Effect of the Interleukin-6 Receptor Antagonist Tocilizumab in Non-ST Elevation Myocardial Infarction

Effect of the Interleukin-6 Receptor Antagonist Tocilizumab in Non-ST Elevation Myocardial Infarction - a Randomized, Double Blind, Placebo Controlled Study.

Acute coronary syndromes (ACS) are still associated with high morbidity and mortality, despite several improvements in their management. This may indicate that important pathogenic mechanisms contribute to both stable and unstable atherosclerotic disease mechanisms.

Based upon previous research, the investigators believe that providing a block in the damaging inflammatory loop though short term inhibition of Interleukin-6 receptor signalling, could be an attractive therapeutic target in ACS; and of particular interest in patients with non-ST elevation myocardial infarction (NSTEMI), a disease often characterized by widespread coronary inflammation with multiple unstable plaques.

The investigators hypothesize that a single administration of the anti-Interleukin 6 receptor antagonist Tocilizumab, in patients with NSTEMI, may interrupt the self-perpetuating inflammatory loops which could improve plaque stability, with potential secondary beneficial effects on myocardial damage.

This will be investigated in a randomized, double blind, placebo-controlled study, including a total of 120 patients.

Study Overview

• Status: Completed
• Conditions: Non-ST Elevation Myocardial Infarction
• Intervention / Treatment: Drug: NaCl 0.9% 100 ml; Drug: Tocilizumab 280 mg

• Study Type: Interventional
• Enrollment (Actual): 120
• Phase: Phase 2

Contacts and Locations

Study Locations

• Norway
  • Oslo, Norway, 0424
    • Oslo University Hospital
  • Sør-Trøndelag
    • Trondheim, Sør-Trøndelag, Norway, 7006
      • St Olavs hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• NSTEMI (ESC Type 1)
• Age 18-80 years
• Troponin T >/= 30 ng/ml
• Informed consent to participation

Exclusion Criteria:

• STEMI
• Known cardiac disease, except coronary disease (cardiomyopathy, heart failure with known EF < 45%, severe valvular heart disease attending regular follow-up, recent PCI/ACB (< 3 months))
• Hemodynamic and/or respiratory instability
• Cardiac arrest in acute phase
• Concurrent condition affecting/potentially affecting CRP (infection, malignancy, autoimmune disease)
• Recent major surgery (< 3 months)
• Recent/concurrent immunosuppressant treatment (< 2 weeks, except NSAIDs)
• Severe renal failure (eGFR < 30 ml/min)
• Pregnancy
• Contraindications to any study investigations and/or medication.
• Expected non-adherence to study protocol

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: NaCl 0.9% 100 ml	Drug: NaCl 0.9% 100 ml; Placebo
EXPERIMENTAL: Tocilizumab 280 mg; Intravenous infusion, 280 mg Tocilizumab (14 ml) added to 86 ml of 0.9% NaCl	Drug: Tocilizumab 280 mg; Intravenous administration of 280 mg Tocilizumab (14 ml), mixed with 86 ml 0.9% NaCl; Other Names: Brand name RoActemra (Roche); ATC: L04A C07

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
high sensitivity C-reactive protein Area under the curve (AUC)	0-56 hrs following inclusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
hs troponin T		0-56 hrs, 3 months and 6 months following inclusion
hs CRP		3 and 6 months following inclusion
pro-BNP		0-56 hrs, 3 and 6 months
Infarct size	Assessed by Echocardiography and MRI at 6 months	6 months
LV size	Assessed by echocardiography	acute phase (0-3 days), 6 months
LV function	Assessed by echocardiography, cardiac MRI at 6 months	acute phase (0-3 days), 6 months
Coronary flow reserve	Assesses coronary microvascular function - for 60 patients only.	acute phase (0-3 days), 6 months
Endothelial function	Assessed by tonometry	Acute phase (0-3 days) and 6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Other inflammatory pathways	TNF-alfa, IL-1, IL-6, IL-18, platelet-derived inflammatory mediators, anti-inflammatory cytokines etc	0-56 hrs, 3 monhts, 6 months

Collaborators and Investigators

• Sponsor: Oslo University Hospital
• Collaborators: University of Oslo; Norwegian University of Science and Technology; St. Olavs Hospital; South-Eastern Norway Regional Health Authority
• Investigators: Study Chair: Rune Wiseth, MD, PhD, St. Olavs Hospital; Study Chair: Pål Aukrust, MD, PhD, Oslo University Hospital; Study Chair: Jan K Damås, MD, PhD, St. Olavs Hospital

Publications and helpful links

General Publications

• Ueland T, Kleveland O, Michelsen AE, Wiseth R, Damas JK, Aukrust P, Gullestad L, Halvorsen B, Yndestad A. Serum PCSK9 is modified by interleukin-6 receptor antagonism in patients with hypercholesterolaemia following non-ST-elevation myocardial infarction. Open Heart. 2018 Sep 18;5(2):e000765. doi: 10.1136/openhrt-2017-000765. eCollection 2018.
• Kleveland O, Ueland T, Kunszt G, Bratlie M, Yndestad A, Broch K, Holte E, Ryan L, Amundsen BH, Bendz B, Aakhus S, Espevik T, Halvorsen B, Mollnes TE, Wiseth R, Gullestad L, Aukrust P, Damas JK. Interleukin-6 receptor inhibition with tocilizumab induces a selective and substantial increase in plasma IP-10 and MIP-1beta in non-ST-elevation myocardial infarction. Int J Cardiol. 2018 Nov 15;271:1-7. doi: 10.1016/j.ijcard.2018.04.136. Epub 2018 Jun 29.

Study record dates

Study Major Dates

• Study Start: August 1, 2011
• Primary Completion (ACTUAL): November 1, 2013
• Study Completion (ACTUAL): April 1, 2014

Study Registration Dates

• First Submitted: December 9, 2011
• First Submitted That Met QC Criteria: December 12, 2011
• First Posted (ESTIMATE): December 13, 2011

Study Record Updates

• Last Update Posted (ESTIMATE): May 19, 2014
• Last Update Submitted That Met QC Criteria: May 16, 2014
• Last Verified: May 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Ischemia; Pathologic Processes; Necrosis; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Myocardial Infarction; Infarction; Non-ST Elevated Myocardial Infarction
• Other Study ID Numbers: 2010/1971 [REK]; 2010-021953-37 (EUDRACT_NUMBER); 2010/1971 (REGISTRY: REK); 10/15070-4 (REGISTRY: SLV); 4947 (HSØ); 2010/19043 (OTHER: PVO)