Sonothrombolysis in Patients With an ST-segment Elevation Myocardial Infarction. A Prospective Single-arm Study.
Phase: PHASE2
Conditions: ST-segment Elevation Myocardial Infarction
Sponsor: Harald Becher

 
 
 
 
Sonothrombolysis in Patients with an ST-segment Elevation 
Myocardial Infarction  
A prospective single-arm study 
Author(s): Kevin R. Bainey and Harald Becher 
 
Protocol # ST2017-Pro00067953 
NCT# 03092089 
Version (3): 13-Feb-2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Coordinating Group: 
ABACUS 
 
Mazankowski Alberta Heart Institute 
 
University of Alberta  
Edmonton, Canada 

 
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Sonothrombolysis in Patients with an ST-segment Elevation Myocardial Infarction 
Protocol #ST2017-Pro00067953 
Version (3): 13-Feb-2017 
T6G 2B7 
 
STUDY SYNOPSIS 
Title 
Sonothrombolysis in Patients with ST-segment Elevation 
Myocardial Infarction (STEMI)  
Investigator(s)/center/study location 
Investigator-initiated prospective, single-center, single-
arm study 
Study Objectives 
  
To assess the efficacy and safety of sonothrombolysis in 
the acute management of STEMI undergoing reperfusion 
therapy with primary percutaneous coronary intervention 
[PPCI].  
Study Design 
The sonothrombolysis in STEMI study will be an 
investigator-initiated prospective, single center, single-
arm 
study 
of 
sonothrombolysis 
performed 
before 
coronary reperfusion with PPCI.    
Study population 
Inclusion criteria:  
 
 
 
 
 
 
 
 
 
 
 
Patients presenting with STEMI within 6 hours of 
symptom onset and: 
1. Are expected to receive reperfusion therapy with 
primary PCI 
2. Have a high-risk STEMI ECG defined as: 
 ≥2mm ST-segment elevation in 2 anterior 
or lateral leads; or 
 ≥2 mm ST-segment elevation in 2 inferior 
leads coupled with ST-segment depression 
in 2 contiguous anterior leads for a total 
ST-segment deviation of ≥4 mm 
3. Age ≥30 years. 
4. Adequate apical and/or parasternal images by 
echocardiography. 
 
                                                         
Exclusion criteria: 
1. Isolated inferior STEMI without anterior ST-segment 
depression 
2. Previous coronary bypass surgery 

 
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Sonothrombolysis in Patients with an ST-segment Elevation Myocardial Infarction 
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3. Cardiogenic shock  
4. Known or suspected hypersensitivity to ultrasound 
contrast agent used for the study 
5. Life expectancy of less than two months or terminally 
ill. 
6. Known bleeding diathesis or contraindication to 
glycoprotein 2b/3a inhibitors, anticoagulants, or 
aspirin 
7. Known large right to left intracardiac shunts. 
 
Evaluation criteria 
Primary Outcome 
1. Spontaneous reperfusion as assessed by a pre PCI 
ECG complete ST-segment resolution (>50%) 
(immediately prior to angiogram) and by pre PCI 
TIMI 2-3 flow on diagnostic angiogram.  
       
 
Secondary Outcomes 
 
1. Complete (>50%) ST-segment resolution at 30 
minutes post PCI as assessed by the worst lead on 
electrocardiogram (ECG core lab). 
 
2. Left ventricular ejection fraction (LVEF) by 
echocardiography 
(ECHO) 
(Simpson method) 
assessed on day 1 (pre and post reperfusion), day 
3±2 (discharge) and 90±2 days after infarction. 
3. Wall motion score index (WMSI) by ECHO 
assessed on day 1 (pre and post reperfusion), day 
3±2 (discharge) and 90±2 days after infarction. 
4. Microvascular perfusion score index (MPSI) by 
ECHO assessed on day 1 (pre and post 
reperfusion), day 3±2 (discharge) and 90±2 days 
after infarction. 
 
