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Trial registered on ANZCTR
Registration number
ACTRN12611000236998
Ethics application status
Approved
Date submitted
2/03/2011
Date registered
3/03/2011
Date last updated
19/09/2019
Date data sharing statement initially provided
19/09/2019
Date results information initially provided
19/09/2019
Type of registration
Prospectively registered
Titles & IDs
Public title
Enhanced control of hypertension and thrombolysis stroke study
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Scientific title
An international randomised controlled trial to compare the effects of low- and standard-dose recombinant tissue plasminogen activator (rtPA) and to establish the effects of early intensive blood pressure (BP) lowering on death and disability in patients with ischaemic stroke
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Secondary ID [1]
259718
0
NIl
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Universal Trial Number (UTN)
Nil
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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:
Ischaemic stroke
261297
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Hypertension
261307
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Condition category
Condition code
Stroke
259445
259445
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0
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Ischaemic
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Cardiovascular
259455
259455
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0
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Hypertension
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
ENCHANTED is a package of 2 linked randomised controlled trials, arms [A] and [B]. Patients will be included in arm [A] only, arm [B] only, or both arms [A] and [B], based on their eligibility and attending clinician’s level of uncertainty as to the balance of benefits and risks of the investigative treatments in an individual patient.
Patients included in arm [A] will be randomised to receive low-dose 0.6 mg/kg (15% bolus and 85% infusion over 60 minutes) or standard-dose 0.9 mg/kg (10% bolus and 90% infusion over 60 minutes) i.v. rtPA (Actylise).
Patients included in arm [B] will be randomised to receive intensive 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) or guideline-based BP lowering to a target systolic BP of <180 mmHg post-rtPA. Standardised locally approved i.v. BP lowering agents such as clevidipine, labetolol hydrochloride, metoprolol tartrate, hydralazine hydrochloride, glyceral trinitrate and phentoloamine are to be used.
Patients included only in arm [B] are eligible if they receive non-study i.v. rtPA (Actylise) as usual care.
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Intervention code [1]
264144
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Treatment: Drugs
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Comparator / control treatment
Usual care (Arm [A]: standard-dose 0.9 mg/kg i.v. rtPA (Actylise). Arm [B]: guideline-based BP lowering.)
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Control group
Active
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Outcomes
Primary outcome [1]
262251
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RtPA dose arm: death and any disability (modified Rankin Scale [mRS] score 2-6)
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Assessment method [1]
262251
0
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Timepoint [1]
262251
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90 days
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Primary outcome [2]
321454
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Blood Pressure intensity arm: mRS ordinal shift
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Assessment method [2]
321454
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Timepoint [2]
321454
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90 days
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Secondary outcome [1]
273390
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symptomatic intracerebral haemorrhage (confirmed by CT [or necropsy] with deterioration in NIH Stroke Scale [NIHSS] score)
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Assessment method [1]
273390
0
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Timepoint [1]
273390
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36 hours
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Secondary outcome [2]
273391
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any intracerebral haemorrhage in CT scans
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Assessment method [2]
273391
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Timepoint [2]
273391
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7 days
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Secondary outcome [3]
273392
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death or disability by shift analysis of scores on modified Rankin Scale (mRS)
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Assessment method [3]
273392
0
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Timepoint [3]
273392
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90 days
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Secondary outcome [4]
273393
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death
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Assessment method [4]
273393
0
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Timepoint [4]
273393
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90 days
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Secondary outcome [5]
273394
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disability (modified Rankin Scale [mRS] score 2-5)
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Assessment method [5]
273394
0
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Timepoint [5]
273394
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90 days
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Secondary outcome [6]
273395
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neurological deterioration (deterioration in NIH Stroke Scale [NIHSS] score and/or Glasgow Coma Scale [GCS] score)
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Assessment method [6]
273395
0
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Timepoint [6]
273395
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72 hours
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Secondary outcome [7]
273396
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health-related quality of life by the EuroQoL
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Assessment method [7]
273396
0
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Timepoint [7]
273396
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90 days
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Secondary outcome [8]
273397
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admission to residential care by in-person or telephone follow-up
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Assessment method [8]
273397
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Timepoint [8]
273397
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90 days
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Secondary outcome [9]
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health service including length of initial hospital stay, re-admission to hospital, visits to outpatient clinics, and visits to primary care physicians obtained by in-person or telephone follow-up
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Assessment method [9]
273398
0
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Timepoint [9]
273398
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90 days
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Eligibility
Key inclusion criteria
Patients with clinical diagnosis of acute ischaemic stroke confirmed by brain imaging within 4.5 hours of onset who fulfill local criteria for use of i.v. rtPA are potentially eligible if they have a sustained systolic BP level of 185 mmHg or below.
