Contrast Enhanced Sonothrombolysis and Sonolysis in Stroke - a Swedish Study (CE-5S) (CE-5S)

Patients with acute ischemic stroke in anterior circulation within 4,5 hours of symptom onset, has a bone window and Trombolysis In Brain Ischemia (TIBI) <=4 in a relevant artery eligible. Both patients receiving thrombolysis and those who do not due to contraindications such as anticoagulation or recent surgery are enrolled, but into different study arms (CE-5S A for thrombolysis and B for non-thrombolysis); the decision to treat with thrombolysis or not is done according to clinical routine.

All included patients are randomized to receive transcranial ultrasound and SonoVue-infusion or sham-ultrasound and placebo; i.e. in CE-5S A, contrast enhanced sonothrombolysis is compared to thrombolysis and in CE-5S B, contrast enhanced sonolysis is compared with conservative management.

Main outcome is improvement in National Institute of Health Stroke Scale (NIHSS) at 24 hours compared to baseline. Main safety outcome is symptomatic intracerebral haemorrhage.

Study Overview

• Status: Terminated
• Conditions: Ischemic Stroke
• Intervention / Treatment: Drug: SonoVue; Procedure: Transcranial Ultrasound; Drug: Sodium chloride; Procedure: Sham Transcranial Ultrasound

• Study Type: Interventional
• Enrollment (Actual): 1
• Phase: Phase 3

Contacts and Locations

Study Locations

• Sweden
  • Västerbotten
    • Umeå, Västerbotten, Sweden, 90821
      • University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female patients ≥18 years with acute ischaemic stroke in the anterior circulation, who has given written consent for his/her participation to the study.
• Remaining neurological deficit that is ≥1 NIHSS points, sufficient to warrant treatment with tPA (not taking possible contraindications into account) and is severe enough that possible improvement is clearly analysable
• Treatment <4½ hours of symptom onset or of waking up in the morning with symptoms
• Sufficient bone window for acceptable or better acquisition of flow information with ultrasound with TIBI ≤ 4 in the symptomatic artery
• In cases with women of Childbearing Capacity (WOCBC): Only if willing to comply with effective contraception methods during the course of the trial. Acceptable methods are such as oral contraceptives, contraceptive patches, contraceptive implant, vaginal contraceptive, double-barrier methods (for example, condom and spermicide), intrauterine device (IUD), hormonal IUD

Exclusion Criteria:

• Patients with premorbid modified Rankin Scale (mRS) score ≥3;
• Patients for whom a complete NIHSS cannot be obtained;
• Hemiplegic migraine with no arterial occlusion on baseline Computed Tomography of brain (CT);
• Seizure at stroke onset and no visible occlusion on baseline CT;
• Intracranial haemorrhage on baseline CT;
• Clinical presentation suggesting subarachnoid haemorrhage even if baseline CT is normal;
• Large areas of hypodense ischaemic changes on baseline CT;
• Pregnancy or breast-feeding, pericarditis; sepsis; any other serious medical illness likely to interact with treatment; confounding pre-existent neurological or psychiatric disease; unlikely to complete follow-up; any investigational drug <14 days;
• Inability to provide informed consent sufficiently clearly that the study physician can be convinced that informed consent has been given by the patient - such as severe aphasia or coma.

Specific sonothrombolysis exclusion criteria

• known hypersensitivity/allergy to SonoVue;
• recent or unstable coronary ischemia or resting angina <7 days;
• acute cardiac insufficiency, cardiac insufficiency class III/IV; serious cardiac arrhythmias;
• any right-left-shunt; severe pulmonary hypertension; uncontrolled hypertension;
• moderate to severe Chronic Obstructive Pulmonary Disease (COPD; baseline O2 saturation <80%);
• acute respiratory distress syndrome (ARDS);

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: CE-5S A: Treatment arm; Gets thrombolysis, transcranial ultrasound on the flow limitation and SonoVue infusion	Drug: SonoVue; SonoVue-infusion over 1 hour; Procedure: Transcranial Ultrasound; Transcranial ultrasound aimed at the blockage
SHAM_COMPARATOR: CE-5S A: Control arm; Gets thrombolysis, sham transcranial ultrasound and placebo (NaCl) infusion	Drug: Sodium chloride; Placebo; Procedure: Sham Transcranial Ultrasound; Placebo - machine is attached, but not active
EXPERIMENTAL: CE-5S B: Treatment arm; Gets NO thrombolysis (due to contraindications), transcranial ultrasound on the flow limitation and SonoVue infusion	Drug: SonoVue; SonoVue-infusion over 1 hour; Procedure: Transcranial Ultrasound; Transcranial ultrasound aimed at the blockage
SHAM_COMPARATOR: CE-5S B: Control arm; Gets NO thrombolysis (due to contraindications), sham transcranial ultrasound and placebo (NaCl) infusion	Drug: Sodium chloride; Placebo; Procedure: Sham Transcranial Ultrasound; Placebo - machine is attached, but not active

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Early clinical Outcome defined as change in NIHSS at 24 hours.	Change in National NIHSS at 24 hours. Defined reaching of primary endpoint is post-treatment 0 Points and/or improves with >=4 Points compared to pre-treatment.	24 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety: Symptomatic Cerebral Hemorrhage (sICH)	Assessed with routine post-treatment CT head and requires an accompanied >=4 Points worsening on NIHSS.	24-36 hours
Long term outcome defined as residual handicap at Three months	90-days modified Rankin Scale (mRS) reaching 0-1.	90 days

Collaborators and Investigators

• Sponsor: Umeå University
• Investigators: Principal Investigator: Elias Johansson, MD, PhD, Umeå University

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 28, 2017
• Primary Completion (ACTUAL): April 18, 2018
• Study Completion (ACTUAL): April 18, 2018

Study Registration Dates

• First Submitted: September 14, 2017
• First Submitted That Met QC Criteria: September 20, 2017
• First Posted (ACTUAL): September 21, 2017

Study Record Updates

• Last Update Posted (ACTUAL): May 11, 2018
• Last Update Submitted That Met QC Criteria: May 4, 2018
• Last Verified: November 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Stroke; Ischemic Stroke
• Other Study ID Numbers: CE-5S

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No