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
Phase: PHASE3
Conditions: Ischemic Stroke, High Blood Pressure
Sponsor: The George Institute

 
 
 
 
 
 
 
The ENCHANTED is 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  
 
STUDY PROTOCOL 
(Version 5.0– 16 Feb 2017) 
 
 
 
 
 
 
CONTACT DETAILS 
ENCHANTED International Coordinating Centre 
The George Institute for Global Health 
University of Sydney 
PO Box M201, Missenden Road 
NSW 2050, Australia 
 
Tel   +61 2 9993 4541 
Fax   +61 2 9993 4501 
Email: ENCHANTED@georgeinstitute.org.au 
 

ENCHANTED Protocol version 5.0 16 Feb 2017  
 
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INVESTIGATOR AGREEMENT 
I have read this protocol and agree that it contains all the necessary details for carrying out the 
study.  I will conduct the study as outlined herein and will complete the study within the time 
designated. 
I will provide copies of the protocol and all pertinent information to all individuals responsible to 
me who assist in the conduct of the study.  I will discuss this material with them to ensure that 
they are fully informed regarding the study intervention and the conduct of the study. 
 
_________________________________________________________________ 
Investigator’s Signature                                                   Date (Day / Month / Year) 
 
_________________________________________________________________ 
Name of Investigator (Printed) 
 
_________________________________________________________________ 
Name of Institution (Printed) 
 
 
 
 
Principal Investigator 
Craig Anderson PhD FRACP 
Professor of Stroke Medicine 
Executive Director,  
The George Institute for Global Health at 
Peking University Health Science Center 
 
 
 
 
 
16 Feb 2017 
Date 
 
 
Signature 
 
 
 
 
 
 
 
 
Trial Statistician 
Mark Woodward, PhD 
Professor of Biostatistics 
The George Institute for Global Health, 
University of Sydney 
 
 
 
 
16 Feb 2017 
Date 
 
 
Signature 
 
 

ENCHANTED Protocol version 5.0 16 Feb 2017  
 
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List of abbreviations and definition of terms 
ACE-I 
Angiotensin Converting Enzyme Inhibitor 
AE/SAE 
Adverse Event / Serious AE 
AHA 
American Heart Association 
AIS 
Acute Ischaemic Stroke 
BP 
Blood Pressure 
CI 
Confidence Interval 
CRF/eCRF 
Case report form / Electronic CRF 
CT 
Computerised tomography 
CV 
Curriculum Vitae 
DSMB 
Data Safety Monitoring Board  
EC 
Executive Committee 
ECG 
Electrocardiogram 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GCS 
Glasgow Coma Scale 
GI 
The George Institute for Global Health 
HR 
Heart Rate 
HREC 
Human Research Ethics Committee 
HRQoL 
Health Related Quality of Life 
IAC 
Imaging Adjudication Committee 
ICC 
International Coordinating Centre 
ICH 
Intracerebral Haemorrhage 
ICH-GCP 
International Conference on Harmonisation for Good Clinical Practice   
ICMJE 
International Committee of Medical Journal Editors 
IRB 
Institutional Review Board   
ITT 
Intention to Treat  
IVRS 
Interactive Voice Randomisation System 
mins 
Minutes 
MRC 
Medical Review Committee 
MRI 
Magnetic Resonance Imaging  
mRS 
Modified Rankin Scale 
NB 
Note 
NHMRC 
National Health and Medical Research Council of Australia 
NIHSS 
National Institute of Health Stroke Scale 
NINDS 
National Institute of Neurological Disorders and Stroke  

ENCHANTED Protocol version 5.0 16 Feb 2017  
 
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OC 
Operations Committee 
OR 
Odds Ratio 
PI  
Principal Investigator 
RCCs 
Regional Coordinating Centres 
rtPA 
Recombinant tissue plasminogen activator  
SAP 
Statistical Analysis Plan 
SC 
Steering committee 
SD 
Standard Deviation 
sICH 
Symptomatic intracerebral haemorrhage 
TCD 
Trans-cranial Doppler 
TOAST 
Trial of Org in Acute Stroke Treatment  
WHO 
World Health Organisation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ENCHANTED Protocol version 5.0 16 Feb 2017  
 
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Table of Contents 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .................................................................................. 3 
SUMMARY PROTOCOL ............................................................................................................................................... 7 
INTRODUCTION .......................................................................................................................................................... 10 
BACKGROUND ............................................................................................................................................................. 10 
1. EPIDEMIOLOGY ...................................................................................................................................................... 10 
2. PATHOPHYSIOLOGY ............................................................................................................................................. 11 
3. ACUTE MANAGEMENT ......................................................................................................................................... 11 
4. RATIONALE FOR LOW –DOSE RTPA IN AIS ................................................................................................... 14 
5. SUMMMARY OF RATIONALE FOR LOW – DOSE RTPA IN AIS .................................................................. 16 
6. EVIDENCE FOR EARLY INTENSIVE BP LOWERING AFTER RTPA IN AIS ............................................. 16 
7. CHOICE OF BP PRESSURE LOWERING AGENT ............................................................................................. 18 
8. SUMMARY OF RATIONALE FOR A TRIAL OF BP LOWERING IN AIS ..................................................... 18 
AIMS AND OBJECTIVES ............................................................................................................................................ 19 
1. PRIMARY AIMS ........................................................................................................................................................ 19 
2. KEY SECONDARY AIMS ........................................................................................................................................ 19 
3. OTHER SECONDARY AIMS .................................................................................................................................. 19 
METHODS ...................................................................................................................................................................... 19 
1. OVERALL DESIGN .................................................................................................................................................. 19 
2. STUDY POPULATION ............................................................................................................................................. 20 
3. INCLUSION AND EXCLUSION CRITERIA .......................................................................................................... 20 
4. ETHICAL ISSUES ..................................................................................................................................................... 21 
4.1 INSTITUTIONAL ETHICS COMMITTEE APPROVAL ................................................................................................... 21 
4.2 CONSENT................................................................................................................................................................ 21 
4.3 CONFIDENTIALITY AND PRIVACY ............................................................................................................................ 24 
5. RANDOMISATION .................................................................................................................................................... 24 
6. ALLOCATED STUDY TREATMENTS .................................................................................................................. 24 
6.1 BP CONTROL ARM ................................................................................................................................................. 24 
6.1.1 Early Intensive BP Lowering Group ..................................................................................................... 24 
6.1.2 Control / Conservative BP Management Group ................................................................................. 25 
6.2 PREVIOUS USE OF ANTIHYPERTENSIVE THERAPY IN BOTH GROUPS .................................................................. 26 
7. DISCONTINUATION OF ALLOCATED MANAGEMENT POLICY .................................................................. 26 
8. BACKGROUND CARE ............................................................................................................................................ 26 
9. STUDY OUTCOMES ................................................................................................................................................ 27 
10. DATA COLLECTION AND FOLLOW-UP ........................................................................................................... 27 
10.1 SCREENING LOGS ................................................................................................................................................ 28 
10.2 PATIENT CONTACT DETAILS LOG........................................................................................................................ 28 
10.3 RANDOMISATION ASSESSMENT ........................................................................................................................... 28 
10.4 BASELINE DATA .................................................................................................................................................. 28 

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10.5 FOLLOW UP DATA ................................................................................................................................................ 29 
11. SERIOUS ADVERSE EVENTS (SAES) .............................................................................................................. 31 
11.1 DEFINITIONS ......................................................................................................................................................... 31 
11.2 RECORDING AND REPORTING ............................................................................................................................. 32 
11.3 MONITORING OF SAES ........................................................................................................................................ 33 
11.4 MONITORING OF SUSARS ................................................................................................................................... 33 
12. QUALITY ASSURANCE ........................................................................................................................................ 33 
12.1 MONITORING OF PARTICIPATING CENTRES ........................................................................................................ 33 
12.2 AUDITING AND INSPECTION BY GOVERNMENT REGULATORY AUTHORITIES ..................................................... 33 
13. DATA MANAGEMENT .......................................................................................................................................... 34 
14. STANDARDISATION OF OUTCOME ASSESSMENT .................................................................................... 34 
15. STATISTICAL CONSIDERATIONS .................................................................................................................... 34 
15.1 SAMPLE SIZE ......................................................................................................................................................... 34 
15.2 STATISTICAL ANALYSES ..................................................................................................................................... 36 
16. PUBLICATIONS AND REPORTS ........................................................................................................................ 36 
17. ORGANISATION .................................................................................................................................................... 37 
17.1 STEERING COMMITTEE (SC) ............................................................................................................................... 38 
17.2 INTERNATIONAL COORDINATING CENTRE (ICC) ................................................................................................ 38 
17.3 REGIONAL COORDINATING CENTRES (RCC) ..................................................................................................... 39 
17.4 IMAGING ADJUDICATION COMMITTEE (CORE LAB/BRAIN IMAGING ANALYSIS) ................................................ 39 
17.5 MEDICAL REVIEW COMMITTEE ............................................................................................................................ 39 
17.6 DATA SAFETY MONITORING BOARD (DSMB) .................................................................................................... 39 
17.7 PARTICIPATING CENTRES .................................................................................................................................... 39 
18. FUNDING ................................................................................................................................................................. 39 
19. TIMELINES .............................................................................................................................................................. 40 
20. OUTCOMES AND SIGNIFICANCE ..................................................................................................................... 40 
REFERENCES ........................................................................................................................................................... 42 
APPENDIX 1A - BP MANAGEMENT PROTOCOL WITHOUT LABETALOL .................................................. 45 
APPENDIX 1B - BP MANAGEMENT PROTOCOL FOR CENTRES WITH LABETALOL .............................. 47 
APPENDIX 1C - BP PROTOCOL FOR CENTRES WITH URAPIDIL (CHINA) ................................................. 49 
APPENDIX 1D - BP PROTOCOL FOR CENTRES WITH PHENTOLAMINE (CHINA) ................................... 51 
APPENDIX 1E - ADDITIONAL IV MEDICATION FOR BP USE IN CHINA ...................................................... 53 
APPENDIX 1F- BP PROTOCOL FOR CENTRES WITH CLEVIDIPINE ............................................................ 55 
APPENDIX 1G - BP PROTOCOL FOR CENTRES WITH NICARDIPINE .......................................................... 57 
APPENDIX 1H - BP PROTOCOL FOR CENTRES WITH NICARDIPINE (VIETNAM) ................................... 59 
APPENDIX 1I - CURRENT GUIDELINE –BASED BP MANAGEMENT ............................................................. 61 
APPENDIX 2 - IMAGING PROTOCOL ..................................................................................................................... 62 
APPENDIX 3 - HEALTH SCALES .............................................................................................................................. 65 
APPENDIX 4 - STANDARD ACUTE CARE PROTOCOL ...................................................................................... 73 
APPENDIX 5 - DECLARATION OF HELSINKI ...................................................................................................... 74 

ENCHANTED Protocol version 5.0 16 Feb 2017  
 
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SUMMARY PROTOCOL 
ENCHANTED is an independent, investigator initiated, international collaborative, quasi-factorial 
randomised controlled trial involving a package of 2 linked comparative treatment arms, which aims to 
address 4 key questions in patients eligible for thrombolysis in the hyperacute 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) i.v. 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 ICH?   
Reason for this Protocol amendment from version 4.0 to version 5.0: 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 is ongoing and the protocol has been modified to reflect changes. 
Background and rationale Modern therapy for acute ischaemic stroke (AIS) is based on the premise 
that early vessel re-canalisation and reperfusion are essential for the preservation of brain function and 
promotion of satisfactory outcome.  RtPA is the only approved treatment of AIS, licensed on the basis of 
the NINDS trial, where an i.v. dose of 0.9 mg/kg within 3 hours of symptom onset was shown to improve 
clinical outcomes with an acceptable risk of sICH, although the time criteria for use has recently been 
extended to 4.5 hours on the basis of subsequent randomised evidence.  However, 0.6 mg/kg is the 
standard approved dose of rtPA in Japan, where non-randomised studies have shown comparable 
clinical outcomes and a reduced risk of sICH compared to expected rates for the standard dose.  Thus, 
low dose rtPA (i.e. which generally requires use of a single 50mg vial of Actilyse ®Boehringer Ingelheim) 
has become an attractive ‘cheaper’ treatment option for patients who cannot afford the full dose (i.e. 2 
vials) in much of Asia.  In the absence of randomised evidence, however, there is ongoing uncertainty as 
to whether low-dose rtPA is truly equivalent in efficacy, or even safer, to the standard dose, not just in 
Asians but in other population groups around the world.  The optimal management of BP in AIS remains 
controversial.  Although BP levels are commonly elevated, the effects of BP lowering in the hyperacute 
phase of stroke remain unknown.  Guidelines for BP control in AIS are consistent in contraindicating use 
of rtPA in patients with systolic BP >185 mmHg and diastolic BP >110 mmHg, but recent data suggests 
that lower BP levels may achieve better outcomes.  The most compelling data are from large-scale 
prospective registry studies, such as SITS-MOST, where elevated baseline systolic BP are associated 
with a worse outcome and elevated risk of sICH post-rtPA.  None of the recently completed (and ongoing) 
trials in the area have been specifically designed to address the role of rapid intensive BP lowering within 
the first few hours of stroke onset, and in particular, as to whether such treatment improves outcomes 
after rtPA. The second main phase INTERACT2 study showed that rapid BP lowering (140 mmHg systolic 
target) is feasible, safe and potential efficacious in improving functional recovery in patients with acute 
intracerebral haemorrhage.  
Hypotheses  In patients with AIS eligible for thrombolysis with rtPA according to local guidelines and 
otherwise able to receive best usual medical care, the primary aims are to determine:  [A] whether 
compared to the standard dose, low-dose rtPA is at least as effective (‘not inferior’) on death or disability 
(i.e. null hypothesis is that low-dose is inferior to standard dose rtPA); [B] whether compared with current 
guideline recommended criteria for BP management, early intensive BP lowering is superior at improving 
functional outcome according to an ordinal comparison of the full range of scores on the modified Rankin 
scale (mRS) between groups (i.e. null hypothesis is that there is no difference in the intensities of BP 
control on this outcome).  The key secondary aims are to determine [C] whether compared with 
standard dose rtPA, low-dose rtPA reduces the risk of sICH; [D] whether compared with standard 
guideline-based BP management, early intensive BP lowering after rtPA reduces the risk of any ICH (i.e. 
null hypothesis is that there is no difference in the rate of any ICH between groups of differing intensities 
of BP lowering).  Other secondary aims are to define the effects of the treatments on symptomatic and 
any ICH; good outcome (mRS 0-1), death or major disability (mRS 3-6); separately on death and disability 

ENCHANTED Protocol version 5.0 16 Feb 2017  
 
8 
(mRS 3-5); early neurological deterioration; health-related quality of life (HRQoL); length of hospital stay; 
and need for permanent residential care. 
Inclusion/exclusion criteria  Patients with clinical diagnosis of AIS confirmed by brain imaging within 4.5 
hours of onset who fulfil local criteria for use of i.v. rtPA are potentially eligible if they have a sustained 
systolic BP level ≤185 mmHg (i.e. the guideline recommended level of eligibility for rtPA; patients with 
higher BP levels at presentation can still be included provided the BP is reduced to the entry level prior to 
commencement of the  treatment).  The attending clinician is required to consider their level of clinical 
uncertainty over the balance of potential benefits and risks pertaining to use of rtPA and the level of BP 
control in each particular patient:  arm [A] of low- vs standard-dose rtPA has now closed; and arm [B] of 
intensive vs guideline recommended BP control: (a) sustained elevated systolic BP level (i.e ≥150 and 
≤185 mmHg over 6 hours from the onset of symptoms; the upper level guideline recommended for the 
use of rtPA); (b) able to receive either intensive BP lowering or conservative BP management [no definite 
indication/contraindication to ‘intensive’ BP lowering (i.e. target 130-140 mmHg systolic)].  Exclusion 
criteria: (a) unlikely to potentially benefit from the therapy (e.g. advanced dementia) or a very high 
likelihood of death within 24 hours of stroke onset; (b) other medical illness that interferes with outcome 
assessments and follow-up (e.g. known significant pre-stroke disability (mRS scores 2-5), advance 
cancer and renal failure); (c) specific contraindications to rtPA (Actilyse) or any of the BP agents to be 
used; (d) participation in another clinical trial involving evaluation of pharmacological agents; and (e) need 
for following concomitant medication, including phosphodiesterase inhibitors and monoamine oxidase 
inhibitors.  
Randomised interventions Randomisation is via a central internet-based system developed by The 
George Institute, Sydney, Australia, either direct or via a specially developed IVRS (only in China), 
stratified by site, time from onset (<3 vs ≥3 hours) and NIHSS (<10 vs ≥10) to ensure balance in key 
prognostic factors.  All patients must be eligible for i.v. rtPA and those with elevated BP are eligible for 
arm [B].  Recruitment of patients into arm A completed in August 2015.   Arm [B] involves intensive BP 
lowering to a target systolic BP range 130-140 mmHg within 60 minutes of randomisation into the BP arm 
and to maintain this level for at least 72 hours (or until hospital discharge or death if this should occur 
earlier) or guideline-based BP lowering to a target systolic BP of <180 mmHg post-rtPA. Standardised 
locally approved i.v. BP lowering agents are to be used. 
Data collection and follow-up Registration, baseline, and randomisation to be achieved in 30 minutes.  
Patients followed daily for 1 week and at 28 and 90 days unless death occurs earlier.  Follow-up data are 
collected at 24 and 72 hours, and 7 (or at time of death or hospital discharge if sooner), 28 and 90 days.  
The 28 and 90 day evaluation will be conducted in-person or by telephone by a trained local staff member 
who is blind to treatment allocation.  Brain imaging (CT scans or MRI) will be conducted according to 
standardised techniques at baseline, within the next 24 hours, and at a later stage in survivors who 
deteriorate or for other reason.  Trial management is by an established internet-based system.  
Outcomes Primary: in Arm A, the efficacy of the treatment was evaluated on the combined endpoint of 
death and disability (mRSscore 2-6) at the end of follow-up.  In Arm B, efficacy of the treatment will be 
evaluated on an ordinal comparison of the full range of scores on the mRS at the end of follow-up.  In 
Arm B, the secondary outcomes involve determining the effects of treatments on any ICH, sICH, good 
outcome (mRS 0-1), death or major disability (mRS 3-6), separately on death and major disability (mRS 
3-5), early neurological deterioration, HRQoL, and health service use for calculation of resources and 
costs. 
Statistical considerations A sample size of 3300 (1650 per group) estimated for arm [A] (i.e. rtPA dose) 
estimated to provide (i) >90% power to detect non-inferiority (relative margin 14% [i.e. relative risk 1.14], 
absolute margin rate 6.5%) of low-dose rtPA on the primary outcome (one-sided α = 0.025) and (ii) ≥80% 
power to detect plausible 40% reductions in risks of sICH with low-dose rtPA (2-sided α = 0.05) with 5% 
drop-out was achieved.  . Arm [A] completed recruitment in August 2015 with 3310 patients randomised.  
A sample size of 2100 (1050 per group) for arm [B] (i.e. BP lowering intensities) will provide ≥80% power 
to detect superiority of intensive BP lowering on the primary outcome and any ICH (2-sided α = 0.10) with 
5% drop-out.  Given overlap of 939 patients in the combined arms [A] and [B], an expected total of 4500 
patients will participate in the study.  

