- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03004703
ASSessing the Effect of Anti-IL-6 Treatment in Myocardial Infarction: The ASSAIL-MI Trial (ASSAIL-MI)
Study Overview
Status
Conditions
Intervention / Treatment
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.
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
-
-
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Oslo, Norway, 0424
- Oslo University Hospital, Rikshospitalet
-
Oslo, Norway, 0424
- Oslo University Hospital, Ullevål
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Trondheim, Norway, 7006
- St. Olav Hospital
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Active drug
Tocilizumab, 20 mg/ml; 14 ml (280 mg) dissolved in 100 ml NaCl 0.9 % i.v.
once.
|
Active drug: Tocilizumab, 20 mg/ml; 14 ml (280 mg) dissolved in 100 ml NaCl 0.9 % i.v.
once.
Other Names:
|
Placebo Comparator: Placebo
Sodium chloride 0.9%; 100 ml i.v.
once.
|
Placebo: Sodium chloride 0.9%; 100 ml i.v.
once.
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
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).
Time Frame: 6 months
|
6 months
|
Secondary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
The between-group difference in the AUC for Troponin T (TnT) during index hospitalisation
Time Frame: 24 -72 hours after randomisation
|
24 -72 hours after randomisation
|
The extent of microvascular obstruction as measured by CMR after 3 - 7 days
Time Frame: 3 - 7 days after randomisation
|
3 - 7 days after randomisation
|
Final infarct size as measured by CMR 6 months after randomisation
Time Frame: 6 months after randomisation
|
6 months after randomisation
|
Left ventricular size as assessed by CMR 6 months after randomisation
Time Frame: 6 months after randomisation
|
6 months after randomisation
|
Baseline-adjusted NT-proBNP at 6 months after randomisation
Time Frame: 6 months after randomisation
|
6 months after randomisation
|
The AUC of Creatine Kinase-MB (CK-MB) during index hospitalisation
Time Frame: 24-72 hours after randomisation
|
24-72 hours after randomisation
|
The AUC of C-reactive protein (CRP) during index hospitalisation
Time Frame: 24-72 hours after randomisation
|
24-72 hours after randomisation
|
Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Lars Gullestad, Professor, MD, PhD, Oslo University Hospital
- Study Chair: Bjørn Bendz, Associate Professor, MD, PhD, Oslo University Hospital
- Study Chair: Pål Aukrust, Professor, MD, PhD, Oslo University Hospital
- Study Chair: Svend Aakhus, Professor, MD, PhD, Oslo University Hospital
- Study Chair: Rune Wiseth, Professor, MD, PhD, St. Olavs Hospital
- Study Chair: Jan Kristian Damaas, Professor, MD, PhD, St. Olavs Hospital
- Study Chair: Geir Øystein Andersen, MD, PhD, Oslo University Hospital, Ullevål
- Study Chair: Nils Einar Kløw, Professor, MD, PhD, Oslo University Hospital, Ullevål
- Study Chair: Anders Opdahl, MD, PhD, Oslo University Hospital, Ullevål
Publications and helpful links
General Publications
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- Rector TS, Cohn JN. Assessment of patient outcome with the Minnesota Living with Heart Failure questionnaire: reliability and validity during a randomized, double-blind, placebo-controlled trial of pimobendan. Pimobendan Multicenter Research Group. Am Heart J. 1992 Oct;124(4):1017-25. doi: 10.1016/0002-8703(92)90986-6.
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- Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med. 2007 Sep 13;357(11):1121-35. doi: 10.1056/NEJMra071667. No abstract available.
- Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005 Apr 21;352(16):1685-95. doi: 10.1056/NEJMra043430. No abstract available.
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- Deftereos S, Giannopoulos G, Angelidis C, Alexopoulos N, Filippatos G, Papoutsidakis N, Sianos G, Goudevenos J, Alexopoulos D, Pyrgakis V, Cleman MW, Manolis AS, Tousoulis D, Lekakis J. Anti-Inflammatory Treatment With Colchicine in Acute Myocardial Infarction: A Pilot Study. Circulation. 2015 Oct 13;132(15):1395-403. doi: 10.1161/CIRCULATIONAHA.115.017611. Epub 2015 Aug 11.
