Conditions: Acute Stroke Endovascular Thrombectomy
Keywords: Blood Pressure Control
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 120
Healthy volunteers: no

Brief summary:
The purpose of this study is to assess the safety of lowering blood pressure in acute stroke patients that are successfully treated with a mechanical thrombectomy procedure. The investogators will evaluate the hypothesis that lower blood pressure management strategies do not result in larger volume of stroke or worse 3-month clinical outcome in these patients.

Detailed description:
Several thousand patients suffer from an ischemic stroke caused by an occlusion of a large blood vessel supplying the brain. Endovascular mechanical thrombectomy (EVT) has revolutionized management of this most devastating type of ischemic stroke by allowing removal of the occlusive clot. However, about half of the successfully EVT-treated patients (\~85% of all treated patients) still remain disabled at 90 days. Early evidence suggests that patients with lower blood pressure (BP) after the thrombectomy procedure have better outcomes. However, safety of lowering BP in these patients has not been determined. The primary safety concern of lowering BP comes from the potential of compromising blood flow to the "at risk" area of the brain following the stroke.

The purpose of this trial is to evaluate the safety of lower BP management strategies in patients who are successfully treated with endovascular treatment for ischemic stroke. The investigator will enroll 120 individuals who qualify and randomly assign them to one of the three systolic BP (SBP) targets: ≤180 mmHg, \<160 mmHg, and \<140 mmHg (40 patients in each group). Treatment will begin soon after the blood clot causing the stroke is removed, using anti-hypertensive medication given intravenously with a goal to lower and maintain the SBP below assigned target for 24 hrs.

The scientists will assess the safety of lower BP targets (\<160 mmHg and \<140 mmHg) by quantifying the volume of stroke measured with an MRI scan obtained at 36+/-12 hours and participants' functional status at 90 days measured with a patient centered disability score. Participants will undergo the 36 +/-12-hour MRI scan as part of their routine clinical care and will not be asked to prolong their hospital stay for study purpose. A phone interview will take place to determine their functional status at 90-days.

Enrollment of 120 patients will provide 80% power to detect a 10 cubic centimeter increase in stroke volume and a 0.10 decrease in utility-weighted modified Rankin score (a patient-centered disability score) for every 20 mmHg decrease in SBP. An interim analysis will be conducted after enrollment of 60 patients at which time the study may stop for safety concerns.

Arms:
arm 1: Lower systolic blood pressure to ≤180 mmHg and maintain for 24 hours. If anti-hypertensive medication used, then maintain ≥160 mmHg. arm 2: Lower systolic blood pressure to \<160 mmHg and maintain for 24 hours. If anti-hypertensive medication used, then maintain \>140 mmHg. arm 3: Lower systolic blood pressure to \<140 mmHg and maintain for 24 hours. If anti-hypertensive medication used, then maintain \>110 mmHg.

Interventions: intervention 1: Nicardipine intervention 2: Labetalol intervention 3: Hydralazine
Intervention descriptions: intervention 1: In the event where SBP values are above the randomly assigned target, intravenous nicardipine will be initiated at 2.5 mg/hr to lower the SBP. If SBP is still not reduced to below assigned target after 15 minutes, nicardipine dose will be increased by 2.5 mg/hr every 15 minutes until the target SBP or a maximum dose of 15 mg/hr is reached. intervention 2: If SBP is above target despite maximum nicardipine infusion for 30 minutes, 10-20 mg of intravenous labetalol will be added every 15 minutes. intervention 3: If SBP remains unresponsive for 1 hr despite the use of maximum doses of nicardipine and labetalol, a Hydralazine will be added at the treating physician's discretion. Incidence of the latter scenario is anticipated to be exceedingly rare.

Protocol document:
Prot_SAP_000.pdf: 
Blood Pressure after Endovascular Stroke Therapy (BEST)-II 
 
National Clinical Trial (NCT) Identified Number: NCT04116112 
Principal Investigator: Eva Mistry, MBBS 
Version Number: v.3.0 
January 5, 2022 
 
 
Summary of Changes from Previous Version: 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
9.1, 9.2, 
The statistical considerations portion is 
The changes are made in 
9.3, 9.4 
updated with the final statistical 
compliance with recommendations 
analysis plan. This includes the 
from DSMB and based on interim 
analysis of primary endpoints and 
analysis. 
safety analyses. . 


BEST-II 
ii 
 
Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................. 1 
1 
PROTOCOL SUMMARY ............................................................................................................................... 2 
1.1 
Synopsis ................................................................................................................................................ 2 
1.2 
Schema ................................................................................................................................................. 3 
1.3 
Schedule of Activities (SoA) ............................................................................................................... 4 
2 
INTRODUCTION ............................................................................................................................................ 5 
2.1 
Study Rationale .................................................................................................................................... 5 
2.2 
Background ........................................................................................................................................... 5 
2.3 
Risk/Benefit Assessment .................................................................................................................... 8 
2.3.1 
Known Potential Risks ..................................................................................................... 8 
2.3.2 
Known Potential Benefits ................................................................................................ 9 
2.3.3 
Assessment of Potential Risks and Benefits ................................................................ 9 
3 
OBJECTIVES AND ENDPOINTS............................................................................................................... 10 
4 
STUDY DESIGN ........................................................................................................................................... 11 
4.1 
Overall Design .................................................................................................................................... 11 
4.2 
Scientific Rationale for Study Design .............................................................................................. 12 
4.3 
Justification for Dose ......................................................................................................................... 12 
4.4 
End of Study Definition ...................................................................................................................... 12 
5 
STUDY POPULATION ................................................................................................................................. 12 
5.1 
Inclusion Criteria ................................................................................................................................ 12 
5.2 
Exclusion Criteria ............................................................................................................................... 12 
5.3 
Lifestyle Considerations .................................................................................................................... 12 
5.4 
Screen Failures .................................................................................................................................. 12 
5.5 
Strategies for Recruitment and Retention ...................................................................................... 13 
6 
STUDY INTERVENTION ............................................................................................................................. 14 
6.1 
Study Intervention(s) Administration................................................................................................ 14 
6.1.1 
Study Intervention Description ...................................................................................... 14 
6.1.2 
Dosing and Administration ............................................................................................ 14 
6.2 
Preparation/Handling/Storage/Accountability ................................................................................. 15 
6.2.1 
Acquisition and accountability ....................................................................................... 15 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ................................................. 15 
6.2.3 
Product Storage and Stability ....................................................................................... 15 
6.2.4 
Preparation ...................................................................................................................... 15 
6.3 
Measures to Minimize Bias: Randomization and Blinding............................................................ 15 
6.4 
Study Intervention Compliance ........................................................................................................ 16 
6.5 
Concomitant Therapy ........................................................................................................................ 16 
7 
DISCONTINUATION/WITHDRAWAL ........................................................................................................ 16 
7.1 
Discontinuation of Study Intervention .............................................................................................. 16 
7.2 
Participant Discontinuation/Withdrawal from the Study ................................................................ 16 
7.3 
Lost to Follow-Up ............................................................................................................................... 17 
8 
STUDY ASSESSMENTS AND PROCEDURES ...................................................................................... 17 
8.1 
Endpoint and other non-safety Assessments ................................................................................ 17 
8.2 
Adverse Events and Serious Adverse Events ............................................................................... 18 
8.2.1 
Definition of Adverse Events (AE) ................................................................................ 18 
8.2.2 
Definition of Serious Adverse Events (SAE) ............................................................... 18 
8.2.3 
Classification of an Adverse Event .............................................................................. 19 


BEST-II 
iii 
 
8.2.4 
Time Period and Frequency for Event Assessment and Follow-Up ........................ 19 
8.2.5 
Adverse Event Reporting .............................................................................................. 20 
8.2.6 
Serious Adverse Event Reporting ................................................................................ 20 
8.2.7 
Reporting Events to Participants .................................................................................. 21 
8.2.8 
Events of Special Interest ............................................................................................. 21 
8.2.9 
Reporting of Pregnancy ................................................................................................. 21 
8.3 
Unanticipated Problems .................................................................................................................... 21 
8.3.1 
Definition of Unanticipated Problems (UP) ................................................................. 21 
8.3.2 
Unanticipated Problem Reporting ................................................................................ 21 
8.3.3 
Reporting Unanticipated Problems to Participants .................................................... 22 
9 
STATISTICAL CONSIDERATIONS ........................................................................................................... 22 
9.1 
Statistical Hypotheses ....................................................................................................................... 22 
9.2 
Sample Size Determination .............................................................................................................. 23 
9.3 
Populations for Analyses .................................................................................................................. 23 
9.4 
Statistical Analyses ............................................................................................................................ 24 
9.4.1 
General Approach .......................................................................................................... 24 
9.4.2 
Analysis of the Primary Endpoint(s) ............................................................................. 24 
9.4.3 
Safety Analyses .............................................................................................................. 25 
9.4.4 
Planned Interim Analyses ............................................................................................. 25 
9.4.5 
missing data .................................................................................................................... 25 
9.4.6 
Subgroup analysis .......................................................................................................... 26 
9.4.7 
Describing the fidelity to intervention ........................................................................... 26 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ................................ 26 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ............................................................ 26 
10.1.1 
Informed Consent Process ........................................................................................... 26 
10.1.2 
Study Discontinuation and Closure .............................................................................. 27 
10.1.3 
Confidentiality and Privacy ............................................................................................ 28 
10.1.4 
Future Use of Stored Specimens and Data ................................................................ 29 
10.1.5 
Key Roles and Study Governance ............................................................................... 29 
10.1.6 
Safety Oversight ............................................................................................................. 29 
10.1.7 
Clinical Monitoring .......................................................................................................... 29 
10.1.8 
Quality Assurance and Quality Control ....................................................................... 30 
10.1.9 
Data Handling and Record Keeping ............................................................................ 30 
10.1.10 
Protocol Deviations ........................................................................................................ 32 
10.1.11 
Publication and Data Sharing Policy ........................................................................... 32 
10.1.12 
Conflict of Interest Policy ............................................................................................... 32 
10.2 
Additional Considerations ................................................................................................................. 32 
10.3 
Abbreviations ...................................................................................................................................... 34 
10.4 
Protocol Amendment History ............................................................................................................ 36 
11 
REFERENCES ............................................................................................................................................. 39 


Blood Pressure After Endovascular Stroke Therapy (BEST)- II 
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 STATEMENT OF COMPLIANCE 
 
 
The trial will be carried out in accordance with International Conference on Harmonization Good 
Clinical Practice (ICH GCP) and the following: 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 
812) 
 