Treatment 
Sonothrombolysis: 
Echocardiographic 
imaging 
with 
intermittent diagnostic high mechanical index (MI) using 
a 
commercially 
available 
echocardiography scanner 
(Epiq,Philips Healthcare) to the myocardium during an 
intravenous 5% Definity infusion (Lantheus Medical) 
over a maximum 30 minute treatment period (started prior 
to PCI)  

 
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Sonothrombolysis in Patients with an ST-segment Elevation Myocardial Infarction 
Protocol #ST2017-Pro00067953 
Version (3): 13-Feb-2017 
Statistical Considerations 
 
 
 
Efficacy Analysis: This is an observational study to 
reproduce findings of a previous study which showed 
angiographic spontaneous reperfusion rates of 80% with 
sonothrombolysis prior to PCI (i.e. pre PCI TIMI 2-3 
flow). If we can demonstrate a patency rate > 60%, a 
multicenter study will be arranged. 
Sample Size 
15 patients 
Duration of Follow-Up 
Minimum of 90 +/- 7 days 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Sonothrombolysis in Patients with an ST-segment Elevation Myocardial Infarction 
Protocol #ST2017-Pro00067953 
Version (3): 13-Feb-2017 
1.0 OVERVIEW OF STUDY DESIGN 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.0 INTRODUCTION AND RATIONALE  
 
Patients presenting with ST-segment elevation myocardial infarction 
undergoing reperfusion therapy (fibrinolysis or primary PCI) 
Sonothrombolysis 
Reperfusion (primary PCI)  
IN-HOSPITAL AND 90-DAY FOLLOW-UP 
 
All patients receive ASA and other standard therapies 
 
Primary Outcome 
1. Spontaneous reperfusion as assessed by a pre PCI ECG complete ST-segment resolution 
(>50%) (immediately prior to angiogram) and by pre PCI TIMI 2-3 flow on diagnostic 
angiogram..  
 
Secondary Outcomes 
 
1. Complete (>50%) ST-segment resolution at 30 minutes post PCI as assessed by the 
worst lead on electrocardiogram (ECG core lab). 
2. Left ventricular ejection fraction (LVEF) by echocardiography (ECHO) (Simpson 
method) assessed on day 1 (pre and post reperfusion), day 3±2 (discharge) and 90±2 
days after infarction. 
3. Wall motion score index (WMSI) by ECHO assessed on day 1 (pre and post 
reperfusion), day 3±2 (discharge) and 90±2 days after infarction. 
4. Microvascular perfusion score index (MPSI) by ECHO assessed on day 1 (pre and post 
reperfusion), day 3±2 (discharge) and 90±2 days after infarction. 
 

 
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Sonothrombolysis in Patients with an ST-segment Elevation Myocardial Infarction 
Protocol #ST2017-Pro00067953 
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2.0 INTRODUCTION AND RATIONALE 
 
In Canada, more than 40,000 patients are hospitalized with an acute coronary syndrome (ACS) 
each year of which one-third suffer an ST-segment elevation myocardial infarction (STEMI) 
(1,2). As such, STEMI remains a significant public health concern given the substantial 
morbidity and mortality associated with the condition (3-7). Prompt reperfusion therapy has been 
shown to reduce mortality, infarct size and improve left ventricular function (8-13).   
 
However, it has been recognized that reperfusion itself may result in adverse events.  Abrupt 
reperfusion therapy can lead to myocardial stunning, ventricular arrhythmias and microvascular 
dysfunction as a result of distal coronary embolization and myocardial inflammation. This injury 
pattern inflicted upon the myocardium has been termed reperfusion injury (14). The 
accumulating effects result in myocyte necrosis, myocardial stunning and impaired infarct 
healing contributing to microvascular dysfunction and subsequent adverse clinical events in 
STEMI (15-19). The bedside electrocardiogram is a simple non-invasive tool that can be used to 
assess microvascular perfusion as defined by the degree of ST-segment resolution following the 
administration of reperfusion therapy (20).   
 
Multiple mechanisms to reduce infarct size have been undertaken with limited success and 
inconsistent results(21).  While transthoracic high mechanical index (MI) impulses from a 
diagnostic ultrasound (DUS) transducer have been utilized to diagnose microvascular obstruction 
and detect myocardial perfusion during a continuous microbubble infusion(22-26), the 
microbubble cavitation induced by these high MI impulses(27) creates shear forces that are 
capable of dissolving epicardial and microvascular thrombi in animal models of acute STEMI 
(28-30). These same high MI impulses, when applied to the microvasculature, also induce nitric 
oxide release (31), which may further augment microvascular flow. Termed sonothrombolysis, 
these effects have been demonstrated and verified in animal models, however the utility of DUS 
in humans has not been well studied during the contemporary management of STEMI, where 
emergent reperfusion (primary percutaneous coronary intervention [PPCI] or fibrinolysis) is 
routinely employed with such rapidity that only brief applications of ultrasound may be possible 
prior to interventional therapies. Recently in a small PPCI STEMI randomized trial (N=20 treated 
with sonothrobolysis), high MI with DUS (continuous microbubble infusion) (sonothrombolysis) 
was associated with improved patency rates of the infarct vessel prior to PCI. Specifically, the 
infarct related artery was found to be open in 80% with sonothrombolysis compared to patients 
with standard of care prior to PCI (~20%). If these results can be reproduced with another 
ultrasound system, a large clinical trial may be warranted (32).  No serious adverse events were 
reported in this study and in a small previous study involving five patients (33). However, in 
another study vasoconstriction in the culprit coronary artery was observed in three out of six 
patients during coronary angiography (34). In this study the pulse duration of the ultrasound 
scanner was prolonged in order to expose the intracoronary thrombus and the ultrasound contrast 
to a higher power. One patient withdrew from the study and was lost during follow up (but still 
alive according to the Dutch national registry), the other two patients had no long term side 
effects. The authors stress the higher ultrasound power used in this trial (20 μs instead of 5 μs 
which is transmitted in diagnostic ultrasound) and explain the findings by a “summative effect of 

