Clinical trial NCT03004703: ASSessing the Effect of Anti-IL-6 Treatment in Myocardial Infarction: The ASSAIL-MI Trial
Official title: ASSessing the Effect of Anti-IL-6 Treatment in Myocardial Infarction: The ASSAIL-MI Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Coronary Disease
Myocardial Infarction
Keywords: Interleukin 6
Tocilizumab
Acute coronary syndrome
STEMI
Inflammation
Lead sponsor: Oslo University Hospital
Sponsor class: OTHER
Collaborators: name: St. Olavs Hospital
name: South-Eastern Norway Regional Health Authority
name: University of Oslo
name: Norwegian University of Science and Technology
First posted: 2016-12-29
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The main goal of this study is to evaluate the ability of a single administration of tocilizumab to reduce myocardial damage in patients presenting with an acute ST-segment elevation myocardial infarction (STEMI). Secondary objectives are to assess the impact of treatment on: (i) final infarct size, (ii) left ventricular size and function, (iii) inflammation, (iv) extracellular matrix remodeling, (v) lipid parameters, (vi) platelet activation and additional pro- and anti-thrombotic parameters, and (vii) study drug safety and tolerability.

Detailed description: Myocardial infarction (MI) is a major contributor to morbidity and mortality in the Western world. The main determinant of death and complications is infarct size, and limitation of the infarct size has therefore been an important objective for strategies to improve outcome. In patients presenting with an acute ST segment elevation myocardial infarction (STEMI), urgent myocardial reperfusion with percutaneous coronary intervention (PCI) is the most effective treatment to this end. However, despite PCI, the morbidity and mortality in patients with STEMI remain substantial. This fact suggests that other, adjuvant strategies are required to reduce infarct size and improve outcome. The inflammatory cytokine interleukin (IL)-6 is an important mediator of plaque destabilisation and rupture in acute coronary syndrome (ACS) and may contribute to the ischemia-reperfusion injury succeeding revascularisation. Experimental studies suggest that IL-6 inhibition can limit infarct size through anti-inflammatory mechanisms.(ref)

The investigators recently conducted a double blind, placebo controlled trial in 117 patients with non-ST segment elevation myocardial infarction (NSTEMI) who presented within 72 hour after the onset of chest pain. In this study, a single, intravenous dose of the IL-6 antagonist tocilizumab reduced the inflammatory activity by more than 50% in the days subsequent to the intervention. Importantly, tocilizumab also reduced troponin T (TnT) levels, suggesting that patients receiving tocilizumab sustained less myocardial damage than patients who received placebo.1

Interleukin-6 inhibition might limit infarct size through reduced myocardial inflammation, but theoretically, it could also inhibit the repair process within the injured area. While the recent study suggests that IL-6 inhibition has largely favourable effects in NSTEMI, it remains to be seen if similar, beneficial effects can be obtained in patients with STEMI. On this background, the investigators want to investigate the effect of tocilizumab in patients with acute STEMI. The postulate is that a single dose of tocilizumab (RoActemra®) will have favourable effects on infarct size, as assessed by markers of myocardial necrosis and cardiac magnetic resonance imaging (CMR), without negative consequences for the repair process in these patients. The hypothesis will be tested in a randomised, double blind, placebo controlled trial comprising 200 patients with acute STEMI.

This is a phase 2 study on a new and exciting anti-inflammatory strategy in cardiovascular disease. It will be conducted at three experienced, high volume centres in Norway, and will target new and yet unmodified mechanisms during myocardial infarction. The ambition is to improve the prognosis of patients with ACS, with potential to change clinical practice.

Eligibility criteria: Inclusion Criteria:

Patients will be screened for eligibility upon admittance due to acute STEMI at either participating site. All of the following conditions must apply to the prospective patient at screening prior to receiving study agent:

* New ST elevation at the J-point in two contiguous leads (cut-points: 0.2mV in men and \>0.15 mV in women in leads V2-V3 and/or \>0.1 mV in other leads) in combination with symptoms consistent with acute MI.
* Presentation within 6 hours of chest pain.
* Indication for urgent coronary angiography with intent to reperfuse presumed occluded vessel.
* Age between 18 and 80 years.
* Informed consent obtained and documented according to ICH/GCP, and national/local regulations.

