MAnagement of Systolic Blood Pressure During Thrombectomy by Endovascular Route for Acute Ischaemic STROKE: the MASTERSTROKE Trial
Phase: NA
Conditions: Stroke, Embolus Cerebral, Blood Pressure
Sponsor: Auckland City Hospital

MASTERSTROKE protocol V 1.4 
 
Page 1 of 24 
 
 
 
 
CLINICAL TRIAL PROTOCOL 
 
 
MAnagement of Systolic blood pressure during Thrombectomy by 
Endovascular Route for acute ischaemic STROKE: 
the MASTERSTROKE trial 
 
 
A multi-centre, patient and assessor-blinded, parallel group, randomised controlled trial 
(RCT) comparing a ‘standard’ and ‘augmented’ systolic blood pressure strategy during 
general anaesthesia for endovascular thrombectomy in acute ischaemic stroke 
 
 
 
Protocol version: 
 
 
 1.4 Dated 8th August 2024 
Funding: 
ADHB Research Trust, Neurological Foundation of New 
Zealand, Auckland Medical Research Foundation, Australia 
New Zealand College of Anaesthetists  
Trial registration: 
 
ACTRN12619001274167 
 
Coordinating centre:  
 
Perioperative Research 
 
 
 
 
 
Department of Anaesthesia, Perioperative Directorate 
 
 
 
 
 
 
Health NZ Te Toka Tumai Auckland 
 
Email:  
 
 
 
anaesresearch@adhb.govt.nz 
 
Global Sponsor: 
 
 
Dr Doug Campbell, Health NZ Te Toka Tumai Auckland 
 
Australian Sponsor:  
 
The University of Queensland 
 
 
 
 
 
Ethical approvals: 
 
 
NZ Ethics - 8892 Health and Disability Ethics Committee 
Australian Ethics – HREC/2020/QMS/70532, Metro South 
Human Research Ethics Committee 

MASTERSTROKE protocol V 1.4 
 
Page 2 of 24 
Table of Contents
Contents 
 
1. 
ADMINISTRATIVE INFORMATION ............................................................................................. 6 
1.1 
Title ........................................................................................................................................... 6 
1.2 
Trial registration ........................................................................................................................ 6 
1.3 
Protocol version ........................................................................................................................ 6 
1.4 
Funding ..................................................................................................................................... 6 
1.5 
Roles and responsibilities .......................................................................................................... 6 
1.5.1 Principal Investigator ................................................................................................................ 6 
1.5.2 Steering Committee .................................................................................................................. 6 
1.5.3 Protocol ..................................................................................................................................... 6 
The protocol was written by DC, CD, AB according to the SPIRIT 2013 guidelines. ............................ 6 
1.5.4 Operations Committee ............................................................................................................. 7 
1.5.5 Data Safety Monitoring Committee .......................................................................................... 7 
1.5.6 Endpoint Adjudication Committee ........................................................................................... 7 
1.5.7 Trial statistician ......................................................................................................................... 7 
1.5.8 Role of the funders.................................................................................................................... 7 
1.5.9 Trial Sponsor ............................................................................................................................. 7 
1.5.10 Study Coordinator, Coordinating/Data Management centre................................................... 7 
2 
INTRODUCTION ......................................................................................................................... 8 
Significance of the health issue ........................................................................................................... 8 
Potential to advance knowledge ......................................................................................................... 8 
Demonstration of the research gap ..................................................................................................... 9 
2.2 
Aims......................................................................................................................................... 10 
2.3 
Trial design .............................................................................................................................. 10 
3 
METHODS: PARTICIPANTS, INTERVENTIONS AND OUTCOMES .............................................. 11 
3.1 
Study setting ........................................................................................................................... 11 
3.2 
Eligibility criteria ...................................................................................................................... 11 
3.2.1 Inclusion criteria ...................................................................................................................... 11 
3.2.2 Exclusion criteria ..................................................................................................................... 11 
3.3 
Interventions ........................................................................................................................... 11 
3.3.1 Study interventions ................................................................................................................. 11 
3.3.2 Criteria for discontinuing or modifying allocated interventions ............................................. 11 

MASTERSTROKE protocol V 1.4 
 
Page 3 of 24 
3.3.3 Strategies to improve adherence to protocols ....................................................................... 12 
3.3.4 Concomitant therapies............................................................................................................ 12 
3.4 
Outcomes ................................................................................................................................ 12 
3.4.1 Primary outcome .................................................................................................................... 12 
3.4.2 Secondary outcomes ............................................................................................................... 12 
3.4.3 Physiological outcomes ........................................................................................................... 12 
3.4.4 Process of care measures ........................................................................................................ 12 
3.5 
Sample size .............................................................................................................................. 13 
3.6 
Recruitment ............................................................................................................................ 13 
4 
METHODS: ASSIGNMENT OF INTERVENTIONS ....................................................................... 13 
4.1 
Sequence generation .............................................................................................................. 13 
4.2 
Allocation concealment .......................................................................................................... 13 
4.3 
Implementation ...................................................................................................................... 13 
4.4 
Blinding ................................................................................................................................... 13 
5 
METHODS: DATA COLLECTION, MANAGEMENT AND ANALYSIS ............................................ 14 
5.1 
Data collection methods ......................................................................................................... 14 
5.2 
Data management .................................................................................................................. 14 
5.3 
Statistical methods .................................................................................................................. 15 
5.3.2 Methods for additional analyses ............................................................................................ 15 
5.3.3 Analysis population ................................................................................................................. 15 
6 
METHODS: MONITORING ....................................................................................................... 16 
6.1 
Data monitoring ...................................................................................................................... 16 
6.1.1 Composition and governance ................................................................................................. 16 
6.1.2 Interim analyses ...................................................................................................................... 16 
6.2 
Harms ...................................................................................................................................... 16 
6.3 
Monitoring of clinical trial sites and investigators .................................................................. 18 
7 
ETHICS AND DISSEMINATION ................................................................................................. 19 
7.1 
Research ethics approval ........................................................................................................ 19 
7.2 
Protocol amendments ............................................................................................................ 19 
7.3 
Consent ................................................................................................................................... 19 
7.3.1 New Zealand consent model .................................................................................................. 19 
7.4 
Confidentiality ......................................................................................................................... 20 
7.5 
Declaration of interests........................................................................................................... 21 
7.6 
Access to data ......................................................................................................................... 21 
7.7 
Post-intervention care ............................................................................................................ 21 