- Piot C, Croisille P, Staat P, Thibault H, Rioufol G, Mewton N, Elbelghiti R, Cung TT, Bonnefoy E, Angoulvant D, Macia C, Raczka F, Sportouch C, Gahide G, Finet G, Andre-Fouet X, Revel D, Kirkorian G, Monassier JP, Derumeaux G, Ovize M. Effect of cyclosporine on reperfusion injury in acute myocardial infarction. N Engl J Med. 2008 Jul 31;359(5):473-81. doi: 10.1056/NEJMoa071142.
- Kleveland O, Kunszt G, Bratlie M, Ueland T, Broch K, Holte E, Michelsen AE, Bendz B, Amundsen BH, Espevik T, Aakhus S, Damas JK, Aukrust P, Wiseth R, Gullestad L. Effect of a single dose of the interleukin-6 receptor antagonist tocilizumab on inflammation and troponin T release in patients with non-ST-elevation myocardial infarction: a double-blind, randomized, placebo-controlled phase 2 trial. Eur Heart J. 2016 Aug 7;37(30):2406-13. doi: 10.1093/eurheartj/ehw171. Epub 2016 May 8.
- Braunwald E, Kloner RA. Myocardial reperfusion: a double-edged sword? J Clin Invest. 1985 Nov;76(5):1713-9. doi: 10.1172/JCI112160. No abstract available.
- Hou T, Tieu BC, Ray S, Recinos Iii A, Cui R, Tilton RG, Brasier AR. Roles of IL-6-gp130 Signaling in Vascular Inflammation. Curr Cardiol Rev. 2008 Aug;4(3):179-92. doi: 10.2174/157340308785160570.
- Ritschel VN, Seljeflot I, Arnesen H, Halvorsen S, Eritsland J, Fagerland MW, Andersen GO. Circulating Levels of IL-6 Receptor and gp130 and Long-Term Clinical Outcomes in ST-Elevation Myocardial Infarction. J Am Heart Assoc. 2016 Jun 13;5(6):e003014. doi: 10.1161/JAHA.115.003014.
- Granger CB, Mahaffey KW, Weaver WD, Theroux P, Hochman JS, Filloon TG, Rollins S, Todaro TG, Nicolau JC, Ruzyllo W, Armstrong PW; COMMA Investigators. Pexelizumab, an anti-C5 complement antibody, as adjunctive therapy to primary percutaneous coronary intervention in acute myocardial infarction: the COMplement inhibition in Myocardial infarction treated with Angioplasty (COMMA) trial. Circulation. 2003 Sep 9;108(10):1184-90. doi: 10.1161/01.CIR.0000087447.12918.85. Epub 2003 Aug 18.
- Biasillo G, Leo M, Della Bona R, Biasucci LM. Inflammatory biomarkers and coronary heart disease: from bench to bedside and back. Intern Emerg Med. 2010 Jun;5(3):225-33. doi: 10.1007/s11739-010-0361-1. Epub 2010 Feb 25.
- Kinlay S, Schwartz GG, Olsson AG, Rifai N, Leslie SJ, Sasiela WJ, Szarek M, Libby P, Ganz P; Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering Study Investigators. High-dose atorvastatin enhances the decline in inflammatory markers in patients with acute coronary syndromes in the MIRACL study. Circulation. 2003 Sep 30;108(13):1560-6. doi: 10.1161/01.CIR.0000091404.09558.AF. Epub 2003 Sep 15.
- Oldfield V, Dhillon S, Plosker GL. Tocilizumab: a review of its use in the management of rheumatoid arthritis. Drugs. 2009;69(5):609-32. doi: 10.2165/00003495-200969050-00007.
- Eitel I, de Waha S, Wohrle J, Fuernau G, Lurz P, Pauschinger M, Desch S, Schuler G, Thiele H. Comprehensive prognosis assessment by CMR imaging after ST-segment elevation myocardial infarction. J Am Coll Cardiol. 2014 Sep 23;64(12):1217-26. doi: 10.1016/j.jacc.2014.06.1194.
