A Trial of Low-dose Adjunctive alTeplase During prIMary PCI

Myocardial Infarction Clinical Trial

— T-TIME  

Official title:

A Randomised, Double Blind, Placebo-controlled, Parallel Group Trial of Low-dose Adjunctive alTeplase During prIMary PCI

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02257294
• Other study ID #: GN12CA450
• Secondary ID: 12/170/45
• Status: Completed
• Phase: Phase 2
• Start date: March 2016
• Est. completion date: May 8, 2019

Study information

• Verified date: September 2019
• Source: NHS Greater Glasgow and Clyde
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to determine the safety and efficacy of reduced doses (10 mg and 20 mg) of intra-coronary alteplase compared with placebo as an adjunct to PCI in reducing MVO and its consequences in high risk patients with STEMI.

Description:

Despite numerous interventions, there remains a need to develop new ways to prevent microvascular obstruction (MVO). The investigators aim to select patients with persistent S-T-elevation on the ECG and an occluded artery and heavy thrombus burden at initial angiography. These characteristics are causally linked to MVO. Patients with a thrombotic culprit coronary artery have reduced myocardial perfusion compared to those without and the presence of coronary thrombus is an independent predictor of adverse ischaemic outcomes post-MI. Intra-luminal thrombus, as revealed by intra vascular imaging with optical coherence tomography (OCT) in STEMI patients, has shown that thrombus commonly persists in the culprit coronary artery, including within the stent post-implantation, even when the thrombus is invisible with conventional angiography. The amount of persistent thrombus predicted the likelihood of persistent S-T-segment elevation, a marker of microvascular injury, and impaired perfusion.Therefore, coronary thrombus represents a therapeutic target in primary PCI. The pathophysiology of MVO and microvascular thrombosis has elucidated in MRI studies of reperfused MI in swine. The investigators demonstrated that LATE MVO corresponds closely with infarct zone haemorrhage as revealed by T2-weighted MRI and pathology. The investigators observations were validated by Robbers et al who showed that in swine 7 days post-MI, when LATE MVO and haemorrhage correspond (which is usually the case), there is severe capillary loss and disruption coupled with thrombosis and inflammation. They concluded that following reperfusion, acute inflammation and microvessel thrombosis result in degradation of endothelial integrity and capillary breakdown. Very interestingly, their histology also demonstrated diffuse microvascular thrombosis within the area of late gadolinium enhancement surrounding the haemorrhagic core which explains reduced perfusion (or wash during first pass of gadolinium contrast MRI) within the ischaemic area-at-risk. This observation points to the therapeutic potential of local thrombolysis within the culprit artery circulation.The study addresses the question of whether a pharmacological strategy involving reduced dose alteplase given early during the primary PCI procedure will both prevent and treat distal microvascular thrombosis and MVO and, subsequently, reduce infarct size.Current evidence around the potential safety and efficacy of reduced dose fibrinolysis in primary PCI is limited. These limitations set-the-scene and support the rationale for the clinical trial: Full systemic dose intravenous fibrinolysis to facilitate primary PCI is potentially harmful and increases the risk of off-target bleeding complications; therefore, the investigators will use reduced-dose fibrinolysis. They will directly infuse alteplase into the culprit artery to achieve effective and sustained local plasma concentrations and much lower systemic concentrations of unbound drug. It is anticipated that bleeding rates may be low; therefore, the investigators will measure fibrinogen in all patients. Fibrinogen and other haemostasis parameters will serve as a surrogate measure of bleeding (and safety). In line with contemporary practice, investigators advise that patients have radial artery access whenever possible. Previous trials have used streptokinase (non-fibrin specific and immunogenic); this study will use the fibrin-specific non-immunogenic second generation thrombolytic, alteplase The only previous trial involved thrombolysis at the end of primary PCI (when microvascular thrombosis may already be established after reperfusion); the efficacy of thrombolysis may be greatest when thrombus is most abundant at the beginning of primary PCI; persistent residual fibrin strands adherent within the culprit territory will be selectively targeted by fibrinolytic therapy during primary PCI; thrombus which forms during the primary PCI procedure could be treated by the sustained 'deep tissue' thrombolytic effects of locally administered intra-coronary alteplase; in terms of ease-of-use and feasibility, there may be advantages to giving alteplase as a single dose.T-TIME is a Phase II evaluation of two reduced doses of alteplase, delivered locally, compared to placebo in STEMI patients receiving PCI in a double-blind, randomised, parallel group, placebo-controlled dose-ranging clinical trial. The investigators believe the strategy with intracoronary fibrinolysis complements other therapeutic approaches which are currently being tested. Should the trial demonstrate EFFICACY then a future trial might involve a factorial design with placebo, alteplase and any other intervention that might also be shown to be effective in the intervening time in order to test the comparative EFFICACY of each (alone or in combination) on surrogate and/or clinical outcomes.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 440
• Est. completion date: May 8, 2019
• Est. primary completion date: July 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Males aged = 18 years; females = 18 years not of child bearing potential (defined as women who are post-menopausal or permanently sterilised (e.g. hysterectomy, tubal occlusion, bilateral salpingectomy)