Investigators and clinical trial site staff who are responsible for the conduct, management, or 
oversight of NIH-funded clinical trials have completed Human Subjects Protection and ICH GCP 
Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval. Approval of both 
the protocol and the consent form will be obtained before any participant is enrolled. Any 
amendment to the protocol will undergo review and approval by the IRB before the changes are 
implemented to the study. In addition, all changes to the consent form will be IRB-approved; a 
determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 


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1.1 
SYNOPSIS 
 
 
 
Title: 
Blood Pressure after Endovascular Stroke Therapy (BEST)- II 
Study Description: 
BEST-II is a prospective, randomized, open-label, blinded-endpoint 
(PROBE), clinical trial where eligible acute stroke patients will be 
randomly assigned (1:1:1) to one of the following systolic blood 
pressure targets: (1) a high target of 180mmHg (control), (2) an 
intermediate target of <160mmHg, and (3) a lower target of 
<140mmHg. The SBP will be maintained below the assigned target 
for 24 hours after a successful endovascular clot retrieval (EVT). In 
this stage, we will test the harm of the two intervention arms. 
Objectives: 
1) To assess the harm of lower SBP targets in successfully EVT- 
treated stroke patients by measuring effect on volume of brain infarct 
and patients’ functional status. 2) To assess the probability of a 
successful future phase 3 trial 
 
Endpoints: 
Primary Endpoints: 1) Final infarct volume at 3612 hours 2) Utility- 
weighted 9014 -day modified Rankin Score 
Secondary Endpoints: 1) Any hemorrhagic transformation 2) 
Symptomatic hemorrhagic transformation 3) Neurological worsening 
associated with anti-hypertensive treatment 4) Follow-up MRI 
perfusion core and penumbra volumes. 
Study Population: 
We will include adult (≥18 years) patients undergoing successful 
EVT for an occlusion in the anterior cerebral circulation large vessel. 
A total of 120 will be randomized to one of the three SBP target 
strategies. 
Phase: 
2b 
Description of 
Sites/Facilities 
Enrolling 
Participants: 
Description of Study 
Intervention: 
Study patients will be enrolled at the Vanderbilt University Medical 
Center for the phase 2b. No centers outside of the US will participate 
in this study. 
 
Management of SBP will start immediately after satisfactory 
achievement of successful recanalization to lower and maintain SBP 
below the randomly assigned target for 24 hours. In the event where 
SBP values are above target, intravenous nicardipine will be initiated 
at 2.5 mg/hr to lower the SBP. If SBP is still not reduced to below 
assigned target after 15 minutes, nicardipine dose will be increased 
by 2.5 mg/hr every 15 minutes until the target SBP or a maximum 
dose of 15 mg/hr is reached. 
Study Duration: 
We project to complete enrollment of initial 120 patients over 36 
months. Data analysis and study reporting will be completed within 
12 months following the enrollment of the last patient. 
Participant Duration: 
9014 days. 
1 
PROTOCOL SUMMARY 


Blood Pressure After Endovascular Stroke Therapy (BEST)- II 
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Acute ischemic 
stroke patient 
Ineligible 
BEST-II 
eligibility 
screen 
Eligible 
Consent 
mTICI 0-2a 
(~15%) 
Recanalization 
status 
Ineligible 
mTICI 2b-3 
Randomly assign 
SBP target 
 180 mmHg 
<160 mmHg 
<140 mmHg 
if 
≥160 
if 
≥140 
if 
≥110 
24 hr NIHSS 
36±12 hr brain MRI 
90±14-day mRS 
 
 
 
 
 
BEST-II Trial Workflow 
 
 
: Treated with antihypertensive medication; mTICI: Modified 
Thrombolysis in Cerebral Ischemia; MRI: Magnetic Resonance 
Image; mRS: Modified Rankin Score; NIHSS: National Institute 
of Health Stroke Scale; SBP: Systolic Blood Pressure 
1.2 
SCHEMA 


Blood Pressure After Endovascular Stroke Therapy (BEST)- II 
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Schedule of Events 
Prior to 
Enrollment 
Enrollment 
24 
hours 
36 (12) 
hours 
Day 7 or D/C 
(whichever 
first) 
Day 
90 
14 
Screening & Eligibility 
X 
Consent 
X 
Randomization 
#/X 
Medical History* 
# 
Home Medications* 
# 
Laboratory Studies* 
# 
NIH stroke scale* 
# 
# 
Vital Signs* 
# 
# 
# 
# 
CT brain* 
X 
X 
CT Perfusion* 
# 
CTA H&N* 
X 
MRI (or CT) brain (FIV & 
Hemorrhage)* 
X 
Nicardipine* 
X 
Labetalol (if needed)* 
X 
Discharge Summary* 
X 
Adverse Events 
X 
X 
Serious Adverse Events 
X 
X 
Modified Rankin Score* 
# 
End of Study 
X 
*= Standard-of-Care; X = Manual task; # = Automated Task; D/C = Discharge; CTA H&N 
= CT Angiogram Head & Neck; FIV: Final Infarct Volume 
1.3 
SCHEDULE OF ACTIVITIES (SOA) 


Blood Pressure After Endovascular Stroke Therapy (BEST)- II 
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 2.1 
STUDY RATIONALE 
 
 
A quarter of all annual acute ischemic strokes (AIS) in the United States are caused by a large 
cerebral vessel occlusion (LVO).1 They have the highest morbidity and mortality rates among all 
AIS etiologies.1,2 Endovascular mechanical thrombectomy (EVT) is a revolutionary AIS 
treatment that rapidly and most efficiently removes the cause of the LVO, which is most often a 
blood clot. However, despite a successful recanalization with restoration of blood flow, about 
half of the EVT-treated patients remain disabled.3 
 
Blood pressure (BP) after successful EVT-mediated recanalization is a readily modifiable 
parameter that may critically influence patient outcomes. The current guideline recommends 
maintaining systolic BP (SBP) 180 mmHg in the first 24 hours after EVT. This guideline permits 
higher than normal SBP without any robust evidence, including randomized studies.24 While a 
higher SBP target may be necessary to improve or maintain perfusion, it may expose vulnerable 
ischemic brain tissue to hyper-perfusion injury and lead to oxidative stress, inflammation, and 
hemorrhage.4-6 Conversely, lower SBP targets can minimize hyper-perfusion injury, but may 
compromise microcirculatory reperfusion and increase infarct volume.7 In our recent multi-center 
prospective cohort study BEST-I and other preliminary work, SBP 160 mmHg in the first 24 
hours after EVT correlated with worse functional outcomes.8-11 In rodent models of transient 
LVO, lowering BP during the first 24 hours of reperfusion results in lower brain infarct volumes 
and incidences of hemorrhage.12 We found considerable heterogeneity in the current practice of 
post-EVT BP management across United States in a recent survey,13 with <140, <160, and 
≤180 mmHg being the most commonly practiced SBP targets. These conflicting post-EVT BP 
management practice needs an urgent resolution to ensure optimal clinical care. Hence, large 
randomized studies are necessary to evaluate the efficacy of different post-EVT BP targets.14,15 
But first, due to legitimate concerns about potentially compromised perfusion and resultant 
worsening ischemia, safety assessments of these lower BP targets are obligatory prerequisites 
to larger efficacy trials. 
 
 2.2 
BACKGROUND 
 
 
2.2.1 Over half of endovascularly-treated stroke patients remain disabled at 90-days. 
The financial burden of ischemic stroke is $40.1 billion annually in the United States and it will 
triple by the year 2035.16 Strokes caused by a large vessel occlusion (LVO) contribute to the 
vast majority of ischemic stroke-related morbidity and mortality.17 Endovascular mechanical 
thrombectomy (EVT) has revolutionized acute stroke treatment by unprecedentedly improving 
the outcomes of patients with LVO stroke.3 Yet, over half of those treated with an EVT remain 
disabled at 90-days despite optimal patient selection and successful clot removal.3 With 
increasing use of EVT for LVO stroke treatment,18 measures to further improve outcomes of this 
devastating type of ischemic stroke is necessary. An important and possibly neuroprotective 
intervention is blood pressure (BP) management following EVT. 
 
2.2.2 Post-EVT BP target may affect ischemic bed reperfusion 
Higher systolic BP (SBP) after recanalization can lead to hyperperfusion. During reperfusion 
after transient LVO in rodent models, cerebral arteries demonstrate impaired in autoregulation 
and fail to maintain a constant cerebral blood flow over a wide range of systemic BP to prevent 
brain injury.19,20 Increased SBP after successful EVT-mediated vessel recanalization following 
2 
INTRODUCTION 


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removal of the obstruction causing an LVO can lead to hyper-perfusion injury resulting in 
inflammation, reactive oxygen species generation, and hemorrhage.5 Conversely, lower SBP 
after recanalization may cause hypoperfusion, especially at the microcirculatory level,7 and raise 
concerns for an increased infarct volume.21,22 
 
2.2.3 Evidence of significant benefit in functional outcome with lower post-EVT SBP 
Table 1. Prior studies on association of Post-EVT Systolic Blood Pressure and Functional Outcome 
Study 
Year 
No. of Patients 
Study Variable 
Outcome 
Measure 
OR with 95% CI 
Mistry et al. 
2017 
228 
Peak SBP (continuous 
decrement) 
mRS shift 
towards worse 
outcome 
0.98 (0.97, 1.0) 
Goyal et al. 
2017 
217 
Peak SBP (10 mmHg 
decrement) 
mRS 3-6 
0.70 (0.56, 0.87) 
Maier et al. 
2018 
168 
Peak SBP (continuous 
decrement) 
mRS 3-6 
0.96 (0.93, 0.99) 
Mistry et al. 
2019 
485 
Peak SBP</=158 
mmHg 
mRS 3-6 
0.77 (0.48, 1.23) 
Prior observational studies8-11 (Table 1) have shown that lower SBP in first 24 hours after EVT is 
associated with lower likelihood to bad functional outcomes, defined as functional dependence 
or death at 90 days (score of 3-6 on modified Rankin scale). Specifically, patients had worse 
outcomes if their SBP was higher than 160 mmHg following EVT. 
 