 
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Sonothrombolysis in Patients with an ST-segment Elevation Myocardial Infarction 
Protocol #ST2017-Pro00067953 
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myocardial ischemia, reperfusion, damage and long-pulse-duration sonoporation on endothelial 
damage, all leading to calcium overload. It was concluded that new trials should proceed with 
short (5 μs) pulse duration. Therefore we will use the pulse duration of 5 μs which is clinically 
used for diagnostic ultrasound in the proposed pilot study. 
 
The purpose of this study was to examine what effect adding emergent DUS guided high MI 
impulses (sonothrrombolysis), applied both before PPCI during an intravenous commercially 
available microbubble infusion (5% Definity, Lantheus Medical Imaging, Inc., North Billerica, 
Massachusetts), have on spontaneous reperfusion (i.e. pre PCI coronary artery patency rates), 
microvascular obstruction, left ventricular function and infarct size in patients presenting with 
their first STEMI. Accordingly, given the potential impact of utilizing this practical application 
for attenuating reperfusion injury, we propose a prospective, single center, single-arm study of 
pre-procedural sonothrombolysis as an adjuvant to contemporary therapy for ST-segment 
elevation myocardial infarction receiving PPCI.        
 
 
3.0 STUDY HYPOTHESIS 
In adult patients with high-risk ST-segment elevation myocardial infarction (STEMI) planned for 
reperfusion therapy (primary PCI), the use of sonothrombolysis will enhance spontaneous 
reperfusion (i.e. pre-PCI ST-resolution and pre-PCI epicardial patency).   We expect that >60% 
of the patients will have an open infarct vessel at the beginning of coronary angiography. 
 
 
4.0 STUDY OBJECTIVES 
 
4.1. Primary Objective 
To determine whether the use of sonothrombolysis along with standard therapy in patients with 
STEMI undergoing reperfusion therapy (primary PCI) is resulting in a higher rate of spontaneous 
reperfusion (i.e. pre-PCI ST-resolution and pre-PCI epicardial patency) compared to standard 
therapy alone.   
4.2. Secondary Objective 
To determine whether the use of sonothrombolysis along with standard therapy in patients with 
STEMI undergoing reperfusion therapy (primary PCI) is resulting in better microvascular 
function than what is reported for standard therapy alone.     
4.3. Tertiary Objective 
 
To determine whether the use of sonothrombolysis along with standard therapy in patients with 
STEMI undergoing reperfusion therapy (primary PCI) is resulting in improved left ventricular 
function compared to what is reported for standard therapy alone.  
 
 

