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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT01422616
Registration number
NCT01422616
Ethics application status
Date submitted
23/08/2011
Date registered
24/08/2011
Date last updated
13/10/2021
Titles & IDs
Public title
Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED)
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Scientific title
An International Randomised Controlled Trial to Establish the Effects of Low-dose rtPA and the Effects of Early Intensive Blood Pressure Lowering in Patients With Acute Ischaemic Stroke
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Secondary ID [1]
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X11-0123
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Universal Trial Number (UTN)
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Trial acronym
ENCHANTED
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Ischemic Stroke
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High Blood Pressure
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Condition category
Condition code
Stroke
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Haemorrhagic
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Stroke
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Ischaemic
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Cardiovascular
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Hypertension
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Cardiovascular
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Diseases of the vasculature and circulation including the lymphatic system
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - Low-dose rtPA
Treatment: Drugs - Standard-dose rtPA
Other interventions - Intensive blood pressure (BP) lowering
Other interventions - BP management policies
Experimental: Low-dose rtPA (Recruitment completed in August 2015) - low-dose 0.6 mg/kg (maximum of 60 mg) i.v. rtPA
Active Comparator: Standard-dose rtPA (Recruitment completed in August 2015) - standard-dose 0.9 mg/kg (maximum of 90 mg) i.v. rtPA
Experimental: Early intensive BP lowering - The trial is an assessment of BP lowering management strategies, using routinely available drugs.
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 (e.g. Labetalol Hydrochloride, Metoprolol tartrate, Hydralazine Hydrochloride, Glycerol Trinitrate, Phentolamine mesylate, Nicardipine, Urapidil, Esmolol, Clonidine, Enalaprilat, Nitroprusside) 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.
Active Comparator: Control / guideline-based BP management - The trial is an assessment of BP lowering management strategies, using routinely available drugs.
Patients allocated to the control group will receive management of BP that is based on a standard guideline, as published by the American Heart Association (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.
Treatment: Drugs: Low-dose rtPA
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).
Treatment: Drugs: Standard-dose 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.
Other interventions: Intensive blood pressure (BP) lowering
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.
Other interventions: BP management policies
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.
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Intervention code [1]
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Treatment: Drugs
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Intervention code [2]
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Other interventions
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Combined death and disability
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Assessment method [1]
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Unadjusted modified Rankin Scale [mRS] score 2-6
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Timepoint [1]
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90 days
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Secondary outcome [1]
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Symptomatic intracerebral hemorrhage
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Assessment method [1]
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Brain imaging (or necropsy) confirmed ICH with deterioration in NIH Stroke Scale (NIHSS) score or death, as defined by the SITS-MOST criteria
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Timepoint [1]
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36 hours
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Secondary outcome [2]
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Symptomatic intracerebral hemorrhage
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Assessment method [2]
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Brain imaging (or necropsy) confirmed ICH with deterioration in NIH Stroke Scale (NIHSS) score or death, as defined by the NINDS trial criteria
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Timepoint [2]
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36 hours
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Secondary outcome [3]
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Death or disability by the alternative, ordinal shift analysis
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Assessment method [3]
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Unadjusted death or functional outcome by the alternative ordinal shift analysis of scores on the modified Rankin Scale [mRS]
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Timepoint [3]
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90 days
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Secondary outcome [4]
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Death
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Assessment method [4]
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Death and 7 and 90 days
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Timepoint [4]
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at 7 and 90 days
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Secondary outcome [5]
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Disability
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Assessment method [5]
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mRS score 2-5
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Timepoint [5]
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90 days
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Secondary outcome [6]
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Neurological deterioration
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Assessment method [6]
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deterioration in NIHSS score
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Timepoint [6]
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72 hours
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Secondary outcome [7]
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Health-related quality of life
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Assessment method [7]
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Health-related quality of life by the EuroQoL
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Timepoint [7]
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90 days
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Secondary outcome [8]
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Admission to residential care
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Assessment method [8]
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Timepoint [8]
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90 days
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Secondary outcome [9]
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Health service use
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Assessment method [9]
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Health service use for calculation of resources and costs
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Timepoint [9]
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90 days
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Secondary outcome [10]
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Symptomatic intracerebral hemorrhage (ICH)
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Assessment method [10]
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By various other centrally adjudicated criteria, including ECASS2, ECASS3, IST-3 criteria, and fatal ICH within 7 days
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Timepoint [10]
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within 7 days
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Secondary outcome [11]
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Any intracerebral hemorrhage (ICH)
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Assessment method [11]
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Centrally adjudicated review of brain imaging for any evidence of ICH
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Timepoint [11]
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any time during 90 days
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Secondary outcome [12]
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Death or disability in as treated per-protocol population
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Assessment method [12]
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Adjusted death or functional outcome by the binary and alternative ordinal shift analysis of scores on the modified Rankin Scale [mRS]
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Timepoint [12]
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90 days
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Secondary outcome [13]
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Death or disability in as treated per-protocol population
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Assessment method [13]
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Adjusted analysis of the modified Rankin Scale [mRS] score 2-6
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Timepoint [13]
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90 days
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Secondary outcome [14]
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Death or neurological deterioration
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Assessment method [14]
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Death or neurological deterioration (defined by 4 points or more increase in NIHSS score from baseline)
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Timepoint [14]
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72 hours
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Secondary outcome [15]
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Length of initial acute hospital stay
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Assessment method [15]
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Length of hospital stay in days
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Timepoint [15]
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within 90 days
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Secondary outcome [16]
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Recurrent acute myocardial infarction and ischemic stroke
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Assessment method [16]
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Recurrent acute myocardial infarction and ischemic stroke
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Timepoint [16]
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within 90 days
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Eligibility
Key inclusion criteria
- Adult (age =18 years)
- A clinical diagnosis of acute ischaemic stroke confirmed by brain imaging
- Able to receive treatment within 4.5 hours after the definite time of onset of
symptoms
- Have a systolic BP =185 mmHg
- Provide informed consent (or via an appropriate proxy, according to local
requirements)
Specific criteria for arm [A] of low-dose vs standard-dose rtPA (Recruitment completed in
August 2015.):
- Able to receive either low-dose or standard-dose rtPA
Specific criteria for arm [B] of intensive BP lowering vs guideline recommended BP control
- Patient will or has received thrombolysis treatment with rtPA, either randomised dose
within the trial or physician decided dose rtPA outside of the trial
- Sustained elevated systolic BP level, defined as 2 readings = 150 mmHg
- Able to commence intensive BP lowering treatment within 6 hours of stroke onset
- Able to receive either immediate intensive BP lowering or conservative BP management
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Minimum age
18
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
- Unlikely to potentially benefit from the therapy (e.g. advanced dementia), or a very
high likelihood of death within 24 hours of stroke onset.