2.2.3 Current landscape and scope of post-EVT BP management practice 
The 2018 American Heart/American Stroke Association guidelines recommend lowering SBP to 
180 mmHg in the first 24 hours after an EVT.23 These guidelines allow for a higher than normal 
SBP but are not supported with robust evidence. No randomized clinical trial has been 
conducted in patients treated with EVT to establish the efficacy of permissive hypertension 
(≤180 mmHg) over lower SBP targets. Not surprisingly, we found in our survey of 51 
comprehensive stroke centers across the US that the current SBP management practice is quite 
heterogenous and deviates widely from these guidelines.13 The post-EVT BP target is an 
 
 
 
 


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individualized decision taken collectively by a team of clinicians involved in each patient’s care. 
There is a lack of expert consensus on the ideal post-EVT BP target (Figure 1). 
Figure 1. Results of StrokeNET Survey of 51 Sites. A) Who decides the post endovascular therapy (EVT) blood 
pressure (BP) target? B) What is the target systolic BP post-EVT in patients with successful recanalization? 
 
2.2.4 Urgent need for a randomized trial on optimal post-EVT BP target 
Evidence based resolution to this anecdotal practice is urgently needed and asserted by the 
2018 AHA/ASA guideline committee and leaders of the Stroke Treatment Academic Industry 
Roundtable as a premier question in stroke that needs an urgent answer.14,15,23 Large 
randomized studies are necessary to evaluate the efficacy of different post-EVT BP targets. 
Optimization of post-EVT BP management may not only improve patient outcomes but also 
standardize all future EVT-related research. 
 
2.2.5 Safety of post-EVT BP management with lower targets remain unestablished. 
Pre-clinical studies in rodent models have shown that antihypertensive treatment with BP 
reduction following a transient LVO results in smaller infarcts and lower rates of hemorrhage.12 
However, safety of BP management strategies aimed at lowering SBP and their effects on brain 
perfusion remain unestablished in humans. Therefore, due to a potential for compromised 
perfusion and resultant worsening ischemia, safety assessments of these lower SBP targets are 
required prior to a larger efficacy trial. 
 
2.2.6 Choice of post-EVT SBP targets 
Targeting post-EVT SBP ≤180 mmHg is the current standard of care and recommended by the 
guidelines. Our prospective multi-center observational study, BEST-I,11 was specifically 
designed to unveil the threshold of post-EVT SBP that best dichotomizes outcomes in EVT- 
treated patients for testing in a randomized trial such as the BEST-II. This study identified that a 
peak post-EVT SBP of 158 mmHg, for practical purposes 160 mmHg, best dichotomizes these 
outcomes. In a nationwide survey,13 we found that most commonly practice post-EVT SBP 
targets were the following: <140 (41%), <160 (21%), and 180 (35%). To capture these most 
commonly utilized post-EVT targets, the BEST-II trial will randomly assign patients to one of 
these three SBP target arms. 
 
2.2.7 Choice of antihypertensive agent 
Intravenous nicardipine is the most commonly used antihypertensive agent across the US 
institutions to control post-EVT BP. As noted in our survey, 74% of the US institutions use 
nicardipine infusion as the first line agent followed by labetalol, which is used in 16% institutions. 
Both these medications have undergone testing for BP reduction in other acute cerebrovascular 
conditions (e.g the ATACH-2 trial and acute stroke trials) and are deemed safe and feasible 
agents. Additionally, both these agents are readily available across the institutions in the US and 
allow a stringent BP control with easy titration. Thus, BEST-II will utilize nicardipine as the first 
line and labetalol as the second line agent for BP reduction post-EVT. 
 
2.2.8 Timing and duration of initiating antihypertensive management 
Our preliminary observational data suggests that antihypertensive management should begin 
immediately after recanalization. During the LVO, there is often a physiological increase in BP to 
attempt to maintain brain perfusion. After a successful recanalization with an EVT, a physiological 


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2.3.1 KNOWN POTENTIAL RISKS 
 
decline in SBP seen in most patients. In BEST-I, patients with who 
died or lived with severe disability (mRS 5-6) had on average the 
highest SBP throughout the 24 hrs. In patients who had a moderate 
disability (mRS 3-4), the physiological decline of SBP failed to 
persist throughout the 24 hrs, often rising during the latter aspect of 
the 24 hrs, unlike those who had favorable outcomes (mRS 0-2) 
(Figure 2). 
 
 2.3 
RISK/BENEFIT ASSESSMENT 
 
 
 
Risks associated with endovascular mechanical 
thrombectomy: As a part of their clinical care, adult patients with 
anterior LVO stroke undergoing EVT are at a risk for death, coma, 
altered mental status requiring endotracheal intubation, bleeding in 
the brain and/or groin, vessel injury, vessel re-occlusion, further 
strokes, malignant cerebral edema, infection, condition that require 
surgical treatment, and long-term cognitive dysfunction among 
several possibilities. 
Risks associated with higher SBP target: Higher SBP may lead to hyperperfusion brain injury 
and hemorrhage in stroke patients treated with EVT. This may clinically manifest as a 
neurological decline. Normally, cerebral arteries have the unique autoregulatory capability to 
maintain a constant cerebral blood flow over a wide range of systemic BPs to prevent brain 
injury. During recanalization after transient LVO in rodent models, cerebral arteries demonstrate 
impaired autoregulation, leading to increased blood flow in response to increased BP.20,21 
Although high SBP values associated with worse outcomes in EVT-treated stroke patients in 
preliminary data, a causal relationship remains to be established with a high-level of evidence. 
Risks associated with lower SBP targets: Lower SBP may compromise reperfusion, 
especially at a microcirculatory level, and worsen ischemia in stroke patients treated with EVT. 
Additionally, chronically hypertensive patients may experience systemic complications from 
targeting lower SBP, for example, kidney hypoperfusion. Although lower SBP associated with 
better outcomes in EVT-treated stroke patients in preliminary data, a causal relationship 
remains to be established with a high-level of evidence. 
Risk associated with selection of SBP target by the study: The above risks are experienced 
by EVT-treated stroke patients randomized to higher or lower SBP targets as part of routine 
care and outside of the context of clinical research. Currently, an ideal post-EVT SBP target 
from both safety and efficacy standpoint is unknown. SBP targets are currently selected 
anecdotally. In BEST-II, the target of SBP will be decided randomly by the study. To ensure that 
this randomly selected target does not pose additional risk to the patient compared to what 
would have selected by a practitioner in routine care, if a treating practitioner feels a specific 
SBP target other than that randomly assigned to the patient is required for safe treatment, the 
SBP target for that patient may be modified using a one-page “Target Modification Form”. The 
Figure 2. Time dependent changes 
in the SBP according to 90-day 
patient outcome in BEST-I. Lines 
with the ribbon represent a fitted 
generalized additive model (mean- 
like) with 95% confidence Interval of 
all (>17,000) SBP values recorded 
over 24 hrs. 


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2.3.2 KNOWN POTENTIAL BENEFITS 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS 
 
BEST-II trial will only control choice of SBP target when the perceived risk associated with each 
randomly assigned target for an individual patient is equivalent in the treating practitioner’s 
opinion. Any risks (or benefits) associated with each target may be enhanced in the trial setting 
due to higher adherence compared to routine care. 
Risks associated with collection of protected health information (PHI): Collection of PHI for 
research involves a small risk for violation of patient confidentiality. To minimize this risk, only 
the minimum amount of PHI needed to conduct the study will be collected. All data collected will 
be generated during clinical care, and no additional data will be collected for research. At no 
time will we reveal subject identities in any manner, including research presentation, 
descriptions, or publications. All data will be entered into a secure, password-protected REDCap 
database. All patients will be assigned a unique patient identifier upon enrollment in the study. 
Patient identifiers will only be accessible to the PI and a select few research staff. Once the 
study results have been published, all study records will be stripped of any PHI in order to 
maximize patient and surrogate confidentiality. 
 
 
The proposed trial is urgent. Thousands of patients undergo EVT every year in the US, yet, 
sparse evidence exists to guide post-EVT BP management. The primary benefit from the 
proposed research is the generation of data of the highest quality for the safety of mostly 
commonly practiced BP managements to inform the optimal BP management approach in EVT- 
treated patients. Results of BEST-II are necessary for the design of larger efficacy trials to 
improve outcomes in half of the successfully EVT-treated acute ischemic stroke patients that 
remain disabled. Even a small improvement in mortality and disability of these patients could 
translate into a great reduction in stroke-related societal economic burden. The findings of this 
study will also significantly improve our understanding of safety, efficacy, and mechanistic 
effects of different post-EVT BP strategies that are all within scope of current practice. 
 
 
 
Every patient in the proposed research would have otherwise been assigned an SBP target 
without clear evidence for safety or efficacy. Patients participating in the trial may benefit from 
participation, to the extent that adherence to one of the assigned SBP targets improves 
outcomes or avoids harm. The minimal risks associated with transferring the selection of the 
SBP target from the treating clinician to the study and violation of confidentiality are greatly 
outweighed by potential improvement in clinical care provided by the research. 
The BEST-II trial is a necessary step towards a larger efficacy trial to generate rigorous 
evidence for optimal post-EVT BP management strategy. With this overarching goal, the BEST 
series of studies will standardize future EVT-related research and translate into improved 
outcomes of numerous EVT-treated acute ischemic stroke patients who still remain disabled 
despite receiving the best treatment currently possible. 


