Clinical trial NCT05836766: Cilostazol Dexborneol Versus Placebo for Microcirculation Dysfunction After Reperfusion Therapy in Patients With Acute Ischemic Stroke With Large Vessel Occlusion
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Acute Ischemic Stroke
Reperfusion
Large Vessel Occlusion
Keywords: microcirculation dysfunction
Y-6
cilostazol
dexborneol
Thrombo-inflammation
acute ischemic stroke
large vessel occlusion
reperfusion therapy
CRYSTAL
Lead sponsor: Beijing Tiantan Hospital
Sponsor class: OTHER
Collaborators: name: Neurodawn Pharmaceutical Co., Ltd.
First posted: 2023-05-01
Enrollment: 120
Sex: ALL
Minimum age (years): 35
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Proportion of mRS score recovered to 0~1 score
timeFrame: 90±7 days after randomization
Secondary outcomes:
measure: The mRS score at 90±7 days after randomization
timeFrame: 90±7 days after randomization
measure: Integrity of BBB evaluated by DCE
timeFrame: 96±7 hours after randomization
measure: Changes of NIHSS score between baseline and immediately after reperfusion therapy
timeFrame: immediately after reperfusion therapy (within 2 hours)
measure: Changes of NIHSS score between baseline and at 24 ± 2 hours, 96 ± 7 hours, 14 ± 2 days and 28 ± 3days after randomization
timeFrame: 24 ± 2 hours, 96 ± 7 hours, 14 ± 2 days and 28 ± 3 days after randomization and baseline NIHSS score
measure: Proportion of study patients with early progression of stroke at 24 ± 2 hours and 96 ± 7 hours after randomization
timeFrame: 24 ± 2 hours and 96 ± 7 hours after randomization
measure: Proportion of study patients with combined vascular events at 90 ± 7 days after randomization
timeFrame: 90 ± 7 days after randomization
Other outcomes:
measure: Integrity evaluation of BBB by FEXI at 96 ± 7 hours after randomization
timeFrame: 96 ± 7 hours after randomization
measure: Integrity evaluation of BBB by FEXI at 28 ± 3 days after randomization
timeFrame: 28 ± 3 days after randomization
measure: Differences of indicators of venous thrombotic inflammation (plasma sGPVI, sADAMTS 13, sCD40L levels) and indirect indicators of BBB disruption (MMP-9, S100B) between baseline and 14±2 days of randomization
timeFrame: 14±2 days of randomization compared with baseline
measure: Differences of indicators of venous thrombotic inflammation (plasma sGPVI, sADAMTS 13, sCD40L levels) and indirect indicators of BBB disruption (MMP-9, S100B) between baseline and 24±2 hours of randomization
timeFrame: 24±2 hours of randomization compared with baseline
Locations:
city: Liuzhou
country: China
facility: Liuzhou Workers' Hospital
state: Guangxi
city: Changsha
country: China
facility: Hunan Provincial People's Hospital
state: Hunan
city: Pingxiang
country: China
facility: Pingxiang people's hospital
state: Jiangxi
Study officials:
affiliation: Beijing Tiantan Hospital, Capital Medical University, Beijing, China
name: Yilong Wang, PhD，MD
role: PRINCIPAL_INVESTIGATOR
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