ARTEMIS - Effects of ziltivekimab versus placebo on cardiovascular outcomes in patients with acute myocardial infarction.

Trial ID: 2023-506876-28-00
Protocol: EX6018-4979
Sponsor: Novo Nordisk A/S

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Diseases & Conditions

Acute myocardial infarction

Objectives

This study evaluates the efficacy and safety of ziltivekimab, a human monoclonal antibody directed against the interleukin-6 (IL-6) ligand, in patients following acute myocardial infarction (AMI), including both ST-elevation myocardial infarction (STEMI) and non-ST-elevation myocardial infarction (NSTEMI). The primary objective is to demonstrate the superiority of a loading dose of ziltivekimab administered subcutaneously versus placebo, followed by monthly subcutaneous maintenance dosing versus placebo, both added to standard of care, in reducing the risk of major adverse cardiovascular events (MACE) in participants with AMI. This objective addresses the critical need to reduce cardiovascular risk through inflammation reduction, as measured by high-sensitivity C-reactive protein (hs-CRP), in the early post-infarction period. The secondary objectives include: demonstrating the superiority of the same ziltivekimab regimen versus placebo in reducing the risk of coronary MACE and expanded MACE in participants with AMI; demonstrating superiority in reducing the risk of heart failure in participants with AMI; and demonstrating superiority in reducing mortality in participants with AMI. These secondary endpoints evaluate the broader cardiovascular protective effects of IL-6 inhibition when initiated as early as possible following myocardial infarction.

Participants

This clinical trial enrolled a total of **6570 participants** hospitalized for **type 1 acute myocardial infarction**, including both **ST-elevation myocardial infarction (STEMI)** and **non-ST-elevation myocardial infarction (NSTEMI)**. The study population consisted of adult participants aged 18 years and above at the time of informed consent, including both male and female subjects. Participants were required to have undergone invasive angiography performed at a site with percutaneous coronary intervention capabilities, with angiographic evidence supporting type 1 MI such as flow-limiting stenosis, thrombus, or plaque rupture features. The trial population was selected based on the presence of at least one additional cardiovascular risk factor or comorbidity, including any prior MI, prior coronary revascularization, diabetes mellitus treated with ongoing glucose-lowering agents, known chronic kidney disease with estimated glomerular filtration rate between 15 and 60 mL/min/1.73 m², prior ischemic stroke, known carotid artery disease or peripheral artery disease in the lower extremities, or multivessel coronary artery disease. For STEMI participants, relevant symptom onset related to the index AMI was required within 12 hours before hospitalization, with characteristic ECG changes showing ST-segment elevation in contiguous leads. For NSTEMI participants, relevant symptom onset or worsening was required within 24 hours before hospitalization, accompanied by elevated cardiac troponin levels above the 99th percentile upper reference limit. Randomization and administration of the study intervention were required as early as possible after the invasive procedure, within 36 hours of hospitalization for STEMI and within 72 hours for NSTEMI. The trial specifically excluded type 2 MI, type 4 MI related to procedural complications, and type 5 MI associated with coronary artery bypass grafting.

Plans and Procedures

This is a **phase IIIa**, **randomized**, **double-blind**, **placebo-controlled** clinical trial designed to evaluate the efficacy and safety of **ziltivekimab**, a human **monoclonal antibody** directed against the **interleukin-6 (IL-6)** ligand, in patients with **type 1 acute myocardial infarction** (including **ST-elevation myocardial infarction** and **non-ST-elevation myocardial infarction**). The investigational medicinal product is administered as a **solution for injection** via **subcutaneous** route. The study aims to demonstrate the superiority of ziltivekimab compared to placebo, both added to standard of care, in reducing the risk of **major adverse cardiovascular events** (MACE) when initiated as early as possible following acute myocardial infarction. The maximum treatment period is 22 months. The trial is expected to commence recruitment in August 2024 and conclude in September 2026.

The primary endpoint is the time to first occurrence of a 3-component MACE comprising **cardiovascular death** (including undetermined cause of death), **non-fatal myocardial infarction** (acute myocardial infarction only), and **non-fatal stroke** (including **ischaemic**, **haemorrhagic**, and undetermined stroke), based on Event Adjudication Committee-confirmed events. Additional primary endpoints include the number of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke; time to first occurrence of a composite MACE endpoint consisting of **all-cause mortality**, non-fatal myocardial infarction, and non-fatal stroke; time to first occurrence of non-fatal myocardial infarction and non-fatal stroke individually; and time to first occurrence of myocardial infarction and stroke (both fatal and non-fatal).

Secondary endpoints include time to first occurrence of a 3-component coronary MACE endpoint comprising cardiovascular death, non-fatal myocardial infarction, and **ischaemia-driven coronary revascularisation**; time to first occurrence of a 5-component expanded MACE endpoint comprising cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, ischaemia-driven coronary revascularisation, and **heart failure hospitalisation** or urgent heart failure visit; time to first occurrence of a 3-component heart failure endpoint comprising cardiovascular death, heart failure hospitalisation or urgent heart failure visit, and outpatient heart failure visit; time to occurrence of cardiovascular death; and time to occurrence of all-cause death. All secondary endpoints are based on Event Adjudication Committee-confirmed events.