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 3 
OBJECTIVES AND ENDPOINTS 
 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION 
FOR ENDPOINTS 
Primary 
To assess the harm of lower 
SBP targets in AIS patients that 
are successfully treated with 
EVT. 
To assess the probability of a 
positive phase-III trial evaluating 
the efficacy of lower SBP targets 
at improving functional 
outcomes of EVT-treated 
patients 
1) Infarct volume on 36 +/-12 hr 
MRI (or CT scan if MRI 
contraindicated) 
2) 9014 -day Utility-weighted 
mRS (UW-mRS) with following 
utility weights: mRS 0 - 1.0; mRS 
1 - 0.91; mRS 2 - 0.76; mRS 3 - 
0.65; mRS 4 - 0.33; mRS 5 - 0; 
mRS 6 – 0. 
Concern for potential 
compromised blood 
flow to the ischemic 
brain tissue and 
resulting increase the 
infarct volume and 
worse functional 
outcome is the 
primary safety 
concern for clinicians 
when targeting lower 
SBP in post-EVT 
patients. The 
multiple-primary 
endpoints are chosen 
to mechanistically 
establish safety of 
lower BP targets after 
a successful EVT. 
Additionally, 
preliminary 
evaluation of efficacy 
will be performed 
using the 9014 -day 
UW-mRS endpoint. 
To evaluate the 
efficacy of lower SBP 
targets at improving 
functional status of 
the patient, trial 
simulations will be 
performed using the 
patient-centered UW- 
mRS as primary 
endpoint after taking 
the observed effect 
and remaining 
uncertainty. 
Secondary 
To evaluate the effects of SBP 
targets on intracerebral 
hemorrhage, neurological 
worsening, and brain perfusion. 
1) Any intracerebral hemorrhage 
on 36 +/- 12 hr MRI/CT 
2) Symptomatic intracerebral 
hemorrhage on 36 +/- 12 hr 
MRI/CT 
To evaluate the effect 
of BP targets on 
brain perfusion, we 
will evaluate 
incidence of any and 


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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION 
FOR ENDPOINTS 
3) Neurological worsening 
associated with anti- 
hypertensive treatment 
symptomatic 
intracerebral 
hemorrhage 
(measures of 
hyperperfusion) as 
well as follow up MRI 
(or CT) infarct 
volumes (to estimate 
hypoperfusion). We 
will also evaluate the 
frequency of 
neurological 
worsening associated 
with antihypertensive 
agent to estimate 
immediate safety 
concerns with BP 
lowering in the post- 
EVT setting. 
Feasibility & Compliance 
To determine the feasibility and 
compliance of maintaining SBP 
below the randomly assigned 
target in EVT-treated patients 
1) Compliance Outcome – Hourly 
maximum SBP above target 
from 2-24 hours post treatment 
initiation 
2) Feasibility Outcome – 
Separation of hourly maximum 
SBP values between three 
SBP target groups 2-24 hours 
after treatment initiation 
Compliance outcome 
is defined as such to 
avoid mislabeling 
spontaneous drops in 
SBP as non- 
compliance. 
 
 
 
 4 
STUDY DESIGN 
 
 
 4.1 
OVERALL DESIGN 
 
 
BEST-II is a prospective, randomized, open-label, blinded-endpoint (PROBE), clinical trial, in 
which eligible acute stroke patients will be randomly assigned (1:1:1) to one of the following 
systolic blood pressure targets: (1) a high target of 180mmHg (control), (2) an intermediate 
target of <160mmHg, and (3) a lower target of <140mmHg. The SBP will be maintained below 
the assigned target for 24 hours after a successful endovascular clot retrieval (EVT). We will 
test the harm and efficacy of two intervention arms. 


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 4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
 
The first stage of the BEST-II trial is designed to test null hypothesis of “no harm” and an 
alternative hypothesis of “harm” of lower SBP targets. Failure to reject null hypothesis (one 
tailed p>0.05) will establish a lack of evidence of “harm”. Thus, BEST-II paradoxically assesses 
safety by directly testing for harm. In other words, we will detect a “lack of evidence of harm” 
rather than “evidence of no harm”. 
 
 4.3 
JUSTIFICATION FOR DOSE 
 
Please refer to section 2.2.6. 
 
 4.4 
END OF STUDY DEFINITION 
 
A participant is considered to have completed the study if he or she has completed all phases of 
the study including the 9014 -day follow-up shown in the Schedule of Activities (SoA), Section 
1.3. The end of the study is defined as completion of the last visit or procedure shown in the 
SoA in the trial globally. 
 
 
 
 
 5 
STUDY POPULATION 
 
 
 5.1 
INCLUSION CRITERIA 
 
 
In order to be eligible to participate in this study, an individual must meet all of the following 
criteria: 
1. Male or female adult patients (≥ 18 years) 
2. Undergoing successful EVT (defined as mTICI ≥2b) for an occlusion in the anterior 
cerebral circulation large vessel (specifically, internal carotid artery and M1 or M2 
segments of the middle cerebral artery). 
 
 5.2 
EXCLUSION CRITERIA 
 
 
We will exclude patients with comorbid conditions that may require condition-specific BP 
management such as those with 1) a diagnosis of heart failure with ejection fraction <30%, 2) 
left ventricular assist device, and 3) extracorporeal membrane oxygenation. Additionally, 
pregnant women and patients enrolled in other clinical trials will also be excluded. 
 
 5.3 
LIFESTYLE CONSIDERATIONS 
 
Not Applicable 
 
 5.4 
SCREEN FAILURES 
 
Screen failures will be defined as participants who consent to participate in the BEST-II trial but 
are not subsequently randomly assigned to the study intervention or entered in the study. A 
minimal set of information on demography, screen failure details, eligibility criteria, and any 
serious adverse event (SAE) will be recorded for these patients. 


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Individuals who do not meet the criteria for participation in this trial (screen failure) because of 
an initial inability to undergo EVT may be rescreened if this decision is revoked. Rescreened 
participants will be assigned the same participant number as for the initial screening. 
 
Of the patients meeting inclusion criteria without meeting the exclusion criteria will have an 
opportunity to participate in the study. Of these, a total of 120 with successful recanalization 
(defined as an angiographic score of 2b or 3 on the modified Thrombolysis in Cerebral Ischemia 
scale, or mTICI) will be randomized to one of the three SBP target strategies. Patients in whom 
a successful recanalization is not achieved will be followed but not intervened upon. These 
patients will not be considered screen failures. 
 
 5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 
 
We will enroll 120 patients with successful EVT of their anterior cerebral circulation large vessel 
stroke in BEST-II at Vanderbilt University Medical Center, with an anticipated accrual rate of 3.3 
patients per month. No other site will participate or enroll patients in this trial. To reach this 
parget sample size, we anticipate screening about 300 patients during the study period of 36 
months. We will not select patients based on gender, race, or ethnicity. The anticipated 
demographics are presented in the table below. 
 
Table. Gender and race/ethnicity of EVT-treated stroke patients since 2012 at Vanderbilt 
University Medical Center. 
Male 
Female 
White 
Black or 
African 
American 
Asian 
Native 
Hawaiian or 
other Pacific 
Islander 
American 
Indian/Alaska 
Native 
Hispanic 
50.1% 
49.9% 
83.4 
12.5% 
1% 
<1% 
<1% 
4.1% 
 
Enrollment will commence after receiving Institutional Review Board approval for human subject 
research. All stroke patients amenable to EVT at Vanderbilt present to the emergency room 
prior to being transported to the angiography suite for intervention. Patients will be screened in 
the emergency room or the angiography suite for eligibility using the study inclusion/exclusion 
criteria by a stroke physician, neuro-interventionist, or study coordinator. Upon meeting 
enrollment criteria, a consent will be obtained electronically using REDCap from the patients or 
their legally authorized representative. The electronic consenting process allows the consenting 
party and study personnel to be on or off site, which is critical given the acute time-frame in 
which stroke patients are treated. Capacity of a potential study subject will be determined by a 
trained study personnel based on the ability to communicate, understand, and ask questions. 
Once consent is obtained, patient will be randomized to one of the three systolic blood pressure 
target groups after satisfactorily successful recanalization is achieved, defined as mTICI ≥2b. 
Study intervention will begin soon after randomization. Members of the study team will be 
available to answer any questions during recruitment process and during the study period. 
 
All consecutive stroke patients presenting to Vanderbilt University Medical Center who meet 
inclusion criteria without meeting exclusion criteria will have an opportunity to participate in this 
study. At Vanderbilt University Medical Center, 90-day follow-up with modified Rankin score is 
obtained via a phone interview by the stroke coordinator with a 90% success rate. We have 
conservatively accounted for a 15% loss to follow-up for this 90-day clinical primary outcome. 
We will ensure that contact information for the patient and legally authorized representative is 


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6.1.1 STUDY INTERVENTION DESCRIPTION 
6.1.2 DOSING AND ADMINISTRATION 
 
documented within patient’s electronic medical record system and electronic consent form to 
minimize loss to 90-day follow-up. A 3612-hr post-EVT MRI scan is performed in all EVT- 
treated stroke patients (unless contraindicated, in which case a CT scan is performed). All EVT- 
treated patients, thus, have either MRI or CT scan as routine care at 3612 hours. We do not 
foresee any loss to follow-up for this radiographic primary outcome. 
 
By the nature of the condition, a considerable portion of patients with acute LVO experience 
acute cognitive dysfunction. They are a vulnerable population. Inclusion of these patients is 
required to inform an optimal BP strategy for all patients undergoing EVT. Exclusion of all 
patients with cognitive impairment at the time of enrollment will result in a study population that 
is not representative of EVT-treated stroke patients in usual practice. Our institution and 
research team have an extensive experience in undertaking investigations that involve 
vulnerable patients, and we will apply our expertise in minimizing risks for these study 
participants. Other special populations, such as fetuses, neonates, pregnant women, children, 
and prisoners will not be eligible for inclusion 
 
Participants will not be compensated in any form for their participation in the study. 
 
 
 
 6 
STUDY INTERVENTION 
 
 
 6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
 
 
Management of SBP will start after randomization to lower and maintain SBP below the 
assigned target for 24 hours. In the event where SBP values are above target, intravenous 
nicardipine will be initiated at 2.5 mg/hr to lower the SBP. If SBP is still not reduced to below 
assigned target after 15 minutes, nicardipine dose will be increased by 2.5 mg/hr every 15 
minutes until the target SBP or a maximum dose of 15 mg/hr is reached. 
 
In the event where SBP values are above the randomly assigned target, intravenous nicardipine 
will be initiated at 2.5 mg/hr to lower the SBP. If SBP is still not reduced to below assigned 
target after 15 minutes, nicardipine dose will be increased by 2.5 mg/hr every 15 minutes until 
the target SBP or a maximum dose of 15 mg/hr is reached. 
If SBP is above target despite maximum nicardipine infusion for 30 minutes, 10-20 mg of 
intravenous labetalol will be added every 15 minutes. If SBP remains unresponsive for 1 hr 
despite the use of maximum doses of nicardipine and labetalol, a third agent, Hydralazine, will 
be added at the treating physician’s discretion. Incidence of the latter scenario is anticipated to 
be exceedingly rare. 
We will only target peak SBP as spontaneous SBP reductions are expected after successful 
recanalization. However, if anti-hypertensive medication is used to lower the SBP then we will 
obey the following protocol. In the high target group, if the SBP falls below 160 mmHg, 
nicardipine will be titrated down until it returns within 160-180 mmHg or nicardipine is 


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6.2.1 ACQUISITION AND ACCOUNTABILITY 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
6.2.3 PRODUCT STORAGE AND STABILITY 
6.2.4 PREPARATION 
 
discontinued. If the SBP falls below 140 mmHg in the lower target group of <160mmHg or below 
110 mmHg in lower target group of <140, nicardipine will be titrated down until it returns within 
140-159 and 110-139, respectively, or nicardipine is discontinued. Attempts to increase the SBP 
will only be made at the discretion of the attending physician (e.g. associated neurologic 
worsening). 
 