Exclusion Criteria:

Patients will be excluded from the study if they meet any of the following criteria:

* NSTEMI (non-ST segment elevation in ECG).
* Left bundle branch block in ECG
* History of previous MI
* Cardiogenic shock.
* Fibrinolytic therapy within 72 hours prior to admission.
* Cardiac arrest / ventricular fibrillation.
* History of severe renal failure with estimated glomerular filtration rate \< 30 ml/minutes.
* Known, current liver disease
* History of concurrent inflammatory, biliary obstructive or malignant disease
* A history of chronic or concurrent infectious disease, including a history of HIV, tuberculosis, or hepatitis B or C.
* Known, uncontrolled lower gastrointestinal (GI) disease such as diverticulitis, Crohn's disease, ulcerative colitis, or other symptomatic lower GI conditions that could predispose to GI perforations
* Major surgery within 8 weeks prior or after baseline
* History of central nervous system demyelinating or seizure disorders
* History of primary or secondary immunodeficiency
* Treatment with immunosuppressants other than low dose corticosteroids (equivalent to 5 mg of prednisone or less) at the time of randomisation
* Immunization with a live/attenuated vaccine within 4 weeks prior to baseline
* History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies or to tocilizumab
* Other contraindications to study medication
* Pregnancy, possible pregnancy or breast-feeding - women of child-bearing potential or breastfeeding mothers cannot participate. A woman is considered of childbearing potential following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.
* Contraindications to CMR (pacemaker, CRT, ICD, certain ferromagnetic implants, severe claustrophobia, allergy to contrast medium).
* Any condition/circumstances believed to interfere with the ability to comply with protocol.
* Any reason why, in the opinion of the investigator, the patient should not participate.
* Failure to obtain written, informed consent by patient or next of kin, for instance in case of patient death after consent has been provided in oral.

Primary outcomes:
measure: The primary endpoint will be the between-group difference in the myocardial salvage index as measured in the acute phase by cardiac magnetic resonance (CMR) imaging with late gadolinium enhancement (LGE).
timeFrame: 6 months
Secondary outcomes:
measure: The between-group difference in the AUC for Troponin T (TnT) during index hospitalisation
timeFrame: 24 -72 hours after randomisation
measure: The extent of microvascular obstruction as measured by CMR after 3 - 7 days
timeFrame: 3 - 7 days after randomisation
measure: Final infarct size as measured by CMR 6 months after randomisation
timeFrame: 6 months after randomisation
measure: Left ventricular size as assessed by CMR 6 months after randomisation
timeFrame: 6 months after randomisation
measure: Baseline-adjusted NT-proBNP at 6 months after randomisation
timeFrame: 6 months after randomisation
measure: The AUC of Creatine Kinase-MB (CK-MB) during index hospitalisation
timeFrame: 24-72 hours after randomisation
measure: The AUC of C-reactive protein (CRP) during index hospitalisation
timeFrame: 24-72 hours after randomisation
Other outcomes:
Locations:
city: Oslo
country: Norway
facility: Oslo University Hospital, Rikshospitalet
city: Oslo
country: Norway
facility: Oslo University Hospital, Ullevål
city: Trondheim
country: Norway
facility: St. Olav Hospital
Study officials:
affiliation: Oslo University Hospital
name: Lars Gullestad, Professor, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Oslo University Hospital
name: Bjørn Bendz, Associate Professor, MD, PhD
role: STUDY_CHAIR
affiliation: Oslo University Hospital
name: Pål Aukrust, Professor, MD, PhD
role: STUDY_CHAIR
affiliation: Oslo University Hospital
name: Svend Aakhus, Professor, MD, PhD
role: STUDY_CHAIR
affiliation: St. Olavs Hospital
name: Rune Wiseth, Professor, MD, PhD
role: STUDY_CHAIR
affiliation: St. Olavs Hospital
name: Jan Kristian Damaas, Professor, MD, PhD
role: STUDY_CHAIR
affiliation: Oslo University Hospital, Ullevål
name: Geir Øystein Andersen, MD, PhD
role: STUDY_CHAIR
affiliation: Oslo University Hospital, Ullevål
name: Nils Einar Kløw, Professor, MD, PhD
role: STUDY_CHAIR
affiliation: Oslo University Hospital, Ullevål
name: Anders Opdahl, MD, PhD
role: STUDY_CHAIR
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