MASTERSTROKE protocol V 1.4 
 
Page 4 of 24 
7.8 
Dissemination policy ............................................................................................................... 21 
7.9 
Authorship eligibility ............................................................................................................... 21 
7.10 
Data access ................................................................................. Error! Bookmark not defined. 
8 
REFERENCES ............................................................................................................................ 23 
 

MASTERSTROKE protocol V 1.4 
 
Page 5 of 24 
ABBREVIATIONS 
 
ANZCA = Australian and New Zealand College of Anaesthetists 
ANZCA CTN = Australian and New Zealand College of Anaesthetists Clinical Trials Network 
ASA-PS = American Society of Anaesthesiologists- Physical Status 
CBF = Cerebral Blood Flow 
CMRO2 = Cerebral Metabolic Rate for Oxygen 
CI = Confidence Interval 
CS/LA = Conscious Sedation or Local Anaesthesia 
CT = Computerised Tomography 
DAH90 = Days Alive at Home at 90 days 
DMC = Data Monitoring Committee 
DWI = Diffusion Weighted Imaging 
EVT = EndoVascular Thrombectomy 
GA = General Anaesthesia 
HDU = High Dependency Unit 
ICA = Internal Carotid Artery 
ICU = Intensive Care Unit 
INR = Interventional NeuroRadiologist 
IQR = Interquartile range 
LVO = Large Vessel Occlusion 
MAP = Mean Arterial Pressure 
MCA = Middle Cerebral Artery 
MASTERSTROKE = MAnagement of Systolic blood pressure during Thrombectomy by 
Endovascular Route for acute ischaemic STROKE 
mRS = modified Rankin Score 
NIHSS = National Institute of Health Stroke Score 
OR = Odds Ratio 
PACU = Post Anaesthesia Recovery Unit 
PI = Principal investigator 
RCT = Randomised Control Trial 
RR = Relative Risk 
SC = Steering Committee 
SBP = Systolic Blood Pressure 
sICH = symptomatic IntraCranial Haemorrhage 

MASTERSTROKE protocol V 1.4 
 
Page 6 of 24 
1. ADMINISTRATIVE INFORMATION 
1.1 
Title 
A multi-centre, patient and assessor-blinded, parallel group, randomised controlled trial 
(RCT) comparing a ‘standard’ and ‘augmented’ systolic blood pressure strategy during 
general anaesthesia for endovascular thrombectomy (EVT) in acute ischaemic stroke. 
 
1.2 
Trial registration 
ANZCTRN: ACTRN12619001274167 
All trial information is available online on the Australian and New Zealand Clinical Trials 
Registry: http://www.anzctr.org.au/ 
 
1.3 
Protocol version 
Version 1.4 
 
1.4 
Funding 
This study is funded by Auckland District Health Board Research Trust, The Neurological 
Foundation of New Zealand, Auckland Medical Research Foundation and Australia New Zealand 
College of Anaesthetists. 
 
1.5 
Roles and responsibilities 
 
1.5.1 
Principal Investigator 
Name:  
 
Dr Doug Campbell 
Title: 
 
Anaesthesia Specialist 
Address: 
 
Dept. of Anaesthesia and Perioperative Medicine, 
Auckland City Hospital, 
2 Park Rd, Grafton, Auckland 
1023 NEW ZEALAND 
 
Contact Number:  
+6421503010 
Fax number:  
+6493754378 
Email:  
 
dcampbell@adhb.govt.nz 
 
1.5.2 
Steering Committee 
Alan Barber (AB)  
Stefan Brew (SB) 
Doug Campbell (DC) 
Carolyn Deng (CD) 
Tim Short (TS) 
Davina McAllister (DM) 
David Highton (DH) 
 
1.5.3 
Protocol  
The protocol was written by DC, CD, AB according to the SPIRIT 2013 guidelines. 
 
 
 

MASTERSTROKE protocol V 1.4 
 
Page 7 of 24 
1.5.4 
Operations Committee 
Doug Campbell  
Davina McAllister 
Incumbent - NeuroAnaesthesia Fellow 
Incumbent – Neurology Research Fellow 
 
1.5.5 
Data Safety Monitoring Committee 
Dr Barry Snow (Chair), Neurologist, Auckland City Hospital 
Prof Jamie Sleigh, Anaesthetist, Waikato Hospital 
Dr Yannan Jiang, Senior Research fellow, Department of Statistics, 
 
1.5.6 
Endpoint Adjudication Committee 
Dr Shane Lee, Interventional Neuroradiology, Auckland City Hospital 
Dr Tin Chiu, Anaesthetist, Auckland City Hospital 
Mr Jason Correia, Neurosurgeon, Auckland City Hospital 
 
1.5.7 
Trial statistician 
Professor Chris Frampton 
 
1.5.8 Role of the funders 
This is an investigator-initiated study. The SC will take responsibility for study design and 
oversight. The funders will have no role in study design, data collection, management, 
analysis, data interpretation, manuscript writing, or in the decision to submit manuscripts 
for publication. 
 
1.5.9 Trial Sponsor 
New Zealand Sponsor:  
Dr Doug Campbell will act as trial sponsor  
Australian Sponsor:   
University of Queensland 
 
1.5.10 Study Coordinator, Coordinating/Data Management centre  
 
Trial Manager:  
 
Ms. Davina McAllister  
Coordinating/  
 
Perioperative Research 
Department of Anaesthesia, Perioperative Directorate 
Te Whatu Ora Te Toka Tumai Auckland 
 

MASTERSTROKE protocol V 1.4 
 
Page 8 of 24 
2 
INTRODUCTION 
2.1 
Background and rationale 
Key concepts 
• EVT for LVO acute ischaemic stroke is a highly effective therapy for reducing 
disability at 3 months 
• There is direct evidence that relative hypotension worsens outcomes during ECR 
• It is unknown if increased SBP during GA improves outcomes. 
• A large RCT is the most robust way to assess the treatment effect. 
 