• Acute myocardial infarction (symptoms onset = 6 hours) with persistent ST-segment elevation or recent left bundle branch block

• Coronary artery occlusion (TIMI coronary flow grade 0 or 1) OR Impaired coronary flow (TIMI flow grade 2, slow but complete filling) in the presence of definite angiographic evidence of thrombus (TIMI grade 2+)

• Proximal-mid culprit lesion location in a major coronary artery (ie the right, left anterior descending, intermediate or circumflex coronary artery)

• Radial artery access

Exclusion Criteria:

• Shock (systolic blood pressure <90 mmHg with clinical signs of peripheral hypoperfusion despite adequate filling)

• Normal coronary flow grade (TIMI flow grade 3) at initial angiography

• Functional coronary collateral supply (Rentrop grade 2/3) to culprit artery

• Multivessel PCI intended before the day 2-7 MRI Scan

• Non-cardiac co-morbidity with expected survival <1 year

• Estimated body weight <60kg

• Contra-indication to contrast-enhanced MRI

• Pacemaker

• Implantable defibrillator

• estimated Glomerular Filtration Rate (eGFR) <30ml/min/1.73m²

• previous infarction in the culprit artery (known or suspected clinically, e.g. wall motion abnormality revealed by echocardiography)

• Significant bleeding problem either at present or within the past 6 months

• Patients with current concomitant oral anticoagulant therapy (INR > 1.3), including apixaban, dabigatran and rivaroxaban

• Any history of central nervous system damage (i.e. neoplasm, aneurysm, intracranial, or spinal surgery)

• Known Haemorrhagic diathesis

• Severe uncontrolled hypertension >180/110 mmHg not controlled by medical therapy

• Major surgery, biopsy of a parenchymal organ, or significant trauma within the past 2 months (this includes any trauma associated with the current STEMI)

• Recent trauma to the head or cranium (<2 months)

• Prolonged cardiopulmonary resuscitation (>2 minutes) within past 2 weeks

• Acute pericarditis and/or subacute bacterial endocarditis e.g. valve mass or vegetation revealed by echocardiography

• Acute pancreatitis

• Severe hepatic dysfunction, including hepatic failure, cirrhosis, portal hypertension (oesophageal varices) and active hepatitis

• Arterial aneurysm and known arterial/venous malformation

• Neoplasm with increased bleeding risk

• Any known history of haemorrhagic stroke or stroke of unknown origin

• Known history of ischaemic stroke or transient ischaemic attack <6 months

• Dementia

• Hypersensitivity to gentamicin

• Women of child-bearing potential (i.e. pre-menopause) or breast feeding

• Previous randomisation to this study or participation in a study with an investigational drug or medical device within 90 days prior to randomisation

• Incapacity or inability to provide informed consent

• requirement for immunosuppressive drug therapy at any time during the past 3 months; whether administered orally, subcutaneously or intravenously. This would include corticosteroids (but not inhaled or topical), drugs used following transplantation (e.g. tacrolimus, cyclosporine), anti-metabolite therapies (e.g. mycophenolic acid (Myfortic), azathioprine, leflunomide (Arava)), and immunomodulators including biologics (e.g. adalimumab (HUMIRA), etanercept (Enbrel), aldesleukin), and DMARDS (cyclophosphamide. methotrexate, etc). Please note that this list is not exhaustive and a requirement for other immunosuppressive drugs not listed would also exclude the patient.

• active or prophylactic treatment with oral or parenteral antibiotic, antifungal or antiviral therapy to prevent or treat infection.

• any anti-cancer treatment (excluding surgery as this is covered above) at any time during the past 3 months including chemotherapy, radiotherapy and treatment with biologics such as Vascular Endothelial Growth Factor Receptor (VEGFR) inhibitors (e.g. bevacizumab, pazopanib). This list is not exhaustive and the sponsor or CI should be contacted for advice if required.

Related Conditions & MeSH terms

• Infarction
• Myocardial Infarction

Intervention

Drug:
• Alteplase
Single treatment consisting of a single slow infusion administration after reperfusion with aspiration thrombectomy ± angioplasty but before stenting during primary PCI.

Other:
• Placebo
Single treatment consisting of a single slow infusion administration after reperfusion with aspiration thrombectomy ± angioplasty but before stenting during primary PCI.

