Clinical trial NCT03092089
Conditions: ST-segment Elevation Myocardial Infarction
Keywords: Sonothrombolysis, STEMI, PPCI, Microbubbles
Sponsor: Harald Becher
Start date: 2017-08-15; Completion date: 2019-10-03
Enrollment: 15 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study evaluates what effect sonothrombolysis may have on spontaneous reperfusion, microvascular obstruction, left ventricular function and infarct size in patients presenting with their first ST-segment Elevation Myocardial Infarction.

Detailed description:
This is a prospective, single center, single-arm study that examines pre-procedural sonothrombolysis as an adjuvant to contemporary therapy in patients with ST-segment elevation myocardial infarction receiving PPCI.This study is to examine what effect adding emergent diagnostic ultrasound (DUS) guided high mechanical index (HMI) impulses (sonothrombolysis), applied both before and after primary percutaneous coronary intervention (PPCI) during an intravenous commercially available microbubble infusion (Definity), 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 ST-segment Elevation Myocardial Infarction.

Patients will immediately receive an intravenous infusion of commercially available ultrasound contrast agent (Definity). After starting the infusion, myocardial contrast echocardiography will be performed. 4-, 2- and 3-chamber views will be recorded to document the size of the perfusion defect. 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 HMI 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. Immediately after the diagnostic ultrasound, the therapeutic ultrasound will start using the same transducer by applying multiple HMI ultrasound impulses. 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. Diagnostic echocardiography will also be scheduled prior to discharge (Day2) and 90 days post procedure.

If this study is successful, a larger study will be designed in order to collect the evidence for using contrast ultrasound for treatment of myocardial infarction in clinical practice.

Arms: arm 1: Adult patients presenting with high-risk STEMI will receive sonothrombolysis with Definity in addition to standard of care (reperfusion therapy with PPCI)
Interventions: intervention 1: Definity, (Lipid Microspheres) Intravenous Suspension intervention 2: Myocardial Contrast Echocardiography intervention 3: Repurfusion therapy with PPCI
Intervention descriptions: intervention 1: Sonothrombolysis (High Impulse therapeutic ultrasound with infusion of ultrasound contrast agent Definity) will be applied before and after standard of care reperfusion therapy with PPCI intervention 2: Myocardial contrast echocardiography will be applied before standard of care reperfusion therapy as well as prior to discharge and at 3 month follow up intervention 3: Patients will receive reperfusion therapy with PPCI as standard of care

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
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 
Protocol #ST2017-Pro00067953 
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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 
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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 
Version (3): 13-Feb-2017 
 
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 
Version (3): 13-Feb-2017 
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 
Protocol #ST2017-Pro00067953 
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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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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Version (3): 13-Feb-2017 
    
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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Sonothrombolysis in Patients with an ST-segment Elevation Myocardial Infarction 
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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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Sonothrombolysis in Patients with an ST-segment Elevation Myocardial Infarction 
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19. REFERENCES 
 