ENCHANTED Protocol version 5.0 16 Feb 2017  
 
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Quality assurance and bias control The study will be conducted at sites with established acute stroke 
units and thrombolysis programs.  Regionally-based clinical research monitors will perform online, on-site 
data verification; and monitor conduct of the study, initially after the first few patients are randomised at a 
site and then at least once annually, according to patient recruitment numbers, whilst participating in the 
trial.  As ENCHANTED is an open trial of differing management strategies in a critical illness, monitoring 
serves to confirm that investigators are adhering to the protocol and GCP Guidelines, and the accuracy of 
data.  Monitoring by trained staff will confirm: (i) demographic and consent details of randomised patients; 
(ii) details of all SAEs against source documents; (iii) collect/correct outstanding/missing data; and (iv) 
check selected variables against source documents in a 10% random selection of patients.   
Study organization A Steering Committee (SC) comprises country academic leaders and includes an 
Executive sub-Committee who are the grant holders from the National Health and Medical Research 
Council (NHMRC) of Australia, an Operational Committee based at the International Coordinating Centre 
(ICC) is in charge of the central coordination of the study from The George Institute, Sydney, Regional 
Coordinating Centres (RCCs), an independent Data Safety Monitoring Board (DSMB), an Imaging 
Adjudication Committee (IAC), a Medical Review Committee, and an Advisory Committee of international 
experts.  A total of 100+ sites are required, most in Asia (approximately 60 sites) and Australia/New 
Zealand, Europe (approximately 40 sites), and South America (approximately 30 sites), to achieve the 
sample of 4500 patients (50% from Asia) over 6 years (av. 6 patients per site per year).  Sites will be 
administratively tied through a structure designed to enhance effective communication and collaboration 
as well as monitor and maintain operations through adherence to a common protocol. Central 
coordination is from The George Institute, Sydney. The inclusion of focused substudies, for which 
separate funding will be sought, will advance the understanding of pathophysiological mechanisms of 
acute ischaemic stroke, the interpretation of the results, and inform clinical care and future studies.  Sites 
will receive AUD $400 per patient to cover administrative and other direct costs.  As rtPA is an expensive 
agent, payments will also be provided to selected sites to subsidise the cost of rtPA.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Completed 
 
 
 
 
Best 
practice 
care 
during 
treatment 
and 
follow-up 
periods 
 
Patient with a definite acute ischaemic stroke <4.5 hours, i.v. rtPA indicated 
and planned, and has a systolic BP ≤185 mmHg 
1, 3, 7, 28 and 90 day review and follow-up 
Systolic BP ≥150 mmHg; no definite indication or contraindication 
to rapid intensive BP lowering to 130-140mmHg systolic target 
No definite indication or contraindication to either rtPA dose 
Randomisation arm [A] 
Low- dose rtPA 
0.6 mg/kg rtPA 
Standard-dose 
rtPA 0.9 mg/kg 
Intensive BP lowering to 
systolic 130-140mmHg 
Standard BP control to 
systolic <180 mmHg 
Randomisation arm [B] 

ENCHANTED Protocol version 5.0 16 Feb 2017  
 
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INTRODUCTION  
Ischaemic stroke caused by acute occlusion of an artery leading to immediate reduction in blood 
flow within the corresponding cerebrovascular territory, causes 9% of all deaths around the 
world, and is associated with a very high health-care and socioeconomic costs. 
Early spontaneous re-canalisation may occur from the endogenous release of rtPA, a serine 
protease of the fibrinolytic system.  However, for most patients, this natural physiological 
function is inadequate to avoid the outcome of infarcted cerebral tissue from the occluded 
vessel.  rtPA is the only approved treatment of acute ischaemic stroke (AIS) despite increased 
risk of symptomatic intracerebral haemorrhage (sICH).  Recent studies suggest that low-dose 
rtPA is an effective treatment and may have a reduced risk of sICH but there is lack of reliable 
randomised evidence to support it. 
BP levels are commonly elevated (systolic >140 mmHg) after the onset of the stroke. The 
effects of BP lowering treatment in the acute phase of stroke remain unknown. As a 
consequence, there are wide ranging guideline recommendations for the management of 
elevated BP in these group of patients.  There is increasing evidence to suggest that early 
intensive BP lowering therapy in patients with acute stroke therapy may benefit, but a large-
scale clinical trial is required to reliably determine the overall balance of risks and benefits of 
such intervention.  
ENCHANTED has been designed to resolve these areas of major persisting clinical uncertainty 
and provide definitive evidence on the effectiveness of a potentially widely applicable treatment 
policy in a large and increasing patient population. 
Novel features of the study include: (a) clinician flexibility in the randomisation of patients; (b) 
ability of analyses to examine the individual and combined effects of the treatments; (c) use of 
an established research infrastructure and global clinical network for 2 large-scale academic 
stroke trials - the third International Stroke Trial (IST-3)1 of i.v. rtPA within 6 hours of acute 
ischaemic stroke, and the Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage 
Trial (INTERACT2) of rapid intensive (140 mmHg systolic target) versus guideline-
recommended level (180 mmHg systolic target) of BP lowering within 6 hours of spontaneous 
intracerebral haemorrhage (ICH)2 - provides efficacy gains and assurance over feasibility, 
recruitment and completion; (d) use of broad inclusion criteria and conduct of the study across 
different health care settings will support the generalisability of results; and (e) a comparative 
effectiveness design with restricted availability of reduced cost rtPA offers ‘active’ equitable 
treatment and ability to improve stroke care at participating sites in developing countries. 
BACKGROUND 
 
1. EPIDEMIOLOGY 
Stroke is the 4th leading cause of global disease burden, resulting in an estimated 16 million 
first-ever events, 62 million survivors, 51 million disability-adjusted life years (DALYs) lost, and 
5.7 million deaths (87% in low-middle income countries) in 2005.3  However, because of the 
ageing population, the burden will increase greatly during the next 20 years, with developing 
countries more affected.  In western societies, about 80% of strokes are caused by focal 
neurological ischaemia, and the remaining 20 % are caused by haemorrhages.  Thirty-day case 
fatality rates for AIS in western societies range between 10 and 17%.  Mortality in the first month 

ENCHANTED Protocol version 5.0 16 Feb 2017  
 
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after stroke has been reported to range from 2.5% in patients with lacunar infarct to 78% in 
patients with space-occupying hemispheric infarction.  
2. PATHOPHYSIOLOGY 
Ischaemic stroke is caused by acute occlusion of an artery leading to immediate reduction in 
blood flow within the corresponding cerebrovascular territory.  The size and site of the occlusion, 
and the efficiency of compensatory collateral blood flow, determine the extent of impaired blood 
flow and resulting neurological symptoms from ‘at risk’ (‘ischaemic’) and/or dead (‘infarcted’) 
brain.  Early spontaneous re-canalisation may occur from the endogenous release of tPA, a 
serine protease of the fibrinolytic system which converts the zymogen plasminogen into the 
active protease plasmin, leading to cleavage of fibrin and the dissolving of newly formed 
thrombin ‘clot’.  However, for most patients, and particularly in those with large occlusions, this 
natural physiological function is inadequate to avoid the outcome of infarcted cerebral tissue 
from the occluded vessel.  
3. ACUTE MANAGEMENT 
The immediate goals of acute ischaemic stroke, as other forms of stroke, include firstly to 
minimise brain injury; and secondly to prevent future neurological damage.  Strong evidence 
has shown that treatment of patients in stroke units reduces mortality, dependency and the 
need for institutional care. 
The general physical examination continues from the original assessment of the ABCs and 
should include pulse oximetry and body temperature.  Deficit should be assessed by a brief but 
thorough neurological examination, several scales has been developed to quantify the severity 
of the neurological deficit.  Standardised examinations help to ensure that major components of 
a neurological examination are performed in timely fashion.  These scores not only help to 
quantify the degree of neurological damage but also identify the possible location of the vessel 
occlusion, provide early prognosis, and help to identify patient eligibility for various interventions 
and the potential for complications.  The National Institutes of Health Stroke Scale (NIHSS) is 
most often used. In addition a further attempt to identify the mechanism that leads to vessel 
occlusion based on Trial of Org in Acute Stroke Treatment (TOAST) criteria (cardio-embolic, 
artery-to-artery embolism, or in-situ small vessel ‘lacunar’ disease) is recommended as 
information should influence both acute treatment and secondary prevention strategies Table 1. 
Table 1 Classification of subtypes of acute ischaemic stroke 
TOAST* (Trial of Org 10 172 in Acute Stroke Treatment) criteria  
 
 
Large-artery atherosclerosis (embolus or thrombosis)* 
Cardioembolism (high-risk or medium-risk)* 
Small-vessel occlusion (lacune)* 
Stroke of other determined cause* 
Stroke of undetermined cause 
Two or more causes identifi ed 
Negative evaluation 
Incomplete evaluation 
 
 
 
*Possible or probable depending on results of ancillary studies. 
 
 
 
 
 
Cardiac examination, cardiac enzymes test and a 12 lead ECG should be performed in all 
stroke patients as cardiac abnormalities are prevalent in this group of patients.  In addition 
routine blood test should be performed in patient with suspected AIS to identify systemic 
conditions that may mimic or cause stroke or that may influence therapeutic options.  These 
tests include blood glucose, electrolytes, complete blood account with platelet account, 

ENCHANTED Protocol version 5.0 16 Feb 2017  
 
12 
prothrombin time, activated partial thromboplastin time, international normalized ratio and renal 
function test. Thrombolytic therapy should not be delayed while waiting for results unless a 
bleeding abnormality or thrombocytopenia is suspected, the patient has been taking warfarin, or 
anticoagulation use is uncertain.  
Additional tests may be performed as indicated by the patient’s history, symptoms, physical 
findings, or co-morbidities.  A toxicology screen, blood alcohol level, arterial blood gas, and 
pregnancy test should be obtained if the physician is uncertain about the patient’s history or as 
suggested by findings on examination. 
Brain imaging remains a required component of the emergency assessment of patients with 
stroke.  Both computed tomography (CT) and magnetic resonance imaging (MRI) are options 
for imaging of the brain.  CT may suffice as compared with MRI, as it is more widely available, 
faster, less susceptive to motion artifacts, and cheaper.  On the other hand, MRI has a much 
higher sensitivity than CT for acute ischaemic changes especially in the posterior fossa.  
Imaging of the intracranial and extracranial vasculature in emergency assessment of patients 
with suspected stroke is useful in institutions providing endovascular recanalisation therapies. 
Restoration of blood flow using thrombolytic therapy is the most effective treatment for salving 
ischaemic brain tissue that is not already undergoing infarction. Therefore, once an ischaemic 
stroke is confirmed by history, clinical examination and neuroimaging (CT brain or MRI), rapid 
determination of patients eligibility for thrombolysis is required as the benefit of i.v. thrombolysis 
decreases rapidly and continuously over time.  Current guidelines recommend 0.9 mg/kg rtPA 
(10% bolus, 1 hour infusion, 90mg max. dose) within 4.5 hours of the onset of symptoms in 
patients eligible for thrombolysis, based on results of the pivotal National Institute of 
Neurological Disorders and Stroke (NINDS) trial.4  Clot-retrieval devices, used either alone or as 
an adjuvant to thrombolysis, have recently been shown to be effective in patients with AIS due 
to occlusion of proximal cerebral vessels.5 But the use of these devices is limited to 
comprehensive stroke centres that have the resources and physician expertise to perform these 
procedures safely.  The administration of anticoagulants or antiplatelet agents is currently 
contraindicated during the first 24 hours after treatment with rtPA based on the protocol used in 
the NINDS trial.  The experience with adjunctive anticoagulation is limited; neither safety nor 
effectiveness has been established. 
Aspirin is the only oral antiplatelet agent that has been evaluated for the treatment of AIS with a 
small but significant decline in mortality and morbidity when started within 48 hours of onset of 
stroke.  However, patients with prior use of aspirin who receive thrombolysis may have an 
increased mortality in AIS.  Aspirin should not be considered a substitute for other acute 
intervention for the treatment of stroke, including the intravenous administration of rtPA. 
Guidelines recommendations regarding BP control in patients with AIS are based in consensus, 
since there are no data supporting any specific antihypertensive regimen.  Given concerns 
about adverse effects of the short-term lowering BP on cerebral perfusion, current guidelines 
recommended withholding antihypertensive therapy during the acute phase of stroke unless the 
BP exceeds 220/120 mmHg in patient who are not candidates for rtPA (see Table 2). 
In patients receiving thrombolytic therapy, BP levels of ≤185/110 should be achieved prior 
receiving rtPA therapy and intravenous antihypertensive therapy is recommended to maintain 
the BP target below 180/105 mmHg after treatment with rtPA (see Table 3). 
 
 
 

ENCHANTED Protocol version 5.0 16 Feb 2017  
 
13 
 
Table 2 Guideline recommendations for BP lowering treatment in patients with acute ischaemic stroke who 
are not candidates for rtPA 
 
Start medication 
Target 
 
American Heart Association  
      BP >220 / 120 mmHg 
     Lower BP by 15 to 20% 
 
National Stroke Foundation (Australia)  
BP ≥220 / 120 mmHg 
Up to 20% reduction 
 
 
 
 
Table 3 Guideline recommendations for BP lowering treatment in patients with acute ischaemic stroke prior 
and after treatment with rtPA 
 
Start medication 
Target 
 
American Heart Association  
 
BP >185 / 110 mmHg 
    BP <180 / 105 mm Hg   
National Stroke Foundation (Australia)  
BP >185 / 110 mmHg 
                  
 
 
 
The most important neurological complications are swelling of the ischemic tissue causing mass 
effect; haemorrhagic transformation of the infarction with or without mass effect; and, less 
commonly, seizures. 
Patients with major infarctions affecting the cerebral hemisphere or cerebellum are at high risk 
for complicating brain oedema and increased intracranial pressure.  Measures to lessen the risk 
of oedema and close monitoring of the patient for signs of neurological worsening during the 
first days after stroke are recommended.  Patients with acute hydrocephalus secondary to an 
ischaemic stroke most commonly affecting the cerebellum can be treated with placement of a 
ventricular drain.  Decompressive surgical evacuation of a space occupying cerebellar infarction 
is a potentially lifesaving measure, and clinical recovery may be very good.  Decompressive 
hemicraniectomy surgery for malignant oedema of the cerebral hemisphere may be life-saving, 
but the impact on morbidity is unknown. 
ICH should be suspected in any patient who develops sudden neurologic deterioration, a 
decline in level of consciousness, new headache, nausea and vomiting, or a sudden rise in BP 
after thrombolytic therapy is administered, especially within the first 24 hours of treatment.  In 
patients with suspected ICH, the rtPA infusion should be discontinued and an urgent non-
contrast head CT or MRI scan should be arranged.  Blood should be drawn for typing and cross 
matching, and measurement of prothrombin time, activated partial thromboplastin time, platelet 
count, and fibrinogen.  No reliable data are available to guide the clinician in the choice of 
effective measures to control ICH in this setting. Current recommended therapy includes the 
infusion of platelets (6 to 8 U) and cryoprecipitate that contains factor VIII to rapidly correct the 
systemic fibrinolytic state created by tPA.  The guidelines for the surgical treatment of ICH after 
fibrinolysis for AIS are the same as those followed for ICH in general, but should be initiated 
only after a sufficient infusion of platelets and cryoprecipitate has stabilized intracranial 
bleeding. 
Recurrent seizures after stroke should be treated in a manner similar to other acute neurological 
conditions.  
Despite the interventions that are described in this outline, the prognosis of such patients often 
is very poor.  Many people would not want to survive if a devastating stroke would lead to a 
persistent vegetative state or other condition of devastating incapacity.  An increasing number of 
patients have advanced directive statements that provide instructions about emergency 
treatment in a situation such as a massive stroke.  Physicians should honour those directives.  

ENCHANTED Protocol version 5.0 16 Feb 2017  
 
14 
In other circumstances, such directives may not be available, and the patient’s neurological 
status usually precludes decision making.  Occasionally, a guardian with medical power of 
attorney can make the decision.  Otherwise, the physician should involve family members.  The 
physician should provide clear information about the nature of the stroke, the prognosis, and the 
treatment options.  The family should be given the opportunity to select or withhold medical 
interventions.  In such situation, the medical care may emphasize measures to keep the patient 
comfortable and to support the family during the terminal aspects of the stroke. 
4. RATIONALE FOR LOW –DOSE rtPA IN AIS 
rtPA is the only approved treatment of AIS, licensed on the basis of the pivotal NINDS trial 
published in 1995,4 where an i.v. dose of 0.9 mg/kg (10% bolus, 1 hour infusion, 90mg max. 
dose) within 3 hours of the onset of symptoms improved outcomes in carefully selected (and 
managed) patients.  On the basis of a meta-analysis of this and several subsequent trials of 
rtPA,6 the time criteria for rtPA has recently been extended to 4.5 hours. The totality of the 
evidence among ~4,000 patients randomised to different forms of thrombolysis is now strong for 
i.v. rtPA providing an overall net benefit despite having an increased risk of bleeding, most 
seriously of symptomatic intracerebral haemorrhage (sICH) (2-10%) but also of any ICH (20-
30%),7 arising either within the area of cerebral ischaemia/infarction (so-called ‘haemorrhagic 
transformation’) or elsewhere in the brain, manifest as anything from small petechial to overt 
lobar haemorrhage with mass effect.  ICH, the most feared complication of rtPA, arises in part 
because rtPA has a prolonged action on thrombi in the body despite having only a short (mins) 
half-life in serum, and in part due to various alterations in blood flow and permeability within and 
around infarcted brain.  Despite this risk, patients who receive rtPA early after the onset of AIS 
have an overall ≥30% relative increased chance of having little or no residual disability.8  The 
treatment effect translates into 1 fewer patient dead or physically dependent for every 10 
treated, 1 fewer dying per 100 treated, and 1 sICH per 14 treated.8  Yet, as rtPA fails in up to 
50% of patients due to there being a severe ischaemic deficit and/or slow and incomplete 
thrombolysis (i.e. re-canalisation), efforts continue to be made towards improving the efficiency 
of the treatment.9  Clot-retrieval devices, used either alone or as an adjuvant to thrombolysis, 
have recently been shown to provide significant benefit to patients with AIS due to occlusion of 
large proximal cerebral vessels. 5 Conversely, there has not been any advance in finding a 
suitable alternative i.v. thrombolytic to rtPA, as older agents are not widely available (e.g. 
urokinase) or have uncertainty over dose and safety (e.g. streptokinase), and new agents have 
not established efficacy (e.g. desmoteplase).56  Thus, further trials of rtPA (e.g. IST-3,1 results in 
2012) with brain imaging, such as ENCHANTED, are still required to strengthen the evidence in 
important subgroups of patients (e.g. age >80 years, diabetes, and various brain scan 
parameters) to allow treatment to be tailored to individuals and increasingly more complex 
patients with acute stroke. 
Standard-dose rtPA was chosen on the basis of pilot dose-escalation studies.  The first used 
doses of 0.35 (n=6), 0.60 (n=12), 0.85 (n=30), 0.95 (n=25) and 1.08 (n=1) mg/kg tested within 
90 minutes of ischaemic stroke,10 and showed that the proportion of patients with major 
neurological improvement at 24 hours was higher in the 0.85 mg/kg tier (55%) compared to the 
0.6mg/kg tier (33%), and there were no sICH in doses <0.95 mg/kg.  The second study used 0.6 
(n=8), 0.85 (n=6) and 0.95 (n=6) mg/kg in patients 90-180 minutes after stroke, with 1 sICH 
occurring in each of 2 highest tiers.11  A small placebo-controlled trial of 0.85 mg/kg had no 
sICHs in the treated group (n=14).12  However, as emphasised by the investigators of these 
studies, the numbers of patients included were too small to reach any firm conclusion regarding 
the optimum dose of rtPA, and as outlined in a letter to Stroke,13 a proposed trial to compare 0.6 
to 0.9 mg/kg of rtPA was not approved for funding by the NINDS in the mid-1990s.  Instead, the 
subsequent main NINDS4 and ECASSII14 trials (note: the first ECASS15 showed that 1.1 mg/kg 

ENCHANTED Protocol version 5.0 16 Feb 2017  
 
15 
of rtPA was no more effective than placebo on neurological outcomes at 3 months due to higher 
rates of death and sICH in the rtPA group) went on to show that the 0.9 mg/kg dose provided 
benefits with an acceptable risk of sICH, so it become the standard approved dose of rtPA.  
However, subsequent studies have shown that thrombolysis is possible with a lower dose of 
rtPA, for example: (a) patients treated with combined i.v. and intra-arterial (i.a) rtPA and/or clot 
retrieval devices (e.g. the Interventional Management of Stroke [IMS] study16) do not always 
receive the full 0.9 mg/kg dose of rtPA, commenced as part of ‘bridging therapy’, because their 
subsequent cerebral angiogram fails to demonstrate a clot treatable by either thrombolysis or 
device, and; (b) real-time transcranial ultrasound used during rtPA9 shows early re-canalisation 
(median onset 17 minutes) often occurs prior to completion of the full 1 hour infusion of 
standard-dose rtPA.   
Low-dose (0.6 mg/kg) of rtPA was first evaluated in 3 small double-blind randomised 
controlled trials of duteplase (similar to rtPA) within 6 hours of acute ischemic stroke in Japan 20 
years ago:17-18 20 mega-international units (MIU) of duteplase was superior to placebo; 20 MIU 
(equal to 0.33 MIU/kg or 0.6 mg/kg of rtPA) was comparable to 30 MIU on both angiographic re-
canalisation and clinical improvement; and massive ICH was more frequent in patients who 
received 30 MIU.  Low-dose rtPA has been used in Japan because of concerns that the 
standard dose has a higher haemorrhage risk in this population.  Studies show racial 
differences in coagulation-fibrinolysis factors,19 such as higher plasma concentrations of 
fibrinogen and plasminogen activator inhibitor among Caucasians than the Japanese,19-20 and 
racial differences in genetic polymorphisms of coagulation factors.21  Despite use of a lower 
dose of rtPA for acute myocardial infarction in Japan (0.5-0.75 vs 1-1.25 mg/kg), coronary artery 
patency rates appear comparable with other countries (60%-80%).19  Thus, the Japan Alteplase 
Clinical Trial (J-ACT)22 was undertaken with 0.6 mg/kg rtPA in an open non-randomised 
evaluation of patients within 3 hours of acute ischaemic stroke and showed equivalent clinical 
outcomes but a reduced risk of sICH compared to expected rates from the standard 0.9 mg/kg 
dose.22  J-ACT and comparable data from subsequent registry studies in Japan23-24 (and 
Taiwan25), led to approval of the 0.6 mg/kg dose as the standard treatment for patients with 
acute ischaemic stroke in Japan.  However, this policy has caused considerable confusion in 
other parts of Asia, where there is continued uncertainty as to the balance of benefits and risks 
of low- versus standard-dose rtPA.  This has led to the 0.9 mg/kg remaining the gold standard 
dose of rtPA but the 0.6 mg/kg dose (which may be require use of a single 50mg vial of Actylise 
®Boehringer Ingelheim) becoming an attractive ‘low-cost’ ‘cheaper’ ‘softer’ option for patients 
who cannot afford the full dose (i.e. 2 vials).  The high cost of rtPA (~US$2,000 per 2x50mg 
vials for 0.9 mg/kg dose)26 is a major out-of-pocket expense for many people in fee-for-service 
health care systems of low-middle income countries.27  
Low-dose rtPA appeared safe and effective but there was no reliable randomised evidence to 
support a widespread policy for its use in Asia or elsewhere in the world.  Low-dose rtPA may 
be safer in Asians due to racial differences in coagulation factors, but any potential pharmaco-
therapeutic differences among races in the response to rtPA may not be specific to the 
Japanese.  For example, enhanced sensitivity to rtPA manifest by increased thrombolytic 
efficacy, systemic fibrinogen breakdown and need for transfusion has been noted among Black-
American patients with acute myocardial infarction.28  The effects of low-dose rtPA in Asians 
could simply be explained on the basis of a lower total dose comparable with a smaller body 
weight/mass, or that Asians have a lower ‘clot volume’ due to the greater proportion of small 
vessel occlusive or ‘lacunar’ forms of ischaemic stroke compared to more large vessel and 
cardio-embolic strokes (i.e. high clot volume) in non-Asians.  Thus, standard-dose rtPA may be 
better in situations of older, harder, larger, fibrin-poor clot/thrombi arising from proximal extra-
cranial atheroma or cardiac sources, whilst low-dose rtPA may be better and safer (i.e. lower 
risk of sICH29) for acute platelet-rich or low volume thrombi in more distal or smaller perforating 

