SONOlysis in Prevention of Brain Infarctions dUring Carotid Stenting and caroTid EndaRterectomy

Internal Carotid Artery Stenosis Clinical Trial

— SONOBUSTER  

Official title:

Risk Reduction of Symptomatic and Silent Brain Infarctions During Carotid Endarterectomy and Carotid Stenting Due to Ultrasound Activation of Endogenous Fibrinolytic System Using Transcranial Doppler Monitoring

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01591005
• Other study ID #: NT11386-5/2010
• Status: Completed
• Phase: Phase 3
• First received: April 23, 2012
• Last updated: August 29, 2015
• Start date: October 2010
• Est. completion date: June 2015

Study information

• Verified date: August 2015
• Source: University Hospital Ostrava
• Contact: n/a
• Is FDA regulated: No
• Health authority: Czech Republic: Ethics Committee
• Study type: Interventional

Clinical Trial Summary

The aim of the project is to demonstrate a fibrinolytic effect of sonothrombolysis (continual transcranial Doppler monitoring) using 2 MHz diagnostic probe on the reduction of risk of brain infarctions due to the activation of endogenous fibrinolytic system during carotid endarterectomy (CEA) and carotid stenting (CS). 240 patients indicated for CEA (120 patients) and CS (120 patients) will be enrolled into the study in order to demonstrate a twenty-percent risk reduction of number and volume of brain infarctions detected using MRI examination 24 hours after CEA or CS in 5% level of significance. Patients will be randomized - subgroup 1 will undergo a 60minute non-diagnostic TCD monitoring during CEA or CS, subgroup 2 will undergo interventions without TCD monitoring. The second aim is to compare number of brain infarctions detected using MRI between CEA and CS patients.

Confirmation of the investigators hypothesis that sonothrombolysis is able to activate endogenous fibrinolytic system during CEA or CS with consecutive reduction of the number and volume of brain infarcts, can lead to the increase of the safety of CEA and CS in patients with internal carotid artery stenosis. The investigators can presume that up to 50% of patients indicated for CEA or CS can be treated using these methods in the future.

In the Substudy "Risk of brain infarction after carotid endarterectomy and stenting" the the risk of asymptomatic and symptomatic brain infarctions, changes in cognitive functions, as well as morbidity and mortality at 30 days between patients with symptomatic and asymptomatic severe ICA stenoses undergoing elective CEA and CAS will be compared.

The sample size of the Substudy was based on an expected 80% difference of new ischemic lesions on DWI-MRI between CEA (estimated prevalence, 30%) and CAS (54%). Pre-study calculations showed that a minimum of 73 patients in each group was needed to reach a significant difference with an alpha value of 0.05 (two-tailed) and a beta value of 0.8 assuming that 15% of subjects would be lost to follow-up or refuse to participate in the study.

Description:

AIM OF THE PROJECT AND HYPOTHESIS The aim of the project is to demonstrate an effect of continual TCD monitoring using 2 MHz diagnostic probe with maximal diagnostic energy on the reduction of risk of brain microinfarctions due to the activation of endogenous fibrinolytic system during CEA and CS. The second aim of the study is to compare the risk of brain infarction between CEA and CS.

240 patients indicated for CEA (120 patients) and CS (120 patients) will be enrolled into the study in order to demonstrate a twenty-percent risk reduction of number and volume of brain infarctions detected using MRI examination 24 hours after CEA or CS in 5% level of statistical significance. Patients will be randomized into 2 subgroups. Subgroup 1 will undergo a 60minute non-diagnostic TCD monitoring during CEA or CS. Subgroup 2 will undergo CEA or CS without TCD monitoring. The second aim is to compare number and volume of brain infarctions detected using MRI between CEA and CS patients.

Substudy "Risk of brain infarction after carotid endarterectomy and stenting" The aim of the prospective, randomized study was to compare the risk of asymptomatic and symptomatic brain infarctions, changes in cognitive functions, as well as morbidity and mortality at 30 days between patients with symptomatic and asymptomatic severe ICA stenoses undergoing elective CEA and CAS.

