ASSessing the Effect of Anti-IL-6 Treatment in Myocardial Infarction: The ASSAIL-MI Trial

NCT ID: NCT03004703

Last Updated: 2021-03-02

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 200 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-03-16
• Study Completion Date: 2021-02-10

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.

Conditions

Coronary Disease; Myocardial Infarction

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Active drug

Tocilizumab, 20 mg/ml; 14 ml (280 mg) dissolved in 100 ml NaCl 0.9 % i.v. once.

Group Type: EXPERIMENTAL

Tocilizumab

Intervention Type: DRUG

Active drug: Tocilizumab, 20 mg/ml; 14 ml (280 mg) dissolved in 100 ml NaCl 0.9 % i.v. once.

Placebo

Sodium chloride 0.9%; 100 ml i.v. once.

Group Type: PLACEBO_COMPARATOR

Sodium chloride 0.9%

Intervention Type: DRUG

Placebo: Sodium chloride 0.9%; 100 ml i.v. once.

Interventions

Tocilizumab

Active drug: Tocilizumab, 20 mg/ml; 14 ml (280 mg) dissolved in 100 ml NaCl 0.9 % i.v. once.

Intervention Type: DRUG

Sodium chloride 0.9%

Placebo: Sodium chloride 0.9%; 100 ml i.v. once.

Intervention Type: DRUG

Other Intervention Names

RoActemra®,; NaCl 0.9%

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

St. Olavs Hospital

OTHER

Sponsor Role: collaborator

South-Eastern Norway Regional Health Authority

OTHER

Sponsor Role: collaborator

University of Oslo

OTHER

Sponsor Role: collaborator

Norwegian University of Science and Technology

OTHER

Sponsor Role: collaborator

Oslo University Hospital

OTHER

Sponsor Role: lead

Responsible Party

Lars Gullestad

Profesor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Lars Gullestad, Professor, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Oslo University Hospital

Bjørn Bendz, Associate Professor, MD, PhD

Role: STUDY_CHAIR

Oslo University Hospital

Pål Aukrust, Professor, MD, PhD

Role: STUDY_CHAIR

Oslo University Hospital

Svend Aakhus, Professor, MD, PhD

Role: STUDY_CHAIR

Oslo University Hospital

Rune Wiseth, Professor, MD, PhD

Role: STUDY_CHAIR

St. Olavs Hospital

Jan Kristian Damaas, Professor, MD, PhD

Role: STUDY_CHAIR

St. Olavs Hospital

Geir Øystein Andersen, MD, PhD

Role: STUDY_CHAIR

Oslo University Hospital, Ullevål

Nils Einar Kløw, Professor, MD, PhD

Role: STUDY_CHAIR

Oslo University Hospital, Ullevål

Anders Opdahl, MD, PhD

Role: STUDY_CHAIR

Oslo University Hospital, Ullevål

Locations

Oslo University Hospital, Rikshospitalet

Oslo, , Norway

Oslo University Hospital, Ullevål

Oslo, , Norway

St. Olav Hospital

Trondheim, , Norway

Countries

Norway

References

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.

Reference Type: BACKGROUND

PMID: 27161611 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 4056048 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 17855673 (View on PubMed)

Libby P. Molecular bases of the acute coronary syndromes. Circulation. 1995 Jun 1;91(11):2844-50. doi: 10.1161/01.cir.91.11.2844. No abstract available.

