Second Enhanced Control of Hypertension and Thrombectomy Stroke Study (ENCHANTED2)
Phase: NA
Conditions: Acute Ischemic Stroke
Sponsor: The George Institute for Global Health, China

 
  
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ENCHANTED2 protocol  
Version 3.0  
Date: 18 Aug 2020 
 
 
 
 
STUDY PROTOCOL 
(Version 3.0 – 18 Aug 2020) 
Trial registration: ClinicalTrials.gov (NCT04140110) 
 
CONTACT DETAILS 
ENCHANTED2 International Coordinating Centre 
The George Institute for Global Health (Australia)  
Beijing Representative Office (TGI, CHINA) 
Room 011, Unit 2, Tayuan Diplomatic Office Building No. 14 Liangmahe Nan Lu, Chaoyang 
District, Beijing, 100600 P.R.China  
 
Tel +86 10 8280 0577 
Fax +86 10 8280 0177 
 
 
This protocol has been developed by the ENCHANTED2 Steering Committee and its contents 
are the intellectual property of this group. It is an offence to reproduce or use the information 
and data in this protocol for any purpose other than the ENCHANTED2 study without prior 
approval from the project office of the ENCHANTED2 study. 
An investigator initiated and conducted, prospective, multicentre, randomised 
outcome-blinded study of blood pressure lowering in patients with acute 
ischaemic stroke with successful recanalization after mechanical thrombectomy 

 
  
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ENCHANTED2 protocol  
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INVESTIGATOR AGREEMENT 
I have read the following protocol: 
Protocol Title:  Second Enhanced Control of Hypertension and Thrombectomy Stroke 
Study (ENCHANTED2) 
Version and Date: Version 3.0 – 18 Aug 2020 
 
I have read this protocol and associated procedure manuals 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 
Co-Principal Investigator 
Professor Jianmin Liu 
Changhai Hospital, China  
 
 
 
 
18 Aug 2020 
Date 
 
 
Signature 
 
 
 
Co-Principal Investigator 
Professor Craig Anderson  
The George Institute for Global Health, China 
 
18 Aug 2020 
Date 
 
 
Signature 
 
Trial Statistician 
A/Professor Laurent Billot 
The George Institute for Global Health, Australia 
 
 
 
 
 
18 Aug 2020 
Date 
 
 
 
Signature 
 

 
 
  
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ENCHANTED2 protocol  
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1. CONTENTS  
1. CONTENTS ....................................................................................................................... 3 
2. ADMINISTRATIVE INFORMATION ................................................................................... 6 
3. PROTOCOL SYNOPSIS .................................................................................................... 9 
4. BACKGROUND AND RATIONALE ................................................................................. 11 
4.1 Overview .....................................................................................................................11 
4.2 Background .................................................................................................................11 
4.2.1 Stroke Epidemiology .............................................................................................11 
4.2.2 Acute Managements for AIS .................................................................................11 
4.2.3 Evidence on BP Control for AIS Patients with MT .................................................12 
4.3 Summary ....................................................................................................................14 
5. AIMS AND OBJECTIVES ................................................................................................ 15 
5.1 Primary aim .................................................................................................................15 
5.2 Secondary aims ..........................................................................................................15 
6. METHODS ....................................................................................................................... 15 
6.1 Design ........................................................................................................................15 
6.2 Study Population .........................................................................................................15 
6.3 Inclusion / exclusion criteria ........................................................................................16 
6.4 Ethical Issues ..............................................................................................................17 
6.4.1 Institutional ethics committee approval .................................................................17 
6.4.2 Consent ................................................................................................................17 
6.4.3 Confidentiality and Privacy ...................................................................................19 
6.5 Site selection ..............................................................................................................19 
6.6 Randomisation ............................................................................................................21 
6.7 Treatments Allocation .................................................................................................21 
6.8. Study Outcomes ........................................................................................................22 
6.9 Economic Evaluation ..................................................................................................23 
6.10 Data Collection and Follow-up ..................................................................................23 
6.10.1 Screening Logs ..................................................................................................24 
6.10.2 Patient Contact Details Log ................................................................................24 
6.10.3 Randomisation Assessment (Form A) ................................................................24 
6.10.4 Baseline Data (Form B) ......................................................................................24 
6.10.5 Follow up Data ...................................................................................................25 
7. SAFETY ........................................................................................................................... 28 
7.1 Data and Safety Monitoring Board (DSMB) .................................................................28 
7.2 SAEs ...........................................................................................................................28 
7.2.1 Definitions ............................................................................................................28 

 
 
  
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7.2.2 Recording and Reporting ......................................................................................28 
7.2.3 Monitoring of SAEs ...............................................................................................29 
8. QUALITY ASSURANCE .................................................................................................. 29 
8.1 Monitoring of Participating Centres/Sites ....................................................................29 
8.2 Auditing and Inspection by Government Regulatory Authorities ..................................30 
9. DATA MANAGEMENT .................................................................................................... 30 
10. STATISTICAL CONSIDERATIONS ............................................................................... 30 
10.1 Sample Size ..............................................................................................................30 
10.2 Statistical Analyses ...................................................................................................30 
11. SUBSTUDIES OF SECONDARY PREVENTION ........................................................... 31 
11.1 Timing of initiating anticoagulation therapy in AIS patients with MT...........................31 
11.1.1 Aims ...................................................................................................................31 
11.1.2 Background and Rationale .................................................................................31 
11.1.3 Study design .......................................................................................................35 
11.1.4 Study outcomes ..................................................................................................35 
11.1.5 Sample size ........................................................................................................36 
11.2 Duration of dual antiplatelet therapy (DAPT) .............................................................36 
11.2.1 Aims ...................................................................................................................36 
11.2.2 Background and rationale ...................................................................................36 
11.2.3 Study design .......................................................................................................37 
11.2.4 Study outcomes ..................................................................................................38 
11.2.5 Data collection and follow-up ..............................................................................38 
11.2.6 Sample size ........................................................................................................39 
12. PUBLICATION, REPORTS AND DATA SHARING ....................................................... 39 
13. ORGANISATION ........................................................................................................... 40 
13.1 Steering Committee (SC) ..........................................................................................40 
13.2 Central Coordinating Centre (CCC)...........................................................................40 
13.3 RCC ..........................................................................................................................41 
13.4 Imaging Adjudication Committee (Core Lab/Brain Imaging Analysis) ........................41 
13.5 Clinical Endpoints Committee ...................................................................................41 
13.6 Data Safety Monitoring Board (DSMB) ......................................................................41 
13.7 Participating Centres .................................................................................................41 
14. FUNDING ....................................................................................................................... 41 
15. TIMELINES .................................................................................................................... 42 
16. REFERNCES ................................................................................................................. 43 
17. APPENDIX ..................................................................................................................... 47 
Appendix 1 - BP management protocol .............................................................................47 

 
 
  
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Appendix 1A - BP protocol for centres with Urapidil (China) ..........................................47 
Appendix 1B - BP protocol for centres with Phentolamine (China) ................................49 
Appendix 1C - BP protocol for centres with Labetalol ....................................................51 
Appendix 1D - BP protocol for centres with Hydralazine ................................................53 
Appendix 1E - BP protocol for centres with Clevidipine .................................................55 
Appendix 1F - Additional IV Medication for BP Use in China .........................................57 
Appendix 1G - Current guideline-based BP management .............................................58 
Appendix 2 - Recommendation for MT devices .................................................................59 
Appendix 3 - Imaging protocol ..........................................................................................60 
Appendix 4 - Health Scales ...............................................................................................62 
Glasgow coma scale (GCS) ..........................................................................................62 
NIH stroke scale (National Institute of Health Stroke Scale) ..........................................63 
Modified Rankin scale (mRS) ........................................................................................69 
European quality of life (EuroQOL) ................................................................................70 
Appendix 5 - Declaration of Helsinki .................................................................................71 
 
 

 
 
  
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2. ADMINISTRATIVE INFORMATION 
Protocol History 
Version Number 
Version Date 
Summary of Revisions Made: 
1.0 
23 Aug 2019 
Original 
1.2 
22 Oct 2019 
Additional exclusion criteria 
2.0 
18 Feb 2020 
International Coordinating Centre changed from 
“Heart Health Research Centre” to “The George 
Institute for Global Health (Australia) Beijing 
Representative Office” 
3.0 
18 Aug 2020 
Revision of “Table 2 Schedule of evaluations” and 
adding subgroup analysis on data collection 
 
Trial/Study Registration 
The study has been registered with ClinicalTrials.gov (NCT04140110), and Chinese Trial 
Registry (ChiCTR1900027785). 
Funding 
This study has received initial funding from a Program Grant of the National Health and Medical 
Research Council (NHMRC) of Australia (APP1149987), China National Health Commission 
Stroke Prevention Committee “China Stroke Prevention and Intervention Project” (GN-2020 
R0008), and grants from Changhai Hospital (including “National Clinical Key Specialist 
Construction Project” 2016). This study also receives funding support from Takeda China. 
Study Management & Oversight 
ENCHANTED2 is an investigator initiated and conducted study managed by TGI, CHINA. The 
study will be overseen by a committee of international experts in the fields of neurology, 
neurosurgery, hypertension, cardiovascular disease, epidemiology and clinical trials. 
Steering Committee (SC):  The SC is responsible 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. The SC will also include the grant holders and its members are to be confirmed.  The 
SC will be co-chaired by Professor Craig Anderson and Professor Jianmin Liu. 
Central Coordinating Centre (CCC):  The CCC is based at TGI, CHINA and is supported by 
project staff. Responsibilities: Day-to-day management of the study, data and project 
management, committee coordination, assistance with ethics committee and regulatory 
applications, protocol and procedures for training of participating sites, overseeing of initiation 
visits and activation of participating centres, monitoring of data quality and adherence to 
protocol, applicable guidelines and regulations, preparation of study data for analysis and 
publications.  
 
 

 
 
  
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Glossary of Abbreviations and Terms 
 
ACE-I 
Angiotensin converting enzyme inhibitor 
AF 
Atrial fibrillation 
AIS 
Acute ischemic stroke 
ARB 
Angiotensin II receptor blocker 
AHA/ASA 
American Heart Association/American Stroke Association 
BP 
Blood pressure 
CCB 
Calcium channel blocker 
CCC 
Central coordinating centre 
CFDA 
China Food and Drug Administration 
CI 
Confidence interval 
CRF/eCRF 
Case record form/electronic CRF 
CSVD 
Cerebral small vessel disease 
CT 
Computerized tomography 
CTA/CTP 
Computerized tomography angiography/ perfusion 
CV 
Cardiovascular 
DALY 
Disability-adjusted-life-years 
DAPT 
Dual antiplatelet therapy 
DSMB 
Data and safety monitoring board 
DOACs 
Direct oral anticoagulants 
EC 
Ethics committee 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
ENCHANTED 
Enhanced Control of Hypertension and Thrombolysis Stroke Study 
EQ-5D 
EuroQoL Group 5-dimension self-report questionnaire 
GCP 
Good Clinical Practice 
GCS 
Glasgow coma scale 
HOQ 
Hospital organization questionnaire 
HT 
Haemorrhage transformation 
HR 
Heart rate 
HREC 
Human research ethics committee 
HRQoL 
Health-related quality of life 
IAC 
Imaging adjudication committee 
IC 
Informed consent 
ICH 
Intracerebral haemorrhage 
ICH-GCP 
ICH Guidelines for Good Clinical Practice 
ICMJE 
International Committee of Medical Journal Editors 
ICP 
Intracranial pressure 
ICU 
Intensive care unit 
INR 
International normalised ratio 
IRB 
Institutional review board 
ITT 
Intension to treat 
IV 
Intravenous 
LAA 
Large artery atherosclerosis 

 
 
  
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LVO 
Large vessel occlusion 
MR CLEAN 
Multicentre Randomised Clinical Trial of Endovascular Treatment for 
Acute Ischemic Stroke in the Netherlands 
MRI 
Magnetic resonance imaging 
MRA 
Magnetic resonance imaging angiography 
MT 
Mechanical thrombectomy 
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 
OAC 
Oral anticoagulant 
OC 
Operations committee 
OR 
Odds ratio 
PI 
Principal investigator 
PIS 
Patient information sheet 
PROBE 
Prospective, randomised, open, blinded end-point assessed 
PTAS 
Percutaneous transluminal angioplasty and stenting 
RCC 
Regional coordinating centre 
RCTs 
Randomised clinical trials 
RR 
Risk ratio 
rt-PA 
recombinant tissue plasminogen activator 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SBP 
Systolic BP 
SC 
Steering committee 
sICH 
Symptomatic intracranial haemorrhage 
SITS-MOST 
Safe Implementation of Thrombolysis in Stroke-Monitoring Study 
SIV 
Site initiation visit 
SOP 
Standard operation process 
TGI CHINA 
The George Institute for Global Health, China 
Or Beijing representative office, the George Institute for Global Health 
(Australia) 
TICI 
Thrombolysis in cerebral infarction  
TMF 
Trial master file 
UAR 
Unexpected adverse reaction 
VKA 
Vitamin K antagonist 
 
 
 

 
 
  
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3. PROTOCOL SYNOPSIS 
Main Sponsors:  
1. Changhai Hospital 
2. TGI, CHINA 
Trial Registration:  
Clinicaltrials.gov (NCT04140110) 
Title: Second Enhanced Control of Hypertension and Thrombectomy Stroke Study 
(ENCHANTED2) 
Study Duration: 4 years 
Clinical Phase: III 
Objectives: To determine the effectiveness of more intensive blood pressure (BP) lowering 
target (<120 mmHg) as compared to a higher BP management target (140-180mmHg) on 
functional outcome in patients who have had successful recanalization with mechanical 
thrombectomy (MT) for acute ischemic stroke (AIS) due to large vessel occlusion (LVO).   
Number of Planed Participants: 2257 patients to be recruited from 80-100 hospital sites  
Study Design: International, multicentre, prospective, randomised, open, blinded end-point 
assessed (PROBE) clinical trial, with the main acute treatment trial of different approaches to BP 
control and two nested substudies evaluating different approaches to secondary prevention, in 
this high-risk stroke population. 
Inclusion Criteria:  
1) Age ≥18 years;  
2) Diagnosis of AIS with LVO confirmed by brain imaging; 
3) To receive MT <24 hours after AIS onset according to local guidelines; 
4) Successful recanalization (TICI score ≥2b) after MT; 
5) Sustained systolic BP ≥140 mmHg (defined as 2 successive readings <10 mins) within 
3 hours after recanalization; 
6) Provide written informed consent (or approved surrogate). 
Exclusion Criteria: 
Patients will NOT be eligible if there is one or more of the following;  
1) Unlikely to potentially benefit from therapy (e.g. advanced dementia) or very high 
likelihood of death within 24 hours post-MT, judged by responsible treating clinician; 
2) Other medical illness that interferes with outcome assessments and follow-up (e.g. 
known significant pre-stroke disability (mRS scores 3-5), advance cancer and renal 
failure);  
3) Definite indication/contraindication to different intensities of BP lowering treatment; 
4) Specific contraindications to any of the BP agents to be used (eg, patients who are 
hypersensitive (allergic) to any of the ingredients);  
5) Patients with aortic isthmus stenosis and arteriovenous shunt (exception: patients with 
haemodynamically inactive dialysis shunt); 
6) Women who are lactating; 
7) Currently participating in another trial which would interfere with outcome 
assessments. 
Outcome Measures 
Primary outcome: functional recovery, defined as a shift (improvement) in scores on the modified 
Rankin scale (mRS) at 90 days. 
Secondary outcomes: any intracranial haemorrhage (ICH), symptomatic intracerebral 
haemorrhage (sICH), early neurological deterioration, imaging assessment (e.g. infarct size, 
edema volume), death, disability, HRQoL, duration of hospitalization, residence; and health 
service use for calculation of resources and costs.  

