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

STEMI Clinical Trial

— RESTORE-MI  

Official title:

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).

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03998319
• Other study ID #: CTC0150
• Status: Recruiting
• Phase: Phase 3
• Start date: October 14, 2021
• Est. completion date: December 31, 2026

Study information

• Verified date: October 2023
• Source: University of Sydney
• Contact: Martin Ng, MBBS (Hons)
• Phone: +614 3407 8507
• Email: martin.ng[@]sydney.edu.au
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 445
• Est. completion date: December 31, 2026
• Est. primary completion date: December 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 5 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.

Related Conditions & MeSH terms

• Elevated IMR (>32)
• ST Elevation Myocardial Infarction
• STEMI

Intervention

Drug:
• Tenecteplase (1/3 systemic weight based dose)
50mg reconstituted to 20mL for intracoronary infusion at 1/3 weight based dose.

Other:
• Sterile water for injection (WFI)
Placebo comparative arm.

Locations

Country	Name	City	State
Australia	Royal Adelaide Hospital	Adelaide	South Australia
Australia	Bankstown-Lidcombe Hospital	Bankstown	New South Wales
Australia	Box Hill Hospital	Box Hill	Victoria
Australia	Royal Prince Alfred Hospital	Camperdown	New South Wales
Australia	Jessie McPherson Private Hospital	Clayton	Victoria
Australia	Monash Medical Centre - Clayton	Clayton	Victoria
Australia	Concord Repatriation General Hospital	Concord	New South Wales
Australia	Lyell McEwin Hospital	Elizabeth Vale	South Australia
Australia	The Northern Hospital	Epping	Victoria
Australia	Frankston Hospital	Frankston	Victoria
Australia	Northern Beaches Hospital	Frenchs Forest	New South Wales
Australia	Liverpool Hospital	Liverpool	New South Wales
Australia	Fiona Stanley Hospital	Murdoch	Western Australia
Australia	John Hunter Hospital	New Lambton Heights	New South Wales
Australia	Royal Perth Hospital	Perth	Western Australia
Australia	Prince of Wales Hospital	Randwick	New South Wales
Australia	Sunshine Hospital	Saint Albans	Victoria
Australia	Wollongong Hospital	Wollongong	New South Wales
New Zealand	Auckland City Hospital	Auckland
New Zealand	Christchurch Hospital	Christchurch
New Zealand	Waikato Hospital	Hamilton
New Zealand	Wellington Hospital	Wellington

Sponsors (1)

Lead Sponsor	Collaborator
University of Sydney

Countries where clinical trial is conducted

Australia,  New Zealand, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Primary	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
Primary	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	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
Secondary	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
Secondary	All-cause mortality	All-cause mortality assessed by physical assessment and medical record review.	24 months after primary PCI procedure
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	TIMI corrected frame count	Thrombolysis in myocardial infarction score with corrected frame count from angiogram to assess myocardial perfusion	0-2 hours
Secondary	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