Significance of the health issue 
Stroke is the third most common cause of death in New Zealand and is one of the leading 
causes of long-term disability at all ages 11. The lifetime costs of a stroke per person were 
estimated at $73,600 in 2009, with a total cost of $450 million per year in New Zealand 12. 
Large vessel anterior circulation stroke is a devastating disease with lifelong disability, 
dependence on others for care and very high mortality. The burden on patients, carers, 
health care providers and society will be higher in these most severe strokes. 
The recent introduction of EVT has resulted in a large improvement in outcomes in these 
patients. New Zealand is at the forefront of introducing this new therapy to patients with 
annual 28 PSI procedures per million population performed in 2017. During a similar 
timeframe, the UK performed 7 per million population annually 13. Essential principles for 
high quality care are a) rapid delivery of patients to tertiary centres providing PSI for 
diagnosis and b) definitive treatment by recanalisation of target vessel. The number of PSI 
procedures is increasing exponentially with faster presentation to hospital, more rapid 
imaging and diagnosis and extended therapeutic windows 14. This means any further 
improvement in care will be increasingly available for New Zealanders. Māori patients are 
younger, have a higher incidence of stroke and worse outcomes 16-18. In the Northern Region 
of New Zealand, Māori represented 17.5% of all ECR patients and were younger than non- 
Māori patients 12. Any further improvements in ECR care will confer extra improvements in 
outcome in Māori over non-Māori in anterior circulation stroke. 
 
Potential to advance knowledge 
Systems of care to deliver eligible patients have reduced time from stroke onset to 
recanalisation since 2011. Rates for successful recanalisation (TICI 2b/3, over 50% vessel 
patency) are up to 88% in some New Zealand centres 19. The DAWN 2 and DEFUSE-3 3 trials 
have extended the therapeutic window from 6 hours to 24 hours in selected patients. 
Improvements in Intervention technology, further extensions of the therapeutic window or 
advances in thrombolytic therapy have limited ability to further improve current outcomes. 
A plausible strategy to improve outcomes in all eligible patients is to initiate therapies that 
protect the ischaemic penumbra until target vessel recanalisation is possible. A recent 
review article outlined investigational therapies that increase perfusion or oxygen delivery, 
or alternatively reduce tissue energy requirements in the ischaemic penumbra15. 

MASTERSTROKE protocol V 1.4 
 
Page 9 of 24 
 
 
Table 1. Investigational therapies that increase penumbral oxygen delivery, penumbral 
blood flow, or reduce tissue oxygen demand. Reproduced from ref 15. 
 
In New Zealand, an anaesthetist is present at all PSI case, and 90% of procedures are 
performed under general anaesthesia. This presents an ideal opportunity to investigate 
pharmacological or physiological interventions used frequently during anaesthesia to 
increase supply (vasopressors, IV fluid, cerebral vasodilators [sevoflurane, desflurane]) or 
reduce demand (propofol, sevoflurane, desflurane, hypothermia) during the hyperacute 
ischaemic period. 
 
Demonstration of the research gap 
Internationally, the debate regarding the use of pharmacological or physiological 
interventions during PSI has centred on observational data suggesting GA confers worse 
outcomes than local anaesthesia or conscious sedation. This outcome difference could be 
accounted for by selection bias, treatment delay, confounding by relative hypotension or 
direct drug effects. A recent individual meta-analysis of observational data within PSI trials 
was able to adjust for baseline severity differences and treatment delay. The worse 
functional outcomes at 3 months after GA compared to CS/LA remained with a covariate 
adjusted OR of 1.53 (CI 1.14-2.04, p=0.0044). None of these trials reported anaesthesia 
drugs used or associated physiology (including SBP) making further inference difficult. A 
meta-analysis by Campbell and Barber of four RCTs 5-8 of GA vs CS/LA, where blood pressure 
(BP) management was equivalent between groups showed functional outcomes at 3 months 
were superior in the GA group with an OR of 0.58 (CI 0.39-0.88). 

MASTERSTROKE protocol V 1.4 
 
Page 10 of 24 
 
Figure 1. Meta-analysis of four RCTs of CS v GA looking at good functional outcome at 3 
months in acute ischemic stroke 
 
An explanation of the differences in outcome in the observational data is that relative 
hypotension confounded the studies and that relative hypotension is harmful rather than  
GA per se. Normalising BP would eliminate the harm, but what effect would augmenting BP 
in this setting have? In the meta-analysis by Campbell et al, GA was superior to CS/LA but BP 
was equivalent in these studies. An important difference is that some anaesthesia agents 
(sevoflurane, desflurane) have a profound effect impairing normal cerebral autoregulation 
(and propofol to a lesser degree) and are cerebral vasodilators. The superiority of GA in this 
setting could be due to equivalent BP in the presence of cerebral vasodilation and impaired 
autoregulation providing flow augmentation. Again, what effect would augmenting BP in 
this setting have? 
 
Usual SBP management in a national dataset has a mean SBP of 141 mm Hg. In published 
randomised comparisons between GA and CS where GA outcomes were not inferior, mean 
SBP in these cohorts ranged from 139 to 146 mm Hg. Current stroke guidelines recommend 
an upper limit of 185mmHg after thrombolysis to reduce haemorrhagic complications. 
Therefore, we have chosen 140 mm Hg +- 10 mm Hg and 170 mm Hg +- 10 mm Hg as the 
comparators. These conform to SBP targets within the range of usual national and 
international practice. 
 
 
2.2 
Aims 
The aim of this study is to establish the optimal approach to SBP management for adults 
undergoing general anaesthesia during endovascular clot retrieval for acute ischaemic 
stroke by comparing the effect of two SBP strategies on functional recovery at 90 days. 
 
We hypothesise that in adults who fulfill the eligibility criteria below that an 
‘augmented’ SBP regime will result in improved disability at 90 days as measured by 
mRS. 
 
2.3 
Trial design 
A multi-centre, patient and assessor-blinded, parallel group, randomised controlled trial 
(RCT) comparing a ‘standard’ and ‘augmented’ systolic blood pressure strategy during 
general anaesthesia for endovascular clot retrieval in acute ischaemic stroke. 
A pre-defined sub-group analysis will compare maintenance of anaesthesia with intravenous 
propofol v inhalational sevoflurane. 