Reference Type: BACKGROUND

PMID: 7758192 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 15843671 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 19936194 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 27412895 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 18669426 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 12925454 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 26265659 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 20182820 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 12975259 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 19368420 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 25236513 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 24509284 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 25179768 (View on PubMed)

Ibanez B, Macaya C, Sanchez-Brunete V, Pizarro G, Fernandez-Friera L, Mateos A, Fernandez-Ortiz A, Garcia-Ruiz JM, Garcia-Alvarez A, Iniguez A, Jimenez-Borreguero J, Lopez-Romero P, Fernandez-Jimenez R, Goicolea J, Ruiz-Mateos B, Bastante T, Arias M, Iglesias-Vazquez JA, Rodriguez MD, Escalera N, Acebal C, Cabrera JA, Valenciano J, Perez de Prado A, Fernandez-Campos MJ, Casado I, Garcia-Rubira JC, Garcia-Prieto J, Sanz-Rosa D, Cuellas C, Hernandez-Antolin R, Albarran A, Fernandez-Vazquez F, de la Torre-Hernandez JM, Pocock S, Sanz G, Fuster V. Effect of early metoprolol on infarct size in ST-segment-elevation myocardial infarction patients undergoing primary percutaneous coronary intervention: the Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction (METOCARD-CNIC) trial. Circulation. 2013 Oct 1;128(14):1495-503. doi: 10.1161/CIRCULATIONAHA.113.003653. Epub 2013 Sep 3.

Reference Type: BACKGROUND

PMID: 24002794 (View on PubMed)

Eitel I, Stiermaier T, Rommel KP, Fuernau G, Sandri M, Mangner N, Linke A, Erbs S, Lurz P, Boudriot E, Mende M, Desch S, Schuler G, Thiele H. Cardioprotection by combined intrahospital remote ischaemic perconditioning and postconditioning in ST-elevation myocardial infarction: the randomized LIPSIA CONDITIONING trial. Eur Heart J. 2015 Nov 21;36(44):3049-57. doi: 10.1093/eurheartj/ehv463. Epub 2015 Sep 17.

Reference Type: BACKGROUND

PMID: 26385956 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 21555455 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 1529875 (View on PubMed)

Lunde K, Solheim S, Aakhus S, Arnesen H, Abdelnoor M, Egeland T, Endresen K, Ilebekk A, Mangschau A, Fjeld JG, Smith HJ, Taraldsrud E, Grogaard HK, Bjornerheim R, Brekke M, Muller C, Hopp E, Ragnarsson A, Brinchmann JE, Forfang K. Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction. N Engl J Med. 2006 Sep 21;355(12):1199-209. doi: 10.1056/NEJMoa055706.

Reference Type: BACKGROUND

PMID: 16990383 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 15489082 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 26961520 (View on PubMed)

Kindberg KM, Broch K, Andersen GO, Anstensrud AK, Akra S, Woxholt S, Tollefsen IM, Ueland T, Amundsen BH, Klow NE, Halvorsen B, Dahl TB, Huse C, Murphy SL, Damas JK, Opdahl A, Wiseth R, Gullestad L, Aukrust P, Santos-Gallego C, Seljeflot I, Stokke MK, Helseth R. Neutrophil Extracellular Traps in ST-Segment Elevation Myocardial Infarction: Reduced by Tocilizumab and Associated With Infarct Size. JACC Adv. 2024 Aug 15;3(9):101193. doi: 10.1016/j.jacadv.2024.101193. eCollection 2024 Sep.

Reference Type: DERIVED

PMID: 39247678 (View on PubMed)

Woxholt S, Ueland T, Aukrust P, Anstensrud AK, Broch K, Tollefsen IM, Ryan L, Bendz B, Hopp E, Klow NE, Seljeflot I, Halvorsen B, Dahl TB, Huse C, Andersen GO, Gullestad L, Wiseth R, Amundsen BH, Damas JK, Kleveland O. Cytokine pattern in patients with ST-elevation myocardial infarction treated with the interleukin-6 receptor antagonist tocilizumab. Open Heart. 2023 Aug;10(2):e002301. doi: 10.1136/openhrt-2023-002301.

Reference Type: DERIVED

PMID: 37591633 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 33858620 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 31673391 (View on PubMed)

Other Identifiers

2016-002581-31

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

ASSAIL-MI 2.0

Identifier Type: -

Identifier Source: org_study_id