ENCHANTED Protocol version 5.0 16 Feb 2017  
 
16 
cerebral vessels producing lacunar strokes.  Of course, i.v. rtPA may not be effective at all in 
older, harder, larger, fibrin-poor clot/thrombi arising from proximal intra- or extra-cranial 
atheroma, or cardiac sources.  Careful in vitro studies indicate no further increase in the degree 
of clot lysis above doses of rtPA equivalent to 0.6 mg/kg,30 while non-randomised comparative 
clinical studies in Singapore suggest poorer outcomes from low- compared to standard-dose 
rtPA in patients with AIS, raising the issue of inferior re-canalisation with the lower dose.31-32  As 
emphasised in the Cochrane review of thrombolysis in AIS, despite no clear differences being 
evident in indirect comparisons of different dose (or forms) of thrombolytic agents,7 in the 
absence of head-to-head direct comparative studies, there was uncertainty over the relative 
benefits and risks of low- versus standard-dose rtPA.  Thus, the current variable (ad-hoc) use of 
low-dose rtPA outside of Japan may be denying benefits (or exposure to unnecessary hazard) 
for many thousands of patients, so that if it could be proven to be safe and effective, it could 
provide evidence to substantiate use of a low cost treatment for stroke in many parts of the 
world. 
5. SUMMMARY OF RATIONALE FOR LOW – DOSE rtPA IN AIS 
rtPA is the only approved treatment of AIS despite increased risk of sICH.  Recent studies 
suggest that low-dose of rtPA is an effective treatment and may have a reduced risk of sICH but 
there is lack of reliable randomised evidence to support a widespread policy for its use in Asia 
or elsewhere in the world.  ENCHANTED was designed as a large-scale study to determine the 
overall balance of risks and benefits associated with the use of low-dose rtPA in patients with 
AIS.  The main results of this arm of the study were published in the New England Journal of 
Medicine in 2016. 34 
6. EVIDENCE FOR EARLY INTENSIVE BP LOWERING AFTER rtPA IN AIS 
The optimal management of BP in AIS remains controversial.  Elevated BP or 
‘hypertension’ (i.e. systolic >140 mmHg) is very common (>60%) early after the onset of AIS,34-5 
with the degree of increase in BP being greater in patients with pre-existing hypertension and 
larger strokes,36,37 and levels tending to decline over the subsequent week.  While generally 
positive associations between BP levels and poor outcomes are evident, very low (systolic <130 
mmHg) BP levels and large reductions in BP are also related to poor outcomes in AIS.5-36  
Various explanations for elevated BP include acute physiological stress, pain, unstable pre-
existing hypertension, or increased intracranial pressure, occurring in the context of a critical set 
of mechanisms operating in relation to the evolving cerebral ischaemia/infarction to produce 
varying degrees of cerebral oedema and haemorrhagic transformation from re-perfusion and 
collateral flow into the injured region of the brain.  However, the observed U- or J-shaped 
relationship of BP and outcome35-36 may not be causally related; rather patients with more 
severe strokes (and who naturally have worse outcomes) may have a more prominent 
autonomic response resulting in higher BP at presentation, and the same type of patients may 
also develop lower BP levels as their condition worsens, sometimes as a pre-terminal event.  To 
complicate matters further, hypertensive patients appear to have their cerebral autoregulation 
shifted to a higher level, whereas in all patients the critically vulnerable penumbral rim of the 
infarct core of AIS, cerebral autoregulation is likely to be disrupted so that cerebral perfusion 
pressure is directly related to systemic BP.37  Even so, experimental models of focal cerebral 
ischemia and reperfusion indicate that BP reduction reduces the size of cerebral ischaemia and 
improves reperfusion.38  In the first IST study, the higher rate of death or dependency in patients 
(n=17,398) with initially high or low systolic BP within 48 hours of ischaemic stroke appears to 
have been mediated in part by increased rates of early recurrence and death from presumed 
cerebral oedema in patients with high BP and increased coronary artery events in those with low 
BP.39  Finally, recent data indicate that wide fluctuations in BP early after AIS is associated with 

ENCHANTED Protocol version 5.0 16 Feb 2017  
 
17 
an increased risk of death, possibly due to altered perfusion pressure in the ischaemic 
penumbra exacerbating cerebral oedema or haemorrhagic transformation.  Any potential 
benefits of rapid BP lowering in AIS must be balanced against potential risks of worsening 
ischaemia from altered autoregulation and/or perfusion in the ischaemic penumbra. However, 
any risks of BP lowering appear to only at very low systolic BP levels (ie <130 mmHg)40 which is 
beyond those outlined in the ENCHANTED protocol. 
More intensive BP lowering may reduce the risk of sICH after rtPA.  Guidelines for BP 
control in AIS are consistent in contraindicating use of rtPA in patients with ‘uncontrolled’ BP 
according to the definitions used in the NINDS rtPA stroke study, that is with systolic BP >185 
mmHg and diastolic BP >110 mmHg.41  However, recent data have emerged to suggest that 
lower and more stable BP levels may improve outcomes, particularly in patients who receive 
rtPA. 40, 42 In the original NINDS study,4 use of antihypertensive therapy was common in both the 
placebo and active groups, so although this treatment did not appear to influence outcomes, the 
small sample size (n=624) and lack of randomised variation precluded firm conclusions to be 
drawn on the role of BP control on the outcomes.40  Subsequent non-randomised studies 
indicate that ‘inadequate control’ of BP (or pre-treatment BP rtPA protocol violations) prior to, 
and after, the use of rtPA is associated with a higher likelihood of sICH.43-44  The most 
compelling data are from the large-scale prospective registry studies: the Safe Implementation 
of Thrombolysis in Stroke-Monitoring STudy (SITS-MOST)45 of 6483 patients from 285 mainly 
European centres between 2002 and 2006; and the Safe Implementation of Thrombolysis in 
Stroke–International Stroke Thrombolysis Register (SITS-ISTR)44 with expanded measures 
including serial BP (baseline, 2 and 24 hours), treatment and outcome data in 11,080 patients 
registered between 2002 and 2006.  In SITS-MOST, elevated baseline systolic BP (odds ratio 
[OR] 1.3, 95% confidence interval [CI] 1.1-1.7 per 20 mmHg standard deviation) was associated 
with sICH, which occurred in 8.5% (95%CI 8-9%) according to the use of a strict definition.  In 
SITS-ISTR, multivariable analyses showed that: elevated systolic BP levels (i) as a continuous 
variable was associated with a worse outcome (P<0.001) and (ii) as a categorical variable had a 
linear association with sICH and a U-shaped association for death and dependency such that 
the best outcome occurred in the nadir 141-150 mmHg; and sICH was 4 times higher in patients 
with a post-rtPA systolic BP >170 mmHg compared with those with levels of 141-150 mmHg.  
Moreover, withholding antihypertensive therapy for several days in patients with prior 
hypertension was associated with worse outcomes, whereas initiation of antihypertensive 
therapy in newly recognised cases of moderate hypertension was associated with a favourable 
outcome.  These data indicate that a ≥15 mmHg difference in systolic BP levels equates to 
≥15% reduction in a poor outcome after rtPA. 
Completed and ongoing trials of early BP lowering in acute stroke Current guidelines for 
BP management in AIS highlight the need for a definitive study since their expert-derived 
recommendations provide only an indication of perceived harm from high BP, with arbitrary 
levels of <185 mmHg systolic BP before rtPA and <180mmHg after rtPA chosen to be 
achieved.41  As emphasized by multiple editorials and reviews,34,46-47 the management of 
elevated BP in AIS is a major research question that needs to be resolved.  None of the major 
trials in this area (e.g. the Scandinavian Candesartan Acute Stroke Trial [SCAST]48) and  
Efficacy of Nitric Oxide in Stroke (ENOS)36-39 in the area have been specifically designed to 
address the role of very early (i.e. within a few hours), rapid and intensive (i.e. i.v. agents) BP 
lowering, and most importantly, as to whether such treatment improves outcomes and reduces 
the risk of ICH after rtPA.  The INTERACT2 study49-50 showed that rapid BP lowering (140 
mmHg systolic target) was feasible, safe and potentially efficacious improving outcome after 
ICH, provides a strong rationale and an appropriate time to test the effectiveness of the 
treatment protocol with rtPA in AIS. 

ENCHANTED Protocol version 5.0 16 Feb 2017  
 
18 
7. CHOICE OF BP PRESSURE LOWERING AGENT 
There are a number of different drug classes that may be used to lower BP in acute stroke, and 
each has potential advantages and disadvantages.  It is uncertain which class of BP lowering 
agent is most desirable in the acute phase of stroke and there are different routes of 
administration.  Effective oral treatment cannot be guaranteed during the acute phase of stroke 
because of the frequent occurrence of dysphagia and/or reduced levels of consciousness, 
which is seen in up to 50% of patients.  In addition, the early insertion of a naso-gastric tube 
may not be possible, and it is often pulled out by confused patients.  Whilst transdermal 
administration might be useful, the onset of a BP lowering effect is slow and produces only a 
modest effect, which is less desirable in patients with severe hypertension.  Intravenous 
treatment is the optimal route of administration during the acute phase of acute ischaemic 
stroke as it allows rapid BP reduction and in a titratable manner.  However, intravenous 
treatment requires close monitoring of BP levels in patients to avoid hypotension, but this is 
readily accomplished within acute stroke units, high dependency units, or intensive care unit.  
Table 4 lists various intravenous medications for BP lowering, their profile of action and 
potential adverse effects. 
Table 4 Possible intravenous medications for BP lowering 
Drug 
Onset 
Duration 
Potential adverse effects 
Esmolol 
5-10 min 
10-30 min 
Hypotension, nausea, asthma, first-degree heart block, heart failure 
Labetalol 
5-10 min 
3-6 h 
Vomiting, scalp tingling, bronchoconstriction, dizziness, nausea, heart 
attack, orthostatic hypotension 
Urapidil 
5-10 min 
3-4 h 
Dizziness, nausea, palpitations, orthostatic hypotension 
Phentolamine 
1-2 min 
10-30 min 
Tachycardia, flushing, headache 
Clonidine 
10-20 min 
3-6 h 
Sedation and other central nervous system effects, dry mouth, 
discontinuation syndrome 
Nicardipine 
5-10 min 
15-30 min 
Hypotension, tachycardia, headache, flushing, local phlebitis 
Hydralazine 
10-20 min 
1-4 h 
Hypotension, tachycardia, flushing, headache, vomiting, aggravation 
of angina 
Nitroglycerin 
2-5 min 
5-10 min 
Headache, vomiting, methaemoglobinaemia, tolerance with prolonged 
use 
Enalaprilat 
15-30 min 
6-12 h 
Precipitous fall in pressure in high-renin status 
Nitroprusside 
Immediate 
1-2 min 
Hypotension, nausea, vomiting, muscle twitching, sweating, 
thiocynate and cyanide intoxication 
Clevidipine 
2-10 min 
10 min 
Hypotension, tachycardia, lipid overload 
Amongst these agents, sodium nitroprusside is arguably the least desirable for routine use 
outside of an intensive care unit because of its potent anti-platelet effects, ability to increase 
intracranial pressure, and profound BP lowering effects.  
Guidelines only recommend use of sodium nitroprusside in patients with extremely high BP 
levels.  Intravenous infusions of the other short acting agents are more desirable for close 
control of BP.  Labetalol is recommended in the AHA Guidelines and is widely available in most 
countries throughout the world, a notable exception being Australia.  The alpha adrenergic 
antagonists urapidil hydrochloride, frusemide and phentolamine are popular in China.  These 
drugs can both be used initially as bolus injections, followed by infusions. 
8. SUMMARY OF RATIONALE FOR A TRIAL OF BP LOWERING IN AIS 
Current guidelines for BP management in AIS highlight the need for a definitive study since their 
expert-derived recommendations provide only an indication of perceived harm from high BP.  
The management of elevated BP in AIS is a major research question that needs to be resolved.  
None of the recently completed and ongoing trials in the area have been specifically designed to 

ENCHANTED Protocol version 5.0 16 Feb 2017  
 
19 
address the role of rapid intensive BP lowering within the first few hours of onset, and in 
particular, as to whether such treatment improves outcomes after rtPA. 
AIMS AND OBJECTIVES 
 
In patients with AIS eligible for thrombolysis using rtPA according to local guidelines and 
otherwise able to receive best usual medical care. 
1. PRIMARY AIMS  
[A] Compared with standard dose i.v. rtPA, low-dose rtPA is at least as effective (‘not inferior’) 
on the major clinical outcome of death or disability at 3 months (i.e. corresponding null 
hypothesis is that low-dose is inferior to standard dose rtPA) (Results published in May 2016);  
[B] Compared with standard guideline-based BP management, early intensive BP lowering is 
superior in improving functional recovery according to a comparison of ordinal scores on the 
mRS at 3 months (i.e. corresponding null hypothesis is that there is no difference in treatments 
on this outcome).49 
2. KEY SECONDARY AIMS  
[C] Compared with standard dose i.v. rtPA, low-dose rtPA reduces the risk of sICH (Results 
published) 
[D] Compared with standard guideline-based BP management, early intensive BP lowering after 
thrombolysis with rtPA reduces the risk of any ICH (i.e. corresponding null hypothesis is that 
there is no difference in the rate of any ICH between groups of differing intensities of BP 
lowering). 
3. OTHER SECONDARY AIMS 
To define effects on a shift (‘improvement’) in measures of disability according to the grading 
system on the modified Rankin Scale (mRS) in arm [A];51 sICH; good recovery (mRS 0-1); death 
or major disability (mRS 3-6); separately on death and disability (mRS 3-5); early neurological 
deterioration; HRQoL; length of hospital stay; need for permanent residential care; and health 
care costs. 
 
 
METHODS  
1. OVERALL DESIGN 
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, blinded endpoint (PROBE), 
controlled trial that will involve 4500 patients (3300 for arm [A] and 2100 for arm [B] with 
overlap of 939 patients) with AIS recruited from over 100+ Clinical Centres from Australia, Asia, 
Europe and South America. The study design is summarised in the following schema. 

ENCHANTED Protocol version 5.0 16 Feb 2017  
 
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Study schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2. STUDY POPULATION 
All patients presenting to participating centres with suspected AIS arriving <4.5 hours of 
symptoms onset will be considered for this trial.  Primary responsibility for recruitment of 
patients will lie with the Principal Investigator (PI) at each centre.  It is anticipated that 
successful recruitment will require the active involvement of Emergency Department staff at 
each centre, since rapid referral of patients early after stroke onset is required.  Rate limiting 
steps after presentation are anticipated to include the time taken for:  
(1)  
completion of brain imaging (CT brain or MRI); 
(2)  
receipt of informed consent and baseline assessment; and  
(3)  
administration of randomised treatment.   
In order to facilitate recruitment, study centres should aim for a ‘door-to-needle’ time of 60 
minutes, which is in line with current guidelines for effective use of rtPA, and a randomisation-to-
treatment time of 15 minutes.   
3. INCLUSION AND EXCLUSION CRITERIA 
To be eligible for inclusion in this study, patients must fulfil local criteria for the routine use of i.v. 
rtPA, and the attending clinician is required to consider their level of clinical uncertainty over the 
 
Completed 
 
 
 
 
Best 
practice 
care 
during 
treatment 
and 
follow-up 
periods 
 
Patient with a definite acute ischaemic stroke <4.5 hours, i.v. rtPA indicated 
and planned, and has a systolic BP ≤185 mmHg 
1, 3, 7, 28 and 90 day review and follow-up 
Systolic BP ≥150 mmHg; no definite indication or contraindication 
to rapid intensive BP lowering to 130-140 mmHg systolic target 
No definite indication or contraindication to either rtPA dose 
Randomisation arm [A] 
Low- dose rtPA 
0.6 mg/kg rtPA 
Standard-dose 
rtPA 0.9 mg/kg 
Intensive BP lowering to 
systolic 130-140 mmHg 
Standard BP control to 
systolic <180 mmHg 
Randomisation arm [B] 

ENCHANTED Protocol version 5.0 16 Feb 2017  
 
21 
balance of potential benefits and risks pertaining to the level of BP control in each particular 
patient, as outlined below. 
1. General criteria for use of thrombolytic treatment with rtPA. 
(a) Adult (age ≥18 years) 
(b) A clinical diagnosis of acute ischaemic stroke confirmed by brain imaging 
(c) Able to receive rtPA treatment within 4.5 hours after the definite time of onset of 
symptoms 
(d) Have a systolic BP ≤185 mmHg within 6 hours of symptom onset (i.e. the guideline 
recommended level of eligibility for rtPA; patients with higher BP levels at presentation 
can still be included provided the BP is reduced to the entry level prior to 
commencement of the treatment) 
(e) Provide informed consent (or via an appropriate proxy, according to local requirements) 
2. Specific criteria for intensive BP lowering vs guideline recommended BP control. 
(a) Patient will or has received routine thrombolysis treatment with rtPA, according to 
physician-decided dose rtPA  
(b) Sustained elevated systolic BP level, defined as 2 readings ≥150 mmHg 
(c) Able to commence intensive BP lowering treatment within 6 hours of stroke onset. 
(d) No definite indication or contraindication to either immediate ‘intensive’ BP lowering (to a 
target of 130-140 mmHg systolic) versus guideline-based BP control (e.g. intensive BP 
lowering is feasible and does not appear to pose excessive hazard to the patient). 
Patients will NOT be eligible if there is one or more of the following: 
(a) Unlikely to potentially benefit from the therapy (e.g. advanced dementia), or a very high 
likelihood of death within 24 hours of stroke onset.  
(b) Other medical illness that interferes with outcome assessments and follow-up [known 
significant pre-stroke disability (mRS scores 2-5)]. 
(c) Specific contraindications to rtPA (Actilyse) or any of the blood pressure agents to be 
used. 
(d) Participation in another clinical trial involving evaluation of pharmacological agents 
(e) Need for following concomitant medication, including phosphodiesterase inhibitors and 
monoamine oxidase inhibitors. 
4. ETHICAL ISSUES 
This study will be conducted in compliance with the principles outlined in the World Medical 
Association’s Declaration of Helsinki (see Appendix 5). 
4.1 Institutional Ethics Committee Approval 
Each participating centre must obtain written approval(s) from their Hospital Research Ethics 
Committee (e.g. Institutional Review Board [IRB]), and other regional or national regulatory 
bodies before patient recruitment can commence.  Any protocol amendments, serious adverse 
event (SAE) reports and routine reporting to the IRB will be the responsibility of the Principal 
Investigator (PI) at each participating centre. 
4.2 Consent 
The majority of patients admitted with AIS require emergency care.  Some aspects of this care 
are thrombolytic treatment with rtPA and management of hypertension which needs to be 
treated urgently.  However, the nature of this acute condition means that the patient may be too 
unwell to comprehend the information that must be given in the consent process and this 
consent needs to be obtained swiftly to avoid delays in urgent treatment.  The optional consent 

ENCHANTED Protocol version 5.0 16 Feb 2017  
 
22 
procedures for this study are detailed below and should be followed according to local IRB 
guidelines. 
 
 
 
Patient Consent 
Wherever possible, the patient will be approached to directly give written informed consent.  An 
information statement will be given to the patient and the implications for consenting to the study 
will be explained by a clinician familiar with the study protocol. 
Person Responsible Consent  
If the patient is not fully competent to give informed consent, for example because of a reduced 
level of consciousness or confusion, the patient’s ‘person responsible’ will be approached to 
provide informed consent on his or her behalf.   
Under the Guardianship Act of 1987 in New South Wales, Australia, a ‘person responsible’ are 
the legally appointed guardian, their spouse or de-facto spouse or same sex partner, or if there 
is none, their unpaid carer, or if there is none, their relative or friend who has a close 
relationship with the person. 
The patient will be made aware of this process as soon as they are well enough and have an 
opportunity to withdraw the consent.  If willing to continue participation in the study, the patient 
will be asked to sign their own consent form. 
If the patient is dying or is still unable to record their personal consent by the time of completed 
follow up on the study, the consent given by their person responsible will stand and trial data will 
be retained.  The reason for not obtaining the patient’s consent will be documented, dated and 
signed in the patient’s file. 
If a patient is discharged from hospital before it has been possible to gain personal consent, the 
PI will make attempts to inform the patient of the study and gain written consent.  If this has 
been unsuccessful after a minimum of 3 documented occasions, the consent given by their 
person responsible will stand and the trial data will be retained.  The reason for not obtaining the 
patient’s consent will be documented, dated and signed in the patient’s file. 
Guardianship tribunal consent 
In the situation where a patient is unable to give consent and a ‘person responsible’ is not 
available or cannot be contacted, clinicians should seek guardianship tribunal approval before 
enrolling eligible patients in the study.  The patient will be made aware of this process as soon 
as they are well enough and have an opportunity to withdraw the consent.  If willing to continue 
participation in the study, the patient will be asked to sign their own consent form.  If the patient 
is not fully competent to give informed consent, for example because of a reduced level of 
consciousness or confusion, the patient’s ’person responsible’ will be approached as soon as 
possible to provide informed consent on his or her behalf. 
In the case of a patient’s death, the PI should use discretion on a case by case basis before 
contacting the ‘person responsible’ in recognition of the potential distress that may exist as the 
result of a death. In either case, an explanation of the lack of patient or surrogate consent will be 
document in the patient’s file. 

ENCHANTED Protocol version 5.0 16 Feb 2017  
 
23 
Delayed consent 
The circumstances surrounding emergency care research are such that it may not always be 
possible to obtain consent from either the patient or next of kin without delaying the initiation of 
treatment, and therefore risk reducing any potential benefits to the patient.  In the situation 
where a patient is unable to give consent and a next of kin or other person responsible is not 
available or cannot be contacted, clinicians may enrol eligible patients and inform the patient or 
their person responsible for the patient as soon as possible so that delayed consent can be 
requested.  The reasons for being unable to obtain prior consent will be documented, dated and 
signed in the patient’s file. 
If the patient should die or continue to be unable to give informed consent at the end of the trial 
follow up period, the next of kin or person responsible should be approached to obtain delayed 
written consent.  In the case of a patient’s death, the PI should use discretion on a case by case 
basis before contacting the next of kin or surrogate, in recognition of the potential distress that 
may exist as the result of a death. In either case, an explanation of the lack of patient or person 
responsible consent will be document in the patient’s file. 
Delayed consent in a clinical trial of emergency care is considered by the World Medical 
Association in the Declaration of Helsinki.  This document states:  
“Research on individuals from whom it is not possible to obtain consent, including 
proxy or advance consent, should be done only if the physical/mental condition that 
prevents obtaining informed consent is a necessary characteristic of the research 
population.”   
This study includes such potentially eligible patients. 
The Australian NHMRC also gives guidance to human research ethics committees on this issue: 
“When the nature of the research procedure is such that conformity to the principle of 
consent is not feasible, and neither the individual nor the individual’s representative 
can consider the proposal and give consent in advance, a Human Research Ethics 
Committee (HREC) may approve a research project without prior consent provided it 
is satisfied that: 
(a)  inclusion in the research project is not contrary to the interests of the patient; 
and 
(b)  the research is intended to be therapeutic and the research intervention poses 
no more of a risk than that which is inherent in the patient’s condition and 
alternative methods of treatment; and 
(c)  the research is based on valid scientific hypotheses which support a 
reasonable possibility of benefit over standard care; and 
(d) as soon as reasonably possible, the patient and/or the patient’s relatives or legal 
representatives will be informed of the patient’s inclusion in the research and of 
the option to withdraw from the research without any reduction in quality of care”. 
All four criteria apply to this study protocol including the uncertainty about the optimal rtPA dose 
and BP management in the medical profession and the current guidelines.   
 