 
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Sonothrombolysis in Patients with an ST-segment Elevation Myocardial Infarction 
Protocol #ST2017-Pro00067953 
Version (3): 13-Feb-2017 
5.0 STUDY DESIGN  
5.1. Study Design 
This clinical study is a prospective single-center, single-arm investigation of sonothrombolysis in 
adult patients presenting with high-risk STEMI within 6 hours of the onset of clinical symptoms 
and receiving reperfusion therapy with PPCI. All patients will receive standard therapy 
according to the current American College of Cardiology / American Heart Association 
(ACC/AHA) or European Society of Cardiology (ESC) STEMI and PCI guidelines (35).  
The Vital Heart Response Program (VHR) facilitates treatment of patients with STEMI within 
the pre-hospital emergency medical services environment as well as within emergency 
departments within the Edmonton region via a STEMI network.  After completion of initial 
clinical assessment and documentation of a 12-lead with diagnostic ST-elevation, patients will be 
approached for participation.   
5.2. Intervention (sonothrombolysis) 
Patients will immediately receive an intravenous infusion of commercially available ultrasound 
contrast agent (5% Definity, Lantheus Medical Imaging, Inc., North Billerica, Massachusetts) 
1.3 mL diluted in 50 ml saline and infused running at 2 to 5 ml/min. After starting the infusion, 
myocardial contrast echocardiography will be performed using a commercially available 
echocardiography scanner (Epiq, Philips) with a diagnostic ultrasound transducer (X5-1) and a 
preset for myocardial perfusion imaging. 4-, 2- und 3-chamber views will be recorded to 
document the size of the perfusion defect according to method published by Porter et al (27). The 
focus will be set at the mitral valve level for all studies. Loops of 15 cardiac cycles will be 
recorded using low mechanical index (MI) ultrasound with a ‘flash’ delivered after the second 
cardiac cycle of the loop. The flash is a short impulse of high MI ultrasound* which is 
transmitted to destroy the ultrasound contrast in the myocardium and then to assess the 
replenishment of myocardial contrast. These recordings will also be used to assess regional wall 
motion as well as the LV volumes and ejection fraction. 
* Mechanical index (MI) is the unit to measure the ultrasound energy transmitted by the 
ultrasound transducer. High MI (>0.8) ultrasound imaging is the standard for 
echocardiographic imaging without contrast agents. In contrast echocardiography, however, 
high MI leads to destruction of the microbubbles in the contrast agent. Therefore contrast 
imaging has to be performed with very low MI (<0.2), fortunately there are very sensitive 
postprocessing tools that can still detect the specific signals from contrast agent at very low 
MI. In myocardial perfusion imaging, high MI ultrasound is applied only briefly to clear the 
myocardium from the contrast agent and to assess the time it takes for the blood from the 
aorta to reach the microvessels. In diagnostic imaging this is performed several times in 
multiple imaging planes in order to detect myocardial thickening and to assess myocardial 
perfusion.  In this pilot trial we are using the same techniques. The ultrasound scanning time 
will be in the range of that of echocardiographic imaging in clinical practice. The total 

 
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Sonothrombolysis in Patients with an ST-segment Elevation Myocardial Infarction 
Protocol #ST2017-Pro00067953 
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amount of the ultrasound contrast agent Definity® will be similar to what is clinically used in 
stress echocardiography and not exceed the maximum dose which is approved for clinical use. 
Immediately after the diagnostic ultrasound, the therapeutic ultrasound will start using the same 
transducer by applying multiple high mechanical index (MI) ultrasound impulses (HMI). The 
HMI are the same as those which are used for assessment of myocardial perfusion in diagnostic 
ultrasound. These pulses will be applied in the apical 4-, 2-, and 3-chamber views to the apical 
windows that contained the risk area. The intervals between HMI impulses will vary from 5 to 
15 s depending on the time required for myocardial contrast replenishment. 
The following measurements will be performed on the recordings obtained before 
sonothrombolysis, after completion of sonothrombolysis, 72h or prior to hospital discharge and 3 
months after sonothrombolysis: 
1. Wall motion score index (WMSI) will be computed by analyzing wall thickening in all 3 
contrast-enhanced apical windows using a 17-segment model as recommended in the 
2015 American Society of Echocardiography Recommendations for Chamber 
Quantification.  
2. Biplane measurements of LVEF by the the Simpson method  
3. Microvascular perfusion score index (MPSI) within the same 17-segment model used for 
assessment of regional wall motion using a scoring system of 1 for myocardial contrast 
replenishment within 4 s of the applied HMI impulse; a score of 2 (mildly reduced) when 
complete replenishment within the risk area is delayed longer than 4 s after the HMI 
impulse; or a score of 3, which was defined as virtually no replenishment of myocardial 
contrast over 10 s after the MI impulse. The score index will be computed as total score 
divided by total number of segments analyzed. Attenuated basal segments will not be 
included in the calculation. 
4. Global longitudinal strain 
Table.1 Diagnostic and therapeutic procedures 
Baseline diagnosis of STEMI (pre-reperfusion) 
day 1 
12-lead electrocardiogram-baseline 
in ER 
day 1 
Diagnostic Ultrasound - baseline 
start in ER or cath lab 
Myocardial Contrast Echo (MCE) 
LV ejection fraction 
WMSI 
Global longitudinal strain 
day 1 
Sonothrombolysis A 
start immediately after MCE 
prior to reperfusion 
 