MASTERSTROKE protocol V 1.4 
 
Page 11 of 24 
3 
METHODS: PARTICIPANTS, INTERVENTIONS AND OUTCOMES 
3.1 
Study setting 
This study will be conducted in angiography suites in New Zealand, Australia and the 
Netherlands. 
 
3.2 
Eligibility criteria 
Adults (≥18 yrs.) who fulfill all of the following inclusion criteria, none of the exclusion 
criteria, and have undergone an appropriate consenting process. 
 
3.2.1 
Inclusion criteria 
Patients diagnosed with anterior circulation stroke (ICA or proximal M1 or M2 segment of 
MCA) treated with ECR within 6 hrs. of stroke onset and ECR patients presenting within 6-
24 hours with ‘wake up’ stroke ; or CT with favourable penumbra on CT perfusion scanning. 
3.2.2 
Exclusion criteria 
 
• pre-stroke mRS>=3 
• not having GA 
• terminal illness with expected survival <1 year 
• pregnancy 
• cardiovascular conditions where BP targeting will be contra-indicated 
• unable to participate in 3-month follow up 
• “Rescue” procedures; e.g. Acute Ischaemic Stroke associated with major medical 
procedures such as coronary artery stenting and coronary artery bypass.  
 
3.3 
Interventions 
3.3.1 
Study interventions 
The procedural anaesthetist will be asked to disclose maintenance anaesthesia agent prior 
to randomisation. Following randomisation, participants will be allocated to one of two 
haemodynamic strategies from ECR until recanalisation. 
 
‘Standard’ – SBP at 140+-10 mm Hg 
‘Augmented’ - SBP at 170+-10 mm Hg 
 
Techniques used to target SBP will be at the discretion of the procedural anaesthetist but 
will include vasopressors, intravenous fluids, titration of anaesthetic maintenance drugs and 
use of other vasoactive drugs. General anaesthesia will be based on an intubated patient 
with control of haemodynamic physiology as described, but also ventilation to normocarbia 
(ETCO2 4.5-6.0 kPa or PaCO2 4.5-6.0 kPa) and maintenance of normothermia and 
normoglycaemia. Doses and timing of administration will be recorded on the electronic 
anaesthesia record and data transcribed to the CRF. 
 
3.3.2 
Criteria for discontinuing or modifying allocated interventions 
The duration of the study intervention will be until the target vessel is recanalised or no 
further attempts at recanalisation are possible. If there is an unexpected anaesthesia or 

MASTERSTROKE protocol V 1.4 
 
Page 12 of 24 
medical event, or procedural complication e.g. vessel dissection or ICH, requiring change of 
SBP for safety reasons, then the study intervention can be terminated and a new clinical SBP 
can be targeted. 
 
3.3.3 Strategies to improve adherence to protocols 
The site PIs will take primary responsibility for training local staff and will use study tools 
provided by the coordinating centre. Early on-site data monitoring will be performed by the 
MasterStroke Project manager,  from the coordinating centre, to ensure protocol 
compliance is achieved. De-Identified Anaesthesia record data, which are sent to the 
project office, with study identifier will be audited by an unblinded auditor (with no access 
to study outcome data) for regular trial adherence and separation reporting. 
 
3.3.4 
Concomitant therapies 
There are no restrictions to concomitant treatments provided to patients in this study. 
 
3.4 
Outcomes 
3.4.1 
Primary outcome 
The primary outcome is improvement in disability measured by ordinal shift in the 
modified Rankin Score assessed at day 90 and assessed by ordinal shift analysis. 
3.4.2 
Secondary outcomes 
1. Excellent functional outcome as measured by a modified Rankin of 0, or 1 at 90 days 
2. Independent functional outcome as measured by a modified Rankin of 0, 1 or 2 at 90 
days 
3. The number of days a participant spends at home in the first 90 days post-stroke 
(home days/DAH90) 
4. All-cause mortality at 90 days 
5. Intra-procedural complications (target vessel dissection, intracerebral haemorrhage, 
groin haematoma) 
6. Symptomatic intracranial haemorrhage within 36 hours of treatment. 
 
3.4.3 Physiological outcomes 
1. Proportion of time within group allocation range 
2. Mean procedural SBP 
3. Mean procedural DBP 
4. Mean procedural MAP 
5. Cumulative time SBP < 140 mm Hg 
6. Mean procedural HR 
7. Mean procedural SpO2 
8. Mean procedural ETCO2 
9. Blood glucose 
10. Temperature 
 
3.4.4 
Process of care measures 
1. Groin puncture to recanalisation time 
2. Airway type 
3. Total time spent in the PACU 
4. Total time spent in HDU/ICU 
5. HLOS 

 
MASTERSTROKE protocol V 1.4 
 
Page 13 of 24 
 
3.5 
Sample size 
Statistical modeling of ordinal shift of mRS based on data on good functional recovery data 
(mRS 0-2) showed that recruiting 550 participants will provide 90% power to detect the 
proportion of patients who will improve 0.5 points on the modified Rankin Scale at 3 
months including 10% loss to follow up. This is equivalent to a group 1 proportion, P1 = 0.58 
(current national data) improving to P2 = 0.68, a clinically important improvement of 10% in 
good functional recovery (mRS 0-2) at 3 months. 
 
3.6 
Recruitment 
All hospitals participating in this study have significant experience undertaking large scale, 
investigator-initiated studies. Many MASTERSTROKE sites are previous BALANCED Trial sites 
which required anaesthetists to simultaneously target a depth of anaesthesia and 
haemodynamic target. The new Australian sites have significant experience running other 
large RCTs through the Australian and New Zealand College of Anaesthesia’s Clinical Trials 
Network.  
 
On the basis of a conservative estimate of 6 participating sites recruiting an average of 3 
eligible patients per month, recruitment of 550 participants will be completed in less than 
31 months. The number of sites required and the expected recruitment rate will be refined 
based on the observed recruitment rate in the initial trial recruitment phase. All sites will 
receive regular study newsletters and support to ensure adequate recruitment is achieved 
All sites will receive individual site group allocation adherence reports. Based on our 
previous experience conducting similar large-scale clinical trials of this nature, our 
recruitment timelines are appropriately conservative. 
 
