Clinical trial NCT03105141: Optimized Remote Ischemic Conditioning (RIC) Treatment for Patients With Chronic Cerebral Ischemia
Official title: The Impact of Repeated Bilateral Limb Remote Ischemic Conditioning on Patients With Chronic Cerebral Ischemia: Establishment of Optimized Algorithm on the Basis of Feasibility, Safety and Efficacy
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
PHASE3
Conditions: Chronic Cerebral Ischemia
Intracranial Atherosclerosis
Keywords: Intracranial atherosclerotic stenosis
Remote ischemic conditioning
Stroke
Lead sponsor: Capital Medical University
Sponsor class: OTHER
First posted: 2017-04-07
Enrollment: 600
Sex: ALL
Minimum age (years): 40
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Recurrent rate of ischemic stroke and/or transient ischemic attack
timeFrame: baseline, within 12 months
Secondary outcomes:
measure: Treatment Related Adverse Events
timeFrame: within 12 months
measure: The incidence of composite vascular events
timeFrame: within 12 months
measure: The incidence of each component of composite vascular events
timeFrame: within 12 months
measure: The incidence of all cause mortality
timeFrame: within 12 months
measure: The evaluation of cognitive function
timeFrame: baseline, within 3, 6 and 12 months
measure: The evaluation of neurological impairment caused by a stroke
timeFrame: baseline, within 3, 6 and 12 months
measure: The evaluation of degree of disability or dependence in the daily activities
timeFrame: baseline, within 3, 6 and 12 months
measure: The evaluation of performance in activities of daily living
timeFrame: baseline, within 3, 6 and 12 months
measure: Mean changes in cerebral blood perfusion and/or collateral circulation
timeFrame: baseline, within 12 months
measure: Mean change in brain function
timeFrame: baseline, within 12 months
measure: Changes in cerebral white matter lesions (WMLs)
timeFrame: baseline, within 12 months
measure: The occurrence of additional neurological events
timeFrame: within 12 months
measure: The evaluation of serum biomarkers
timeFrame: baseline, within 1, 3, 6 and 12 months
measure: Number of participants with abnormal lab values
timeFrame: baseline, within 1, 3, 6 and 12 months
Other outcomes:
Locations:
city: Beijing
country: China
facility: Xuanwu Hospital, Capital Medical University
state: Beijing
city: Beijing
country: China
facility: Xuanwu Hospital, Capital Medical University
Study officials:
affiliation: Xuanwu Hospital, Beijing
name: Xuming Ji, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Xuanwu Hospital, Beijing
name: Ran Meng, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Meng R, Asmaro K, Meng L, Liu Y, Ma C, Xi C, Li G, Ren C, Luo Y, Ling F, Jia J, Hua Y, Wang X, Ding Y, Lo EH, Ji X. Upper limb ischemic preconditioning prevents recurrent stroke in intracranial arterial stenosis. Neurology. 2012 Oct 30;79(18):1853-61. doi: 10.1212/WNL.0b013e318271f76a. Epub 2012 Oct 3.
citation: Meng R, Ding Y, Asmaro K, Brogan D, Meng L, Sui M, Shi J, Duan Y, Sun Z, Yu Y, Jia J, Ji X. Ischemic Conditioning Is Safe and Effective for Octo- and Nonagenarians in Stroke Prevention and Treatment. Neurotherapeutics. 2015 Jul;12(3):667-77. doi: 10.1007/s13311-015-0358-6.
citation: Wang Y, Zhao X, Liu L, Soo YO, Pu Y, Pan Y, Wang Y, Zou X, Leung TW, Cai Y, Bai Q, Wu Y, Wang C, Pan X, Luo B, Wong KS; CICAS Study Group. Prevalence and outcomes of symptomatic intracranial large artery stenoses and occlusions in China: the Chinese Intracranial Atherosclerosis (CICAS) Study. Stroke. 2014 Mar;45(3):663-9. doi: 10.1161/STROKEAHA.113.003508. Epub 2014 Jan 30.