 
 

ENCHANTED Protocol version 5.0 16 Feb 2017  
 
24 
Withdrawal of Consent 
The information statement provided to the patient and/or the next of kin or surrogate will clearly 
state that the patient can be withdrawn from the study at any time without prejudice and 
explanation.  Such withdrawal should be documented in the patient’s file.  If withdrawal of 
consent relates to the BP management alone, data collection can continue on documentation of 
this fact in the patient’s files. 
4.3 Confidentiality and privacy 
Every precaution should be taken to respect the privacy of patients in the conduct of the study.  
Only de-identified data will be submitted to the ICC at The George Institute for Global Health to 
maintain patient confidentiality.  However, in the course of monitoring data quality and 
adherence to the study protocol the study monitor will refer to medical records at the 
participating hospital. 
5. RANDOMISATION 
After confirmation of eligibility, patients are randomised via a central internet-based system at 
The George Institute, Sydney, Australia, either direct or via a specially developed Interactive 
Voice Randomisation System (in China).  This will be done by connecting the study centre (e.g. 
emergency department or stroke unit) to the server at the ICC where the patient will be 
registered and the randomised treatments will be assigned for that particular patient. 
The randomisation sequence will use a minimisation algorithm to ensure balance in key 
prognostic factors.  Patients will be stratified according to: 
1. site of recruitment 
2. time from onset <3 hours versus ≥3 hours; 
3. NIHSS score <10 versus ≥10; 
From August 2015, the study allows patients only to be allocated to arm [B] ‘level of BP control’ 
only:  
 
 intensive BP lowering to a target systolic BP range 130-140 mmHg within 60 minutes of 
Randomisation into the BP arm and to maintain this level for at least 72 hours (or until 
hospital discharge or death if this should occur earlier) or guideline-based BP lowering to 
a target systolic BP of <180 mmHg post-rtPA. 
6. ALLOCATED STUDY TREATMENTS 
From August 2015, the attending clinician is required to consider their level of clinical 
uncertainty over the balance of potential benefits and risks pertaining to the level of BP control 
in each particular patient.  Investigators are encouraged to adhere to study protocols, provide 
active care, but are free to modify a patient’s treatment as required according to clinical 
judgment.  
6.1 BP control arm 
6.1.1 Early Intensive BP Lowering Group 
The aim is to achieve a systolic BP level 130-140 mmHg within 60 minutes of Randomisation 
into the BP arm and to maintain this BP level for the next 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.  

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25 
BP lowering will be titrated by repeat i.v. bolus or infusion, with a systolic BP of <130 mmHg 
being the safety threshold for cessation of therapy.  It is anticipated that i.v. agents will be 
required for at least the first several hours in most cases but the timing of switch to oral BP 
lowering agents will be at the discretion of the responsible clinician according to BP control and 
patient status.  It is also expected that i.v. therapy will continue to be required during the 
initiation of oral anti-hypertensive therapy, to maintain the systolic BP levels 130-140 mmHg. 
When administering BP lowering treatment, care is required to ensure that severe hypotension 
is avoided in patients by checking first for potential dehydration and providing intravenous fluids.   
Since the study seeks to address the impact of BP lowering and not a specific agent, and to 
ensure the trial result is maximally generalisable to existing routine practice, some flexibility is 
allowed in the use of locally available i.v. agents (e.g. urapidil, labetolol, hydralazine, metoprolol, 
clevidipine), but all other aspects treatment are standardised across sites.  Patients on prior oral 
BP lowering agents should have this continued if possible and antihypertensive therapy 
prescribed when patients are clinically stable as per guidelines for secondary stroke prevention.  
Investigators are encouraged to adhere to study protocols, provide active care, but are free to 
modify a patient’s treatment as required according to clinical judgment. 
Intravenous treatment protocol 
Intravenous treatment protocols, based on available medications, are provided in Appendices 
1A to 1H.  The intravenous treatment will be titrated against regular BP monitoring to achieve a 
target systolic BP range (130-140 mmHg) within 60 minutes.  It is anticipated that intravenous 
control of systolic BP will be required for at least the first several hours. 
Oral treatment protocol 
The switch from intravenous to oral BP lowering treatment will be made at the discretion of the 
responsible physician, depending upon the control and stability of the BP and the clinical status 
of the patient.  It is anticipated that oral treatment will be started by 24 hours.  An oral treatment 
protocol is provided in Appendices 1A to 1H.  Combination treatment with an ACE inhibitor and 
diuretic will be recommended on top of other therapy as the first line oral treatment on the basis 
of the results of the PROGRESS trial and established best practice for the long-term prevention 
of BP-related events in patients with cerebrovascular disease. 
The oral treatment protocol will also include a defined strategy for titration of treatment to 
achieve effective early systolic BP control once oral treatment is commenced.  If the patient is 
unable to swallow, treatment should be administered via nasogastric tube. 
For the intervention group, the goal is to maintain systolic BP levels within (130-140 mmHg) for 
72 hours of hospital stay.  If the patient is transferred to another hospital facility within 72 hours, 
then attempts should be made to continue therapy to achieve the systolic BP target of (130-
140mmHg).  The target systolic BP after hospital discharge remains <140 mmHg, as per 
guideline-based recommendations for high risk vascular disease patients.  BP levels will be 
reviewed at 28 days follow-up and medication adjusted as necessary to maintain systolic BP 
<140 mmHg. 
6.1.2 Control / Conservative BP Management Group 
Patients allocated to the control group will receive management of BP that is based on a 
standard guideline, as published by the AHA (refer to table 3 in Background section).  
Appendix 1I outlines the protocol for Control patients.  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 or according to local regulatory approval if applicable.  Should control of 
systolic BP not be achieved via these routes, i.v. treatment may be started until the target 

ENCHANTED Protocol version 5.0 16 Feb 2017  
 
26 
systolic BP of 180 mmHg is achieved.  The oral and i.v. agents used will be the same as in the 
intensive BP lowering group as detailed in Appendices 1A to 1H.  Oral anti-hypertensive 
therapy may be started at any time the treating physician feels the patient is stable.  Oral 
therapy must be started by Day 7. The target systolic BP after hospital discharge is <140 mmHg, 
as per guideline-based recommendations for high risk vascular disease patients.  
6.2 Previous Use of Antihypertensive Therapy in Both Groups 
Patients who have been taking antihypertensive therapy prior to randomisation will have their 
usual medication continued when oral administration is possible, unless the agents are 
considered to be inappropriate by the responsible physician (e.g. poor compliance, intolerance, 
or adverse events).  Otherwise, based on the results of the PROGRESS trial, a combination of 
an ACE inhibitor and diuretic should be added to any existing antihypertensive therapy when the 
patient is considered medically stable. 
7. DISCONTINUATION OF ALLOCATED MANAGEMENT POLICY 
The investigator must not deviate from the protocol except the patient/surrogate chooses to 
withdraw consent to participation in the study.  However, allocated management in either group 
should be discontinued or modified if any of the following occur: 
a. SAEs, which are in the opinion of the investigator, related to the trial protocol (refer to 
appropriate section for definitions). 
b. The investigator feels it is in the subject’s best interest. 
Follow-up data will be collected for all treated subjects except those who specifically withdraw 
consent for release of such information. 
8. BACKGROUND CARE 
All patients will be managed in a facility with an adequate nurse/patient ratio and capacity for 
repeated neurological examination and non-invasive BP and heart rate monitoring (consistent 
recordings using automatic devices, every 15 minutes for 1 hour, then 6 hourly for 24 hours, 
then twice daily for 1 week).  All BP measurements are from the non-paretic arm (or right arm in 
situations of coma or tetraparesis), with the patient resting supine for ≥3 minutes.  All patients 
are to receive active care and best practice management according to guidelines, and 
neurointervention with intra-arterial thrombolysis and/or mechanical clot retrieval is still allowed 
according to local practice. 
An acute stroke unit is defined as an area that: 
1. is a geographically specific area where patients with acute stroke are managed; 
2. has staff organised as part of a coordinated multidisciplinary team; 
3. has staff who have special knowledge and skills in the management of acute stroke; 
4. provides ongoing education about stroke management for staff, patients and caregivers; 
5. has written protocols for assessment and management of common problems related to 
 
stroke. 
During the study treatment and follow-up period, the usual management of acute stroke patients 
will be followed according to published guidelines (see Appendix 4) for the acute stroke care 
protocol. It is anticipated that background care may include significant use of treatments 
including drugs and endovascular intervention.  Use of other therapies will be documented and 
compared between countries and should be balanced between randomised groups. 

ENCHANTED Protocol version 5.0 16 Feb 2017  
 
27 
9. STUDY OUTCOMES 
Primary outcome for arm [A] was the combined endpoint of death and disability as defined by 
the conventional dichotomised ‘0-1’ versus ‘2-6’ cut-point on the mRS51 at 3 months. Primary 
outcome for arm [B] is a comparison of ordinal shift in scores on mRS at 3 months.52,53  The 
mRS is a widely used instrument for grading the impact of stroke treatments,48 with scaling of: 0 
= no symptoms at all; 1 = no significant disability despite symptoms, but able to carry out all 
usual duties and activities; 2 = slight disability, unable to carry out all previous activities but able 
to look after own affairs without assistance; 3 = moderate disability requiring some help, but 
able to walk without assistance; 4 = moderate-severe disability, unable to walk without 
assistance and unable to attend to own bodily needs without assistance; 5 = severe disability, 
bedridden incontinent, and requiring constant nursing care and attention; 6 = dead.   
Secondary outcomes are: (a) symptomatic ICH based on NINDS criteria of brain imaging (or 
necropsy) confirmed ICH with ≥1 points deterioration in NIHSS score or death within 36 hours 
from baseline; (b) symptomatic ICH, defined by SITS-MOST criteria,45 as large (‘type II’) 
parenchymal ICH with ≥4 points decline in NIHSS score or death within 36 hours from baseline; 
and (c) ICH of any type in brain imaging ≤7 days of treatment; (d) good outcome, defined by 
scores 0-1 on the mRS (e) death or major disability, defined by scores 3-6 on the mRS,  (e) 
death, (f) disability (mRS score 3-5), (g) neurological deterioration ≥4 points decline in NIHSS 
score over 72 hours, (h) HRQoL by the EuroQoL,54 (i) admission to residential care, and (j) 
health service use for calculation of resources and costs. 
RESULTS AND OUTCOME OF ARM [A] 
In arm [A], the primary outcome occurred in 855 of 1607 participants (53.2%) in the low-dose 
group and in 817 of 1599 participants (51.1%) in the standard-dose group (OR 1.09; 95% CI 
0.95 to 1.25; the upper boundary exceeded the noninferiority margin of 1.14; P = 0.51 for 
noninferiority).  Low-dose rtPA was noninferior in the ordinal analysis of mRS scores 
(unadjusted common OR 1.00; 95% CI 0.89 to 1.13; P = 0.04 for noninferiority). Major sICH 
occurred in 1.0% of the participants in the low-dose group and in 2.1% of the participants in the 
standard-dose group (P = 0.01); fatal events occurred within 7 days in 0.5% and 1.5%, 
respectively (P = 0.01).  Mortality at 90 days did not differ significantly between the two groups 
(8.5% and 10.3%, respectively; P = 0.07).  Conclusion:  In patients with AIS low dose rtPA was 
not shown to be noninferiority of standard-dose rtPA with respect to death and disability at 90 
days.  However, there were significantly fewer sICH and deaths with low-dose rtPA.  
10. DATA COLLECTION AND FOLLOW-UP 
Registration, baseline assessment, and randomisation should be achieved over 30 minutes.  
Doctor/nursing attendance with the randomised patient is likely to be required for 1-2 hours 
post-randomisation to ensure safe and effective thrombolysis, the titration of BP lowering in the 
active group, and consistent BP recordings.  All patients are followed daily for 1 week and then 
at 28 and 90 days unless death occurs earlier.  Investigators will be reimbursed for their time 
involved in data collection and for local expenses (e.g. printing, internet connection, purchase of 
medications, copying of brain imaging (CT scans and/or MRIs).  Data collection will be kept to a 
minimum to ensure rapid enrolment and follow-up of patients within the context of routine 
clinical practice.  Key demographic and clinical data will be collected at randomisation.  Follow-
up data will be collected on 5 occasions: 24 and 72 hours, and 7 (or hospital discharge if 
sooner), 28 and 90 days.  The 28 and 90 day evaluations will be conducted in-person or by 
telephone, by a trained staff member at the local site who is blind to the treatment allocation.  
Original records entered directly into database, e.g. data entered directly into database from 
patient interview or assessment, are acceptable as source data.  Brain imaging (CT scan and/or 

ENCHANTED Protocol version 5.0 16 Feb 2017  
 
28 
MRI, with any associated diffusion/perfusion and angiogram images) will be conducted 
according to standardised techniques at baseline, within 24 hours (ie next day follow-up scan), 
and at a later stage in all surviving patients who may deteriorate or for other clinical reason 
during follow-up.  Brain imaging (CT scan and/or MRI) must be uploaded to the ENCHANTED 
server, either directly from the hospital site (if they have suitable broadband internet) or via the 
RCC office, to be analysed centrally for measurement of any ICH or haemorrhagic 
complications of the ischaemic lesion, and for future measurement of areas of infarction, 
ischaemic, penumbra, sites of vessel occlusion.  The LCC will keep a hard copy in an 
uncompressed DICOM format onto a CD-ROM for monitor site verification.  Trial management 
is facilitated by an established internet-based system.  
All randomised patients will be followed up to 90 days, or death if prior to 90 days.  Patients who 
do not follow the protocol and/or discontinue allocated management should still be followed up 
to 90 days as their data will be analysed on the ‘intention to treat’ principle.  Table 5 illustrates 
the schedule and nature of the data collection required during the study period.  The paper 
version of the case report forms (CRFs) will be supplied with the procedure manual, as a 
reference only, together with a guide to completion of each data element and a definition of 
terms. 
All data entry will be completed on a password protected study website.  This web-based data 
management system will allow for real time data query generation for values entered outside of 
pre-set valid ranges and consistency checking.  This system will speed up data reporting and 
assist overall trial management for all participating centres.  In addition to the web-based data 
entry, BP and drug usage will also be recorded on a paper CRF at the patient’s bedside as part 
of the patient’s usual medical record management. 
10.1 Screening logs 
Each LCC should keep log of all patients presenting to their institution with a diagnosis of acute 
ischaemic stroke and who were considered for the study but subsequently excluded.  The 
screening log will record patients’ initials and date of admission together with a brief description 
of the main reason as to why a patient was not randomised.  The log will be used by the 
Research Coordinator, PI and the ICC to monitor recruitment and to identify specific barriers to 
randomisation of eligible patients.  It is also a requirement for the reporting of results of clinical 
trials. 
10.2 Patient Contact Details log  
Each centre will keep a record of the contact details and information of next-of-kin for all 
randomised patients.  This will be kept at the participating centre in a locked filing cabinet and in 
accordance with local policies on the custody of confidential clinical trial data.  The Patient 
Contact Details Log will also be used to document any issues arising from the consent 
procedure, attempts at follow up and information on protocol violations.  The Patient Contact 
Details Log will be used by the Research Coordinator and PI in managing the consent process, 
follow-up schedule, and in responding to queries from the ICC. 
10.3 Randomisation assessment  
All patients admitted with AIS will be assessed by the responsible physician for eligibility to the 
study using a checklist of the eligibility criteria described previously.  This form will be kept at the 
participating site in a locked filling cabinet with the study patient’s file.  
10.4 Baseline Data 
The following information is to be collected on admission: 

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  Medical history 
  Medications at time of admission 
  BP, Heart rate (HR), Body weight and scores on the GCS and NIHSS 
  Brain imaging findings to confirm the diagnosis of AIS 
  Management with neurointervention if performed 
  Baseline blood tests 
    rtPA details 
    Pattern of neurological deficits 
All baseline and follow-up brain imaging (CT scans and/or MRI) is to be copied in an 
uncompressed DICOM format onto a CD-ROM to be uploaded to the ENCHANTED server, 
either direct from the site or via the RCC.  The CD-ROM copy must be kept in the site for 
monitoring visit (see Appendix 2). 
10.5 Follow up Data 
Day 1 (from randomisation) 
The primary goal of assessments within the first 24 hours will be to ensure adherence to the 
allocated ‘rtPA dose’ and/or ‘BP management’ protocol.  BP and administered medication will be 
recorded.  BP will be recorded supine in the non-paretic arm from the automated, electronic 
device used at the Clinical Centre.  After the commencement of rtPA, BP will be recorded every 
15 minutes for the first hour, then hourly from 1 hour to 6 hours, and 6 hourly from 6 hours to 24 
hours.  After the commencement of BP lowering treatment, BP will be recorded every 15 
minutes for the first hour.  When intravenous boluses are given, HR and BP should be re-
checked and recorded 5 and 15 minutes later.  In addition, the number of systolic BP excursions 
<140 mmHg, and minimum and maximum systolic BP levels in the first 24 hours, will be 
recorded.  The following information will be recorded. 
 
BP 
 
BP lowering medication 
 
GCS and NIHSS scores at 24 hours 
 
Follow up brain imaging (CT brain or MRI) should be undertaken within 24 hours after 
baseline brain imaging and results recorded 
 
If other imaging investigations are performed (i.e. transcranial doppler), these should be 
documented in the CRFs 
 
Follow up blood tests 
 
Standard stroke care assessment 
Day 3 
At day 3, the goal will continue to ensure adherence to the allocated BP management protocol.  
BP levels will be recorded twice a day after the first 24 hours.  The following information will be 
recorded: 
 BP 
 GCS and NIHSS scores 
 Standard stroke care assessment 
Day 7 
On day 7 or on the day of hospital discharge/transfer or death if prior to day 7, the contact 
details of the patient or caregiver should be confirmed to facilitate follow up assessments.  The 
following information will be recorded: 

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30 
 BP 
 BP lowering medication (medications used during day 2 to day 7) 
 Disability assessed with the mRS 
 Standard stroke care assessment 
 Date of discharge from hospital if this should have occurred at this time 
Day 28 and Day 90 
These assessments are to be undertaken by an investigator who was not involved in the clinical 
management of the patient, and blind to the randomised treatment allocation.  On 28±3 days 
and 90±7 days, all surviving patients will be evaluated through a telephone interview or at a 
face-to-face consultation.  Use of BP lowering agents will be recorded (see Appendices 1A to 
1C).  In addition to the mRS, HRQoL (using the EQ 5D) will be assessed. 
Death  
Patients who have died prior to any of the above scheduled assessments, cause of death 
documentation will be collected with date and time of death.  Copies of post-mortem reports, 
hospital record entry or death certificate, should be kept with the Patient Contact Details log to 
assist in trial monitoring by the ICC. 
Withdrawal of allocated management and protocol violations  
A form will be provided to record the date and circumstances surrounding any deviation from the 
protocol or missed assessments. 
Consent 
Consent will be documented in the patient’s progress notes and CRF and the type(s) of consent 
obtained will also be recorded on the database. 
Serious Adverse Events (SAEs) 
All SAEs will be recorded on the SAE form, and completed on the electronic CRF or 
faxed/emailed from a printed form to the ICC within the prescribed time.  Additional information 
may be requested to provide supplementary information on the event and outcome. 
 
Table 5 Schedule of evaluations  
 
Prior to 
Randomisation 
Day 
Evaluation 
 
1/2 
3a 
7a  
28b 
90b  
Eligibility 
X 
 
 
 
 
 
Brain imaging (CT or MRI ± angiogram) 
X 
X 
 
 
 
 
BP  
X 
BP x 2 
      X ** 
For time points 
see the footer 
X 
12 
hourly 
X 
12 
hourly 
 
 
Heart rate 
X 
 
 
 
 
 
Consent (a) 
X 
 
 
 
 
 

ENCHANTED Protocol version 5.0 16 Feb 2017  
 
31 
 
Prior to 
Randomisation 
Day 
Evaluation 
 
1/2 
3a 
7a  
28b 
90b  
Clinical history prior medications 
X 
 
 
 
 
 
Body weight (kg) 
X 
 
 
X 
 
 
Physical exam GCS/NIHSS 
X 
X 
X 
 
 
 
Functional assessment with mRS  
 
 
 
X 
X 
X 
HRQoL assessment with EQ 5D 
 
 
 
 
X 
X 
Routine blood tests 
X 
X 
 
 
 
 
BP lowering treatment 
 
X 
X 
X 
X 
X 
Standard stroke care  
 
X 
X 
X 
 
 
Hospitalised or not 
 
 
 
X 
X 
X 
Contact details for Follow-up 
 
X 
 
X 
 
 
**  
Q 15 min for 1 hour after initiation of rtPA 
Q 15 min for 1 hour after initiation of BP lowering 
Hourly from 1 hour to 6 hour after initiation of rtPA 
6 hourly from 6 hour to 24 hour after initiation of rtPA 
At any point where intravenous bolus drugs are administered, BP and HR should be recorded 5 and 15 minutes later.  
(a) Or the day of discharge if prior to day 7,  
(b) Information collected at a face to face consultation or through a telephone interview 
 
 
 
 
 
11. SERIOUS ADVERSE EVENTS (SAEs) 
11.1 Definitions 
The mechanisms for reporting and notifying SAE are based on the guidelines of the 
International Conference on Harmonisation Good Clinical Practice (ICH-GCP).  As defined by 
the WHO International Drug Monitoring Centre (1994): 
A SAE is any untoward medical occurrence that: 
 
results in death 
 
is life threatening in the opinion of the attending clinician (ie the patient was at risk of 
death at the time of the event; it does not refer to an event that might hypothetically have 
caused death had it been more severe) 
 
requires inpatient hospitalisation or prolongation of existing hospitalisation 
 
results in persistent or significant disability or incapacity 

ENCHANTED Protocol version 5.0 16 Feb 2017  
 
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 
results in congenital anomaly or birth defect (Note that the females in the study 
population are likely to be post-menopausal) 
 
is an important medical event in the opinion of the attending clinician that is not 
immediately life-threatening and does not result in death or hospitalisation but which may 
jeopardise the patient or may require intervention to prevent one of the other outcomes 
listed above 
 
An unexpected adverse reaction (UAR) is an adverse reaction that is not consistent with 
the product information  
 
A suspected unexpected serious adverse reaction (SUSAR) is any UAR that at any 
dose: 
• 
results in death;  
• 
is life threatening (i.e. the subject was at risk of death at the time of the event; it does not 
refer to an event which hypothetically might have caused death if it were more severe);  
• 
requires hospitalisation or prolongation of existing hospitalisation;  
• 
results in persistent or significant disability or incapacity;  
• 
is a congenital anomaly or birth defect.  
 