 
4 
METHODS: ASSIGNMENT OF INTERVENTIONS 
4.1 
Sequence generation 
A permuted block randomisation method with block size of 8, will be used to allocate 
eligible patients in a 1:1 ratio to ‘standard’ or ‘augmented’ haemodynamic strategies.  
This has been aligned into the ALEA trial data base.  
 
4.2 
Allocation concealment 
ALEA clinical trials database has been set up to provide electronic sequential 
randomisation as per 4.1 and concealed from participants, investigators and outcome 
assessors. 
 
4.3 
Implementation 
Following determination of screening eligibility, and consent, subjects will be randomized, on 
a one-to-one basis,to either to ‘standard’ or ‘augmented’ haemodynamic strategies.    The 
Participants will be enrolled by clinical staff at the study sites.  
 
4.4 
Blinding 
Blinding of treatment providers is not possible.  
 
Participants, interventional neuroradiologists, neurologists and all outcome assessors will 
be blinded.  
 

 
MASTERSTROKE protocol V 1.4 
 
Page 14 of 24 
 
One unblinded research coordinator at each site will collect SBP related to the 
intraprocedural data points.  
 
All other site researchers, investigators and research coordinators, will be remain blinded as 
to treatment allocation and will collect data relating to primary and secondary outcomes.  
They will remain blind to group allocation by avoiding review of the intraoperative section of the 
medical record.   
 
Unblinding of patients or observers during the trial is not envisaged as the attending anaesthetist 
will be aware of group assignment and the assigned treatment will be recorded in the medical 
record. If unblinding is deemed necessary, research staff at the participating site will contact the 
Trial Coordinating Centre for approval. 
 
 
 
5 
METHODS: DATA COLLECTION, MANAGEMENT AND ANALYSIS 
5.1 
Data collection methods 
Baseline data will include patient demographics (age, sex, ethnicity), ASA status, chronic 
comorbidities, medications, thrombolysis administration, baseline NIHSS, anatomical stroke 
territory, partial or complete occlusion, ,. Baseline physiological parameters will include 
SpO2, respiratory rate, temperature, heart rate and blood pressure. Data will be collected by 
trained research coordinators at each site. DAH30 will be calculated from the electronic 
health record, and information provided by the patient and/or their next of kin as soon as 
possible after 30 days have elapsed following the day of surgery. Additionally, for New 
Zealand participants, outcome data will be obtained from the Ministry of Health (MoH) 
National Minimum Dataset (NMDS) linked with baseline and exposure data from the MoH 
NMDS and the anaesthesia record. Data quality and protocol standardisation will be 
optimised by arranging a start-up meeting, providing an early on-site monitoring visit, 
regular feedback to each centre via phone and the trial web-site, and a regular newsletter. A 
complete study procedures manual will be produced. All study personnel will have 24-hour 
access to the study coordinating centre to resolve any questions. 
 
5.2 
Data management 
A central electronic database will be designed, constructed and maintained for the purposes of the 
trial. The structure and data flow of the database will follow that of the case report form. Data entry 
onto the database at each participating site will be via a secure, password protected, online web-
based portal. The database will have the facility for transmitting data queries and requests for 
missing data, directly or via email notifications, to site research coordinators, as well as data 
interrogation and cross-checking algorithms to minimize incorrect data entries and maximize data 
capture and completeness. Data at each site will be entered into the portal either via an electronic 
case report form networked to the portal or after data entry onto a paper case report form. 
 
Access to study data at all sites will be restricted to approved trial personnel. Electronic data will be 
password protected while paper records will be kept in locked cabinets/offices, in compliance with 
ICH-GCP guidelines and local policies of participating sites. Study data must be kept at the site for at 
least 15 years following the date of completion of the trial.  
 
 
The study website will incorporate internal consistency checks, and require manual 
verification of extreme data values. Study data will be stored for 10 years in New Zealand 

 
MASTERSTROKE protocol V 1.4 
 
Page 15 of 24 
 
and 15 years in Australia in a secure archive as per usual practice at each recruiting site. 
Australian data will be held at the University of Queensland via UQ RDM as per the UQ 
Research Data Management Policy. 
 
5.3 
Statistical methods 
5.3.1 
Methods for analysing the primary outcomes and secondary outcomes 
Analyses will be performed in the intention-to- treat population. A full statistical analysis 
plan (SAP) will be lodged on ANZCTR and the trial website before recruitment is complete 
and before unblinding of the database. 
 
5.3.2 
Methods for additional analyses 
Baseline covariates will include age, gender, ethnicity, country of recruitment, baseline 
NIHSS, stroke territory, partial or complete vessel obstruction, use of alteplase, 
maintenance GA agent used. 
 
5.3.3 
Analysis population 
All analyses will be conducted on an intention-to treat basis with no imputation of missing 
data. A secondary per protocol analysis is planned. 
 
 
 

 
MASTERSTROKE protocol V 1.4 
 
Page 16 of 24 
 
6 
METHODS: MONITORING 
6.1 
Data monitoring 
6.1.1 
Composition and governance 
An independent Data Safety Monitoring Committee (DSMC), consisting of experts in 
anaesthesia, neurology, clinical research and biostatistics will be established before patient 
enrolment and will review all trial protocols. A set of DSMC guidelines and a DSMC Charter 
will be prepared by the SC and signed by the members of the DSMC before the trial 
commences. 
 
6.1.2 
Interim analyses 
We will perform an interim analysis for safety after 300 participants have been recruited. 
Primary safety outcome will be mRS at 90 days and secondary safety outcomes 90-day all- 
cause mortality, procedural complications and sICH. All outcome variables will be reviewed 
by the DMC. 
 
6.2 
Harms 
Patients undergoing ECR may experience complications as a direct result of the procedure. 
All study outcomes, serious adverse events (SAE); for example pneumonia leading to death,  
and any adverse events (AE) which are considered to be potentially causally related to the 
study intervention or are otherwise of concern in the investigator’s judgment will be 
reported. 
 
ADVERSE EVENTS  
Reporting adverse events to national regulatory authorities and IRBs / Ethics Committees (EC) will be 
performed in accordance with the applicable regulations and the local requirements.  
 
The Investigator will submit all STUDY OUTCOMES noted above and SAE reports to the Sponsor in a 
timely manner. 
 