1. 
Tu JV, Austin PC, Filate WA, et al. Outcomes of acute myocardial infarction in Canada. 
Can J Cardiol 2003;19:893-901. 
2. 
Tu JV, Donovan LR, Lee DS, et al. Quality of Cardiac Care in Ontario. Toronto: ICES, 
2004. 
3. 
An international randomized trial comparing four thrombolytic strategies for acute 
myocardial infarction. The GUSTO investigators. N Engl J Med 1993;329:673-82. 
4. 
Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management 
of patients with ST-elevation myocardial infarction: a report of the American College of 
Cardiology/American Heart Association Task Force on Practice Guidelines (Committee 
to Revise the 1999 Guidelines for the Management of Patients with Acute Myocardial 
Infarction). Circulation 2004;110:e82-292. 
5. 
Van De Werf F, Adgey J, Ardissino D, et al. Single-bolus tenecteplase compared with 
front-loaded alteplase in acute myocardial infarction: the ASSENT-2 double-blind 
randomised trial. Lancet 1999;354:716-22. 
6. 
Cannon CP, Gibson CM, Lambrew CT, et al. Relationship of symptom-onset-to-balloon 
time and door-to-balloon time with mortality in patients undergoing angioplasty for acute 
myocardial infarction. JAMA 2000;283:2941-7. 
7. 
Stone GW, Grines CL, Cox DA, et al. Comparison of angioplasty with stenting, with or 
without abciximab, in acute myocardial infarction. N Engl J Med 2002;346:957-66. 
8. 
De Luca G, Suryapranata H, Ottervanger JP, Antman EM. Time delay to treatment and 
mortality in primary angioplasty for acute myocardial infarction: every minute of delay 
counts. Circulation 2004;109:1223-5. 
9. 
Indications for fibrinolytic therapy in suspected acute myocardial infarction: 
collaborative overview of early mortality and major morbidity results from all 
randomised trials of more than 1000 patients. Fibrinolytic Therapy Trialists' (FTT) 
Collaborative Group. Lancet 1994;343:311-22. 
10. 
Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. 
Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico (GISSI). 
Lancet 1986;1:397-402. 
11. 
Armstrong PW, Collen D, Antman E. Fibrinolysis for acute myocardial infarction: the 
future is here and now. Circulation 2003;107:2533-7. 
12. 
Boersma E, Mercado N, Poldermans D, Gardien M, Vos J, Simoons ML. Acute 
myocardial infarction. Lancet 2003;361:847-58. 
13. 
De Luca G, Suryapranata H, Zijlstra F, et al. Symptom-onset-to-balloon time and 
mortality in patients with acute myocardial infarction treated by primary angioplasty. J 
Am Coll Cardiol 2003;42:991-7. 
14. 
Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med 2007;357:1121-
35. 
15. 
Bolli R. Mechanism of myocardial "stunning". Circulation 1990;82:723-38. 
16. 
Frangogiannis NG, Smith CW, Entman ML. The inflammatory response in myocardial 
infarction. Cardiovasc Res 2002;53:31-47. 
17. 
Braunwald E, Kloner RA. Myocardial reperfusion: a double-edged sword? J Clin Invest 
1985;76:1713-9. 


 
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Sonothrombolysis in Patients with an ST-segment Elevation Myocardial Infarction 
Protocol #ST2017-Pro00067953 
Version (3): 13-Feb-2017 
18. 
Kloner RA, Ganote CE, Jennings RB. The "no-reflow" phenomenon after temporary 
coronary occlusion in the dog. J Clin Invest 1974;54:1496-508. 
19. 
Moens AL, Claeys MJ, Timmermans JP, Vrints CJ. Myocardial ischemia/reperfusion-
injury, a clinical view on a complex pathophysiological process. Int J Cardiol 
2005;100:179-90. 
20. 
Buller CE, Fu Y, Mahaffey KW, et al. ST-segment recovery and outcome after primary 
percutaneous coronary intervention for ST-elevation myocardial infarction: insights from 
the Assessment of Pexelizumab in Acute Myocardial Infarction (APEX-AMI) trial. 
Circulation 2008;118:1335-46. 
21. 
Bainey KR, Patel MR, Armstrong PW. Evaluation of Cardiac Magnetic Resonance as a 
Surrogate in ST-Segment Elevation Myocardial Infarction. Am J Cardiol 2015;115:1607-
14. 
22. 
Ito H, Tomooka T, Sakai N, et al. Lack of myocardial perfusion immediately after 
successful thrombolysis. A predictor of poor recovery of left ventricular function in 
anterior myocardial infarction. Circulation 1992;85:1699-705. 
23. 
Kenner MD, Zajac EJ, Kondos GT, et al. Ability of the no-reflow phenomenon during an 
acute myocardial infarction to predict left ventricular dysfunction at one-month follow-
up. Am J Cardiol 1995;76:861-8. 
24. 
Caldas MA, Tsutsui JM, Kowatsch I, et al. Value of myocardial contrast 
echocardiography for predicting left ventricular remodeling and segmental functional 
recovery after anterior wall acute myocardial infarction. J Am Soc Echocardiogr 
2004;17:923-32. 
25. 
Trindade ML, Caldas MA, Tsutsui JM, et al. Determination of size and transmural extent 
of acute myocardial infarction by real-time myocardial perfusion echocardiography: a 
comparison with magnetic resonance imaging. J Am Soc Echocardiogr 2007;20:126-35. 
26. 
Tsutsui JM, Elhendy A, Anderson JR, Xie F, McGrain AC, Porter TR. Prognostic value 
of dobutamine stress myocardial contrast perfusion echocardiography. Circulation 
2005;112:1444-50. 
27. 
Xie F, Lof J, Everbach C, et al. Treatment of acute intravascular thrombi with diagnostic 
ultrasound and intravenous microbubbles. JACC Cardiovasc Imaging 2009;2:511-8. 
28. 
Xie F, Gao S, Wu J, et al. Diagnostic ultrasound induced inertial cavitation to non-
invasively restore coronary and microvascular flow in acute myocardial infarction. PLoS 
One 2013;8:e69780. 
29. 
Xie F, Slikkerveer J, Gao S, et al. Coronary and microvascular thrombolysis with guided 
diagnostic ultrasound and microbubbles in acute ST segment elevation myocardial 
infarction. J Am Soc Echocardiogr 2011;24:1400-8. 
30. 
Xie F, Lof J, Matsunaga T, Zutshi R, Porter TR. Diagnostic ultrasound combined with 
glycoprotein IIb/IIIa-targeted microbubbles improves microvascular recovery after acute 
coronary thrombotic occlusions. Circulation 2009;119:1378-85. 
31. 
Belcik JT, Mott BH, Xie A, et al. Augmentation of limb perfusion and reversal of tissue 
ischemia produced by ultrasound-mediated microbubble cavitation. Circ Cardiovasc 
Imaging 2015;8. 
32. 
Mathias W, Jr., Tsutsui JM, Tavares BG, et al. Diagnostic Ultrasound Impulses Improve 
Microvascular Flow in Patients With STEMI Receiving Intravenous Microbubbles. J Am 
Coll Cardiol 2016;67:2506-2515. 