11.2 Recording and Reporting 
An SAE form must be used to record the details of the event and this will include a full 
description of the event, classification of the event using the above definitions, the PI’s opinion 
on the causal relationship to the randomised management group and the timing of the event.  
All SAEs should be reported to the ICC within 24 hours or as soon as the event is recognised.  
The PI will be required to submit a follow up report to provide further information so that the 
outcome of the SAE can also be recorded.  The PI is responsible for reporting the SAE to the 
IRB according to local guidelines. 
A SUSAR form must be used to record the details of the event and this will include a full 
description of the event, classification of the event using the above definitions, the PI’s opinion 
on the causal relationship to the suspected medicinal product, and the details of the suspected 
medicinal product.  All SUSARs should be reported to the ICC within 24 hours or as soon as the 
event is recognised.  The PI may be required to provide further details to supplement the initial 
SAE report and the outcome of the SUSAR will also need to be recorded.  The PI is responsible 
for reporting the SUSAR to the IRB or regulatory administration according to local guidelines 
and regulatory requirements. 
For China sites, apart from the above, all SAEs in relation to use of urapidil (Ebrantil) must also 
be reported in English by facsimile to Takeda Pharmacovigilance or designee: (i) Fatal and Life 
Threatening SAEs within 24 hours of the sponsor-investigator’s observation or awareness of the 
event; and (ii) All other serious (non-fatal/non-life threatening) events within 4 calendar days of 
the sponsor-investigator’s observation or awareness of the event. 
 

ENCHANTED Protocol version 5.0 16 Feb 2017  
 
33 
11.3 Monitoring of SAEs 
The ICC will closely monitor all SAEs for any relationship to the study procedures and protocol 
and clustering of events at a particular site.  The protocol will be amended or the study will be 
stopped earlier if an excess of particular SAEs appear to be protocol related, for example 
severe hypotensive events requiring emergency treatment in the intensive BP lowering group.  
In addition, the ICC will submit all SAEs to the independent Data Safety Monitoring Board 
(DSMB) for review outside of the planned interim analysis meetings. 
11.4 Monitoring of SUSARs 
The ICC will closely monitor all SUSARs for any relationship to the study procedures and 
Protocol or clustering of events at a particular LCC.  The ICC will submit all SUSARs to the 
independent DSMB for review outside of the planned interim analysis meetings.  The ICC will 
also report all SUSARs to the MHRA and in addition will report to local regulatory authorities 
according to local requirements and guidelines. 
12. QUALITY ASSURANCE 
The study will be conducted at sites experienced in rtPA through established acute stroke unit 
thrombolysis programs.  Regionally-based clinical research monitors will perform online and on-
site data verification; and monitor conduct of the study, initially after the first few patients are 
randomised at a site and then at least once annually, according to patient recruitment numbers, 
whilst participating in the trial.  As ENCHANTED is an open trial of differing management 
strategies in a critical illness, monitoring serves to confirm that investigators are adhering to the 
protocol and Good Clinical Practice (GCP) Guidelines, and the accuracy of the data.  To ensure 
adherence to the study protocol, trained staff will undertake monitoring visits to confirm: (i) 
demographic and consent details of randomised patients; (ii) details of all SAEs against source 
documents; (iii) collect/correct outstanding/missing data; and (iv) check selected variables 
against source medical documents in a 10% random selection of patients.  
12.1 Monitoring of Participating Centres 
Prior to the initiation of the study at any participating centre, all designated research staff 
including the PI, Co-Investigator(s) and Research Nurse(s) will attend a training meeting on the 
study procedures.  A study monitor, appointed by the ICC, will visit each participating centre to 
confirm there are adequate facilities and medical resources to conduct the study. In addition, all 
Investigators will be provided with materials detailing all study procedures.  Before initiating the 
study, the PI and any Co-Investigators will provide up-to-date curriculum vitae (CV) in English to 
the ICC. The CVs of other designated research staff at the participating centre will be collected 
during the course of the study. 
During the study, representatives of the ICC will visit all participating centres a minimum of twice 
in the recruitment phase of the study.  The purpose of these visits will be to ensure that the 
study is conducted according to the protocol, ICH-GCP guidelines and meets relevant regional 
regulatory requirements.  The monitor will verify relevant source documents according to a 
detailed monitoring plan available as a separate document. 
At completion of the study, the monitor will ensure that there are plans in place for the long-term 
storage of all the relevant data and source documentation (for 15 years). 
12.2 Auditing and Inspection by Government Regulatory Authorities 
In addition, the study may also be audited by the third party and inspected by inspectors 
appointed by government regulatory authorities.  CRFs, source documents and other study files 

ENCHANTED Protocol version 5.0 16 Feb 2017  
 
34 
must be accessible at all study sites at the time of auditing and inspection during the course of 
the study and after the completion of the study. 
13. DATA MANAGEMENT  
Randomisation and data entry will be performed at the participating centres via the password 
protected, internet based data management system (some centres may use a 24 hour 
telephone system for randomisation).  This system, developed at the ICC includes reporting and 
data query management.  Paper CRFs will be provided to centres, which prefer to use them for 
the initial data collection.  All computerised forms will be electronically signed (via a unique 
password) by the authorised study staff and all changes made following the electronic signing 
will have an electronic audit trail with a signature and date.  Centralised coding of outcomes will 
be performed by a trained medical coder. 
14. STANDARDISATION OF OUTCOME ASSESSMENT 
A Medical Review Committee (MRC) will review  SAEs reported, brain imaging scans uploaded, 
and medical queries raised, in order to ensure that selected variables  meet the same medical 
criteria.  The MRC comprises experts in cerebrovascular disease.  The brain imaging scans are 
analysed by Imaging Adjudication Committee (IAC) for any ICH.  The adjudication of every scan 
is made without knowledge of which randomised group the patient was allocated.  The IAC 
comprises expert clinical scientists.  The members of the MRC and IAC are provided with 
explicit instructions and manuals detailing the criteria to be followed. 
15. STATISTICAL CONSIDERATIONS  
15.1 Sample size  
Arm [A] comparison of low- versus standard-dose rtPA  Based on pooled trials data in the 
Cochrane review of thrombolysis in AIS, the rate of death or disability (mRS score of 2-6) in 
patients who receive standard-dose i.v. rtPA is 50%.7  Non-randomised studies suggest that 
low-dose rtPA provides similar clinical outcomes to the standard-dose rtPA (i.e. risk ratio 1.0).22-
24  For comparison between low- and standard-dose rtPA, a non-inferiority margin is based on 
the pooled Cochrane review of thrombolysis in AIS,7 where the overall risk ratio of standard-
dose rtPA versus control (placebo) with respect to death or disability was 0.76 (95%CI 0.66-
0.87).  Taking a conservative approach, as used in the Ongoing Telmisartan Alone and in 
Combination with Ramipril Global Endpoint Trial (ONTARGET),55 the 40th percentile point 
around the risk reduction estimate (0.77) rather than the observed risk ratio has been chosen as 
a more robust reference to describe the effects of standard-dose rtPA, which can be translated 
into a margin of excess risk of placebo versus standard-dose rtPA of 1.29.  As recommended by 
the United States Food and Drug Administration (FDA), the clinical margin representing the 
largest acceptable inferiority of the test to control is set at 50% (i.e. risk ratio 1.14) of the margin 
of the excess risk of 1.29.  Thus, a relative non-inferiority margin of 14% (i.e. risk ratio 1.14) 
provides assurance that low-dose rtPA retains at least half of the effects of standard-dose rtPA, 
provided the upper limit of the 95% CI of low- versus standard-dose rtPA is less than this non-
inferiority margin.  However, as there is potential for a negative interaction between intensive BP 
lowering and low-dose rtPA, the primary event rates will be 46.25% in patients who receive 
standard-dose rtPA and 46.75% in those who receive low-dose rtPA (Table 6), such that the 
absolute non-inferiority margin rate will be 6.5% (relative non-inferiority margin of 14% x the 
primary event rate in standard-dose rtPA group of 46.75%).  A sample size of 3300 (1650 per 
group) provided >90% power (1-sided α =0.025) to achieve the non-inferiority setting (assuming 

ENCHANTED Protocol version 5.0 16 Feb 2017  
 
35 
a 5% drop-out) with the ability also to make an assessment of the superiority of low- versus 
standard-dose rtPA.  Arm [A] recruitment completed with 3310 patients in August 2015.  
Table 6 Primary outcome event rates taking account of any interaction between treatment arms 
  
Standard-dose rtPA 
Low-dose rtPA 
AVERAGE 
 Guideline-based BP lowering 
50.00% 
50.00% 
50.00% 
 Intensive BP lowering 
42.50% 
43.50% 
43.00% 
 AVERAGE 
46.25% 
46.75% 
 
Arm [B] comparison of early intensive versus guideline-based BP lowering  The SITS-ISTR 
registry44 indicates a ≥15 mmHg systolic BP difference between randomised groups (i.e. 140-
150 mmHg vs 180 mmHg systolic targets) is likely to be associated with ≥15% reduction in the 
outcome of death or disability in patients who receive standard-dose rtPA.  However, assuming 
a potential interaction between low-dose rtPA and intensive BP lowering, a more conservative 
13% reduction in outcome is expected in patients who receive low-dose rtPA in combination 
with intensive BP lowering.  Assuming event rates of 50% in guideline-based BP lowering group 
and 43% in the intensive BP lowering group (Table 6), a sample size of 2100 (1050 per group) 
will provide >80% power (2-sided α = 0.1) to detect 14% relative reductions in the primary 
outcome in the intensive BP lowering group, with 5% drop-out. 
Table 7 Event rates for sICH taking account of potential interaction between 2 treatment arms  
 
 
Standard-dose rtPA 
Low-dose rtPA AVERAGE 
 
Guideline-based BP lowering  
7.00% 
4.20% 
5.60% 
 
Intensive BP lowering 
4.20% 
2.69% 
3.44% 
 
AVERAGE 
5.60% 
3.44% 
 
 
Table 8 Event rates for any ICH taking account of potential interaction between 2 treatment arms  
 
 
Standard-dose rtPA 
Low-dose rtPA AVERAGE 
 
Guideline-based BP lowering  
23.00% 
17.00% 
20.00% 
 
Intensive BP lowering 
13.80% 
10.90% 
12.30% 
 
AVERAGE 
18.40% 
14.00% 
 
Assessment of the secondary outcomes of sICH  In the Cochrane review, the overall risk of 
sICH following standard-dose rtPA was 7%,7 while registry studies have reported rates of 4-10% 
depending on definitions and other factors.44,45  Observational studies of Japanese patients who 
have received low-dose i.v. rtPA suggest lower risks of sICH (3-4%, risk reduction >40%).22-24  
Based on the SITS-ISTR registry,44 an expected 15 mmHg difference between randomised 
groups of BP lowering is likely to be associated with ≥40% reduction in sICH in those who 
receive standard-dose rtPA.  Assuming a potential interaction between low-dose rtPA and 
intensive BP lowering, a more conservative 36% reduction is expected in patients who receive 
low-dose rtPA.  Event rates are estimated to be 5.6% in patients who receive standard-dose 
rtPA and 3.44% in those who receive low-dose rtPA (Table 7).  The sample size of 3300 (1650 
patients in each group) provided >80% power (2-sided α =0.05) to detect >40% relative 
reductions in sICH for the low-dose rtPA group with 5% of drop-out.   
In the Cochrane review, the overall risk of any ICH following standard-dose rtPA was 23%.7  
Observational studies of Japanese patients who have received low-dose i.v. rtPA suggest lower 
risks of any ICH (17%, risk reduction 23%).22-24  Based on the SITS-ISTR registry,44 an expected 
15 mmHg difference between randomised groups of BP lowering is likely to be associated with 
≥40% reduction in any ICH in those who receive standard-dose rtPA.  Assuming a potential 
interaction between low-dose rtPA and intensive BP lowering, a more conservative 36% 

ENCHANTED Protocol version 5.0 16 Feb 2017  
 
36 
reduction is expected in patients who receive low-dose rtPA.  With an average of 20% rate of 
any ICH among patients who receive guideline-based BP lowering and 12.30% among those 
with intensive BP lowering (Table 8), the study will provide >90% power (2-sided α =0.05) to 
detect reductions in any ICH from intensive BP lowering, with 5% of drop out.   
In summary, a sample size of 3300 (1650 per group) for arm [A] (i.e. rtPA dose) provided >90% 
power to detect (i) non-inferiority (relative margin 14% [i.e. relative risk 1.14], absolute margin 
rate 6.5%) of low-dose rtPA on the primary outcome (one-sided α = 0.025), and (ii) ≥80% power 
to detect plausible 40% reductions in risks of sICH with low-dose rtPA, with 5% drop-out. Arm 
[A] recruitment completed with 3310 patients in August 2015.  A sample size of 2100 (1050 per 
group) for arm [B] (i.e. BP lowering intensities) will provide ≥80% power to detect superiority of 
intensive BP lowering and any ICH (2-sided α =0.10) with 5% drop-out.  Given overlap of 939 
patients in the combined arms [A] and [B], an expected total of 4500 patients will participate in 
the study. 
15.2 Statistical Analyses 
In arm [B], the intention to treat principle will be applied in analyses. Baseline characteristics will 
be summarised by treatment group.  For patients ‘lost to final follow-up’, data collected from 
randomisation to the time of last contact will be included in analyses.  The primary end-point of 
functional recovery will be based upon a comparison of ordinal shift in scores on the mRS for 
superiority using ordinal logistic regression.  The categorical secondary outcomes will be 
analysed by means of a chi-square test.  Continuous endpoints will be summarised by means or 
medians, with the treatment effects tested by a Wilcoxon test that assumes skewed data.  
HRQoL EQ5D scores will be combined to provide an overall health utility score that will be 
calculated with population norms from the United Kingdom.  The primary analysis will be 
unadjusted.  Safety data will be tabulated using MedDRA terminology.  Heterogeneity of 
treatment on the primary endpoint will be assessed in subgroups: age (<65 vs ≥65 years), sex 
(male vs female), ethnicity (Asian vs Non-Asian), time to randomisation (<3 vs ≥3 hours), 
baseline systolic BP (above vs below median), NIHSS at baseline (above vs below median), 
final diagnosis of ischaemic stroke subtype, cerebral Infarction on CT scan, antiplatelet agent 
used, and evidence of atrial fibrillation.  Analyses will be specified in detail in a full Statistical 
Analysis Plan.  There are interim efficacy analyses planned after approximately 33% and 66% 
of the patients have been followed up at 90 days.  The external DSMB will employ the Haybittle-
Peto rule of an α <0.001 for any interim analyses finding in favour of a treatment to be 
considered significant.  The DSMB will regularly monitor SAEs (i.e. deaths, sICH, and 
neurological deterioration), for which any excess would trigger discussions over stopping for 
harm.  The α-level for the final analysis will be the conventional significance level (α = 0.10) 
given the infrequent interim analyses, their extremely low α levels, and the requirement for 
confirmation in subsequent analyses.  
16. PUBLICATIONS AND REPORTS 
Publication of the main reports from the study will be in the name of the Enhanced Control of 
Hypertension and Thrombolysis Stroke Trial (ENCHANTED) Investigators.  Full editorial control 
will reside with a Writing Committee approved by the SC. 
Investigators have the right to publish or present the results of the study.  However, as this is a 
multi-site academic study, investigators agree not to publish or publicly present any interim 
results of the study without the prior written consent of the SC.  Investigators further agree to 
provide the SC at least 30 days prior to submission for publication or presentation, review of 
copies of abstracts or manuscripts (including without limitation, text and PowerPoint 

ENCHANTED Protocol version 5.0 16 Feb 2017  
 
37 
presentation slides and any other texts of transmissions or media presentations) that report any 
results of the study.  
The SC shall have the right to review and comment with respect to publications, abstracts, 
slides, and manuscripts.  The SC also have the right to review and comment on the data 
analysis and presentation with regard to the accuracy of the information, the protection of the 
rights of individuals, and to ensure that the presentation is fairly balanced and in compliance 
with appropriate regulations. 
If the parties disagree concerning the appropriateness of the data analysis and presentation, 
and/or confidentiality, the particular investigator(s) will agree to meet with members of the SC at 
the clinical site or as otherwise agreed, prior to submission for publication, for the purpose of 
making good faith efforts to discuss and resolve any disagreements. 
Writing Committees will be formed from members of the various committees, statisticians, 
research fellows and investigators.  They will prepare the main reports of the study to be 
published in the name of “ENCHANTED Investigators” with credit assigned to the collaborating 
investigators and other research staff.  Presentations of the study findings will be made at 
national and international meetings concerned with the management of stroke, cardiovascular 
disease, and hypertension.  
Authors of publications must meet the International Committee of Medical Journal Editors 
(ICMJE) guidelines for authorship that follow: 
1 
Authors must make substantial contributions to the conception and design of the trial, 
acquisition of data, or analysis of data and interpretation of results; 
2 
Authors must draft the publication or, during draft review, provide contributions (data 
analysis, interpretation, or other important intellectual content) leading to significant 
revision of the manuscript with agreement by the other authors; 
3 
Authors must provide approval of the final draft version of the manuscript before it is 
submitted to the journal for publication. 
All contributors who do not meet the 3 criteria for authorship should be listed in an 
acknowledgments section within the publication, if allowed by the journal, per ICMJE guidelines 
for acknowledgement. 
17. ORGANISATION 
ENCHANTED is an academic initiated and conducted study to be managed by an ICC based at 
the George Institute for Global Health, University of Sydney, Australia.  The study is overseen 
by an International Steering Committee comprised of world experts in the fields of stroke, 
hypertension, neurology, geriatrics, cardiovascular epidemiology and clinical trials.  The ICC 
communicates with regional committees and approximately 100+ participating hospitals in 
Australia/New Zealand, Asia, Europe and South America.  Sites will be administratively tied 
through a structure designed to enhance effective communication and collaboration as well as 
monitor and maintain operations through adherence to a common protocol.  Central 
coordination is from The George Institute, Sydney; RCCs are located in Beijing, Ludhiana, Ho 
Chi Minh City, Leicester, Porto Alegre, and Santiago.  The inclusion of focussed substudies, 
using CT/MRI diffusion perfusion and angiography, and TCD, for which separate funding will be 
sought, will advance the understanding of pathophysiological mechanisms of acute ischaemic 
stroke, the interpretation of the results of ENCHANTED, and inform clinical care and future 
studies. 

ENCHANTED Protocol version 5.0 16 Feb 2017  
 
38 
17.1 Steering Committee (SC) 
Responsibilities: Overall responsibility for the execution of the study design, protocol, data 
collection and analysis plan, as well as publications.  The SC has the right to appoint new 
members and co-opt others to add to the integrity of the conduct of the study and analyses. 
Provisional list of SC is given below: 
Professor Craig Anderson (Principal Investigator), The George Institute, University of Sydney, 
Australia 
Professor John Chalmers (Chair), The George Institute, University of Sydney, Australia 
Professor Richard Lindley, The George institute, University of Sydney, Australia 
Professor Hisatomi Arima, Department of Preventive Medicine and Public Health, Faculty of 
Medicine, Fukuoka University, Fukuoka, Japan 
Professor Jiguang Wang, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 
Shanghai, China 
A/Prof Mark Parsons, John Hunter Hospital, Newcastle Neurosciences Institute, Australia 
A/Prof Christopher Levi, John Hunter Hospital, Newcastle Neurosciences Institute, Australia 
Professor Yining Huang, Peking University First Hospital, Peking 
A/Professor Vijay K Sharma, National University Hospital, Singapore 
Dr Nguyen Huy Thang, 115 The People Hospital, Ho Chi Minh City, Vietnam 
Professor Jeyaraj D Pandian, Christian Medical College, Ludhiana, Punjab, India 
Professor Jong Sung Kim, Asan University Hospital, Seoul, South Korea 
Professor Christian Stapf, Neurologie Vasculaire, Hôpital Notre-Dame - Pavillon Deschamps 
and Université de Montréal Chercheur Régulier, Montreal, Canada 
Professor Pablo Lavados, Clinica Alemana de Santiago, Universidad del Desarrollo and 
Universidad de Chile-Instituto de Neurocirugia, Santiago, Chile 
Professor Tom Robinson, University of Leicester, United Kingdom 
Professor Tsong-Hai Lee, Neurology Department, Linkou Chang Gung Memorial Hospital, 
Taoyuan, Taiwan 
Professor Sheila Martins, Brazilian Stroke Network and Hospital de Clínicas de Porto Alegre, 
Brazil 
Professor Octavio Pontes-Neto, Neurology Department, Ribeirão Preto School of Medicine, 
Brazil 
Dr Shoichiro Sato, National Cerebral and Cardiovascular Center, Osaka, Japan 
Professor Joanna Wardlaw, Centre for Clinical Brain Science, University of Edinburgh, 
Edinburgh, UK 
 
17.2 International Coordinating Centre (ICC) 
The ICC is at The George Institute for Global Health (GI), University of Sydney 
Responsibilities: Day to day management of the study, data and project management, 
committee coordination, assistance with ethics committee applications, protocol and procedures 
training for participating centres, initiation visits to participating centres, monitoring of data 
quality and adherence to applicable guidelines and regulations, preparation of study data for 
analysis and publication. 

