Reducing Edema After intraCerebral Hemorrhage

Study Overview
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Brief Summary
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The REACH trial is a prospective multicenter double-blind randomized placebo-controlled trial with blinded end-point adjudication. Participants are randomized (1:1) to receive either sodium aescinate or matching placebo (0.9% saline). The primary outcome is the absolute volume of PHE evaluated based on brain CT image on day 14 after ICH.

Detailed Description
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The REACH trial is a prospective multicenter double-blind randomized placebo-controlled trial with blinded end-point adjudication. Participants are randomized (1:1) to receive either sodium aescinate or matching placebo (0.9% saline). The primary outcome is the absolute volume of PHE evaluated based on brain CT image on day 14 after ICH. Functional outcome is assessed face to face at 3-month after onset. Meanwhile, central telephone follow-up determines functional outcomes at 3-month after onset. Brain imaging (CT) is performed as part of routine care prior to enrolment. A research CT scan is performed after 24h of symptom onset to assess hematoma expansion; a second research CT scan is performed at 72 hours after onset to assess brain swelling and dynamic change of PHE. The study was approved by the ethics committee of the Beijing Tiantan hospital. The study is conducted according to GCP guidelines.

Official Title
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Reducing Edema After intraCerebral Hemorrhage

Conditions
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Edema Brain

Intervention / Treatment
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* Drug: Sodium Aescinate
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients aged between 18-80 years old; Spontaneous ICH confirmed by cranial CT; Time from onset to randomization within 24 hours; Superatentorial ICH; Hematoma volume between 10-30 ml (calculated using ABC/2 method); Glasgow coma scale (GCS) > 9 on admission; informed and consent. Exclusion Criteria: Suspected secondary cause of ICH (e.g. aneurysm, vascular malformation, neoplasia, cerebral venous thrombosis, hemorrhagic transformation of recent ischemic stroke, thrombolysis or endovascular treatment, anticoagulation, et al); ICH secondary to trauma； Primary intraventricular hemorrhage (IVH); Signs of herniation, such as progressive decline in consciousness, decreased or disappearance of pupillary light reflection, bilateral pyramidal tract signs, etc; Other serious, advanced or terminal illness such that life expectancy is less than one year (e.g. advanced metastatic cancer); Severe cardiac insufficiency (NYHA class III or IV); High-risk arrhythmia, such as sick sinus syndrome, second or third degree atrioventricular block, bradycardia-related syncope without a pacemaker, etc; Severe liver insufficiency; severe liver insufficiency is defined as ALT > 2 times the upper limit of normal or AST greater than 2 times the upper limit of normal; Severe renal insufficiency: Severe renal insufficiency is defined as creatinine greater than 1.5 times the upper limit of normal; History of severe asthma or chronic obstructive pulmonary disease (COPD); History of coagulopathy or systemic bleeding; A thrombocyte count below <100 x 10^9/L or leukocytosis < 2 x 10^9/L on admission; Patients who plan to undergo surgical intervention before the first administration, including but not limited to hematoma removal (including minimally invasive and conventional surgery), decompressive craniectomy, hematoma aspiration, and ventricular puncture external drainage; Patients with preexisting disability of a modified Rankin Scale (mRS) score greater than 2 prior to ICH; Unable to understand the research procedures and/or complete follow-up due to mental illness, cognitive impairment, affective disorder, etc; Women of childbearing potential, pregnant, or breastfeeding at randomization; Contraindication to sodium aescinate； Participate in other clinical studies within 3 months or are participating in other clinical studies.