 
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Protocol #ST2017-Pro00067953 
Version (3): 13-Feb-2017 
33. 
Slikkerveer J, Kleijn SA, Appelman Y, Porter TR, Veen G, Van Rossum AC, Kamp O.    
Ultrasound Enhanced Prehospital Thrombolysis Using Microbubbles Infusion in Patients 
with Acute ST Elevation Myocardial Infarction: Pilot of the Sonolysis Study. Ultrasound 
in Med & Biol.2011; 38 (2):247-252. 
34.  
Roos ST, Juffermans LJM, Van Royen N, Van Rossum AC, Xie F,  Appelman Y, Porter 
TR and Kamp O. Unexpected High Incidence of Coronary Vasoconstriction in the 
Reduction of Microvascular Injury Using Sonolysis (ROMIUS) Trial. Ultrasound in Med 
& Biol. 2016; 42 (8): 1919-1928. 
35. 
O'Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the 
management of ST-elevation myocardial infarction: a report of the American College of 
Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J 
Am Coll Cardiol 2013;61:e78-140. 
36. 
Schroder R, Wegscheider K, Schroder K, Dissmann R, Meyer-Sabellek W. Extent of 
early ST segment elevation resolution: a strong predictor of outcome in patients with 
acute myocardial infarction and a sensitive measure to compare thrombolytic regimens. A 
substudy of the International Joint Efficacy Comparison of Thrombolytics (INJECT) 
trial. J Am Coll Cardiol 1995;26:1657-64. 
37. 
Bainey KR, Fu Y, Wagner GS, et al. Spontaneous reperfusion in ST-elevation myocardial 
infarction: comparison of angiographic and electrocardiographic assessments. Am Heart J 
2008;156:248-55. 
38. 
Kushner FG, Hand M, Smith SC, Jr., et al. 2009 focused updates: ACC/AHA guidelines 
for the management of patients with ST-elevation myocardial infarction (updating the 
2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on 
percutaneous coronary intervention (updating the 2005 guideline and 2007 focused 
update) a report of the American College of Cardiology Foundation/American Heart 
Association Task Force on Practice Guidelines. J Am Coll Cardiol 2009;54:2205-41. 
39. 
Van de Werf F, Bax J, Betriu A, et al. Management of acute myocardial infarction in 
patients presenting with persistent ST-segment elevation: the Task Force on the 
Management of ST-Segment Elevation Acute Myocardial Infarction of the European 
Society of Cardiology. Eur Heart J 2008;29:2909-45. 
40. 
Canadian Institutes of Health, Natural Sciences and Engineering Research Council of 
Canada, and Social Sciences and Humanities Research Council of Canada. Tri-council 
policy statement: ethical conduct for research involving humans. 2006:Available:  
http://www.pre.ethics.gc.ca/english/policystatement/goals.cfm. 
41. 
Health Canada. International Conference on Harmonization of Technical Requirements 
for the Registration of Pharmaceuticals for Human UseGuideance E6: Good Clinical 
Practice: Revised Consolidated Guideline 2004. Available  http://www.hc-sc.gc.ca/dhp-
mps/prodpharma/applic-demande/guide-ld/ich/efficac/e6-eng.php#fn_1. 
 
