Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12618000778280
Ethics application status
Approved
Date submitted
12/04/2018
Date registered
9/05/2018
Date last updated
2/10/2023
Date data sharing statement initially provided
3/05/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A phase 3 study of low-dose intracoronary thrombolytic therapy in STEMI (heart attack) patients
Scientific title
Restoring Microcirculatory Perfusion in ST-Elevation Myocardial Infarction (STEMI): A randomised trial to evaluate the efficacy of low-dose intracoronary tenecteplase in STEMI patients with high microvascular resistance post-percutaneous coronary intervention (PCI).
Secondary ID [1] 291234 0
Nil known
Universal Trial Number (UTN)
Trial acronym
RESTORE-MI
Linked study record

Health condition
Health condition(s) or problem(s) studied:
ST elevation myocardial infarction 302154 0
Condition category
Condition code
Cardiovascular 301768 301768 0 0
Coronary heart disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
All patients will have their Index of Micro-circulatory Resistance (IMR) measured using a standard pressure wire. Patients with an IMR greater than 32 who are randomised to the treatment arm will receive one intracoronary injection of tenecteplase (one-third of the weight-based systemic dose) after their percutaneous coronary intervention (procedure to open narrowed arteries).

The systematic dose is sourced by the manufacturer on the product information form.
The intracoronary injection will be administered by an authorised study investigator or study nurse. The administration will be supervised by a separated study investigator or study nurse.

The study treatment will be blinded (patients and the study team will not know which treatment arm was assigned).
Intervention code [1] 297234 0
Treatment: Drugs
Comparator / control treatment
Patients with an IMR measurement greater than 32 who are randomised to the placebo arm will receive one intracoronary injection of placebo (water for injection of equal volume to the tenecteplase dose specified above) immediately after their percutaneous coronary intervention (procedure to open narrowed arteries).

The intracoronary injection will be administered by an authorised study investigator or study nurse. The administration will be supervised by a separated study investigator or study nurse.
Control group
Placebo

Outcomes
Primary outcome [1] 301164 0
Cardiovascular mortality assessed by medical record review
Timepoint [1] 301164 0
24 months after primary PCI procedure
Primary outcome [2] 305293 0
Re-hospitalisation for heart failure assessed by medical record review
Timepoint [2] 305293 0
24 months after primary PCI procedure
Secondary outcome [1] 331904 0
Major Adverse Coronary Events (these are combination events involving cardiovascular death, non-fatal MI, non-fatal stroke and unstable angina) assessed from physical assessment and medical record review
Timepoint [1] 331904 0
24 months after primary PCI procedure
Secondary outcome [2] 331905 0
All-cause mortality assessed by physical assessment and medical record review.
Timepoint [2] 331905 0
24 months after primary PCI procedure
Secondary outcome [3] 331906 0
Stroke events will be assessed by medical record review. Assessment will cover all aspects of the stroke event (including type, severity, frequency).
Timepoint [3] 331906 0
24 months after primary PCI procedure
Secondary outcome [4] 331907 0
Use of Bailout treatment for no-reflow syndrome assessed by medical record review
Timepoint [4] 331907 0
24 months after primary PCI procedure
Secondary outcome [5] 331908 0
Major (Type 3 or greater) and minor (Type 2) bleeding as defined by the Bleeding Academic Research Consortium. Assessed by medical record review.
Timepoint [5] 331908 0
24 months after primary PCI procedure
Secondary outcome [6] 331909 0
Index of microcirculatory resistance (IMR) measurement assessed by coronary pressure wire data output review
Timepoint [6] 331909 0
prior to randomisation and immediately after primary PCI
Secondary outcome [7] 331910 0
Fractional Flow Reserve measurement assessed by coronary pressure wire data output review
Timepoint [7] 331910 0
prior to randomisation and immediately after primary PCI
Secondary outcome [8] 331911 0
Coronary Flow Reserve measurement assessed by coronary pressure wire data output review
Timepoint [8] 331911 0
prior to randomisation and immediately after primary PCI
Secondary outcome [9] 331912 0
Wall Motion Score measurement from echocardiogram will be used to assess cardiac function.
Timepoint [9] 331912 0
prior to randomisation, 48 hours and 6 months post primary PCI
Secondary outcome [10] 331913 0
Left ventricular ejection fraction measurement from echocardiogram will be used to assess cardiac function
Timepoint [10] 331913 0
prior to randomisation, 48 hours and 6 months post primary PCI
Secondary outcome [11] 331914 0
Myocardial Blush Grade measurement from angiogram will be used to assess cardiac function.
Timepoint [11] 331914 0
prior to randomisation and post primary PCI
Secondary outcome [12] 331915 0
Thrombolysis in myocardial infarction score from angiogram will be used to assess myocardial perfusion
Timepoint [12] 331915 0
prior to randomisation and post primary PCI
Secondary outcome [13] 344756 0
Cardiac function as a composite measure of cardiac enzymes including troponin T, creatine kinase, creatine kinase-MB and high sensitivity troponin T, from blood samples collected during hospitalisation
Timepoint [13] 344756 0
prior to primary PCI and at 8, 16, 24 and 32 hours post primary PCI
Secondary outcome [14] 344757 0
Thrombolysis in myocardial infarction score with corrected frame count from angiogram to assess myocardial perfusion
Timepoint [14] 344757 0
prior to randomisation and post primary PCI

