Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED)

Study Overview
=================
Brief 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.

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.

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

Conditions
-----------------
Ischemic Stroke, High Blood Pressure

Intervention / Treatment
-----------------
* Drug: Low-dose rtPA
* Drug: Standard-dose rtPA
* Other: Intensive blood pressure (BP) lowering
* Other: BP management policies


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low-dose rtPA (Recruitment completed in August 2015)<br>low-dose 0.6 mg/kg (maximum of 60 mg) i.v. rtPA | Drug: Low-dose rtPA<br>* 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).<br>* Other names: Actilyse;|
| Active Comparator: Standard-dose rtPA (Recruitment completed in August 2015)<br>standard-dose 0.9 mg/kg (maximum of 90 mg) i.v. rtPA | Drug: Standard-dose rtPA<br>* 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.<br>* Other names: Actilyse;|
| Experimental: Early intensive BP lowering<br>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<br>* 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.<br>* Other names: Niroprusside;|
| Active Comparator: Control / guideline-based BP management<br>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<br>* 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.<br>* Other names: Niroprusside;|

What is the study measuring?
-----------------
Primary Outcome Measures

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

Secondary Outcome Measures

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

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Ischemic stroke, High blood pressure, Thrombolysis, Antihypertensive drugs, Disability, Clinical trial