Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED) (ENCHANTED)
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| ClinicalTrials.gov Identifier: NCT01422616 |
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Recruitment Status :
Completed
First Posted : August 24, 2011
Last Update Posted : October 13, 2021
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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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Ischemic Stroke High Blood Pressure | Drug: Low-dose rtPA Drug: Standard-dose rtPA Other: Intensive blood pressure (BP) lowering Other: BP management policies | Phase 3 |
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 4587 participants |
| Allocation: | Randomized |
| Intervention Model: | Factorial Assignment |
| Masking: | Single (Outcomes Assessor) |
| Primary Purpose: | Treatment |
| 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 |
| Actual Study Start Date : | March 2012 |
| Actual Primary Completion Date : | August 2018 |
| Actual Study Completion Date : | August 2018 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: Low-dose rtPA (Recruitment completed in August 2015)
low-dose 0.6 mg/kg (maximum of 60 mg) i.v. rtPA
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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 Name: Actilyse |
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Active Comparator: Standard-dose rtPA (Recruitment completed in August 2015)
standard-dose 0.9 mg/kg (maximum of 90 mg) i.v. rtPA
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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 Name: Actilyse |
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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:
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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:
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- Combined death and disability [ Time Frame: 90 days ]Unadjusted modified Rankin Scale [mRS] score 2-6
- 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
- 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
- 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]
- Death [ Time Frame: at 7 and 90 days ]Death and 7 and 90 days
- Disability [ Time Frame: 90 days ]mRS score 2-5
- Neurological deterioration [ Time Frame: 72 hours ]deterioration in NIHSS score
- Health-related quality of life [ Time Frame: 90 days ]Health-related quality of life by the EuroQoL
- Admission to residential care [ Time Frame: 90 days ]
- Health service use [ Time Frame: 90 days ]Health service use for calculation of resources and costs
- 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
- Any intracerebral hemorrhage (ICH) [ Time Frame: any time during 90 days ]Centrally adjudicated review of brain imaging for any evidence of ICH
- 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]
- Death or disability in as treated per-protocol population [ Time Frame: 90 days ]Adjusted analysis of the modified Rankin Scale [mRS] score 2-6
- Death or neurological deterioration [ Time Frame: 72 hours ]Death or neurological deterioration (defined by 4 points or more increase in NIHSS score from baseline)
- Length of initial acute hospital stay [ Time Frame: within 90 days ]Length of hospital stay in days
- Recurrent acute myocardial infarction and ischemic stroke [ Time Frame: within 90 days ]Recurrent acute myocardial infarction and ischemic stroke
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01422616
| Australia, New South Wales | |
| Royal Prince Alfred Hospital | |
| Sydney, New South Wales, Australia, 2050 | |
| Principal Investigator: | Craig S Anderson, MD | The George Institute |
Documents provided by The George Institute:
Other Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | The George Institute |
| ClinicalTrials.gov Identifier: | NCT01422616 |
| Other Study ID Numbers: |
X11-0123 |
| First Posted: | August 24, 2011 Key Record Dates |
| Last Update Posted: | October 13, 2021 |
| Last Verified: | October 2021 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Yes |
| Plan Description: | Data sharing upon approval through formal application to the Research Office of The George Institute for Global Health, Australia |
| Supporting Materials: |
Study Protocol Statistical Analysis Plan (SAP) Informed Consent Form (ICF) Clinical Study Report (CSR) Analytic Code |
| Time Frame: | available |
| Access Criteria: | approved protocol, ethics committee and data sharing agreement |
| Studies a U.S. FDA-regulated Drug Product: | No |
| Studies a U.S. FDA-regulated Device Product: | No |
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Ischemic stroke High blood pressure Thrombolysis |
Antihypertensive drugs Disability Clinical trial |
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Stroke Ischemic Stroke Hypertension Ischemia Cerebrovascular Disorders Brain Diseases Central Nervous System Diseases Nervous System Diseases Vascular Diseases Cardiovascular Diseases Pathologic Processes Metoprolol Clonidine Labetalol Hydralazine |
Nicardipine Phentolamine Urapidil Enalaprilat Enalapril Tissue Plasminogen Activator Nitroglycerin Esmolol Glycerol Anti-Arrhythmia Agents Antihypertensive Agents Sympatholytics Autonomic Agents Peripheral Nervous System Agents Physiological Effects of Drugs |