 
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Sonothrombolysis in Patients with an ST-segment Elevation Myocardial Infarction 
Protocol #ST2017-Pro00067953 
Version (3): 13-Feb-2017 
day 1 
12-lead electrocardiogram-immediately 
prior to PPCI 
in cath lab 
Reperfusion (PPCI) 
day 1 
Sonothrombolysis B 
start immediately after 
reperfusion 
to complete a total of 30 min 
same method as before 
reperfusion 
day 1 
12-lead electrocardiogram-30 min post 
PCI 
in CCU 
day 1 
Diagnostic ultrasound – post intervention 
Myocardial Contrast Echo 
LV ejection fraction 
WMSI 
Global longitudinal strain 
day3/discharge 
Diagnostic ultrasound 
Myocardial Contrast Echo 
LV ejection fraction 
WMSI 
Global longitudinal strain 
day3/discharge 
12-lead electrocardiogram-discharge 
in CCU/Ward 
3 months 
Diagnostic ultrasound 
Myocardial Contrast Echo 
LV ejection fraction 
WMSI 
Longitudinal strain 
 
5.3. Study periods 
Follow-up visit is scheduled at 90 (+/-7) days. The maximal observational period for a 
randomized patient would be 90 (+/- 7) days. The study end date will be at 90 days after the last 
patient. At this time, it is expected that the majority of patients will have complete follow-up at 
90 days. All patients must be followed for 90 days or until death prior to completion of study 
period.   
 
6. STUDY POPULATION 
Adult patients with STEMI diagnosed through the VHR Program will be reviewed for treatment. 
For patients presenting direct to the cardiac catheterization laboratory patients will be assessed 
by the study team prior to treatment.  Fifteen (15) patients will be enrolled once inclusion / 
exclusion criteria are fulfilled and informed consent is obtained.           
6.1. Inclusion Criteria 
       Patients presenting with STEMI within 6 hours of symptom onset and: 
 
1. Are expected to receive reperfusion therapy with primary PCI 
 
2. Have a high-risk STEMI ECG defined as: 
o ≥2mm ST-segment elevation in 2 anterior or lateral leads; or 

 
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Sonothrombolysis in Patients with an ST-segment Elevation Myocardial Infarction 
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Version (3): 13-Feb-2017 
o ≥2 mm ST-segment elevation in 2 inferior leads coupled with ST-segment 
depression in 2 contiguous anterior leads for a total ST-segment deviation of 
≥4mm 
     3. Age ≥30 years. 
 
4. Adequate apical and/or parasternal images by echocardiography  
 
6.2. Exclusion Criteria 
1. Isolated inferior STEMI without anterior ST-segment depression 
2. Previous coronary bypass surgery 
3. Cardiogenic shock  
      4. Known or suspected hypersensitivity to ultrasound contrast agent used for the study 
5. Life expectancy of less than two months or terminally ill. 
6. Known bleeding diathesis or contraindication to glycoprotein 2b/3a inhibitors, 
anticoagulants, or aspirin 
7. Known large right to left intracardiac shunts. 
 
 
7.0 STUDY OUTCOME EVENTS 
7.1 Primary Outcome 
Spontaneous reperfusion as assessed by pre PCI ECG complete ST-segment resolution 
(>50%) (immediately prior to angiogram) and pre PCI TIMI 2-3 flow on the diagnostic 
angiogram.   
 
 
7.2 Secondary Outcomes 
 
1. Complete ST-segment resolution (≥50%) at 30 minutes post PCI as assessed by the 
worst lead on electrocardiogram  
2. Left ventricular function as assessed by left ventricular ejection fraction (LVEF) by 
echocardiography (ECHO) (Simpson method) assessed on day 1 (pre and post 
reperfusion), day 3±2 (discharge) and 90±2 days after infarction. 
3. Left ventricular function as assessed by wall motion score index (WMSI) by ECHO 
assessed on day 1 (pre and post reperfusion), day 3±2 (discharge) and 90±2 days 
after infarction. 
4. Left ventricular function as assessed by microvascular perfusion score index (MPSI) 
by ECHO assessed on day 1 (pre and post reperfusion), day 3±2 (discharge) and 
90±2 days after infarction. 
5. Left ventricular function as assessed by global longitudinal strain by ECHO assessed 
on day 1 (pre and post reperfusion), day 3±2 (discharge) and 90±2 days after 
infarction. 
      
