StrokeSOLUTION-ICDNCT07514949
The Feasibility and Safety of RK-4 Injection Bypassing Blood-brain Barrier in the Treatment of Acute Large Hemispheric Infarction Using Intracalvariosseous Injection Device
A study testing RK-4 ICO injection and Conventional treatment in people with Stroke and Acute Ischemic Stroke, run by yilong Wang at 1 site in China.
Trial summary
A pilot study confirmed the feasibility and safety of neuroprotectant RK-4 intracalvariosseous(ICO) injection in patients with malignant middle cerebral artery infarction (mMCAI), showing a trend in improving 90-day functional scores compared to conventional treatment. Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- Stroke, Acute Ischemic Stroke, Blood-Brain Barrier
- What is being tested?
- RK-4 ICO injection and Conventional treatment
- Type of treatment
- Injection or infusion, Medical device
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 6 participants
- Where
- 1 siteChina
- Study dates
- 15 Apr 2026to 15 Nov 2026
- Phase
- Interventional
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 18≤Age≤80 years;
- First stroke or complete self-care before the onset of current stroke (mRS 0-1);
- Administration of drugs can be completed within 24h of the onset of signs and symptoms of neurological deficits (in patients with wake-up strokes or unwitnessed strokes, the time of onset is defined as the time of last normal presentation);
- Clinical symptoms, signs and imaging diagnosis of cerebral infarction in the area supplied by the middle cerebral artery, together with the following features:
- 16≤ NIHSS ≤32 points, and the sum of the scores of motor arm and motor leg is ≥6;
- Imaging suggestive of core infarct area: apparent diffusion coefficient (ADC) values <620×10-6mm2/s lesion volume on magnetic resonance imaging (MRI) diffusion-weighted imaging (DWI) sequences or cerebral blood flow (CBF) <30% of volume 70-300 ml on computed tomography perfusion imaging (CTP) or an Alberta Stroke Program Early CT Score (ASPECTS) of 0-6, with inconsistent findings, the investigator is required to make a reasoned judgement by taking into account all the information (scanning time, the imaging method that best responds to the size of infarct, etc.) and record it.
- NIHSS score not improving or progressing after reperfusion therapy and total score still ≤32.
- Informed consent signed.
Who cannot join
- Complications with other cerebrovascular diseases meet one of the following conditions:
- Complicated with acute cerebral hemorrhage and subarachnoid hemorrhage;
- Complicated with acute posterior circulation cerebral infarction or severe posterior circulation stenosis (>70%);
- Or imaging suggests that the area of cerebral infarction is involved bilaterally;
- The cause of the TOAST classification was considered as intracranial artery dissection, vasculitis, moyamoya disease and other etiological types.
- Hemorrhage transformation in the infarction area, hematoma area ≥30% of the infarction area, and has obvious space-occupying effect;
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- Presence of clinical signs of brain herniation formation, e.g., unilateral or bilateral pupil dilation and fixation; cerebral oedema-associated loss of consciousness (NIHSS 1a > 2 points), or other loss of brainstem reflexes in the judgement of the investigator, caused by cerebral oedema or cerebral herniation formation; or other signs of instability of vital signs that are difficult to control;
- Craniotomy decompression was planned before randomization;
- Refractory hypertension (systolic > 200mmHg or diastolic > 110mmHg) or hypotension (systolic < 70mmHg or diastolic < 50mmHg) that is difficult to control with medication;
- Abnormal blood glucose before randomization (random venous blood glucose < 2.8mmol/L or > 23mmol/L);
- Presence of significant abnormal liver function markers or renal function markers prior to randomization; Note: Severe liver function abnormalities were defined as serum alanine aminotransferase (ALT), or aspartate aminotransferase (AST) > 3 times the upper limit of normal (ULN). Significant renal insufficiency is defined as eGFR less than 60 mL/min/1.73 m2 (eGFR, calculated using the CKD-EPI formula)
- Acute ST-elevation myocardial infarction (MI) and/or decompensated heart failure (meeting the New York College of Cardiology (NYHA) Heart function grades III and IV) within the past 3 months;
