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

Sponsor

Beijing Tiantan Hospital (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05836766

Collaborator

NeuroDawn Pharmaceutical Co., Ltd. (Other)

120

Enrollment

Locations

Arms

Anticipated Duration (Months)

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Acute Ischemic Stroke Reperfusion Large Vessel Occlusion	Drug: Y-6 sublingual tablets Drug: Placebo tablets of Y-6 sublingual tablet	Phase 2

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

120 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

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

Anticipated Study Start Date :

May 1, 2023

Anticipated Primary Completion Date :

Jun 1, 2023

Anticipated Study Completion Date :

Jul 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Y-6 sublingual tablets 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 Take Y-6 sublingual tablets for 28 days continuously.
Placebo Comparator: Placebo tablets of Y-6 sublingual tablet 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 Take Placebo tablets of Y-6 sublingual tablet for 28 days continuously.

Arm

Intervention/Treatment

Active Comparator: Y-6 sublingual tablets

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

Take Y-6 sublingual tablets for 28 days continuously.

Placebo Comparator: Placebo tablets of Y-6 sublingual tablet

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

Take Placebo tablets of Y-6 sublingual tablet for 28 days continuously.

Outcome Measures

Primary Outcome Measures

Proportion of mRS score recovered to 0~1 score [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.

Secondary Outcome Measures

The mRS score at 90±7 days after randomization [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.
Integrity of BBB evaluated by DCE [96±7 hours after randomization]
BBB permeability is assessed by DCE-MRI
Changes of NIHSS score between baseline and immediately after reperfusion therapy [immediately after reperfusion therapy (within 2 hours)]
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.
Changes of NIHSS score between baseline and at 24 ± 2 hours, 96 ± 7 hours, 14 ± 2 days and 28 ± 3days after randomization [24 ± 2 hours, 96 ± 7 hours, 14 ± 2 days and 28 ± 3 days after randomization and baseline NIHSS score]
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.
Proportion of study patients with early progression of stroke at 24 ± 2 hours and 96 ± 7 hours after randomization [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.
Proportion of study patients with combined vascular events at 90 ± 7 days after randomization [90 ± 7 days after randomization]
Symptomatic stroke, myocardial infarction and vascular death

Other Outcome Measures

Integrity evaluation of BBB by FEXI at 96 ± 7 hours after randomization [96 ± 7 hours after randomization]
BBB permeability is assessed by FEXI
Integrity evaluation of BBB by FEXI at 28 ± 3 days after randomization [28 ± 3 days after randomization]
BBB permeability is assessed by FEXI
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 [14±2 days of randomization compared with baseline]
Collecting blood samples to evaluate venous thrombotic inflammation (plasma sGPVI, sADAMTS 13, sCD40L levels) and indirect indicators of blood-brain barrier disruption (MMP-9, S100B)
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 [24±2 hours of randomization compared with baseline]
Collecting blood samples to evaluate venous thrombotic inflammation (plasma sGPVI, sADAMTS 13, sCD40L levels) and indirect indicators of blood-brain barrier disruption (MMP-9, S100B)

Eligibility Criteria

Criteria

Ages Eligible for Study:

35 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.