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Trial registered on ANZCTR


Registration number
ACTRN12620000807954
Ethics application status
Approved
Date submitted
24/06/2020
Date registered
11/08/2020
Date last updated
11/08/2020
Date data sharing statement initially provided
11/08/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
The role of high power ultrasound in restoring blood flow for patients presenting with a major heart attack.
Scientific title
REstoring microvascular circulation with Diagnostic Ultrasound and Contrast agEnt (REDUCE): A multicentred, randomised, double blinded, controlled trial in patients presenting with ST elevation myocardial infarction.
Secondary ID [1] 301219 0
Vanguard Grant Number 102251 (Heart Foundation)
Universal Trial Number (UTN)
U1111-1253-5681
Trial acronym
REDUCE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Ischaemic Heart Disease 317372 0
ST Elevation Myocardial Infarction 317373 0
Coronary Microvascular Dysfunction 317374 0
Microvascular Obstruction 317375 0
Heart Failure 318276 0
Condition category
Condition code
Cardiovascular 315476 315476 0 0
Coronary heart disease
Cardiovascular 316292 316292 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The intervention is the focused application of high mechanical index ultrasound to the heart while the patient is receiving an intravenous infusion of a microbubble contrast known as "Definity®".

“Definity®" is an injectable cardiovascular ultrasound contrast agent comprised of lipid-coated echogenic microbubbles filled with octafluoropropane gas that enhances clinicians’ view of the left ventricle of the heart during an echocardiogram to aid with diagnosis.

Contrast Dosage
The commercially-available microbubbles (Definity®) to be utilized for these studies will be manufactured by Lantheus Medical. In each session, one vial (1.5 millilitres) will be mixed with approximately 48.5 millilitres of saline (approximately a 3% infusion) and then infused at the rate of 1~2ml/min (adjusted with image quality). The Pre-PCI infusion will last for ~10 minutes, while the post-PCI infusion will last for ~20 minutes. This dose and duration will be exactly the same for the intervention group and the sham echo group. The pre-Sonothrombolysis/Sham intervention in all groups will be administered 10 minutes prior to the PCI, and will end immediately prior to the PCI procedure commencing. The post Sonothrombolysis/sham will be administered immediately after the PCI and will continue for 20 minutes.

The intervention will be administered by an imaging cardiologist or a cardiology sernior registrar (advanced trainee) who is competent at delivering sonothrombolysis. All echocardiographic images for both intervention groups and sham control groups will be recorded and stored on a secure drive for further analysis.

Sham Echocardiography
- This sham procedure is our trial's placebo group. This group will receive a Definity contrast infusion at exactly the same rate as the interventional group for the same duration as the intervention arm. The low mechanical index ultrasound range will be <0.2 MI. Gain settings will be at 60-70% with a frame rate of 20 to 25 Hertz

1. Group 1: Pre- and Post-PCI arm
Participants in this group will undergo sonothrombolysis before and after their PCI procedure.
Sonothrombolysis means that these patients will receive frequent image-guided, high mechanical index (MI) (1.8 MHz; 1.1 – 1.3 MI; <5-µs pulse duration) impulses applied to the myocardial contrast-enhanced areas (using Definity®) in the apical 4-, 2-, and 3-chamber views before and after PCI.

2. Group 2: Post-PCI arm
Participants in this group will undergo a sham echocardiography with low mechanical index ultrasound before their PCI procedure, and sonothrombolysis using high mechnical index ultrasound after their PCI procedure.

3. Group 3: Control arm
Participants in this group will undergo sham echocardiography with low mechanical index (control group) before and after their PCI procedure.
Intervention code [1] 317551 0
Treatment: Other
Comparator / control treatment
The control group will consist of a sham echocardiography study
- Participants in this group will undergo low mechanical index (<0.2) imaging only to assess regional wall motion before and/or after percutaneous coronary intervention. The intravenous Definity® infusion will still be administered in the control group with the same dosing protocol as the interventional group
- The control group will still receive coronary intervention in the same way as the interventional group, and interventionalists will be blinded to whether patients are in the high mechanical index arm or the sham arm