- Presence of contraindications to intracalvariosseous injection, e.g., skull fracture in the last 3 months, skull infection, subdural/extradural hematoma, subcutaneous hematoma, skin or subcutaneous infection of the scalp, poorly displayed skull bone marrow niches;
- Bleeding tendencies considered by the investigators to be detrimental to the procedure include, but are not limited to, platelet counts < 100×109/L, and the presence of clotting disorders such as hemophilia;
- Presence of severe or very severe anemia (hemoglobin <60 g/L) at randomization;
- Patients with severe respiratory diseases (severe chronic obstructive pulmonary disease, respiratory failure, etc.) should be corrected by intubation, tracheotomy, or ventilator;
- The subjects were considered to have developed clinically significant serious infections, including severe local infections or systemic infections;
- Diagnosed severe degenerative diseases of the central nervous system such as Alzheimer's Disease (AD), Parkinson's Disease (PD), and severe dementia of all causes, or psychiatric disorders (e.g., schizophrenia, depression, etc.);
- Subjects with a life expectancy of less than 3 months due to conditions not considered current by the investigators, such as tumors;
- Known allergy to any component of investigational process therapy drugs and contrast agents;
- Subjects who are pregnant, breastfeeding or have the possibility of becoming pregnant or plan to become pregnant;
- Subjects are unable to comply with trial protocols or follow-up requirements;
- Other circumstances deemed by the investigators to be unsuitable for enrollment (registration of reasons for inability to enroll is required);
- Have participated in other interventional clinical trials.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
About this study
A pilot study confirmed the feasibility and safety of neuroprotectant RK-4 intracalvariosseous(ICO) injection in patients with malignant middle cerebral artery infarction (mMCAI), showing a trend in improving 90-day functional scores compared to conventional treatment. The aim of this trial is to investigate the feasibility and safety of neuroprotective agent RK-4 injection using intracalvariosseous injection device in patients with acute large hemispheric infarction (LHI) who has contraindications of reperfusion therapy or have got poor reperfusion therapy outcomes.
Read the detailed description
The mortality rate of large hemispheric infarction (LHI) is up to 40%-60%, while current available treatment is limited. Mainstream therapeutics include endovascular reperfusion therapy and decompressive craniectomy. But endovascular-reperfusion has limits such as short time window and hemorrhagic transformation risk, while decompressive craniectomy can reduce mortality but not infarct volume. Curative effect of intravenous injection of neuroprotective drugs is severely limited because of the blood-brain barrier. Microchannels connecting the skull bone marrow and dura may be effective drug delivery shortcuts bypassing the blood-brain barrier. Cytoprotective drug RK-4 affects dual aspects of ischemic cascade by disrupting both function of the synaptic folding post-synaptic density protein 95 (PSD-95), as well as α2-v#Aminobutyric acid type A receptor (α2-GABAAR) agonist. Phase I and Phase II clinical trials have confirmed the safety and efficacy of intravenous infusion of RK-4 in treating cerebral infarction, with the optimal dosage being 40mg. Preclinical testing proved that ICO injection of RK-4 solution 24h post rat permanent middle cerebral artery infarction reduced rat infarction volume and improved neurological function. Previously, our team has conducted the RK-4 intracalvariosseous administration in the earlier SOLUTION clinical trail through the existing neurosurgical devices. Although the safety and efficacy were preliminarily demonstrated, present administration device is not minimally invasive and requires operation in the ICU, which leads to a higher risk of the inner plate penetration. The new intracalvariosseous injection device shows promising prospective in precise control of the drilling speed and depth, and better achievement of accurate, high-efficiency and microinvasive drug delivery.