Eligibility
Key inclusion criteria
1) Adult men and women aged over 18 who present with STEMI within 12 hours of symptom onset. Patients will be eligible if they have symptoms consistent with myocardial ischaemia (chest pain, dyspnoea) for at least 20 minutes accompanied by definite ECGs indicating STEMI as defined by Australian NHF guidelines;

2) Willing and able to comply with all study requirements, including treatment, assessment and clinic visit attendances;

3) Able to personally read and understand the Participant Information and Consent Form and provide written, signed and dated informed consent to participate in the study.

4) (At time of PCI) Patient has received metallic drug-eluting stent
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
At the time of screening or prior to randomisation, no known:
1) Previous coronary bypass grafting
2) Patients with other residual lesions with >50% diameter stenosis in the culprit vessel
3) Patients with prior myocardial infarction in the target territory
4) Presence of contraindications to thrombolytic therapy (including history of stroke and recent brain surgery active internal bleeding; history of cerebrovascular accident; intracranial or intraspinal surgery, or trauma within 2 months; intracranial neoplasm, arteriovenous malformation, or aneurysm; known bleeding diathesis; and severe uncontrolled hypertension)
5) Presence of contraindications to adenosine infusion for IMR measurement including sinus node disease, moderate to severe bronchoconstrictive disease and second or third-degree AV block
6) Concurrent illness, including severe infection that may jeopardise the ability of the patient to undergo the procedures outlined in this protocol with reasonable safety
7) Serious medical or psychiatric conditions that might limit the ability of the patient to comply with the protocol
8) Pregnancy, lactation, or inadequate contraception. Women must be post-menopausal, infertile, or use a reliable means of contraception. Women of childbearing potential must have a negative pregnancy test done within 7 days prior to registration. Men must have been surgically sterilised or use a (double if required) barrier method of contraception.
9) (Imaging (CMR) substudy only) Presence of contraindications to contrast enhanced MRI including pacemakers, metallic prostheses and estimated glomerular filtration rate of <30mL/min.
10) (At time of PCI) Patients who do not undergo primary PCI due to lack of severity of culprit lesion or other reasons.

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)
central randomisation by computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Treatment allocation will be balanced using minimisation for the following characteristics; location of infarct (LAD vs. non-LAD), symptom to balloon time (<3 hours > 3+), hours), known diabetes (yes/no), age (65+ vs. younger than 65), gender, whether the participant had prior MI and study site.

Patients will be allocated to 2 treatment groups in a ratio of 1:1.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
Intervention assignment
Parallel
Other design features
RESTORE-MI is a multi-centre double-blind placebo-controlled randomised trial.

The first 20 randomised patients were single-blind placebo-controlled (patient and person assessing are not aware of treatment received) in a pilot study (recruitment completed Feb 2021).
Phase
Phase 3
Type of endpoint/s
Efficacy
Statistical methods / analysis
The study is powered on the primary endpoint. Fifty-two percent of screened subjects post-PCI are expected to have an IMR less than or equal to 32 (IMR International Registry data), with a mean IMR of 15. The 2-year event rate among such individuals (death or rehospitalisation for heart failure) is expected to be about 6.9% (IMR International Registry data, personal communication), and these subjects will enter the RESTORE MI Low-IMR register.
The proportion of screened patients with a post-PCI IMR greater than 32, making them high risk and eligible for the randomised clinical trial, is predicted to be 48% with a mean IMR of approximately 50. For those subjects receiving placebo treatment, the post-placebo IMR is expected to remain unchanged, with an expected 2-year event rate of 19.8% (IMR International Registry data, personal communication,). Among those who receive active tenecteplase, the post-TNK IMR is expected to fall to an average value of 20, with an event rate for the primary endpoint of 12.5% (a 37% risk reduction, reflecting an assumed treatment benefit of about 60% of that afforded by an intrinsically lower IMR post-PCI and a possible TNK-non-response rate of 20% (i.e. IMR does not change and event rate remains high). Other data generally supports these assumptions. While not separated by post-PCI IMR values, the TASTE and TOTAL trials found 1-year mortality rates of 5.3% and 4.5% respectively, equating to around 8% projected for 2-year mortality, and at least 20% projected for death and hospitalisation for heart failure combined. Further, a 30 unit intrinsically lower post-PCI IMR was associated with a 5.1% smaller infarct size (as percent of left ventricle) in a Scottish study (54), which might be expected to translate in to around a 7% lower 2-year composite risk of death or heart failure hospitalisation (assuming roughly quadratically increasing risk with increasing MI size, Stone G et al, Trans-Catheter Cardiovascular Therapeutics Congress, 2014), if achievable. Making allowance for a), non-compliance with TNK administration of 1% (the drug is given as an intra-coronary bolus immediately after PCI and IMR stratification, and so “non-delivery” should be very rare), a total of 800 randomised patients would offer at least 80% power at 2P=0.05 to identify such a risk reduction as statistically significant. Hence, a total of 1666 subjects will need to be screened to recruit 866 into the Low-IMR register and 800 subjects into the randomised RESTORE-MI trial.