Locations

Country	Name	City	State
United Kingdom	Edinburgh Royal Infirmary	Edinburgh
United Kingdom	Golden Jubilee National Hospital	Glasgow
United Kingdom	Leeds General Infirmary	Leeds
United Kingdom	Glenfield Hospital	Leicester
United Kingdom	Liverpool Heart and Chest Hospital	Liverpool
United Kingdom	Barts Health Centre, St Bartholomew's Hospital	London
United Kingdom	University Hospital of South Manchester NHS Foundation Trust	Manchester
United Kingdom	James Cook University Hospital	Middlesbrough
United Kingdom	Freeman Hospital	Newcastle
United Kingdom	University Hospital Southampton NHS Foundation Trust	Southampton
United Kingdom	Heart and Lung Centre, New Cross Hospital	Wolverhampton

Sponsors (3)

Lead Sponsor	Collaborator
NHS Greater Glasgow and Clyde	National Institute for Health Research, United Kingdom, University of Glasgow

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Histopathology (sub-study)	Fibrin histopathology in thrombus aspirate	0 hours
Other	Angiogram	Intra-procedural changes in TIMI Coronary Flow Grade; Intra-procedural changes in TIMI blush grade; Intra-procedural changes in TIMI Frame Count; Intra-procedural changes in TIMI Thrombus Grade; Intra-procedural thrombotic events	0-2 hours
Other	Coronary Physiology (sub-study)	IMR; CFR	0-2 hours
Other	Optical Coherence Tomography (sub-study)	Thrombus area	0-2 hours
Other	Biochemistry	Blood chemistry (standard of care blood tests)	24 hours
Other	Haematology	Haemoglobin (standard of care blood tests)	24 hour
Other	Safety	Haemoglobin (standard of care blood tests)	24 hours
Other	ECG	Surrogate ECG measures of infarct size - Anderson ST Acuteness score and Selvester QRS score; Acuteness of the ECG changes - Anderson Wilkins score;	12 weeks
Other	MRI	First pass MVO extent (% of LV); Early MVO extent (% of LV) on 1 min post-gadolinium contrast enhanced MRI , adjusted for area-at-risk at baseline; LV remodelling index (minimum infarct wall thickness / maximum remote zone thickness mid-diastole); LV diastolic myocardial wall thickness to volume; LV sphericity index at end diastole (maximal longitudinal LV diameter (i.e. tip mitral valve to LV index) / maximal short-axis diameter); LV sphericity index at end-systole (maximal longitudinal LV diameter (i.e. tip mitral valve to LV apex) / maximal short-axis diameter); LV wall motion; Myocardial strain; Myocardial haemorrhage; Myocardial perfusion in the infarct zone; Myocardial perfusion in the remote zone; Infarct zone perfusion indexed to remote zone perfusion; Extracellular volume in the infarct zone; Extracellular volume in the remote zone; Extracellular in the infarct core; LV wall motion;	12 weeks
Other	Quality of life	Blood chemistry (standard of care blood tests); EQ5D-5L (52 weeks)	2 years
Other	Health outcomes	Death; MI; Heart Failure; Stroke/TIA; Acute bleeds	3 years
Primary	The amount of MVO (% of Left Ventricular (LV) mass) revealed by late (10 - 15 min) gadolinium contrast enhancement MRI 2 days post-MI.	Amount of MVO (% of LV mass) revealed by late gadolinium contrast-enhanced MRI 10-15 minutes after contrast administration on an MRI scan performed 2-7 days post-MI.	2-7 days
Secondary	Angiogram	TIMI Coronary flow grade at the end of PCI; TIMI blush grade at the end of PCI; TIMI frame count at the end of PCI; TIMI thrombus grade at the end of PCI	0-2 hours
Secondary	ECG	% ST segment resolution on the 12-lead ECG (pre- vs. 60 mins post-reperfusion with primary PCI)	0-2 hours
Secondary	Haematology	Coagulation	24 hours
Secondary	MRI	Late MVO (presence/absence); Infarct size; Myocardial salvage index (infarct size/area-at-risk); LV end-diastolic volume (LVEDV); LV end-systolic volume (LVESV); LV ejection fraction (LVEF); Myocardial haemorrhage (presence/absence); Myocardial haemorrhage extent (% of LV)	2-7 days
Secondary	Safety	Acute cerebral (stroke) and systemic (GI, peripheral) bleeding (if any) with alteplase; Coagulation (fibrinogen concentration);	2-7 days
Secondary	MRI	Infarct size; Myocardial salvage index (final infarct size/initial area-at-risk); LV end-diastolic volume (LVEDV); LV end-systolic volume (LVESV); LV ejection fraction (LVEF);	12 weeks
Secondary	ECG	ECG for final infarct size	12 weeks
Secondary	Biochemistry	Troponin T; NT-pro BNP	12 weeks
Secondary	Quality of Life	EQ5D-5L assessment (2-7 days, 12 weeks)	12 weeks