 
 6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
 
 
Both nicardipine and labetalol are routinely used in the Neurological ICU as standard-of-care for 
BP management and are readily available in the central pharmacy and medication dispensing 
system. 
 
 
 
 
Not Applicable. 
 
 
Nicardipine and labetalol will be stored per Vanderbilt University Medical Center Pharmacy 
protocols. 
 
 
Nicardipine and labetalol will be prepared and dispensed per Vanderbilt University Medical 
Center Pharmacy protocols. 
 
 6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 
 
Randomization: Enrolled patients will be randomized (1:1:1; stratified permuted block 
randomization) after the achievement of recanalization while in the angiography suite using 
REDCap randomization tool integrated within EHR, to one of the following groups where SBP 
will be lowered and maintained for 24 hours after a successful EVT: (1) High SBP target 
(180mmHg; standard-of-care), (2) Lower SBP target (<160mmHg; intervention), and (3) Lower 
SBP target (<140mmHg; intervention). 
Blinding: Given the nature of the experiment, the treating neuro-intensivist and other neuro-ICU 
staff will not be blinded to the treatment group assignment. Imaging outcome assessment will be 
performed by a central blinded imaging reader with an adjudication by a blinded 
neuroradiologist. A blinded stroke coordinator will assess clinical outcomes. 


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 6.4 
STUDY INTERVENTION COMPLIANCE 
 
 
SBP Monitoring: BP will be monitored in a recumbent position using a BP cuff with the 
following frequency: Every 5 minutes for the first 15 minutes following nicardipine initiation or 
dose adjustment, then every 15 minutes for the 1st hr, followed by at least every 30 minutes until 
the end of 24 total hours after EVT. Arterial line and more frequent BP measurements will not be 
required but may be used by the treating physician based on medical indication. 
Feedback on SBP Compliance: Study personnel will remotely monitor SBP values in real-time 
8am-5pm Monday through Friday. 10% of the hours during nights and weekends will also be 
monitored. Real-time monitoring will aid identification of any lags between out-of-range SBP 
values and nicardipine titration and provision of timely feedback to nurses and ICU staff. This 
will allow us to identify barriers to SBP target compliance. Study personnel will regularly attend 
unit, nursing, and physician meetings to educate clinical personnel, solicit safety concerns, and 
address barriers to SBP target compliance. 
 
 
 6.5 
CONCOMITANT THERAPY 
 
Not Applicable. 
 
 7 
DISCONTINUATION/WITHDRAWAL 
 
 
 7.1 
DISCONTINUATION OF STUDY INTERVENTION 
 
 
If at any point during the treatment period of 24 hours following EVT the treating clinician feels 
that the SBP target should be different from that of the randomly assigned target for patient 
safety, the target will be modified to what is judged best by the treating clinician. These 
scenarios can include but are not limited to the following: 1) Neurologic deterioration associated 
with anti-hypertensive treatment or permissive hypertension 2) Follow-up radiographic findings 
(e.g. intracerebral hemorrhage on CT scan) requiring more stringent BP control 3) Vessel re- 
occlusion requiring more liberal BP control. These findings will be reported as AE or SAEs. 
This can be done using a one-page “Target Modification Form” outlining the rationale for 
modification, new SBP target, and any additional comments. No re-challenge of the randomly 
assigned SBP target intervention will be made. These patients will complete all study activities 
including the standard of care 9014 -day follow-up per the study protocol. All efforts will be 
made to undertake protocol-specified safety follow-up procedures to capture adverse events 
(AE), serious adverse events (SAE), and unanticipated problems (UPs). 
 
 
 7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
 
Participants will have the right to voluntarily withdraw from participation in the study at any time 
upon request. An investigator may discontinue the study intervention for the following reasons: 


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• 
Pregnancy diagnosed after enrollment 
• 
If any clinical adverse event (AE), laboratory abnormality, or other medical condition or 
situation occurs such that continued participation in the study would not be in the best 
interest of the participant 
• 
Disease progression which requires discontinuation of the study intervention 
• 
If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
• 
Participant unable to receive study intervention for >1.5 hours following successful 
recanalization. 
 
The reason for participant discontinuation or withdrawal from the study will be recorded on the 
electronic Case Report Form (CRF). Subjects who sign the informed consent form and are 
randomized but do not receive the study intervention may be replaced. Subjects who sign the 
informed consent form, and are randomized and receive the study intervention, and 
subsequently withdraw, or are withdrawn or discontinued from the study, will not be replaced. 
 
 
 7.3 
LOST TO FOLLOW-UP 
 
 
A participant will be considered lost to follow-up for the primary end-point of UW-mRS if he or 
she is unable to be contacted by the study site staff, either via a telephone or an in-person 
meeting at 90 14-days after randomization. A participant will be considered lost to follow-up for 
the primary end-point of infarct volume if neither MRI or CT scan is obtained at 36  12 hours 
following randomization. The latter scenario is expected to never occur during the study as 
obtaining a follow-up brain imaging in form or either MRI or CT is not only standard of care but 
also best medical practice. 
 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, 
a certified letter to the participant’s last known mailing address or local equivalent methods). 
These contact attempts will be documented in the participant’s medical record or study file. 
 
 8 
STUDY ASSESSMENTS AND PROCEDURES 
 
 
 8.1 
ENDPOINT AND OTHER NON-SAFETY ASSESSMENTS 
 
 
Primary endpoints assessment: 
1) 9014 -day Utility-weighted modified Rankin score: An attempt to obtain a modified Rankin 
score is obtained at 9014 days after the day of admission is made for all stroke patients 
admitted to the Vanderbilt University Medical Center. This attempt is made by the stroke- 
coordinator via a phone call or clinic follow-up. The stroke coordinator will be blinded to the 
SBP target assignment. The modified Rankin score (mRS) is an ordinal disability score 
ranging from 0 (no symptoms) to 6 (death). Utility weights are assigned to this ordinal scale 
for practical applicability since the difference between any two points on the scale is not 
linearly proportional to the difference in ‘value’ placed by humans to their corresponding 
levels of disability. Thus, to make this scoring system more patient-centered, utility weights 
will be assigned as follows- mRS 0 - 1.0; mRS 1 - 0.91; mRS 2 - 0.76; mRS 3 - 0.65; mRS 4 
- 0.33; mRS 5 - 0; mRS 6 – 0 


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8.2.1 DEFINITION OF ADVERSE EVENTS (AE) 
8.2.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 
 
2) Infarct volume on 36 (±12)-hr MRI or CT scan (FIV): At 36±12-hours post randomization, 
patients undergo an MRI scan with at least DWI, T2 FLAIR, and GRE or SWAN sequences 
as standard-of-care. In case of contraindication to an MRI, a 36-hour CT scan will be 
obtained. The infarct volume will be manually calculated by a blinded imaging reader and 
will be adjudicated by a blinded neuroradiologist. 
 
Other assessments for BEST-II include radiographic, physical, and questionnaire type 
evaluations outlined below: 
• 
Radiographic or other imaging assessments. 
In addition to the FIV, the following imaging endpoints will be assessed: 
1) Baseline CT scan (standard-of-care): ASPECT score determined by the reading 
radiologist and extracted from the radiology report. 
2) Baseline CT angiogram (standard-of-care): Location of the large vessel occlusion 
determined by the reading radiologist and extracted from the radiology report and 
modified Tan collateral grade determined by a trained personnel as part of the study 
procedure. 
3) Baseline CT perfusion (standard-of-care): CTP will be processed using the 
iSchemaview RAPID software to automatically determine the core and penumbra 
volumes as well as the hypoperfusion intensity ratio (HIR; used to assess collateral 
circulation) which will be extracted. 
4) 36 (±12)-hr MRI or CT scan (standard-of-care): Presence or absence of hemorrhage 
will be determined by the reading radiologist and extracted from the radiology report. In 
case of contraindication to an MRI, a 36-hr CT scan will be obtained. 
• 
Physical examination. NIH stroke scale will be calculated at baseline and 24 hours by 
trained personnel. Patients will be closely monitored in the Neurological ICU during the 
study procedure and any changes in the neurological examination will be rapidly 
identified by the ICU staff. 
• 
Laboratory evaluations. Baseline standard-of-care laboratory values of glucose, 
platelet, International Normalized Ratio, Blood Urea Nitrogen, and creatinine will be 
recorded. 36 (±12) hr Blood Urea Nitrogen and creatinine will be obtained as standard- 
of-care. 
• 
Administration of questionnaires or other instruments. Baseline modified Rankin 
score will be obtained when possible by trained personnel prior to EVT. 
• 
Other clinical care during 24 hours of the study period and all clinical care after 24 
hours will be provided according to the American Heart Association/ American Stroke 
Association guidelines. 
 
 
 8.2 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
 
An adverse event (AE) will be any untoward medical occurrence for a patient enrolled in BEST- 
II, regardless of whether the event was considered intervention-related or not. Events tracked as 
clinical outcomes are not considered adverse events. 
 
 
AEs that meet any of the following criteria will be considered Serious AEs (SAEs): 
a) Results in death 


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8.2.3 CLASSIFICATION OF AN ADVERSE EVENT 
8.2.3.1  SEVERITY OF EVENT 
8.2.3.2  RELATIONSHIP TO STUDY INTERVENTION 
8.2.3.3  EXPECTEDNESS 
8.2.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND 
FOLLOW-UP 
 
b) Is life-threatening (defined as an event in which the participant was at risk of death at the 
time of event and NOT an event that hypothetically might have caused death if it would 
have been more severe) 
c) Prolongs existing hospitalization 
d) Results in persistent or significant disability above and beyond what would be expected 
for the underlying ischemic stroke. 
e) Results in a congenital anomaly or birth defect 
f) Medical event that requires intervention to prevent any of the above a-e. 
 
 
 
For adverse events (AEs) not included in the protocol defined grading system, the following 
guidelines will be used to describe severity. 
 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s 
daily activities. 
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic 
drug therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating. 
 
All adverse events (AEs) must have their relationship to study intervention assessed by the 
clinician who examines and evaluates the participant based on temporal relationship and his/her 
clinical judgment. The degree of certainty about causality will be graded using the categories 
below. 
 
• 
Related – The AE is known to occur with the study intervention, there is a reasonable 
possibility that the study intervention caused the AE, or there is a temporal relationship 
between the study intervention and event. Reasonable possibility means that there is 
evidence to suggest a causal relationship between the study intervention and the AE. 
• 
Not Related – There is not a reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study 
intervention and event onset, or an alternate etiology has been established. 
 
