ENCHANTED is an independent, investigator initiated, international collaborative, quasi-factorial randomised controlled trial involving a package of 2 linked comparative randomised treatment arms, which aims to address 4 key questions in patients eligible for thrombolysis in the acute phase of ischaemic stroke. (1) Does low-dose (0.6 mg/kg) intravenous (i.v.) recombinant tissue plasminogen activator (rtPA) provide equivalent benefits compared to standard-dose (0.9 mg/kg) rtPA? (2) Does intensive blood pressure (BP) lowering (130-140 mmHg systolic target) improve outcomes compared to the current guideline recommended level of BP control (180 mmHg systolic target)? (3) Does low-dose (0.6 mg/kg) intravenous (i.v.) recombinant tissue plasminogen activator (rtPA) reduce the risk of symptomatic intracerebral haemorrhage (sICH)? (4) Does the addition of intensive BP lowering to thrombolysis with rtPA reduce the risk of any intracerebral haemorrhage (ICH)? The rtPA dose arm of the study addressing questions (1) and (3) concluded with a publication of the results in May 2016. The BP intensity arm of the study addressing questions (2) and (4) concluded with a publication of the results in February 2019.
This study is an international, multicentre, prospective, fixed-time point (optional) randomisation for two arms (\[A\] 'dose of rtPA' and \[B\] 'level of BP control'), open-label, blinded endpoint (PROBE) controlled trial that involved 4587 patients (3310 for rtPA arm {recruitment completed in August 2015} and 2227 for BP arm {recruitment completed in April 2018} with 939 overlap) with acute ischaemic stroke recruited from over 100+ Clinical Centres from Australia, Asia, Europe and South America.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Enrollment
4,587
Patients allocated to low-dose will receive 0.6 mg/kg (maximum of 60 mg) i.v. (15% bolus \[maximum bolus dose of 9mg\] and 85% infusion over 60 mins) recombinant tissue plasminogen activator (rtPA).
Patients allocated to standard-dose will receive 0.9 mg/kg (maximum of 90 mg) i.v. (10% bolus and 90% infusion over 60 mins) rtPA.
Intensive blood pressure (BP) lowering to a target systolic BP range 130-140 mmHg within one hour and to maintain this level for at least 72 hours (or until hospital discharge or death if this should occur earlier). A standardised i.v. BP lowering regimen using locally available and approved i.v. BP lowering agents will be used, commenced in the emergency department and later in a high dependency area (e.g. acute stroke or neurointensive care unit) as is usual for patients receiving rtPA. The trial is an assessment of BP lowering management strategies, using routinely available drugs. There is some flexibility in the use of particular BP lowering agents to achieve BP targets.
Patients allocated to the control group will receive management of BP that is based on a standard guideline, as published by the AHA. For this group, the attending clinician may consider commencing BP treatment if the systolic level is greater than 180 mmHg, however and the first line treatment will be oral (including nasogastric if required) and/or transdermal routes. Should control of systolic BP not be achieved via these routes, i.v. treatment may be started until the target systolic BP of 180 mmHg is achieved. The trial is an assessment of BP lowering management strategies, using routinely available drugs. There is some flexibility in the use of particular BP lowering agents to achieve BP targets.
Royal Prince Alfred Hospital
Sydney, New South Wales, Australia
Combined death and disability
Unadjusted modified Rankin Scale \[mRS\] score 2-6
Time frame: 90 days
Symptomatic intracerebral hemorrhage
Brain imaging (or necropsy) confirmed ICH with deterioration in NIH Stroke Scale (NIHSS) score or death, as defined by the SITS-MOST criteria
Time frame: 36 hours
Symptomatic intracerebral hemorrhage
Brain imaging (or necropsy) confirmed ICH with deterioration in NIH Stroke Scale (NIHSS) score or death, as defined by the NINDS trial criteria
Time frame: 36 hours
Death or disability by the alternative, ordinal shift analysis
Unadjusted death or functional outcome by the alternative ordinal shift analysis of scores on the modified Rankin Scale \[mRS\]
Time frame: 90 days
Death
Death and 7 and 90 days
Time frame: at 7 and 90 days
Disability
mRS score 2-5
Time frame: 90 days
Neurological deterioration
deterioration in NIHSS score
Time frame: 72 hours
Health-related quality of life
Health-related quality of life by the EuroQoL
Time frame: 90 days
Admission to residential care
Time frame: 90 days
Health service use
Health service use for calculation of resources and costs
Time frame: 90 days
Symptomatic intracerebral hemorrhage (ICH)
By various other centrally adjudicated criteria, including ECASS2, ECASS3, IST-3 criteria, and fatal ICH within 7 days
Time frame: within 7 days
Any intracerebral hemorrhage (ICH)
Centrally adjudicated review of brain imaging for any evidence of ICH
Time frame: any time during 90 days
Death or disability in as treated per-protocol population
Adjusted death or functional outcome by the binary and alternative ordinal shift analysis of scores on the modified Rankin Scale \[mRS\]
Time frame: 90 days
Death or disability in as treated per-protocol population
Adjusted analysis of the modified Rankin Scale \[mRS\] score 2-6
Time frame: 90 days
Death or neurological deterioration
Death or neurological deterioration (defined by 4 points or more increase in NIHSS score from baseline)
Time frame: 72 hours
Length of initial acute hospital stay
Length of hospital stay in days
Time frame: within 90 days
Recurrent acute myocardial infarction and ischemic stroke
Recurrent acute myocardial infarction and ischemic stroke
Time frame: within 90 days
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