- Erlinge D, Gotberg M, Lang I, Holzer M, Noc M, Clemmensen P, Jensen U, Metzler B, James S, Botker HE, Omerovic E, Engblom H, Carlsson M, Arheden H, Ostlund O, Wallentin L, Harnek J, Olivecrona GK. Rapid endovascular catheter core cooling combined with cold saline as an adjunct to percutaneous coronary intervention for the treatment of acute myocardial infarction. The CHILL-MI trial: a randomized controlled study of the use of central venous catheter core cooling combined with cold saline as an adjunct to percutaneous coronary intervention for the treatment of acute myocardial infarction. J Am Coll Cardiol. 2014 May 13;63(18):1857-65. doi: 10.1016/j.jacc.2013.12.027. Epub 2014 Feb 5.
- Atar D, Arheden H, Berdeaux A, Bonnet JL, Carlsson M, Clemmensen P, Cuvier V, Danchin N, Dubois-Rande JL, Engblom H, Erlinge D, Firat H, Halvorsen S, Hansen HS, Hauke W, Heiberg E, Koul S, Larsen AI, Le Corvoisier P, Nordrehaug JE, Paganelli F, Pruss RM, Rousseau H, Schaller S, Sonou G, Tuseth V, Veys J, Vicaut E, Jensen SE. Effect of intravenous TRO40303 as an adjunct to primary percutaneous coronary intervention for acute ST-elevation myocardial infarction: MITOCARE study results. Eur Heart J. 2015 Jan 7;36(2):112-9. doi: 10.1093/eurheartj/ehu331. Epub 2014 Sep 1.
- Galderisi M, Henein MY, D'hooge J, Sicari R, Badano LP, Zamorano JL, Roelandt JR; European Association of Echocardiography. Recommendations of the European Association of Echocardiography: how to use echo-Doppler in clinical trials: different modalities for different purposes. Eur J Echocardiogr. 2011 May;12(5):339-53. doi: 10.1093/ejechocard/jer051.
- Gibbons RJ, Valeti US, Araoz PA, Jaffe AS. The quantification of infarct size. J Am Coll Cardiol. 2004 Oct 19;44(8):1533-42. doi: 10.1016/j.jacc.2004.06.071.
- Engblom H, Heiberg E, Erlinge D, Jensen SE, Nordrehaug JE, Dubois-Rande JL, Halvorsen S, Hoffmann P, Koul S, Carlsson M, Atar D, Arheden H. Sample Size in Clinical Cardioprotection Trials Using Myocardial Salvage Index, Infarct Size, or Biochemical Markers as Endpoint. J Am Heart Assoc. 2016 Mar 9;5(3):e002708. doi: 10.1161/JAHA.115.002708.
- Broch K, Anstensrud AK, Woxholt S, Sharma K, Tollefsen IM, Bendz B, Aakhus S, Ueland T, Amundsen BH, Damas JK, Berg ES, Bjorkelund E, Bendz C, Hopp E, Kleveland O, Stensaeth KH, Opdahl A, Klow NE, Seljeflot I, Andersen GO, Wiseth R, Aukrust P, Gullestad L. Randomized Trial of Interleukin-6 Receptor Inhibition in Patients With Acute ST-Segment Elevation Myocardial Infarction. J Am Coll Cardiol. 2021 Apr 20;77(15):1845-1855. doi: 10.1016/j.jacc.2021.02.049.
- Anstensrud AK, Woxholt S, Sharma K, Broch K, Bendz B, Aakhus S, Ueland T, Amundsen BH, Damas JK, Hopp E, Kleveland O, Stensaeth KH, Opdahl A, Klow NE, Seljeflot I, Andersen GO, Wiseth R, Aukrust P, Gullestad L. Rationale for the ASSAIL-MI-trial: a randomised controlled trial designed to assess the effect of tocilizumab on myocardial salvage in patients with acute ST-elevation myocardial infarction (STEMI). Open Heart. 2019 Oct 15;6(2):e001108. doi: 10.1136/openhrt-2019-001108. eCollection 2019.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- ASSAIL-MI 2.0
- 2016-002581-31 (EudraCT Number)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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