PATIENTS AND METHODS 240 patients with ICA stenosis indicated for CEA or CS according to the criteria of the American Heart Association will be enrolled into the study during a 4-year period. Altogether 120 patients indicated for CEA and 120 patients indicated for CS will be randomized for standard CEA / CS and TCD monitored CEA / CS.

Randomization: Randomization using computer generated random allocation will be used, separately for CEA and CS patients.

Substudy "Risk of brain infarction after carotid endarterectomy and stenting" Minimally146 patients with ICA stenosis >70% (symptomatic or asymptomatic) detected by duplex sonography and confirmed using computed tomography angiography (CTA); indication for carotid intervention (CEA or CAS) according to criteria set by the American Heart Association5; age 40-80 years; (iv) functionally independent (modified Rankin score 0-2 points); no contraindication to magnetic resonance imaging (MRI), CTA or digital angiography (DSA) will be enrolled to the Substudy.

Randomization: Randomization using computer generated random allocation to CEA or CS will be used.

Sonothrombolysis: In patients randomized into sonothrombolysis subgroup, MCA segment in depth 55 mm will be monitored for 40 minutes using a diagnostic 2 MHz probe with maximal diagnostic energy. Non-diagnostic TCD monitoring will be performed without detection of microembolic signals or detection of changes in blood flow. The second (control) subgroup will undergo a standard CEA or CS without sonothrombolysis.

MRI protocol will consists of 4 sequences: 1. Localizer; 2. T2TSE; 3. FLAIR; 4. DWI. Sequences 1-3 will be applied in the same level, they will have the same slice thickness and the same cut number. The slice thickness comprises its own cut thickness (5 mm) + distant factor (30%). Standard number of slices is 19. Standard slice level is considered to be a modified level of skull base due to the minimalization of distant artifacts EPI sequence. T2TSE: TR=4000/TE=99/ETL=9, FOV 230, FOV ph. 75%, matrix 256x256. FLAIR: 8050/112/ETL=21/2 conc., FOV 230, FOV ph. 76,6%, matrix 256x151. EPI-DWI: 4200/139/EPI f.=96/6 av., FOV 230, FOV ph. 100%, phase enc. direction A-P, matrix 128x96 with interpolation, phase partial Fourier 6/8, Bw 1346 Hz/Px, echo spacing 0.83 ms, TA. Sequence called "trace" with three types of MR pictures in every slice: (a) T2*EPI b=0; (b) DWI b=500; (c) DWI b=1000. The fourth type of images automatically created an ADC map (in-line postprocessing). DWI show a middle (average) diffusivity of every point of examined brain tissue when b value is 500 and 1000. This sequence is applied in order to assess hemorrhage (T2*EPI) and monitor sites of reduced diffusion (DWI, b=500 and 1000). New infarctions will be evaluated only in the territory of treated ICA.

Adverse effects: All adverse effects during 1 month after UM will be registered, especially all causes for new admissions to the hospital, worsening of neurological symptoms (>4 points in NIH stroke scale), brain edema, symptomatic and asymptomatic intracranial bleeding detected in control brain MRI.

Statistic evaluation: All statistical tests will be performed at the Department of Biophysics, Informatics and Biometry, Palacký University Medical School, Olomouc. Statistical evaluation in 5% level of significance of differences in the number and volume of brain infarctions detected using MRI between patients with TCD monitoring and without TCD monitoring during CEA or CS will be performed using Student T-test, χ2-test, Mann-Whitney U-test, ANOVA and multivariate analysis. Differences in the number and volume of brain infarctions between patients after CEA and CS will be evaluated as secondary end-points. Influence of other factors, e.g. age, gender, symptoms in the territory of treated artery, number of infarctions before CEA or CS, results of cognitive tests will be evaluated.

Statistic evaluation for Substudy: The normality of distribution of all data will be checked using the Shapiro-Wilk test. Categorical variables in the two arms will be compared by Fisher's exact test. Continuous variables will be compared by the Student's t-test for normally distributed values and by Mann-Whitney U test for other values. Multiple logistic regression analyses were used to determine the possible predictors of a new brain infarction. All tests were carried out at an alpha level of significance of 0.05.

