EFfects of Y-6 SUblingual Tablets foR PaTients With AcUte Ischemic StRokE (FUTURE)

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, 24 ± 2 hours, 7 ± 2 days, 28 + 3 days and 90 ± 7 days after randomization, and in case of any events.

Official Title
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Effects of Y-6 Sublingual Tablets for Patients With Acute Ischemic Stroke: A Phase Ⅱ, Randomized, Double-blind, Double-dummy, Placebo-controlled Parallel Trial

Conditions
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Acute Ischemic Stroke, Large Vessel Occlusion, Reperfusion

Intervention / Treatment
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* Drug: Low-dose Y-6 sublingual tablets
* Drug: High-dose Y-6 sublingual tablets
* Drug: Low-dose Cilostazol
* Drug: High-dose Cilostazol
* Drug: Placebo


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 diagnosed within 24 hours of onset (time from onset to start of endovascular treatment); Patients with first stroke or mRS score 0-1 prior to this onset ; Patients with acute intracranial large vessel occlusion (LVO) confirmed by imaging examination, including occlusion of intracranial segments of internal carotid arteries, T-shaped bifurcation, MCA M1 and/or M2 segments and ACA A1 and/or A2 segments; ASPECTS score ≥ 6 when screening; 6<NIHSS score ≤ 25 after this onset; Patients who had the indications for mechanical thrombectomy and were scheduled for endovascular treatment; Patients or his/her legal representatives were able to understand and sign the informed consent. Exclusion Criteria: Severe disorder of consciousness: NIHSS 1a consciousness level ≥2 points; Patients with definite history of intracranial hemorrhage, including parenchymal hemorrhage, intraventricular hemorrhage, subarachnoid hemorrhage, subdural/external hematoma, etc. when screening; Patients with previously diagnosed intracranial tumor, arteriovenous malformation, or aneurysm when screening; Patients with bilateral LVO at anterior circulation or LVO at posterior circulation when screening; Patients with LVO of unknown or rare etiology, e.g., due to dissection, vasculitis, etc. when screening; Patients who have received treatment with tirofiban, warfarin, novel oral anticoagulants, argatroban, snake venom, defibrase, lumbrokinase or other defibrase therapy after onset, or platelet count <100×10^9/L; Patients with severe hepatic insufficiency or renal insufficiency and received dialysis for various reasons when screening (severe hepatic insufficiency was defined as ALT > 3 × ULN or AST >3 × ULN; severe renal insufficiency was defined as serum creatinine >3.0 mg/dl (265.2 μmol/L) or creatinine clearance < 30 ml/min); Patients with previously diagnosed hemorrhagic tendency (including but not limited to): with hereditary hemorrhagic disorders, such as hemophilia, when screening; 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 history of major head trauma or stroke within 1 month 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 previously diagnosed hemorrhagic retinopathy; Male subjects (or their mates) 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 agents or other contrast agents; patients 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 life expectancy of less than 3 months due to advanced stage of comorbidity; Patients who have received treatment of investigational drugs or devices within previous 3 months; Other investigator-evaluated conditions which may influence the compliance of patients or where it is not suitable for patients to participate in this trial.