An IMR validation study will be performed on the first 20 patients enrolled for the clinical trial at RPA Hospital and Concord Hospital. Following tenecteplase/placebo bolus, coronary guidewire measurements will be taken at 10, 15 and 30 minutes post infusion. This will enable the determination of the speed at which tenecteplase acts in the coronary microcirculation. During the pilot study, IMR validation will also be performed for participants in the registry (who have not been allocated to a study treatment arm) at 10, 15 and 30 minutes post PCI.
Any adjustment to the time point of IMR re-measurement, to ensure it can adequately capture the effect of treatment while minimising procedure time, will be made before the main trial is launched.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
30/06/2018
Actual
16/10/2018
Date of last participant enrolment
Anticipated
30/06/2020
Actual
6/12/2020
Date of last data collection
Anticipated
30/06/2022
Actual
5/09/2023
Sample size
Target
50
Accrual to date
Final
50
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 7520 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [2] 7521 0
Concord Repatriation Hospital - Concord
Recruitment postcode(s) [1] 15345 0
2050 - Camperdown
Recruitment postcode(s) [2] 15346 0
2139 - Concord

Funding & Sponsors
Funding source category [1] 295686 0
Government body
Name [1] 295686 0
National Health and Medical Research Council
Country [1] 295686 0
Australia
Funding source category [2] 299102 0
Commercial sector/Industry
Name [2] 299102 0
Abbott Pty Ltd
Country [2] 299102 0
Australia
Primary sponsor type
University
Name
University of Sydney
Address
c/o NHMRC Clinical Trials Centre, Locked bag 77, Camperdown NSW 1450
Country
Australia
Secondary sponsor category [1] 294529 0
None
Name [1] 294529 0
Address [1] 294529 0
Country [1] 294529 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296996 0
Sydney Local Health District Human Research Ethics Committee – Concord Repatriation General Hospital
Ethics committee address [1] 296996 0
Ethics committee country [1] 296996 0
Australia
Date submitted for ethics approval [1] 296996 0
24/01/2017
Approval date [1] 296996 0
26/06/2017
Ethics approval number [1] 296996 0
CH62/6/2017-017

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 72658 0
Prof Martin Ng
Address 72658 0
Department of Cardiology
Royal Prince Alfred Hospital
Missenden Road, Camperdown NSW 2050
Country 72658 0
Australia
Phone 72658 0
+61 2 9562 5000
Fax 72658 0
Email 72658 0
[email protected]
Contact person for public queries
Name 72659 0
RESTORE-MI Trial Coordinator
Address 72659 0
NHMRC Clinical Trial Centre
Locked Bag 77
Camperdown
NSW 1450
Country 72659 0
Australia
Phone 72659 0
+61 2 9562 5000
Fax 72659 0
Email 72659 0
[email protected]
Contact person for scientific queries
Name 72660 0
Martin Ng
Address 72660 0
Department of Cardiology
Royal Prince Alfred Hospital
Missenden Road, Camperdown NSW 2050
Country 72660 0
Australia
Phone 72660 0
+61 2 9562 5000
Fax 72660 0
Email 72660 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
To be confirmed. Please refer to the CTC publication policy for more information.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
Dimensions AIThrombus Embolisation: Prevention is Better than Cure2019https://doi.org/10.15420/icr.2019.11
EmbaseIn Acute ST-Segment Elevation Myocardial Infarction, Coronary Wedge Pressure Is Associated with Infarct Size and Reperfusion Injury as Evaluated by Cardiac Magnetic Resonance Imaging.2020https://dx.doi.org/10.1155/2020/2863290
EmbasePathophysiology and diagnosis of coronary microvascular dysfunction in ST-elevation myocardial infarction.2020https://dx.doi.org/10.1093/cvr/cvz301
Dimensions AIRisk Stratification Guided by the Index of Microcirculatory Resistance and Left Ventricular End-Diastolic Pressure in Acute Myocardial Infarction2021https://doi.org/10.1161/circinterventions.120.009529
EmbaseAngiography derived assessment of the coronary microcirculation: is it ready for prime time?.2022https://dx.doi.org/10.1080/14779072.2022.2098117
EmbaseIs Platelet Reactivity a Therapeutic Target to Limit Microvascular Obstruction?.2022https://dx.doi.org/10.1161/JAHA.121.024930
N.B. These documents automatically identified may not have been verified by the study sponsor.