The study is a single-centered, prospective, randomized, open-label study. The purpose of this study is to investigate the feasibility and safety of RK-4 injection using intracalvariosseous injection device in acute LHI patients with contraindications of reperfusion therapy or poor outcomes.
Patients will be randomly assigned to one of the following 2 groups at 1:1 ratio.
ICO injection group: RK-4 ICO injection through intracalvariosseous injection device (using an electric bone drill to drill 3 holes (each for 1-time administration) from the outer plate of the skull without penetrating the inner cranial plate), dose was given as 32 ug/kg once a day for 3 consecutive days, as well as standard treatment and management according to the related guidelines. Conventional treatment group: Conventional treatment group will receive standard treatment and management according to related guidelines.
Face to face interviews will be made on baseline, 4±1 days after randomization, 8±1 days after randomization, 14±1 days after randomization or discharge day, and 90±7 days,180±14 days after randomization.
The primary outcomes include feasibility outcomes and safety outcomes. Feasibility Outcomes include the internal plate of skull was drilled thoroughly, drug leakage during injection, the patient refused to continue, failure for other reasons during 3 days'treatment. Safety Outcomes includes Infection events (skin infection, osteomyelitis, or intracranial infection), symptomatic and non- symptomatic intracranial hemorrhage, moderate to severe bleeding (defined by the GUSTO), hepatic insufficiency, severe renal insufficiency during the treatment, severe or extremely severe anaemia (hemoglobin <60g / L), mortality, incidence of other adverse events / serious adverse events reported.
The secondary outcomes include the effectiveness outcomes. The effectiveness outcomes include change of Glasgow Coma Scale (GCS) scores from baseline values to 14±1 days or at discharge, the change of the The National Institutes of Health Stroke Scale (NIHSS) scores from baseline to 14±1 days or at discharge, the modified Rankin Scale(mRS) 0-3 points at 90±7 days and the mRS 0-3 points at 180±14 days.
A Data and Safety Monitoring Board (DSMB) will regularly monitor safety during the study. The trial has been approved by Institutional Review Board (IRB) and Ethics Committee (EC) in Being Tiantan hospital, Capital Medical University.
- Conditions
- Stroke, Acute Ischemic Stroke, Blood-Brain Barrier
- Being tested
- RK-4 ICO injection, Conventional treatment
- Keywords
- large hemispheric infarction, postsynaptic density protein 95 inhibitor, BBB-bypassing route, brain drug delivery, intracalvariosseous injection, intracalvariosseous injection device
- Medical subject headings
- Stroke, Ischemic Stroke
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
RK-4 ICO injectionDevice
Patients included will be given skull outer plate drilling surgery and RK-4 ICO injection under local anesthesia and sedation using the intracalvariosseous injection device. The drilling and injection will be conducted once a day for 3 consecutive days.
Conventional treatmentOther
standard treatment and management according to related guidelines
| Study group | Role | What they receive |
|---|---|---|
| ICO injection group | Experimental | RK-4 ICO injection through intracalvariosseous injection device (drilling 3 holes (each for 1-time administration) from the outer cranial plate without penetrating the inner plate), dose was given as 32 ug/kg once a day for 3 consecutive days, as well as standard treatment and management according to the related guidelines. Receives: Device: RK-4 ICO injection; Other: Conventional treatment |
| Conventional treatment group | Sham comparator | standard treatment and management according to related guidelines. Receives: Other: Conventional treatment |
What is being measured
The primary outcome is the main question the study is designed to answer.