 
 
 
 
 
 
 


 
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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 
 
 

ICF_001.pdf: 
 
 
Version: March 13, 2017 
 
 
NCT# 03092089 
Department of Medicine, Division of Cardiology, University of Alberta Hospital 
2C2 Walter C. Mackenzie Centre, 8440-112 Street, Edmonton, Alberta, Canada, T6G 2B7 
1/5 
INFORMATION SHEET 
 
TITLE:   
 
Sonothrombolysis in Patients with an ST-segment Elevation 
Myocardial Infarction 
A prospective single-arm study 
  
 
INVESTIGATORS: 
 
H. Becher, MD 
 U of A, Division of Cardiology 
 
 
780-407-3731 
J. Choy, MD 
 U of A, Division of Cardiology 
 
 
780-407-3581 
K. Bainey, MD 
   U of A, Division of Cardiology 
 
 
780-407-2176 
 
BACKGROUND 
You were asked to take part in this research study because you were having a heart attack 
(myocardial infarction). The myocardial infarction happened because one of the arteries on your 
heart muscle had been blocked by a blood clot. The current treatment is coronary angiography, to 
re-open the blocked artery with a balloon catheter and keep it open with a stent.  
 
 
The research procedure was explained to you prior to the initial treatment and you have signed 
a shorter version of this form. Before you make a decision to continue with this study one of the 
researchers will go over this form with you.  You are encouraged to ask questions if you feel 
anything needs to be made clearer.  You will be given a copy of this form for your records.   
 
 
This research study is looking to see if the way we re-open the blocked artery can be improved 
using ultrasound and ultrasound contrast agent. Ultrasound uses sound waves to develop images 
of the inside of the body. Ultrasound contrast agents are medications injected into a vein during 
ultrasound to help make pictures of the inside of the body more clear.  Ultrasound contrast agents 
consist of microbubbles which make small movements in the blood when exposed to ultrasound. 
There is evidence that these tiny movements can be used to dissolve blood clots. A previous 
study has shown that the coronary arteries blocked by blood clots were opened faster when 
ultrasound imaging of the heart with contrast agent is combined with the standard treatment for 
heart attack. That study used an ultrasound scanner which was different from the ultrasound 
scanner used here in Edmonton at the Heart Institute. This study is looking at whether we can 
achieve similar effects with our ultrasound equipment. 
 
 
PURPOSE 
You have had a heart attack. Standard treatment at this hospital is coronary angiography, to re-
open the blocked artery with a balloon catheter and keep it open with a stent. The aim of this 
research study is to see whether ultrasound applied to the patient’s chest and use of ultrasound 
contrast agent can open the blocked arteries.  This treatment was given in addition to the 
standard treatment and while you were being prepared for the standard treatment. After the 
standard clinical treatment (coronary angiography), additional ultrasound applications were 
performed.  The additional ultrasound was intended to dissolve smaller blood clots in smaller 


 
 
Version: March 13, 2017 
 
 
NCT# 03092089 
Department of Medicine, Division of Cardiology, University of Alberta Hospital 
2C2 Walter C. Mackenzie Centre, 8440-112 Street, Edmonton, Alberta, Canada, T6G 2B7 
2/5 
arteries and to assess whether the ultrasound treatment was successful in opening the arteries. A 
previous study has shown this treatment resulted in opening of the blocked arteries. However, we 
would like to find out whether similar results can be obtained with a newer ultrasound machine. 
 