Contrast Dosage
The commercially-available microbubbles (Definity®) to be utilized for these studies will be manufactured by Lantheus Medical. In each session, one vial (1.5 millilitres) will be mixed with approximately 48.5 millilitres of saline (approximately a 3% infusion) and then infused at the rate of 1~2ml/min (adjusted with image quality). The Pre-PCI infusion will last for ~10 minutes, while the post-PCI infusion will last for ~20 minutes. This dose and duration will be exactly the same for the intervention group and the sham echo group.
Control group
Placebo

Outcomes
Primary outcome [1] 323969 0
Infarct Size will be assessed on Cardiac Magnetic Resonance (CMR) Imaging as the volume of late Gadolinium enhancement (expressed as % of total myocardium)
Timepoint [1] 323969 0
At 3 days and 6 months (Primary endpoint) post intervention
Primary outcome [2] 324461 0
Infarct size will be measured by cardiographic determination of the left ventricular Ejection Fraction on cardiac magnetic resonance imaging
Timepoint [2] 324461 0
At 3 days and 6 months (Primary endpoint) post intervention
Secondary outcome [1] 383459 0
Chest pain as rated on a Likert scale of 1-10
Timepoint [1] 383459 0
Immediately post percutaneous coronary intervention
Secondary outcome [2] 383460 0
Sizes of microvascular obstruction as assessed on cardiac magnetic resonance imaging
Timepoint [2] 383460 0
3 days post percutaneous coronary intervention, and 6 months post percutaneous coronary intervention
Secondary outcome [3] 383461 0
Event-Free Survival (EFS), defined as the time from the start of treatment to first Major Adverse Cardiac Event (MACE) or death as a first event. Cardiac events include left ventricular remodelling, death, non-fatal myocardial infarction (recurrence), congestive heart failure, ventricular arrhythmias and need for prophylactic defibrillator (primary and secondary). This will be collected through clinical visits, electronic medical records and telephone follow-up.
Timepoint [3] 383461 0
3 days, 1 month and 6 months post percutaneous coronary intervention
Secondary outcome [4] 383463 0
Global longitudinal strain (GLS) as assessed by echocardiography
Timepoint [4] 383463 0
3 days and 6 months post percutaneous coronary intervention
Secondary outcome [5] 383464 0
Safety Endpoint: Arrhythmias during the administration of sonothrombolysis as measured by continuous ECG monitoring.
Timepoint [5] 383464 0
Measured for the total duration of the patient being in the cardiology cath lab during their primary percutaneous coronary intervention, as well as during both intervention/sham echos
Secondary outcome [6] 384727 0
The rate of ST-segment resolution assessed on the ECG
Timepoint [6] 384727 0
Assessed immediately post percutaneous coronary intervention.
Secondary outcome [7] 384728 0
Angiographic Recanalization rate determined by invasive angiography
Timepoint [7] 384728 0
Assessed with the first diagnostic images of invasive angiography during the initial presentation
Secondary outcome [8] 384729 0
Change in Index of microvascular resistance (IMR) -> invasive measure which is obtained during invasive angiography using a pressure wire and thermodilution set-up. It will be performed by the interventional cardiologist
Timepoint [8] 384729 0
Immediately after completion of the primary percutaneous coronary intervention, and then again after the post-PCI definity contrast infusion while the patient is still on the table (approximately 20 minutes later)
Secondary outcome [9] 384730 0
Safety Endpoint: Arrhythmias during the index admission as assessed by cardiac telemetry during the patient's stay, as well as daily 12 lead ECGs
Timepoint [9] 384730 0
Measured for 3 days of admission post percutaneous intervention.
Secondary outcome [10] 384731 0
Left Ventricular Ejection Fraction as assessed by echocardiography
Timepoint [10] 384731 0
at 3 days and 6 months post percutaneous intervention
Secondary outcome [11] 384732 0
Quality of Life Score, as assessed by the EQ-5D instrument
Timepoint [11] 384732 0
Assessed 3 days, 1 month and 6 months post percutaneous coronary intervention