 
 

 
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Sonothrombolysis in Patients with an ST-segment Elevation Myocardial Infarction 
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7.3 Safety Outcomes:  
1. Allergic reaction to Definity®  
2. Vasospasm in culprit coronary artery 
3. Adverse events (see appendix) 
 
8. DEFINITIONS OF STUDY OUTCOMES 
8. 1 ST-segment Resolution 
ECGs will be evaluated centrally at the ECG core laboratories (Canadian VIGOUR Centre, 
Edmonton, Canada) without knowledge of treatment, procedural results, or clinical outcomes. 
ST-E will be measured at the J point with magnified calipers to the nearest 0.05 mV. ST-E sums 
(ST-E) will be calculated as follows: for anterior infarction, the sum of ST-E in V1 to V6, I, and 
aVL; for inferior infarction, the sum of ST-E in leads II, III, aVF, V5, and V6. ST-segment 
depression will also be measured at the J point by similar methods. ST-segment deviation sums 
(ST-D) will be calculated by adding the sum of ST-segment depression measured in reciprocal 
leads to _ST-E. Leads II, III, and aVF will be considered potential reciprocal leads for anterior 
infarctions, and leads V1 through V4 will be considered potential reciprocal leads for inferior 
infarctions. 
The resolution of ST-segment elevation (worst lead) prior to PCI and at 30 minutes post PCI  
will be classified according to the number of patients achieving complete ST-segment resolution 
(>50%) versus no ST-segment resolution (≤50%). The resolution of ST-segment elevation (worst 
lead) at discharge will be calculated using the discharge ECG using the above criteria.  
 
8.2 Spontaneous Reperfusion 
 
 
8.2.1 
Angiographic spontaneous reperfusion 
Angiographic spontaneous reperfusion is defined as TIMI flow grade 2-3 of 
the infarct related artery before PCI (first contrast injection) (37).  
Other definitions of spontaneous reperfusion (will be collected but not 
included as the primary endpoint) 
 
8.2.2. Electrocardiographic (ECG) spontaneous reperfusion  
ECG spontaneous reperfusion is defined as those patients who achieved 
complete (>50%) ST-segment resolution on the 12-lead ECG (worst lead) 
performed immediately prior to the coronary angiogram in patients 
undergoing primary PCI (37).  
 
 
8.2.3 
Echocardiographic spontaneous reperfusion  
Echocardiographic spontaneous reperfusion is defined as score 1 or 2 in the 
infarct segments and/or recovery of systolic function during follow-up 
 

 
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Sonothrombolysis in Patients with an ST-segment Elevation Myocardial Infarction 
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9. STATISTICAL AND ANALYTICAL METHODS    
The primary efficacy analysis will include 15 patients in the study regardless of treatment they 
actually received in accordance to the intention-to-treat (ITT) principle. A per protocol analysis 
will be performed on those patients who actually received sonothrombolysis.  For the primary 
outcome, 12-lead electrocardiograms will be collected prior to PPCI and epicardial patency will 
be assessed at the time of the diagnostic angiogram. For the secondary endpoints, myocardial 
perfusion will be assessed based on the 12-lead ECG 30 minutes post PCI for complete ST-
segment resolution. Myocardial contrast echocardiography will be performed using a 
commercially available echocardiography scanner (Epiq, Philips) with a diagnostic ultrasound 
transducer (X5-1) and a preset for myocardial perfusion imaging. 4-, 2- und 3-chamber views.  
 
10. TRIAL ORGANIZATION 
This study will be conducted in Edmonton through the Vital Heart Response Program and the 
Alberta Cardiovascular and Stroke center (ABACUS). The principle investigator, co-
investigators and research coordinator will meet regularly (monthly) and will address the day-to-
day operations of the trial.  
    
11. DATA MANAGEMENT 
Data will be managed at Alberta Cardiovascular and Stroke center (ABACUS) located at the 
University of Alberta Hospital Edmonton, Canada.  
11.1. Case Report Forms 
Case report forms (CRF) will be designed and managed by the principle investigators involved in 
the research study. Key demographic and procedural data along with outcome and adverse events 
will be collected. The CRF must be signed by the investigator or designate at study completion. 
Signing of the ‘Study completion – Investigator’s statement CRF’ is considered to be the final 
authorization of the CRFs. 
11.2. Data Quality Control 
All data will be reviewed to ensure completeness and accuracy of information (CRF). Any 
concerns will be immediately addressed with modifications made accordingly.  
 