 
ABOUT THE STUDY TREATMENT 
The study treatment includes ultrasound and contrast agent.  We will use an ultrasound machine 
which is in clinical use for diagnostic imaging.  The contrast agent, called Definity®, is also 
normally used in clinic to enhance the ultrasound images.  However, in this study we are using 
both the ultrasound machine and contrast agent as part of the treatment for heart attack (instead 
of for diagnosis) and this is considered research.  Health Canada has approved this study to test 
this treatment.  
 
DESCRIPTION OF THE STUDY 
While you were being prepared for angiography in the emergency room or cath lab, an 
ultrasound probe was placed on your chest by a physician and the ultrasound contrast agent 
Definity® was injected through a venous catheter which had already been inserted in the 
ambulance. The physician scanned your heart using the same technique which is the standard 
in clinical practice to assess the blood flow to and from the heart muscle. By alternating the 
power of the ultrasound the physician assessed the flow of the contrast agent in vessels of the 
heart muscle.  While this takes usually a few minutes for diagnostic purposes, this was 
performed for 15-20 minutes during study. The ultrasound scanning was performed while the 
preparations for the coronary angiography took place. Thus, there was no delay in receiving the 
standard medical treatment. 
 
This was followed by coronary angiography which is the standard of care in your case. The 
physicians checked whether the blocked coronary artery was already open and if not, attempts 
were made to open the artery with a balloon catheter and kept open with a stent. Then 
additional ultrasound imaging with contrast infusion was performed for another 10 minutes.   
 
In addition to what described above, participation in this study will require two further diagnostic 
ultrasound examinations of the heart (echocardiograms), one prior to discharge from the 
hospital which is standard of care and another after 3 months. At these two time points, an 
echocardiogram with intravenous injection of the ultrasound contrast agent Definity® will be 
performed. Each ultrasound examination will take around 30 minutes and will allow us to assess 
the recovery from the heart attack.   
  
The study will involve 15 patients. If this study shows benefit in opening of the arteries, a larger 
study will be arranged in order to collect the evidence required for using contrast ultrasound for 
treatment of myocardial infarction in clinical practice. 
 
If you decide not to take part in this project, this does not affect your treatment plan in any way. 
You will still receive all required tests and assessments for your care.  
 
POSSIBLE BENEFITS  
There may be no direct benefit to those patients participating in this study. If this study shows 
benefit, it will allow us to proceed with further studies that can lead to more effective treatment 
of patients with myocardial infarction.  
 


 
 
Version: March 13, 2017 
 
 
NCT# 03092089 
Department of Medicine, Division of Cardiology, University of Alberta Hospital 
2C2 Walter C. Mackenzie Centre, 8440-112 Street, Edmonton, Alberta, Canada, T6G 2B7 
3/5 
 
RISKS 
During ultrasound scanning some discomfort may be experienced from the slight pressure 
applied to the probe on the chest.   
 
The contrast agent Definity® has been widely used for diagnostic purposes. Small risks are 
involved with the injection. The undesirable effects reported with Definity® are, in general, non-
serious, temporary and resolve spontaneously without residual effects. The following transient 
side effects have been observed in clinical trials: headache 2.35%, back pain 1.2%, flush 1.1%, 
nausea 1 %, chest pain 0.8%. Severe allergic reactions are very rare- around 1 in 10,000 
applications.  
 
Spasm of the heart arteries has been reported in a sonothrombolysis study that used higher 
ultrasound energies. Spasm of the heart arteries has not been reported in any study that has 
used ultrasound energies similar to what was used in this study. 
 
 
In the unlikely event that any of the above reactions should occur, the department is fully 
equipped with all the necessary equipment, medication and experienced personnel needed to 
treat you appropriately. 
 
 
COMPENSATION FOR INJURY 
If you become ill or injured as a result of being in this study, you will receive necessary medical 
treatment, at no additional cost to you. By signing this consent form you are not releasing the 
investigator(s), institution(s) and/or sponsor(s) from their legal and professional responsibilities. 
 