Eligibility
Key inclusion criteria
- Chest Pain with ST segment elevation >0.1 mV in two contiguous leads
- Eligible for emergent PCI/antithrombotic/antiplatelet therapy.
- Adequate apical and/or parasternal images by echocardiography.
- No contraindications or hypersensitivities to ultrasound contrast agents.
Minimum age
30 Years
Maximum age
80 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Unable to provide written consent to participate in the trial
- Chest pain lasting >12 hours
- Cardiogenic shock
- Fibrinolytic therapy prior to arrival in the emergency department
- Life expectancy of less than six months from any other co-morbidity or terminally ill
- Prior ST-segment elevation myocardial infarction (STEMI)
- Known or suspected hypersensitivity to perflutren, the contrast agent used for the study
- Known cardiomyopathy
- Known severe valvular heart disease
- Known bleeding diathesis or contraindication to glycoprotein 2b/3a inhibitors, anticoagulants, or aspirin
- Known large right to left intra-cardiac shunts
- Pregnancy

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Once consented, the participating sites will determine the randomised treatment using an electronic website that is available seven days a week. The investigator who assesses for eligibility and consents the patient for the trial will not be aware of which trial arm the patient is allocated to.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
We will use the REDCap (Research Electronic Data Capture) Randomisation Module to allocate participants into the study groups. Only research staff delegated to this task will be given rights to randomise a participant. Access to the randomisation page will be through the study’s REDCap page where data will be stored.

REDCap will be stratifying patients by participating site.

REDCap will stratify and allocate participants according to their diagnosis of diabetes mellitus (DM) as this may influence outcome risk. Specifically, heart failure or cardiomyopathy in patients with DM have been associated with coronary microvascular dysfunction
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Participants will be randomised to three intervention groups, with a 1:1:1 allocation ratio, stratified firstly by known diagnosis of diabetes mellitus and participating site. Participants, PCI operators and those taking the measurements from CMRI/echocardiography will be blinded to the participants’ group allocation. The sonographer/imaging specialist performing sonothrombolysis and/or acquiring the images will not be blinded.
Phase
Not Applicable
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
The primary outcome for the study is the infarct size at 6 months. Assuming mean infarct sizes of 40g for the control arm and 29g for the pre- and post- arm (and SD of 22g from the study by Mathias et al , and assuming a mean of 33g for the post only arm, a total of 110 patients are required for each group (total 330) in order to achieve 90% power (5% significance) with 10% non-compliance.

Our statistical power calculations have shown that this study will require 330 participants across the three arms, with 110 participants per arm.

The intention to treat population will be used in the analysis. Participants will be compared according to the group to which they were randomly allocated, regardless of compliance, crossover, or withdrawal from the trial.

Descriptive statistics will be used to compare participants’ baseline characteristics between the three groups. Parametric and non-parametric tests will be used to compare the three study arms, depending on the distributions of the quantitative variables. Sizes of myocardial infarction and microvascular obstruction will be compared using ANOVA and multivariable regression. The chi-square test or logistic regression analysis will be used for variables with categorical endpoints. A P-value of less than 0.05 will be considered statistically significant for all analysis. Ongoing consultation with the on site biostatistician will be conducted.

Formal interim analyses of outcomes will be performed when approximately 30% (n=100) and 60% (n=200) of patients have completed 6-month follow-up, respectively. We will use an O’Brien-Fleming monitoring boundary (truncated at 3 standard deviations) to assess whether the interim results are sufficient to conclude that the sonothrombolysis with percutaneous coronary intervention is effective. We will also apply a futility monitoring rule at the time of the two interim analyses. The monitoring boundary p-values associated with the 2 interim looks using the O’Brien-Fleming spending function truncated at 3.00 will be 0.0005 and 0.014, with the final analysis being done with p=0.045.

