The Norwegian Sonothrombolysis in Acute Stroke Study (NOR-SASS)
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).
Other: Sham ultrasound
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Outcomes Assessor)
Primary Purpose: Treatment
|Official Title:||Randomised Trial of Contrast-enhanced Sonothrombolysis in Acute Ischaemic Stroke|
- Clinical: Functional handicap [ Time Frame: 90 days ] [ Designated as safety issue: No ]Sliding dichotomy/responder analysis: Excellent outcome is defined as modified Rankin Scale (mRS) 0 with baseline National Institutes of Health Stroke Scale (NIHSS), as mRS 0-1 with baseline NIHSS 8-14, as mRS 0-2 with baseline NIHSS ≥15
- Proof of concept: Early neurological improvement [ Time Frame: 22-36 hours ] [ Designated as safety issue: No ]NIHSS=0 or reduction of ≥4 NIHSS points compared with baseline
- Symptomatic intracerebral hemorrhage [ Time Frame: 24-36 hours ] [ Designated as safety issue: Yes ]Local or remote parenchymal haemorrhage type 2 on the 22-36 h post-treatment imaging scan, combined with a neurological deterioration of 4 points or more on the NIHSS from baseline or from the lowest NIHSS value between baseline and 24 h, or leading to death (SITS-MOST criteria).
- Hemorrhagic transformation [ Time Frame: 24-36 hours ] [ Designated as safety issue: Yes ]Any hemorrhagic changes (infarct or parenchymal hematoma)
- Short term functional outcome [ Time Frame: 7 days ] [ Designated as safety issue: No ]Sliding dichotomy/responder analysis: Excellent outcome is defined as mRS 0 with baseline NIHSS ≤7, as mRS 0-1 with baseline NIHSS 8-14, as mRS 0-2 with baseline NIHSS ≥15
- Brain infarct size and location [ Time Frame: 22-36 hours ] [ Designated as safety issue: No ]MRI infarct volume and ASPECTS score
|Study Start Date:||September 2012|
|Estimated Study Completion Date:||November 2015|
|Estimated Primary Completion Date:||August 2015 (Final data collection date for primary outcome measure)|
Active Comparator: Ultrasound
Patients eligible (NOR-SASS A/B) and ineligible (NOR-SASS C) for intravenous thrombolysis all receive intravenous ultrasound contrast (microbubbles). The groups are separately randomised to 2 megahertz (MHz) transcranial ultrasound treatment for one hour.
SonoVue solution 10 ml (2 vials / 80 µl microbubbles) is given as an infusion of 0,3 ml/min for ~30 minutes, using a Bracco infusion pump.
Placebo Comparator: Sham ultrasound
Patients eligible (NOR-SASS A/B) and ineligible (NOR-SASS C) for intravenous thrombolysis all receive intravenous ultrasound contrast (microbubbles). The two groups are separately randomised to sham ultrasound treatment for one hour.
Other: Sham ultrasound
Mounting the ultrasound headframe but connecting this to a non-operative channel
NOR-SASS is superimposed on NOR-TEST (Norwegian Tenecteplase Stroke Trial), in which eligible patients are randomized 1:1 to either tenecteplase or alteplase. NOR-SASS aims at testing contrast enhanced sonothrombolysis in all patients with acute ischemic stroke. Patients eligible for thrombolysis and randomised in NOR-TEST to tenecteplase or alteplase are therefore 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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01949961
|Contact: Lars Thomassen, MD PhD Prof.||+47 55 97 50 firstname.lastname@example.org|
|Contact: Christopher E Kvistad, MD||+47 55 97 50 email@example.com|
|Dept. of Neurology, Haukeland University Hospital||Recruiting|
|Bergen, Norway, 5021|
|Sub-Investigator: Christopher E Kvistad, MD|
|Sub-Investigator: Aliona Nacu, MD|
|Study Director:||Lars Thomassen, MD PhD Prof.||Dept. Neurology, Haukeland University Hospital, Bergen, Norway|
|Study Chair:||Christopher E Kvistad, MD||Dept. Neurology, Haukeland University Hospital, Bergen, Norway|
|Principal Investigator:||Aliona Nacu, MD||Dept. Neurology, Haukeland University Hospital, Bergen, Norway|