title: A pragmatic approach to sonothrombolysis in acute ischaemic stroke: the Norwegian randomised controlled sonothrombolysis in acute stroke study (NOR-SASS).
abstract: BACKGROUND
  Ultrasound accelerates thrombolysis with tPA (sonothrombolysis). Ultrasound in the absence of tPA also accelerates clot break-up (sonolysis). Adding intravenous gaseous microbubbles may potentiate the effect of ultrasound in both sonothrombolysis and sonolysis. The Norwegian Sonothrombolysis in Acute Stroke Study aims in a pragmatic approach to assess the effect and safety of contrast enhanced ultrasound treatment in unselected acute ischaemic stroke patients.
  
  
  METHODS
  Acute ischaemic stroke patients ≥ 18 years, with or without visible arterial occlusion on computed tomography angiography (CTA) and treatable ≤ 4(½) hours after symptom onset, are included in NOR-SASS. NOR-SASS is superimposed on a separate trial randomising patients with acute ischemic stroke to either tenecteplase or alteplase (The Norwegian Tenecteplase Stroke Trial NOR-TEST). The NOR-SASS trial has two arms: 1) the thrombolysis-arms (NOR-SASS A and B) includes patients given intravenous thrombolysis (tenecteplase or alteplase), and 2) the no-thrombolysis-arm (NOR-SASS C) includes patients with contraindications to thrombolysis. First step randomisation of NOR-SASS A is embedded in NOR-TEST as a 1:1 randomisation to either tenecteplase or alteplase. Second step NOR-SASS randomisation is 1:1 to either contrast enhanced sonothrombolysis (CEST) or sham CEST. Randomisation in NOR-SASS B (routine alteplase group) is 1:1 to either CEST or sham CEST. Randomisation of NOR-SASS C is 1:1 to either contrast enhanced sonolysis (CES) or sham CES. Ultrasound is given for one hour using a 2-MHz pulsed-wave diagnostic ultrasound probe. Microbubble contrast (SonoVue®) is given as a continuous infusion for ~30 min. Recanalisation is assessed at 60 min after start of CEST/CES. Magnetic resonance imaging and angiography is performed after 24 h of stroke onset. Primary study endpoints are 1) major neurological improvement measured with NIHSS score at 24 h and 2) favourable functional outcome defined as mRS 0-1 at 90 days.
  
  
  CONCLUSIONS
  NOR-SASS is the first randomised controlled trial designed to test the superiority of contrast enhanced ultrasound treatment given ≤ 4(½) hours after stroke onset in an unselected acute ischaemic stroke population eligible or not eligible for intravenous thrombolysis, with or without a defined arterial occlusion on CTA. If a positive effect and safety can be proven, contrast enhanced ultrasound treatment will be an option for all acute ischaemic stroke patients. EudraCT No 201200032341; www.clinicaltrials.gov NCT01949961.
authors.affiliation: Department of Neurology, Haukeland University Hospital, N-5021, Bergen, Norway. aliona.nacu@helse-bergen.no.|Department of Clinical Medicine, University of Bergen, Bergen, Norway. aliona.nacu@helse-bergen.no.
authors.forename: Aliona
authors.initials: A
authors.lastname: Nacu
authors.affiliation: Department of Neurology, Haukeland University Hospital, N-5021, Bergen, Norway. echr@helse-bergen.no.|Department of Clinical Medicine, University of Bergen, Bergen, Norway. echr@helse-bergen.no.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Kvistad
authors.affiliation: Department of Neurology, Haukeland University Hospital, N-5021, Bergen, Norway. nalo@helse-bergen.no.
authors.forename: Nicola
authors.initials: N
authors.lastname: Logallo
authors.affiliation: Department of Neurology, Haukeland University Hospital, N-5021, Bergen, Norway. haln@helse-bergen.no.|Department of Clinical Medicine, University of Bergen, Bergen, Norway. haln@helse-bergen.no.|Centre for age-related medicine, Stavanger University Hospital, Stavanger, Norway. haln@helse-bergen.no.
authors.forename: Halvor
authors.initials: H
authors.lastname: Naess
authors.affiliation: Department of Neurology, Haukeland University Hospital, N-5021, Bergen, Norway. uwan@helse-bergen.no.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Waje-Andreassen
authors.affiliation: Department of Neurology, Oslo University Hospital, Oslo, Norway. anhaam@ous-hf.no.
authors.forename: Anne Hege
authors.initials: AH
authors.lastname: Aamodt
authors.affiliation: Department of Neurology, Arendal Hospital, Arendal, Norway. ragnar.solhoff@sshf.no.
authors.forename: Ragnar
authors.initials: R
authors.lastname: Solhoff
authors.affiliation: Department of Neurology, Oslo University Hospital, Oslo, Norway. clund@ous-hf.no.
authors.forename: Christian
authors.initials: C
authors.lastname: Lund
authors.affiliation: Department of Neurology, Skien Hospital, Skien, Norway. htobro@yahoo.no.
authors.forename: Håkon
authors.initials: H
authors.lastname: Tobro
authors.affiliation: Department of Neuroly, Akershus University Hospital, Nordbyhagen, Norway. ole.morten.ronning@ahus.no.
authors.forename: Ole Morten
authors.initials: OM
authors.lastname: Rønning
authors.affiliation: Department of Neurology, Bodø Hospital, Bodo, Norway. rolf.salvesen@nlsh.no.
authors.forename: Rolf
authors.initials: R
authors.lastname: Salvesen
authors.affiliation: Department of Neurology, St. Olavs Hospital, Trondheim, Norway. titto.idicula@stolav.no.
authors.forename: Titto T
authors.initials: TT
authors.lastname: Idicula
authors.affiliation: Department of Neurology, Haukeland University Hospital, N-5021, Bergen, Norway. ltho@helse-bergen.no.|Department of Clinical Medicine, University of Bergen, Bergen, Norway. ltho@helse-bergen.no.
authors.forename: Lars
authors.initials: L
authors.lastname: Thomassen
mesh_terms: D002545:Brain Ischemia / Q000628:therapy*; D003131:Combined Modality Therapy; D003287:Contrast Media / Q000008:administration & dosage; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D006801:Humans; D045423:Microbubbles; D020521:Stroke / Q000628:therapy*; D000077785:Tenecteplase; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use; D014464:Ultrasonic Therapy / Q000379:methods
chemical_list: D003287:Contrast Media; D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator; D000077785:Tenecteplase