 
Serious Adverse Events (SAE):  
Adverse event that led to any of the following:  
a) death,  
b) serious deterioration in the health of the subject, users, or other persons ad defined by one or more of 
the following:  
1) a life-threatening illness or injury, or  
2) a permanent impairment of a body structure or a body function including chronic diseases, or  
3) in-patient or prolonged hospitalization, or  
4) medical or surgical intervention to prevent life-threatening illness or injury or permanent impairment 
to a body structure or a body function,  
c) foetal distress, foetal death or a congenital abnormality or birth defect including physical or mental 
impairment  
NOTE Planned hospitalization for a pre-existing condition, or a procedure required by the CIP, without serious 
deterioration in health, is not considered a serious adverse event. 
 
All adverse events will be recorded on the CRF by the Investigator or his/her designee. However, it is the 
responsibility of the Investigator to ensure that all information is correct and appropriately documented.  
 

 
MASTERSTROKE protocol V 1.4 
 
Page 17 of 24 
 
All adverse events should be followed until they are adequately resolved or explained. In the unusual 
circumstance that an AE has not resolved by the time of the subject’s completion of the study, an 
explanation will be entered on the appropriate CRF. 
 
Adverse Event Severity  
The Investigator will use the following definitions to rate the severity of each adverse event:  
Table 6. Adverse Event Severity Severity  
Description  
Mild  
 
• 
Awareness of a sign or symptom that does not 
interfere with the patient’s usual activity or is 
transient, resolved without treatment and  
• 
No sequelae  
 
Moderate  
 
• 
Interferes with the patient’s usual activity and/or  
• 
Requires symptomatic treatment  
 
Severe  
 
• 
Symptom(s) causing severe discomfort and  
• 
Significant impact of the patient’s usual activity and 
Requires treatment  
 
 
Intervention-Related  
The relationship of the adverse event to the investigational intervention will be assessed according to the 
following definitions: 
 
Adverse Event Intervention Relationship  
Description  
Definite  
The adverse event is clearly related to the investigational 
Intervention: the event has a temporal relationship to the 
investigational Intervention, follows a known pattern of 
response, or is otherwise logically related to the 
investigational Intervention, and no alternative cause is 
present.  
Probable  
The adverse event is likely related to the investigational 
Intervention: the event has a temporal relationship to the 
investigational Intervention, follows a known or suspected 
pattern of response, or is otherwise logically related to the 
investigational Intervention, but an alternative cause may 
be present.  
Not Likely  
The adverse event is unlikely related to the investigational 
Intervention: the event does not follow a clear temporal 
relationship to the investigational Intervention or does not 
follow a known pattern of response or is otherwise likely 
to be due to the subject’s clinical state or other modes of 
therapy.  
Not Related  
The adverse event is clearly not related to the 
investigational Intervention: the event has no temporal or 
other relationship to the administration of the 
investigational Intervention, follows no known or 
suspected pattern of response, and an alternative cause is 
present.  
Unknown  
Unable to determine the relationship based on all 
available information.  
 
 

 
MASTERSTROKE protocol V 1.4 
 
Page 18 of 24 
 
Procedure-Related  
The relationship of the adverse event to the procedure will be assessed according to the following 
definitions: 
Adverse Event Procedure Relationship 
Relationship  
Description 
Definite  
The adverse event is clearly related to the procedure: the 
event has a temporal relationship to the procedure, 
follows a known pattern of response, or is otherwise 
logically related to the procedure, and no alternative cause 
is present.  
Probable  
The adverse event is likely related to the procedure: the 
event has a temporal relationship to the procedure, 
follows a known or suspected pattern of response, or is 
otherwise logically related to the procedure, but an 
alternative cause may be present.  
Not Likely  
The adverse event is unlikely related to the procedure: the 
event does not follow a clear temporal relationship to the 
procedure or does not follow a known pattern of response 
or is otherwise likely to be due to the subject’s clinical 
state or other modes of therapy.  
Not Related  
The adverse event is clearly not related to the procedure: 
the event has no temporal or other relationship to the 
procedure, follows no known or suspected pattern of 
response, and an alternative cause is present.  
Unknown  
Unable to determine the relationship based on all available 
information.  
 
 
6.3 
Monitoring of clinical trial sites and investigators 
The MasterStroke Trial Manager /monitors and/or designees will perform clinical trial monitoring 
of 100% of randomized subjects. This monitoring will include review of eCRF data with 
verification to the source documentation.  
 
Information on the eCRF must match the same information on the source documents or a data 
query will be issued. Queries will be resolved with the site.  
 
If the MASTERSTROKE Trial Manager determines that an Investigator is not in compliance with 
any requirements outlined in this investigational plan or the investigator agreement, the 
MASTERSTROKE Trial Manager, in conjunction with the local Sponsor shall promptly secure 
compliance.  
 
In addition, assessments including overall compliance with the investigational plan, accurate 
eCRFs, and compliance with Good Clinical Practices (GCP), ECs and local regulatory requirements 
will be monitored on an ongoing basis by the MASTERSTROKE Trial Manager and/or its designees.  
 
Periodic monitoring visits will be made at the investigational site throughout the clinical 
trial to ensure that the Investigator obligations are fulfilled and all applicable regulations 
and guidelines are being followed. These visits will ensure that the facilities are still 
acceptable, the protocol is being followed, the IRB / EC and local authorities have been 
notified of approved protocol changes as required, complete records are being 
maintained, appropriate and timely reports have been made to the MASTERSTROKE Trial 
Manager and/or its designees and the IRB / EC. 
 

 
MASTERSTROKE protocol V 1.4 
 
Page 19 of 24 
 
The Sponsor will reserve the right to remove either the Investigator or the investigational 
site from the trial for noncompliance with the protocol or regulations. 
 
 
7 
ETHICS AND DISSEMINATION 
7.1 
Research ethics approval 
Research ethics approval will be obtained prior to the start of the study at each institution 
from the responsible local and/or national human research ethics committee. 
 
7.2 
Protocol amendments 
Protocol amendments will be updated on relevant clinical trial registries by the Study 
Coordinator. Amendments will be communicated by regular newsletters, teleconferences, 
and emails to site Principal Investigators and Research Coordinators. 
 