 
 
  
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Randomisation and intervention Randomisation is via a central internet-based system, stratified 
by site, recanalization time from onset (<6 vs ≥6 hours), neurological impairment on the National 
Institutes for Health Stroke Scale at admission (NIHSS <17 vs ≥17), to ensure balance in key 
prognostic factors. 
Intensive BP lowering group: to commence intravenous BP lowering therapy immediately after 
randomised to intervention group. The BP target is to achieve BP level of <120 mmHg within 1 
hour, and maintain this level at least 72 hours (or hospital discharge if earlier).  
Control group: the patient allocated to this group will receive a higher BP target strategy to maintain 
BP level 140-180 mmHg after MT procedure. BP lowering treatment can be given only when BP 
level >150 mmHg in order to achieve the target of ≥140 mmHg. 
Substudies: The patients who have been enrolled in the main study will be randomised into 2 
substudies according to separate eligibility criteria. Both are pilot studies imbedded in the main 
trial is to recruit as many patients to inform the sample size estimates for the further main study. 
Timing of anticoagulation  
Objective: To determine the effectiveness of early initiation of anticoagulation (at Day 4±2 of stroke 
onset) compared with late initiation (at Day 12±2) on secondary prevention of vascular events 
within 90 days in patients with AF-related AIS due to LVO who receive MT. Randomisation 
(allocation 1:1 ratio) will be done via the same system as the main study and stratified by site and 
randomisation of BP intervention. Randomised patients will be allocated to either early group of 
initiating OAC therapy at Day 4±2 day of stroke onset, or late group of initiating OAC therapy at 
Day 12±2 of stroke onset. Primary outcome: composite of recurrent AIS, sICH, systemic embolism 
and/or vascular death within 90 days after randomisation.  
Duration of dual antiplatelet therapy (DAPT):  
Objective: To determine the effectiveness of short duration of DAPT (6 weeks) compared with 
standard duration (3 months) on recurrence rate within 12 months in patients with AIS due to large 
artery atherosclerosis (LAA) who receive MT. Randomisation (allocation 1:1 ratio) will be done via 
the same system as the main study and stratified by site and randomisation of BP intervention. 
Randomised patients will be allocated to either short duration group of receiving DAPT (aspirin 
100 mg and clopidogrel 75 mg per day) for 6 weeks, or standard duration group of receiving DAPT 
for 3 months. DAPT treatment will be started within 48 hours after randomisation, and maintained 
by antiplatelet monotherapy (aspirin or clopidogrel) thereafter. Primary outcome is new stroke 
event (AIS or ICH) over 12 months. 
 
 
 
 

 
 
  
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4. BACKGROUND AND RATIONALE 
4.1 Overview 
This is an investigator initiated and conducted, multicentre, prospective, randomised, open, 
blinded end-point assessed (PROBE) clinical trial. ENCHANTED2 has the principle aim of 
determining the effectiveness of more intensive BP lowering management (systolic target <120 
mmHg) compared to less intensive BP management range (systolic 140-180 mmHg) in AIS 
patients with large vessel occlusion (LVO), to improve functional outcomes after achieving 
successful recanalization from contemporary mechanical thrombectomy (MT) therapy. There 
are two embedded substudies evaluating different approaches to secondary prevention in this 
patient group: early versus delayed initiation of anticoagulation in those with associated atrial 
fibrillation (AF); and short versus conventional duration of dual antiplatelet therapy (DAPT) in 
those patients with a clear indication for such therapy following MT.  
4.2 Background 
4.2.1 Stroke Epidemiology 
Stroke is a one of the leading causes of death and adult chronic disability around the world.1 
Although the mortality in high-income countries is decreasing with better management and 
treatments, the burden of stroke in low-income and middle-income countries (LMICs) is still 
rising.2 It is currently the second largest contributor to lives lost through disability after 
ischaemic heart disease globally in developing countries, and it is third largest contributor to 
death and disability in developed countries (after ischaemic heart disease and low back and 
neck pain). In 2015, there were 9 million new onset stroke patients, 42 million stroke survivors, 
and over 100 million disability adjusted life year (DALYs) lost, worldwide.3 
Stroke incidence in China was greater than in other countries. The current stroke incidence 
(247/100 000 person-years [95% CI, 211–283]) and mortality rates (115/100 000 person-years) 
in China appear to be the highest in the world.4 It has been the leading cause of death in China 
in recent years,4, 5 constituting almost one-third of the total number of deaths from stroke 
worldwide.3 There are about 2.4 million new strokes and 1.1 million stroke-related deaths 
annually, with 11.1 million stroke survivors alive at any given time in China.5 
Most strokes are due to AIS caused by acute occlusion (‘clot’) of an artery leading to immediate 
reduction in AIS stroke include large-artery atherosclerosis (LAA), cardioembolism (generally 
due to AF) and small-vessel occlusion (lacunar), most typically classified according to the Trial 
of Org in Acute Stroke Treatment (TOAST) criteria.6  
4.2.2 Acute Managements for AIS 
Despite the heavy burden of AIS, progress has been slow in established clear evidence of 
benefit for acute management strategies. For patients with AIS, timely restoration of blood flow 
is effective in reducing long-term morbidity. Reperfusion therapy with intravenous thrombolysis 
(alteplase or recombinant tissue plasminogen activator [rt-PA]) and MT, with either a stent 
retriever or aspiration device, are now accepted standard of care treatments for AIS patients.  
Thrombolysis therapy with intravenous rt-PA is the only licenced medical treatment for patients 
with AIS, on the basis of the pivotal National Institute of Neurological Disorders and Stroke 
(NINDS) trial published in 1995, in which 624 patients with AIS were treated with placebo or 
intravenous rt-PA (0.9 mg/kg IV, maximum 90 mg) within 3 hours of symptom onset.7 
Irrespective of age or stroke severity, and despite an increased risk of fatal ICH during the first 
few days after treatment, rt-PA significantly improves the overall odds of a good stroke 
outcome when delivered within 4.5 h of stroke onset, with earlier treatment associated with 
bigger proportional benefits.8   

 
 
  
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However, the global effect of the therapy is relatively limited, largely due to the narrowed time 
window for rt-PA, and contraindications such as a history of ICH, coagulation abnormalities 
and recent history of surgery. In addition, intravenous rt-PA is less effective to patients with 
LVO. Only about one-third patients with the internal-carotid-artery terminus have an early 
recanalization after receiving intravenous rt-PA, while other patients will generally have a poor 
prognosis.9, 10  
In recent guideline, MT with a stent retriever was recommended after receiving intravenous rt-
PA treatment within 4.5 hours of stroke onset, based on the results from five randomised 
controlled trials (RCTs: Multicentre Randomised Clinical Trial of Endovascular Treatment for 
Acute Ischemic Stroke in the Netherlands [MR CLEAN], Endovascular Treatment for Small 
Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to 
Recanalization Times [ESCAPE], Solitaire with the Intention for Thrombectomy as Primary 
Endovascular Treatment [SWIFT PRIME], Extending the Time for Thrombolysis in Emergency 
Neurological Deficits - Intra-Arterial [EXTEND-IA] and  Randomised Trial of Revascularization 
with Solitaire FR Device versus Best Medical Therapy in the Treatment of Acute Stroke Due 
to Anterior Circulation Large Vessel Occlusion Presenting within Eight Hours of Symptom 
Onset [REVASCAT]), which were carried out from 2010 to 2015 to evaluate the effects of 
endovascular treatment with primarily stent retrievers plus standard care in AIS patients.11-15 
The following two trials DAWN (DWI or CTP Assessment with Clinical Mismatch in the Triage 
of Wake-Up and Late Presenting Strokes Undergoing Neurointervention with Trevo) and 
DEFUSE 3 (The Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke) 
further extended the time window for MT with careful imaging selection.16, 17 Furthermore, the 
results of COMPASS (A comparison of direct aspiration versus stent retriever as a first 
approach) trial demonstrated that compared with stent retriever, direct aspiration had a non-
inferior functional outcome, with a shorter recanalization time.18 However, either intravenous 
rt-PA or MT has many utility limits with strict onset-to-treatment time, high request to hospital 
facility and capacity, as well as high cost.  
Although strong evidence supporting the use of MT, more evidence regarding on optimizing 
patient selection with imaging methods,16, 17 shorten door to puncture time (DPT),19, 20 and 
improving perioperative management, especially BP management before, during and after MT 
is warranted to facilitate the procedure and benefit more patients. 
4.2.3 Evidence on BP Control for AIS Patients with MT 
Although MT has significantly improved the rate of successful recanalization for patients with 
LVO, there is still a large proportion of patients who may have a poor outcome (Table 1). 11-17 
Except for recanalization status, one of the most powerful predictors of outcomes, other factors 
including baseline NIHSS score, time to reperfusion, age, hypertension, glucose levels, history 
of AF and occlusion site may contribute a lot to the outcomes of AIS patients with LVO in the 
anterior circulation.21 Among all the factors, BP control emerges as one of the most important 
controllable factors, which may promote a better outcome if good management has been 
implemented. However, the evidence on the optimal BP targets after MT, especially for those 
with successful reperfusion still remains undetermined. 
The optimal management of BP in AIS patients remains controversial 
The American Heart Association/American Stroke Association (AHA/ASA) guidelines 2018 
recommend maintaining BP ≤180/105 mmHg during and for 24 hours after the reperfusion 
therapy, and < 180/105 mmHg if with successful reperfusion for AIS patients who undergo 
MT.22 However, these recommendations are mainly based on the evidence of intravenous rt-
PA, as there very limited data to guide BP therapy before, during and after MT. 

 
 
  
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In particular, clinicians are confused over optimal BP management post-MT, especially for 
patients with successful recanalization, with variable opinions being expressed. Some 
recommend a level of 140-160 mmHg, while others insist on normalising systolic BP levels in 
the range 120-140 mmHg, and a minority consider maintaining high systolic BP around 180 
mmHg may enhance collateral blood flow.23, 24 A US survey of 58 institutions25 indicate that BP 
varies according to the success of reperfusion: for those with unsuccessful reperfusion, most 
institutions accept a systolic BP value ≤180 mmHg; whereas in patients with successful 
reperfusion there was inconsistency among institutions with 36% (n = 21) using a target 
systolic BP 120-139 mmHg, 21% (n = 12) 140-159 mmHg, and 28% (n = 16) any value ≤180 
mmHg. 
Table 1 Recanalization-outcome mismatch in RCTs 
Trials 
TICI 2b/3 
90d mRS 0-2 
MR CLEAN 11 
75.4% 
32.6% 
ESCAPE 12 
72.4% 
53% 
REVASCAT 13 
65.7% 
43.7% 
SWIFT PRIME 14 
88% 
60.2% 
EXTEND IA 15 
86% 
71% 
DAWN 16 
84% 
49% 
DEFUSE317 
76% 
45% 
Evidence on BP lowering after MT  
Some evidence indicated that higher BP levels were associated with poorer collateral status, 
worse recanalization results and adverse outcomes in patients with MT treatment.21, 26 
However, evidence on BP lowering and the optimal target after MT has not been established.  
Muilder et al. did a post-hoc analysis of the MR CLEAN trial, and confirmed a U-shaped 
association between baseline systolic BP and functional outcome, with both low and high 
baseline levels associated with poor outcome such that the optimum outcome nadir was 
around 120 mmHg.27 A prospective cohort study consecutively enrolled a total of 217 AIS 
patients with LVO, who had complete reperfusion after MT to evaluate the association between 
BP levels and the early outcome.28 The patients were stratified into 3 groups based on their 
post-MT BP levels (intensive <140/90 mmHg, moderate <160/90 mmHg and permissive 
hypertension <220/110 mmHg, or <180/105 mmHg for patients with intravenous thrombolysis). 
The results showed that high maximum systolic BP levels following MT were independently 
associated with increased likelihood of 3-month mortality and adverse functional outcome. 
Martins et al. conducted a retrospective cohort study in 674 AIS patients with acute reperfusion 
therapy (intravenous thrombolysis or intra-arterial therapies), and also identified a J-shaped 
association of BP in the first 24 hours and functional outcomes in those who failed 
recanalization, and a continuous association in those with complete recanalization.29 Finally, 
Goyal et al. found that wide BP excursions from mean level during the first 24 hours after MT 
were associated with poor prognosis.30  
However, the evidence based on all these studies is complicated by post-hoc bias, chance and 
confounding errors. Randomised clinical trials (RCTs) are warranted to reliably determine the 
optimal target of BP for informed recommendation in MT AIS patients. 

 
 
