Sodium Valproate Improves Clinical Outcomes in Patients With Acute Ischemic Stroke

Study Overview
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Brief Summary
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This prospective pilot study is intended to clarify whether the use of sodium valproate in patients with acute ischemic stroke can improve clinical outcomes, and to explore the mechanism: whether valproate could increase peripheral anti-inflammatory CD177+ neutrophils levels. Patients with acute ischemic stroke included in the study will be randomly assigned to low-dose sodium valproate group, high-dose sodium valproate group and placebo group. Besides receiving conventional treatment for stroke, 10mg/kg sodium valproate, 20mg/kg sodium valproate or normal saline were given intravenously for 3 consecutive days, respectively. The investigators evaluate whether sodium valproate can improve clinical outcomes and increase peripheral CD177+ neutrophil levels.

Detailed Description
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Ischemic stroke is one of the leading causes of disability and mortality worldwide, which imposes a huge burden on families and society. Currently, the effective treatment strategies of ischemic stroke are limited. It is of great clinical value and significance to explore effective neuroprotective medications besides reperfusion therapy. Sodium valproate is widely used in clinical practice, and its safety and tolerability has been confirmed. It is mainly used in the treatment of epilepsy, bipolar disorder, neuropathic pain and other diseases. In recent years, a number of preclinical studies have found that valproic acid has a potential neuroprotective effect in acute ischemic brain injury, which can decrease infarct volume, reduce blood-brain barrier damage, and improve neurological function. However, the neuroprotective mechanism of sodium valproate has not been fully revealed, and there is still a lack of clinical studies to clarify the neuroprotective effect of sodium valproate in patients with ischemic stroke. The goal of this study is to test whether sodium valproate could become a new therapeutic approach to improve the functional outcome after ischemic stroke. This prospective pilot study is intended to clarify whether the use of sodium valproate in patients with acute ischemic stroke can improve clinical outcomes, and to explore the mechanism: whether valproate could increase peripheral anti-inflammatory CD177+ neutrophils levels to reduce neuroinflammation caused by the infiltrated peripheral immune cells. Patients with acute ischemic stroke included in the study will be randomly assigned to low-dose sodium valproate group, high-dose sodium valproate group and placebo group. Besides receiving conventional treatment for stroke, 10mg/kg sodium valproate, 20mg/kg sodium valproate or normal saline were given intravenously for 3 consecutive days, respectively. The investigators evaluate whether sodium valproate can improve clinical outcomes and increase peripheral CD177+ neutrophil levels.

Official Title
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Sodium Valproate Improves Clinical Outcomes in Patients With Acute Ischemic Stroke: a Pilot Randomized Controlled Trial

Conditions
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Acute Ischemic Stroke

