Cilostazol Dexborneol Versus Placebo for Microcirculation Dysfunction After Reperfusion Therapy in Patients With Acute Ischemic Stroke With Large Vessel Occlusion

Study Overview
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Brief Summary
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This study aims to evaluate the efficacy of Y-6 sublingual tablets in improving microcirculation dysfunction and reducing thrombo-inflammation in patients who had AIS caused by LVO and received reperfusion therapy. Moreover, we expect to evaluate the safety of using Y-6 sublingual tablet in such study population.

Detailed Description
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This study rationale is based on the following scheme: in patients with acute ischemic stroke caused by LVO, receiving reperfusion therapy may cause futile recanalization and thus lead to microcirculation dysfunction and thrombo-inflammation as consequences. Cilostazol has antiplatelet effects and BBB protection and Dexborneol has anti-inflammatory effects; therefore, the multi-component tablet may exert neuroprotective effects in terms of improving microcirculation dysfunction and reducing thrombo-inflammation in patients with AIS after reperfusion therapy. The primary purpose of this study is to investigate the proportion of modified-Rankin scale (mRS) score recovered to 0 1 score at 90±7 days after randomization. The follow-up duration is 3 months, and the visit schedule is as follows: Subjects enrolled based on randomization procedures will receive visits at screening/baseline period, first drug administration, immediately after reperfusion therapy(within 2 hours), 24 ± 2 hours, 96 ± 7 hours, 14 ± 2 days, 28 ± 2 days and 90 ± 7 days after randomization, and in case of any events.

Official Title
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Cilostazol Dexborneol Versus Placebo for Microcirculation Dysfunction After Reperfusion Therapy in Patients With Acute Ischemic Stroke With Large Vessel Occlusion: A Phase Ⅱa,Prospective,Multicenter,Randomized, Double-blind,Placebo-controlled Parallel Trial

Conditions
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Large Vessel Occlusion, Acute Ischemic Stroke, Reperfusion

Intervention / Treatment
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* Drug: Y-6 sublingual tablets
* Drug: Placebo tablets of Y-6 sublingual tablet


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: 35 years old ≤ Age ≤ 80 years old Patients with acute ischemic stroke was diagnosed within 24 hours of onset (time from onset to completion of reperfusion therapy) Patients with first stroke or prior to stroke onset (mRS score 0-1) Patients with acute large vessel occlusion (LVO) confirmed by imaging, including the responsible vessel was located in the intracranial internal carotid artery, the T-shaped branch, the M1/M2 segment of the middle cerebral artery, or the A1/A2 segment of the anterior cerebral artery ASPECTS score ≥ 6 6<NIHSS score ≤ 25 after the onset of this disease Patients who meet the indications for reperfusion therapy, including mechanical thrombectomy, bridging therapy (intravenous r-tPA thrombolytic therapy), and plan to undergo mechanical thrombectomy Patients or his/her legal representatives are able to understand and sign the informed consent Exclusion criteria: Severe consciousness disturbance: NIHSS 1a consciousness level ≥2 points Patients with definite history of intracranial hemorrhage (such as subarachnoid hemorrhage, cerebral hemorrhage, etc.) Patients with intracranial tumor, arteriovenous malformation, or aneurysm Patients with bilateral anterior or posterior circulation ischemic stroke Patients with large vascular occlusion of rare or unknown etiology, such as dissection, vasculitis, etc. Patients who have received treatment with dual antiplatelet drugs, tirofiban, warfarin, novel oral anticoagulant, argatroban, snake venom, defibrase, lumbrokinase and other defibrase therapy after the onset of disease Patients with severe hepatic insufficiency or renal insufficiency and received dialysis for various reasons before randomization (severe hepatic insufficiency is defined as ALT > 3 × ULN or AST >3 × ULN; severe renal insufficiency is defined as serum creatinine >3.0 mg/dL (265.2 μmol/L) or creatinine clearance < 30 mL/min) Patients with haemorrhagic diathesis (including but not limited to): platelet count < 100 × 109/L; heparin treatment within the last 48 hours; taking oral warfarin; taking novel oral anticoagulant; administration with direct thrombin or Xa factor inhibitors; with hereditary hemorrhagic disorders, such as hemophilia Patients with refractory hypertension that is difficult to be controlled by medication (systolic blood pressure > 180 mmHg or diastolic blood pressure > 110 mmHg) Patients with significant head trauma or stroke within 3 months prior to randomization Patients who have received intracranial or spinal surgery within 3 months prior to randomization Patients with history of major surgery or serious physical trauma within 1 month prior to randomization Patients with hemorrhagic retinopathy Male subjects (or their partners) or female subjects who had planned to have a child during the whole study period and within 3 months after the end of the study period or were unwilling to use one or more non-drug contraceptive methods (e.g., complete abstinence, condoms, ligation, etc.) during the study period Patients with contraindications to known contrast agent or other contrast agents; subjects who are allergic to cilostazol or dexborneol Patients who plan to receive other surgical or intervention therapy within 3 months, which might require discontinuation of the study drugs Patients with advanced disease, leading to life expectancy of < 6 months Patients who have received treatment of investigational drug or device within 3 months Other conditions where it is not suitable for patients to participate in the clinical trial, such as inability to understand and/or follow the study procedures and/or follow-up schedule due to psychiatric disorders or cognitive/emotional disorders, or contraindications to thrombectomy or MRI, etc.

