EXTEND (International): Extending the Time for Thrombolysis in Emergency Neurological Deficits (International)

• Categorical shift in modified Rankin Score (mRS) [ Time Frame: 3 months ] [ Designated as safety issue: No ]
• Change in ≥ 8 National Institutes of Health Stroke Scale (NIHSS) points or reaching ≤ 1 on this scale [ Time Frame: 3 months ] [ Designated as safety issue: No ]
• Death due to any cause [ Time Frame: 3 months ] [ Designated as safety issue: Yes ]
• Symptomatic Intracerebral Hemorrhage (ICH) [ Time Frame: 24 hours ] [ Designated as safety issue: Yes ]
  Symptomatic hemorrhage defined by SITS-MOST criteria: type 2 parenchymal hematoma associated with ≥4 point increase in NIHSS
• Reperfusion [ Time Frame: 24 hours ] [ Designated as safety issue: No ]
• Recanalisation [ Time Frame: 24 hours ] [ Designated as safety issue: No ]
• Infarct growth [ Time Frame: 24 hours ] [ Designated as safety issue: No ]
  Difference in volumetric Diffusion Weighted Image (DWI) volume between baseline and 24 hour Magnetic Resonance Imaging (MRI)
• Recurrent stroke [ Time Frame: 3 and 12 months ] [ Designated as safety issue: No ]

• Categorical shift in modified Rankin Score (mRS) [ Time Frame: 3 months ] [ Designated as safety issue: No ]
• Change in ≥ 8 NIHSS points or reaching ≤ 1 on this scale [ Time Frame: 3 months ] [ Designated as safety issue: No ]
• Death due to any cause [ Time Frame: 3 months ] [ Designated as safety issue: Yes ]
• Symptomatic ICH [ Time Frame: 24 hours ] [ Designated as safety issue: Yes ]
  Symptomatic hemorrhage defined by SITS-MOST criteria: type 2 parenchymal hematoma associated with ≥4 point increase in NIHSS
• Reperfusion [ Time Frame: 24 hours ] [ Designated as safety issue: No ]
• Recanalisation [ Time Frame: 24 hours ] [ Designated as safety issue: No ]
• Infarct growth [ Time Frame: 24 hours ] [ Designated as safety issue: No ]
  Difference in volumetric DWI volume between baseline and 24 hour MRI
• Recurrent stroke [ Time Frame: 3 and 12 months ] [ Designated as safety issue: No ]

The primary hypothesis being tested in this trial is that ischaemic stroke patients selected with significant penumbral mismatch (according to imaging criteria) at 4.5 (or 3 hours depending on local guidelines) - 9 hours post onset of stroke or after 'wake up stroke' (WUS) will have improved clinical outcomes when given intravenous tissue plasminogen activator (tPA) compared to placebo.

• Drug: Tissue Plasminogen Activator (Alteplase)
  0.9 mg/kg up to a maximum of 90mg, intravenous, 10% as bolus and the remainder over 1 hour
  Other Names:

  • Actilyse
  • Activase
  • tPA
  • r-tPA
• Drug: Placebo
  placebo provided as 50mg lyophilised powder to be reconstituted with sterile water in glass vials indistinguishable from active drug

• Experimental: intravenous tissue plasminogen activator
  Intervention: Drug: Tissue Plasminogen Activator (Alteplase)
• Placebo Comparator: Placebo
  Intervention: Drug: Placebo

Inclusion Criteria:

• Patients presenting with hemispheric acute ischaemic stroke
• Patient, family member or legally responsible person depending on local ethics requirements has given informed consent
• Patient's age is ≥18 years (or as per local requirements)
• Treatment onset can commence within 4.5 - 9 hours after stroke onset according to registered product information, or within 3 - 9 hours according to locally accepted guidelines.
• Patients who wake with stroke may be included if neurological and other exclusion criteria are satisfied. These 'wake up' strokes are defined as having no symptoms at sleep onset, but stroke symptoms on waking. The time of stroke onset is to be taken as the mid-point between sleep onset (or last known to be normal) and time of waking. The maximum time window for randomisation is then 9 hours from the mid-point as described.
• Significant neurological deficit (eg. NIHSS score of ≥ 4 - 26) with clinical signs of hemispheric infarction.
• Penumbral mismatch - A "hypo-perfusion to core" volume ratio of greater than 1.2, and an absolute difference greater than 10ml (using a Magnetic Resonance (MR) or Computed Tomography (CT) Tmax > 6 second delay), between perfusion lesion and MR-DWI or Computed Tomography-Cerebral Blood Flow (CT-CBF) core lesion.
• An infarct core lesion of less than or equal to 70ml using MR-DWI or CT-CBF

Exclusion Criteria:

• Intracranial haemorrhage (ICH) identified by CT or MRI
• Rapidly improving symptoms, particularly if in the judgment of the managing clinician that the improvement is likely to result in the patient having an NIHSS score of < 4 at randomization
• Pre-stroke MRS score of ≥ 2 (indicating previous disability)
• Contra indication to imaging with contrast agents
• Infarct core >1/3 Middle Cerebral Artery (MCA) territory qualitatively
• Participation in any investigational study in the previous 30 days
• Any terminal illness such that patient would not be expected to survive more than 1 year
• Any condition that could impose hazards to the patient if study therapy is initiated or affect the participation of the patient in the study (this applies to patients with severe microangiopathy such as haemolytic uremic syndrome or thrombotic thrombocytopenic purpura). The judgment is left to the discretion of the Investigator.
• Pregnant women (clinically evident)
• Previous stroke within last three months
• Recent past history or clinical presentation of ICH, subarachnoid haemorrhage (SAH), arterio-venous (AV) malformation, aneurysm, or cerebral neoplasm. At the discretion of each Investigator.
• Current use of oral anticoagulants and a prolonged prothrombin time (INR > 1.6)
• Use of heparin, except for low dose subcutaneous heparin, in the previous 48 hours and a prolonged activated thromboplastin time exceeding the upper limit of the local laboratory normal range.
• Use of glycoprotein IIb - IIIa inhibitors within the past 72 hours. Use of single or dual agent oral platelet inhibitors (clopidogrel and/or low-dose aspirin) prior to study entry is permitted.
• Clinically significant hypoglycaemia.
• Uncontrolled hypertension defined by a blood pressure > 185 mmHg systolic or >110 mmHg diastolic on at least 2 separate occasions at least 10 minutes apart, or requiring aggressive treatment to reduce the blood pressure to within these limits. The definition of "aggressive treatment" is left to the discretion of the responsible Investigator.
• Hereditary or acquired haemorrhagic diathesis
• Gastrointestinal or urinary bleeding within the preceding 21 days
• Major surgery within the preceding 14 days which poses risk in the opinion of the investigator.
• Exposure to a thrombolytic agent within the previous 72 hours