7.3 
Consent 
7.3.1 New Zealand consent model 
Patients presenting for ECR may be incompetent to consent because of the presenting 
illness. In addition, the urgent requirement for medical treatment leads to a time pressured 
scenario where full explanation, understanding and reflection of the risks and benefits of 
participating can be assimilated. In New Zealand, we will use two physician best interest 
agreement. The two arms of the trial are within the range of normal clinical practice so 
inclusion in the trial adds no further burden to the patient.   National Health and Disability 
Ethics Committee approval for the consent process was sought prior to study 
commencement. 
 
 
 

 
MASTERSTROKE protocol V 1.4 
 
Page 20 of 24 
 
7.3.2 Australian consent model 
As in the New Zealand patient cohort, patients presenting for ECR may be incompetent to 
consent because of the presenting illness. Unlike New Zealand, Australia does not 
facilitate a two-physician best interest agreement. In Australia, the proposed consent 
model will be based on the guidelines set out in the National Statement section 4.4; 
which is to gain consent from the individual where possible and substitute decision-
makers where it is not; and provide an opportunity to withdraw if the participant's 
capacity changes. 
 
A Participant Information Sheet and Consent form along with a Substitute Decision Maker 
Verbal and In Person Consent Forms will be utilised to obtain consent before enrolment 
into the research. Written consent to continue will then be obtained later directly from 
the patient, if not possible prior, when and if the patient regains capacity. If the patient 
chooses not to continue in the trial, all data collected prior to this point will be withdrawn 
and will not be used in analysis.   
 
In cases where no Substitute Decision Maker is available, a limited waiver of consent will 
be sought from the HREC to enroll patients, providing a Consent to Continue is obtained 
later from the patient, when and if the patient regains capacity. 
 
7.4 
Confidentiality 
Patients will be allocated a unique study number. The site research coordinator will keep an 
enrolment log that includes the patients’ details and a unique study number. Study data will 
be obtained from the patients’ medical records. Study data and enrolment logs will be kept 
separately. Contact details for participants and their next of kin will be provided to the 
Research Office and home days and mRS categorisation will be obtained by a blinded central 
assessor at the Research Office by questioning at routine clinic visits or phoning participants 
and / or their next of kin if a clinic visit is not scheduled at 90 days post-stroke. 
 
At all times throughout this study, all parties shall strictly observe the confidentiality of subject’s health 
information. All data shall be secured against unauthorized access. Each subject participating in this study 
will be assigned a unique identifier. All eCRFs will be tracked, evaluated, and stored using only this unique 
identifier.  
 
The Investigator will maintain a confidential study subject list identifying all enrolled subjects. This list will 
contain the assigned study subject’s unique identifier and name. The Investigator bears responsibility for 
keeping this list confidential. This list will not be provided to the study Sponsor and is only to be used at 
the study center.  
 
Monitors and auditors will have access to the study subject list and other personally identifying 
information of study subjects to ensure that data reported in the eCRFs corresponds to the person 
documented on the consent form and the information contained in the original source documents. Such 
personal identifying information may include, but is not limited to, the subject’s name, address, date of 
birth, gender, race and medical record number.  
 
Any source documents copied for monitoring purposes by the MASTERSTROKE Trial Manager or 
designee, will be identified by using the assigned subject’s unique identifier and obscuring 
personal identifying data in an effort to protect subject confidentiality. 

 
MASTERSTROKE protocol V 1.4 
 
Page 21 of 24 
 
 
7.5 
Declaration of interests 
All study investigators have confirmed that they do not have any financial or other conflicts 
of interest to declare in relation to this study. 
 
7.6 
Access to data 
The Steering Committee will oversee data sharing with the following groups: Steering Committee 
members, site investigators, sub-study and sub-analysis groups formed by the Steering 
Committee, and external investigators. Details will be found in a trial data sharing statement.  
 
The final trial dataset will be available to the Steering Committee. Other co-investigators 
will have access to site level data and jurisdictional data. There are no contractual 
agreements in place which limit access to study data. 
 
To allow for the use of the information derived from this study and to ensure compliance 
with applicable regulations, the Investigator is obliged to provide MASTERSTROKE Trial 
Steering Committee with all data developed from this study. 
 
MASTERSTROKE Trial Steering Committee will have final approval authority on the proposed 
content for an abstract or manuscript submitted for presentation / publication. 
 
Investigators will submit abstracts, articles, and scientific presentations to the 
MASTERSTROKE Trial Steering at least sixty (60) days in advance for comment regarding 
consistency with monitored database and to protect the Sponsor’s Intellectual Property. 
 
7.7 
Post-intervention care 
After completion of the intervention patients will receive standard treatment. 
Haemodynamic goals post recanalisation will be determined as per local institutional 
practice and therapies to treat hypertension or hypotension within 24 hours will be 
recorded in the CRF. Participants will be transferred to PACU, HDU or ICU at the discretion 
of the procedural anaesthetist, INR and neurologist, and to the Stroke Unit thereafter. 
 
7.8 
Dissemination policy 
The trial will be conducted in the name of the MASTERSTROKE Investigators and the ANZCA 
CTN. The principal publications from the trial will be in the name of the MASTERSTROKE 
Investigators with full credit assigned to all collaborating investigators, research 
coordinators and institutions. Where individuals’ names are required for publication, they 
will be the members of the management committee, with the PI listed first and subsequent 
authors listed alphabetically. Members of additional committees with a major contribution 
e.g. DSMB will be listed by PubMed attribution. Funding bodies will be acknowledged in the 
publication. 
 
7.9 
Authorship eligibility 
 
Authorship of the primary manuscript and trial methodology paper will be attributed to the principal 
investigator, investigators, trial statistician, and trial manager.  First author will be Doug Campbell, last author 
Prof Alan Barber. Second author to be discussed at Steering Committee. 
 

 
MASTERSTROKE protocol V 1.4 
 
Page 22 of 24 
 
Where permitted by journal policy, authorship will also be attributed to “The MASTERSTROKE Study 
investigators and the Australian and New Zealand College of Anaesthetists Clinical Trials Network”. Authorship 
may be extended or altered (e.g., to include site investigators who make substantial contributions to the trial), 
according to a majority vote of the Steering Committee. The order of the authors on the primary manuscript 
and trial methodology paper will be determined by the Writing Committee.  
 