  
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Intensive BP lowering after reperfusion therapy for AIS patients appears safe   
Most AIS patients achieve successful recanalization after MT, with effective restoration of 
blood flow and less clinical concerns over sICH and other complications. High BP may cause 
brain injury through promotion of secondary edema and ICH from enhanced reperfusion in 
ischaemic tissue. Conversely, with impaired cerebral autoregulation in the context of AIS, 
intensive BP lowering may aggravate cerebral ischemia. Theoretically, the benefits may out 
way the risks of intensive BP control in patients with complete reperfusion post-MT.  
The Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED), was 
an international, randomised, open-label, blinded-endpoint, phase 3 trial that assessed the 
effects of intensive versus guideline-recommend BP lowering in thrombolysis-treated AIS.31 
Among a total of 2196 rt-PA eligible AIS patients with AIS, 1081 were allocated to the intensive 
group (target systolic BP 130–140 mmHg within 1 hour and 1115 to guideline group (target 
<180 mmHg) between 2012 and 2018. The mean systolic BP over 24 hours was 144 and 150 
mmHg in the intensive and guideline groups, respectively (P <0.0001). Although there with no 
improvement in the primary outcome of functional recovery, the results showed a reduction in 
ICH (odds ratio [OR] 0.75; 95% confidence interval [95% CI] 0.60-0.94; P = 0.0137), and no 
harms from intensive BP lowering within these ranges.31 
Intensive BP lowering may reduce the risk of sICH after MT   
Other studies have shown a reduced risk of sICH with lower systolic BP post-MT. Post-hoc 
analysis of MR CLEAN trial showed that higher systolic BP was associated with an increased 
risk of sICH (adjusted OR 1.25, 95% CI 1.09-1.44 per 10 mmHg increase).27 A retrospective 
cohort study of Martins et al. showed that systolic BP was an independent predictor of sICH 
(OR 1.032, 95% CI 1.014-1.049; P < 0.001),29 while another study showed that higher systolic 
BP over 24 hours post-MT were associated the more severe haemorrhage within 48 hours and 
worse 90-day functional outcome.32  
Rationale for intensive BP control in AIS after successful recanalization post-MT 
As from the evidence above, different reperfusion status may have different BP patterns. A line 
correlation between post-MT BP and outcomes may exist for patients who had successful 
recanalization post-MT. In addition, intensive BP lowering is safe and may potentially reduce 
the risk of ICH for patients with reperfusion therapy.  
Despite the neutral overall clinical effect seen in the ENCHANTED trial, intensive BP lowering 
after reperfusion therapy was safe and provided a strong signal for reduced harms associated 
from ICH/sICH. There were far too few MT patients included in ENCHANTED to make any 
sensible recommendations over the optimal BP management in this important clinical group. 
Thus, the hypotheses for testing in the ENCHANTED2 study is that intensive BP lowering post-
MT recanalized AIS patients leads to improved functional status with reduced ICH and no other 
harms. 
4.3 Summary 
Although MT provides effective recanalization for AIS patients with LVO, many patients survive 
with residual disability which appears related to systolic BP levels. There is considerable 
variation in the BP management for this important and increasingly large patient group where 
current guidelines are based on extrapolating data from those who have received thrombolysis 
treatment.7 A definitive randomised trial is required to guide clinical practice, worldwide. 
Reliable evidence is now required to guide the BP management for post-MT AIS patients who 
continue to have severe and devastating outcomes. This research program aims to (i) 
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outcomes for AIS patients with successful recanalization after MT (TICI ≥2b), and (ii) provide 
preliminary data to inform antithrombotic therapy in two nested additional randomised trials.  
5. AIMS AND OBJECTIVES 
5.1 Primary aim 
To test that compared with a higher systolic BP management strategy (140-180 mmHg), 
intensive BP lowering (systolic target <120 mmHg) after achieving successful recanalization 
from MT is superior on functional outcome (shift mRS) in scores on the modified Rankin scale 
(mRS) at 90 days in LVO patients with AIS (i.e. corresponding null hypothesis is that there is 
no difference in 90 day functional outcome between treatment groups).  
5.2 Secondary aims 
Compared with a higher systolic BP management target (140-180 mmHg), intensive BP 
lowering (systolic target <120 mmHg) after successful recanalization with MT leads to reduced 
risk of: any ICH; sICH; early improvement in neurological recovery as measured by NIHSS at 
7 days; imaging measurements of infarct size at 24-48 hours; death or major disability (mRS 
3-6); separately on death and disability (mRS 3-5); health-related quality of life (HRQoL) using 
EQ-5D; duration of hospitalisation; residence; and hospital service cost. 
6. METHODS   
6.1 Design  
ENCHANTED2 is an international, multicentre, prospective, randomised controlled, open 
label, blinded outcome assessment (PROBE) clinical trials involving 2257 AIS patients with 
LVO to be recruited from 80-100 hospitals in China, and up to 50 hospitals in other countries 
dependent on funding. Consent will be obtained upon the patient’s presentation to hospital 
and before undergoing the cerebral angiography, but randomisation will be undertaken post-
MT according to eligibility criteria. Randomised allocation (1:1 ratio) of intervention will be 
done in a, using a central, automated, mobile APP-based randomisation software according 
to minimized method stratified by hospital, time from onset to recanalization (<6 vs ≥6 hours), 
NIHSS scores at admission (<17 vs ≥17). All required data will be collected by investigators 
and entered into internet-based electronic data capture (EDC) system. Endpoint 
assessment will be undertaken by experts blind to treatment allocation. The study design is 
summarised in Figure 1. 
6.2 Study Population  
All AIS patients presenting to participating centres with LVO confirmed by brain imaging, 
who meet standard criteria for MT therapy according to local guidelines will be considered 
for the trial. Primary responsibility for recruitment of patients will lie with each site Principle 
Investigator (PI). It is anticipated that successful recruitment will require the active 
involvement and disciplinary cooperation of stroke team staff, including emergency 
department, neurologists, interventionists and anaesthetists, since rapid referral and 
treatment of patients early after symptom onset and successful recanalization after receiving 
MT therapy is required. Rate limiting steps after presentation are anticipated to include:   
1) completion of brain imaging 
2) receipt of informed consent 
3) assessment at admission and completion of MT-related procedures 
4) assessment of patients eligible to receive intensive BP lowering treatment after 
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5) administration of randomised treatments    
In order to facilitate recruitment, study centres should try to obtain consent from the patient 
or guardian before the MT procedure, and to confirm/determine a patient’s eligibility as early 
as possible within 3 hours after the LVO is successfully re-canalized according to TICI score, 
and with the goal of the randomisation-to-treatment time being 15 minutes.    
All devices for MT approved by China Food and Drug Administration (CFDA) for this 
purpose, are allowed in the trial as a first line of devices. Other mechanical devices are 
allowed as a second option, when the first device has failed according to the interventionist, 
usually after 3 passes (Appendix 2). The further choice of the particular device for a certain 
patient is left to the discretion of the interventionist. 
Figure 1. Study schema  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.3 Inclusion / exclusion criteria 
To be eligible for inclusion for this study, patients ARE to satisfy all of the following criteria: 
1) Adult (age  ≥18 years) 
2) Clinical diagnosis of AIS with LVO (anterior or posterior circulation) on imaging 
3) To receive MT <24 hours after AIS onset according to local guidelines 
4) Successful recanalization (TICI score ≥2b) 
5) Sustained systolic BP ≥140 mmHg (defined as 2 successive readings <10 minutes) 
within 3 hours after recanalization 
6) Provide informed consent (or by appropriate proxy, according to local requirements) 
   Acute LVO patients for MT with TICI score ≥2b  
   BP ≥140 mmHg <3 hour post-MT 
Baseline, Day 1, Day 7 
Clinical and imaging data collection 
R 
Day 90 functional outcome  
modified Rankin scale (mRS) scores 
Intensive BP lowering  
SBP <120 mmHg <1 hour 
Maintain for 72 hours 
Higher BP target 
Treatment only if SBP >150mmHg  
Maintain for 72 hours 
Standard 
nursing 
and 
medical 
care  
(Local 
Guidelines) 

 
 
  
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Patients will NOT be eligible if there is one or more of the following: 
1) Considered unlikely to benefit from therapy (e.g. advanced dementia, major pre-
stroke disability, high likelihood of death within 24 hours post-MT on the basis of 
clinical assessment), as judged by the responsible treating clinician 
2) Other medical illness that interferes with outcome assessments and follow-up (e.g. 
known significant pre-stroke disability (mRS scores 3-5), advance cancer and renal 
failure) 
3) Definite indication/contraindication to either immediate intensive BP lowering (SBP 
<120 mmHg) or a higher BP target (SBP 140-180 mmHg) 
4) Specific contraindications to any of the BP agents to be used (eg, patients who are 
hypersensitive (allergic) to any of the ingredients)  
5) Patients with aortic isthmus stenosis and arteriovenous shunt (exception: patients 
with haemodynamically inactive dialysis shunt) 
6) Women who are lactating 
7) Currently participating in another trial which may interfere with outcome assessments  
All AIS patients screened for the study that are not included, as well as recruited patients, 
must be recorded on a screening/enrolment log. This information is to be uploaded to the 
CCC database. The decision of eligibility is on the attending clinician’s interpretation and 
consideration for the balance of potential benefits and risks pertaining to the level of BP 
control on each particular patient. 
6.4 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).  
6.4.1 Institutional ethics committee approval  
Each participating centre must obtain written approval(s) from their Hospital Human 
Research Ethics Committee (HREC) (or 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 site PI, who has the responsibility of delegating aspects of 
the study procedures to prospectively approved members of his research staff.  
6.4.2 Consent  
The majority of patients admitted with AIS require emergency care, and aspects of MT 
therapy and management of hypertension need to be undertaken urgently.  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 which needs to be obtained swiftly to avoid 
delays in urgent treatment. The optional consent procedures for this study are detailed 
below and should be followed according to local IRB guidelines.  
Ideally, the consent to participate in the study is to be undertake prior to MT, and only 
patients who are eligible post-MT will be randomised into the study. 
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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.    
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.  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 the approval of a guardianship 
tribunal or other appropriate authority, before enrolling eligible patients into 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.  
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 

 
 
  
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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 National Health and Medical Research Council (NHMRC) also give 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 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 BP management 
after MT in the medical profession and the current guidelines.      
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.  
6.4.3 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 CCC at TGI, CHINA 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. This 
information will be included in the PISCF.   
6.5 Site selection 
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1) Have an established acute stroke service (i.e. in an acute stroke unit, neurosurgical 
unit, neurology unit), defined by (i) having staff organised as part of a coordinated 
multidisciplinary team; (ii) having staff with some knowledge and skills in the stroke 
management; (iii) have staff interested and capable of participating in research; 
2) At least 50 cases of MT per year; 
3) Multimodal imaging (CT angiography (CTA) / CT perfusion (CTP) and/or MRI) is 
available; 
4) Obtain necessary HREC and other relevant approvals from hospital management;  
5) Agree to enter data via the internet to a secure server built and based on the Taimei, 
Alibaba cloud, in China; 
6) Nominate key research staff assigned to the project to obtain consent from participants;  
7) Comply with the requirements of good clinical practice (GCP/ICH-GCP); 
8) Agree to the following conditions:  
➢ adhere to the protocol 
➢ collect data on patients’ stay in hospital 
➢ record any SAEs noted during the 3 months of follow-up of patients 
➢ Sign a contract agreement before the commencement of recruitment.  
Responsibilities of the regional leader are: 
1) work with hospitals to ensure investigators comply with the protocol in a seamless way; 
2) provide regular training for MT and oversee the operation procedures after patient 
enrolment; 
3) liaise with the CCC staff on issues of site eligibility. 
Responsibilities of the site PI are: 
1) ensure all sub-investigators, nursing staff and coordinators, undertake the necessary 
pre-study training programs regarding the protocol and positioning of the patients;  
2) agree to comply with GCP/ICH-GCP requirements; 
3) submit and obtain EC approval and ensure compliance to EC requirements;  
4) receive training on the protocol, and to ‘champion’ the study at the hospital;  
5) provide refresher training for existing and new staff on the intervention on a regular 
basis; 
6) conduct spot checks adherence to the randomised intervention; 
7) assist in problem-solving and propose solutions to resolve any local issue that may 
pose a barrier to the adherence to the intervention; 
8) oversee the data collection; 
9) conduct spot checks of the patient screening and enrolment log (Form A); 
10)  record and report all SAEs during 3 months’ follow-up period. 
In the selection of suitable sites, there is a healthcare organization questionnaire (HOQ), 
provided by local leader to collect preliminary information about the site, so the CCC can 
ascertain the suitability of the site to participate in the study.  

 
 
  
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Hospital organisational questionnaire (HOQ):  To assist the implementation of the 
intervention in each site, it is important to know the organisational structure of the site and 
the various areas within the site that will be involved in the intervention. Therefore, each site 
will have to complete a HOQ to assist the CCC prepare the training and site initiation visit.   
6.6 Randomisation  
After confirmation of eligibility within 3 hours post-MT, patients will be randomised via a central 
mobile APP-based, password protected randomisation system developed by Taimei, China. 
This will be done by connecting the study centre (e.g. catheter lab or stroke unit) to the server 
at Ali Cloud where the patient will be registered and the randomised treatments will be 
assigned for each 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 to recanalization (<6 vs ≥6 hours)  
3) NIHSS score at admission (<17 vs ≥17) 
6.7 Treatments Allocation 
Attending clinicians are 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. 
Intensive BP lowering group  
The aim is to achieve a systolic BP level of <120mmHg within 1 hour after randomisation 
and to maintain this BP level for the next 72 hours (or until hospital discharge or death if this 
should occur earlier). A standardised intravenous (i.v.) BP lowering regimen using locally 
available and approved i.v. BP lowering agents will be used, commenced immediately after 
randomisation in either the catheter lab or a high dependency area (e.g. acute stroke or 
neurointensive care unit) as is usual for patients receiving MT.  
BP lowering will be titrated by repeat i.v. bolus or infusion, with a systolic BP of 100 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 antihypertensive therapy, to maintain the systolic BP levels 100-120 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 generalizable to existing routine practice, some 
flexibility is allowed in the use of locally available i.v. agents (e.g. urapidil, hydralazine, 
metoprolol, clevidipine), but all other aspects treatment are standardized 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 
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I.v. treatment protocol  
I.v. treatment protocols, based on available medications, are provided in Appendixes 1A to 
1F. The i.v. treatment will be titrated against regular BP monitoring to achieve a target 
systolic BP range (100-120 mmHg) within 3 hours after successful reperfusion with MT. It is 
anticipated that i.v. control of systolic BP will be required for at least several hours.  
Oral treatment protocol  
The switch from i.v. 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.  
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 <120 mmHg for at least 
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 <120mmHg. The target systolic BP after hospital discharge remains 130/140 mmHg, as 
guideline-based recommendations for second stroke prevention. BP levels will be reviewed 
at 90 days follow-up and medication adjusted as necessary to maintain systolic BP 
<130/140 mmHg as per contemporary guidelines.  
Control group (higher BP target) 
Patients allocated to the control group will receive management of BP to maintain systolic 
BP 140-180mmHg. Appendix 1G outlines the protocol for control patients. For this group, 
the attending clinician should stop BP lowering treatment if the systolic BP is ≤150 mmHg 
in order to maintain a higher BP target level of 140-180 mmHg comparing to intensive group. 
The oral and i.v. agents used will be the same as in the intensive BP lowering group as 
detailed in Appendixes 1A to 1G. Oral antihypertensive 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 <130/140 mmHg, as per contemporary 
guideline-based recommendations for high risk cardiovascular disease patients.  
Discontinuation of allocated management  
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.  
6.8. Study Outcomes 
Primary outcome 
Functional outcomes defined as a shift (improvement) in scores on the mRS at 90 days (3 
months). The mRS is a widely used instrument for grading the impact of stroke treatments, 
with scaling of: 0 = no symptoms at all; 1 = no significant disability despite symptoms, but 
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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:  
1) ICH: a) sICH, based on National Institutes of Neurological Diseases and Stroke 
(NINDS) criteria of brain imaging (or necropsy) confirmed ICH with ≥ 1 points 
deterioration in NIHSS score or death within 36 hours from baseline; b) sICH, defined by 
Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) criteria, 
as large (‘type II’) parenchymal ICH with ≥ 4 points decline in NIHSS score or death within 
36 hours from baseline; c) sICH, defined by the new Heidelberg Bleeding Classification 
(HBC) criteria; d) ICH of any type in brain imaging ≤ 7 days of treatment; e) any 
symptomatic ICH (sICH) after MT within 90 days. ICH will be assessed by CT imaging 
and adjudicated centrally.33 
2) Imaging endpoints: a) infarct size growth assessed by MRI at 48 hours; b) edema 
volume assessed by CT at Day 7. 
3) Death or dependency measured by NIHSS at 7 days;  
4) The followings at 90 days: Death or major disability (mRS 3-6); separately on death 
and disability (mRS 3-5); health-related quality of life (HRQoL) using EQ-5D; duration of 
hospitalisation; residence and hospital service cost.  
6.9 Economic Evaluation 
Economic evaluation provides value judgement for health policy makers when they consider 
to scale-up the health intervention. In ENCHANTED2 trial, the intervention of BP lowering will 
be initiated after successful recanalization and the BP target will be maintained for at least 3 
days (or hospital discharge if earlier). Since an increasing number of patients receive MT 
annually, it is important to know whether the ENCHANTED2 is cost effective compared to the 
conventional care. A within-trial economic evaluated will be conducted to compare the 
incremental costs including costs of intervention and difference in health service cost versus 
the incremental effectiveness which is expressed using quality-adjusted life years (QALYs). 
The (trial-based) incremental cost effectiveness ratio will be calculated and then compared to 
the willingness-to-pay threshold in China and other countries to determine the cost-
effectiveness of ENCHANTED2. The economic evaluation will be conducted from the 
healthcare payer’s perspective.  
6.10 Data Collection and Follow-up 
Registration, baseline assessment, and randomisation should be achieved over 15 minutes. 
Doctor/nursing attendance with the randomised patient is likely to be required for 1-2 hours 
post-randomisation to ensure the titration of BP lowering in the active group, and consistent 
BP recordings. All patients are followed daily for 1 week, and then 90 days unless death occurs 
earlier. Key demographic and clinical data will be collected at randomisation. Follow-up data 
will be collected on 3 occasions: 24 hours, 7 days (or hospital discharge if sooner), and 90 
days. The 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. Brain imaging (CT scan and/or 
MRI, with any associated diffusion/perfusion and angiogram images) will be conducted 
according to standardized techniques at baseline, within 24-48 hours (ie next day follow-up 
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reason during follow-up. Brain imaging (CT scan and/or MRI) must be uploaded to the 
ENCHANTED2 server, either directly from the hospital site (if they have suitable broadband 
internet) or via the RCC office, to be analyzed centrally for measurement of any ICH or 
haemorrhagic complications of the ischemic lesion, and for future measurement of areas of 
infarction, ischemic penumbra, and site of LVO. The LCC will keep a hard copy in an 
uncompressed DICOM format onto a CD-ROM for monitor site verification (see Appendix 3). 
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 analyzed on the ‘intention to treat’ principle. Table 
3 illustrates the schedule and nature of the data collection required during the study period. 
The paper version of the case reports 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.  
6.10.1 Screening Logs  
Each site should keep log of all AIS patients with LVO confirmed by brain imaging arriving <24 
hours of symptom onset (or last known well) 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 CCC 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.  
6.10.2 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 CCC.  
6.10.3 Randomisation Assessment (Form A) 
All AIS patients obtaining successful recanalization after MT 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.  
6.10.4 Baseline Data (Form B) 
The following information is to be collected on admission:  
• 
BP, Heart rate (HR) and blood glucose (BG) at admission 
• 
Demography, and medical history  