- Other medical illness that interferes with outcome assessments and follow-up [known
significant pre-stroke disability (mRS scores 2-5)].
- Specific contraindications to rtPA (Actilyse) or any of the blood pressure agents to
be used.
- Participation in another clinical trial involving evaluation of pharmacological
agents.
- Need for following concomitant medication, including phosphodiesterase inhibitors and
monoamine oxidase inhibitors.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Blinded (masking used)
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Who is / are masked / blinded?
The people assessing the outcomes
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Intervention assignment
Factorial
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Other design features
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Phase
Phase 3
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
1/03/2012
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
1/08/2018
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Sample size
Target
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Accrual to date
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Final
4587
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Recruitment in Australia
Recruitment state(s)
NSW
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Recruitment hospital [1]
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Royal Prince Alfred Hospital - Sydney
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Recruitment postcode(s) [1]
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2050 - Sydney
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Funding & Sponsors
Primary sponsor type
Other
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Name
The George Institute
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Address
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Country
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Other collaborator category [1]
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Other
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Name [1]
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National Health and Medical Research Council, Australia
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Address [1]
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Country [1]
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Other collaborator category [2]
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Other
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Name [2]
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The Stroke Association, United Kingdom
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Address [2]
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Country [2]
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Other collaborator category [3]
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Other
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Name [3]
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Conselho Nacional de Desenvolvimento Científico e Tecnológico
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Address [3]
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Other collaborator category [4]
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Commercial sector/Industry
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Name [4]
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Takeda
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Address [4]
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Ethics approval
Ethics application status
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Summary
Brief summary
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.
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Trial website
https://clinicaltrials.gov/ct2/show/NCT01422616
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Trial related presentations / publications
Anderson CS, Woodward M, Arima H, Chen X, Lindley RI, Wang X, Chalmers J; ENCHANTED Investigators. Statistical analysis plan for evaluating low- vs. standard-dose alteplase in the ENhanced Control of Hypertension and Thrombolysis strokE stuDy (ENCHANTED). Int J Stroke. 2015 Dec;10(8):1313-5. doi: 10.1111/ijs.12602. Epub 2015 Aug 18.
Huang Y, Sharma VK, Robinson T, Lindley RI, Chen X, Kim JS, Lavados P, Olavarria V, Arima H, Fuentes S, Nguyen HT, Lee TH, Parsons MW, Levi C, Demchuk AM, Bath PM, Broderick JP, Donnan GA, Martins S, Pontes-Neto OM, Silva F, Pandian J, Ricci S, Stapf C, Woodward M, Wang J, Chalmers J, Anderson CS; ENCHANTED investigators. Rationale, design, and progress of the ENhanced Control of Hypertension ANd Thrombolysis strokE stuDy (ENCHANTED) trial: An international multicenter 2 x 2 quasi-factorial randomized controlled trial of low- vs. standard-dose rt-PA and early intensive vs. guideline-recommended blood pressure lowering in patients with acute ischaemic stroke eligible for thrombolysis treatment. Int J Stroke. 2015 Jul;10(5):778-88. doi: 10.1111/ijs.12486. Epub 2015 Apr 2.
Anderson CS, Woodward M, Arima H, Chen X, Lindley RI, Wang X, Chalmers J, Robinson TG. Statistical analysis plan for evaluating different intensities of blood pressure control in the ENhanced Control of Hypertension And Thrombolysis strokE stuDy. Int J Stroke. 2019 Jul;14(5):555-558. doi: 10.1177/1747493018806170. Epub 2018 Oct 9.
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Public notes
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Contacts
Principal investigator
Name
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Craig S Anderson, MD
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Address
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The George Institute
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Country
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Phone
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Fax
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Email
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Contact person for public queries
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Fax
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT01422616
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