Intervention / Treatment
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* Drug: Sodium valproate
* Drug: Normal saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18≤age<75; Admitted to hospital within 24 hours after the onset of neurological impairment symptoms and diagnosed as acute ischemic stroke by CT or MRI; Not suitable for thrombolysis and mechanical thrombectomy, including: contraindication of thrombolysis, no large vessel occlusion, responsible vessel stenosis <70%; Give written informed consent. Exclusion Criteria: Patients with mRS ≥ 2 before the disease onset; Patients with refractory hypertension (SBP>180mmHg or DBP>110mmHg after antihypertensive treatment); Patients with history of cerebral hemorrhage, intracranial tumor, cerebral arteriovenous malformation and aneurysm; Patients with clear history of brain trauma, intracranial or spinal surgery within 3 months, major surgery or severe physical trauma within 1 month; Patients with signs of infection before or within 72 hours after admission; Patients with history of malignancy or autoimmune disease; Patients using glucocorticoids or other immunosuppressive medications; Patients with contraindications of the use of sodium valproate: pregnancy; liver disease or severe hepatic insufficiency (ALT, AST 3 times higher than the upper normal limit); hemorrhagic tendency (such as platelet count <100x109/L, APTT≥35s); allergy to sodium valproate, sodium divalproate, or valproamide; hepatic porphyria; combined use of mefloquine; patients known to have mitochondrial diseases related to POLG mutations; patients known to have disorders of the urea cycle; Patients have used other medications containing active ingredients that can be converted to valproic acid, including sodium divalproate, valproamide; Patients who have MRI contraindications or cannot tolerate MRI; Patients undergoing other clinical trials; Any other conditions for which the investigator considers the patient ineligible to participate in this trial, such as mental illness, cognitive impairment, or inability to follow trial procedures.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low-dose sodium valproate group<br>Within 3 days after admission, 10mg/kg sodium valproate will be given daily. Specifically, sodium valproate will be intravenously infused at the dose of 5mg/kg within 15 minutes, followed by intravenous drip (1mg/kg/h) for 5 hours. | Drug: Sodium valproate<br>* Patients with acute ischemic stroke included in the study are randomly assigned to low-dose sodium valproate group, high-dose sodium valproate group and placebo group. Besides receiving conventional treatment for stroke, 10mg/kg sodium valproate, 20mg/kg sodium valproate or normal saline were given intravenously for 3 consecutive days, respectively.<br>|
| Experimental: High-dose sodium valproate group<br>Within 3 days after admission, 20mg/kg sodium valproate will be given daily. Specifically, sodium valproate will be intravenously infused at the dose of 15mg/kg within 15 minutes, followed by intravenous drip (1mg/kg/h) for 5 hours. | Drug: Sodium valproate<br>* Patients with acute ischemic stroke included in the study are randomly assigned to low-dose sodium valproate group, high-dose sodium valproate group and placebo group. Besides receiving conventional treatment for stroke, 10mg/kg sodium valproate, 20mg/kg sodium valproate or normal saline were given intravenously for 3 consecutive days, respectively.<br>|
| Placebo Comparator: Placebo group<br>Within 3 days after admission, normal saline will be given daily in the same way. | Drug: Normal saline<br>* Patients with acute ischemic stroke included in the study are randomly assigned to low-dose sodium valproate group, high-dose sodium valproate group and placebo group. Besides receiving conventional treatment for stroke, 10mg/kg sodium valproate, 20mg/kg sodium valproate or normal saline were given intravenously for 3 consecutive days, respectively.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Favorable outcome at 90 days (the Modified Rankin Scale (mRS) score≤2) | The proportion of patients with favorable outcome, which is defined as the Modified Rankin Scale (mRS) score 0-2. | Day 90 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Modified Rankin Scale (mRS) score at 90 days | The detailed distribution of Modified Rankin Scale (mRS) score will be recorded. The mRS score ranges from 0 to 5, where high scores mean a worse outcome. | Day 90 | 
| Favorable outcome at 30 days (the Modified Rankin Scale (mRS) score≤2) | The proportion of patients with favorable outcome, which is defined as the Modified Rankin Scale (mRS) score 0-2. | Day 30 | 
| The Modified Rankin Scale (mRS) score at 30 days | The detailed distribution of Modified Rankin Scale (mRS) score will be recorded. The mRS score ranges from 0 to 5, where high scores mean a worse outcome. | Day 30 | 
| NIH Stroke Scale (NIHSS) score at 3 days | The NIH Stroke Scale (NIHSS) score ranges from 0 to 42, where high scores mean a worse outcome. | Day 3 | 
| NIH Stroke Scale (NIHSS) score at 7 days | The NIH Stroke Scale (NIHSS) score ranges from 0 to 42, where high scores mean a worse outcome. | Day 7 | 
| Changes of lesion volume from baseline to day 7 | The infarct lesion volume will be measures on magnetic resonance imaging DWI and FLAIR. | Day 7 | 
| Length of hospital stay | Record the time when patients discharge from hospital. | Up to 30 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sodium valproate, Acute ischemic stroke