan Medical College
state: Sichuan
city: Nanchong
country: China
facility: Langzhong People's Hospital
state: Sichuan
city: Nanchong
country: China
facility: Nanchong Central Hospital
state: Sichuan
city: Nanchong
country: China
facility: Yilong County People's Hospital
state: Sichuan
city: Neijiang
country: China
facility: Neijiang Second People's Hospital
state: Sichuan
city: Panzhihua
country: China
facility: Pangang Group General Hospital
state: Sichuan
city: Panzhihua
country: China
facility: Panzhihua Central Hospital
state: Sichuan
city: Pingchang
country: China
facility: Pingchang County People's Hospital
state: Sichuan
city: Shifang
country: China
facility: Shifang People's Hospital
state: Sichuan
city: Suining
country: China
facility: Suining Central Hospital
state: Sichuan
city: Suining
country: China
facility: Suining First People's Hospital
state: Sichuan
city: Xichang
country: China
facility: Liangshan Prefecture Second People's Hospital
state: Sichuan
city: Xichang
country: China
facility: Liangshan Prefecture First People's Hospital
state: Sichuan
city: Ya'an
country: China
facility: Ya'an People's Hospital
state: Sichuan
city: Yibin
country: China
facility: Yibin First People's Hospital
state: Sichuan
city: Yibin
country: China
facility: Yibin Second People's Hospital
state: Sichuan
city: Zigong
country: China
facility: Zigong First People's Hospital
state: Sichuan
city: Zigong
country: China
facility: Zigong Fourth People's Hospital
state: Sichuan
city: Zigong
country: China
facility: Zigong Third People's Hospital
state: Sichuan
city: Ziyang
country: China
facility: Lezhi County People's Hospital
state: Sichuan
city: Ziyang
country: China
facility: Ziyang First People's Hospital
state: Sichuan
city: Qujing
country: China
facility: Qujing First People's Hospital
state: Yunnan
city: Jinhua
country: China
facility: Jinhua Central Hospital
state: Zhejiang
city: Taizhou
country: China
facility: Taizhou First People's Hospital
state: Zhejiang
city: Taizhou
country: China
facility: Taizhou Hospital of Zhejiang Province
state: Zhejiang
city: Yongkang
country: China
facility: Yongkang First People's Hospital
state: Zhejiang
Study officials:
affiliation: Sichuan Academy of Medical Sciences
name: Fu-Qiang Guo, M.D.
role: PRINCIPAL_INVESTIGATOR
References: