A Study of Low-dose Intracoronary Thrombolytic Therapy in STEMI (Heart Attack) Patients. (RESTORE-MI)

A Randomised Trial to Evaluate the Efficacy of Low-dose Intracoronary Tenecteplase in ST-Elevation Myocardial Infarction (STEMI) Patients With High Microvascular Resistance Post-percutaneous Coronary Intervention (PCI).

Heart attacks are caused by a blood clot blocking the blood vessels of the heart, preventing blood getting to the heart muscle. Opening up the artery with a balloon (angioplasty) and a small mesh tube (stent) although life saving can cause this clot to break up and get washed downstream, which can make the heart attack worse. The investigators can measure the amount of damage caused to the microcirculation by calculating the IMR (Index of Microcirculatory resistance).

This can be measured by a wire in the coronary artery with a pressure sensor at the tip. If the IMR is elevated, it is suggestive of extensive microcirculatory damage. A clot dissolving medicine can be administered in the artery to try and reduce the IMR which can reduce damage to the heart muscle and improve outcomes.

Impaired microcirculatory perfusion in patients as a result of ST-elevation myocardial infarction (STEMI) is associated with poor clinical outcomes. This project seeks to identify patients with impaired microcirculatory perfusion after STEMI and to assess whether acute improvement in microcirculatory perfusion in these patients by the use of intracoronary thrombolytic therapy results in improved clinical outcomes.

Study Overview

• Status: Recruiting
• Conditions: STEMI; Elevated IMR (>32)
• Intervention / Treatment: Drug: Tenecteplase (1/3 systemic weight based dose); Other: Sterile water for injection (WFI)

Detailed Description

Patients presenting to the participating hospitals with a heart attack will be approached to participate in the study. After angioplasty has been performed, the IMR will be measured in the infarct related artery. If the IMR is >32 patients will be randomised to receive intracoronary clot dissolving therapy in the form of low dose tenecteplase (TNK) or water as a placebo. Patients who have an IMR ≤32 will be followed up in a registry. Cardiac enzymes will be measured at baseline and discharge. Randomised participants will receive a cardiac MRI at discharge (3-7 days post primary PCI) and at 6 months post PCI. All participants will be followed up at 30 days, and 6, 12 and 24 months following discharge.

• Study Type: Interventional
• Enrollment (Estimated): 445
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Martin Ng, MBBS (Hons); Phone Number: +614 3407 8507; Email: martin.ng@sydney.edu.au
• Study Contact Backup: Name: Rebecca Mister; Phone Number: 5342 +612 9562 5000; Email: RESTORE-MI.Study@sydney.edu.au

Study Locations

• Australia
  • New South Wales
    • Bankstown, New South Wales, Australia, 2200
      • Not yet recruiting
      • Bankstown-Lidcombe Hospital
      • Contact: Kaleab Asrress; Phone Number: +612 9722 8486; Email: kaleab.asrress@sydney.edu.au
    • Camperdown, New South Wales, Australia, 2050
      • Recruiting
      • Royal Prince Alfred Hospital
      • Contact: Martin Ng, MBBS (Hons); Phone Number: +614 3407 8507; Email: martin.ng@sydney.edu.au
    • Concord, New South Wales, Australia, 2139
      • Recruiting
      • Concord Repatriation General Hospital
      • Contact: Andy Yong, MBBS; Phone Number: +614 0130 1790; Email: sze.yong@sydney.edu.au
    • Frenchs Forest, New South Wales, Australia, 2086
      • Not yet recruiting
      • Northern Beaches Hospital
      • Contact: Antony Lau
    • Liverpool, New South Wales, Australia, 2170
      • Recruiting
      • Liverpool Hospital
      • Contact: Sidney Lo; Phone Number: (02) 8738 3051; Email: sidney.lo@health.nsw.gov.au
    • New Lambton Heights, New South Wales, Australia, 2305
      • Recruiting
      • John Hunter Hospital
      • Contact: Andrew Boyle; Phone Number: (02) 4921 4720; Email: Andrew.Boyle@health.nsw.gov.au
    • Randwick, New South Wales, Australia, 2031
      • Not yet recruiting
      • Prince of Wales Hospital
      • Contact: Sze-Yuan Ooi; Phone Number: (02) 9382 0770; Email: szeyuan.ooi@ehc.com.au
    • Wollongong, New South Wales, Australia, 2500
      • Withdrawn
      • Wollongong Hospital
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Recruiting
      • Royal Adelaide Hospital
      • Contact: Jerrett Lau; Phone Number: (08) 7074 1796; Email: jerrett.lau@sa.gov.au
    • Elizabeth Vale, South Australia, Australia, 5112
      • Recruiting
      • Lyell McEwin Hospital
      • Contact: Purendra Pati; Email: Purendra.Pati@sa.gov.au
  • Victoria
    • Box Hill, Victoria, Australia, 3128
      • Recruiting
      • Box Hill Hospital
      • Contact: Jaya Chandrasekhar
    • Clayton, Victoria, Australia, 3168
      • Recruiting
      • Victorian Heart Hospital
      • Contact: Robert Gooley
    • Clayton, Victoria, Australia, 3168
      • Recruiting
      • Jessie McPherson Private Hospital
      • Contact: Robert Gooley
    • Epping, Victoria, Australia, 3076
      • Recruiting
      • The Northern Hospital
      • Contact: William van Gaal; Email: William.vangaal@nh.org.au
    • Frankston, Victoria, Australia, 3199
      • Recruiting
      • Frankston Hospital
      • Contact: Jamie Layland; Phone Number: (03) 9748 2687; Email: jlayland@phcn.vic.gov.au
    • Saint Albans, Victoria, Australia, 3021
      • Recruiting
      • Sunshine Hospital
      • Contact: William Chan; Phone Number: 0435 612 868; Email: william.chan@unimelb.edu.au
  • Western Australia
    • Murdoch, Western Australia, Australia, 6150
      • Not yet recruiting
      • Fiona Stanley Hospital
      • Contact: Matthew Erickson; Phone Number: 08 6152 6604; Email: matthew.erickson@health.wa.gov.au
    • Perth, Western Australia, Australia, 6000
      • Recruiting
      • Royal Perth Hospital
      • Contact: Jonathan Spiro; Phone Number: (08) 9224 3290; Email: Jonathan.Spiro@health.wa.gov.au
• New Zealand
  • Auckland, New Zealand, 1023
    • Not yet recruiting
    • Auckland City Hospital
    • Contact: Jithendra Somaratne
  • Christchurch, New Zealand, 4710
    • Not yet recruiting
    • Christchurch Hospital
    • Contact: Aniket Puri
  • Hamilton, New Zealand, 3240
    • Recruiting
    • Waikato Hospital
    • Contact: Sanjeevan Pasupati
  • Wellington, New Zealand, 2820
    • Not yet recruiting
    • Wellington Hospital
    • Contact: Scott Harding

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Adult men and women aged over 18 who present with STEMI within 6 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 National Heart Foundation (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
5. Participant consents to have a 3-7 day (discharge) and 6 month follow up cardiac MRI

Exclusion Criteria:

At the time of screening and/or prior to randomisation, no known;

1. Previous coronary bypass grafting
2. Other residual lesions with ≥50% diameter stenosis in the culprit vessel
3. 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 atrioventricular (AV) block
6. Diagnosis of metastatic disease
7. Concurrent illness, including severe infection that may jeopardise the ability of the patient to undergo the procedures outlined in this protocol with reasonable safety
8. Serious medical or psychiatric conditions that might limit the ability of the patient to comply with the protocol
9. 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.

10. Participation in any investigational study in the previous 30 days

    Other exclusion criteria:

11. (Cardiac MRI cohort only) Presence of contraindications to contrast enhanced MRI including severe claustrophobia, pregnancy, pacemakers, non-MRI compatible aneurysm clips, defibrillators and estimated glomerular filtration rate of <30mL/min.

    (At time of PCI)

12. Patients who received GpIIb/IIIa treatment prior to IMR measurement
13. Patients who do not undergo primary PCI due to lack of severity of culprit lesion or other reasons.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tenecteplase (1/3 systemic weight based dose); Tenecteplase will be reconstituted in 20mL sterile water for injection at 1/3 of the weight based dose, and administered by intracoronary infusion over 3 minutes.	Drug: Tenecteplase (1/3 systemic weight based dose); 50mg reconstituted to 20mL for intracoronary infusion at 1/3 weight based dose.; Other Names: TNKase
Placebo Comparator: Sterile Water for injection (WFI); Water for injection will be prepared to 20mL over an equivalent time period to the reconstitution time of the experimental arm, in order to maintain the blind, and administered by intracoronary infusion over 3 minutes.	Other: Sterile water for injection (WFI); Placebo comparative arm.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To compare the number of participants who experience cardiovascular mortality and rehospitalisation for heart failure at 24 months in those given tenecteplase with those given placebo (Cardiac MRI cohort only)	Cardiovascular mortality and rehospitalisation for heart failure assessed by medical record review.	24 months
To compare MI size as a % of LV mass and intramyocardial bleeding rates in participants at 6 months post PCI in those given low dose tenecteplase with those given placebo.	MI size and intramyocardial bleeding rates will be assessed upon cardiac MRI at discharge (3-7 days post procedure) as a baseline measure, and at 6 months post-PCI.	6 months after primary PCI procedure.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants who experience individual components of the primary endpoint: (a) cardiovascular mortality at 24 months, (b) rehospitalisation for heart failure at 24 months;	Cardiovascular mortality and rehospitalisation for heart failure assessed by medical record review, respectively.	24 months after primary PCI procedure
Number of Major Adverse Cardiac Events (MACE)	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	24 months after primary PCI procedure
All-cause mortality	All-cause mortality assessed by physical assessment and medical record review.	24 months after primary PCI procedure
Number of stroke events	Stroke events will be assessed by medical record review. Assessment will cover all aspects of the stroke event (including type, severity, frequency).	24 months after primary PCI procedure
Number of incidences of bailout treatment use for no-reflow syndrome	Use of Bailout treatment for no-reflow syndrome assessed by medical record review	24 months after primary PCI procedure
Occurrence of major (Type 3 or greater) and minor (Type 2) bleeding as defined by the Bleeding Academic Research Consortium	Major (Type 3 or greater) and minor (Type 2) bleeding as defined by the Bleeding Academic Research Consortium. Assessed by medical record review.	24 months after primary PCI procedure
Index of Microcirculatory Resistance (IMR)	Index of microcirculatory resistance (IMR) measurement assessed by coronary pressure wire data output review. This is a simple unit scale, with a higher number indicating a worse outcome with a score of more than 25 indicating abnormal microcirculatory function in the heart.	0-2 hours
Fractional Flow Reserve (FFR)	Fractional Flow Reserve measurement assessed by coronary pressure wire data output review prior to randomisation and immediately after primary PCI	0-2 hours
Coronary Flow Reserve (CFR)	Coronary Flow Reserve measurement assessed by coronary pressure wire data output review, prior to randomisation and immediately after primary PCI.	0-2 hours
Wall Motion Score	The score is measured by simple unit scale (1 = normal, 2 = hypokinetic (muscle impaired), 3= akinetic (muscle dead)). Each of the 16 segments of the hearts is scored, with the total being divided by 16 to derive the score.	0-6 months
Left ventricular ejection fraction (LVEF)	Left ventricular ejection fraction measurement from echocardiogram will be used to assess cardiac function prior to randomisation, 48 hours and 6 months post primary PCI	0-6 months
Myocardial Blush Grade	Myocardial Blush Grade measurement from angiogram will be used to assess cardiac function. The score goes from 0 to 3, with 3 being normal and 0 being absence of myocardial blush	0-2 hours
TIMI Myocardial Perfusion Grade	Thrombolysis in myocardial infarction score from angiogram will be used to assess myocardial perfusion. This score goes from 0 to 3, 3 indicates normal flow within the artery and 0 indicates a complete coronary occlusion.	0-2 hours
TIMI corrected frame count	Thrombolysis in myocardial infarction score with corrected frame count from angiogram to assess myocardial perfusion	0-2 hours
Cardiac enzyme measurements	Cardiac enzyme levels including troponin T, creatine kinase, creatine kinase-MB and high sensitivity troponin T, from blood samples collected during the hospitalisation period (prior to primary PCI and at 8, 16, 24 and 32 hours post primary PCI).	0-32 hours