12. FEASIBILITY AND LIMITATIONS 
Considering the patients admitted with STEMI during the last year, recruitment of 15 
participants within 1 year appears to be feasible. An Epiq/Philips ultrasound scanner will be 
available for almost 24/7 in ABACUS and can be moved within minutes into ER or the cath 
laboratory. However, a sonographer or fellow to perform the ultrasound imaging may not always 

 
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be available when a suitable patient with STEMI arrives. In order to avoid delays in the standard 
treatment of the myocardial infarct, the sonographer or fellow on call will receive a telephone 
call from the attendings in the cath lab immediately after they were notified by the ambulance 
that a patient with STEMI is approaching. That will give the echo fellow or sonographer enough 
time to be ready for ultrasound imaging with contrast, when the patient arrives. If the echo 
personnel arrive too late, no sonothrombolysis will be performed. 
The current protocol mandates contemporary treatment for patients with STEMI undergoing 
reperfusion therapy. We do advocate therapy according to the current consensus guidelines to 
promote universal care (38, 39).     
 
13.  ETHICAL AND REGULATORY STANDARDS 
13.1. Good Clinical Practice 
The study will be conducted in accordance with both the Tri-Council Policy Statement (40) and 
Good Clinical Practice Guidelines (41).  
13.2. Informed Consent of the Patient 
Patients who meet all inclusion criteria and none of the exclusion criteria are deemed eligible. 
Before being enrolled into the clinical study, the patient must provide written consent to 
participate in the study after the nature, scope and possible consequences of the clinical study 
have been explained both orally and in writing.  
13.3. Approval of the Study Protocol 
Before the start of the study, the study protocol and the informed consent form used at the site 
and other appropriate documents must be submitted to and approved by the local Ethics 
Committee or Institutional Review Board (REB) and the appropriate regulatory authorities in 
accordance with local legal requirements.   
 
13.4. Maintenance of Records 
 
The Investigator agrees to obtain a correctly completed informed consent form for each patient 
included in the study.  The investigator will maintain a personal list of patient numbers and 
patient names to enable records to be found at a later date.   
 
The Investigator must maintain all study records, patient files and other source data for the 
maximum period of time permitted by the hospital, institution or private practice.  However 
national regulations should be taken into account, the longest time having to be considered. 
 
 
 
 
 
14. STUDY MONITORING 

 
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Sonothrombolysis in Patients with an ST-segment Elevation Myocardial Infarction 
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14.1. Responsibilities of the investigator(s) 
 
The Investigator(s) undertake(s) to perform the study in accordance with Good Clinical Practice 
(41).  
 
The Investigator is required to ensure compliance with respect to the invasive strategy schedule, 
visit schedule and procedures required by the protocol.  The Investigator agrees to provide all 
information requested in the CRF in an accurate and legible manner according to instructions 
provided. 
 
14.2. The use and completion of case report forms (CRFs) 
 
It is the responsibility of the Investigator to prepare and maintain adequate and accurate CRFs. 
All CRFs should be completed in their entirety in a neat, legible manner to ensure accurate 
interpretation of data.  
 
 
15. ADMINISTRATIVE RULES 
 
15.1. Curriculum vitae 
 
An updated copy of the curriculum vitae for each Investigator and co-Investigator will be 
provided to the principle investigator prior to the beginning of the study. 
 
15.2. Confidentiality agreement 
 
All goods, materials, information (oral or written) and unpublished documentation provided to 
the Investigators, inclusive of this protocol and the patient case report forms are the exclusive 
property of the ABACUS.  
 
They may not be given or disclosed by the Investigator or by any person within his authority 
either in part or in totality to any unauthorized person without the prior written formal consent of 
the PI. 
 
It is specified that the submission of this protocol and other necessary documentation to the 
Ethics Research Committee is expressly permitted, the Ethics Committee members having the 
same obligation of confidentiality. 
 
The Investigator shall consider as confidential and shall take all necessary measures to ensure 
that there is no breach of confidentiality in respect of all information accumulated, acquired or 
deduced in the course of the trial, other than that information to be disclosed by law. 

 
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15.3. Record retention in investigating center(s) 
 
The Investigator must maintain all study records, patient files and other source data for the 
maximum period of time permitted by the institution. 
 
 
16. OWNERSHIP OF DATA AND USE OF THE STUDY RESULTS 
 
The investigators of the study have ownership of all data and results collected during this study. 
Full publication rights of the study data solely reside with the investigators. 
 
 
17. PUBLICATIONS 
 
All study presentations and/or publication of the results will be based on clean, checked and 
validated data in order to ensure the accuracy of the results.  All analyses for publication will be 
provided by ABACUS. The responsibility for presentations and/or publications belongs to the 
investigators. The final content of the manuscript is the responsibility of the investigators.  
Publication of the main findings of this study will be authored based on the contributions of the 
individuals to the overall study.   
 
