Safety and Efficacy of RIC in Pediatric Moyamoya Disease Patients Treated With Revascularization Therapy

Study Overview
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Brief Summary
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Revascularization surgery has been the standard treatment to prevent ischemic stroke in pediatric Moyamoya disease (MMD) patients with ischemic symptoms. However, perioperative complications, such as hyperperfusion syndrome, new infarct on imaging, or ischemic stroke, are inevitable. Remote ischemic conditioning (RIC) is a noninvasive and easy-to-use neuroprotective strategy, and it has potential effects on preventing hyperperfusion syndrome and ischemic infarction.

Detailed Description
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This study will provide insights into the preliminary proof of principle, safety, and efficacy of RIC in pediatric MMD patients undergoing revascularization surgery therapy, and this data will provide parameters for future larger scale clinical trials if efficacious.

Official Title
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Safety and Efficacy of Remote Ischemic Conditioning in Pediatric Moyamoya Disease Patients Treated With Revascularization Therapy

Conditions
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Moyamoya Disease, Pediatric

Intervention / Treatment
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* Device: RIC group
* Device: sham group


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age: ≥0 and ≤18 All of the patients underwent digital subtraction angiography and met the current diagnostic criteria recommended by the Research Committee on MMD (Spontaneous Occlusion of the Circle of Willis) of the Ministry of Health and Welfare of Japan in 2012 Suzuki stages concentrated in Stage III and IV Presentation with ischemic symptoms, such as transient ischemic attack (TIA), headache, seizure, hemorrhagic stroke, and ischemic stroke confirmed by MRI Informed consent obtained from patient or acceptable patient's surrogate Exclusion Criteria: Severe hepatic or renal dysfunction Severe hemostatic disorder or severe coagulation dysfunction Patients with unilateral MMD or the presence of secondary moyamoya phenomenon caused by autoimmune disease, Down syndrome, neurofibromatosis, leptospiral infection, or previous skull-base radiation therapy Any of the following cardiac disease - rheumatic mitral and or aortic stenosis, prosthetic heart valves, atrial fibrillation, atrial flutter, sick sinus syndrome, left atrial myxoma, patent foramen ovale, left ventricular mural thrombus or valvular vegetation, congestive heart failure, bacterial endocarditis, or any other cardiovascular condition interfering with participation Serious, advanced, or terminal illnesses with anticipated life expectancy of less than one year Patient participating in a study involving other drug or device trial study Patients with existing neurological or psychiatric disease that would confound the neurological or functional evaluations Unlikely to be available for follow-up for 3 months Contraindication for RIC - severe soft-tissue injury, fracture, or peripheral vascular disease in the upper limbs.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 18 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RIC group<br>Patients allocated to the RIC group will undergo RIC procedure during which bilateral arm cuffs are inflated to a pressure of 50 mmHg over systolic blood pressure for five cycles of 5 min followed by 5 min of relaxation of the cuffs. | Device: RIC group<br>* Patients allocated to the RIC group will undergo RIC procedure during which bilateral arm cuffs are inflated to a pressure of 50 mmHg over systolic blood pressure for five cycles of 5 min followed by 5 min of relaxation of the cuffs.<br>|
| Sham Comparator: sham group<br>patients allocated to the sham group will undergo a sham RIC procedure during which bilateral arm cuffs are inflated to a pressure of 30 mmHg for five cycles of 5 min, followed by 5 min of relaxation of the cuffs. | Device: sham group<br>* patients allocated to the sham group will undergo a sham RIC procedure during which bilateral arm cuffs are inflated to a pressure of 30 mmHg for five cycles of 5 min, followed by 5 min of relaxation of the cuffs.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| cerebral perfusion cerebral perfusion | cerebral perfusion status in the operation side at 6 months posttreatment as assessed by single photon emission computed tomography (SPECT). | change from baseline（pre-RIC treatment) at 180 days after revascularization therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The score of National Institute of Health stroke scale score | National Institute of Health Stroke Scale (NIHSS) is considered as a standardized assessment of neurological functions in the acute phase of stroke, and it is generally used to quantify patient's neurological impairments on 15 items in 11 fields of different neurological status.The score of the scale ranges from 0 to 42.And higher score indicates worse neurological function. | change from baseline (preoperation) at 24 hours, 48 hours, 72 hours, and at 5-7 days or if discharged earlier | 