Ages Eligible for Study
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Minimum Age: 35 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Y-6 sublingual tablets<br>Y-6 sublingual tablets (each tablet contains 25 mg cilostazol and 6 mg dexborneol) Manufacturer: Nanjing Neurodawn Pharmaceutical Co., Ltd. | Drug: Y-6 sublingual tablets<br>* Take Y-6 sublingual tablets for 28 days continuously.<br>|
| Placebo Comparator: Placebo tablets of Y-6 sublingual tablet<br>Y-6 strength: Placebo tablets of Y-6 sublingual tablet (each tablet contains 0 mg cilostazol and 0.06 mg dexborneol) Manufacturer: Nanjing Neurodawn Pharmaceutical Co., Ltd. | Drug: Placebo tablets of Y-6 sublingual tablet<br>* Take Placebo tablets of Y-6 sublingual tablet for 28 days continuously.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of mRS score recovered to 0 1 score | The modified Rankin Scale (mRS) decreasing to 0 1 score. mRS Mainly measures patients' independent living ability, including physical function, activity ability and participation in daily life. A score of 0 on the mRS Scale indicates no symptoms and a score of 5 indicates severe disability. | 90±7 days after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The mRS score at 90±7 days after randomization | The modified Rankin Scale (mRS) evaluated at 90±7 days after randomization. mRS Mainly measures patients' independent living ability, including physical function, activity ability and participation in daily life. A score of 0 on the mRS Scale indicates no symptoms and a score of 5 indicates severe disability. | 90±7 days after randomization | 
| Integrity of BBB evaluated by DCE | BBB permeability is assessed by DCE-MRI | 96±7 hours after randomization | 
| Changes of NIHSS score between baseline and immediately after reperfusion therapy | NIHSS score after reperfusion therapy within 2 hours changing compared with baseline NIHSS. The NIHSS score ranges from 0 to 42. The higher the score, the more severe the nerve damage. | immediately after reperfusion therapy (within 2 hours) | 
| Changes of NIHSS score between baseline and at 24 ± 2 hours, 96 ± 7 hours, 14 ± 2 days and 28 ± 3days after randomization | NIHSS score changing compared with baseline NIHSS. The NIHSS score ranges from 0 to 42. The higher the score, the more severe the nerve damage. | 24 ± 2 hours, 96 ± 7 hours, 14 ± 2 days and 28 ± 3 days after randomization and baseline NIHSS score | 
| Proportion of study patients with early progression of stroke at 24 ± 2 hours and 96 ± 7 hours after randomization | NIHSS score increasing by ≥ 2 points, or the score of hemiplegia increasing by≥1 point, or the score of conscious disturbance increasing by ≥ 1 point compared with baseline within 7 days of onset, and intracranial hemorrhage is excepted by CT or MRI. Exacerbations not attributable to stroke are also excluded such as cardiac failure, liver and renal failure, etc. | 24 ± 2 hours and 96 ± 7 hours after randomization | 
| Proportion of study patients with combined vascular events at 90 ± 7 days after randomization | Symptomatic stroke, myocardial infarction and vascular death | 90 ± 7 days after randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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large vessel occlusion, microcirculation dysfunction, Y-6, cilostazol, dexborneol, Thrombo-inflammation, acute ischemic stroke, reperfusion therapy, CRYSTAL