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
DNA analyses (Subject to funding)	Samples of whole blood will be used for DNA analyses at baseline, post-PCI, discharge and 6 month follow up (6m follow up for Randomised participants only).	0-6 months
MicroRNA analyses (Subject to funding)	Samples of whole blood will be used for microRNA analyses at baseline, post-PCI, discharge and 6 month follow up (6m follow up for Randomised participants only).	0-6 months
Vasoactive markers (Subject to funding)	Samples of whole blood will be used for vasoactive marker analyses at baseline, post-PCI, discharge and 6 month follow up (6m follow up for Randomised participants only).	0-6 months
Inflammatory markers (Subject to funding)	Samples of whole blood will be used for inflammatory marker analyses at baseline, post-PCI, discharge and 6 month follow up (6m follow up for Randomised participants only).	0-6 months
Angiogenic markers (Subject to funding)	Samples of whole blood will be used for angiogenic marker analyses at baseline, post-PCI, discharge and 6 month follow up (6m follow up for Randomised participants only).	0-6 months
Liver function (Subject to funding)	Samples of whole blood will be used for liver function analyses at baseline, post-PCI, discharge and 6 month follow up (6m follow up for Randomised participants only).	0-6 months
Thyroid Function (Subject to funding)	Samples of whole blood will be used for thyroid function analyses at baseline, post-PCI, discharge and 6 month follow up (6m follow up for Randomised participants only).	0-6 months
Lipid profile (Subject to funding)	Samples of whole blood will be used for lipid profile analyses at baseline, post-PCI, discharge and 6 month follow up (6m follow up for Randomised participants only).	0-6 months
Lipoprotein profile (Subject to funding)	Samples of whole blood will be used for lipoprotein profile analyses at baseline, post-PCI, discharge and 6 month follow up (6m follow up for Randomised participants only).	0-6 months

Collaborators and Investigators

• Sponsor: University of Sydney
• Collaborators: Genentech, Inc.
• Investigators: Study Chair: Martin Ng, MBBS (Hons), Royal Prince Alfred Hospital, Sydney, Australia; Study Chair: Andy Yong, MBBS, Concord Repatriation General Hospital; Study Chair: Anthony Keech, MBBS, National Health and Medical Research Council, Australia; Study Chair: William Fearon, MD, Stanford University; Study Chair: Jamie Layland, MBBS, Peninsula Health; Study Chair: Harvey White, FRCS, Green Lane Cardiovascular Service

Study record dates

Study Major Dates

• Study Start (Actual): October 14, 2021
• Primary Completion (Estimated): December 31, 2024
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: May 6, 2019
• First Submitted That Met QC Criteria: June 23, 2019
• First Posted (Actual): June 26, 2019

Study Record Updates

• Last Update Posted (Actual): September 27, 2024
• Last Update Submitted That Met QC Criteria: September 25, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Keywords: thrombolysis; PCI; STEMI; myocardial infarction; microcirculation; angioplasty; physiology; IMR; microvascular obstruction; thrombolysis treatment
• Additional Relevant MeSH Terms: Ischemia; Pathologic Processes; Necrosis; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Myocardial Infarction; Infarction; ST Elevation Myocardial Infarction; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Tenecteplase
• Other Study ID Numbers: CTC0150

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Please refer to the NHMRC Clinical Trials Centre publication and data sharing Standard Operating Procedure.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes