Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED)

The George Institute

Status and phase: Completed; Phase 3

Conditions: Ischemic Stroke; High Blood Pressure

Treatments: Other: BP management policies; Drug: Low-dose rtPA; Other: Intensive blood pressure (BP) lowering; Drug: Standard-dose rtPA

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT01422616

X11-0123

Details and patient eligibility

About

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.

Full 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-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.

Enrollment: 4,587 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Factorial Assignment

Masking: Single Blind

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4,587 participants in 4 patient groups

Low-dose rtPA (Recruitment completed in August 2015)

Experimental group

Description:

low-dose 0.6 mg/kg (maximum of 60 mg) i.v. rtPA

Treatment:

Drug: Low-dose rtPA

Standard-dose rtPA (Recruitment completed in August 2015)

Active Comparator group

Description:

standard-dose 0.9 mg/kg (maximum of 90 mg) i.v. rtPA

Treatment:

Drug: Standard-dose rtPA

Early intensive BP lowering

Experimental group

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 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.

Treatment:

Other: Intensive blood pressure (BP) lowering

Control / guideline-based BP management

Active Comparator group

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 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:

Other: BP management policies