ENCHANTED Protocol version 5.0 16 Feb 2017  
 
39 
17.3 Regional Coordinating Centres (RCC) 
Responsibilities: Provide advice to the ICC on regional issues relevant to the set up and 
management of the study. In conjunction with the ICC, provide assistance and support and 
monitor study progress at regional participating centres, including data quality and adherence to 
the study protocol.   
17.4 Imaging Adjudication Committee (Core Lab/Brain Imaging Analysis) 
Responsibilities: To measure haemorrhagic complications (haematoma volume) and 
ischaemic/infarction on all de-identified and blinded brain imaging scans (blinded by allocation 
group and timing of scan). 
17.5 Medical Review Committee 
Responsibilities: To review SAEs reported, brain imaging scans uploaded and medical queries 
raised, in order to ensure that selected variables meet the same medical criteria.   
17.6 Data Safety Monitoring Board (DSMB) 
Responsibilities: Monitor blinded response variables and serious adverse events for early 
dramatic benefits or potential harmful effects using the approach developed by Sir Richard Peto 
for safety monitoring and provide reports to the ICC on recommendations to continue or 
temporarily halt recruitment to the study.   
Members of the DSMB include:  
Professor John Simes (Chair), University of Sydney, Sydney, (NSW) Australia;  
Professor Peter Sandercock, University of Edinburgh, Edinburgh, Scotland;  
Professor Graeme Hankey, Royal Perth Hospital, Perth, (WA) Australia;  
Professor Marie-Germaine Bousser, Hôpital Lariboisière, Paris, France;  
Professor KS Lawrence Wong, Prince of Wales Hospital, Chinese University of Hong Kong, 
Hong Kong. 
A DSMB will review unblinded data from the study at regular intervals during follow-up, and will 
monitor BP separation (between the two groups), drop-out and event rates. Two interim efficacy 
analyses are planned after 30% and 60% of the patients have been followed up at 90 days.  
Prior to the first interim analysis a detailed Statistics Analysis Plan (SAP) will be completed and 
placed in the file.  The SAP will contain a more comprehensive explanation than described 
herein of the methodology used in the statistical analyses, and in particular will specify the 
stopping rule used.  The SAP will also contain the rules and data handling conventions used to 
perform the analyses, and the procedure used for accounting for missing data.  
17.7 Participating Centres 
Neurology Wards / Neuroscience Departments / Acute Stroke Units 
Responsibilities: Overall management of study at own hospital in line with the study protocol; 
study nurse recruitment and orientation; protocol education of colleagues, patient recruitment, 
data collection and data transfer to the ICC, data query resolutions, liaison with local Hospital 
Research Ethics Committee/Institutional Review Board, adherence to local ethics guidelines 
and reporting requirements, adverse event reporting to local Hospital Research Ethics 
Committee/Institutional Review Board and to the ICC in accordance with protocol. 
18. FUNDING 
ENCHANTED is supported by two Project Grants from the NHMRC of Australia for the period 
2012 to 2018.  In addition, the Stroke Association of the United Kingdom provides two grants to 
support the study coordination in the United Kingdom for 5 years from 2012 to 2018; the 

ENCHANTED Protocol version 5.0 16 Feb 2017  
 
40 
National Council for Scientific and Technological Development of Brazil supports the study in 
Brazil; the Ministry for Health, Welfare and Family Affairs of the Republic of Korea provided 
funding to support some coordination costs in Korea for Arm A of the study until 2015; Takeda 
China provides project grant support for the study only in China for the period 2016 to 2019. The 
funding allows for some monies to be provided to selected sites to subsidise the cost of rtPA 
used in participating patients in those sites with fee-for-service health care.  The funders of the 
study have no role in the study design, the collection, analysis or interpretation of the data, or in 
writing of reports. 
19. TIMELINES 
Over 100 sites have expressed interest in participating, most in Asia (60 sites) Australia/New 
Zealand (12), Europe (60), and South America (30).  The required total sample of 4800 patients 
([50%] from Asia) being achieved over 6 years, with each site recruiting an average of 6 patients 
per year, appears realistic given that these sites treat 20-60 patients with rtPA for AIS annually.  
With extra time for developing the database and systems, employment and training of staff, 
ethics committee and regulatory approvals across multiple sites/countries (~12-24 months), and 
for 3-month follow-up and close-out periods, respectively, the total duration of the study was 
originally estimated at 5 years.  However, recruitment was faster for the rtPA dose arm 
compared to the BP intensity arm of the study: the former completing recruitment of 3300+ 
patients whilst the latter recruited 1000+ patients, in August 2015.  Recruitment in the BP 
intensity arm of the study, therefore, continues for the period 2016 to 2018, with presentation of 
the results planned for mid-2019. 
 
2011 
2012 
2013 
2014 
2015 
2016 
2017 
2018 
2019 
Start-up phase (n=200) 
 
 
 
 
 
 
 
 
 
Expansion phase (n=1100) 
 
 
 
 
 
 
 
 
 
Main phase (n=3200) 
 
 
 
 
 
 
 
 
 
Close-out phase and analyses 
of rtPA dose arm 
 
 
 
 
 
 
 
 
 
Main results of rtPA dose arm 
presentation 
 
 
 
 
 
X 
 
 
 
Ongoing recruitment into BP 
intensity arm 
 
 
 
 
 
 
 
 
 
Close-out phase and analyses 
of BP intensity arm 
 
 
 
 
 
 
 
 
 
Main results of BP intensity arm 
presentation 
 
 
 
 
 
 
 
 
X 
 
20. OUTCOMES AND SIGNIFICANCE 
Stroke is a major global disease burden, for which the thrombolytic agent rtPA is the only 
proven medical treatment for AIS, yet used in only a minority of cases due to problems of 
access from low awareness of stroke symptoms, poor transport, limited expert care and 
diagnostic facilities, and the high cost of treatment in many parts of the world.  As most strokes 
occur in the developing countries, only treatments that are low cost and widely applicable will 
have significant public health impact.  Arm [A] of the study has shown that low-dose rtPA was 
not non-inferior to standard-dose rtPA according to the primary endpoint defined by the 
conventional binary cut-point analysis of the mRS; however, it was non-inferior according to the 
modern shift analysis of the full range of categories of the mRS.  Moreover, low-dose rtPA 

ENCHANTED Protocol version 5.0 16 Feb 2017  
 
41 
produced significantly fewer sICH and early deaths.  Since low-dose rtPA and early intensive 
BP lowering both fulfil this requirement, ENCHANTED could have a major impact in reducing 
the burden of stroke by providing evidence that could underpin access to cheaper, safer and 
effective treatments, used either alone and in combination, in the management of this condition.  
As a large sample size is required to establish effects on clinical meaningful outcomes, the 
research cannot be undertaken just within Australia; international collaboration is required to 
provide the first reliable evidence regarding the balance of benefits and risks of different doses 
of rtPA and intensities of BP lowering in acute ischaemic stroke.  Given their applicability to 
millions of people with acute ischaemic stroke worldwide each year, the results will be 
published in prominent medical journals, presented at national and international meetings, 
incorporated into national clinical guidelines, and widely published in the media to further 
facilitate the rapid transfer into clinical practice. 

ENCHANTED Protocol version 5.0 16 Feb 2017  
 
42 
REFERENCES 
 
1. 
Sandercock P, Lindley R, Wardlaw J, Dennis M, Lewis S, Venables G, et al. Third international 
stroke trial (IST-3) of thrombolysis for acute ischaemic stroke. Trials. 2008;9:37. 
2. 
Anderson CS, Heeley E, Huang Y, et al.  Rapid blood pressure lowering in acute intracerebral 
haemorrhage.  New Engl J Med 2013;368:2355-65. 
3. 
Strong K, Mathers C, Bonita R. Preventing stroke: saving lives around the world. Lancet Neurol. 
2007 Feb;6(2):182-7. 
4. 
Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological 
Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med. 1995 Dec 14;333(24):1581-7. 
5. 
Goyal M, Menon BK, van Zwam WH, et al. Endovascular thrombectomy after large-vessel 
ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Lancet 
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Appendix 1A - BP management protocol WITHOUT Labetalol 
Early intensive 
BP lowering group 
TREATMENT PROTOCOL 
INITIAL therapy 
BP Target 
SBP 130-140 mmHg reached within 60 minutes of Randomisation into the 
BP arm 
Monitoring 
 
Continuous HR monitoring 
 
Record BP/HR q 5 mins during active treatment, then q 15 min for 
first hour, q 30 min for next 5 hours and then hourly to 24 h 
Hydralazine (IV) 
 
Hydralazine test dose: 5 mg IV bolus over 1 minute 
 
If SBP >140 mmHg, repeat 5 mg IV bolus in 5 minutes 
 
If SBP still > 140mmHg, give 10 mg IV bolus q 5 mins until target 
SBP reached 
 
Increase to 20 mg bolus if required 
 
Maximum hydralazine dose = 240mg 
Metoprolol (IV) 
If BP persistently > 140 mmHg: 
 
ADD Metoprolol 5 mg IV bolus over 3-5 minutes, repeat 5mg bolus 
in 5 minutes x 2 if necessary but do NOT give if HR<55bpm 
Glyceryl Trinitrate (topical) 
If BP persistently > 140 mmHg: 
ADD topical glyceryl trinitrate (paste or patch) at a rate of 5-10 mg/24 hour 
(≈ 200-400 μg/hour).  NB: also known as topical nitroglycerin 
Continuous IV Infusions 
(requires ICU admission) 
If BP persistently > 140 mmHg: 
 
Start infusion of hydralazine - 50-150 g/min 
 
If target still not reached ADD infusion of glyceryl trinitrate 1-100 
g /min 
 
OR start infusion of Nicardipine 5-15 mg/hour 
MAINTENANCE therapy 
BP Target 
Maintenance of SBP 130-140 mmHg  
Monitoring 
Once SBP is under target (confirmed by 4 readings 15 minutes apart):  
 
Record BP/HR q 30 minutes for 5 hours and then q 1 h for 18 h 
IV treatment prn 
If SBP exceeds 140mmHg at any point: 
 
Give Hydralazine 10-20 mg boluses. BP and HR should then be 
recorded 5 and 15 minutes after each bolus 
 
If SBP is <140mmHg, give further Hydralazine 10-20 mg boluses 
(dependent on initial dose) q 6 hours for first 24 hours (total of 3 
doses) 
 
If SBP < 130 mmHg, cease therapy 

ENCHANTED Protocol version 5.0 16 Feb 2017  
 
46 
Oral treatment 
Start treatment by 24 hours (use nasogastric if required) 
 
If not contraindicated and no other drug is specifically indicated, 
start combination therapy of ACEI + diuretics ± previous 
antihypertensives 
 
Note: Monoamine oxidase inhibitors are not recommended with this BP lowering agent and 
phosphodiesterase inhibitors must not be used with GTN. 
 
Key to abbreviations: 
ACEI – Angiotensin converting enzyme inhibitor;  BP – blood pressure;  bpm – beats per minute;  HR – heart rate;  ICU – intensive 
care unit;  q – every;  prn – as required;  g/Kg/min – micrograms per kilogram per minute;  g/min – micrograms per minute.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ENCHANTED Protocol version 5.0 16 Feb 2017  
 
47 
Appendix 1B - BP management protocol for centres WITH labetalol  
 
Early intensive 
BP lowering group 
TREATMENT PROTOCOL 
INITIAL therapy 
BP Target 
SBP 130-140 mmHg reached within 60 minutes of Randomisation into the 
BP arm  
Monitoring 
 
Continuous HR monitoring 
 
Record BP/HR q 5 mins during active treatment, then q 15 min for 
first hour, q 30 min for next 5 hours and then hourly to 24 h 
Labetalol (IV) 
 
Labetalol test dose: 10 mg IV bolus over 1 minute 
 
If SBP > 140 mmHg and HR > 55 bpm, repeat 10 mg bolus in 5 
minutes. 
 
20 mg IV push q 5 mins until target SBP reached (< 140mmHg) or 
HR <55 bpm; increase to 40 mg bolus if required 
 
Maximum labetalol dose: 300 mg / 24 hours 
Hydralazine (IV) 
If BP persistently > 140 mmHg: 
 
ADD Hydralazine with a test dose: 5 mg IV bolus over 1 minute 
 
If SBP > 140 mmHg, repeat 5 mg IV bolus in 5 minutes 
 
If SBP still >140mmHg, give 10 mg IV bolus q 5 mins until target 
SBP reached.  Increase to 20 mg bolus if required 
 
Maximum hydralazine dose = 240mg/24 hours 
Glyceryl Trinitrate (Topical) 
If BP persistently > 140 mmHg: 
 
ADD topical glyceryl trinitrate (paste or patch) at a rate of 5-10 
mg/24hour 
(≈200-400 μg/hour).  NB: also known as topical nitroglycerin 
Continuous IV Infusions 
(requires ICU admission) 
If BP persistently > 140 mmHg: 
 
Labetalol infusion 2-8 mg/min to a maximum of 300 mg/24 hours 
(consider this if response to labetalol boluses is adequate but 
brief) 
 
If target still not reached, ADD infusion of hydralazine 50-150 
g/min OR 
glyceryl trinitrate 1-100 g /min 
 
OR start infusion of Nicardipine 5-15 mg/hour 
MAINTENANCE therapy 
BP Target 
Maintenance of SBP 130-140 mmHg  
Monitoring 
Once SBP is under target (confirmed by 4 readings 15 minutes apart):  
 
Record BP/HR q 30 minutes for 5 hours and then q 1 h for 18 h 
IV treatment prn 
If SBP exceeds 140mmHg at any point: 
 
Give Labetalol (20-40 mg) and/or hydralazine (10-20 mg) boluses. 
BP and HR should then be recorded 5 and 15 minutes later 
 
If SBP is <140mmHg, Labetalol 10-40 mg (dose dependent on 
initial response) should be administered q 6 hours for the first 24 
hours after symptom onset (total of 3 doses) 
 
If SBP < 130 mmHg or HR < 55 bpm, then cease treatment. 

ENCHANTED Protocol version 5.0 16 Feb 2017  
 
48 
 
Maximum labetalol dose: 300 mg/24 hours 
 
Note: labetalol and hydralazine may be used together during 
the maintenance phase 
Oral treatment 
Start treatment by 24 hours (use nasogastric if required). 
 
If not contraindicated and no other drug is specifically indicated, 
start combination therapy of ACEI + diuretics in addition to 
previous anti-hypertensives 
 
Note: Monoamine oxidase inhibitors are not recommended with labetalol. Phosphodiesterase 
inhibitors must not be used with GTN. 
 
Key to abbreviations:  ACEI – Angiotensin converting enzyme inhibitor;  BP – blood pressure;  bpm – 
beats per minute;  HR – heart rate;  ICU – intensive care unit;  q – every;  prn – as required;  g/Kg/min – 
micrograms per kilogram per minute;  g/min – micrograms per minute. 

ENCHANTED Protocol version 5.0 16 Feb 2017  
 
49 
Appendix 1C - BP protocol for centres with Urapidil (China) 
 
 
Early intensive 
BP lowering group 
TREATMENT PROTOCOL 
INITIAL therapy 
BP Target 
SBP 130-140 mmHg reached within 60 minutes of Randomisation into the 
BP arm  
Monitoring 
 
Continuous HR monitoring 
 
Record BP/HR q 5 mins during active treatment, then q 15 min for 
first hour, q 30 min for next 5 hours and then hourly to 24 h 
Urapidil (IV) 
 
Urapidil test dose: 5 mg IV bolus over 1 minute 
 
If SBP > 140 mmHg and HR >55 bpm, repeat 5 mg bolus in 5 
minutes 
 
10-25 mg IV push q 5 mins until target SBP reached (< 
140mmHg) or HR <55 bpm 
 
If HR increases by >15 bpm or is >90 bpm, add IV beta 
blocker 
Hydralazine (IV) 
If BP persistently >140 mmHg: 
 
ADD Hydralazine with a test dose: 5 mg IV bolus over 1 minute 
 
If SBP > 140 mmHg, repeat 5 mg IV bolus in 5 minutes 
 
If SBP still > 140mmHg, give 10 mg IV bolus q 5 mins until target 
SBP reached.  Increase to 20 mg bolus if required 
 
Maximum hydralazine dose = 240mg/24 hours 
Glyceryl Trinitrate (Topical) 
If BP persistently > 140 mmHg: 
 
ADD topical glyceryl trinitrate (paste or patch) at a rate of 5-10 
mg/24hour 
(≈200-400 μg/hour).  NB: also known as topical nitroglycerin 
Continuous IV Infusions 
(requires ICU admission) 
If BP persistently >140 mmHg: NB: It is recognized that many sites will 
proceed directly to urapidil infusion following an initial bolus. 
 
Urapidil infusion 5-30 mg/hour  
 
If target still not reached, ADD infusion of hydralazine 50-150 
g/min OR 
glyceryl trinitrate 1-100 g/min 
MAINTENANCE therapy 
BP Target 
Maintenance of SBP 130-140 mmHg  
Monitoring 
Once SBP is under target (confirmed by 4 readings 15 minutes apart):  
 
Record BP/HR q 30 minutes for 5 hours and then q 1 h for 18 h. 
IV treatment prn 
If SBP exceeds 140mmHg at any point: 
 
Give Urapidil (10-25 mg) and/or hydralazine (10-20 mg) boluses. 
BP and HR should then be recorded 5 and 15 minutes later 
 
If SBP is <140mmHg, Urapidil 10-25 mg (dose dependent on 
initial response) should be administered q 6 hours for the first 24 
hours after symptom onset (total of 3 doses) 

ENCHANTED Protocol version 5.0 16 Feb 2017  
 
50 
 
If SBP < 130 mmHg or HR < 55 bpm, then cease treatment 
 
If HR increases by >15 bpm or is >90 bpm, add IV beta 
blocker 
 
Note: urapidil and hydralazine may be used together during the 
maintenance phase 
Oral treatment 
Start treatment by 24 hours (use nasogastric if required) 
 
If not contraindicated and no other drug is specifically indicated, 
start combination therapy of ACEI + diuretics in addition to 
previous anti-hypertensives 
 
Note: Monoamine oxidase inhibitors are not recommended with this BP lowering agent and 
phosphodiesterase inhibitors must not be used with GTN. 
 
Key to abbreviations:  ACEI – Angiotensin converting enzyme inhibitor;  BP – blood pressure;  bpm – 
beats per minute;  HR – heart rate;  ICU – intensive care unit;  q – every;  prn – as required;  g/Kg/min – 
micrograms per kilogram per minute;  g/min – micrograms per minute. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ENCHANTED Protocol version 5.0 16 Feb 2017  
 
51 
Appendix 1D - BP protocol for centres with Phentolamine (China)  
 
Early intensive 
BP lowering group 
TREATMENT PROTOCOL 
INITIAL therapy 
BP Target 
SBP 130-140 mmHg reached within 60 minutes of Randomisation into the 
BP arm  
Monitoring 
 
Continuous HR monitoring 
 
Record BP/HR q 5 mins during active treatment, then q 15 min for 
first hour, q 30 min for next 5 hours and then hourly to 24 h 
Phentolamine (IV) 
 
Phentolamine test dose: 2.5 mg IV bolus over 1 minute 
 
If SBP > 140 mmHg and HR >55 bpm, repeat 2.5 mg bolus in 5 
minutes 
 
5 mg IV push q 5 mins until target SBP reached (130-140mmHg) 
or HR <55 bpm 
 
If HR increases by >15 bpm or is >90 bpm, add IV beta 
blocker 
Hydralazine (IV) 
If BP persistently >140 mmHg: 
 
ADD Hydralazine with a test dose: 5 mg IV bolus over 1 minute 
 
If SBP > 140 mmHg, repeat 5 mg IV bolus in 5 minutes 
 
If SBP still >140mmHg, give 10 mg IV bolus q 5 mins until target 
SBP reached.  Increase to 20 mg bolus if required 
 
Maximum hydralazine dose = 240mg/24 hours 
Glyceryl Trinitrate (Topical) 
If BP persistently >140 mmHg: 
 
ADD topical glyceryl trinitrate (paste or patch) at a rate of 5-10 
mg/24hour 
(≈200-400 μg/hour).  NB: also known as topical nitroglycerin 
Continuous IV Infusions 
(requires ICU admission) 
If BP persistently >140 mmHg:  
 
Phentolamine infusion 0.2-5 mg/minute  
 
If target still not reached, ADD infusion of hydralazine 50-150 
g/min OR 
glyceryl trinitrate 1-100 g /min 
MAINTENANCE therapy 
BP Target 
Maintenance of SBP 130-140 mmHg  
Monitoring 
Once SBP is under target (confirmed by 4 readings 15 minutes apart):  
 
Record BP/HR q 30 minutes for 5 hours and then q 1 h for 18 h. 
IV treatment prn 
If SBP exceeds 140mmHg at any point: 
 
Give Phentolamine (5 mg) and/or hydralazine (10-20 mg) 
boluses. BP and HR should then be recorded 5 and 15 minutes 
later 
 
If SBP is <140mmHg, Phentolamine 5 mg (dose dependent on 
initial response) should be administered q 6 hours for the first 24 
hours after symptom onset (total of 3 doses) 
 
If SBP < 130 mmHg or HR <55 bpm, then cease treatment 
 
If HR increases by >15 bpm or is >90 bpm, add IV beta 

ENCHANTED Protocol version 5.0 16 Feb 2017  
 
52 
blocker 
 
Note: phentolamine and hydralazine may be used together during 
the maintenance phase 
Oral treatment 
Start treatment by 24 hours (use nasogastric if required) 
 
If not contraindicated and no other drug is specifically indicated, 
start combination therapy of ACEI + diuretics in addition to 
previous anti-hypertensives 
 
Note: Monoamine oxidase inhibitors are not recommended with this BP lowering agent and 
phosphodiesterase inhibitors must not be used with GTN. 
 
Key to abbreviations:  ACEI – Angiotensin converting enzyme inhibitor;  BP – blood pressure;  bpm – 
beats per minute;  HR – heart rate;  ICU – intensive care unit;  q – every;  prn – as required;  g/Kg/min – 
micrograms per kilogram per minute;  g/min – micrograms per minute. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ENCHANTED Protocol version 5.0 16 Feb 2017  
 
53 
Appendix 1E - Additional IV Medication for BP Use in China  
 
The drugs listed in this Appendix are additional medications for BP lowering that can be used in China 
sites. 
 
1. Suggested IV medication for BP lowering 
 
1) Esmolol 
Dosage and administration: 
Bolus or infusion: It is recommended that an initial loading dose of 0.5 milligrams/kg body weight (500 
micrograms/kg) infused over a one-minute duration, followed by a maintenance infusion of 0.05 
milligrams/kg/min (50 micrograms/kg/min) for the next 4 minutes. If it is efficacious, the maintenance 
infusion may be continued at 0.05 mg/kg/min. If an adequate therapeutic effect is not observed, repeat 
the same loading dosage and follow with a maintenance infusion. The maintenance infusion may be 
continued at 0.05 mg/kg/min or increased step wise (e.g. 0.1 mg/kg/min, 0.15 mg/kg/min or a maximum of 
0.2 mg/kg/min) with each step being maintained for 4 or more minutes. The maintenance infusion may be 
increased to a maximum of 0.3 mg/kg/min. Maintenance dosages above 200 g/kg/min (0.2 mg/kg/min) 
have not been shown to have significantly increased benefits. 
 