Failed of drilling
The rate of the internal plate of skull was drilled through
Measured: during 3 days of treatment
Number of drug-leakage events
Number of drug-leakage events
Measured: during 3 days of treatment
Patients' tolerance of therapy
The number of patients who refused to continue the treatment because of the intolerance
Measured: during 3 days of treatment
Failed for other reasons
Number of failed for other reasons
Measured: during 3 days of treatment
Rate of participants with infection events
Rate of participants with infection events (including skin infection, osteomyelitis of skull, or intracranial infection)
Measured: within 90±7 days after randomization
Rate of intracranial hemorrhage
Rate of symptomatic and non-symptomatic intracranial hemorrhage
Measured: within 90±7 days after randomization
Rate of bleeding
Rate of bleeding (moderate to severe bleeding, defined by the GUSTO)
Measured: within 90±7 days after randomization
Rate of hepatic insufficiency
Rate of hepatic insufficiency: serum alanine aminotransferase (ALT), or aspartate aminotransferase (AST) > 5 times the upper limit of normal (ULN), or alkaline phosphatase (APL)> 2 times the ULN or the multiple of the abnormal baseline value before medication; Or, serum total bilirubin (TBil) > 2.5 mg/dL (42.75 μmol/L), accompanied by increased levels of serum AST, ALT or ALP.
Measured: within 90±7 days after randomization
Rate of severe renal insufficiency
Rate of severe renal insufficiency: estimated glomerular filtration rate (eGFR)<30 ml/min/1.73m2 during the treatment.
Measured: within 90±7 days after randomization
Severe or extremely severe anaemia
Severe or extremely severe anaemia (hemoglobin <60g / L)
Measured: within 90±7 days after randomization
Mortality
Mortality
Measured: within 90±7 days after randomization
Adverse events / serious adverse events
Incidence of other adverse events / serious adverse events reported.
Measured: within 90±7 days after randomization
Secondary outcomes (4)
Change of GCS scores from baseline
The Glasgow Coma Scale (GCS) score is a validated and reliable scale to evaluate level of consciousness in patients. The scale assesses 3 functions: Eye Opening, Verbal Response, and Motor Response. GCS scores range from 15 (best) to 3 (worst).
Measured: baseline#14±1 days after randomization or at discharge
Change of the NIHSS scores from baseline
Change of the National Institutes of Health Stroke Scale (NIHSS) scores from baseline to 14±1days or at discharge. The NIHSS is a standardized neurological examination score that is a valid and reliable measure of disability and recovery after acute stroke. Scores range from 0 to 42, with higher scores indicating increasing severity.
Measured: 14±1 days after randomization or at discharge
90 days functional improvement
The modified Rankin Scale 0-3 points at 90±7 days. Functional improvement is defined as a dichotomized modified Rankin Scale(mRS) 0-3 outcome.
The mRS is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. The scale runs from 0-6 with "0" being perfect health without symptoms to "6" being death.
Score 0: No symptoms Score 1: No significant disability. Able to carry out all usual activities, despite some symptoms.
Score 2: Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities.
Score 3: Moderate disability. Requires some help, but able to walk unassisted. Score 4: Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted.
Score 5: Severe disability. Requires constant nursing care and attention, bedridden, incontinent.
Score 6: Dead
Measured: 90±7 days after randomization
180 days functional improvement
The modified Rankin Scale 0-3 points at 180±14 days. Functional improvement is defined as a dichotomized modified Rankin Scale(mRS) 0-3 outcome.
The mRS is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. The scale runs from 0-6 with "0" being perfect health without symptoms to "6" being death.
Score 0: No symptoms Score 1: No significant disability. Able to carry out all usual activities, despite some symptoms.
Score 2: Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities.
Score 3: Moderate disability. Requires some help, but able to walk unassisted. Score 4: Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted.
Score 5: Severe disability. Requires constant nursing care and attention, bedridden, incontinent.
Score 6: Dead
Measured: 180±14 days after randomization
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Apr 2026
- Study start15 Apr 2026 (estimated)
- Primary completion15 Nov 2026 (estimated)
- Study completion15 Nov 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (19)Papers the sponsor has linked to this study.
