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

Recruiting

Phase 3 Results N/A

Trial Description

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.

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.

Conditions

Interventions

  • Low-dose rtPA Drug
    Other Names: Actilyse
    Intervention Desc: 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).
    ARM 1: Kind: Experimental
    Label: Low-dose rtPA
    ARM 2: Kind: Experimental
    Label: Low-dose rtPA (Recruitment completed in August 2015)
    Description: low-dose 0.6 mg/kg (maximum of 60 mg) i.v. rtPA
  • Standard-dose rtPA Drug
    Other Names: Actilyse
    Intervention Desc: 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.
    ARM 1: Kind: Experimental
    Label: Standard-dose rtPA
    ARM 2: Kind: Experimental
    Label: Standard-dose rtPA (Recruitment completed in August 2015)
    Description: standard-dose 0.9 mg/kg (maximum of 90 mg) i.v. rtPA
  • BP management policies Other
    Other Names: Labetalol Hydrochloride; Metoprolol tartrate; Hydralazine Hydrochloride; Glycerol Trinitrate; Phentolamine mesylate; Nicardipine; Urapidil; Esmolol; Clonidine; Enalaprilat; Niroprusside
    Intervention Desc: 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.
    ARM 1: Kind: Experimental
    Label: Early intensive BP lowering
    Description: Intensive blood pressure (BP) lowering to a target systolic BP range 140-150 mmHg within 30 minutes of rtPA 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.
    ARM 2: Kind: Experimental
    Label: Control / conservative BP management
    Description: 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.
    ARM 3: Kind: Experimental
    Label: Control / guideline-based BP management
    Description: 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 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.
  • Intensive blood pressure (BP) lowering Other
    Other Names: Labetalol Hydrochloride; Metoprolol tartrate; Hydralazine Hydrochloride; Glycerol Trinitrate; Phentolamine mesylate; Nicardipine; Urapidil; Esmolol; Clonidine; Enalaprilat; Niroprusside
    Intervention Desc: 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.
    ARM 1: Kind: Experimental
    Label: Early intensive BP lowering
    Description: 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 140-150 mmHg within 30 minutes of rtPA 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, Niroprusside) 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.

Trial Design

  • Allocation: Randomized
  • Masking: Open Label
  • Purpose: Treatment
  • Endpoint: Safety/Efficacy Study
  • Intervention: Factorial Assignment

Outcomes

Type Measure Time Frame Safety Issue
Primary Combined death and any disability 90 days Yes
Secondary Symptomatic intracerebral hemorrhage 36 hours Yes
Secondary Intracerebral hemorrhage of any type in CT scans 7 days Yes
Secondary Death or disability by the alternative, but less widely used, shift analysis 90 days Yes
Secondary Death 90 days Yes
Secondary Disability 90 days Yes
Secondary Neurological deterioration 72 hours Yes
Secondary Health-related quality of life 90 days No
Secondary Admission to residential care 90 days No
Secondary Health service use 90 days No
Primary Combined death and disability 90 days
Secondary Death or disability by the alternative, ordinal shift analysis 90 days
Secondary Symptomatic intracerebral hemorrhage (ICH) within 7 days
Secondary Any intracerebral hemorrhage (ICH) any time during 90 days
Secondary Death or disability in as treated per-protocol population 90 days
Secondary Death or neurological deterioration 72 hours
Secondary Length of initial acute hospital stay within 90 days
Secondary Recurrent acute myocardial infarction and ischemic stroke within 90 days

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