 
COSTS 
You will not have to pay for the assessments that you receive in our clinic and your prescribed 
treatments will be covered by your current health plan. All visits to the clinic will be part of routine 
care. 
 
 
CONFIDENTIALITY 
During the study we will be collecting health data about you.  We will do everything we can to 
make sure that this data is kept private.  No data relating to this study that includes your name 
will be released outside of the study doctor’s office or published by the researchers. Sometimes, 
by law, we may have to release your information with your name so we cannot guarantee 
absolute privacy. However, we will make every legal effort to make sure that your health 
information is kept private. 
 
The study doctor/study staff may need to look at your personal health records held at the study 
doctor’s office, and/or kept by other health care providers that you may have seen in the past 
(i.e. your family doctor). Any personal health information that we get from these records will be 
only what is needed for the study. 
 


 
 
Version: March 13, 2017 
 
 
NCT# 03092089 
Department of Medicine, Division of Cardiology, University of Alberta Hospital 
2C2 Walter C. Mackenzie Centre, 8440-112 Street, Edmonton, Alberta, Canada, T6G 2B7 
4/5 
During research studies it is important that the data we get is accurate. For this reason your 
health data, including your name, may be looked at by people from the University of Alberta 
clinical auditors, the Health Research Ethics Board, and/or Health Canada.     
 
By signing the consent form you are giving permission for the study doctor/staff to collect, use 
and disclose information about you from your personal health records as described above.  
Study information is required to be kept for 25 years.  If you leave the study, we will not collect 
new health information about you, but we will need to keep the data that we have already 
collected. 
 
VOLUNTARY PARTICIPATION 
You do not have to be in this study to receive care at this hospital.  Further, even if you decided 
to be in the study, you are free to withdraw at any time, and your continuing medical care will 
not be affected in any way.  If any knowledge gained from this or any other study becomes 
available which could influence your decision to continue in the study, you will be promptly 
informed.   
 
CONTACT INFORMATION 
If you have any questions or concerns, please contact the investigators listed below:  
Dr Kevin Bainey at 780 407- 2176, Dr Harald Becher at 780 407-3731 and Dr Jonathan Choy at 
780 407-3581 
 
If you have any questions or concerns about your rights as a study participant, you may contact 
the Research Ethics Office at 780 492-2615.  This office is independent of the study 
investigators.  
 


 
 
Version: March 13, 2017 
 
 
NCT# 03092089 
Department of Medicine, Division of Cardiology, University of Alberta Hospital 
2C2 Walter C. Mackenzie Centre, 8440-112 Street, Edmonton, Alberta, Canada, T6G 2B7 
5/5 
CONSENT FORM 
 
TITLE:   
Sonothrombolysis in Patients with an ST-segment Elevation 
Myocardial Infarction 
A prospective single-arm study 
 
 
Investigators 
H. Becher, MD 
 U of A, Division of Cardiology 
 
 
780-407-3731 
J. Choy, MD 
 U of A, Division of Cardiology 
 
 
780-407-3581 
K. Bainey, MD 
 U of A, Division of Cardiology 
 
 
780-407-2787 
 
 
 
Please answer the following questions:  
Yes 
No 
 
Do you understand that you are being asked to participate in a study? 
___ 
___ 
 
Have you read and received a copy of an attached information sheet? 
___ 
___ 
 
Do you understand the benefits and risks in taking part? 
___ 
___ 
 
Have you had an opportunity to ask questions and discuss this study? 
___ 
___ 
 
Do you understand that you are free to withdraw at any time 
without having to give a reason and without affecting your future medical care? 
___ 
___ 
 
Has the issue of confidentiality been explained to you, and do you understand 
who will have access to your medical records? 
___ 
___ 
 
Do you want the investigator(s) to inform your family doctor that you are participating 
in this research study?   
___ 
___ 
    If yes, give his/her name:  ____________________________________________ 
 
Who explained this study to you?  _______________________________________ 
 
 
I agree to take part in this study.  
 
 
Name and signature of the research participant  
 
 
 
Date 
 
Signature of the person who obtained consent  
 
I believe that the person signing this form understands what is involved in the study and voluntarily agrees 
to participate. 
 
 
Name and signature of the person who obtained consent 
 
 
Date