- Other trials for StrokeStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 6 participants (estimated)
Sponsor and investigators
- Lead sponsor
- yilong Wang
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor-investigator, yilong Wang, Beijing Tiantan Hospital
- Investigators
- Yilong Wang, PhD#MD, Principal investigator, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07514949
- Sponsor's protocol ID
- Z231100004823036
- Acronym
- SOLUTION-ICD
- Status last verified
- Nov 2025
- First submitted
- 27 Nov 2025
- Last updated
- 7 Apr 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Mazzitelli JA, Smyth LCD, Cross KA, Dykstra T, Sun J, Du S, Mamuladze T, Smirnov I, Rustenhoven J, Kipnis J. Cerebrospinal fluid regulates skull bone marrow niches via direct access through dural channels. Nat Neurosci. 2022 May;25(5):555-560. doi: 10.1038/s41593-022-01029-1. Epub 2022 Mar 17.
PubMed 35301477Pulous FE, Cruz-Hernandez JC, Yang C, Kaya Zeta, Paccalet A, Wojtkiewicz G, Capen D, Brown D, Wu JW, Schloss MJ, Vinegoni C, Richter D, Yamazoe M, Hulsmans M, Momin N, Grune J, Rohde D, McAlpine CS, Panizzi P, Weissleder R, Kim DE, Swirski FK, Lin CP, Moskowitz MA, Nahrendorf M. Cerebrospinal fluid can exit into the skull bone marrow and instruct cranial hematopoiesis in mice with bacterial meningitis. Nat Neurosci. 2022 May;25(5):567-576. doi: 10.1038/s41593-022-01060-2. Epub 2022 May 2.
PubMed 35501382Brioschi S, Wang WL, Peng V, Wang M, Shchukina I, Greenberg ZJ, Bando JK, Jaeger N, Czepielewski RS, Swain A, Mogilenko DA, Beatty WL, Bayguinov P, Fitzpatrick JAJ, Schuettpelz LG, Fronick CC, Smirnov I, Kipnis J, Shapiro VS, Wu GF, Gilfillan S, Cella M, Artyomov MN, Kleinstein SH, Colonna M. Heterogeneity of meningeal B cells reveals a lymphopoietic niche at the CNS borders. Science. 2021 Jul 23;373(6553):eabf9277. doi: 10.1126/science.abf9277. Epub 2021 Jun 3.
PubMed 34083450Herisson F, Frodermann V, Courties G, Rohde D, Sun Y, Vandoorne K, Wojtkiewicz GR, Masson GS, Vinegoni C, Kim J, Kim DE, Weissleder R, Swirski FK, Moskowitz MA, Nahrendorf M. Direct vascular channels connect skull bone marrow and the brain surface enabling myeloid cell migration. Nat Neurosci. 2018 Sep;21(9):1209-1217. doi: 10.1038/s41593-018-0213-2. Epub 2018 Aug 27.
PubMed 30150661Xie J, Shen Z, Anraku Y, Kataoka K, Chen X. Nanomaterial-based blood-brain-barrier (BBB) crossing strategies. Biomaterials. 2019 Dec;224:119491. doi: 10.1016/j.biomaterials.2019.119491. Epub 2019 Sep 14.
PubMed 31546096Charabati M, Rabanel JM, Ramassamy C, Prat A. Overcoming the Brain Barriers: From Immune Cells to Nanoparticles. Trends Pharmacol Sci. 2020 Jan;41(1):42-54. doi: 10.1016/j.tips.2019.11.001. Epub 2019 Dec 12.
PubMed 31839374Terstappen GC, Meyer AH, Bell RD, Zhang W. Strategies for delivering therapeutics across the blood-brain barrier. Nat Rev Drug Discov. 2021 May;20(5):362-383. doi: 10.1038/s41573-021-00139-y. Epub 2021 Mar 1.
PubMed 33649582Daneman R, Prat A. The blood-brain barrier. Cold Spring Harb Perspect Biol. 2015 Jan 5;7(1):a020412. doi: 10.1101/cshperspect.a020412.