Study protocol has been approved by the Ethics Committees in accordance with the principles and guidelines of the Declaration of Helsinki, 1975.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 242
• Est. completion date: June 2015
• Est. primary completion date: July 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 40 Years to 80 Years

Eligibility

Inclusion Criteria:

• stenosis of internal carotid artery

• indication to endarterectomy or stenting

• age 40-80 years

• sufficient temporal bone window for TCD with detectable blood flow in MCA

• independent patient (modified Rankin score 0-2)

• informed consent signed by the patient.

Exclusion Criteria:

• contraindication to MRI examination (pace-maker, implanted metal material, claustrophobia)

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Outcomes Assessor), Primary Purpose: Prevention

Related Conditions & MeSH terms

• Brain Infarction
• Carotid Stenosis
• Internal Carotid Artery Stenosis

Intervention

Procedure:
• sonolysis
continual transcranial Doppler monitoring with max. diagnostic intensity for 60 minutes
• endarterectomy
carotid endarterectomy
• carotid stenting
percutaneous transluminal angioplasty and stenting

Locations

Country	Name	City	State
Czech Republic	University Hospital Ostrava	Ostrava

Sponsors (2)

Lead Sponsor	Collaborator
University Hospital Ostrava	Palacky University

Country where clinical trial is conducted

Czech Republic, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Complications	Any complication during CEA and CS, sonolysis or 30 days after intervention in all subgroups.	24 hours and 30 days after intervention	Yes
Primary	New brain infarction detected using MRI	Reduction of number and volume of brain infarctions in sonolysis group detected using MRI examination 24 hours after CEA or CS.; Substudy: The incidence of new ischemic lesions on brain DWI-MRI performed 24 hours after intervention in CEA and CAS groups.	24 hours after intervention	Yes
Secondary	New brain infarctions detected using MRI in endarterectomy and stenting groups	The number and volume of brain infarctions and brain infarctions >0.5 cm3 detected using MRI examination 24 hours after intervention between endarterectomy and stenting using periprocedural sonolysis.; Substudy: The number and volume of brain infarctions and brain infarctions >0.5 cm3 detected using MRI examination 24 hours after intervention between CEA and CS groups.	24 hours after intervention	No
Secondary	Cognitive decline	The reduction of cognitive decline after CEA and CS measured by ADAS, MMSE, Clock Drawing Test and Verbal Fluency Test using periprocedural sonolysis.; Substudy: The reduction of cognitive decline after intervention measured by ADAS, MMSE, Clock Drawing Test and Verbal Fluency Test between CEA and CS groups.	24 hours after intervention	No
Secondary	Clinical manifested brain infarction	The reduction of risk of stroke or TIA (at 24 hours and 30 days) due to the activation of endogenous fibrinolytic system during CEA and CS using periprocedural sonolysis.; Substudy: The reduction of risk of stroke or TIA (at 24 hours and 30 days) due to the activation of endogenous fibrinolytic system between CEA and CS groups.	24 hours and 30 days after intervention	Yes
Secondary	New ipsilateral brain infarctions detected using MRI in endarterectomy and stenting groups	The number and volume of ipsilateral brain infarctions detected using MRI examination 24 hours after intervention between endarterectomy and stenting using periprocedural sonolysis.; Substudy: The number and volume of ipsilateral brain infarctions detected using MRI examination 24 hours after intervention between CEA and CS groups.	24 hours after intervention	No
Secondary	Clinical vascular event or death	The reduction of risk of the occurrence of death, any stroke, or myocardial infarction within 30 days (myocardial infarction was defined as a post-interventional cardiac troponin T level increase >2-fold the upper limit of normal in addition to either chest pain or symptoms consistent with ischemia or electrocardiographic evidence of ischemia) after CEA and CS using periprocedural sonolysis.; Substudy: The reduction of risk of the occurrence of death, any stroke, or myocardial infarction within 30 days (myocardial infarction was defined as a post-interventional cardiac troponin T level increase >2-fold the upper limit of normal in addition to either chest pain or symptoms consistent with ischemia or electrocardiographic evidence of ischemia) between CEA and CS groups.	30 days after intervention	Yes

External Links

•   University Hospital Ostrava