Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED)

Ischemic Stroke Clinical Trial

— ENCHANTED  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01422616
• Other study ID #: X11-0123
• Status: Completed
• Phase: Phase 3
• Start date: March 2012
• Est. completion date: August 2018

Study information

• Verified date: October 2021
• Source: The George Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 4587
• Est. completion date: August 2018
• Est. primary completion date: August 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• High Blood Pressure
• Hypertension
• Ischemia
• Ischemic Stroke
• Stroke

Intervention

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).
• 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:
• 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.
• 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.

Locations

Country	Name	City	State
Australia	Royal Prince Alfred Hospital	Sydney	New South Wales

Sponsors (5)

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

Country where clinical trial is conducted

Australia, 

References & Publications (5)

Anderson CS, Huang Y, Lindley RI, Chen X, Arima H, Chen G, Li Q, Billot L, Delcourt C, Bath PM, Broderick JP, Demchuk AM, Donnan GA, Durham AC, Lavados PM, Lee TH, Levi C, Martins SO, Olavarria VV, Pandian JD, Parsons MW, Pontes-Neto OM, Ricci S, Sato S, — View Citation

Anderson CS, Robinson T, Lindley RI, Arima H, Lavados PM, Lee TH, Broderick JP, Chen X, Chen G, Sharma VK, Kim JS, Thang NH, Cao Y, Parsons MW, Levi C, Huang Y, Olavarría VV, Demchuk AM, Bath PM, Donnan GA, Martins S, Pontes-Neto OM, Silva F, Ricci S, Rof — View Citation

Anderson CS, Woodward M, Arima H, Chen X, Lindley RI, Wang X, Chalmers J, Robinson TG. Statistical analysis plan for evaluating different intensities of blood pressure control in the ENhanced Control of Hypertension And Thrombolysis strokE stuDy. Int J Stroke. 2019 Jul;14(5):555-558. doi: 10.1177/1747493018806170. Epub 2018 Oct 9. — View Citation

Anderson CS, Woodward M, Arima H, Chen X, Lindley RI, Wang X, Chalmers J; ENCHANTED Investigators. Statistical analysis plan for evaluating low- vs. standard-dose alteplase in the ENhanced Control of Hypertension and Thrombolysis strokE stuDy (ENCHANTED). Int J Stroke. 2015 Dec;10(8):1313-5. doi: 10.1111/ijs.12602. Epub 2015 Aug 18. — View Citation

Huang Y, Sharma VK, Robinson T, Lindley RI, Chen X, Kim JS, Lavados P, Olavarría V, Arima H, Fuentes S, Nguyen HT, Lee TH, Parsons MW, Levi C, Demchuk AM, Bath PM, Broderick JP, Donnan GA, Martins S, Pontes-Neto OM, Silva F, Pandian J, Ricci S, Stapf C, Woodward M, Wang J, Chalmers J, Anderson CS; ENCHANTED investigators. Rationale, design, and progress of the ENhanced Control of Hypertension ANd Thrombolysis strokE stuDy (ENCHANTED) trial: An international multicenter 2 × 2 quasi-factorial randomized controlled trial of low- vs. standard-dose rt-PA and early intensive vs. guideline-recommended blood pressure lowering in patients with acute ischaemic stroke eligible for thrombolysis treatment. Int J Stroke. 2015 Jul;10(5):778-88. doi: 10.1111/ijs.12486. Epub 2015 Apr 2. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Combined death and disability	Unadjusted modified Rankin Scale [mRS] score 2-6	90 days
Secondary	Symptomatic intracerebral hemorrhage	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
Secondary	Symptomatic intracerebral hemorrhage	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
Secondary	Death or disability by the alternative, ordinal shift analysis	Unadjusted death or functional outcome by the alternative ordinal shift analysis of scores on the modified Rankin Scale [mRS]	90 days
Secondary	Death	Death and 7 and 90 days	at 7 and 90 days
Secondary	Disability	mRS score 2-5	90 days
Secondary	Neurological deterioration	deterioration in NIHSS score	72 hours
Secondary	Health-related quality of life	Health-related quality of life by the EuroQoL	90 days
Secondary	Admission to residential care		90 days
Secondary	Health service use	Health service use for calculation of resources and costs	90 days
Secondary	Symptomatic intracerebral hemorrhage (ICH)	By various other centrally adjudicated criteria, including ECASS2, ECASS3, IST-3 criteria, and fatal ICH within 7 days	within 7 days
Secondary	Any intracerebral hemorrhage (ICH)	Centrally adjudicated review of brain imaging for any evidence of ICH	any time during 90 days
Secondary	Death or disability in as treated per-protocol population	Adjusted death or functional outcome by the binary and alternative ordinal shift analysis of scores on the modified Rankin Scale [mRS]	90 days
Secondary	Death or disability in as treated per-protocol population	Adjusted analysis of the modified Rankin Scale [mRS] score 2-6	90 days
Secondary	Death or neurological deterioration	Death or neurological deterioration (defined by 4 points or more increase in NIHSS score from baseline)	72 hours
Secondary	Length of initial acute hospital stay	Length of hospital stay in days	within 90 days
Secondary	Recurrent acute myocardial infarction and ischemic stroke	Recurrent acute myocardial infarction and ischemic stroke	within 90 days