 
The PI will be responsible for determining whether an adverse event (AE) is expected or 
unexpected. An AE will be considered unexpected if the nature, severity, or frequency of the 
event is not consistent with the risk information previously described in the literature for SBP 
lowering in acute cerebrovascular conditions. 
 


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8.2.5 ADVERSE EVENT REPORTING 
8.2.6 SERIOUS ADVERSE EVENT REPORTING 
 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the 
attention of study personnel during study visits and interviews of a study participant presenting 
for medical care, or upon review by a study monitor. 
Study personnel will monitor enrolled patients for AEs throughout the trial and follow all AEs 
until they are resolved. All AEs will be recorded on the electronic case report form (eCRF). 
Information on event description, time of onset, clinician’s assessment of severity, relationship 
to intervention, and time of resolution/stabilization of the event will be collected. 
Any medical condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. However, if the study participant’s condition 
deteriorates at any time during the study, it will be recorded as an AE. 
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of 
the event at each level of severity to be performed. 
 
Study coordinator will record all reportable events with start dates occurring any time after 
informed consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last 
day of study participation. Events will be followed for outcome information until resolution or 
stabilization. 
 
 
 
All AEs will be recorded in the eCRF and communicated to the PI within 5 days. PI will in turn 
report all AEs to the Institutional Review Board (IRB) and DSMB as part of annual review 
process as required. 
 
The BEST-II trial will monitor, track, and report all Clinical Outcomes and AEs as required by 
regulatory bodies. 
Clinical Outcomes (not considered Adverse Events): Stroke-related mortality, disability, and 
intracranial hemorrhage are expected clinical outcomes for patients included in this study and 
will be tracked and collected as a study outcome on the eCRF and will be included in the 
statistical analysis. For reporting purposes, events listed below will not be reported as AEs 
unless believed to be study related or more severe or prolonged than expected given the 
underlying stroke. 
1. Death (all deaths occurring prior to discharge be reported in the eCRF). 
2. Intraparenchymal intracranial hemorrhage without or without receipt of surgical or 
medical intervention. 
3. Neurological decline within 24 hours post-treatment initiation (defined as 4 points of 
more increase in NIH stroke scale) 
4. Disability scored on the modified Rankin scale at 9014 - days post-stroke. 
 
 


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8.2.7  REPORTING EVENTS TO PARTICIPANTS 
8.2.8  EVENTS OF SPECIAL INTEREST 
8.2.9  REPORTING OF PREGNANCY 
8.3.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
8.3.2 
UNANTICIPATED PROBLEM REPORTING 
 
SAEs will be reported to the PI within 72 hours and the PI will report to IRB, DSMB, and NINDS 
no later than 7 days of occurrence. 
The study clinician will immediately report to the sponsor any serious adverse event, whether or 
not considered study intervention related and will include an assessment of whether there is a 
reasonable possibility that the study intervention caused the event. Study endpoints that are 
serious adverse events (listed in 8.2.5) will be reported in accordance with the protocol unless 
there is evidence suggesting a causal relationship between the study intervention and the event. 
In that case, the PI will immediately report the event to the sponsor. 
 
All serious adverse events (SAEs) will be followed until satisfactory resolution or until the PI 
deems the event to be chronic or the participant is stable. Other supporting documentation of 
the event may be requested by the IRB/DSMB/NINDS and will be provided as soon as possible. 
 
 
Participants will be informed about AEs and SAEs, and study-related results on an individual 
level via an in-person visit prior to discharge or a telephone call after discharge from the 
Vanderbilt University Medical Center. 
 
 
Not Applicable 
 
Not Applicable 
 
 8.3 
UNANTICIPATED PROBLEMS 
 
 
 
Unanticipated problems are those that involve risks to participants or others to include, in 
general, any incident, experience, or outcome that meets all of the following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the Institutional Review 
Board (IRB)-approved research protocol and informed consent document; and (b) the 
characteristics of the participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means 
there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously known 
or recognized. 
 
 
 


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8.3.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS 
 
The principal investigator will report unanticipated problems (UPs) to the Vanderbilt Institutional 
Review Board (IRB). The UP report will include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB 
project number; 
• 
A detailed description of the event, incident, experience, or outcome; 
• 
An explanation of the basis for determining that the event, incident, experience, or 
outcome represents an UP; 
• 
A description of any changes to the protocol or other corrective actions that have been 
taken or are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following 
timeline: 
 
• 
UPs that are serious adverse events (SAEs) will be reported to the IRB and to the 
DCC/study sponsor within 7 days of the investigator becoming aware of the event. 
• 
Any other UP will be reported to the IRB and to the DCC/study sponsor within 30 days of 
the investigator becoming aware of the problem. 
 
Not Applicable 
 
 9 
STATISTICAL CONSIDERATIONS 
 
 
 9.1 
STATISTICAL HYPOTHESES 
 
 
 
 
Hypothesis 1: A 10 cubic centimeter (cc) increase in the FIV is considered clinically meaningful 
and known to be associated with worse outcome. A 10 cc increase in FIV with each 20 mmHg 
decrease in SBP equates to a slope of 0.5 of a linear regression of FIV with SBP. Therefore, the 
alternative hypothesis is that the slope of a linear relationship between SBP and FIV is 
numerically greater 0.5. Hence, a significant finding would be evidence that decreasing SBP 
increases FIV beyond a level which is considered safe, informing the lower limit for targeting 
SBP for testing in future trials (Figure 1). 
 
 
Hypothesis 2: We consider 0.10 decrease in the UW-mRS scale from 0 (worst outcome) to 1 
(best outcome) as clinically meaningful. A 0.10 decrease on the UW-mRS scale for every 20 
mmHg decrease in SBP equates to a slope of -0.005 of a linear regression of UW-mRS with 
SBP. Therefore, the alternative hypothesis is that the slope of a linear relationship between SBP 
and the UW-mRS numerically less than -0.005, i.e. a larger negative slope. Hence, a significant 
finding would be evidence that decreasing SBP worsens UW-mRS, also informing the lower 
limit for targeting SBP for testing in future trials (Figure 1). 


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Figure 1. Statistical Hypotheses 
 
 
 
 
 9.2 SAMPLE SIZE DETERMINATION 
 
 
Using the DEFUSE-3 trial data, we calculated the standard deviation of the difference in 
infarct volume from baseline to final for all patients. We conservatively assumed that collectively 
these values of the difference could represent the residuals of a linear regression between SBP 
as an independent variable and FIV in the worst-case scenario, where FIV demonstrates no 
association with SBP values. The standard deviation of residuals was 50 cc. Using the BEST-I 
data (our prospective, observational, multi-center study), we estimated the slope for the linear 
relationship of SBP and the UW-mRS. From this model, we calculated the standard deviation of 
residuals to be 0.37 and inflated this to 0.5 to be conservative. 
With 101 subjects total, we will have 80% power using a one-sided test with the level of 
significance, alpha, of 0.05 to test both these hypotheses (Table 1). After accounting for a 15% 
loss to follow up for 9014 -day outcome, our final sample size is 120 patients. FIV and UW- 
mRS will be treated as continuous variables with normal distribution.25 
 
 
 
 
Table 1: Sample size calculation 
Outcome 
Effect sizea 
Minimum Patients 
Powerb 
Attrition 
FIV Linear 
10 cc  
101 
80% 
0% 
UW-mRS 
Linear 
0.10  
101 
80% 
15% 
Final Sample Size= 120 patients 
aper 20 mmHg decrease in post-EVT peak SBP target; bone-tailed =0.05 
 
 
 
 9.3 POPULATIONS FOR ANALYSES 
 


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9.4.1 GENERAL APPROACH 
9.4.2 ANALYSIS OF THE PRIMARY ENDPOINT(S) 
 
 
 
Intention-to-Treat (ITT) Analysis Dataset (i.e., all randomized participants) will be used for 
primary analysis. The assigned intervention SBP groups will be used and evaluated, not the 
patients actual BP. Thus, the slopes of FIV and UW-mRS will be determined using the patient 
intervention SBP group assignment in regression models. 
 
 
 9.4 STATISTICAL ANALYSES 
 
 
 
 
The BEST-II trial is designed to detect harm of the lower SBP targets; therefore, all statistical 
tests pertaining to the harm hypotheses will be one-tailed with an alpha to reject null hypothesis 
set at 0.05. Strength of evidence (e.g., confidence intervals around estimates) will be 
emphasized in addition to the level of significance in our reporting. Data will be screened for 
integrity prior to analysis. Statistical assumptions will be tested and appropriate data 
transformations and model adjustments will be made as needed. If it is determined that the 
proposed statistical plan cannot be conducted after reasonable adjustments, we will revert to 
alternative techniques (such as non-parametric approaches and non-linear modeling) to 
address the study aims. 
 
 
 
 
 
A mixed effects linear regression model will be generated to quantify the slopes of FIV and UW- 
mRS with low (<140 and <160 mmHg) and high (180 mmHg) SBP targets. The assigned 
intervention SBP groups will be used and evaluated, not the patients actual BP. Thus, the 
slopes of FIV and UW-mRS will be determined using the patient intervention SBP group 
assignment in regression models. Rejection of the null hypothesis with a significant alpha would 
be evidence that decreasing SBP is unsafe. No corrections will be made for multiple hypothesis 
testing (please see below for justification). Covariables for the models for primary outcomes are 
defined a priori. We will adjust FIV for baseline ASPECT score and UW-mRS for baseline UW- 
mRS. We will also adjust analysis for both of the outcomes with the following variables as 
appropriate: age, baseline NIH stroke scale, and collateral circulation (assessed with modified 
Tan score), and site (where site will be treated as random effects). Regression diagnostics will 
be conducted on both models (for example, diagnostics for collinearity among predictor 
variables and overfitting). Age and baseline NIH stroke scale will be treated as continuous 
variables allowing for non-linearity using cubic splines with 3-5 knots that are not pre-positioned. 
 
 
Justification for forgoing multiplicity correction: BEST-II is designed to detect harm of lowering 
SBP in successfully EVT-treated acute ischemic stroke patients. In this case, a type II error, 


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9.4.3 SAFETY ANALYSES 
9.4.4 PLANNED INTERIM ANALYSES 
9.4.5 MISSING DATA 
 
which is failing to detect harm, is more detrimental than type I error. We will not correct for 
multiplicity in order to maintain power at the expense of type I error. For example, with 
Bonferroni correction for multiplicity, a p-value less than 0.025 would be required for statistical 
significance. However, a p-value of 0.03 for primary safety endpoint (FIV), increases concern for 
harm of the intervention, despite being non-significant after multiplicity correction. By not 
correcting for multiplicity, BEST-II will more rigorously test for harm of the low SBP targets. 
 
