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

October 5, 2021 updated by: The George Institute

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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-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.

Study Type

Interventional

Enrollment (Actual)

4587

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Australia
    • New South Wales
      • Sydney, New South Wales, Australia, 2050
        • Royal Prince Alfred Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Factorial Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
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 Names:
  • 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 Names:
  • 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:
  • Urapidil
  • Esmolol
  • Labetalol Hydrochloride
  • Metoprolol tartrate
  • Hydralazine Hydrochloride
  • Glycerol Trinitrate
  • Phentolamine mesylate
  • Nicardipine
  • 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:
  • Urapidil
  • Esmolol
  • Labetalol Hydrochloride
  • Metoprolol tartrate
  • Hydralazine Hydrochloride
  • Glycerol Trinitrate
  • Phentolamine mesylate
  • Nicardipine
  • Clonidine
  • Enalaprilat
  • Niroprusside

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
36 hours
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
36 hours
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]
90 days
Death
Time Frame: at 7 and 90 days
Death and 7 and 90 days
at 7 and 90 days
Disability
Time Frame: 90 days
mRS score 2-5
90 days
Neurological deterioration
Time Frame: 72 hours
deterioration in NIHSS score
72 hours
Health-related quality of life
Time Frame: 90 days
Health-related quality of life by the EuroQoL
90 days
Admission to residential care
Time Frame: 90 days
90 days
Health service use
Time Frame: 90 days
Health service use for calculation of resources and costs
90 days
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
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
any time during 90 days
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]
90 days
Death or disability in as treated per-protocol population
Time Frame: 90 days
Adjusted analysis of the modified Rankin Scale [mRS] score 2-6
90 days
Death or neurological deterioration
Time Frame: 72 hours
Death or neurological deterioration (defined by 4 points or more increase in NIHSS score from baseline)
72 hours
Length of initial acute hospital stay
Time Frame: within 90 days
Length of hospital stay in days
within 90 days
Recurrent acute myocardial infarction and ischemic stroke
Time Frame: within 90 days
Recurrent acute myocardial infarction and ischemic stroke
within 90 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

The George Institute

Collaborators

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

Investigators

  • Principal Investigator: Craig S Anderson, MD, The George Institute

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 1, 2012

Primary Completion (Actual)

August 1, 2018

Study Completion (Actual)

August 1, 2018

Study Registration Dates

First Submitted

August 23, 2011

First Submitted That Met QC Criteria

August 23, 2011

First Posted (Estimate)

August 24, 2011

Study Record Updates

Last Update Posted (Actual)

October 13, 2021

Last Update Submitted That Met QC Criteria

October 5, 2021

Last Verified

October 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • X11-0123

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Yes

IPD Plan Description

Data sharing upon approval through formal application to the Research Office of The George Institute for Global Health, Australia

IPD Sharing Time Frame

available

IPD Sharing Access Criteria

approved protocol, ethics committee and data sharing agreement

IPD Sharing Supporting Information Type

  • Study Protocol
  • Statistical Analysis Plan (SAP)
  • Informed Consent Form (ICF)
  • Clinical Study Report (CSR)
  • Analytic Code

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Ischemic Stroke

Clinical Trials on Low-dose rtPA

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Morocco

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

3
Subscribe