 
 
  
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• 
Medications at time of admission  
• 
Baseline GCS and NIHSS scores 
• 
Initial brain imaging (CT and/or MRI)  
• 
Other imaging (CTA/MRA, CTP/MRP, DSA) 
• 
Management with rt-PA if performed 
• 
Details of MT procedure: anesthesia methods, use of GP IIb/IIIa receptor inhibitors, MT 
device(s) and their sequence, number of retrieval attempts, door-to-puncture time 
(DPT), onset to reperfusion time, TICI score after MT, NIHSS score after MT. 
• 
Baseline blood tests and electrocardiogram (ECG) 
• 
Pattern of neurological deficits  
6.10.5 Follow up Data  
Day 1 (Form C) 
The primary goal of assessments within the first 24 hours will be to ensure adherence to the 
allocated the 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. 
BP will be recorded every 15 minutes for the first hour, then hourly for the next 5 hours, and 6 
hourly from 6 hours to 24 hours. When i.v. boluses are given, HR and BP should be re-checked 
and recorded 5 and 15 minutes later. The following information will be recorded.  
• 
BP  
• 
BP lowering medication  
• 
GCS and NIHSS scores at 24 hours  
• 
Follow up brain imaging (CT brain and/or MRI) should be undertaken at 24-48 hours 
post-MT  
• 
If other imaging investigations are performed (i.e. transcranial Doppler), these should 
be documented in the CRFs  
• 
Antithrombotic medications 
• 
Follow up blood tests  
• 
Standard stroke care assessment  
Day 7 or discharge if earlier (Form D) 
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:  
• 
GCS and NIHSS score 
• 
Dependency assessed with the mRS 
• 
BP 
• 
BP lowering medication (medications used during Days 2 to 7) 
• 
Medications and key specific treatment received during hospitalization  
• 
Other aspects of acute stroke management during hospitalization 

 
 
  
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• 
Prognosis prediction from clinicians 
• 
Date of discharge or transfer from hospital  
• 
Repeat brain CT or MRI 
• 
Healthcare costs and details of blood pressure lowering treatment. 
BP Monitoring Chart (Form E) 
As usual nursing care during the study period, the BP assessments in 7 days will be used to 
check adherence to BP management protocol. 
Day 90 Follow-up (Form F) 
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 90±7 
days, all surviving patients will be evaluated through a telephone interview or at a face-to-face 
consultation.  
Detailed resource utilization data, hospital billing data, physical function and patient reported 
quality of life data were collected for patients from the time of randomisation through 90-day 
follow-up. These data were used to calculate direct healthcare costs and QALY during the 
initial 90-day period based on international and national guidelines.34, 35 
• 
BP 
• 
Dependency assessed with the mRS 36 
• 
HRQoL measured by the EQ-5D 37 
• 
Patient living status (e.g. home, high care) 
• 
Any complications or hospitalization since going home 
• 
Any medication currently used 
• 
Healthcare related cost. 
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 CCC. An SAE form is to be completed for all deaths during the 
study period, stating the primary and underlying cause of death. 
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 CCC within the prescribed time. Additional information 
may be requested to provide supplementary information on the event and outcome. 

 
 
  
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Table 2 Schedule of evaluations 
Evaluation 
Baseline (Prior 
Randomisation) 
Day 
 
1 
7a 
90b 
365b 
Eligibility 
X 
 
 
 
 
Brain imaging (CT ± 
angiogram or MRI± 
angiogram or DSA) 
X 
X 
X 
 
 
BP 
X (BP x 2) 
X** q 15 
min 1h 6h 
X q12h 
X 
 
HR 
X 
 
 
 
 
ECG 
X 
 
 
 
 
Consent 
X 
 
 
 
 
Medical history, prior 
medications 
X 
 
 
 
 
Details of rt-PA (if 
performed) and MT 
X 
 
 
 
 
Physical exam GCS/ 
NIHSS 
X 
X 
X 
 
 
Functional assessment 
with mRS 
X 
 
X 
X 
 
HRQoL assessment 
with EQ-5D 
 
 
 
X 
 
Routine blood tests 
X 
X 
 
 
 
BP lowering treatment 
 
X 
X 
X 
 
Antithrombotic and 
other medications 
 
X 
X 
X 
 
Standard stroke care 
 
X 
X 
 
 
Hospitalized or not 
 
 
X 
X 
 
Contact details for 
Follow-up 
 
X 
X 
 
 
Hospital service cost 
 
 
X 
X 
 
SAEs 
Xc 
X 
X 
X 
X 
** At any point where intravenous antihypertensive agents are administered, BP and HR should be recorded 5 and 15 minutes 
later.  
(a) Or the day of discharge if prior to day 7. 

 
 
  
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(b) Information collected at a face to face consultation or through a telephone interview. 
(c) After informed consent. 
 
7. SAFETY 
7.1 Data and Safety Monitoring Board (DSMB) 
Responsibilities: Monitor efficacy variables and safety outcomes for early dramatic benefits or 
potential harmful effects and provide reports to the SC on recommendations to continue or 
temporarily halt recruitment to the study. The DSMB will be governed by a charter that will 
outline their responsibilities, procedures and confidentiality. They will review unblinded data 
from the study at regular intervals during follow-up and monitor BP differences between the 
two groups, drop-out, and event rates. The first meeting will be held within 3-6 months after 
the start of the study recruitment. Two formal interim analyses will be planned to review data 
relating to treatment efficacy, participant safety and quality of trial conduct. Prior to the first 
interim analysis a detailed plan will be developed to: 
• Describe the methodology to be used in the statistical analyses.  
• Specify rules if the study is to be halted. 
• Specify rules on data handling conventions used to perform the analyses.  
• Describe the procedure to be used to account for missing data.  
• Outline interim analysis. 
7.2 SAEs  
7.2.1 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  
• 
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  
7.2.2 Recording and Reporting  
A 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 

 
 
  
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should be reported to the CCC 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.  
7.2.3 Monitoring of SAEs  
The CCC 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 CCC will submit all SAEs to the independent Data Safety Monitoring Board 
(DSMB) for review outside of the planned interim analysis meetings.  
8. QUALITY ASSURANCE  
The study will be conducted at sites which successfully pass the site selection process, in 
accordance with the principles of the ICH-GCP and all relevant local, national and international 
guidelines and regulations. RCCs will be set-up in the various regions to facilitate the 
compliance of the protocol to local requirements. The RCCs will receive training and assistance 
to set-up documentation required for the study from the CCC. There will be regular 
meetings/teleconference between the RCC and CCC staff. Manuals and Guidance will be 
developed by the CCC in liaison with the Operations committee (OC). 
8.1 Monitoring of Participating Centres/Sites  
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 CCC, 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 CCC. 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 CCC 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. 
A report of each visit will be prepared by the monitor and reviewed by the CCC.  
In summary, the specific aims of the monitoring program will be to:  
• 
confirm the existence of each patient  
• 
confirm that the consent procedure has been documented  
• 
confirm the eligibility of each patient  
• 
review source documents for 100% of the SAEs and primary outcomes  
• 
review 100% of source data from 10% of randomly selected patients at each centre  
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 5 years).  

 
 
  
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8.2 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 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.  
9. DATA MANAGEMENT  
The internet based data management system is managed at Taimei, which has extensive 
experience in clinical trial data capture and security. Registration and data entry will be 
performed at the participating sites via the password protected, via the encrypted HTTPS 
connection. Only staff listed in the delegation log will be given unique individual password to 
access the internet-based data management system.  
This system, developed by Taimei for data capturing and the data variables will have logic 
checks within the acceptable ranges and mandatory fields to ensure accuracy and reduce 
missing data. Reports and data query management will also be included in the system to assist 
with centralised online monitoring by the CCC and the RCC.  
Paper CRFs will be provided for sites preferring to use these for the initial collection of data. 
These forms will be used as source document and will need to be signed and dated by the 
investigator completing the form. 
All computerized forms will be electronically signed (by use of the unique password) by the 
authorised study staff and all changes made following the initial entry will have an electronic 
dated audit trail.  It is the requirement that the collection of data and transfer of information for 
the 90 day follow-up assessment has to be approved by the local IRB for each site.   
10. STATISTICAL CONSIDERATIONS 
10.1 Sample Size  
The study is designed with 90% power to detect an odds ratio (OR) of 0.77 at 90 days between 
the randomised groups in AIS patients with successful post-MT reperfusion using an ordinal 
logistic regression. Assuming a distribution of mRS in control group is 10.0%, 16.9%, 19.1%, 
16.9%, 15.6%, 6.2%, and 15.3% for scores of 0 to 6, respectively, corresponding to a 6.48% 
absolute decrease in the proportion of patients experiencing a bad outcome (mRS of 3-6), from 
54% down to 47.52%, according to the results of the meta-analysis made by HERMES 
collaboration.38 This also translates to a 12% relative risk reduction (relative risk of 0.88). The 
sample size is 2257 subjects to demonstrate this treatment effect with 90% power and 4.82% 
type-1 error which we used the Haybittle-Peto boundaries taking into account 2 interim analyse 
during the study period. The sample size allows for 5% lost to follow-up and 5% drop-in/drop-
out.  
10.2 Statistical Analyses  
The intention to treat (ITT) principle will be applied in analyzes. Baseline characteristics will be 
summarised by treatment group. The primary end-point will be analyzed by means of an ordinal 
logistic regression with adjustment for stratification variables. Sensitivity analyses including 
additional covariate adjustments and different assumptions about the missing data mechanism 
will be conducted to assess the robustness of the results. Continuous endpoints, such as blood 
pressure will be analysed using a repeated-measure linear mixed model adjusted for the 
stratification factors. The number of patients reporting any SAE, the occurrence of specific 
SAEs, and discontinuation due to SAEs, will be tabulated using MedDRA terminology. 

 
 
  
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Heterogeneity of treatment on the primary endpoint and sICH will be assessed in subgroups: 
age (<65 vs ≥65 years), onset time to recanalization (<6 vs ≥6 hours), systolic and diastolic BP 
(above vs below median), ethnicity, presumed etiological AIS subtype, NIHSS at baseline 
(above vs below median), ASPECT score (<6 vs ≥6) in the intensive BP lowering group, 
whether the patients enrolled after 6 hours meet DEFUSE 3 perfusion imaging criteria late 
window thrombectomy (ASPECT score and perfusion imaging criteria will be assessed by 
RAPID software, which will be installed at the sites by iSchemaView, Inc.).  
Details of all analyses will be specified a priori in a full Statistical Analysis Plan (SAP).  
We anticipate conducting 2 interim efficacy analyses when 30% and 60% of the 90-day data 
are available and using Haybittle-Peto stopping boudaries. The α-level for the final analysis 
will be the conventional significance level (α = 0.0482). 
11. SUBSTUDIES OF SECONDARY PREVENTION 
Patients who survive an AIS are at high risk of a recurrent event, which is often more disabling, 
fatal and costly. The risk of recurrent AIS is highest within the first month after the initial event, 
with event frequencies being approximately 1% at 6 hours, 5% at 7 days and 10% at 14 days.39-
41 Moreover, recurrent AIS constitute a substantial proportion (25-30%) of all preventable 
strokes, which highlights the importance of effective secondary prevention.42  Immediate and 
sustained implementation of appropriate secondary prevention strategies in patients with first-
ever AIS is an important aspect of efforts to reduce the burden of AIS.  
11.1 Timing of initiating anticoagulation therapy in AIS patients with MT 
11.1.1 Aims 
Compared with late initiation of anticoagulation (commence therapy at Day 12±2 of stroke 
onset), early initiation (commence therapy at Day 4±2 of stroke onset) is superior at improving 
net benefit by balancing AIS recurrence and bleeding within 90 days in patients with AF-related 
AIS due to LVO who receive MT.  
11.1.2 Background and Rationale 
Anticoagulation therapy for secondary prevention in AF-related AIS 
Cardioembolic AIS, most often attributable to non-valvular AF, accounts for approximately 13–
26% of all AIS,43, 44 and the frequency is likely to be higher in patients who have MT for LVO.44-
46  Aspirin is less effective than warfarin anticoagulation in preventing recurrent AIS in patients 
with AIS related to AF.45  Vitamin K antagonists (VKAs) are, therefore still recommended as 
first-line therapy in patients with AF in many countries. Compared with aspirin, warfarin with 
an international normalised ratio (INR) of 2.0-3.0 can significantly reduce the risk of recurrent 
AIS and systemic embolism (OR 0.49, 95% CI 0.33-0.72), despite an increased risk of major 
extracranial bleeding events (OR 5.2, 95% CI 2.1-12.8).45, 46 However, four direct oral 
anticoagulants (DOACs), apixaban, dabigatran, edoxaban and rivaroxaban, have been 
approved for stroke prevention in patients with non-valvular AF since 2010.47-50 Various 
systematic reviews and meta-analyses have shown that DOACs are at least as effective as 
VKAs in primary and secondary prevention of stroke, but with reduced risk of ICH.51, 52  
Current guideline recommendations on timing of initiating oral anticoagulation therapy 
Current guidelines are inconsistent in their recommendations regarding timing of initiation of 
oral anticoagulation therapy after recent AF-related AIS.  In 2013, the European Society of 
Cardiology (EHRA-ESC) introduced ‘1-3-6-12’ rule to guide oral anticoagulation therapy, which 
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few days and delaying initiation for large infarcts with higher risk of HT.53  However, such time-
points and definitions of stroke severity are based on expert consensus.  The AHA/ASA 2018 
guidelines recommend a wide window (4-14 days) for commencing oral anticoagulation after 
symptoms onset in AF-related AIS, based on mainly on the findings of the Early Recurrence 
and Cerebral Bleeding in Patients With Acute Ischemic Stroke and Atrial Fibrillation (RAF) 
study,22, 54 of a prospective cohort of 1029 consecutively enrolled AIS patients and known or 
newly diagnosed AF. The results indicate that initiating anticoagulants 4-14 days from stroke 
onset was associated with a significant reduction in primary composite event outcome, 
compared with initiation either before 4 or after 14 days (adjusted HR 0.53, 95% CI 0.30-0.93). 
54 However, no guidelines distinguish between VKAs and DOACs, despite there are substantial 
differences in the mechanism and pharmacodynamics of these compounds.  
Uncertainty over the optimal timing of initiating anticoagulation therapy in patient with 
acute AF-related ischemic stroke 
The optimal timing of OAC following an AIS is unknown. The risks of both early recurrence and 
HT are highest in the first few days.55, 56 So initiating OAC in this period could offer benefits, 
but how much of these offset by early major bleeding is uncertain.57, 58 Clinicians intend to 
delay initiation of anticoagulation therapy in those who they suspect are at increasing risk ICH, 
based on petechial or parenchymal ICH.58,59  An online survey of UK stroke physicians showed 
that 95% were uncertain about optimal timing.44  
Several non-randomised, prospective observational studies have explored the potential risks 
and benefits of early anticoagulation with DOACs in patients with AF-related AIS. Seiffge et al. 
assessed the risk of both ICH and recurrent AIS with different initiation time of DOACs during 
follow-up (at least 3 months) in 204 patients.60  The study showed the rate of recurrent AIS 
was 6 times higher than ICH, and there was no significant difference on recurrent AIS between 
early (<7 days) and late (>7 days) start of a DOAC. cRAF-NOACs, a prospective observational 
multicentre study, included 1127 AF-related AIS patients treated with DOACs to evaluate the 
risk of early recurrence and major bleeding within 90 days,61 showed that the primary outcome 
occurred in 12.4% of those with DOACs initiated within 2 days after onset, 2.1% between 3 
and 14 days, and 9.1% after 14 days (P <0.0001). However, the multivariate model estimated 
no signiﬁcant marginal effect with the timing of administration (<3 days as reference, 3-7 days: 
OR 1.30, 95% CI 0.54-3.71; 8-14 days: OR 1.44, 95% CI 0.36-3.02; >14 days: OR 0.59, 95% 
CI 0.15–1.95). In addition, Wilson et al. found that compared with late OAC (5 days and 
onwards or anticoagulation never started), early OAC (4 days or earlier) after AIS/TIA 
associated with AF was not associated with a significant difference in the rate of the composite 
outcome of stroke/TIA or death at 90 days, after adjustment for confounding baseline 
variables.57  
All these studies suggest that early DOAC administration in patients with AF-related AIS has 
a low frequency of ICH (including HT). However, these observational studies are limited by 
indication bias where patients suspected of lower risk of ICH are more likely to receive early 
treatment. They are also biased towards the inclusion of mild-moderate severity of stroke 
(median NIHSS scores 3–8) and small infarcts (generally less than one third of affected arterial 
territory).  
Ongoing trials of early versus late initiation of DOAC anticoagulation therapy 
Several ongoing RCTs are investigating the balance of risk and benefit of early versus late 
initiation of DOACs in patients with a recent AF-related ischemic stroke (Table 3): ELAN 
(NCT03148457; Switzerland), OPTIMAS (EudraCT, 2018-003859-38; UK), TIMING 
(NCT02961348; Sweden), and START (NCT03021928; USA).44  All these studies use any 