 
 
 
 
Interim analysis will be planned after a completed follow-up of 60 enrolled patients. We will 
terminate the study in favor of the alternative hypothesis (evidence of harm) for a p-value 
<0.025. Trial will not be terminated early for efficacy. No correction for alpha (i.e., alpha 
spending) will be made in the final analysis to maintain power. 
 
 
AEs will be coded using the Medical Dictionary for Regulatory Activities. Each AE will be 
counted once only for a given participant. Severity, frequency, and relationship of AEs to study 
intervention will be presented by System Organ Class (SOC) and preferred term groupings. 
Start date, stop date, severity, relationship, expectedness, outcome, and duration will be 
reported for each AE. Adverse events leading to premature discontinuation from the study 
intervention and serious AEs will be presented either in a table or a listing. 
 
 
 
 
Interim analysis will be planned after a completed follow-up of 60 enrolled patients. Study will be 
terminated in favor of the alternative hypothesis of aim 1 (evidence of harm) for a p-value 
<0.025 for a slope of less than -0.5 for FIV or greater than 0.005 for UW-mRS. Trial will not be 
terminated early for efficacy. No correction for alpha (i.e., alpha spending) will be made in the 
final analysis to maintain power. 
 
 
 
 
All attempts will be made to minimize missingness of the data. Any remaining missing data on 
covariates will be imputed using multiple imputations. Missingness of the primary outcomes is 
accounted for in the sample size calculations. However, to determine if missing data on primary 
outcomes is not at random, a sensitivity analysis will be conducted. We will fit a model to predict 
the missing FIV and UW-mRS (this model will not include the treatment variable) and this 
predicted outcome will be used to run an analysis similar to the primary analysis to determine 
the relationship of the treatment group with each outcome variable. 


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9.4.7  DESCRIBING THE FIDELITY TO INTERVENTION 
10.1.1 INFORMED CONSENT PROCESS 
10.1.1.1 
CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS 
PROVIDED TO PARTICIPANTS 
10.1.1.2 
CONSENT PROCEDURES AND DOCUMENTATION 
 
 
 
 
 
Differential effect of SBP groups on each outcome will be determined according to age (as 
continuous variable), baseline ASPECT score, collateral grade, and reperfusion grade using 
interaction terms. In case of a significant interaction, a formal subgrouping analysis will be 
undertaken. An exploratory subgroup analysis according to ant-hypertensive use (yes or no) 
prior to admission will be undertaken. 
 
 
 
 
Fidelity to the assigned intervention will be represented both graphically and numerically. We 
will generate temporal profile plots for each patients observed SBP values (color coded 
according to assigned SBP groups) and by plotting average hourly SBP for each group against 
time. Further, we will report the average time spent below target for each group and the number 
of anti-hypertensives used (% of patients on 1,2,3, or >3 anti-hypertensive agents during the 
study period). 
 
 
 
 10  SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
 
 10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
 
 
 
 
Consent forms describing in detail the study intervention, study procedures, and risks are given 
to the participant if they are able to provide informed consent or their legally authorized 
representative as soon as the study team is able to contact them. The informed consent form is 
submitted with this protocol. 
 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to 
participate in the study and continues throughout the individual’s study participation. 
Consent forms will be Institutional Review Board (IRB)-approved and the participant or 
their surrogate healthcare decision maker will be asked to read and review the 
document. The investigator will explain the research study to the participant or their 
surrogate healthcare decision maker and answer any questions that may arise. A verbal 
explanation will be provided in terms suited to the participant’s or their surrogate 
9.4.6 SUBGROUP ANALYSIS 


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10.1.2 STUDY DISCONTINUATION AND CLOSURE 
 
healthcare decision maker’s comprehension of the purposes, procedures, and potential 
risks of the study and of their rights as research participants. Participants or their 
surrogate healthcare decision makers will have the opportunity to carefully review the 
written consent form and ask questions prior to signing. The participants or 
their surrogate healthcare decision makers will have the opportunity to discuss the study 
with their family or surrogates or think about it prior to agreeing to participate. 
Participants and their surrogate healthcare decision makers will be informed that 
participation is voluntary and that they may withdraw from the study at any time, without 
prejudice. A copy of the informed consent document, either physical or electronic, will 
be given to the participants for their records. The rights and welfare of the participants 
will be protected by emphasizing to them that the quality of their medical care will not be 
adversely affected if they decline to participate in this study. 
 
All three arms of the BEST-II trial that the participants will be randomized to are 
considered standard of care with a documented equipoise. Any participant undergoing 
successful recanalization with mechanical thrombectomy could undergo blood pressure 
management similar to any of the arms in practice either at VUMC or other institution 
within the US. Additionally, our prior studies have shown that the blood pressure 
management must started immediately after recanalization to derive ideal benefit of 
each arm. On an average, after the first contact with the participant, all efforts are made 
to initiate the thrombectomy procedure and achieve recanalization as soon as possible. 
 
1. If the participant is cognitively intact and is able to provide consent, the informed 
consent procedure will take place either in person or remotely using an electronic 
consent form. The study intervention will only be commenced once the 
participant has signed the informed consent form. 
2. If the participant is cognitively impaired at presentation, the study personnel will 
reach their surrogate healthcare decision maker to obtain an informed consent. If 
the surrogate healthcare decision maker is remote from the study personnel 
obtaining consent, an electronic consent form can be sent via text message or 
email for their signature. 
3. If the participant or their legally authorized representative decide to withdraw their 
participation in the study, the study intervention will be immediately stopped and 
patient will be provided standard of care as determined appropriate by the 
treating clinicians. The participant’s data that is collected prior to the withdrawal 
will be used for research purposes and final analysis of the trial 
 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to study participants and 
funding agency. If the study is prematurely terminated or suspended, the Principal Investigator 
(PI) will promptly inform study participants, the Institutional Review Board (IRB), and sponsor 


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10.1.3 CONFIDENTIALITY AND PRIVACY 
 
and will provide the reason(s) for the termination or suspension. Study participants will be 
contacted, as applicable, and be informed of changes to study visit schedule. 
 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination that the primary endpoint has been met 
• 
Determination of futility 
 
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed and satisfy the IRB. 
 
 
 
 
 
Participant confidentiality and privacy is strictly held in trust by the participating investigator and 
her staff. This confidentiality is extended to cover the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be 
held in strict confidence. 
 
All data will be entered into electronic case report forms in a secured, password-protected 
database. The trial will utilize REDCap for data collection, transmission, and storage. REDCap 
is a secure, web-based application for building and managing online databases. VUMC 
maintains an institutionally-developed and updated software toolset and workflow methodology 
for electronic collection and management of research and clinical trial data. All study data will be 
entered via a password-protected REDCap database website unique for this study. REDCap 
servers are housed in an institutional, secured data center with regular backup, and all web- 
based information transmission is encrypted. REDCap was developed specifically to comply 
with all HIPAA-Security guidelines and is recommended by both the VUMC Privacy Office and 
Institutional Review Board. REDCap has been disseminated for use locally at other institutions 
and currently supports >140 academic/non-profit consortium partners and 11,000 research end- 
users (www.projectredcap.org). 
Only the minimum amount of PHI needed to conduct the study will be collected. All data 
collected will be generated during clinical care, and no additional data will be collected for 
research. At no time will we reveal subject identities in any manner, including research 
presentation, descriptions, or publications. As described above, all data will be entered into a 
secure, password-protected REDCap database. All patients will be assigned a unique patient 
identifier upon enrollment in the study. Patient identifiers will only be accessible to the PI and a 
select few research staff. Once the study results have been published, all study records will be 
stripped of any PHI in order to maximize patient and surrogate confidentiality. 
The study participant’s contact information will be securely stored at each clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by the reviewing IRB, Institutional policies, or sponsor 
requirements 


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10.1.5 KEY ROLES AND STUDY GOVERNANCE 
10.1.6 SAFETY OVERSIGHT 
10.1.7 CLINICAL MONITORING 
 
 
 
 
 
Database will be locked and maintained a read-only mode once data are verified after the last 
patient completes the 9014 -day follow up and until the time of study publication. At the time of 
publication, a de-identified version of the database will be generated. If a participant chooses to 
withdraw their authorization for study staff to access Protected Health Information (PHI), he or 
she may do so by notifying study staff in writing (the address will be provided on the consent 
form). In this case, actions will be taken to ensure that the data are properly destroyed and that 
the appropriate documentation is maintained, as is outlined in VUMC manual of standard 
operating procedures. 
 
 
 
 
 
 
 
Principal Investigator 
Eva Mistry, MBBS 
Vanderbilt University Medical Center 
2525 West End Ave Suite 612 
Nashville, TN, 37203 
615-936-3376 
Eva.a.mistry@vumc.org 
 
 
 
A DSMB is appointed for study oversight and consists of physicians experienced in acute 
stroke, neuro-intensive care, and critical care medicine as well as a biostatistical expert. The 
DSMB will review the trial protocol and statistical analysis plan prior to enrollment of the first 
patient and suggest necessary changes. Following this, they will meet the earlier of hospital 
discharge of the 30th patient enrolled or 6 months from the date of the first participant 
enrollment via a teleconference meeting to review enrollment, protocol compliance, adverse 
events, and data quality. Following this first meeting, they will meet once every six months via 
teleconference.The DSMB will decide on their first meeting if members will be unblinded. In 
case the DSMB decides to remain blinded, one member will be unmasked. The DMSB will 
operate under the rules of an approved charter that will be written and reviewed at the 
organizational meeting of the DSMB. At this time, each data element that the DSMB needs to 
assess will be clearly defined. Additionally, the DSMB will perform an interim analysis for safety 
events. In case of urgent issues, DSMB may convene a meeting at any time during the course 
of the trial. The DSMB will provide its input National Institutes of Health staff. Finally, DSMB will 
review final abstract and manuscript to ensure adequate study reporting. 
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA 


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10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
10.1.9 DATA HANDLING AND RECORD KEEPING 
10.1.9.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES 
 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants 
are protected, that the reported trial data are accurate, complete, and verifiable, and that the 
conduct of the trial is in compliance with the currently approved protocol/amendment(s), with 
International Conference on Harmonisation Good Clinical Practice (ICH GCP), and with 
applicable regulatory requirement(s). 
 