2) Enalaprilat 
Dosage and administration: 
Therapy should be individualised. For patients on diuretic therapy, the dosage of enalaprilat should be 
reduced. Dose in hypertension is 1.25 mg every six hours administered intravenously over a five minute 
period. Doses higher than 5 mg every six hours are not suggested. 
 
2. IV medication for BP lowering which can also be used 
 
1) Diltiazem 
Dosage and administration: 
An initial dose of 10 mg or 0.5 mg - 0.25 mg/kg body weight infused within 3 minutes can be used. 
Diltiazem should be diluted in normal or glucose solutions to a concentration of 1% before use. This dose 
can be repeated after 15 minutes. A maintenance infusion of 5 g - 15 g/kg/min is also permitted. 
 
2) Nitroglyceride 
Dosage and administration: 
Nitroglyceride injection 10 mg is diluted in 0.9% normal solution 500 ml or 5% glucose solution 500 ml.  
The initial dose of nitroglyceride is 5 drops/min, and under close BP monitoring may increase by 5 
drops/min every 3-5 minutes.  If the dose of 20 drops/min is still not efficacious, 10 drops/min can be 
added every 3-5 minutes.  Doses usually can be from 5 to 50 drops/min. 
 
Note: Phosphodiesterase inhibitors must not be used with GTN.  
 
3) Nimodipine 
Dosage and administration: 
Nimodipine 50 ml/50 mg should be put in a micro pump and infused in a constant speed 4 ml/hour, once 
a day. Usually it can be used for 5 to 14 days. Then, change to oral nimodipine. However, the BP 
lowering effect of oral nimodopine is not obvious. 
 
4) Furosemide 

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Dosage and administration: 
The usual initial dose of furosemide is 20-80 mg. If needed, the same dose can be repeated every 2 
hours. The total dosage cannot be more than 1 g/d. If it is not effective, the dose should not be increased, 
to avoid renal toxicity. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix 1F- BP protocol for centres with Clevidipine 
Early intensive 
BP lowering group 
TREATMENT PROTOCOL 
INITIAL therapy 
BP Target 
SBP 130-140 mmHg reached within 60 minutes of Randomisation into the 
BP arm  
Monitoring 
 Continuous HR monitoring 
 Record BP/HR q 2 mins during active treatment, then q 15 min for first 
hour, q 30 min for next 5 hours and then hourly to 24 h 
Clevidipine (Continuous IV 
Infusion)  
(requires ICU admission) 
 Clevidipine initiation dose: 2 mg/hour continuous IV for the first 
1.5minuts 
 If SBP >140 mmHg, DOUBLE the dose every 2-10 minutes (4, 8, 16 
and then 32 mg/hour) 
 Maximum dose = 32.0mg/hour  
Hydralazine (IV) 
If BP persistently >140 mmHg: 
 ADD Hydralazine with a test dose: 5 mg IV bolus over 1 minute 
 If SBP >140 mmHg, repeat 5 mg IV bolus in 5 minutes 
 If SBP still > 140mmHg, give 10 mg IV bolus q 5 mins until target SBP 
reached.  Increase to 20 mg bolus if required 
 Maximum hydralazine dose = 240mg/24 hours 
Glyceryl Trinitrate (Topical) 
If BP persistently >140 mmHg: 
 ADD topical glyceryl trinitrate (paste or patch) at a rate of 5-10 
mg/24hour 
(≈200-400 μg/hour).  NB: also known as topical nitroglycerin 
Continuous IV Infusions 
(requires ICU admission) 
If BP persistently >140 mmHg:  
 ADD infusion of hydralazine 50-150 g/min OR 
glyceryl trinitrate 1-100 g /min 
MAINTENANCE therapy 
BP Target 
Maintenance of SBP 130-140 mmHg  
Monitoring 
Once SBP is under target (confirmed by 4 readings 15 minutes apart):  
 Record BP/HR q 30 minutes for 5 hours and then q 1 h for 18 h. 
Continuous IV treatment 
prn 
If SBP exceeds 140mmHg at any point: 
 DOUBLE the dose of Clevidipine every 2-10 minutes (4, 8, 16 and then 
maximum dose of 32 mg/hour) 
 If SBP is <140mmHg, Keep the dose of Clevidipine 
 If SBP < 130 mmHg or HR < 55 bpm, then HALVE the dose of 
Clevidipine every 2-10 minutes and then cease treatment 
 If HR increases by >15 bpm or is >90 bpm, add IV beta blocker 
Oral treatment 
Start treatment by 24 hours (use nasogastric if required) 
 If not contraindicated and no other drug is specifically indicated, start 
combination therapy of ACEI + diuretics in addition to previous anti-

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56 
hypertensives 
 
Note: Monoamine oxidase inhibitors are not recommended with this BP lowering agent and 
phosphodiesterase inhibitors must not be used with GTN. 
 
Key to abbreviations:  ACEI – Angiotensin converting enzyme inhibitor;  BP – blood pressure;  bpm – 
beats per minute;  HR – heart rate;  ICU – intensive care unit;  q – every;  prn – as required;  mg/hour – 
milligram per hour;  g/Kg/min – micrograms per kilogram per minute;  g/min – micrograms per minute. 
 
 
 
 
 
 
 
 
 
 

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Appendix 1G - BP protocol for centres with Nicardipine 
Early intensive 
BP lowering group 
TREATMENT PROTOCOL 
INITIAL therapy 
BP Target 
SBP 130-140 mmHg reached within 60 minutes of Randomisation into the 
BP arm  
Monitoring 
 Continuous HR monitoring 
 Record BP/HR q 2 mins during active treatment, then q 15 min for first 
hour, q 30 min for next 5 hours and then hourly to 24 h 
Nicardipine (Continuous IV 
Infusion)  
(requires ICU admission) 
 Nicardipine initiation dose: 5 mg/hour continuous IV for the first 15 
minutes 
 If SBP >140 mmHg, increase the dose by 2.5 mg/hour every 15 
minutes (7.5, 10, 12.5 and then 15 mg/hour) 
 Maximum dose = 15 mg/hour  
Hydralazine (IV) 
If BP persistently >140 mmHg: 
 ADD Hydralazine with a test dose: 5 mg IV bolus over 1 minute 
 If SBP >140 mmHg, repeat 5 mg IV bolus in 5 minutes 
 If SBP still > 140mmHg, give 10 mg IV bolus q 5 mins until target SBP 
reached.  Increase to 20 mg bolus if required 
 Maximum hydralazine dose = 240mg/24 hours 
Glyceryl Trinitrate (Topical) 
If BP persistently >140 mmHg: 
 ADD topical glyceryl trinitrate (paste or patch) at a rate of 5-10 
mg/24hour 
(≈200-400 μg/hour).  NB: also known as topical nitroglycerin 
Continuous IV Infusions 
(requires ICU admission) 
If BP persistently >140 mmHg:  
 ADD infusion of hydralazine 50-150 g/min OR 
glyceryl trinitrate 1-100 g /min 
MAINTENANCE therapy 
BP Target 
Maintenance of SBP 130-140 mmHg  
Monitoring 
Once SBP is under target (confirmed by 4 readings 15 minutes apart):  
 Record BP/HR q 30 minutes for 5 hours and then q 1 h for 18 h. 
Continuous IV treatment 
prn 
If SBP exceeds 140mmHg at any point: 
 INCREASE the dose of Nicardipine by 2.5 mg/hour every 15 minutes 
(7.5, 10, 12.5 and then 15 mg/hour) 
 If SBP is <140mmHg, Keep the dose of Nicardipine 
 If SBP < 130 mmHg or HR < 55 bpm, then DECREASE the dose of 
Nicardipine by 2.5mg/hour every 2-15 minutes and then cease 
treatment 
 If HR increases by >15 bpm or is >90 bpm, add IV beta blocker 

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Oral treatment 
Start treatment by 24 hours (use nasogastric if required) 
 If not contraindicated and no other drug is specifically indicated, start 
combination therapy of ACEI + diuretics in addition to previous anti-
hypertensives 
 
Note: Monoamine oxidase inhibitors are not recommended with this BP lowering agent and 
phosphodiesterase inhibitors must not be used with GTN. 
 
Key to abbreviations:  ACEI – Angiotensin converting enzyme inhibitor;  BP – blood pressure;  bpm – 
beats per minute;  HR – heart rate;  ICU – intensive care unit;  q – every;  prn – as required;  mg/hour – 
milligram per hour;  g/Kg/min – micrograms per kilogram per minute;  g/min – micrograms per minute. 
 
 
 
 
 
 

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Appendix 1H - BP protocol for centres with Nicardipine (Vietnam) 
Early intensive 
BP lowering group 
TREATMENT PROTOCOL 
INITIAL therapy 
Indication 
SBP > 140 mmHg, then at least 2 times, 5 min apart 
BP Target 
SBP < 140mmHg reached within 60 minutes of Randomisation into the BP 
arm  
Monitoring 
 Continuous HR monitoring 
 Record BP/HR q 5 mins during active treatment, then q 15 min for first 
hour, q 30 min for next 5 hours , then hourly for next 18h to 24 h 
(totally for initial 24h), and then every 3h in next 72h  
Medication 
 
Nicardipine (Continuous IV 
Infusion)  
(requires ICU admission) 
 Nicardipine initiation dose: 5 mg/hour continuous IV for the first 15 
minutes 
 If SBP >140 mmHg, increase the dose by 1-2.5 mg/hour every 5 
minutes (7.5, 10, 12.5 and then 15 mg/hour) 
 Maximum dose = 15 mg/hour  
Nitroglycerin 
If SBP > 140 mmHg after treatment maximum dose of Nicardipine 
Nitroglycerin dose: 1 – 100 µg /min 
MAINTENANCE therapy 
BP Target 
Maintenance of SBP 130-140 mmHg/72h  
Monitoring 
Once SBP is under target (confirmed by 4 readings 15 minutes apart):  
 Record BP/HR q 30 minutes for 5 hours and then q 1 h for 18 h. 
Continuous IV treatment 
prn 
IV infusion according to BP level, increasing or decreasing doses depends 
on BP stability. 
If SBP exceeds 140mmHg at any point: 
 INCREASE the dose of Nicardipine by 2.5 - 5 mg/2 – 5 minutes  
 If no reaching SBP target, increase IV infusion maintenance doses 
(amend 1 – 2.5 mg for each dose increase (e.g  if maintenance dose of 
2.5 mg/h, dose increased will be 3 – 4.5 mg/h) 
 If SBP is <140mmHg, Keep the dose of Nicardipine 
 If SBP < 130 mmHg or HR < 55 bpm: Cease treatment then if SBP≥140 
mmHg, repeat the Nicardipine IV infusion with a half of the Dose 
before ceasing treatment. If SBP still >140 mmHg at maximum dose of 
Nicardipine, Nitroglycerine is able to be amended.  
 

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Oral treatment 
When the BP is stable in 4 consecutive recording times (starting at the 
20th hour), oral medications are able to be used.  
 The patient using BP medication before stroke:  previous anti-
hypertensives can be used or switch to new suitable anti-
hypertensives starting with a half of the dose which was used before 
stroke 
 Patient with no BP medication before stroke: ACEI is prioritized and/or 
combination therapy of ACEI + diuretics by increasing diuretics prn 
from low dose. 
 Monitoring HR and BP every 3 hrs to 72h 
 
Note: Monoamine oxidase inhibitors are not recommended with this BP lowering agent and 
phosphodiesterase inhibitors must not be used with GTN. 
 
Key to abbreviations:  ACEI – Angiotensin converting enzyme inhibitor;  BP – blood pressure;  bpm – 
beats per minute;  HR – heart rate;  ICU – intensive care unit;  q – every;  prn – as required;  mg/hour – 
milligram per hour;  g/Kg/min – micrograms per kilogram per minute;  g/min – micrograms per 
minute. 

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Appendix 1I - Current guideline –based BP management 
 
RANDOMISED GROUP 
TREATMENT 
CONTROL 
GUIDELINE-BASED 
BP 
MANAGEMENT 
Use acute intravenous therapy ONLY IF SBP >180 mmHg 
Oral anti-hypertensives and / or topical nitrates can be used when 
patient medically stable, as assessed by responsible clinician. Oral 
treatment should be started by discharge / transfer (use nasogastric 
if required).  
 
If not contraindicated and no other drug is specifically required, 
start combination therapy ACEI + diuretic therapy in addition to 
previous anti-hypertensives 
 
Key to abbreviations: 
ACEI – Angiotensin converting enzyme inhibitor; SBP – systolic blood pressure. 
 

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Appendix 2 - Imaging protocol 
 
It would be desirable to use the same modality for both pre-randomisation and follow-up 
imaging from the same subject. However if for technical or practical reasons this is not possible, 
mixed CT and MR acquisitions (eg CT pre-randomisation and MR follow-up) are acceptable. 
CT scans should cover the entire brain from the foramen magnum to the vertex with 4–5 mm 
thick slices through the posterior fossa and 8–10 mm thick for the cerebral hemispheres, with no 
slice gap. Scans should be windowed on a width of 80 Hounsfield Units (HU) and a centre level 
of 35–40 HU. All patients (irrespective of treatment allocation) should have a follow-up scan at 
24 hours.  In addition a repeat scan is required if the patient deteriorates neurologically or ICH is 
suspected for any reason.   
In addition to the diffusion/perfusion MRI or perfusion CT series, any structural MRI (GRE, T2, 
FLAIR) orCT (spiral CT, etc) sequences acquired at the same time should be included.  For CT, 
spiral CT is to be preferred over CT MPR data or sequential axial CT acquisitions with thick 
slices.  Suggested acquisition parameters are given in Table A1- A4 below. 
If angiography (either MR or CT) have also been acquired, these should be submitted as well.  
Suggested acquisition parameters are given in Table A5 below. 
Table A1.Recommended Acquisition Protocol for Perfusion-CT (PCT) 
Acquisition Rate 
1 image per second, (ideally at one source rotation per second 
Total Acquisition Time 
Base Line Period 
40 to 60 seconds 
5-10 volumes should be acquired prior to contrast arrival 
Kvp and 
80 kVp (not 120 kVp) 
mAs 
100 mAs or higher 
Contrast Volume 
35-50 mL (with saline flush) 
Delivery Rate 
4-6 mL per second 
Coverage 
As dictated by configuration of hardware 
 
Table A2.Recommended Acquisition Protocols for Perfusion-Weighted (PWI) MR Imaging 
Sequence 
Single-shot gradient-echo echoplanar imaging 
TR 
TR = 1500 to 2000 ms 
TE 
TE=35 to 45 ms @ 1.5T 
TE=25 to 30 ms @ 3T 
Flip angle 
flip angle =60 to 90° @ 1.5T, 60° @ 3.0T 
Baseline 
At least 10-12 Baseline images (please note the first few images prior to steady state are 
discarded) 
Coverage 
At least 12 slices, with same slice thickness and gap as DWI, increase TR and slice gap 
to achieve reasonable coverage. 
 
 

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Table A3. Recommended Acquisition Protocols for Diffusion-Weighted (DWI) MR Imaging 
Sequence 
Single-shot spin-echo echoplanar imaging 
TR 
Should be at least 4000 ms (but can be larger) 
TE 
Minimum achievable 
Diffusion weighting 
(b values) 
b=0 and 1000 sec/mm2 
Coverage 
At least 10-12 slices, with same slice thickness and gap as PWI. 
 
Table A4 Example Acquisition Protocol for Spiral CT 
Kvp 
120 
mAs 
310 
slice collimation 
0.75 mm 
pitch 
0.65 
Gantry Rotation 
Maximum 
Table feed speed 
less than 7.5mm per gantry rotation 
 
Table A5. Recommended Acquisition Protocol for CT angiography (CTA) and MR angiography 
(MRA) 
CTA 
 
 
MRA 
 
Kvp 
100 
 
Sequence 
3D TOF 2 slab HR 
mAs 
120 
 
TR (ms) 
23 
Contrast (volume/type/rate) 
50ml Omnipaque 300 at 4ml/sec 
 
TE (ms) 
2.7 
Flush (volume/type/rate) 
40ml saline at 4ml/sec 
 
Flip angle 
20° 
delay 
15secs 
 
Locs / slab 
32 
coverage 
circle of Willis (upwards) 
 
Slice thickness 
1.6 
slice collimation 
0.75mm 
 
Slice gap 
0 
pitch 
1.25 
 
Matrix 
320 x 224 
 
 
 
ФFOV 
1 
FOV 
16 
Slice orient 
Straight axial 
T-scan 
5:46 
 

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Brain imaging (CTscan and/or MRI) must be uploaded to the ENCHANTED server to be 
analysed centrally for measurement of ischaemic lesion, measurement of areas of penumbra, 
sites of vessel occlusion, and haemorrhagic complications. The LCC will keep a hard copy in an 
uncompressed DICOM format onto a CD-ROM for site monitoring verification. 
Brain images are only to be removed from the scanner server after confirmation of receipt of 
images has been sent to the study centre. 
 
 
 
 
 
 
 

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Appendix 3 - Health Scales   
 
Glasgow Coma Scale (GCS) 
 
Assessment 
Measure 
Score 
Eye opening (E) 
4= Spontaneous 
3= To sound 
2= To pain 
1= Never 
 
Verbal response (V) 
5= Oriented 
4= Confused conversation 
3= Inappropriate words 
2= Incomprehensible sounds 
1= None 
 
Motor response (M) 
6= Obeys command 
5= Localises pain 
4= Withdrawal flexion 
3= Abnormal flexion 
2= Extension 
1= None 
 
TOTAL 
 
……. / 15 
(E + M + V) 
NB. 
If the patient is intubated the verbal response should be scored 1. 
 
 
When scoring the motor response, assess the response for the extremities of side unaffected by 
partial or complete paralysis. 

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NIH Stroke scale (National Institute of Health Stroke Scale) 
 
Assessment 
Response 
Score 
1a. Level of Consciousness: 
The investigator must choose a response, 
even if a full evaluation is prevented by 
such obstacles as an endotracheal tube, 
language 
barrier, 
orotracheal 
trauma/bandages. A 3 is scored only if the 
patient makes no movement (other than 
reflexive posturing) in response to noxious 
stimulation. 
0 = Alert; keenly responsive. 
1 = Not alert, but arousable by minor stimulation to 
obey, answer, or respond. 
2 = Not alert, requires repeated stimulation to attend, 
or is obtunded and requires strong or painful 
stimulation to make movements (not stereotyped). 
3 = Responds only with reflex motor or autonomic 
effects or totally unresponsive, flaccid, areflexic.  
 
1b. LOC Questions: 
The patient is asked the month and 
his/her age. The answer must be correct - 
there is no partial credit for being close. 
Aphasic and stuporous patients who do 
not comprehend the questions will score 
2. Patients unable to speak because of 
endotracheal 
intubation, 
orotracheal 
trauma, severe dysarthria from any cause, 
language barrier or any other problem not 
secondary to aphasia are given a 1. It is 
important that only the initial answer be 
graded and that the examiner not "help" 
the patient with verbal or non-verbal cues. 
0 = Answers both questions correctly. 
1 = Answers one question correctly. 
2 = Answers neither question correctly. 
 
1c. LOC Commands:  
The patient is asked to open and close the 
eyes and then to grip and release the non-
paretic hand. Substitute another one step 
command if the hands cannot be used. 
Credit is given if an unequivocal attempt is 
made but not completed due to weakness. 
If the patient does not respond to 
command, 
the 
task 
should 
be 
demonstrated to them (pantomime) and 
score the result (i.e., follows none, one or 
two commands). Patients with trauma, 
amputation, or other physical impediments 
should 
be 
given 
suitable 
one-step 
commands. Only the first attempt is 
scored. 
0 = Performs both tasks correctly. 
1 = Performs one task correctly. 
2 = Performs neither task correctly. 
 
2. Best Gaze: 
Only horizontal eye movements will be 
tested. 
Voluntary 
or 
reflexive 
(oculocephalic) eye movements will be 
scored but caloric testing is not done. If 
the patient has a conjugate deviation of 
0 = Normal. 
1 = Partial gaze palsy. This score is given when 
gaze is abnormal in one or both eyes, but where 
forced deviation or total gaze paresis are not 
present. 
2 = Forced deviation, or total gaze paresis not 
 

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67 
Assessment 
Response 
Score 
the eyes that can be overcome by 
voluntary or reflexive activity, the score 
will be 1. If a patient has an isolated 
peripheral nerve paresis (CN III, IV or VI) 
score a 1. Gaze is testable in all aphasic 
patients. Patients with ocular trauma, 
bandages, pre-existing blindness or other 
disorder of visual acuity or fields should 
be tested with reflexive movements and a 
choice 
made 
by 
the 
investigator. 
Establishing eye contact and then moving 
about the patient from side to side will 
occasionally clarify the presence of a 
partial gaze palsy. 
overcome by the oculocephalic maneuver. 
3. Visual:  
Visual fields (upper and lower quadrants) 
are tested by confrontation, using finger 
counting or visual threat as appropriate. 
Patient must be encouraged, but if they 
look at the side of the moving fingers 
appropriately, this can be scored as 
normal. If there is unilateral blindness or 
enucleation, visual fields in the remaining 
eye are scored. Score 1 only if a clear-cut 
asymmetry, including quadrantanopia is 
found. If patient is blind from any cause 
score 3. Double simultaneous stimulation 
is performed at this point. If there is 
extinction patient receives a 1 and the 
results are used to answer question 11.  
0 = No visual loss. 
1 = Partial hemianopia. 
2 = Complete hemianopia. 
3 = Bilateral hemianopia (blind including cortical 
blindness). 
 
4. Facial Palsy:  
Ask, or use pantomime to encourage the 
patient to show teeth or raise eyebrows 
and close eyes. Score symmetry of 
grimace in response to noxious stimuli in 
the 
poorly 
responsive 
or 
non-
comprehending 
patient. 
If 
facial 
trauma/bandages, orotracheal tube, tape 
or other physical barrier obscures the 
face, these should be removed to the 
extent possible.  
0 = Normal symmetrical movement. 
1 = Minor paralysis (flattened nasolabial fold, 
asymmetry on smiling). 
2 = Partial paralysis (total or near total paralysis of 
lower face). 
3 = Complete paralysis of one or both sides 
(absence of facial movement in the upper and lower 
face). 
 