 
 
  
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stroke (includes both AIS and ICH), and 3 include mortality, as the primary outcome.  A pooled 
individual patient data meta-analysis of these trials is planned. 
Rationale of early initiation of anticoagulation therapy in AF-related AIS patients due to 
LVO treated with MT 
Although the patients who received MT procedure after AIS due to LVO have increasing risk 
of HT (given having higher average baseline severity, the procedure itself and reperfusion 
injury), early initiation of anticoagulation therapy may bring bigger net benefit via reduced risk 
of recurrent AIS and improving patient compliance when medication is started in hospital. In 
addition, successful reperfusion after MT and usage of DOACs may further reduce the risk of 
HT through decreasing infarct size and increasing safety. 
Summary 
Although the effectiveness of anticoagulation for secondary prevention of recurrent AIS is 
well recognized, the optimal timing of this therapy after symptom onset remains uncertain 
due to the perceived increased risk of ICH. Although several ongoing trials may provide 
robust evidence to assess the safety and efficacy of early DOAC treatment, it is unlikely that 
they will recruit an adequate sample of high-risk patients who have received MT procedure. 
We have included a specific substudy to determine the balance of effectiveness and safety of 
early initiation of anticoagulation in patients with AF-related AIS who receive MT. 

 
 
  
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Table 3 Summary of ongoing RCTs investigating early versus late initiation of DOACs in patients with recent AF-related ischemic stroke 
 
Sample size 
Intervention 
(early initiation) 
Control  
(late initiation) 
Follow-up 
period 
Primary Outcomes 
Patients 
with HT 
included 
NIHSS 
Exclusion 
criteria 
Estimated 
end of 
study 
ELAN 
NCT03148457 
2000 
<48 h after 
symptom 
onset (minor and 
moderate stroke) or 
at day 6 (±1 day) 
after symptom onset 
(major stroke)* 
Current recommendations 
(ie, minor stroke after day 
3 [±1 day], moderate 
stroke after day 6 [±1 day] 
and major stroke after day 
12 [±2 days])* 
30 days 
(secondary 
outcomes 
after 90 days) 
Composite outcome (major bleeding, 
recurrent ischaemic stroke, systemic 
embolism, or vascular death, or a 
combination of these outcomes) 
Yes 
No 
Exclusion 
criteria 
Oct 2021 
OPTIMAS 
NCT03759938 
EudraCT, 2018-
003859-38 
3474 
≤4d 
7-14d 
90 days 
Composite outcome at 90 days (combined 
incidence of recurrent symptomatic ischaemic 
stroke, sICH [including extradural, subdural, 
subarachnoid and ICH, and HT of the 
qualifying infarct], and systemic embolism) 
Yes 
No 
Exclusion 
criteria 
2021–22 
TIMING 62 
NCT02961348 
3000 
≤4 days after acute 
ischaemic stroke 
5–10 days after acute 
ischaemic stroke 
90 days 
Composite outcome (recurrent ischaemic 
stroke, sICH, or all-cause mortality, or a 
combination of these outcomes) 
Yes 
No 
Exclusion 
criteria 
Dec 2020 
START 
NCT03021928 
1500 
(1000 patients 
with mild or 
moderate 
stroke, 500 with 
severe stroke)  
Time-to-treatment 
delay of 3, 6, 10, or 
14 days for mild or 
moderate stroke; 6, 
10, 14, or 21 days 
for severe stroke† 
Time-to-treatment delay of 
3, 6, 10, or 14 days for 
mild or moderate stroke; 6, 
10, 14, or 21 days for 
severe stroke† 
30 days 
(secondary 
outcomes 
after 90 days) 
Composite of any CNS haemorrhagic or 
other major haemorrhagic events and 
the ischaemic events of stroke or systemic 
embolism within 30 days of the index stroke 
Yes 
Score >3 
and score 
<23 
Aug 2021 
NIHSS: National Institutes of Health Stroke Scale; sICH: symptomatic intracranial haemorrhage. 
ELAN=Early Versus Late Initiation of Direct Oral Anticoagulants in Post-ischaemic Stroke Patients with Atrial fibrillation. OPTIMAS=OPtimal TIMing of Anticoagulation after AF-
associated acute cardioembolic ischaemic Stroke. TIMING=Timing of oral anticoagulant therapy in acute ischemic stroke with atrial fibrillation. START=Optimal Delay Time to 
Initiate Anticoagulation After Ischemic Stroke in Atrial Fibrillation.  
*Small infarct size is defined by lesions smaller than 1·5 cm in the anterior or posterior circulation; medium infarct size by lesions in a cortical superficial branch of middle cerebral 
artery (MCA), in the MCA deep branch, in the internal border zone territories, in a cortical superficial branch of posterior cerebral artery, or in a cortical superficial branch of the 
anterior cerebral artery; large infarct size by lesions that involve the complete territory of MCA, posterior cerebral artery, or anterior cerebral artery, in two cortical superficial 
branches of MCA, in a cortical superficial branch of MCA associated to the MCA deep branch, or in more than one artery territory.  
†Minor stroke is defined by a NIHSS score <8, mild stroke by a NIHSS score of 8–15, and severe stroke by a NIHSS score >15, as per the European Society of Cardiology and 
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11.1.3 Study design  
This substudy - Timing of anticoagulation - is a pilot study imbedded in the main 
ENCHANTED2 study. Consent will be obtained prior to MT procedure, but randomisation will 
be undertaken post-MT at the same time of the main study, according to separate eligibility 
criteria.  Randomised allocation (1:1 ratio) of intervention will be done via the same central, 
automated, mobile APP-based randomisation software as the main study, according to 
minimized method stratified by site and randomisation of BP intervention.   
Study population 
Among all patients are randomised into the main trial, those eligible for this substudy are those 
with a final diagnosis of AF-related AIS. 
Inclusion and exclusion criteria 
To be eligible for inclusion for this sub-study, patients enrolled in the main study ARE much 
satisfy all of the following criteria:     
a) AIS due to permanent, persistent, or paroxysmal spontaneous AF documented previously 
or diagnosed during hospitalization  
b) Agreement of treating physician to prescribe either a DOAC or warfarin anticoagulation 
c) Provision of written informed consent (or via an appropriate proxy, according to local 
requirements) 
Patients will NOT be eligible if there is one or more of the following: 
a) AF due to clear reversible causes (e.g. thyrotoxicosis, pericarditis, recent surgery, acute 
myocardial infarction) 
b) Patients with serious bleeding in the last 6 months or is at high risk of bleeding (e.g. active 
peptic ulcer disease, platelet count <100,000/mm3 or hemoglobin <10 g/dl or INR ≥1.7, 
documented hemorrhagic tendencies or blood dyscrasias) 
c) Specific contraindication to any form of oral anticoagulation  
Treatment allocation 
Attending clinicians are required to consider their level of clinical uncertainty over the balance 
of potential benefits and risks pertaining to the level of anticoagulation treatment 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.  A 
DOAC is the preferred recommendation, but a VKA is accepted if DOACs are not available or 
not affordable for patients. Postponing, stopping or restarting anticoagulation therapy is at the 
discretion of the attending clinician if the patient suffers from an adverse bleeding event. 
Early initiation of oral anticoagulation therapy  
Early treatment will be started at Day 4±2 of stroke onset.  
Late initiation of oral anticoagulation therapy  
Late treatment will be started as per current recommendations at Day 12±2 of stroke onset.  
11.1.4 Study outcomes 
Primary outcome 
Composite of recurrent AIS, sICH, systemic embolism and/or death within 90 days after 
randomisation 
Secondary outcomes are: 

 
 
  
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a) Functional outcomes defined as a shift (improvement) in scores on the mRS at 90 days 
b) Any ICH reported by investigators or after central adjudication of relevant brain imaging 
within 90 days after randomisation 
c) sICH, in which ICH is associated with substantial neurological deterioration or death 
according to various definitions within 90 days 
d) Death or disability by scores 3-6 on the mRS at 3 months 
e) Separately on death and disability at 3 months  
f) Length of hospital stay  
g) HRQoL by the EuroQoL at 3 months 
11.1.5 Sample size 
In this and the other substudy, the aim is to recruit as many patients to inform the sample size 
estimates for the main study. Our preliminary sample size calculation to provide a reliable 
assessment of the treatment effect is outlined below. 
The results of Pre-TIMING study in Sweden revealed 12% of primary outcomes (4% of 
recurrent ischemic stroke, 3% of sICH, and 4% of all-cause mortality) in AF-related AIS patients 
with OAC therapy at 90 days.62 Given more severe patients are being enrolled in 
ENCHANTED2, the event rate is expected to be around20%. A sample size of 2418 subjects 
provides 90% power to detect a 5% absolute (25% relative) risk reduction on a composite 
outcomes at 90 days between the randomised groups in AIS patients with successful post-MT 
reperfusion.  
11.1.6 Data collection and follow up 
Day 90 (± 7d)  
The adherence of the anticoagulation therapy in each randomised group will be collected 
through 90-day follow-up.  
11.2 Duration of dual antiplatelet therapy (DAPT) 
11.2.1 Aims 
Compared with a standard duration of DAPT (3 months), a short duration (6 weeks) of DAPT 
is at least as effective (‘not inferior ‘) in reducing the risk of recurrent stroke over 12 months, in 
AIS patients with LAA who undertook MT (i.e. corresponding null hypothesis is that short 
duration of treatment is inferior than standard duration on this outcome).  
11.2.2 Background and rationale 
The effectiveness of APT for the secondary prevention of AIS is well recognized,63 but the 
efficacy and safety of DAPT in MT-LVO patients remains controversial.64, 65  Whilst European 
guidelines do not recommend long-term DAPT in AIS patients, AHA/ASA guidelines (2018) 
recommend 21-days of DAPT with aspirin and clopidogrel commenced within 24 hours of 
symptom onset with minor stroke (Class IIa; Level of Evidence B) based on the Clopidogrel in 
High-Risk Patients With Acute Nondisabling Cerebrovascular Events (CHANCE) 41 and 
Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT)69 trials. In CHANCE, 
5170 Chinese minor AIS/high-risk TIA patients were randomly assigned to either DAPT 
(clopidogrel at an initial dose of 300 mg, followed by 75 mg per day for 90 days, plus aspirin at 
a dose of 75 mg per day for the first 21 days) or placebo plus aspirin (75 mg per day for 90 
days), to show DAPT was superior in reducing the risk of recurrent stroke at 90 days (HR 0.68, 

 
 