 
Each clinical site will perform internal quality management of study conduct, data, 
documentation and completion. 
 
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. The PI and study coordinator 
will be responsible for resolution of any missing data or data anomalies. 
 
Following department written Standard Operating Procedures (SOPs), the monitors will verify 
that the clinical trial is conducted and data are generated and collected, documented (recorded), 
and reported in compliance with the protocol, International Conference on Harmonisation Good 
Clinical Practice (ICH GCP). 
 
 
 
 
 
Data collection will be the responsibility of the clinical trial staff at VUMC under the supervision 
of the PI. The PI is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. VUMC uses electronic medical record system for clinical 
documentation and data will be extracted from that and entered in to the REDCap electronic 
case report form. The PI will be responsible to ensure that the data recorded in the electronic 
case report form (eCRF) derived from source documents is consistent with the data recorded on 
the source documents. 
 
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse 
reactions data) and clinical laboratory data will be entered into REDCap electronic case report 
form, a 21 CFR Part 11-compliant data capture system provided by the VUMC. The data system 
includes password protection and internal quality checks, such as automatic range checks, to 
identify data that appear inconsistent, incomplete, or inaccurate. Clinical data will be entered 
directly from the source documents. 
The proposed research will primarily use data generated by the routine clinical care. All blood 
pressure data is exported daily from the electronic health record to the Enterprise Data 
Warehouse at VUMC, which will be electronically extracted. Quality of this data extraction has 
been previously validated with two-physician manual chart review.31,40,41 This data will also be 
used for compliance monitoring. Data will also be automatically pulled from Vanderbilt University 
Medical Center (VUMC)’s electronic health record system integrated with this project-specific 
REDcap database using the Dynamic Data Pull on Fast Healthcare Interoperability Resources 
(DDP on FHIR) feature. 


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10.1.9.2 
STUDY RECORDS RETENTION 
 
Electronic data elements to be collected: [1] Baseline Characteristics: age; gender; ethnicity; 
admission, ICU, and discharge vital signs (SBP, diastolic BP, mean arterial BP, pulse); baseline 
comorbidities (hypertension, diabetes, hyperlipidemia, stroke, atrial fibrillation, smoking); home 
medications (antiplatelets, anticoagulants, antihypertensives); baseline NIH stroke scale; 
laboratory values (blood serum glucose, international normalized ratio, platelets) [2] 
Medications: intravenous tissue plasminogen activator administration, in-hospital Medications: 
total amount of nicardipine and labetalol administered; use of any other anti-hypertensive 
agents; vasopressor requirement [3] Clinical Outcome Measures: 24-hr NIH stroke scale; in- 
hospital death; 9014 -day modified Rankin score. 
Additionally, trained study personnel will manually extract the following elements collected as 
routine clinical care: [1] Time of events such as patient’s last known well, arrival to emergency 
department, groin puncture to initiate EVT, final recanalization, and intervention initiation; [2] all 
adverse events and protocol violations; [3] final mTICI score on angiogram. 
Automated imaging data to be collected: All LVO stroke patients at VUMC undergo baseline CT 
perfusion studies with automatic, computationally generated calculations of core and penumbra 
volumes and hypoperfusion intensity ratios (to assess collateral circulation) using the 
iSchemaView RAPID software. These values will be extracted. Additionally, core and penumbra 
volumes on 36±12-hr MRI perfusion sequence will also be calculated using the iSchemaView 
RAPID software. 
Manual imaging data to be collected: [1] Alberta Stroke Program Early CT score (ASPECTs) on 
the baseline brain CT [2] location of vessel occlusion on baseline CT angiogram [3] presence 
and characteristic of any hemorrhage on 36±12-hr MRI brain [4] 36±12-hr MRI or CT scan brain 
infarct volume by a blinded trained person and confirmed by an expert neuroradiologist. 
Validation: The study coordinator will manually collect all BP values within 24-hr post-treatment 
initiation and a 9014 -day modified Rankin score on 100% of the patients, in addition to all 
variables of data on randomly selected (i.e. 33% [n=40]) patients for validation. 
 
 
 
 
 
Study database will be locked and maintained a read-only mode once data are verified after the 
last patient completes the 9014 -day follow up and until the time of study publication. At the 
time of publication, a de-identified version of the database will be generated. If a participant 
chooses to withdraw their authorization for study staff to access Protected Health Information 
(PHI), he or she may do so by notifying study staff in writing (the address will be provided on the 
consent form). In this case, actions will be taken to ensure that the data are properly destroyed 
and that the appropriate documentation is maintained, as is outlined in VUMC manual of 
standard operating procedures. 


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10.1.11 
PUBLICATION AND DATA SHARING POLICY 
10.1.12 
CONFLICT OF INTEREST POLICY 
 
 
 
A protocol deviation is any noncompliance with the clinical trial protocol, International 
Conference on Harmonisation Good Clinical Practice (ICH GCP), or Manual of Procedures 
(MOP) requirements. The noncompliance may be either on the part of the participant, the 
investigator, or the study site staff. As a result of deviations, corrective actions are to be 
developed by the site and implemented promptly. 
 
These practices are consistent with ICH GCP: 
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3 
• 
5.1 Quality Assurance and Quality Control, section 5.1.1 
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2. 
 
PI will be responsible to use continuous vigilance to identify and report deviations within 5 
working days of identification of the protocol deviation. All deviations will be addressed in study 
source documents, reported to NINDS Program Official. Protocol deviations will be sent to the 
reviewing Institutional Review Board (IRB) per their policies. 
 
 
This study will be conducted in accordance with the following publication and data sharing 
policies and regulations: 
 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has 
access to the published results of NIH funded research. It requires scientists to submit final 
peer-reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed 
Central upon acceptance for publication. 
 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH- 
Funded Clinical Trial Information and the Clinical Trials Registration and Results Information 
Submission rule. As such, this trial will be registered at ClinicalTrials.gov, and results 
information from this trial will be submitted to ClinicalTrials.gov. In addition, every attempt will be 
made to publish results in peer-reviewed journals. Data from this study may be requested from 
other researchers 1 years after the completion of the primary endpoint by contacting Eva Mistry, 
MBBS at Vanderbilt University Medical Center (eva.a.mistry@vumc.org). 
 
 
 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who 
have a role in the design, conduct, analysis, publication, or any aspect of this trial will be 
disclosed and managed. Furthermore, persons who have a perceived conflict of interest will be 
required to have such conflicts managed in a way that is appropriate to their participation in the 
design and conduct of this trial. The study leadership in conjunction with the NINDS will ensure 
that study group members to disclose all conflicts of interest and will establish a mechanism for 
the management of all reported dualities of interest. 
 
 10.2 ADDITIONAL CONSIDERATIONS 
 
None 
10.1.10 
PROTOCOL DEVIATIONS 


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 10.3 ABBREVIATIONS 
 
The list below includes abbreviations utilized in this template. However, this list should be 
customized for each protocol (i.e., abbreviations not used should be removed and new 
abbreviations used should be added to this list). 
 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CONSORT Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DSMB 
Data Safety Monitoring Board 
DRE 
Disease-Related Event 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
FFR 
Federal Financial Report 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GWAS 
Genome-Wide Association Studies 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ISO 
International Organization for Standardization 
ITT 
Intention-To-Treat 
LSMEANS 
Least-squares Means 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
MSDS 
Material Safety Data Sheet 
NCT 
National Clinical Trial 
NIH 
National Institutes of Health 
NIH IC 
NIH Institute or Center 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 


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SAP 
Statistical Analysis Plan 
SMC 
Safety Monitoring Committee 
SOA 
Schedule of Activities 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
US 
United States 


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 10.4 PROTOCOL AMENDMENT HISTORY 
 
The table below is intended to capture changes of IRB-approved versions of the protocol, 
including a description of the change and rationale. A Summary of Changes table for the current 
amendment is located in the Protocol Title Page. 
 
Version 
Date 
Description of Change 
Brief Rationale 
1.0 
11/13/2019 
It is clarified that the Final infarct 
volume will be calculated on 
3612 hours and modified Rankin 
Score will be obtained at 9014 
days. 
The changes are made for 
consistency throughout the 
protocol and allow for the 
number of days that it might 
take to reach the patient at 
90 days. 
1.0 
11/13/2019 
Time of randomization is changed 
to after achievement of 
successful recanalization. 
The changes are requested 
in order to allow the 
separation of clinical and 
research consenting process 
to allow adequate time for 
research consenting. 
Additionally, the changes 
requested will simplify the 
trial logistics and will provide 
a more homogenous 
population of interest (only 
successfully treated patients) 
for the primary intention to 
treat analysis. In the original 
protocol, the intention was to 
only follow patients with 
unsuccessful recanalization. 
1.0 
11/13/2019 
Study intervention will start after 
randomization (which will occur 
after successful recanalization is 
achieved per the change 
requested above) 
The change requested 
reflects the slight change in 
the trial workflow to allow 
randomization to occur after 
successful recanalization and 
to let the intervention begin 
promptly after randomization. 
1.0 
11/13/2019 
Method of randomization is 
changed to stratified permuted 
block randomization from simple 
randomization. 
The requested change will 
allow a homogenous 
distribution of 40 patients in 
each arm. Simple 
randomization may have led 
to unequal distribution of 
number of patients in each 
arm. 
1.0 
11/13/2019 
Spelling and language changes 
are made 
Changes are requested for 
clarity 
1.0 
11/13/2019 
It is clarified that the PI, and not 
the DSMB, will be responsible for 
determining whether an adverse 
event is expected or unexpected. 
The changes requested will 
allow for faster reporting of 
the AEs to the IRB, as the 
DSMB meetings will be 


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schedule on a biannual 
basis. 
2.0 
10/20/20 
Perfusion criteria requiring 
baseline CT or MR perfusion is 
deleted 
This inclusion criteria was 
initially required to account 
for the differences in the 
baseline infarct volumes of 
patients included in the trial 
in the final analysis. Recent 
data has suggested that the 
baseline non-contrast CT 
brain (acquired as routine 
care in all stroke patients) 
can reliably measure this 
infarct burden and advances 
scanning techniques such as 
perfusion scans are no better 
at this estimation. Thus to 
simplify trial enrollment 
criteria, the requirement of a 
baseline CT or MR perfusion 
scan is no longer required. 
2.0 
10/20/20 
Follow-up perfusion outcome 
removed 
This outcome is removed as 
it is not routinely obtained as 
clinical care. 


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