The attending clinician is required to sequentially consider their level of clinical uncertainty over the balance of potential benefits and risks pertaining to the appropriate dose of rtPA and the level of BP control in each particular patient, as outlined below.
Arm [A]: no definite indication/contraindication for either dose of rtPA; and able to pay for a 50mg vial of rtPA if in a fee-paying health system.
Arm [B]: 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
Years
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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)
Patients are randomised via a central internet-based system developed by The George Institute, Sydney, Australia, either direct or via a specially developed IVRS (only in China).
Most patients will be eligible for arm [A] as the overall inclusion criteria is eligibility for rtPA, but only a proportion (~60%) of patients with acute ischaemic stroke are anticipated to have elevated BP and thus eligible for arm [B]. Investigators have the choice of randomising patients into 1 or 2 treatment arms.
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Assignment to a treatment group is determined by a computerised algorithm which runs on the central database and uses the minimisation method. The stratification factors are country, site, time from onset (<3 vs 3 hours or longer) and NIHSS (<10 vs 10 or more).
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Parallel
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Other design features
ENCHANTED is a package of 2 linked randomised controlled trials, arms [A] and [B]. Patients will be included in arm [A] only, arm [B] only, or both arms [A] and [B], based on their eligibility and attending clinician’s level of uncertainty as to the balance of benefits and risks of the investigative treatments in an individual patient.
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Phase
Phase 3 / Phase 4
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Type of endpoint/s
Safety/efficacy
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Date of first participant enrolment
Anticipated
1/08/2011
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Actual
3/03/2012
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Date of last participant enrolment
Anticipated
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Actual
30/04/2018
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Date of last data collection
Anticipated
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Actual
22/08/2018
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Sample size
Target
4500
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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 postcode(s) [1]
3734
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2010
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Recruitment postcode(s) [2]
3735
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2050
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Recruitment postcode(s) [3]
3736
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2065
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Recruitment postcode(s) [4]
3737
0
2138
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Recruitment postcode(s) [5]
3738
0
2145
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Recruitment postcode(s) [6]
3739
0
2217
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Recruitment postcode(s) [7]
3740
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2305
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Recruitment postcode(s) [8]
3741
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2250
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Recruitment postcode(s) [9]
3742
0
2606
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Recruitment postcode(s) [10]
3743
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3004
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Recruitment postcode(s) [11]
3744
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3050
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Recruitment postcode(s) [12]
3745
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3065
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Recruitment postcode(s) [13]
3746
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3084
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Recruitment postcode(s) [14]
3747
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3128
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Recruitment postcode(s) [15]
3748
0
3168
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Recruitment postcode(s) [16]
3749
0
4029
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Recruitment postcode(s) [17]
3750
0
5000
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Recruitment postcode(s) [18]
3751
0
5011
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Recruitment postcode(s) [19]
3752
0
5042
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Recruitment postcode(s) [20]
3753
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6009
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Recruitment outside Australia
Country [1]
3265
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Hong Kong
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State/province [1]
3265
0
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Country [2]
3266
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United Kingdom
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State/province [2]
3266
0
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Country [3]
3267
0
France
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State/province [3]
3267
0
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Country [4]
3268
0
Austria
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State/province [4]
3268
0
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Country [5]
3269
0
Swaziland
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State/province [5]
3269
0
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Country [6]
3270
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Italy
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State/province [6]
3270
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Country [7]
3271
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Portugal
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State/province [7]
3271
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Country [8]
3272
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Spain
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State/province [8]
3272
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Country [9]
3273
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China
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State/province [9]
3273
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Country [10]
3274
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New Zealand
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State/province [10]
3274
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Country [11]
3275
0
Singapore
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State/province [11]
3275
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Country [12]
3276
0
Korea, Republic Of
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State/province [12]
3276
0
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Country [13]
3277
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Viet Nam
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State/province [13]
3277
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Country [14]
3278
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India
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State/province [14]
3278
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Country [15]
3279
0
Pakistan
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State/province [15]
3279
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Country [16]
3280
0
Chile
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State/province [16]
3280
0
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Country [17]
3281
0
Thailand
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State/province [17]
3281
0
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Funding & Sponsors
Funding source category [1]
264597
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Government body
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Name [1]
264597
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National Health and Medical Research Council (NHMRC)
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Address [1]
264597
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GPO Box 1421 Canberra ACT2601
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Country [1]
264597
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Australia
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Primary sponsor type
Other
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Name
The George Institute for Global Health
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Address
PO Box M201 Missenden Rd, Camperdown NSW2050
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Country
Australia
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Secondary sponsor category [1]
263736
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None
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Name [1]
263736
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Address [1]
263736
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Country [1]
263736
0
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Ethics approval
Ethics application status
Approved
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Ethics committee name [1]
260593
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Sydney South West Area Health Service Ethics Review Committee (RPAH Zone)
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Ethics committee address [1]
260593
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Research Development Office, Royal Prince Alfred Hospital, Missenden Road, Camperdown 2050
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Ethics committee country [1]
260593
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Australia
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Date submitted for ethics approval [1]
260593
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11/04/2011
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Approval date [1]
260593
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30/06/2011
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Ethics approval number [1]
260593
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HREC\EXECOR\11-06
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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)?