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68 
Assessment 
Response 
Score 
5 & 6. Motor Arm and Leg: 
The limb is placed in the appropriate 
position: extend the arms (palms down) 
90 degrees (if sitting) or 45 degrees (if 
supine) and the leg 30 degrees (always 
tested supine). Drift is scored if the arm 
falls before 10 seconds or the leg before 5 
seconds. 
The 
aphasic 
patient 
is 
encouraged using urgency in the voice 
and 
pantomime 
but 
not 
noxious 
stimulation. Each limb is tested in turn, 
beginning with the non-paretic arm. Only 
in the case of amputation or joint fusion at 
the shoulder or hip may the score be "9" 
and the examiner must clearly write the 
explanation for scoring as a "9". 
 
0 = No drift, limb holds 90 (or 45) degrees for full 10 
seconds. 
1 = Drift, Limb holds 90 (or 45) degrees, but drifts 
down before full 10 seconds; does not hit bed or 
other support. 
2 = Some effort against gravity, limb cannot get to or 
maintain (if cued) 90 (or 45) degrees, drifts down to 
bed, but has some effort against gravity. 
3 = No effort against gravity, limb falls. 
4 = No movement 
9 = Amputation, joint fusion explain: 
- 
5a. Left Arm  
 
5b. Right Arm  
 
0 = No drift, leg holds 30 degrees position for full 5 
seconds. 
1 = Drift, leg falls by the end of the 5 second period 
but does not hit bed. 
2 = Some effort against gravity; leg falls to bed by 5 
seconds, but has some effort against gravity. 
3 = No effort against gravity, leg falls to bed 
immediately. 
4 = No movement. 
9 = Amputation, joint fusion explain:  
- 
6a. Left Leg 
 
6b. Right Leg  
 
7. Limb Ataxia: 
This item is aimed at finding evidence of a 
unilateral cerebellar lesion. Test with eyes 
open. In case of visual defect, insure 
testing is done in intact visual field. The 
finger-nose-finger and heel-shin tests are 
performed on both sides, and ataxia is 
scored only if present out of proportion to 
weakness. Ataxia is absent in the patient 
who cannot understand or is paralyzed. 
Only in the case of amputation or joint 
fusion may the item be scored "9", and the 
examiner 
must 
clearly 
write 
the 
explanation for not scoring. In case of 
blindness test by touching nose from 
extended arm position.  
0 = Absent . 
1 = Present in one limb . 
2 = Present in two limbs If present, is ataxia in? 
 
Right arm     1 = Yes     2 = No 
9 
= 
amputation 
or 
joint 
fusion, 
explain: 
________________ 
- 
Left arm     1 = Yes     2 = No 
9 
= 
amputation 
or 
joint 
fusion, 
explain 
: 
________________ 
- 
Right leg     1 = Yes     2 = No 
9 
= 
amputation 
or 
joint 
fusion, 
explain: 
________________ 
- 
Left leg     1 = Yes     2 = No 
9 
= 
amputation 
or 
joint 
fusion, 
explain: 
________________ 
- 

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Assessment 
Response 
Score 
8. Sensory: 
Sensation or grimace to pin prick when 
tested, 
or 
withdrawal 
from 
noxious 
stimulus in the obtunded or aphasic 
patient. Only sensory loss attributed to 
stroke is scored as abnormal and the 
examiner should test as many body areas 
[arms (not hands), legs, trunk, face] as 
needed 
to 
accurately 
check 
for 
hemisensory loss. A score of 2, "severe or 
total," should only be given when a severe 
or total loss of sensation can be clearly 
demonstrated. Stuporous and aphasic 
patients will therefore probably score 1 or 
0. The patient with brain stem stroke who 
has bilateral loss of sensation is scored 2. 
If the patient does not respond and is 
quadriplegic score 2. Patients in coma 
(item 1a=3) are arbitrarily given a 2 on this 
item.  
0 = Normal; no sensory loss.  
1 = Mild to moderate sensory loss; patient feels 
pinprick is less sharp or is dull on the affected side; 
or there is a loss of superficial pain with pinprick but 
patient is aware he/she is being touched.  
2 = Severe to total sensory loss; patient is not aware 
of being touched in the face, arm, and leg. 
 
9. Best Language:  
A 
great 
deal 
of 
information 
about 
comprehension will be obtained during the 
preceding sections of the examination. 
The patient is asked to describe what is 
happening in the attached picture, to 
name the items on the attached naming 
sheet, and to read from the attached list of 
sentences. Comprehension is judged from 
responses here as well as to all of the 
commands in the preceding general 
neurological exam. If visual loss interferes 
with the tests, ask the patient to identify 
objects placed in the hand, repeat, and 
produce speech. The intubated patient 
should be asked to write. The patient in 
coma (question 1a=3) will arbitrarily score 
3 on this item. The examiner must choose 
a score in the patient with stupor or limited 
cooperation but a score of 3 should be 
used only if the patient is mute and follows 
no one step commands.  
0 = No aphasia, normal. 
1 = Mild to moderate aphasia; some obvious loss of 
fluency 
or 
facility 
of 
comprehension, 
without 
significant limitation on ideas expressed or form of 
expression. 
Reduction 
of 
speech 
and/or 
comprehension, 
however, 
makes 
conversation 
about provided material difficult or impossible. For 
example in conversation about provided materials 
examiner can identify picture or naming card from 
patient's response.  
2 = Severe aphasia; all communication is through 
fragmentary expression; great need for inference, 
questioning, and guessing by the listener. Range of 
information that can be exchanged is limited; listener 
carries burden of communication. Examiner cannot 
identify materials provided from patient response.  
3 = Mute, global aphasia; no usable speech or 
auditory comprehension. 
 
10. Dysarthria:  
If patient is thought to be normal an 
adequate sample of speech must be 
obtained by asking patient to read or 
repeat words from the attached list. If the 
0 = Normal. 
1 = Mild to moderate; patient slurs at least some 
words and, at worst, can be understood with some 
difficulty.  
2 = Severe; patient's speech is so slurred as to be 
 

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Assessment 
Response 
Score 
patient has severe aphasia, the clarity of 
articulation of spontaneous speech can be 
rated. Only if the patient is intubated or 
has other physical barrier to producing 
speech, may the item be scored "9", and 
the examiner must clearly write an 
explanation for not scoring. Do not tell the 
patient why he/she is being tested.  
unintelligible in the absence of or out of proportion to 
any dysphasia, or is mute/anarthric.  
9 = Intubated or other physical barrier, explain: 
________________ 
11. 
Extinction 
and 
Inattention  
(formerly Neglect): 
Sufficient information to identify neglect 
may be obtained during the prior testing. If 
the patient has a severe visual loss 
preventing visual double simultaneous 
stimulation, and the cutaneous stimuli are 
normal, the score is normal. If the patient 
has aphasia but does appear to attend to 
both sides, the score is normal. The 
presence of visual spatial neglect or 
anosagnosia may also be taken as 
evidence 
of 
abnormality. 
Since 
the 
abnormality is scored only if present, the 
item is never untestable.  
0 = No abnormality.  
1 = Visual, tactile, auditory, spatial, or personal 
inattention or extinction to bilateral simultaneous 
stimulation in one of the sensory modalities.  
2 = Profound hemi-inattention or hemi-inattention to 
more than one modality. Does not recognize own 
hand or orients to only one side of space. 
 
TOTAL 
 
/ 
Additional item, not a part of the NIH 
Stroke Scale score. 
 
- 
A. 
Distal 
Motor 
Function:  
The patient's hand is held up at the 
forearm by the examiner and patient is 
asked to extend his/her fingers as much 
as possible. If the patient can't or doesn't 
extend the fingers the examiner places 
the fingers in full extension and observes 
for any flexion movement for 5 seconds. 
The patient's first attempts only are 
graded. Repetition of the instructions or of 
the testing is prohibited.  
0 = Normal (No flexion after 5 seconds). 
1 = At least some extension after 5 seconds, but not 
fully extended. Any movement of the fingers which is 
not command is not scored.  
2 = No voluntary extension after 5 seconds. 
Movements of the fingers at another time are not 
scored.  
- 
a. Left Arm  
 
b. Right Arm 
 

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Modified Rankin Scale (mRS) 
 
 
 
Score 
0 = No symptoms at all. 
 
1 = No significant disability despite symptoms, able to carry out all usual duties and 
activities 
 
2 = Slight disability, unable to carry out all previous activities but able to look after own 
affairs without assistance. 
 
3 = Moderate disability requiring some help, but able to walk without Assistance. 
 
4 = Moderate severe disability, unable to walk without assistance and unable to attend to 
own bodily needs without assistance. 
 
5 = Severe disability, bedridden incontinent, and requiring constant nursing care and 
attention. 
 
6 = Dead. 
 
 
 
/ 6 
 

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European Quality Of Life (EuroQOL) 
 
 
 
Numbers 
1. Mobility 
1= I have no problems in walking about 
2= I have some problems in walking about 
3= I am confined to bed 
 
2. Self-care 
1= I have no problems with self-care 
2= I have some problems washing or dressing myself 
3= I am unable to wash or dress myself 
 
3. Usual 
activities 
(e.g. work, study, 
housework, 
family, or leisure 
activities) 
1= I have no problems with performing my usual activities 
2= I have some problems with performing my usual activities 
3= I am unable to perform my usual activities 
 
4. Pain/ discomfort 
1= I have no pain or discomfort 
2= I have moderate pain or discomfort 
3= I have extreme pain or discomfort 
 
5. Anxiety/ 
depression 
1= I am not anxious or depressed 
2= I am moderately anxious or depressed 
3= I am extremely anxious or depressed 
 
 
 
 
 

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Appendix 4 - Standard acute care protocol  
 
 
Airway Management: 
Objectives: Normal SpO2 (≥ 92%) 
 
Monitor oxygen saturation continuously 
 
Oxygen supplementation is recommended only if patients de-saturate 
 
Intubate patients, who are unable to protect their airway, due to decreased level of 
consciousness and / or hypoxia / hypercarbia (pO2 <60 mm Hg or pCO2 >50 mm Hg) 
 
Fluid Management: 
Objectives: Isovolaemia with an isotonic solution; avoid hypokalemia 
 
Isotonic intravenous therapy, avoid hypotonic solutions 
 
Rate to be determined by oral/nasogastric intake 
 
Consider potassium supplementation if therapy is prolonged 
 
Body Temperature: 
Objectives: Maintain normothermia 
 
Monitor body temperature 4 times a day 
 
Investigate for infectious cause of any fevers 
 
Treat all fevers with paracetamol and / or cooling fans / blankets 
 
Diet: 
Objectives: Avoidance of aspiration, maintenance of nutrition, avoidance of ulcers 
 
Patients with dysphagia or suspected dysphagia should be kept nil by mouth until a 
formal swallowing assessment can be performed 
 
Alternative diets may be required, i.e. thickened fluids/diced 
 
Nasogastric feeding is recommended for patients who remain obtunded or severely 
dysphagic >24 hours 
 
Consider cytoprotective agents (proton pump inhibitor or H-2 antagonist) 
 
Activity: 
Objectives: Mobilize safely, avoid complications of immobility 
 
Patients should be mobilized only with supervision 
 
Delay mobilization in patients where elevated ICP is suspected 
 
Start physiotherapy as soon as patient is medically stable 
 
DVT Prophylaxis: 
Objectives: Avoid deep venous thrombosis / pulmonary embolism 
 
Compression stockings or pneumatic devices are recommended immediately 
 
Consider prophylactic sub-cutaneous heparinoids in patients with poor mobilization 

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Appendix 5 - Declaration of Helsinki 
 
 
Appendix 5 - Declaration of Helsinki 
 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical Principles for Medical Research Involving Human Subjects 
 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 
and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000  
53rd WMA General Assembly, Washington DC, USA, October 2002 (Note of Clarification added) 
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added) 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
 
Preamble 
 
1. 
The World Medical Association (WMA) has developed the Declaration of Helsinki as 
a statement of ethical principles for medical research involving human subjects, 
including research on identifiable human material and data. 
The Declaration is intended to be read as a whole and each of its constituent 
paragraphs should be applied with consideration of all other relevant paragraphs. 
 
2. 
Consistent with the mandate of the WMA, the Declaration is addressed primarily to 
physicians. The WMA encourages others who are involved in medical research 
involving human subjects to adopt these principles. 
General Principles 
 
3. 
The Declaration of Geneva of the WMA binds the physician with the words, “The 
health of my patient will be my first consideration,” and the International Code of 
Medical Ethics declares that, “A physician shall act in the patient's best interest when 
providing medical care.” 
 
4. 
It is the duty of the physician to promote and safeguard the health, well-being and 
rights of patients, including those who are involved in medical research. The 
physician's knowledge and conscience are dedicated to the fulfilment of this duty. 
 
5. 
Medical progress is based on research that ultimately must include studies involving 
human subjects. 
 
6. 
The primary purpose of medical research involving human subjects is to understand 
the causes, development and effects of diseases and improve preventive, diagnostic 
and therapeutic interventions (methods, procedures and treatments). Even the best 
proven interventions must be evaluated continually through research for their safety, 
effectiveness, efficiency, accessibility and quality. 

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7. 
Medical research is subject to ethical standards that promote and ensure respect for 
all human subjects and protect their health and rights. 
 
8. 
While the primary purpose of medical research is to generate new knowledge, this 
goal can never take precedence over the rights and interests of individual research 
subjects. 
 
9. 
It is the duty of physicians who are involved in medical research to protect the life, 
health, dignity, integrity, right to self-determination, privacy, and confidentiality of 
personal information of research subjects. The responsibility for the protection of 
research subjects must always rest with the physician or other health care 
professionals and never with the research subjects, even though they have given 
consent. 
 
10.  Physicians must consider the ethical, legal and regulatory norms and standards for 
research involving human subjects in their own countries as well as applicable 
international norms and standards. No national or international ethical, legal or 
regulatory requirement should reduce or eliminate any of the protections for research 
subjects set forth in this Declaration. 
 
11. Medical research should be conducted in a manner that minimises possible harm to 
the environment. 
 
12. Medical research involving human subjects must be conducted only by individuals 
with the appropriate ethics and scientific education, training and qualifications. 
Research on patients or healthy volunteers requires the supervision of a competent 
and appropriately qualified physician or other health care professional. 
 
13. Groups that are underrepresented in medical research should be provided 
appropriate access to participation in research. 
 
14. Physicians who combine medical research with medical care should involve their 
patients in research only to the extent that this is justified by its potential preventive, 
diagnostic or therapeutic value and if the physician has good reason to believe that 
participation in the research study will not adversely affect the health of the patients 
who serve as research subjects. 
 
15. Appropriate compensation and treatment for subjects who are harmed as a result of 
participating in research must be ensured. 
 
Risks, Burdens and Benefits  

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16. In medical practice and in medical research, most interventions involve risks and 
burdens. 
Medical research involving human subjects may only be conducted if the importance 
of the objective outweighs the risks and burdens to the research subjects. 
 
17. All medical research involving human subjects must be preceded by careful 
assessment of predictable risks and burdens to the individuals and groups involved 
in the research in comparison with foreseeable benefits to them and to other 
individuals or groups affected by the condition under investigation. 
Measures to minimise the risks must be implemented. The risks must be 
continuously monitored, assessed and documented by the researcher. 
 
18. Physicians may not be involved in a research study involving human subjects unless 
they are confident that the risks have been adequately assessed and can be 
satisfactorily managed. 
When the risks are found to outweigh the potential benefits or when there is 
conclusive proof of definitive outcomes, physicians must assess whether to continue, 
modify or immediately stop the study. 
 
19. Some groups and individuals are particularly vulnerable and may have an increased 
likelihood of being wronged or of incurring additional harm. 
All vulnerable groups and individuals should receive specifically considered 
protection. 
 
20. Medical research with a vulnerable group is only justified if the research is responsive 
to the health needs or priorities of this group and the research cannot be carried out 
in a non-vulnerable group. In addition, this group should stand to benefit from the 
knowledge, practices or interventions that result from the research. 
 
Scientific Requirements and Research Protocols  
 
21. Medical research involving human subjects must conform to generally accepted 
scientific principles, be based on a thorough knowledge of the scientific literature, 
other relevant sources of information, and adequate laboratory and, as appropriate, 
animal experimentation. The welfare of animals used for research must be 
respected. 

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22. The design and performance of each research study involving human subjects must 
be clearly described and justified in a research protocol. 
The protocol should contain a statement of the ethical considerations involved and 
should indicate how the principles in this Declaration have been addressed. The 
protocol should include information regarding funding, sponsors, institutional 
affiliations, potential conflicts of interest, incentives for subjects and information 
regarding provisions for treating and/or compensating subjects who are harmed as a 
consequence of participation in the research study. 
In clinical trials, the protocol must also describe appropriate arrangements for post-
trial provisions. 
Research Ethics Committees 
 
23. The research protocol must be submitted for consideration, comment, guidance and 
approval to the concerned research ethics committee before the study begins. This 
committee must be transparent in its functioning, must be independent of the 
researcher, the sponsor and any other undue influence and must be duly qualified. It 
must take into consideration the laws and regulations of the country or countries in 
which the research is to be performed as well as applicable international norms and 
standards but these must not be allowed to reduce or eliminate any of the protections 
for research subjects set forth in this Declaration.  
The committee must have the right to monitor ongoing studies. The researcher must 
provide monitoring information to the committee, especially information about any 
serious adverse events. No amendment to the protocol may be made without 
consideration and approval by the committee. After the end of the study, the 
researchers must submit a final report to the committee containing a summary of the 
study’s findings and conclusions. 
Privacy and Confidentiality  
 
24. Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information. 
Informed Consent  
 
25. Participation by individuals capable of giving informed consent as subjects in medical 
research must be voluntary. Although it may be appropriate to consult family 
members or community leaders, no individual capable of giving informed consent 
may be enrolled in a research study unless he or she freely agrees. 

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26. In medical research involving human subjects capable of giving informed consent, 
each potential subject must be adequately informed of the aims, methods, sources of 
funding, any possible conflicts of interest, institutional affiliations of the researcher, 
the anticipated benefits and potential risks of the study and the discomfort it may 
entail, post-study provisions and any other relevant aspects of the study. The 
potential subject must be informed of the right to refuse to participate in the study or 
to withdraw consent to participate at any time without reprisal. Special attention 
should be given to the specific information needs of individual potential subjects as 
well as to the methods used to deliver the information. 
After ensuring that the potential subject has understood the information, the 
physician or another appropriately qualified individual must then seek the potential 
subject’s freely-given informed consent, preferably in writing. If the consent cannot be 
expressed in writing, the non-written consent must be formally documented and 
witnessed.       
All medical research subjects should be given the option of being informed about the 
general outcome and results of the study. 
 
27. When seeking informed consent for participation in a research study the physician 
must be particularly cautious if the potential subject is in a dependent relationship 
with the physician or may consent under duress. In such situations the informed 
consent must be sought by an appropriately qualified individual who is completely 
independent of this relationship.  
 
28. For a potential research subject who is incapable of giving informed consent, the 
physician must seek informed consent from the legally authorised representative. 
These individuals must not be included in a research study that has no likelihood of 
benefit for them unless it is intended to promote the health of the group represented 
by the potential subject, the research cannot instead be performed with persons 
capable of providing informed consent, and the research entails only minimal risk and 
minimal burden. 
 
29. When a potential research subject who is deemed incapable of giving informed 
consent is able to give assent to decisions about participation in research, the 
physician must seek that assent in addition to the consent of the legally authorised 
representative. The potential subject’s dissent should be respected.  
 
30. Research involving subjects who are physically or mentally incapable of giving 
consent, for example, unconscious patients, may be done only if the physical or 
mental condition that prevents giving informed consent is a necessary characteristic 
of the research  group. In such circumstances the physician must seek informed 
consent from the legally authorised representative. If no such representative is 
available and if the research cannot be delayed, the study may proceed without 
informed consent provided that the specific reasons for involving subjects with a 
condition that renders them unable to give informed consent have been stated in the 
research protocol and the study has been approved by a research ethics committee. 
Consent to remain in the research must be obtained as soon as possible from the 
subject or a legally authorised representative. 

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31. The physician must fully inform the patient which aspects of their care are related to 
the research. The refusal of a patient to participate in a study or the patient’s decision 
to withdraw from the study must never adversely affect the patient-physician 
relationship. 
 
32. For medical research using identifiable human material or data, such as research on 
material or data contained in biobanks or similar repositories, physicians must seek 
informed consent for its collection, storage and/or reuse. There may be exceptional 
situations where consent would be impossible or impracticable to obtain for such 
research. In such situations the research may be done only after consideration and 
approval of a research ethics committee. 
Use of Placebo 
 
33. The benefits, risks, burdens and effectiveness of a new intervention must be tested 
against those of the best proven intervention(s), except in the following 
circumstances: 
Where no proven intervention exists, the use of placebo, or no intervention, is 
acceptable; or 
Where for compelling and scientifically sound methodological reasons the use of any 
intervention less effective than the best proven one, the use of placebo, or no 
intervention is necessary to determine the efficacy or safety of an intervention  
and the patients who receive any intervention less effective than the best proven one, 
placebo, or no intervention will not be subject to additional risks of serious or 
irreversible harm as a result of not receiving the best proven intervention.  
Extreme care must be taken to avoid abuse of this option. 
Post-Trial Provisions 
 
34. In advance of a clinical trial, sponsors, researchers and host country governments 
should make provisions for post-trial access for all participants who still need an 
intervention identified as beneficial in the trial. This information must also be 
disclosed to participants during the informed consent process. 
Research Registration and Publication and Dissemination of Results 
 
35. Every research study involving human subjects must be registered in a publicly 
accessible database before recruitment of the first subject. 

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36. Researchers, authors, sponsors, editors and publishers all have ethical obligations 
with regard to the publication and dissemination of the results of research. 
Researchers have a duty to make publicly available the results of their research on 
human subjects and are accountable for the completeness and accuracy of their 
reports. All parties should adhere to accepted guidelines for ethical reporting. 
Negative and inconclusive as well as positive results must be published or otherwise 
made publicly available. Sources of funding, institutional affiliations and conflicts of 
interest must be declared in the publication. Reports of research not in accordance 
with the principles of this Declaration should not be accepted for publication. 
Unproven Interventions in Clinical Practice 
 
37. In the treatment of an individual patient, where proven interventions do not exist or 
other known interventions have been ineffective, the physician, after seeking expert 
advice, with informed consent from the patient or a legally authorised representative, 
may use an unproven intervention if in the physician's judgement it offers hope of 
saving life, re-establishing health or alleviating suffering. This intervention should 
subsequently be made the object of research, designed to evaluate its safety and 
efficacy. In all cases, new information must be recorded and, where appropriate, 
made publicly available.