r-tPA Thrombolytic Therapy in Combination With Remote Ischemic Conditioning for Acute Ischemic Stroke Recovery

Overview

to detect the efficiency and safety of intravenous rtPA combined with RIPC in acute ischemic stroke patients

Full Title of Study: “Intravenous Rt-PA Thrombolysis Combined With Remote Ischemic Post-Conditioning for Acute Ischemic Stroke Patients”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Single (Outcomes Assessor)
  • Study Primary Completion Date: February 2019

Detailed Description

Remote ischemic post-conditioning, which consists of several brief cycles of intermittent ischemia-reperfusion of the arm or leg, may potentially confer a powerful systemic protection against prolonged ischemia in a distant organ. Numerous reports have confirmed it strongest endogenous neuroprotection against brain injury after stroke. Ren et al demonstrated that remote ischemic post-conditioning (RIPC) performed in the hind limbs can not only significantly reduce the stroke volume within 3 hours in rat model, but also ameliorate the outcome of the behavioral test. A long-term repeated RIPC therapy can also help improving neurological functions. A combination of RIPC and tPA can help with neuroprotection which improves the neurological functions. Thus, it is meaningful to transform these basic experimental results to the clinical treatment. In the RECAST-1 trial, RIC has shown it safety and efficiency in AIS patients without tPA. However, there is no further explanation for the patients with IVT. Thus, in this study, we aim to demonstrate the efficiency and safety of RIPC in AIS patients performed rt-PA within 4.5 hours.

Interventions

  • Device: ischemic conditioning
    • In this study, the remote ischemic conditioning treatment was composed of five cycles of bilateral upper limb ischemia intervened by reperfusion, which was induced by two cuff placed around the upper arms respectively and inflated to 200 mm Hg for 5 minutes followed by 5 minutes of reperfusion by cuff deflation.

Arms, Groups and Cohorts

  • Experimental: RIC group
    • The upper limb ischemic conditioning is composed of five cycles of bilateral upper limb ischemia intervened by reperfusion, which is induced by two cuff placed around the upper arms respectively and inflated to 200 mm Hg for 5 minutes followed by 5 minutes of reperfusion by cuff deflation. This therapy started within 2 hours after r-tPA thrombolytic therapy. In addition, all participants receive a standard clinical therapy.
  • No Intervention: Control group
    • The participants received r-tPA thrombolytic therapy after diagnosed ischemic stroke. In addition, all participants receive a standard clinical therapy.

Clinical Trial Outcome Measures

Primary Measures

  • infarction volume in brain between two groups
    • Time Frame: measured during 72 h
    • assess by MRI-DWI and ADC

Secondary Measures

  • The score of Modified Rankin scale score
    • Time Frame: measured at baseline(before RIPC),24 hours, at 5-7 days,30±7 days, 90±7 days
    • 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
  • proportional of Modified Rankin scale scored 0-1
    • Time Frame: measured at baseline(before RIPC),24 hours, at 5-7 days,30±7 days, 90±7 days
    • 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
  • The score of National Institute of Health stroke scale score
    • Time Frame: measured at baseline(before RIPC),24 hours, at 5-7 days,30±7 days, 90±7 days
    • 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.
  • The score of Barthel Index(BI)
    • Time Frame: measured at baseline(before RIPC),24 hours, at 5-7 days,30±7 days, 90±7 days
    • the BI is used to measure performance in activities of daily living.The score of the scale ranges from 0 to 100. And lower score indicates worse activities of daily living.
  • recurrence of stroke and TIA
    • Time Frame: changes from baseline(before RIPC) to 90±7 days
    • Stroke recurrence was defined as sudden functional deterioration in neurologic status with a decrease of 4 or more in the NIHSS, or a new stroke lesion on MRI/DWI located at the territory of the affected intracranial arteries.
  • death and any other adverse events
    • Time Frame: changes from baseline(before RIPC) to 90±7 days
    • The investigator will record the number.
  • any ICH
    • Time Frame: changes from baseline(before RIPC) to 90±7 days
    • 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.
  • Distal radial pulses
    • Time Frame: during 90 days
    • professional doctors will check the distal radial pulses
  • Visual inspection for local edema
    • Time Frame: during 90 days
    • Professional oculists will check the fundus oculi to evaluate whether there is local edema.
  • The number of patients with erythema,and/or skin lesions related to RIC
    • Time Frame: during 90 days
    • Professional doctors will check it and the investigator will record the number.
  • Palpation for tenderness
    • Time Frame: during 90 days
    • Professional doctors will check it.
  • The number of patients not tolerating RIC procedure,and refuse to continue the RIC procedure
    • Time Frame: during 90 days
    • The investigator will record the number.
  • the score of Numeric Rating Scale (NRS)
    • Time Frame: during 90 days
    • The Numeric Rating Scale (NRS-11) is an 11-point scale for patient self-reporting of pain. The score from 0-10. the higher
  • the score of Hamilton Rating Scale for Depression(HAMAD)
    • Time Frame: change from baseline(before rtPA) to 90 days
    • this score was used to provide an indication of depression, and as a guide to evaluate recovery.
  • level of MMP-9
    • Time Frame: measured at baseline(before RIPC,after rtPA) and 7 days
    • Blood samples will be drawn from cubital vein to test these biomarkers.These samples will be centrifuged immediately after collection and stored at – 80 until batch evaluation
  • level of IL-6
    • Time Frame: measured at baseline(before RIPC,after rtPA) and 7 days
    • Blood samples will be drawn from cubital vein to test these biomarkers.These samples will be centrifuged immediately after collection and stored at – 80 until batch evaluation
  • level of HS-CRP
    • Time Frame: measured at baseline(before RIPC,after rtPA) and 7 days
    • Blood samples will be drawn from cubital vein to test these biomarkers.These samples will be centrifuged immediately after collection and stored at – 80 until batch evaluation
  • The level of vascular endothelial growth factor
    • Time Frame: measured at baseline(before RIPC,after rtPA) and 7 days
    • 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

Participating in This Clinical Trial

Inclusion Criteria

  • Male or female, age≥18;
  • Clinical sign and symptoms consistent with the diagnosis of an acute ischemic stroke, onset of stroke symptoms within 4.5 h before initiation of intravenous rt-PA thrombolytic therapy;
  • Baseline National Institutes of Health Stroke Scale (NIHSS) score of 4-15 (assessed before intravenous alteplase), mRS ≤1 before onset of stroke symptom;
  • No contraindication for MRI.
  • Informed consent obtained

Exclusion Criteria

  • Cardioembolism;
  • Contraindication for remote ischemic conditioning: severe soft tissue injury, fracture, or peripheral vascular disease in the upper limbs;
  • Life expectancy < 1 year;
  • Pregnant or breast-feeding women;
  • Unwilling to be followed up or poor compliance for treatment; (5) Patients being enrolled or having been enrolled in other clinical trial within 3 months prior to this clinical trial.

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 80 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Capital Medical University
  • Provider of Information About this Clinical Study
    • Principal Investigator: Ji Xunming,MD,PhD, professor – Capital Medical University
  • Overall Official(s)
    • Xunming Ji, MD. PhD, Principal Investigator, Xuanwu Hospital, Beijing
  • Overall Contact(s)
    • Xunming Ji, MD. PhD, +86-10-83198952, jixm@ccmu.edu.cn

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