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Completed

NCT Number: NCT01422616

Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED)

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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Key information

Conditions

Ischemic Stroke Brain Diseases Cardiovascular Diseases Central Nervous System Diseases Cerebrovascular Disorders High Blood Pressure Hypertension Nervous System Diseases Stroke Vascular Diseases

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 3

Primary location

Royal Prince Alfred Hospital

Sydney, New South Wales, 2050, Australia

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

Low-dose rtPA

Drug

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 names: Actilyse

Standard-dose rtPA

Drug

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 names: Actilyse

Intensive blood pressure (BP) lowering

Other

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

BP management policies

Other

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

Primary outcomes

  1. Combined death and disability

    Time frame: 90 days

    Unadjusted modified Rankin Scale [mRS] score 2-6

Secondary outcomes

  1. 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

  2. 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

  3. 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]

  4. Death

    Time frame: at 7 and 90 days

    Death and 7 and 90 days

  5. Disability

    Time frame: 90 days

    mRS score 2-5

  6. Neurological deterioration

    Time frame: 72 hours

    deterioration in NIHSS score

  7. Health-related quality of life

    Time frame: 90 days

    Health-related quality of life by the EuroQoL

  8. Admission to residential care

    Time frame: 90 days

  9. Health service use

    Time frame: 90 days

    Health service use for calculation of resources and costs

  10. 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

  11. Any intracerebral hemorrhage (ICH)

    Time frame: any time during 90 days

    Centrally adjudicated review of brain imaging for any evidence of ICH

  12. 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]

  13. Death or disability in as treated per-protocol population

    Time frame: 90 days

    Adjusted analysis of the modified Rankin Scale [mRS] score 2-6

  14. Death or neurological deterioration

    Time frame: 72 hours

    Death or neurological deterioration (defined by 4 points or more increase in NIHSS score from baseline)

  15. Length of initial acute hospital stay

    Time frame: within 90 days

    Length of hospital stay in days

  16. Recurrent acute myocardial infarction and ischemic stroke

    Time frame: within 90 days

    Recurrent acute myocardial infarction and ischemic stroke

Sponsors and collaborators

Lead sponsor

The George Institute

Other

Collaborators

  • Conselho Nacional de Desenvolvimento Científico e Tecnológico
  • National Health and Medical Research Council, Australia
  • Takeda
  • The Stroke Association, United Kingdom

Registry information

Official study 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

Acronym: ENCHANTED

Important dates

Study start
2012
Primary completion
2018
Study completion
2018
First posted
Aug 24, 2011
Registry last updated
Oct 13, 2021

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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