Safety and Efficacy of RIC in Pediatric Moyamoya Disease Patients Treated With Revascularization Therapy (RIC-PMD)

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

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.

Study Overview

• Status: Unknown
• Conditions: Moyamoya Disease; Pediatric
• Intervention / Treatment: Device: RIC group; Device: sham group

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 68
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Xunming Ji, MD PhD; Phone Number: 108613911077166; Email: 807595234@qq.com
• Study Contact Backup: Name: Sijie Li, MD; Phone Number: 1083199439; Email: phoenix0537@sina.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: RIC group; 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; 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.
Sham Comparator: sham group; 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; 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Capital Medical University

Publications and helpful links

General Publications

• Kuriyama S, Kusaka Y, Fujimura M, Wakai K, Tamakoshi A, Hashimoto S, Tsuji I, Inaba Y, Yoshimoto T. Prevalence and clinicoepidemiological features of moyamoya disease in Japan: findings from a nationwide epidemiological survey. Stroke. 2008 Jan;39(1):42-7. doi: 10.1161/STROKEAHA.107.490714. Epub 2007 Nov 29.
• Kim SK, Seol HJ, Cho BK, Hwang YS, Lee DS, Wang KC. Moyamoya disease among young patients: its aggressive clinical course and the role of active surgical treatment. Neurosurgery. 2004 Apr;54(4):840-4; discussion 844-6. doi: 10.1227/01.neu.0000114140.41509.14.
• Kim JE, Oh CW, Kwon OK, Park SQ, Kim SE, Kim YK. Transient hyperperfusion after superficial temporal artery/middle cerebral artery bypass surgery as a possible cause of postoperative transient neurological deterioration. Cerebrovasc Dis. 2008;25(6):580-6. doi: 10.1159/000132205. Epub 2008 May 16.
• Fujimura M, Shimizu H, Inoue T, Mugikura S, Saito A, Tominaga T. Significance of focal cerebral hyperperfusion as a cause of transient neurologic deterioration after extracranial-intracranial bypass for moyamoya disease: comparative study with non-moyamoya patients using N-isopropyl-p-[(123)I]iodoamphetamine single-photon emission computed tomography. Neurosurgery. 2011 Apr;68(4):957-64; discussion 964-5. doi: 10.1227/NEU.0b013e318208f1da.
• Funaki T, Takahashi JC, Takagi Y, Kikuchi T, Yoshida K, Mitsuhara T, Kataoka H, Okada T, Fushimi Y, Miyamoto S. Unstable moyamoya disease: clinical features and impact on perioperative ischemic complications. J Neurosurg. 2015 Feb;122(2):400-7. doi: 10.3171/2014.10.JNS14231. Epub 2014 Nov 28.
• Zhao W, Meng R, Ma C, Hou B, Jiao L, Zhu F, Wu W, Shi J, Duan Y, Zhang R, Zhang J, Sun Y, Zhang H, Ling F, Wang Y, Feng W, Ding Y, Ovbiagele B, Ji X. Safety and Efficacy of Remote Ischemic Preconditioning in Patients With Severe Carotid Artery Stenosis Before Carotid Artery Stenting: A Proof-of-Concept, Randomized Controlled Trial. Circulation. 2017 Apr 4;135(14):1325-1335. doi: 10.1161/CIRCULATIONAHA.116.024807. Epub 2017 Feb 7.

Study record dates

Study Major Dates

• Study Start (Anticipated): December 30, 2019
• Primary Completion (Anticipated): December 30, 2020
• Study Completion (Anticipated): December 30, 2020

Study Registration Dates

• First Submitted: March 12, 2018
• First Submitted That Met QC Criteria: June 3, 2018
• First Posted (Actual): June 6, 2018

Study Record Updates

• Last Update Posted (Actual): November 20, 2019
• Last Update Submitted That Met QC Criteria: November 19, 2019
• Last Verified: November 1, 2019

More Information

Terms related to this study

• Keywords: remote ischemic conditioning; pediatric moyamoya disease; revascularization therapy
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Arterial Occlusive Diseases; Carotid Artery Diseases; Cerebral Arterial Diseases; Intracranial Arterial Diseases; Moyamoya Disease
• Other Study ID Numbers: RIC-PMD

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No