  
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95% CI 0.57-0.81; P <0.001), with no significant increase in ICH risk (HR 1.41, 95% CI 0.95-
2.10; P = 0.09) compared to monotherapy. The multinational POINT trial showed a 28% 
reduction in stroke recurrence with DAPT compared to aspirin monotherapy, but major 
bleeding events were double.66  A meta-analysis published in 2013 included 14 RCTs of DAPT 
versus aspirin among 9102 AIS/TIA patients, showed that DAPT significantly reduce the risk 
of recurrent stroke in 3 months (RR 0.69, 95% CI 0.6-0.8), without increasing the major 
bleeding events (RR 1.35, 95%CI 0.7-2.59).65  However, a recent meta-analysis including 
POINT further explored the optimal duration of DAPT to show that short-term (one month) 
reduced the risk of recurrent AIS (RR 0.53; 95% CI 0.37-0.78) without a significant increased 
the risk of major bleeding (RR 1.82; 95% CI 0.91-3.62).67 
The application of these findings to LVO/MT patients is limited as they are confined to those 
with minor AIS (NIHSS < 4) or high-risk TIA as an acute therapy in an unstable plaque. The 
only trial focussed on the efficacy of DAPT in patients with LAA was Stenting and Aggressive 
Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS), 
which included patients with recent AIS/TIA attributed to 70-99% stenosis of a major 
intracranial artery, randomly assigned to aggressive medical management alone (including 
with a dose of 325 mg aspirin and 75 mg clopidogrel per day for 90 days) or aggressive medical 
management plus percutaneous transluminal angioplasty and stenting (PTAS) with the use of 
the Wingspan stent system.68  Enrolment was stopped after 451 patients were randomised 
because the 30-day rate of stroke or death in the PTAS group was significantly higher than 
medical-management group (14.7 vs. 5.8%, P =0.002), indicating aggressive medical 
management was superior to PTAS alone. Despite the lack of direct evidence, many clinicians 
prescribe DAPT to those patients with LAA where there is high risk of recurrent stenosis, for 
example intra-MT endothelial trauma or placement of a stent to maintain reperfusion. The 
standard duration of DAPT in such cases is 3 months post-MT. A shorter duration of DAPT for 
LAA patients post-MT may provide greater benefit over ongoing risk of major bleeding.   
In summary, the efficacy and safety of DAPT for secondary prevention as well as the optimal 
duration in patients with major stroke remains unresolved. This imbedded substudy aims to 
determine the effectiveness of a short duration of DAPT in patients with LAA who receive MT. 
11.2.3 Study design 
This substudy – Duration of DAPT - is a pilot study imbedded in the main ENCHANTED2 
study. Consent will be obtained prior to MT procedure, but randomisation will be undertaken 
post-MT at the same time of the main study, according to separate eligibility criteria.  
Randomised allocation (1:1 ratio) of intervention will be done via the same randomisation 
system as the main study, according to minimized method stratified by site and randomisation 
of BP intervention. The patients will be either allocated to short duration (6 weeks) or standard 
duration (3 months) of DAPT within 48 hours after AIS onset, and to be maintained on 
antiplatelet monotherapy (aspirin or clopidogrel) thereafter. 
Study population 
All patients randomised in the main trial, who have a final diagnosis of LAA-related AIS will be 
considered for enrolment in this sub-study. In comparison to all other randomised patients, 
patients included in this substudy are followed up for 12 months. 
Inclusion and exclusion criteria 
To be eligible for inclusion for this substudy, patients who has been enrolled into the main 
study ARE to still satisfy all of the following criteria:     
a) Final diagnosis of LAA confirmed by imaging during MT procedure  

 
 
  
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b) Provision of written informed consent (or via an appropriate proxy, according to local 
requirements) 
Patients will NOT be eligible if there is one or more of the following: 
c) Definite contraindication to both aspirin and clopidogrel 
Treatment allocation 
Short duration of DAPT  
The patients will receive oral (including nasogastric if required) DAPT (aspirin 100 mg and 
clopidogrel 75 mg per day) for 6 weeks within 48 hours after stroke onset if no PH confirmed 
by imaging after MT. If the patient is intolerance with aspirin or clopidogrel, cilostazol / 
dipyridamole can be used as a substitute. 
Standard duration of DAPT  
The patients will receive oral (including nasogastric if required) DAPT (aspirin 100 mg and 
clopidogrel 75 mg per day) for 3 months within 48 hours after stroke onset if no PH confirmed 
by imaging after MT. If the patient is intolerance with aspirin or clopidogrel, cilostazol / 
dipyridamole can be used as a substitute. 
11.2.4 Study outcomes 
Primary outcome: new stroke event (ischaemic or haemorrhagic) over 12 months 
Secondary outcomes are: 
a) Major adverse cardiovascular events (MACE), defined as a combination of recurrent AIS, 
myocardial infarction (MI) and all-cause mortality over 3 and 12 months 
b) Recurrent AIS over 3 months and 12 months 
c) Any ICH reported by investigators or after central adjudication of relevant brain imaging 
over 3 months and 12 months 
d) sICH, in which ICH is related to substantial neurological deterioration or death according 
to various definitions over 3 months and 12 months 
e) Death or disability by shift analysis of scores on the mRS at 3 months and 12 months 
f) 
Separately on death and disability at 3 months and 12 months 
g) Neurological deterioration ≥4 points decline in NIHSS score over 7 days after 
randomisation 
h) Length of hospital stay 
i) 
HRQoL by the EuroQoL at 3 months and 12 months 
11.2.5 Data collection and follow-up 
Day 365 (±1 month)  
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 365 
± 30 days, all surviving patients will be evaluated through a telephone interview or at a face-
to-face consultation. Use of BP lowering agents (see Appendix 1), antiplatelet agents, and 
adherence will be recorded. In addition to the mRS, cardiovascular events (CV death, non-
fatal stroke, non-fatal myocardial infarction, major bleeding), HRQoL (using the EQ-5D) will be 
assessed.  

 
 
  
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11.2.6 Sample size 
In this and the other substudy, the aim is to recruit as many patients to inform the sample size 
estimates for the main study. Our preliminary sample size calculation to provide a reliable 
assessment of the treatment effect is outline below. 
Ma et al. reported the proportion of post-stenting events of recurrent AIS and ICH over 12 
months was 5.8% among patients with symptomatic intracranial atherosclerotic stenosis in 
China.69 Considering on a broader inclusion of hospital sites and severe study population, the 
event rates were set up as 10%. 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% of the margin of the excess risk. In this study, a relative non-
inferiority margin of 40% (i.e. risk ratio 1.4) was used to provide assurance that short duration 
of DAPT retains at least 60% of the effects of reducing stroke recurrence risk compared with 
standard duration. A sample size of 2366 provides 90% power (1-sided α =0.025) to reject a 
non-inferiority margin of 1.4 from an expected event rate of 10% in the standard duration arm 
and assuming no true difference between the two durations. 
12. PUBLICATION, REPORTS AND DATA SHARING 
Publication of the main reports from the study will be in the name of the ENCHANTED2 
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 
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 “ENCHANTED2 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;  

 
 
  
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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.  
At the completion of the study, requests for secondary analysis will be in accordance with a 
defined protocol from an experience research group with an agreed analysis plan with The 
George Institute. In addition, data will be shared with other investigators on the study, and 
investigators from other institutions around the word, according to a strict data sharing 
agreement. 
Data sharing will be available from 12 months after publication of the main results. The 
consent form will include information as to the purpose of this activity. Investigators are to 
make a formal request for data sharing through the Research Office of TGI, CHINA and get 
approval from the SC. 
13. ORGANISATION 
Central coordination is from TGI, CHINA, and the study will be overseen by an International 
SC comprised of world experts in the fields of stroke, hypertension, neurology, geriatrics, 
cardiovascular epidemiology and clinical trials. The CCC will also be supported by key grant 
holders and regional experts in the OC. The CCC communicates with regional committees and 
approximately 80-100 participating hospitals in China in the first instance, and up to 50 sites 
outside of China depending on funding. 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. 
13.1 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 (Co-Principal Investigator), The George Institute for Global Health, 
China; University of New South Wales, Australia 
Professor Jianmin Liu (Co-Principal Investigator), Changhai Hospital, China 
Dr Lili Song, (Co-Senior clinical lead) The George Institute for Global Health, China; University 
of New South Wales, Australia 
A/Prof Pengfei Yang (Co-Senior clinical lead), Changhai Hospital, China  
Additional SC members, and international advisors, will be invited to join at the discretion of 
Professors Liu and Anderson according to their expertise and contribution to successful 
conduct for the study, within and outside of China. 
13.2 Central Coordinating Centre (CCC)  
The CCC is at TGI, CHINA 

 
 
  
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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.  
13.3 RCC  
Responsibilities: Provide advice to the CCC on regional issues relevant to the set up and 
management of the study. In conjunction with the CCC, provide assistance and support and 
monitor study progress at regional participating centres, including data quality and adherence 
to the study protocol. 
13.4 Imaging Adjudication Committee (Core Lab/Brain Imaging Analysis)  
Responsibilities: To measure haemorrhagic complications (hematoma volume) and 
ischemia/infarction on all de-identified and blinded brain imaging scans (blinded by allocation 
group and timing of scan).  
13.5 Clinical Endpoints Committee  
Responsibilities: Review blinded study outcomes to ensure endpoints meet the consistent 
diagnostic criteria in line with pre-determined criteria. 
13.6 Data Safety Monitoring Board (DSMB)  
Responsibilities: Review the safety, ethics and outcomes of the study.   
13.7 Participating Centres  
Neurology Wards / Neurosurgery 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 CCC, 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 CCC in accordance with protocol.  
14. FUNDING  
Funding for the study is part of a consortium, with research grants held by TGI, CHINA and 
Changhai Hospital. This study has received initial funding from a Program Grant from the 
National Health and Medical Research Council (NHMRC) of Australia (APP1149987), China 
National Health Commission Stroke Prevention Committee “China Stroke Prevention and 
Intervention Project” (GN-2020 R0008), and grants from Changhai Hospital (including 
“National Clinical Key Specialist Construction Project’ 2016). This study also receives funding 
support from Takeda China.  
 

 
 
  
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15. TIMELINES  
Milestones for main study 
2019 
2020 
2021 
2022 
2023 
Protocol design and materials 
development 
 
 
 
 
Sign contract with investigators 
 
 
 
 
Set-up of regional centres 
 
  
  
  
Ethics applications 
  
  
 
  
Training sites 
  
  
  
  
Commence recruitment and intervention   
  
  
  
Outcomes assessment 
  
  
  
  
Close out 
  
  
  
  
Analysis and Results 
  
  
  
  
Presentation / publication of main result   
  
  
  A 
 
 
 
 

 
 
  
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16. REFERNCES 
1. 
Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, et al. Global and 
regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: A 
systematic analysis for the global burden of disease study 2010. Lancet. 
2012;380:2095-2128 
2. 
Strong K, Mathers C, Bonita R. Preventing stroke: Saving lives around the world. 
Lancet Neurol. 2007;6:182-187 
3. 
Disease GBD, Injury I, Prevalence C. Global, regional, and national incidence, 
prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: A 
systematic analysis for the global burden of disease study 2015. Lancet. 
2016;388:1545-1602 
4. 
Wang W, Jiang B, Sun H, Ru X, Sun D, Wang L, et al. Prevalence, incidence, and 
mortality of stroke in china: Results from a nationwide population-based survey of 480 
687 adults. Circulation. 2017;135:759-771 
5. 
Liu L, Wang D, Wong KS, Wang Y. Stroke and stroke care in china: Huge burden, 
significant workload, and a national priority. Stroke. 2011;42:3651-3654 
6. 
Adams HP, Jr., Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, et al. 
Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter 
clinical trial. Toast. Trial of org 10172 in acute stroke treatment. Stroke. 1993;24:35-
41 
7. 
National Institute of Neurological D, Stroke rt PASSG. Tissue plasminogen activator 
for acute ischemic stroke. N Engl J Med. 1995;333:1581-1587 
8. 
Hacke W, Kaste M, Bluhmki E, Brozman M, Davalos A, Guidetti D, et al. 
Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 
2008;359:1317-1329 
9. 
Christou I, Burgin WS, Alexandrov AV, Grotta JC. Arterial status after intravenous tpa 
therapy for ischaemic stroke. A need for further interventions. Int Angiol. 
2001;20:208-213 
10. 
Lima FO, Furie KL, Silva GS, Lev MH, Camargo EC, Singhal AB, et al. Prognosis of 
untreated strokes due to anterior circulation proximal intracranial arterial occlusions 
detected by use of computed tomography angiography. JAMA Neurol. 2014;71:151-
157 
11. 
Berkhemer OA, Fransen PS, Beumer D, van den Berg LA, Lingsma HF, Yoo AJ, et 
al. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J 
Med. 2015;372:11-20 
12. 
Goyal M, Demchuk AM, Menon BK, Eesa M, Rempel JL, Thornton J, et al. 
Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl 
J Med. 2015;372:1019-1030 
13. 
Jovin TG, Chamorro A, Cobo E, de Miquel MA, Molina CA, Rovira A, et al. 
Thrombectomy within 8 hours after symptom onset in ischemic stroke. N Engl J Med. 
2015;372:2296-2306 
14. 
Saver JL, Goyal M, Bonafe A, Diener HC, Levy EI, Pereira VM, et al. Stent-retriever 
thrombectomy after intravenous t-pa vs. T-pa alone in stroke. N Engl J Med. 
2015;372:2285-2295 
15. 
Campbell BC, Mitchell PJ, Kleinig TJ, Dewey HM, Churilov L, Yassi N, et al. 
Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J 
Med. 2015;372:1009-1018 
16. 
Nogueira RG, Jadhav AP, Haussen DC, Bonafe A, Budzik RF, Bhuva P, et al. 
Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct. 
N Engl J Med. 2018;378:11-21 
17. 
Albers GW, Marks MP, Kemp S, Christensen S, Tsai JP, Ortega-Gutierrez S, et al. 
Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging. N Engl 
J Med. 2018;378:708-718 

 
 
  
44 
ENCHANTED2 protocol  
Version 3.0  
Date: 18 Aug 2020 
18. 
Turk AS, 3rd, Siddiqui A, Fifi JT, De Leacy RA, Fiorella DJ, Gu E, et al. Aspiration 
thrombectomy versus stent retriever thrombectomy as first-line approach for large 
vessel occlusion (compass): A multicentre, randomised, open label, blinded outcome, 
non-inferiority trial. Lancet. 2019;393:998-1008 
19. 
De Silva DA, Brekenfeld C, Ebinger M, Christensen S, Barber PA, Butcher KS, et al. 
The benefits of intravenous thrombolysis relate to the site of baseline arterial 
occlusion in the echoplanar imaging thrombolytic evaluation trial (epithet). Stroke. 
2010;41:295-299 
20. 
Saqqur M, Uchino K, Demchuk AM, Molina CA, Garami Z, Calleja S, et al. Site of 
arterial occlusion identified by transcranial doppler predicts the response to 
intravenous thrombolysis for stroke. Stroke. 2007;38:948-954 
21. 
Nogueira RG, Liebeskind DS, Sung G, Duckwiler G, Smith WS, Merci, et al. 
Predictors of good clinical outcomes, mortality, and successful revascularization in 
patients with acute ischemic stroke undergoing thrombectomy: Pooled analysis of the 
mechanical embolus removal in cerebral ischemia (merci) and multi merci trials. 
Stroke. 2009;40:3777-3783 
22. 
Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, et 
al. 2018 guidelines for the early management of patients with acute ischemic stroke: 
A guideline for healthcare professionals from the american heart 
association/american stroke association. Stroke. 2018;49:e46-e110 
23. 
Al-Mufti F, Dancour E, Amuluru K, Prestigiacomo C, Mayer SA, Connolly ES, et al. 
Neurocritical care of emergent large-vessel occlusion: The era of a new standard of 
care. J Intensive Care Med. 2017;32:373-386 
24. 
Bosel J. Intensive care management of the endovascular stroke patient. Semin 
Neurol. 2016;36:520-530 
25. 
Mistry EA, Mayer SA, Khatri P. Blood pressure management after mechanical 
thrombectomy for acute ischemic stroke: A survey of the strokenet sites. J Stroke 
Cerebrovasc Dis. 2018;27:2474-2478 
26. 
Goyal N, Tsivgoulis G, Iftikhar S, Khorchid Y, Fawad Ishfaq M, Doss VT, et al. 
Admission systolic blood pressure and outcomes in large vessel occlusion strokes 
treated with endovascular treatment. J Neurointerv Surg. 2017;9:451-454 
27. 
Mulder M, Ergezen S, Lingsma HF, Berkhemer OA, Fransen PSS, Beumer D, et al. 
Baseline blood pressure effect on the benefit and safety of intra-arterial treatment in 
mr clean (multicenter randomized clinical trial of endovascular treatment of acute 
ischemic stroke in the netherlands). Stroke. 2017;48:1869-1876 
28. 
Goyal N, Tsivgoulis G, Pandhi A, Chang JJ, Dillard K, Ishfaq MF, et al. Blood 
pressure levels post mechanical thrombectomy and outcomes in large vessel 
occlusion strokes. Neurology. 2017;89:540-547 
29. 
Martins AI, Sargento-Freitas J, Silva F, Jesus-Ribeiro J, Correia I, Gomes JP, et al. 
Recanalization modulates association between blood pressure and functional 
outcome in acute ischemic stroke. Stroke. 2016;47:1571-1576 
30. 
Goyal N, Tsivgoulis G, Pandhi A, Dillard K, Alsbrook D, Chang JJ, et al. Blood 
pressure levels post mechanical thrombectomy and outcomes in non-recanalized 
large vessel occlusion patients. J Neurointerv Surg. 2018;10:925-931 
31. 
Anderson CS, Huang Y, Lindley RI, Chen X, Arima H, Chen G, et al. Intensive blood 
pressure reduction with intravenous thrombolysis therapy for acute ischaemic stroke 
(enchanted): An international, randomised, open-label, blinded-endpoint, phase 3 
trial. Lancet. 2019;393:877-888 
32. 
Mistry EA, Mistry AM, Nakawah MO, Khattar NK, Fortuny EM, Cruz AS, et al. Systolic 
blood pressure within 24 hours after thrombectomy for acute ischemic stroke 
correlates with outcome. J Am Heart Assoc. 2017;6 
33. 
Anderson CS, Woodward M, Arima H, Chen X, Lindley RI, Wang X, et al. Statistical 
analysis plan for evaluating different intensities of blood pressure control in the 

