Optimized Remote Ischemic Conditioning (RIC) Treatment for Patients With Chronic Cerebral Ischemia
Optimized Remote Ischemic Conditioning (RIC) Treatment for Patients With Chronic Cerebral Ischemia
This prospective, randomized, single-center clinical trial is designed to figure out the most
 optimal algorithm of remote ischemic conditioning on patients with chronic cerebral ischemia.
Chronic cerebral ischemia (CCI) refers to a prevalent pathophysiological condition in which
 cerebral hypoperfusion is caused by a reduction in cerebral blood flow over a long period of
 time. CCI, as a consequence of intracranial atherosclerotic stenosis (ICAS) has been
 identified as one of the major culprits that are responsible for occurrence/recurrence of
 acute cerebrovascular accidents such as ischemic stroke and transient ischemic attack, as
 well as vascular cognitive dysfunction. The prevalence of ICAS related CCI among stroke
 patients is remarkably higher in the Chinese population than in the whites, and there are no
 quite effective therapies for the general patient population with ICAS up to now.
 Endovascular intervention appears to be a promising option for a group of patients with
 severe ICAS, but may not be applicable for those with certain vascular risk features that are
 supposed to increase the rate of complications or result in unsatisfactory clinical outcomes.
 In addition, high cost and adverse effects of medications pose huge burdens to patients,
 their families and even the whole society as well.

 RIC is a novel therapeutic approach whereby repetitive, transient, non-lethal ischemia
 intervened by reperfusion employed on a distant organ or tissue confers protection to
 targeted organs against subsequent major ischemic attack. Preclinical experimental studies
 have demonstrated the neuroprotective effects of RIC in ischemic stroke models. Meanwhile,
 small-scale, proof of concept clinical trials revealed that long-term RIC was able to lower
 the stroke recurrence and enhance the cerebral reperfusion, without inducing adverse events
 in patients with ICAS. Nevertheless, current protocol of RIC utilited in this scenario was
 mainly based on previous animal studies or cardiovascular clinical trials. Whether modifying
 the ischemic pressure, numbers of cycles, duration of ischemia as well as the method for
 application can lead to different outcomes remain to be settled. In this study, 600 patients
 satisfied with the inclusion criteria will be recruited and randomly allocated into four
 substudies to receive RIC treatment (Doctormate®) under different algorithms. The most
 optimal algorithm of RIC on patients with ICAS related CCI would be determined according to
 clinical endpoints. Other medical managements are guaranteed based on the best medical
 judgment from clinical practitioners.
Inclusion Criteria:

 -  1. Age ranging from 45 to 80 years of age, both genders;

 2. Patients diagnosed with an ischemic stroke or TIA before admission and the
 following requirements should be satisfied as well:

 1. The occurrence of an ischemic stroke within 30 days and with a baseline modified
 Rankin Scale (mRS) score≤4.

 2. The occurrence of an TIA within 15 days and with a baseline Oxfordshire Community
 Stroke Project on the basis of age, blood pressure (BP), clinical features, and
 duration of TIA symptoms (ABCD2) score≥4.

 3. Patients with symptomatic intracranial atherosclerotic stenosis (sIAS) that is
 attributed to at least 50% stenosis of the diameter of a major intracranial artery
 (carotid artery, or middle cerebral artery (M1)) verified by magnetic resonance
 angiography (MRA) or computed tomographic angiography (CTA).

 4. Informed consent obtained patients or health care proxy, as appropriate, able to
 cooperate and participate follow-up visits.

 Exclusion Criteria:

 -  1. Received intravenous or intraarterial thrombolytic therapy such as recombinant
 tissue plasminogen activator (rtPA) within 24 hours prior to inclusion.

 2. Progressive deterioration of neurological manifestations within 24 hours prior to
 inclusion.

 3. Intracranial arterial stenosis due to any of the following non-atherosclerotic
 etiologies, for instance, moyamoya disease, artery dissection, any known vasculitic
 disease, any intracranial infection, radiation induced vasculopathy, cerebrospinal
 fluid (CSF) pleocytosis associated intraarterial stenosis, genetic or developmental
 abnormalities such as fibromuscular dysplasia, neurofibromatosis, sickle cell disease,
 and mitochondrial encephalopathy, intracranial granulomatous arteritis, postpartum
 angiopathy, suspected vasospasm or embolism, iatrogenic trauma.

 4. Intracranial abnormalities such as tumor, abscess, vascular malformation, cerebral
 venous sinus stenosis or thrombosis.

 5. Any hemorrhagic transformation or large area of cerebral infarction (more than 1/3
 of middle cerebral artery perfusion territory).

 6. Any type of intracranial hemorrhage within 90 days prior to inclusion.

 7. Potential cardiac source of embolism such as rheumatic mitral and or aortic
 stenosis, prosthetic heart valves, atrial flutter, atrial fibrillation, left atrial
 myxoma, sick sinus syndrome, patent foramen ovale, left ventricular mural thrombus or
 valvular vegetation, congestive heart failure, and bacterial endocarditis.

 8. Previous stent, angioplasty, or other mechanical device in the target lesion, or
 plan to receive any of the above procedures within 12 months after inclusion.

 9. Refractory hypertension (systolic blood pressure (SBP) >180 mmHg; diastolic blood
 pressure (DBP) >110 mmHg) that cannot be controlled by medical intervention.

 10. Above 50% stenosis of extracranial artery (carotid artery or vertebral artery).

 11. Above 50% stenosis of subclavian artery or subclavian steal syndrome.

 12. Retinal hemorrhage or visceral bleeding within 30 days prior to inclusion.

 13. Myocardial infarction within previous 30 days prior to inclusion.

 14. Previous history of major surgery within 30 days prior to inclusion, or arranged
 for any of the procedure within 12 months after inclusion.

 15. Severe hemostatic or coagulation disorders (Haemoglobin <10 g/dL, blood platelet
 count < 100 × 109/L).

 16. Hepatic or renal dysfunctions (aspartate transaminase (AST) and/or alanine
 transaminase (ALT) >3×upper limit of normal range, creatinine clearance <0.6 ml/s
 and/or serum creatinine >265 μmol/l (>3.0 mg/dl)).

 17. Current or having a history of chronic physical diseases or mental disorders.

 18. Life expectancy < 3 years due to concomitant life-threatening illness.

 19. Contraindications for remote ischemic conditioning: significant peripheral
 arterial disease, soft tissue or vascular injury, wounds, and fracture affecting the
 upper limbs.

 20. Pregnant or lactating women.

 21. Patients unlikely to be compliant with intervention or return for follow-up
 visits.

 22. No consent obtained from the patient or available legally authorized
 representatives.

 23. Patients recruited into another clinical investigation with medication or device,
 which is likely to impact the outcome of this study.