Inter-observer variability in measurements of left ventricular volumes will be determined in a subset of 20 randomly chosen subjects enrolled in the study, with measurements performed by two investigators. Comparisons between these measurements will be determined with an intra-class correlation coefficient. These same variability measurement techniques will be done to examine the inter-observer variability in infarct size and microvascular obstruction measurements.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD
Recruitment hospital [1] 17101 0
Nepean Hospital - Kingswood
Recruitment hospital [2] 17102 0
The Prince Charles Hospital - Chermside
Recruitment hospital [3] 17103 0
Gosford Hospital - Gosford
Recruitment postcode(s) [1] 30777 0
2747 - Kingswood
Recruitment postcode(s) [2] 30778 0
4032 - Chermside
Recruitment postcode(s) [3] 30779 0
2250 - Gosford

Funding & Sponsors
Funding source category [1] 305956 0
Charities/Societies/Foundations
Name [1] 305956 0
Heart Foundation
Address [1] 305956 0
80 William St, Woolloomooloo NSW 2011
Country [1] 305956 0
Australia
Primary sponsor type
Individual
Name
Professor Kazuaki Negishi
Address
Nepean Hospital
Derby Street, Kingswood
NSW 2747
Country
Australia
Secondary sponsor category [1] 306413 0
None
Name [1] 306413 0
Address [1] 306413 0
Country [1] 306413 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 305950 0
Nepean Blue Mountains Local Health District Human Research Ethics Committee
Ethics committee address [1] 305950 0
PO Box 63
Penrith NSW 2750
Ethics committee country [1] 305950 0
Australia
Date submitted for ethics approval [1] 305950 0
22/10/2019
Approval date [1] 305950 0
14/04/2020
Ethics approval number [1] 305950 0
2019/ETH13335

Summary
Brief summary
Heart attack is the leading cause of morbidity and mortality globally, claiming 8,623 Australian lives in 2014 (i.e. 24 deaths/day). The heart attack is caused by the blockage of the blood flow in the heart, requiring emergent life-saving treatment to restore the blood flow using a balloon or a stent. For the last 30 years, however, death rates for the heart attack have not improved. One of the key reasons for this is the blockage of smaller micro-vessels of the heart. This micro-vessel abnormality occurs in up to 60% of patients with heart attacks and is independently associated with worse outcomes. Nevertheless, currently no established therapeutic options exist. Therefore, we will perform a prospective randomised controlled trial (RCT) to treat the micro-vessel blockages with a novel method using ultrasound with contrast agent (i.e. sonothrombolysis).

Many animal studies have demonstrated that sonothrombolysis can break up blood clots of both large and small vessels, and improve the blood flow. A recent, single-centre human RCT led by Prof Porter in USA confirmed that sonothrombolysis opens the micro-vessel blockages after heart attack and improves the heart function. Next logical step is to evaluate this method in multicentre setting with a larger scale. After close communications with Prof Porter, we established our protocol for a prospective multicentre RCT with sham procedure to test our hypothesis that additional sonothrombolysis to standard treatment for heart attack would reduce heart muscle damage and improve heart function in short term and improve patient survival long term. We will run this trial across three Australian hospitals. We will be studying their outcomes during their hospital stay and following their progress with cardiac imaging over 6 months.

The findings from this trial have the potential to significantly improve the overall prognosis for patients having a life-threatening heart attack and to change our standard of care and clinical guidelines.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 102178 0
Prof Kazuaki Negishi
Address 102178 0
Nepean Hospital
Derby Street Kingswood
NSW 2747
Country 102178 0
Australia
Phone 102178 0
+61 2 4734 2000
Fax 102178 0
Email 102178 0
kazuaki.negishi@sydney.edu.au
Contact person for public queries
Name 102179 0
Prof Kazuaki Negishi
Address 102179 0
Nepean Hospital
Derby Street Kingswood
NSW 2747
Country 102179 0
Australia
Phone 102179 0
+61 2 4734 2000
Fax 102179 0
Email 102179 0
kazuaki.negishi@sydney.edu.au
Contact person for scientific queries
Name 102180 0
Prof Kazuaki Negishi
Address 102180 0
Nepean Hospital
Derby Street Kingswood
NSW 2747
Country 102180 0
Australia
Phone 102180 0
+61 2 4734 2000
Fax 102180 0
Email 102180 0
kazuaki.negishi@sydney.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
Study protocol
Ethical approval
How or where can supporting documents be obtained?
Type [1] 8231 0
Study protocol
Citation [1] 8231 0
Link [1] 8231 0
Email [1] 8231 0
Other [1] 8231 0
Type [2] 8232 0
Ethical approval
Citation [2] 8232 0
Link [2] 8232 0
Email [2] 8232 0
Other [2] 8232 0
Summary results
No Results