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 |
| --- | --- |
| Experimental: Low-dose Y-6 sublingual tablet group<br>One Y-6 sublingual tablet (each tablet contains 25 mg Cilostazol and 6 mg Dexborneol), one placebo of Y-6 sublingual tablet (each tablet contains 0 mg Cilostazol and 0.06 mg Dexborneol to simulate the cool taste of Y-6 sublingual tablets when taken), and two halves Cilostazol mimicry tablets (each tablet contains 0 mg Cilostazol). | Drug: Low-dose Y-6 sublingual tablets<br>* Take one Y-6 sublingual tablet (each tablet contains 25 mg Cilostazol and 6 mg Dexborneol), one placebo of Y-6 sublingual tablet (each tablet contains 0 mg Cilostazol and 0.06 mg Dexborneol to simulate the cool taste of Y-6 sublingual tablets when taken), and two halves Cilostazol mimicry tablets (each tablet contains 0 mg Cilostazol) for 28 days continuously.<br>|
| Experimental: High-dose Y-6 sublingual tablet group<br>Two Y-6 sublingual tablets (each tablet contains 25 mg Cilostazol and 6 mg Dexborneol), and two halves Cilostazol mimicry tablets (each tablet contains 0 mg Cilostazol). | Drug: High-dose Y-6 sublingual tablets<br>* Take two Y-6 sublingual tablets (each tablet contains 25 mg Cilostazol and 6 mg Dexborneol), and two halves Cilostazol mimicry tablets (each tablet contains 0 mg Cilostazol) for 28 days continuously.<br>|
| Experimental: Low-dose Cilostazol group<br>Two tablets of placebo of Y-6 sublingual tablets (each tablet contains 0 mg Cilostazol and 0.06 mg Dexborneol to simulate the cool taste of Y-6 sublingual tablets when taken), one half Cilostazol tablet (each tablet contains 50 mg Cilostazol), and one half Cilostazol mimicry tablet(each tablet contains 0 mg Cilostazol). | Drug: Low-dose Cilostazol<br>* Take two tablets of placebo of Y-6 sublingual tablets (each tablet contains 0 mg Cilostazol and 0.06 mg Dexborneol to simulate the cool taste of Y-6 sublingual tablets when taken), one half Cilostazol tablet (each tablet contains 50 mg Cilostazol), and one half Cilostazol mimicry tablet(each tablet contains 0 mg Cilostazol) for 28 days continuously.<br>|
| Experimental: High-dose Cilostazol group<br>Two tablets of placebo of Y-6 sublingual tablets (each tablet contains 0 mg Cilostazol and 0.06 mg Dexborneol to simulate the cool taste of Y-6 sublingual tablets when taken), and two halves Cilostazol tablet (each tablet contains 50 mg Cilostazol). | Drug: High-dose Cilostazol<br>* Take two tablets of placebo of Y-6 sublingual tablets (each tablet contains 0 mg Cilostazol and 0.06 mg Dexborneol to simulate the cool taste of Y-6 sublingual tablets when taken), and two halves Cilostazol tablet (each tablet contains 50 mg Cilostazol) for 28 days continuously.<br>|
| Placebo Comparator: Placebo group<br>Two tablets of placebo of Y-6 sublingual tablets (each tablet contains 0 mg Cilostazol and 0.06 mg Dexborneol to simulate the cool taste of Y-6 sublingual tablets when taken), and two halves Cilostazol mimicry tablets (each tablet contains 0 mg Cilostazol). | Drug: Placebo<br>* Take two tablets of placebo of Y-6 sublingual tablets (each tablet contains 0 mg Cilostazol and 0.06 mg Dexborneol to simulate the cool taste of Y-6 sublingual tablets when taken), and two halves Cilostazol mimicry tablets (each tablet contains 0 mg Cilostazol) 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. | At 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) 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. | At 90±7 days after randomization | 
| Changes of NIHSS score between baseline and at 24 ± 2 hours, 7 ± 2 days and 28 + 3 days after randomization | 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. | At 24 ± 2 hours, 7 ± 2 days and 28 + 3 days after randomization | 
| Proportion of patients with early progression of stroke at 24 ± 2 hours after randomization | Early progression of stroke was defined as: within 7 days after onset, compared to baseline, an increase of ≥ 2 points in NIHSS; or an increase of ≥ 1 point in limb hemiplegia; or an increase of ≥ 1 point in consciousness disorder, excluding those caused by intracranial hemorrhage and other non-stroke causes such as cardiac insufficiency, liver insufficiency, renal insufficiency, etc. | At 24 ± 2 hours after randomization | 
| Proportion of patients with combined vascular events at 90 ± 7 days after randomization | Combined vascular events were defined as: symptomatic stroke, myocardial infarction and vascular death. | At 90 ± 7 days after randomization | 

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