| The score of Modified Rankin scale score | The Modified Rankin Scale Score (mRS) is the most comprehensive and most widely used primary outcome measurement to assess the neurological functional disability in contemporary acute stroke trials. The mRS is an ordinal, graded interval scale that assigns patients among 7 global disability levels, which ranges from 0 (no symptom) to 5 (severe disability) and 6 (death). We will use mRS to evaluate the degree of disability or dependence during daily activities. The mRS will be assessed by certified study investigator, who is blinded to the treatment assignment, at 90 days postoperation. The distribution of mRS will be compared between groups | change from baseline (pre-RIC treatment) at 180 days after revascularization therapy | 
| Symptomatic intracerebral hemorrhage | Symptomatic intracranial hemorrhage, including any subarachnoid hemorrhage associated with clinical symptoms and symptomatic intracerebral hemorrhage. Head computed tomography or magnetic reasoning imaging (MRI) scan will be performed to confirm intracerebral hemorrhage, and the imaging will be evaluated by two independent neuroradiologists who are blinded to the study assignment. | during the first 180 days after revascularization therapy | 
| Incidence of new infarct in brain | Head MRI is a precise method which is commonly used to evaluate weather there's new infarct in brain. | during 72 hours and 180 days after revascularization therapy | 
| Angiographic outcome | Angiographic outcome will be assessed following Matsushima's criteria (proportion of the middle cerebral artery territory with revascularization from collaterals from the external carotid artery through the burr holes): Grade A: >2/3; Grade B: between 1/3 and 2/3; Grade C: <1/3. | 180 days after revascularization therapy | 
| Death and adverse event | All causes of death will be included to compute mortality at 180 days postoperation, and mortality will be compared between groups. Any adverse event will be reported and its relationship with the RIC intervention will be evaluated. | 180 days after revascularization therapy | 
| Infarct volume in brain | Head MRI is a precise method which is commonly used to evaluate infarct size. | during 72 hours and 180 days after revascularization therapy | 
| Distal radial pulses | professional doctors will check the distal radial pulses | within 7 days after RIC treatment | 
| Visual inspection for local edema | Professional oculists will check the fundus oculi to evaluate whether there is local edema. | within 7days after RIC treatment | 
| The number of patients with erythema,and/or skin lesions related to RIC | Professional doctors will check it and the investigator will record the number. | within 7days after RIC treatment | 
| Palpation for tenderness | Professional doctors will check it. | within 7days after RIC treatment | 
| The number of patients not tolerating RIC procedure,and refuse to continue the RIC procedure | The investigator will record the number. | within 7days after RIC treatment | 
| The number of patients with any other adverse events related to RIC intervention | The investigator will record the number. | within 7days after RIC treatment | 
| The score of ABCD2 | We use this scale to evaluate the patients' risk of stroke who with TIA .The score of the scale ranges from 0 to 7, and the higher score indicates higher risk of stroke in the patients who with TIA.The scale will be assessed by qualified investigator who are blinded to the treatment assignment | change from baseline (pre-RIC treatment) at 180 days after revascularization therapy | 
| The level of S-100A4 | Blood samples will be drawn from cubital vein to test these biomarkersThese samples will be centrifuged immediately after collection and stored at - 80 until batch evaluation | change from baseline (pre-RIC treatment) at 7 days after RIC treatment, 24 (-6/+12) hours, 72 ± 6 hours and 6 months postoperation | 
| The level of matrix metalloproteinase 9 (MMP-9) | Blood samples will be drawn from cubital vein to test these biomarkersThese samples will be centrifuged immediately after collection and stored at - 80 until batch evaluation | change from baseline (pre-RIC treatment) at 7 days after RIC treatment, 24 (-6/+12) hours, 72 ± 6 hours and 6 months post-operation | 
| The level of basic fibroblast growth factor | Blood samples will be drawn from cubital vein to test these biomarkersThese samples will be centrifuged immediately after collection and stored at - 80 until batch evaluation | change from baseline (pre-RIC treatment) at 7 days after RIC treatment, 24 (-6/+12) hours, 72 ± 6 hours and 6 months post-operation | 
| The level of platelet derived growth factor | Blood samples will be drawn from cubital vein to test these biomarkersThese samples will be centrifuged immediately after collection and stored at - 80 until batch evaluation | change from baseline (pre-RIC treatment) at 7 days after RIC treatment, 24 (-6/+12) hours, 72 ± 6 hours and 6 months post-operation | 
| The level of vascular endothelial growth factor | Blood samples will be drawn from cubital vein to test these biomarkersThese samples will be centrifuged immediately after collection and stored at - 80 until batch evaluation | change from baseline (pre-RIC treatment) at 7 days after RIC treatment, 24 (-6/+12) hours, 72 ± 6 hours and 6 months post-operation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pediatric moyamoya disease, remote ischemic conditioning, revascularization therapy