Clinical trial NCT01949961: The Norwegian Sonothrombolysis in Acute Stroke Study Part 2
Official title: Randomised Trial of Contrast-enhanced Sonothrombolysis in Acute Ischaemic Stroke
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: NA
Conditions: Ischemic Stroke
Keywords: intervention
sonothrombolysis
Ultrasound treatment
Lead sponsor: Haukeland University Hospital
Sponsor class: OTHER
Collaborators: name: University of Bergen
name: Sykehuset Telemark
First posted: 2013-09-25
Enrollment: 59
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: PROBE: Prospective randomized open-label blinded-endpoint
Primary purpose: TREATMENT

Brief summary: BACKGROUND: Thrombolytic drugs may dissolve blood vessel clots in acute ischemic stroke. The overall benefit of intravenous thrombolysis is substantial, but up to 2/3 of patients with large clots may not achieve re-opening of the vessel and up to 40% of the patients may remain severely disabled or die. Ultrasound accelerates clot break-up (lysis) when combined with thrombolysis (sonothrombolysis) and increases the likelihood of functional independence at 3 months. Adding intravenous ultrasound contrast (gaseous microspheres) further enhances the thrombolytic effect (contrast enhanced sonothrombolysis = CEST). Contrast enhanced ultrasound may also accelerate clot break-up in the absence of thrombolytic drugs (contrast enhanced sonolysis = CES).

HYPOTHESIS: Contrast enhanced ultrasound treatment administered within 4 1/2 hours after symptom onset may be given safely to patients with acute ischemic stroke, both to those receiving intravenous thrombolysis and those not receiving intravenous thrombolysis, and will improve clinical outcome.

AIMS: To compare efficacy and safety of contrast enhanced ultrasound treatment vs. no ultrasound treatment in patients with acute ischemic stroke receiving or not receiving intravenous thrombolysis.

STUDY ENDPOINTS: The primary endpoints are 1) neurological improvement at 24 hours (proof of concept) and 2) excellent clinical outcome at 3 months (effect). Secondary endpoints are bleeding complications (safety), brain damage (infarct size/location) and early clinical improvement (effect).

Detailed description: NOR-SASS aims at testing contrast enhanced sonothrombolysis in all patients with acute ischemic stroke. Patients eligible for thrombolysis (randomized tenecteplase or alteplase) are included in the NOR-SASS A sub-study, patients receiving standard (non-trial) thrombolysis with alteplase are included in the NOR-SASS B sub-study, and patients not eligible for thrombolysis are included in the NOR-SASS C sub-study.

DESIGN: NOR-SASS is a PROBE (prospective randomised, open-label, blinded endpoint) trial, designed to establish the superiority of contrast-enhanced ultrasound treatment given within 4½ hours after stroke onset in consecutively admitted patients with acute ischaemic stroke, as compared with 1) standard iv thrombolysis with tenecteplase (TNK) or alteplase (tPA) in patients eligible for thrombolytic treatment, and 2) no specific treatment in patients not eligible for thrombolytic treatment.

HYPOTHESIS: 1.) In patients eligible for intravenous thrombolysis, contrast enhanced sonothrombolysis (CEST) has superior effect as compared with standard intravenous thrombolysis and may be given safely. 2.) In patients not eligible for thrombolysis, contrast enhanced sonolysis (CES) has superior effect as compared with no specific treatment and may be given safely.

RANDOMISATION: In NOR-SASS-A (two step randomisation), 1st randomisation is 1:1 to either tenecteplase (TNK) or alteplase (tPA); 2nd randomisation is 1:1 to either CEST or no CEST. In NOR-SASS-B, randomisation is 1:1 to either CEST or no CEST. In NOR-SASS-C, randomisation is 1:1 to either CES or no CES.

Eligibility criteria: Inclusion Criteria:

* Ischemic stroke in the anterior circulation
* Treatment within 4.5 hours after stroke onset
* Informed consent

Exclusion Criteria:

* Patients with premorbid modified Rankin Scale (mRS) score ≥3;
* Patients for whom a complete NIH Stroke Score cannot be obtained;
* Hemiplegic migraine with no arterial occlusion on baseline CT;
* Seizure at stroke onset and no visible occlusion on baseline CT;
* Intracranial haemorrhage on baseline CT;
* Clinical subarachnoid haemorrhage even if baseline CT is normal;
* Large areas of hypodense ischaemic changes on baseline CT;
* Patients with primary endovascular treatment;
* Female, pregnant 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;

Primary outcomes:
measure: Clinical: Functional handicap
timeFrame: 90 days
measure: Proof of concept: Early neurological improvement
timeFrame: 22-36 hours
Secondary outcomes:
measure: Symptomatic intracerebral hemorrhage
timeFrame: 24-36 hours
measure: Hemorrhagic transformation
timeFrame: 24-36 hours
measure: Short term functional outcome
timeFrame: 7 days
measure: Brain infarct size and location
timeFrame: 22-36 hours
Other outcomes:
Locations:
city: Skien
country: Norway
facility: Dept. of Neurology, Telemark Hospital
Study officials:
affiliation: Dept. Neurology, Haukeland University Hospital, Bergen, Norway
name: Lars Thomassen, MD PhD Prof.
role: STUDY_DIRECTOR
affiliation: Dept. Neurology, Haukeland University Hospital, Bergen, Norway
name: Christopher E Kvistad, MD
role: STUDY_CHAIR
affiliation: Dept. Neurology, Sykehuset Telemark, Skien
name: Haakon Tobro, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Nacu A, Kvistad CE, Logallo N, Naess H, Waje-Andreassen U, Aamodt AH, Solhoff R, Lund C, Tobro H, Ronning OM, Salvesen R, Idicula TT, Thomassen L. A pragmatic approach to sonothrombolysis in acute ischaemic stroke: the Norwegian randomised controlled sonothrombolysis in acute stroke study (NOR-SASS). BMC Neurol. 2015 Jul 11;15:110. doi: 10.1186/s12883-015-0359-4.
citation: Nacu A, Kvistad CE, Naess H, Oygarden H, Logallo N, Assmus J, Waje-Andreassen U, Kurz KD, Neckelmann G, Thomassen L. NOR-SASS (Norwegian Sonothrombolysis in Acute Stroke Study): Randomized Controlled Contrast-Enhanced Sonothrombolysis in an Unselected Acute Ischemic Stroke Population. Stroke. 2017 Feb;48(2):335-341. doi: 10.1161/STROKEAHA.116.014644. Epub 2016 Dec 15.