 
 
  
45 
ENCHANTED2 protocol  
Version 3.0  
Date: 18 Aug 2020 
enhanced control of hypertension and thrombolysis stroke study. Int J Stroke. 
2018:1747493018806170 
34. 
Murray CJ, Evans DB, Acharya A, Baltussen RM. Development of who guidelines on 
generalized cost-effectiveness analysis. Health Econ. 2000;9:235-251 
35. 
Oostenbrink JB, Koopmanschap MA, Rutten FF. Standardisation of costs: The dutch 
manual for costing in economic evaluations. Pharmacoeconomics. 2002;20:443-454 
36. 
Saver JL. Optimal end points for acute stroke therapy trials: Best ways to measure 
treatment effects of drugs and devices. Stroke. 2011;42:2356-2362 
37. 
Rabin R, de Charro F. Eq-5d: A measure of health status from the euroqol group. Ann 
Med. 2001;33:337-343 
38. 
Goyal M, Menon BK, van Zwam WH, Dippel DW, Mitchell PJ, Demchuk AM, et al. 
Endovascular thrombectomy after large-vessel ischaemic stroke: A meta-analysis of 
individual patient data from five randomised trials. Lancet. 2016;387:1723-1731 
39. 
Chandratheva A, Mehta Z, Geraghty OC, Marquardt L, Rothwell PM, Oxford Vascular 
S. Population-based study of risk and predictors of stroke in the first few hours after a 
tia. Neurology. 2009;72:1941-1947 
40. 
Giles MF, Rothwell PM. Risk of stroke early after transient ischaemic attack: A 
systematic review and meta-analysis. Lancet Neurol. 2007;6:1063-1072 
41. 
Wang Y, Wang Y, Zhao X, Liu L, Wang D, Wang C, et al. Clopidogrel with aspirin in 
acute minor stroke or transient ischemic attack. N Engl J Med. 2013;369:11-19 
42. 
Rothwell PM, Coull AJ, Giles MF, Howard SC, Silver LE, Bull LM, et al. Change in 
stroke incidence, mortality, case-fatality, severity, and risk factors in oxfordshire, uk 
from 1981 to 2004 (oxford vascular study). Lancet. 2004;363:1925-1933 
43. 
Bejot Y, Ben Salem D, Osseby GV, Couvreur G, Durier J, Marie C, et al. 
Epidemiology of ischemic stroke from atrial fibrillation in dijon, france, from 1985 to 
2006. Neurology. 2009;72:346-353 
44. 
Seiffge DJ, Werring DJ, Paciaroni M, Dawson J, Warach S, Milling TJ, et al. Timing of 
anticoagulation after recent ischaemic stroke in patients with atrial fibrillation. Lancet 
Neurol. 2019;18:117-126 
45. 
Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic 
attack or minor stroke. Eaft (european atrial fibrillation trial) study group. Lancet. 
1993;342:1255-1262 
46. 
Saxena R, Koudstaal PJ. Anticoagulants for preventing stroke in patients with 
nonrheumatic atrial fibrillation and a history of stroke or transient ischaemic attack. 
Cochrane Database Syst Rev. 2004:CD000185 
47. 
Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, et al. 
Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 
2011;365:981-992 
48. 
Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. 
Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 
2009;361:1139-1151 
49. 
Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, et al. 
Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 
2013;369:2093-2104 
50. 
Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban 
versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883-891 
51. 
Salazar CA, del Aguila D, Cordova EG. Direct thrombin inhibitors versus vitamin k 
antagonists for preventing cerebral or systemic embolism in people with non-valvular 
atrial fibrillation. Cochrane Database Syst Rev. 2014:CD009893 
52. 
Bruins Slot KM, Berge E. Factor xa inhibitors versus vitamin k antagonists for 
preventing cerebral or systemic embolism in patients with atrial fibrillation. Cochrane 
Database Syst Rev. 2018;3:CD008980 

 
 
  
46 
ENCHANTED2 protocol  
Version 3.0  
Date: 18 Aug 2020 
53. 
Heidbuchel H, Verhamme P, Alings M, Antz M, Hacke W, Oldgren J, et al. Ehra 
practical guide on the use of new oral anticoagulants in patients with non-valvular 
atrial fibrillation: Executive summary. Eur Heart J. 2013;34:2094-2106 
54. 
Paciaroni M, Agnelli G, Falocci N, Caso V, Becattini C, Marcheselli S, et al. Early 
recurrence and cerebral bleeding in patients with acute ischemic stroke and atrial 
fibrillation: Effect of anticoagulation and its timing: The raf study. Stroke. 
2015;46:2175-2182 
55. 
Hart RG, Coull BM, Hart D. Early recurrent embolism associated with nonvalvular 
atrial fibrillation: A retrospective study. Stroke. 1983;14:688-693 
56. 
D'Amelio M, Terruso V, Famoso G, Di Benedetto N, Realmuto S, Valentino F, et al. 
Early and late mortality of spontaneous hemorrhagic transformation of ischemic 
stroke. J Stroke Cerebrovasc Dis. 2014;23:649-654 
57. 
Wilson D, Ambler G, Banerjee G, Shakeshaft C, Cohen H, Yousry TA, et al. Early 
versus late anticoagulation for ischaemic stroke associated with atrial fibrillation: 
Multicentre cohort study. J Neurol Neurosurg Psychiatry. 2019;90:320-325 
58. 
Paciaroni M, Agnelli G, Corea F, Ageno W, Alberti A, Lanari A, et al. Early 
hemorrhagic transformation of brain infarction: Rate, predictive factors, and influence 
on clinical outcome: Results of a prospective multicenter study. Stroke. 
2008;39:2249-2256 
59. 
Kablau M, Kreisel SH, Sauer T, Binder J, Szabo K, Hennerici MG, et al. Predictors 
and early outcome of hemorrhagic transformation after acute ischemic stroke. 
Cerebrovasc Dis. 2011;32:334-341 
60. 
Seiffge DJ, Traenka C, Polymeris A, Hert L, Peters N, Lyrer P, et al. Early start of 
doac after ischemic stroke: Risk of intracranial hemorrhage and recurrent events. 
Neurology. 2016;87:1856-1862 
61. 
Paciaroni M, Agnelli G, Falocci N, Tsivgoulis G, Vadikolias K, Liantinioti C, et al. Early 
recurrence and major bleeding in patients with acute ischemic stroke and atrial 
fibrillation treated with non-vitamin-k oral anticoagulants (raf-noacs) study. J Am 
Heart Assoc. 2017;6 
62. 
Asberg S, Hijazi Z, Norrving B, Terent A, Ohagen P, Oldgren J. Timing of oral 
anticoagulant therapy in acute ischemic stroke with atrial fibrillation: Study protocol for 
a registry-based randomised controlled trial. Trials. 2017;18:581 
63. 
Sandercock PA, Counsell C, Gubitz GJ, Tseng MC. Antiplatelet therapy for acute 
ischaemic stroke. Cochrane Database Syst Rev. 2008:CD000029 
64. 
Alvarez-Sabin J, Maisterra O, Santamarina E, Kase CS. Factors influencing 
haemorrhagic transformation in ischaemic stroke. Lancet Neurol. 2013;12:689-705 
65. 
Wong KS, Wang Y, Leng X, Mao C, Tang J, Bath PM, et al. Early dual versus mono 
antiplatelet therapy for acute non-cardioembolic ischemic stroke or transient ischemic 
attack: An updated systematic review and meta-analysis. Circulation. 2013;128:1656-
1666 
66. 
Johnston SC, Easton JD, Farrant M, Barsan W, Conwit RA, Elm JJ, et al. Clopidogrel 
and aspirin in acute ischemic stroke and high-risk tia. N Engl J Med. 2018;379:215-
225 
67. 
Rahman H, Khan SU, Nasir F, Hammad T, Meyer MA, Kaluski E. Optimal duration of 
aspirin plus clopidogrel after ischemic stroke or transient ischemic attack. Stroke. 
2019;50:947-953 
68. 
Chimowitz MI, Lynn MJ, Derdeyn CP, Turan TN, Fiorella D, Lane BF, et al. Stenting 
versus aggressive medical therapy for intracranial arterial stenosis. N Engl J Med. 
2011;365:993-1003 
69. 
Ma N, Zhang Y, Shuai J, Jiang C, Zhu Q, Chen K, et al. Stenting for symptomatic 
intracranial arterial stenosis in china: 1-year outcome of a multicentre registry study. 
Stroke Vasc Neurol. 2018;3:176-184 
 
 

 
 
  
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17. APPENDIX 
Appendix 1 - BP management protocol 
Appendix 1A - BP protocol for centres with Urapidil (China)                                
Intensive BP lowering 
group  
TREATMENT PROTOCOL 
INITIAL therapy 
 
BP Target  
SBP <120mmHg achieved within 1 hour after randomisation  
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) 
• 
If SBP ≥ 120 mmHg and HR >55 bpm, repeat 10-25 mg IV bolus 
q5 mins until target SBP reached (<120mmHg) or HR <55 bpm 
• 
If HR increases by >15 bpm or is >90 bpm, add IV beta blocker 
Hydralazine (IV)  
• 
Hydralazine test dose: 5 mg IV bolus over 1 minute  
• 
If SBP ≥ 120 mmHg, repeat 5 mg IV bolus in 5 minutes  
• 
If SBP still ≥ 120mmHg, give 10 mg IV bolus q 5 mins until target 
SBP reached  
• 
Increase to 20 mg bolus if required  
• 
Maximum hydralazine dose = 240mg  
Glyceryl Trinitrate 
(topical)  
If BP persistently ≥ 120 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 ≥ 120 mmHg:  
• 
Urapidil infusion 5-30 mg/hour 
• 
If target still not reached ADD infusion of hydralazine 50-150 
μg/min OR glyceryl trinitrate 1-100 μg/Kg/min 
MAINTENANCE therapy  
BP Target  
Maintenance of SBP 100-120 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 120mmHg 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 100-120mmHg, 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) 
• 
If SBP ≤ 100 mmHg, cease therapy  
• 
If HR increases by >15 bpm or is >90 bpm, add IV beta blocker 
• 
Note: urapidil and hydralazine may be used together during the 
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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 ± 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; μg/Kg/min – 
micrograms per kilogram per minute; μg/min – micrograms per minute.  
 
 

 
 
  
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Appendix 1B - BP protocol for centres with Phentolamine (China)  
Intensive BP lowering 
group  
TREATMENT PROTOCOL  
INITIAL therapy  
BP Target  
SBP < 120 mmHg reached within 1 hours after randomisation 
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) 
• 
If SBP ≥120 mmHg and HR >55 bpm, repeat 5 mg IV push q 5 mins 
until target SBP reached (<120mmHg) or HR <55 bpm  
• 
If HR increases by >15 bpm or is >90 bpm, add IV beta blocker 
Hydralazine (IV)  
If BP persistently ≥ 120 mmHg:  
• 
ADD Hydralazine with a test dose: 5 mg IV bolus over 1 minute  
• 
If SBP ≥ 120 mmHg, repeat 5 mg IV bolus in 5 minutes  
• 
If SBP still ≥120mmHg, 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 ≥ 120 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 ≥ 120 mmHg:  
• 
Phentolamine infusion 0.2-5 mg/minute  
• 
If target still not reached, ADD infusion of hydralazine 50-150 μg/min 
OR glyceryl trinitrate 1-100 μg/Kg/min 
MAINTENANCE therapy  
BP Target  
Maintenance of SBP 100-120 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 120mmHg 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 100-120mmHg, 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 ≤ 100 mmHg or HR < 55 bpm, then cease treatment.  
• 
If HR increases by >15 bpm or is >90 bpm, add IV beta blocker  
• 
Note: phentolamine and hydralazine may be used together during 
the maintenance phase 

 
 
  
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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; μg/Kg/min – 
micrograms per kilogram per minute; μg/min – micrograms per minute. 
 
 

 
 
  
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Appendix 1C - BP protocol for centres with Labetalol 
Early intensive BP 
lowering group  
TREATMENT PROTOCOL  
INITIAL therapy  
BP Target  
SBP < 120 mmHg reached within 1 hour after randomisation 
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) 
• 
If SBP ≥ 120 mmHg and HR >55 bpm, repeat 20 mg IV push q 
5 mins until target SBP reached (< 120mmHg) or HR <55 bpm; 
increase to 40 mg bolus if required 
• 
Maximum labetalol dose: 300 mg / 24 hours 
Hydralazine (IV)  
If BP persistently ≥ 120 mmHg:  
• 
ADD Hydralazine with a test dose: 5 mg IV bolus over 1 minute  
• 
If SBP ≥ 120 mmHg, repeat 5 mg IV bolus in 5 minutes  
• 
If SBP still ≥ 120mmHg, 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 ≥ 120 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 ≥ 120 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 
μg/min OR glyceryl trinitrate 1-100 μg/Kg/min  
• 
OR start infusion of Nicardipine 5-15 mg/hour 
MAINTENANCE therapy  
BP Target  
Maintenance of SBP 100-120 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 120mmHg 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 100-120mmHg, 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 ≤ 100 mmHg or HR < 55 bpm, then cease treatment  
• 
Maximum labetalol dose: 300 mg/24 hours  

 
 
  
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• 
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 
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; μg/Kg/min – 
micrograms per kilogram per minute; μg/min – micrograms per minute. 
 
