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Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED) (ENCHANTED)

This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2016 by The George Institute
Sponsor:
Collaborators:
National Health and Medical Research Council, Australia
The Stroke Association, United Kingdom
Conselho Nacional de Desenvolvimento Científico e Tecnológico
Ministry for Health, Welfare and Family Affairs of the Republic of Korea
Takeda China (for the BP lowering arm of the study in China, from March 2016)
Information provided by (Responsible Party):
The George Institute
ClinicalTrials.gov Identifier:
NCT01422616
First received: August 23, 2011
Last updated: December 12, 2016
Last verified: October 2016
  Purpose

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 is ongoing.


Condition Intervention Phase
Ischemic Stroke
High Blood Pressure
Drug: Low-dose rtPA
Drug: Standard-dose rtPA
Other: Intensive blood pressure (BP) lowering
Other: BP management policies
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Single Blind (Outcomes Assessor)
Primary Purpose: Treatment
Official 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

Resource links provided by NLM:


Further study details as provided by The George Institute:

Primary Outcome Measures:
  • Combined death and disability [ Time Frame: 90 days ]
    Unadjusted modified Rankin Scale [mRS] score 2-6


Secondary Outcome Measures:
  • Symptomatic intracerebral hemorrhage [ Time Frame: 36 hours ]
    Brain imaging (or necropsy) confirmed ICH with deterioration in NIH Stroke Scale (NIHSS) score or death, as defined by the SITS-MOST criteria

  • Symptomatic intracerebral hemorrhage [ Time Frame: 36 hours ]
    Brain imaging (or necropsy) confirmed ICH with deterioration in NIH Stroke Scale (NIHSS) score or death, as defined by the NINDS trial criteria

  • Death or disability by the alternative, ordinal shift analysis [ Time Frame: 90 days ]
    Unadjusted death or functional outcome by the alternative ordinal shift analysis of scores on the modified Rankin Scale [mRS]

  • Death [ Time Frame: at 7 and 90 days ]
    Death and 7 and 90 days

  • Disability [ Time Frame: 90 days ]
    mRS score 2-5

  • Neurological deterioration [ Time Frame: 72 hours ]
    deterioration in NIHSS score

  • Health-related quality of life [ Time Frame: 90 days ]
    Health-related quality of life by the EuroQoL

  • Admission to residential care [ Time Frame: 90 days ]
  • Health service use [ Time Frame: 90 days ]
    Health service use for calculation of resources and costs

  • Symptomatic intracerebral hemorrhage (ICH) [ Time Frame: within 7 days ]
    By various other centrally adjudicated criteria, including ECASS2, ECASS3, IST-3 criteria, and fatal ICH within 7 days

  • Any intracerebral hemorrhage (ICH) [ Time Frame: any time during 90 days ]
    Centrally adjudicated review of brain imaging for any evidence of ICH

  • Death or disability in as treated per-protocol population [ Time Frame: 90 days ]
    Adjusted death or functional outcome by the binary and alternative ordinal shift analysis of scores on the modified Rankin Scale [mRS]

  • Death or disability in as treated per-protocol population [ Time Frame: 90 days ]
    Adjusted analysis of the modified Rankin Scale [mRS] score 2-6

  • Death or neurological deterioration [ Time Frame: 72 hours ]
    Death or neurological deterioration (defined by 4 points or more increase in NIHSS score from baseline)

  • Length of initial acute hospital stay [ Time Frame: within 90 days ]
    Length of hospital stay in days

  • Recurrent acute myocardial infarction and ischemic stroke [ Time Frame: within 90 days ]
    Recurrent acute myocardial infarction and ischemic stroke


Estimated Enrollment: 4700
Study Start Date: March 2012
Estimated Study Completion Date: February 2019
Estimated Primary Completion Date: December 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Low-dose rtPA (Recruitment completed in August 2015)
low-dose 0.6 mg/kg (maximum of 60 mg) i.v. rtPA
Drug: 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).
Other Name: Actilyse
Active Comparator: Standard-dose rtPA (Recruitment completed in August 2015)
standard-dose 0.9 mg/kg (maximum of 90 mg) i.v. rtPA
Drug: 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 Name: Actilyse
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.

Other: 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 Names:
  • Labetalol Hydrochloride
  • Metoprolol tartrate
  • Hydralazine Hydrochloride
  • Glycerol Trinitrate
  • Phentolamine mesylate
  • Nicardipine
  • Urapidil
  • Esmolol
  • Clonidine
  • Enalaprilat
  • Niroprusside
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.

Other: 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.

Other Names:
  • Labetalol Hydrochloride
  • Metoprolol tartrate
  • Hydralazine Hydrochloride
  • Glycerol Trinitrate
  • Phentolamine mesylate
  • Nicardipine
  • Urapidil
  • Esmolol
  • Clonidine
  • Enalaprilat
  • Niroprusside

Detailed Description:
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, blinded endpoint (PROBE), controlled trial that will involve over 4700 patients (3310 for rtPA arm {recruitment completed in August 2015} and 2304 for BP arm with 939 overlap) with acute ischaemic stroke recruited from over 100+ Clinical Centres from Australia, Asia, Europe and South America.
  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01422616

Contacts
Contact: Craig Anderson, MD +61 2 9993 4500 canderson@georgeinstitute.org.au

Locations
Australia, New South Wales
Royal Prince Alfred Hospital Recruiting
Sydney, New South Wales, Australia, 2050
Contact: Craig S Anderson, MD    +61 2 933 4500    canderson@georgeinstitute.org.au   
Sponsors and Collaborators
The George Institute
National Health and Medical Research Council, Australia
The Stroke Association, United Kingdom
Conselho Nacional de Desenvolvimento Científico e Tecnológico
Ministry for Health, Welfare and Family Affairs of the Republic of Korea
Takeda China (for the BP lowering arm of the study in China, from March 2016)
Investigators
Principal Investigator: Craig S Anderson, MD The George Institute
  More Information

Publications:

Responsible Party: The George Institute
ClinicalTrials.gov Identifier: NCT01422616     History of Changes
Other Study ID Numbers: X11-0123 
Study First Received: August 23, 2011
Last Updated: December 12, 2016

Keywords provided by The George Institute:
Ischemic stroke
High blood pressure
Thrombolysis
Antihypertensive drugs
Disability
Clinical trial

Additional relevant MeSH terms:
Stroke
Ischemia
Cerebral Infarction
Hypertension
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases
Pathologic Processes
Brain Infarction
Brain Ischemia
Urapidil
Enalaprilat
Enalapril
Metoprolol
Phentolamine
Nicardipine
Hydralazine
Labetalol
Clonidine
Esmolol
Tissue Plasminogen Activator
Glycerol
Antihypertensive Agents
Vasodilator Agents
Serotonin Receptor Agonists
Serotonin Agents
Neurotransmitter Agents

ClinicalTrials.gov processed this record on February 28, 2017