Ages Eligible for Study
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Minimum Age: 18 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: sodium aescinate group<br>Trial treatment is administered as sodium Aescinate 10mg in 250ml sodium chloride 0.9% infusion bag intravenously once daily for 10 days. | Drug: Sodium Aescinate<br>* sodium Aescinate 10mg in 250ml sodium chloride 0.9% infusion bag intravenously once daily for 10 days.<br>* Other names: Sodium Aescinate for Injection;|
| Placebo Comparator: placebo group<br>Trial treatment is administered as 250ml sodium chloride 0.9% infusion bag intravenously once daily for 10 days. | Drug: Placebo<br>* 250ml sodium chloride 0.9% infusion bag intravenously once daily for 10 days.<br>* Other names: 0.9% sodium chloride injection;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute edema volume on day 14 after ICH | Absolute edema volume is based on brain CT image | on day 14 after ICH | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relative edema volume on day 14 after ICH | Relative edema volume is based on edema volume divided by hematoma volume | on day 14 after ICH | 
| Absolute edema volume and relative edema volume on 24 ±12 hour and 72±12 hour after ICH symptom onset | absolute edema volume is based on brain CT image；relative edema volume is based on edema volume divided by hematoma volume | on 24±12 hour and 72±12 hour after ICH symptom onset | 
| Cytotoxic edema on 72 ±12 hour after ICH symptom onset | Cytotoxic edema is based on brain MRI image | on 72 ±12 hour after ICH symptom onset | 
| Dynamic changes of serum IL-x levels(ng/ml) within 14 days of symptom onset | The purpose is to evaluate dynamic changes of serum inflammatory factor levels within 14 days of symptom onset | within 14 days of symptom onset | 
| Dynamic changes of serum NF-kB levels(ug/ml) within 14 days of symptom onset | The purpose is to evaluate dynamic changes of serum inflammatory factor levels within 14 days of symptom onset | within 14 days of symptom onset | 
| Dynamic changes of serum TNF levels(ng/ml) within 14 days of symptom onset | The purpose is to evaluate dynamic changes of serum inflammatory factor levels within 14 days of symptom onset | within 14 days of symptom onset | 
| Dynamic changes of serum MMPs levels(ug/ml) within 14 days of symptom onset | The purpose is to evaluate dynamic changes of serum inflammatory factor levels within 14 days of symptom onset | within 14 days of symptom onset | 
| Dynamic changes of serum VEGF levels(pg/ml) within 14 days of symptom onset | The purpose is to evaluate dynamic changes of serum inflammatory factor levels within 14 days of symptom onset | within 14 days of symptom onset | 
| Dynamic changes of serum EPO levels(ng/ml) within 14 days of symptom onset | The purpose is to evaluate dynamic changes of serum inflammatory factor levels within 14 days of symptom onset | within 14 days of symptom onset | 
| Dynamic changes of serum angiopoietin-1 levels(pg/ml) within 14 days of symptom onset | The purpose is to evaluate dynamic changes of serum inflammatory factor levels within 14 days of symptom onset | within 14 days of symptom onset | 
| Change of neurological dysfunction within 14 days of symptom onset | Change of neurological dysfunction within 14 days of symptom onset is based on National institute of health stroke scale(NIHSS）14d-NIHSS enrollment.（The minimum and maximum values of NIHSS is 0 and 42,respectively, higher scores mean a worse outcome.） | within 14 days of symptom onset | 
| Cognition（MMSE) at 14 days of symptom onset | Cognition is based on Mini-mental State Examination（MMSE）. （The minimum and maximum values of MMSE is 0 and 30,respectively, higher scores mean a better outcome. ） | at 14 days of symptom onset | 
| Cognition（MoCA) at 14 days of symptom onset | Cognition is based on Montreal Cognitive Assessment（MoCA）. （The minimum and maximum values of MoCA is 0 and 30,respectively, higher scores mean a better outcome.） | at 14 days of symptom onset | 
| Dependency at 90±7 days after onset | Dependency at 90±7 days after onset Dependency is based on Modified Rankin Scale（mRS ）. （The minimum and maximum values of mRS is 0 and 5,respectively, higher scores mean a worse outcome.） | at 90±7 days after onset | 
| Quality of life at 90±7 days after onset | Quality of Life is based on five-level version of EuroQol Five Dimensions Questionnaire（EQ-5D-5L）. （The scale mainly contains 5 dimensions, including mobility, self-care ability, ability to perform daily activities, pain or discomfort, and anxiety or depression. Each dimension is divided into 5 levels: no difficulty, mild difficulty, moderate difficulty, severe difficulty, extreme difficulty or inability） | at 90±7 days after onset | 
| Cognition（MMSE） at 90±7 days after onset | Cognition is based on Mini-mental State Examination（MMSE）. （The minimum and maximum values of MMSE is 0 and 30,respectively, higher scores mean a better outcome. ） | at 90±7 days after onset | 
| Cognition（MoCA） at 90±7 days after onset | Cognition is based on Montreal Cognitive Assessment（MoCA）. （The minimum and maximum values of MoCA is 0 and 30,respectively, higher scores mean a better outcome.） | at 90±7 days after onset | 
| adverse events(AEs) and serious adverse events（SAEs) through 14 days | Any complications associated with sodium aescinate treatment (e.g. allergy, gastrointestinal complications, bleedings, thrombotic, or infectious complications) were defined as adverse events (AEs). SAEs are defined as any untoward medical occurrence or effect that at any dose results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity. SAEs and safety endpoints are reported in line with expedited reporting regulations and then adjudicated by an independent panel. | up to 14 days | 
| all serious adverse events(SAEs) throughout the study follow-up period up to 3 months | SAEs are defined as any untoward medical occurrence or effect that at any dose results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity. | up to 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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edema, intracerebral hemorrhage, sodium aescinate