 
18. POTENTIAL IMPACT OF STUDY 
Once completed, this will provide prospective data on the efficacy and safety of 
sonothrombolysis which we believe will lead to a randomized clinical trial of contemporary PCI 
STEMI patients (treated with PPCI or fibrinolysis) aimed at assessing the efficacy of 
sonothrombolysis as an adjuvant therapy to improve microvascular function.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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APPENDIX  
Adverse Events 
An Adverse Event (AE) is defined as any untoward medical occurrence, including an exacer-
bation of a pre-existing condition, in a patient in a clinical investigation who received a 
pharmaceutical product. The event does not necessarily have to have a causal relationship with 
this treatment. 
A Serious Adverse Event (SAE) is defined as any AE which results in death, is immediately 
life-threatening, results in persistent or significant disability / incapacity, requires or prolongs 
patient hospitalisation, is a congenital anomaly / birth defect, or is to be deemed serious for any 
other reason representing a significant hazard, which is comparable to the aforementioned 
criteria. 
Adverse events occurring during the course of the clinical trial (i.e. from signing the informed 
consent) will be collected, documented and reported by the investigator. 
 
Reporting of Serious Adverse Events (SAE)s: 
 On an SAE form: 
For the following events an SAE form (in addition to entering the SAE data in the CRF) will 
need to be completed and mailed for expedited reporting: 
o Serious and treatment-related SAEs 
o Serious, not treatment-related and not mentioned on the ‘list of STEMI-related 
events’ 
For each SAE, the investigator will provide the onset, end, treatment required, outcome, 
seriousness and action taken with the investigational drug. The investigator will also determine 
the relationship of the investigational drug to all SAEs. 
The basis for judging the causal relationship between the investigational product and the SAE is 
described below. 
Causal Relationship* 
Yes 
 
No 
There is a reasonable causal relationship between the study drug 
administered and the AE. 
There is no reasonable causal relationship between the study drug 
administered and the AE. 
 
*Medical judgement should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 

 
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confounding factors such as concomitant medication, concomitant diseases and relevant history.  
These completed SAE forms need to be mailed within 24 hours (1 workday) to the co-
investigators after the Investigator (or any member of the study team) has become aware of the 
event. Timelines are the same for initial reports and for follow-up reports. The investigator and 
the coinvestigators will assess the treatment relationship, the category classification, listedness 
and seriousness of reported SAE cases. Expedited reporting of serious adverse events, e.g. 
suspected unexpected serious adverse reactions (SUSARs), will be done according to local 
regulatory requirements within the required timelines.  
 In the eCRF: 
Any SAE, whether or not considered related to the study medication, and whether or not the 
study medication has been administered, must be reported immediately in the eCRF.   
 
Reporting of Non-Serious Adverse Events: 
Non-serious events need to be recorded in the CRF  
 
THE FOLLOWING ADVERSE EVENTS ARE EXPECTED AS DISEASE-RELATED 
EVENTS (I.E. RELATED TO ACUTE MYOCARDIAL INFARCTION): 
Arrhythmias 
All arrhythmias occurring later than 3 hours after fibrinolysis 
All arrhythmias in patients who did not receive fibrinolysis 
 
Ischaemia and symptoms of coronary artery disease 
Angina pectoris (stable) 
Angina pectoris (unstable) 
Back pain (of cardiac origin) 
Cardiac enzymes (abnormal) 
Cardiac markers (abnormal) 
Chest pain 
Electrocardiogram abnormalities 
Myocardial ischaemia 
Myocardial reinfarction 
Recurrent myocardial ischaemia 
ST-elevation 
Substernal chest pain 
Substernal pain 

 
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Artery disorders 
Aortic dissection 
Coronary artery dissection 
Coronary artery disorder 
Coronary artery thrombosis 
Coronary occlusion 
Vascular anomaly 
 
Cardiac failure 
Acute pulmonary oedema 
Cardiogenic shock 
Congestive heart failure 
Cor pulmonale 
Heart failure 
Left heart failure 
Pulmonary oedema 
Haemodynamic and circulatory shock 
 
Pericardium disorders 
Pericardial effusion 
Pericarditis 
 
Other cardiac disorders 
Acute mitral regurgitation 
Acute ventricular septum defect 
Cardiac rupture  
Cardiomyopathy 
Electro-mechanical dissociation 
 
Other events 
Deep thrombophlebitis 
Hypertension 
Livedo reticularis 
Peripheral oedema 
Peripheral vascular disorder 
Syncope 

 
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Thrombocytosis 
Vascular disorder 
Venous thrombosis