 

 
 
  
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Appendix 1D - BP protocol for centres with Hydralazine 
Early intensive BP 
lowering group  
TREATMENT PROTOCOL  
INITIAL therapy  
BP Target  
SBP < 120 mmHg reached within 1 hour after randomisation 
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) 
• 
If BP persistently ≥ 120 mmHg:  
• 
ADD Hydralazine with a test dose: 5 mg IV bolus over 1 minute  
• 
If SBP ≥140mmHg, repeat 5 mg IV bolus in 5 minutes 
• 
If SBP still ≥ 120mmHg, 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 ≥ 120 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 ≥ 120 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 ≥ 120 mmHg:  
• 
Start infusion of hydralazine - 50-150 μg/min 
• 
If target still not reached, ADD infusion of glyceryl trinitrate 1-100 
μg/Kg/min  
• 
OR start infusion of Nicardipine 5-15 mg/hour 
MAINTENANCE therapy  
BP Target  
Maintenance of SBP 100-120 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 120mmHg 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 100-120mmHg, give further Hydralazine 10-20 mg boluses 
(dependent on initial dose) q 6 hours for first 24 hours (total of 3 
doses) 
• 
If SBP ≤ 100 mmHg or HR <55 bpm, then cease treatment  
Oral treatment  
 
Start treatment by 24 hours (use nasogastric if required)  

 
 
  
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• 
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; μg/Kg/min – 
micrograms per kilogram per minute; μg/min – micrograms per minute. 

 
 
  
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Appendix 1E - BP protocol for centres with Clevidipine 
Early intensive BP 
lowering group  
TREATMENT PROTOCOL  
INITIAL therapy  
BP Target  
SBP < 120 mmHg reached within 1 hour after randomisation 
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  
Clevidipine 
(IV)( requires ICU 
admission) 
If BP persistently ≥120mmHg: 
• 
Initial Clevidipine dose: 2mg/h iv in first 1.5min 
• 
If SBP≥120mmHg, add double dosage ever 2-10min(4,8,16 until 
32mg/h) 
• 
Max dosage = 32mg/h 
Hydralazine (IV) 
If BP persistently ≥ 120 mmHg:  
• 
ADD Hydralazine with a test dose: 5 mg IV bolus over 1 minute  
• 
If SBP ≥140mmHg, repeat 5 mg IV bolus in 5 minutes 
• 
If SBP still ≥ 120mmHg, give 10 mg IV bolus q 5 mins until target 
SBP reached  
• 
Increase to 20 mg bolus if required  
• 
Maximum hydralazine dose = 240mg 
Glyceryl Trinitrate 
(Topical)  
If BP persistently ≥ 120 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 ≥ 120 mmHg:  
• 
ADD infusion of hydralazine - 50-150 μg/min OR  
glyceryl trinitrate 1-100 μg/Kg/min  
MAINTENANCE therapy  
BP Target  
Maintenance of SBP 100-120 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 120mmHg 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 130-140mmHg, Keep the dose of Clevidipine  
• 
If SBP < 120 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)  

 
 
  
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• 
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; μg/Kg/min – 
micrograms per kilogram per minute; μg/min – micrograms per minute. 
 
 

 
 
  
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Appendix 1F - 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 μg/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 μg - 15 μg/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) Frusemide  
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 1G – Control group-higher BP target  
 
RANDOMISED GROUP  
TREATMENT  
CONTROL - HIGHER BP 
TARGET 
 
Use acute intravenous therapy if SBP >180 mmHg, and stop BP 
lowering agents when SBP ≤ 150 mmHg; 
Any BP lowering treatment could be used ONLY if SBP >150 mmHg 
and maintain a SBP range 140-180 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 – Recommendation for MT devices 
MT is the background treatment in this trial. All devices listed below (including but not limited 
to), which are approved by China Food and Drug Administration (CFDA) during the study 
period, are recommended as first-line devices for MT.  
Device name 
Manufacturer 
Description 
Aspiration catheter 
  
 
   ACE 
Penumbra 
Aspiration catheter 
Retriever 
 
 
    Solitaire  
Medtronic 
Stent Retriever 
    Trevo  
Stryker  
Stent Retriever  
    Revive 
Cerenovous 
Stent Retriever 
    Aperioa 
Acandis 
Stent Retriever 
    Reco 
Minitech Medical 
Stent Retriever 
 
 

 
 
  
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Appendix 3 - 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.  
 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  

 
 
  
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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  
  
Kvp  
100  
mAs  
120  
Contrast (volume/type/rate)  
50ml Omnipaque 300 at 4ml/sec  
Flush (volume/type/rate)  
40ml saline at 4ml/sec  
delay  
15secs  
coverage  
circle of Willis (upwards)  
slice collimation  
0.75mm  
pitch  
1.25  
MRA  
  
Sequence  
3D TOF 2 slab HR  
TR (ms)  
23  
TE (ms)  
2.7  
Flip angle  
20°  
Locs / slab  
32  
Slice thickness  
1.6  
Slice gap  
0  
Matrix  
320 x 224  
ФFOV  
1  
FOV  
16  
Slice orient  
Straight axial  
T-scan  
5:46  
Brain imaging (CT scan and/or MRI) must be uploaded to the ENCHANTED2 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 4 - 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 
0 = Performs both tasks correctly. 
1 = Performs one task correctly. 
2 = Performs neither task correctly. 
 

 
 
  
 
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Assessment 
Response 
Score 
commands. Only the first attempt is 
scored. 
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 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. 
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 
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 
0 = Normal symmetrical movement. 
1 = Minor paralysis (flattened nasolabial fold, 
asymmetry on smiling). 
 

 
 
  
 
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Assessment 
Response 
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.  
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). 
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 
0 = Absent . 
1 = Present in one limb . 
2 = Present in two limbs If present, is ataxia 
in? 
 

 
 
  
 
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Assessment 
Response 
Score 
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.  
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: 
________________ 
- 
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 
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 
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Assessment 
Response 
Score 
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.  
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 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.  
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 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 
 
/ 

 
 
  
 
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Assessment 
Response 
Score 
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/  
      1= I am not anxious or depressed  
  
depression               2= I am moderately anxious or depressed  
      3= I am extremely anxious or depressed  
  
 
 

 
 
  
 
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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 and the 52nd WMA General Assembly, Edinburgh, Scotland, 
October 2000   
Note of Clarification on Paragraph 29 added by the WMA General Assembly, 
Washington 2002 Note of Clarification on Paragraph 30 added by the WMA General 
Assembly, Tokyo 2004   
  
A.    INTRODUCTION  
1. 
The World Medical Association has developed the Declaration of Helsinki as a 
statement of ethical principles to provide guidance to physicians and other 
participants in medical research involving human subjects. Medical research 
involving human subjects includes research on identifiable human material or 
identifiable data.  
2. 
It is the duty of the physician to promote and safeguard the health of the people. 
The physician's knowledge and conscience are dedicated to the fulfillment of this 
duty.  
3. 
The Declaration of Geneva of the World Medical Association 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 only in 
the patient's interest when providing medical care which might have the effect of 
weakening the physical and mental condition of the patient."  
4. 
Medical progress is based on research which ultimately must rest in part on 
experimentation involving human subjects.  
5. 
In medical research on human subjects, considerations related to the well-being 
of the human subject should take precedence over the interests of science and 
society.  
6. 
The primary purpose of medical research involving human subjects is to improve 
prophylactic, diagnostic and therapeutic procedures and the understanding of the 
aetiology and pathogenesis of disease. Even the best proven prophylactic, 
diagnostic, and therapeutic methods must continuously be challenged through 
research for their effectiveness, efficiency, accessibility and quality.   
7. 
In current medical practice and in medical research, most prophylactic, diagnostic 
and therapeutic procedures involve risks and burdens.   
8. 
Medical research is subject to ethical standards that promote respect for all 
human beings and protect their health and rights. Some research populations are 
vulnerable and need special protection. The particular needs of the economically 

 
 
  
 
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and medically disadvantaged must be recognized. Special attention is also 
required for those who cannot give or refuse consent for themselves, for those 
who may be subject to giving consent under duress, for those who will not benefit 
personally from the research and for those for whom the research is combined 
with care.   
9. 
Research Investigators should be aware of the ethical, legal and regulatory 
requirements for research on human subjects in their own countries as well as 
applicable international requirements. No national ethical, legal or regulatory 
requirement should be allowed to reduce or eliminate any of the protections for 
human subjects set forth in this Declaration.  
  
B. BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH  
10. It is the duty of the physician in medical research to protect the life, health, privacy, 
and dignity of the human subject.   
11. 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 on adequate laboratory and, where 
appropriate, animal experimentation.  
12. Appropriate caution must be exercised in the conduct of research which may 
affect the environment, and the welfare of animals used for research must be 
respected.  
13. The design and performance of each experimental procedure involving human 
subjects should be clearly formulated in an experimental protocol. This protocol 
should be submitted for consideration, comment, guidance, and where 
appropriate, approval to a specially appointed ethical review committee, which 
must be independent of the investigator, the sponsor or any other kind of undue 
influence. This independent committee should be in conformity with the laws and 
regulations of the country in which the research experiment is performed. The 
committee has the right to monitor ongoing trials. The researcher has the 
obligation to provide monitoring information to the committee, especially any 
serious adverse events. The researcher should also submit to the committee, for 
review, information regarding funding, sponsors, institutional affiliations, other 
potential conflicts of interest and incentives for subjects.   
14. The research protocol should always contain a statement of the ethical 
considerations involved and should indicate that there is compliance with the 
principles enunciated in this Declaration.   
15. Medical research involving human subjects should be conducted only by 
scientifically qualified persons and under the supervision of a clinically competent 
medical person. The responsibility for the human subject must always rest with a 
medically qualified person and never rest on the subject of the research, even 
though the subject has given consent.   
16. Every medical research project involving human subjects should be preceded by  
careful assessment of predictable risks and burdens in comparison with 
foreseeable benefits to the subject or to others. This does not preclude the 

 
 
  
 
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participation of healthy volunteers in medical research. The design of all studies 
should be publicly available.  
17. Physicians should abstain from engaging in research projects involving human 
subjects unless they are confident that the risks involved have been adequately 
assessed and can be satisfactorily managed. Physicians should cease any 
investigation if the risks are found to outweigh the potential benefits or if there is 
conclusive proof of positive and beneficial results.   
18. Medical research involving human subjects should only be conducted if the 
importance of the objective outweighs the inherent risks and burdens to the 
subject. This is especially important when the human subjects are healthy 
volunteers.   
19. Medical research is only justified if there is a reasonable likelihood that the 
populations in which the research is carried out stand to benefit from the results 
of the research.   
20. The subjects must be volunteers and informed participants in the research project.  
21. The right of research subjects to safeguard their integrity must always be 
respected. Every precaution should be taken to respect the privacy of the subject, 
the confidentiality of the patient's information and to minimize the impact of the 
study on the subject's physical and mental integrity and on the personality of the 
subject.  
22. In any research on human beings, 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. The subject should be 
informed of the right to abstain from participation in the study or to withdraw 
consent to participate at any time without reprisal. After ensuring that the subject 
has understood the information, the physician should then obtain the subject's 
freely-given informed consent, preferably in writing. If the consent cannot be 
obtained in writing, the nonwritten consent must be formally documented and 
witnessed.   
23. When obtaining informed consent for the research project the physician should 
be particularly cautious if the subject is in a dependent relationship with the 
physician or may consent under duress. In that case the informed consent should 
be obtained by a well-informed physician who is not engaged in the investigation 
and who is completely independent of this relationship.   
24. For a research subject who is legally incompetent, physically or mentally 
incapable of giving consent or is a legally incompetent minor, the investigator 
must obtain informed consent from the legally authorized representative in 
accordance with applicable law. These groups should not be included in research 
unless the research is necessary to promote the health of the population 
represented and this research cannot instead be performed on legally competent 
persons.  
25. When a subject deemed legally incompetent, such as a minor child, is able to give 
assent to decisions about participation in research, the investigator must obtain 
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26. 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. The specific reasons for involving research subjects with a 
condition that renders them unable to give informed consent should be stated in 
the experimental protocol for consideration and approval of the review committee. 
The protocol should state that consent to remain in the research should be 
obtained as soon as possible from the individual or a legally authorized surrogate.  
27. Both authors and publishers have ethical obligations. In publication of the results 
of research, the investigators are obliged to preserve the accuracy of the results. 
Negative as well as positive results should be published or otherwise publicly 
available. Sources of funding, institutional affiliations and any possible conflicts of 
interest should be declared in the publication. Reports of experimentation not in 
accordance with the principles laid down in this Declaration should not be 
accepted for publication.   
  
C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH MEDICAL  
CARE  
  
28. The physician may combine medical research with medical care, only to the 
extent that the research is justified by its potential prophylactic, diagnostic or 
therapeutic value. When medical research is combined with medical care, 
additional standards apply to protect the patients who are research subjects.  
29. The benefits, risks, burdens and effectiveness of a new method should be tested 
against those of the best current prophylactic, diagnostic, and therapeutic 
methods. This does not exclude the use of placebo, or no treatment, in studies 
where no proven prophylactic, diagnostic or therapeutic method exists. 
30. At the conclusion of the study, every patient entered into the study should be 
assured of access to the best proven prophylactic, diagnostic and therapeutic 
methods identified by the study. 
31. The physician should fully inform the patient which aspects of the care are related 
to the research. The refusal of a patient to participate in a study must never 
interfere with the patient-physician relationship.  
32. In the treatment of a patient, where proven prophylactic, diagnostic and 
therapeutic methods do not exist or have been ineffective, the physician, with 
informed consent from the patient, must be free to use unproven or new 
prophylactic, diagnostic and therapeutic measures, if in the physician's judgement 
it offers hope of saving life, reestablishing health or alleviating suffering. Where 
possible, these measures should be made the object of research, designed to 
evaluate their safety and efficacy. In all cases, new information should be 
recorded and, where appropriate, published. The other relevant guidelines of this 
Declaration should be followed.   
  

 
 
  
 
75 
ENCHANTED2 protocol  
Version 3.0  
Date: 18 Aug 2020 
Note: Note of clarification on paragraph 29 of the WMA Declaration of Helsinki  
The WMA hereby reaffirms its position that extreme care must be taken in making use 
of a placebo-controlled trial and that in general this methodology should only be used 
in the absence of existing proven therapy. However, a placebo-controlled trial may be 
ethically acceptable, even if proven therapy is available, under the following 
circumstances:  
- 
Where for compelling and scientifically sound methodological reasons 
its use is necessary to determine the efficacy or safety of a prophylactic, 
diagnostic or therapeutic method; or   
- 
Where a prophylactic, diagnostic or therapeutic method is being 
investigated for a minor condition and the patients who receive placebo 
will not be subject to any additional risk of serious or irreversible harm.   
All other provisions of the Declaration of Helsinki must be adhered to, especially the 
need for appropriate ethical and scientific review.  
Note: Note of clarification on paragraph 30 of the WMA Declaration of Helsinki  
The WMA hereby reaffirms its position that it is necessary during the study planning 
process to identify post-trial access by study participants to prophylactic, diagnostic 
and therapeutic procedures identified as beneficial in the study or access to other 
appropriate care. Post-trial access arrangements or other care must be described in 
the study protocol so the ethical review committee may consider such arrangements 
during its review.  
The Declaration of Helsinki (Document 17.C) is an official policy document of the World  
Medical Association, the global representative body for physicians. It was first adopted 
in 1964 (Helsinki, Finland) and revised in 1975 (Tokyo, Japan), 1983 (Venice, Italy), 
1989 (Hong Kong), 1996 (Somerset-West, South Africa) and 2000 (Edinburgh, 
Scotland). Note of clarification on Paragraph 29 added by the WMA General Assembly, 
Washington 2002.