The Norwegian Sonothrombolysis in Acute Stroke Study "NOR-SASS"

Terminated

Phase 2/3 Results N/A

Trial Description

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 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.

Trial Stopped: Lack of funding for researchers

Conditions

Interventions

  • Ultrasound Device
    Intervention Desc: 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.
    ARM 1: Kind: Experimental
    Label: Ultrasound
    Description: Patients eligible (NOR-SASS 1) and ineligible (NOR-SASS 2) for intravenous thrombolysis all receive intravenous ultrasound contrast (microbubbles). The two groups are separately randomised to 2 MHz transcranial ultrasound treatment for one hour.
  • Sham ultrasound Other
    Intervention Desc: Mounting the ultrasound headframe but connecting this to a non-operative channel
    ARM 1: Kind: Experimental
    Label: Sham ultrasound
    Description: Patients eligible (NOR-SASS 1) and ineligible (NOR-SASS 2) for intravenous thrombolysis all receive intravenous ultrasound contrast (microbubbles). The two groups are separately randomised to sham ultrasound treatment for one hour.

Trial Design

  • Allocation: Randomized
  • Masking: Double Blind (Subject, Outcomes Assessor)
  • Purpose: Treatment
  • Endpoint: Safety/Efficacy Study
  • Intervention: Parallel Assignment

Outcomes

Type Measure Time Frame Safety Issue
Primary Functional handicap 90 days No
Secondary Symptomatic intracerebral hemorrhage 24-36 hours Yes
Secondary Hemorrhagic transformation 24-36 hours Yes
Secondary Early clinical outcome 2 and 24 hours No
Secondary Short term functional outcome 7 days No
Primary Clinical: Functional handicap 90 days No
Primary Proof of concept: Early neurological improvement 22-36 hours No
Secondary Brain infarct size and location 22-36 hours No

Sponsors