Members of the trial committees (i.e., Steering Committee, Operations Committee, Data Quality Committee, 
Data and Safety Monitoring Committee, Endpoint Adjudication Committee and Writing Committee) will be 
listed in an appendix to the primary manuscript. The chair will be listed first with other members in 
alphabetical order. Site investigators and coordinators of sites randomising at least one participant will be 
listed in an appendix to the primary manuscript. The number of site investigators and coordinators that may 
be listed for each site will be decided by the Writing Committee based on final site recruitment to the trial, 
and site investigators will be advised. Regions and sites will be listed alphabetically. Site investigators and 
coordinators will be listed in the order determined by the site.  
 
Authorship of sub-studies and sub-analyses will be determined by the Steering Committee. 
Authorship may be offered to investigators and statisticians who led sub-studies and sub-analyses, 
and may be offered to Steering Committee members and site principal investigators who made 
substantial contributions to the trial. 
 
 
 

 
MASTERSTROKE protocol V 1.4 
 
Page 23 of 24 
 
8 
REFERENCES 
 
1. Goyal M, Menon BJ, van Zwam WH, Dippel DWJ, Mitchell PJ, Dernchuk AM, el al, for 
the HERMES Collaboration. Endovascular thrombectomy after large-vessel ischaemic 
stroke: a meta- analysis of individual data from five randomized trials. Lancet 2016; 
387: 1723-31 
 
2. Nogueira RG, Jadhav AP, Haussen DC, Bonafe A, Budzik RF, Bhuva P, et al, for the 
DAWN Trial Investigators. Thrombectomy 6 to 24 hours after stroke with a mismatch 
between deficit and infarct. NEJM 2018; 378: 11-21 
 
3. Albers GW, Marks MP, Kemp S, Christensen S, Tsai JP, Ortega-Gutierrez S, et al, for 
the DEFUSE-3 Investigators. Thrombectomy for stroke at 6 to 16 hours with selection 
by perfusion imaging. NEJM 2018; 378: 707-18 
 
4. Campbell BCV, van Zwam WH, Goyal M, Menon BK, Dippel DWJ, Demchuk AM et al 
for the HERMES collaborators. Effects of general anaesthesia on functional outcome 
in patients with anterior circulation ischemic stroke having endovascular 
thrombectomy versus standard care: a meta-analysis of individual patient data. 
Lancet Neurology 2018; 17: 47-53 
 
5. Schonenberger S, Uhlmann L, Hacke W, et al. Effect of Conscious Sedation vs General 
Anaesthesia on Early Neurological Improvement Among Patients with Ischaemic 
Stroke Undergoing Endovascular Thrombectomy. JAMA. 2016; 316(19):1986-96 
 
 
6. Henden PL, Rentzos A, Karlsson JE, Rosengren L, Leiram B, Sundeman H, et al. 
General anesthesia versus conscious sedation for endovascular treatment of acute 
ischemic stroke. The AnStroke trial. Stroke 2017; 48: 1601-7 
 
7. Simonsen CZ, Yoo AJ, Sorensen LH, Juul N, Johnsen SP, Andersen G, et al. Effect of 
general anesthesia and conscious sedation during endovascular therapy in infarct 
growth and clinical outcomes in acute ischemic stroke. JAMA Neurology 2018 Jan 16. 
Doi: 10.1001/jamaneurol.2017.4474 
 
 
8. * Campbell D, Diprose WK, Deng C, Barber PA. General anaesthesia versus conscious 
sedation in endovascular thrombectomy for stroke: a meta-analysis of randomized 
controlled trials. J Neurosurg Anaesthesiology 2019; in review 
 
9. Jordan JD; Powers WJ. Cerebral autoregulation and acute ischemic stroke. American 
Journal of Hypertension 2012; 25(9): 946-50 
 
 
10. Strebel S, Lam A, Matta B, Mayberg T, Aaslid R, Newell D. Dynamic and static 
cerebral autoregulation during isoflurane, desflurane, and propofol anaesthesia. 
Anesthesiology 1995; 83: 66-76. 
 
11. Brown P. Economic burden of stroke in New Zealand. Three decades of Auckland 

 
MASTERSTROKE protocol V 1.4 
 
Page 24 of 24 
 
regional Community Stroke (ARCOS) studies: What have we learned and what is next 
for stroke care and stroke research? Wellington, New Zealand: Stroke Foundation of 
New Zealand; 2009 
 
 
12. * Barber PA, Liu Q, Brew S, McGuinness B, Hope A, Moriarty M, *Campbell D, Tse D. 
Endovascular clot retrieval for acute ischaemic stroke: the Auckland City Hospital 
experience. NZMJ 2015; 128(1423): 57-62. 
 
13. 21st century management and prevention of stroke. Editorial. Lancet 2018; 392: 1167 
 
14. * Burnell AL, Ranta A, Wu T, Fink J, McGuiness B, Caldwell J, Collecut W, Brew S, 
Barber PA. Endovascular clot retrieval for acute ischaemic stroke in New Zealand. 
NZMJ 2018, Vol 131(10): XXX-XXX 
 
15. Baron JC. Protecting the ischaemic penumbra as an adjunct to thrombectomy for 
acute stroke. Nature Reviews Neurology 2018; 14: 325-37 
 
16. * Feigin V, Carter K, Hackett M, Barber PA, McNaughton H, Dyall L, Chen MH, 
Anderson C. Ethnic disparities in incidence of stroke subtypes: Auckland Regional 
Community Stroke Study, 2002-2003. Lancet Neurol 2006;5(2):130-9. 
 
 
17. *McNaughton H, Feigin V, Kerse N, Barber PA, Weatherall M, Bennett D, Carter K, 
Hackett M, Anderson C. Ethnicity and functional outcome after stroke. Stroke 
2011;42(4):960-4. 
 
18. McNaughton H, Weatherall M, McPherson K, Taylor W, Harwood M. The 
comparability of community outcomes for European and non-European survivors of 
stroke in New Zealand. N Z Med J 2002;115(1149):98-100. 
 
19. māori-research-ethics-framework-researcher#navigation  
http://www.hrc.govt.nz/news-and-publications/publications/te-ara-tika-guidelines-