ANZCTR - Registration

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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

Date results information initially provided

3/05/2022

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]

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

Condition category

Condition code

Cardiovascular

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]

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]

Cardiovascular mortality assessed by medical record review

Timepoint [1]

24 months after primary PCI procedure

Primary outcome [2]

Re-hospitalisation for heart failure assessed by medical record review

Timepoint [2]

24 months after primary PCI procedure

Secondary outcome [1]

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]

24 months after primary PCI procedure

Secondary outcome [2]

All-cause mortality assessed by physical assessment and medical record review.

Timepoint [2]

24 months after primary PCI procedure

Secondary outcome [3]

Stroke events will be assessed by medical record review. Assessment will cover all aspects of the stroke event (including type, severity, frequency).

Timepoint [3]

24 months after primary PCI procedure

Secondary outcome [4]

Use of Bailout treatment for no-reflow syndrome assessed by medical record review

Timepoint [4]

24 months after primary PCI procedure

Secondary outcome [5]

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]

24 months after primary PCI procedure

Secondary outcome [6]

Index of microcirculatory resistance (IMR) measurement assessed by coronary pressure wire data output review

Timepoint [6]

prior to randomisation and immediately after primary PCI

Secondary outcome [7]

Fractional Flow Reserve measurement assessed by coronary pressure wire data output review

Timepoint [7]

prior to randomisation and immediately after primary PCI

Secondary outcome [8]

Coronary Flow Reserve measurement assessed by coronary pressure wire data output review

Timepoint [8]

prior to randomisation and immediately after primary PCI

Secondary outcome [9]

Wall Motion Score measurement from echocardiogram will be used to assess cardiac function.

Timepoint [9]

prior to randomisation, 48 hours and 6 months post primary PCI

Secondary outcome [10]

Left ventricular ejection fraction measurement from echocardiogram will be used to assess cardiac function

Timepoint [10]

prior to randomisation, 48 hours and 6 months post primary PCI

Secondary outcome [11]

Myocardial Blush Grade measurement from angiogram will be used to assess cardiac function.

Timepoint [11]

prior to randomisation and post primary PCI

Secondary outcome [12]

Thrombolysis in myocardial infarction score from angiogram will be used to assess myocardial perfusion

Timepoint [12]

prior to randomisation and post primary PCI

Secondary outcome [13]

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]

prior to primary PCI and at 8, 16, 24 and 32 hours post primary PCI

Secondary outcome [14]

Thrombolysis in myocardial infarction score with corrected frame count from angiogram to assess myocardial perfusion

Timepoint [14]

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]

Royal Prince Alfred Hospital - Camperdown

Recruitment hospital [2]

Concord Repatriation Hospital - Concord

Recruitment postcode(s) [1]

2050 - Camperdown

Recruitment postcode(s) [2]

2139 - Concord

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

National Health and Medical Research Council

Address [1]

GPO Box 1421
Canberra ACT 2601

Country [1]

Australia

Funding source category [2]

Commercial sector/Industry

Name [2]

Abbott Pty Ltd

Address [2]

299 Lane Cove Road
Macquarie Park, NSW 2113
Australia

Country [2]

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]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Sydney Local Health District Human Research Ethics Committee – Concord Repatriation General Hospital

Ethics committee address [1]

HREC Executive Committee
CRGH Research Office
Ground Floor – Building 20
Concord Repatriation General Hospital
Hospital Road
Concord
NSW 2139

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

24/01/2017

Approval date [1]

26/06/2017

Ethics approval number [1]

CH62/6/2017-017

Summary

Brief summary

In patients with ST-elevated myocardial infarction, percutaneous coronary intervention restores epicardial coronary blood flow. Yet half of these patients continue to have impaired perfusion on the myocardial level and this portends a poor prognosis. Poor microcirculatory reperfusion has also been shown to be a predictor of death or rehospitalisation for heart failure after three years in post-PCI STEMI patients . The development of the index of microcirculatory resistance (IMR) by the study team has allowed easy assessment of the coronary microcirculation. Small, randomised trials have shown that intracoronary administration of the thrombolytic agent streptokinase improved the status of the coronary microcirculation and in turn reduced infarct size, preserved left ventricular dimensions and left ventricular function at six months follow-up. Despite these promising results, there has been no adequately powered clinical trial to confirm the long-term benefits of improving microvascular perfusion.
PILOT STUDY COHORT:
The study hypothesis is that in 50 adults with STEMI who have undergone primary PCI and have an IMR score greater than 32, low dose tenecteplase, compared with placebo treatment, improves long term clinical outcomes, benefits other clinical cardiovascular measures, and does not increase rates of MACE.

Trial website

https://ctc.usyd.edu.au/our-work/research-divisions/cardiovascular/start-up-and-active-trials/restore-mi/

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Prof Martin Ng

Address

Department of Cardiology
Royal Prince Alfred Hospital
Missenden Road, Camperdown NSW 2050

Country

Australia

Phone

+61 2 9562 5000

Fax

Email

[email protected]

Contact person for public queries

Name

Ms RESTORE-MI Trial Coordinator

Address

NHMRC Clinical Trial Centre
Locked Bag 77
Camperdown
NSW 1450

Country

Australia

Phone

+61 2 9562 5000

Fax

Email

[email protected]

Contact person for scientific queries

Name

Prof Martin Ng

Address

Department of Cardiology
Royal Prince Alfred Hospital
Missenden Road, Camperdown NSW 2050

Country

Australia

Phone

+61 2 9562 5000

Fax

Email

[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

Source	Title	Year of Publication	DOI
Embase	Is Platelet Reactivity a Therapeutic Target to Limit Microvascular Obstruction?.	2022	https://dx.doi.org/10.1161/JAHA.121.024930
Embase	Angiography derived assessment of the coronary microcirculation: is it ready for prime time?.	2022	https://dx.doi.org/10.1080/14779072.2022.2098117
Embase	In Acute ST-Segment Elevation Myocardial Infarction, Coronary Wedge Pressure Is Associated with Infarct Size and Reperfusion Injury as Evaluated by Cardiac Magnetic Resonance Imaging.	2020	https://dx.doi.org/10.1155/2020/2863290
Embase	Pathophysiology and diagnosis of coronary microvascular dysfunction in ST-elevation myocardial infarction.	2020	https://dx.doi.org/10.1093/cvr/cvz301
Dimensions AI	Thrombus Embolisation: Prevention is Better than Cure	2019	https://doi.org/10.15420/icr.2019.11
Dimensions AI	Risk Stratification Guided by the Index of Microcirculatory Resistance and Left Ventricular End-Diastolic Pressure in Acute Myocardial Infarction	2021	https://doi.org/10.1161/circinterventions.120.009529

N.B. These documents automatically identified may not have been verified by the study sponsor.