PubMed 25561720Hill MD, Goyal M, Menon BK, Nogueira RG, McTaggart RA, Demchuk AM, Poppe AY, Buck BH, Field TS, Dowlatshahi D, van Adel BA, Swartz RH, Shah RA, Sauvageau E, Zerna C, Ospel JM, Joshi M, Almekhlafi MA, Ryckborst KJ, Lowerison MW, Heard K, Garman D, Haussen D, Cutting SM, Coutts SB, Roy D, Rempel JL, Rohr AC, Iancu D, Sahlas DJ, Yu AYX, Devlin TG, Hanel RA, Puetz V, Silver FL, Campbell BCV, Chapot R, Teitelbaum J, Mandzia JL, Kleinig TJ, Turkel-Parrella D, Heck D, Kelly ME, Bharatha A, Bang OY, Jadhav A, Gupta R, Frei DF, Tarpley JW, McDougall CG, Holmin S, Rha JH, Puri AS, Camden MC, Thomalla G, Choe H, Phillips SJ, Schindler JL, Thornton J, Nagel S, Heo JH, Sohn SI, Psychogios MN, Budzik RF, Starkman S, Martin CO, Burns PA, Murphy S, Lopez GA, English J, Tymianski M; ESCAPE-NA1 Investigators. Efficacy and safety of nerinetide for the treatment of acute ischaemic stroke (ESCAPE-NA1): a multicentre, double-blind, randomised controlled trial. Lancet. 2020 Mar 14;395(10227):878-887. doi: 10.1016/S0140-6736(20)30258-0. Epub 2020 Feb 20.
PubMed 32087818Zhou L, Li F, Xu HB, Luo CX, Wu HY, Zhu MM, Lu W, Ji X, Zhou QG, Zhu DY. Treatment of cerebral ischemia by disrupting ischemia-induced interaction of nNOS with PSD-95. Nat Med. 2010 Dec;16(12):1439-43. doi: 10.1038/nm.2245. Epub 2010 Nov 21.
PubMed 21102461Ugalde-Trivino L, Diaz-Guerra M. PSD-95: An Effective Target for Stroke Therapy Using Neuroprotective Peptides. Int J Mol Sci. 2021 Nov 22;22(22):12585. doi: 10.3390/ijms222212585.
PubMed 34830481Kolias AG, Kirkpatrick PJ, Hutchinson PJ. Decompressive craniectomy: past, present and future. Nat Rev Neurol. 2013 Jul;9(7):405-15. doi: 10.1038/nrneurol.2013.106. Epub 2013 Jun 11.
PubMed 23752906Vahedi K, Hofmeijer J, Juettler E, Vicaut E, George B, Algra A, Amelink GJ, Schmiedeck P, Schwab S, Rothwell PM, Bousser MG, van der Worp HB, Hacke W; DECIMAL, DESTINY, and HAMLET investigators. Early decompressive surgery in malignant infarction of the middle cerebral artery: a pooled analysis of three randomised controlled trials. Lancet Neurol. 2007 Mar;6(3):215-22. doi: 10.1016/S1474-4422(07)70036-4.
PubMed 17303527Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, Biller J, Brown M, Demaerschalk BM, Hoh B, Jauch EC, Kidwell CS, Leslie-Mazwi TM, Ovbiagele B, Scott PA, Sheth KN, Southerland AM, Summers DV, Tirschwell DL. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2019 Dec;50(12):e344-e418. doi: 10.1161/STR.0000000000000211. Epub 2019 Oct 30.
PubMed 31662037Wu S, Wu B, Liu M, Chen Z, Wang W, Anderson CS, Sandercock P, Wang Y, Huang Y, Cui L, Pu C, Jia J, Zhang T, Liu X, Zhang S, Xie P, Fan D, Ji X, Wong KL, Wang L; China Stroke Study Collaboration. Stroke in China: advances and challenges in epidemiology, prevention, and management. Lancet Neurol. 2019 Apr;18(4):394-405. doi: 10.1016/S1474-4422(18)30500-3.
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