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Trial website
http://www.enchanted.org.au
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
32300
0
Prof Craig Anderson
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Address
32300
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The George Institute for Global Health PO Box M201 Missenden Rd, Camperdown NSW2050
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Country
32300
0
Australia
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Phone
32300
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+61 2 9993 4500
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Fax
32300
0
+61 2 9993 4502
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Email
32300
0
[email protected]
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Contact person for public queries
Name
15547
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Prof Craig Anderson
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Address
15547
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The George Institute for Global Health
PO Box M201 Missenden Rd, Camperdown NSW2050
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Country
15547
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Australia
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Phone
15547
0
+61 2 9993 4500
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Fax
15547
0
+61 2 9993 4502
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Email
15547
0
[email protected]
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Contact person for scientific queries
Name
6475
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Prof Craig Anderson
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Address
6475
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The George Institute for Global Health
PO Box M201 Missenden Rd, Camperdown NSW2050
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Country
6475
0
Australia
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Phone
6475
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+61 2 9993 4500
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Fax
6475
0
+61 2 9993 4502
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Email
6475
0
[email protected]
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Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
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What data in particular will be shared?
De-identified participant data collected during the trial, individual participant data underlying published results only.
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When will data be available (start and end dates)?
After publication of the main results for both arms (rtPA and BP), and no end date.
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Available to whom?
Eligible investigators who provide a methodologically proposal and approved by the sponsor of the study.
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Available for what types of analyses?
Secondary analysis
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How or where can data be obtained?
Subject to approvals by Principal Investigator, requirement to sign data access agreement, etc.
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What supporting documents are/will be available?
No Supporting Document Provided
Results publications and other study-related documents
Documents added manually
Type
Is Peer Reviewed?
DOI
Citations or Other Details
Attachment
Study results article
Yes
BP arm results: Lancet. 2019 Feb 6. pii: S0140-673...
[
More Details
]
336622-(Uploaded-28-02-2019-14-51-12)-Journal results publication.pdf
Other files
No
BP arm conference presentation: https://profession...
[
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]
336622-(Uploaded-28-02-2019-14-56-22)-Other results publication.pdf
Study results article
Yes
rtPA arm results: N Engl J Med. 2016 Jun 16;374(24...
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]
336622-(Uploaded-28-02-2019-15-00-18)-Journal results publication.pdf
Other files
No
rtPA conference presentation: http://emdstudio.co....
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More Details
]
336622-(Uploaded-28-02-2019-15-10-14)-Other results publication.pdf
Documents added automatically
Source
Title
Year of Publication
DOI
Embase
Rationale, design, and progress of the ENhanced Control of Hypertension ANd Thrombolysis strokE stuDy (ENCHANTED) trial: An international multicenter 2x2 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.
2015
https://dx.doi.org/10.1111/ijs.12486
Embase
Statistical analysis plan for evaluating different intensities of blood pressure control in the ENhanced Control of Hypertension And Thrombolysis strokE stuDy.
2019
https://dx.doi.org/10.1177/1747493018806170
N.B. These documents automatically identified may not have been verified by the study sponsor.
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