Eligible participants are adults aged 18 years or above hospitalized for acute myocardial infarction with evidence of type 1 myocardial infarction confirmed by **invasive angiography** performed at a site with **percutaneous coronary intervention** capabilities. For **ST-elevation myocardial infarction**, relevant onset of symptoms suggestive of cardiac **ischaemia** must occur no longer than 12 hours before hospitalization, with **electrocardiogram** changes showing **ST-segment elevation** at the J point in at least two contiguous leads. For non-ST-elevation myocardial infarction, relevant onset or worsening of symptoms must occur no longer than 24 hours before hospitalization, with rise and/or fall in cardiac **troponin** I or T with at least one value above the 99th percentile upper reference limit. Participants must have at least one of the following criteria: any prior myocardial infarction, prior coronary revascularisation, **diabetes mellitus** treated with ongoing glucose-lowering agents, known **chronic kidney disease** (estimated glomerular filtration rate ≥15 and <60 mL/min/1.73 m²), prior **ischaemic stroke**, known **carotid artery disease** or **peripheral artery disease** in the lower extremities, or **multivessel coronary artery disease**.

The study involves a screening and inclusion visit during hospitalization for the index acute myocardial infarction. Randomization and administration of the first dose of study intervention must occur as early as possible after the invasive procedure, and no later than 36 hours of hospitalization for ST-elevation myocardial infarction or 72 hours of hospitalization for non-ST-elevation myocardial infarction. Hospitalization is defined as the first hospital contact with physical presence by the patient, where the patient is registered as actively present in the hospital system, including but not limited to waiting area, emergency room, coronary care unit, internal medicine, or other department. Following the initial dose, ziltivekimab is administered once monthly via subcutaneous injection for up to 22 months. Participants will attend scheduled follow-up visits throughout the study period to assess efficacy and safety outcomes, including the occurrence of major adverse cardiovascular events. An end-of-study visit will be conducted upon completion of the treatment period or upon early termination. Early termination from the study may occur due to withdrawal of consent, safety concerns, protocol violations, or other conditions as determined by the investigator or sponsor.

Treatment

The experimental treatment consists of **ziltivekimab**, a protein-based therapeutic agent manufactured by Novo Nordisk A/S. Ziltivekimab is administered as a **solution for injection** via the **subcutaneous route**. The treatment regimen involves an initial loading dose followed by monthly maintenance dosing. The maximum treatment period is 22 months. Ziltivekimab is added to **standard of care** therapy in participants with **acute myocardial infarction**.

The comparator treatment is **placebo**, which is administered according to the same dosing schedule and route of administration as the experimental medication to maintain blinding integrity throughout the trial. Placebo is also added to standard of care therapy. Both treatment arms receive standard of care therapy for acute myocardial infarction in addition to the assigned investigational product or placebo.

Efficacy

Efficacy will be assessed through multiple cardiovascular endpoints evaluated over the course of the trial. The primary efficacy endpoints include time to first occurrence of a 3-component **major adverse cardiovascular event (MACE)** endpoint comprising cardiovascular death (including undetermined cause of death), non-fatal myocardial infarction (acute MI only), and non-fatal stroke (including ischaemic, haemorrhagic and undetermined stroke). Additionally, the number of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke will be evaluated. A composite MACE endpoint consisting of all-cause mortality (including undetermined cause of death), non-fatal myocardial infarction, and non-fatal stroke will also be assessed, along with the number of all-cause mortality, non-fatal myocardial infarction or non-fatal stroke. Further primary endpoints include time to first occurrence of non-fatal myocardial infarction, time to first occurrence of myocardial infarction (fatal and non-fatal), time to first occurrence of non-fatal stroke, and time to first occurrence of stroke (fatal and non-fatal, including ischaemic, haemorrhagic and undetermined stroke). All primary efficacy assessments are based on events confirmed by an endpoint adjudication committee.

Secondary efficacy endpoints include time to first occurrence of a 3-component coronary MACE endpoint comprising cardiovascular death (including undetermined cause of death), non-fatal myocardial infarction (acute MI only), and ischaemia-driven coronary revascularisation. A 5-component expanded MACE endpoint will assess time to first occurrence of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke (including ischaemic, haemorrhagic and undetermined stroke), ischaemia-driven coronary revascularisation, and **heart failure** hospitalisation or urgent heart failure visit. Time to first occurrence of a 3-component heart failure endpoint comprising cardiovascular death, heart failure hospitalisation or urgent heart failure visit, and outpatient heart failure visit will be evaluated. Additional secondary endpoints include time to occurrence of cardiovascular death and time to occurrence of all-cause death. All secondary efficacy assessments are based on events confirmed by an endpoint adjudication committee.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Hospitalisation (a) for acute myocardial infarction with evidence of type 1 MI (b) by invasive angiography performed at site with PCI capabilities (c).
Presence of at least one of the following criteria confirmed based on the participant’s medical records and/or medical history interview: Any prior MI (e), Prior coronary revascularisation (f), Diabetes mellitus treated with ongoing glucose-lowering agent(s) (e), Known CKD (eGFR ≥15 and <60 mL/min/1.73 m2) (g), Prior ischaemic stroke (e), Known carotid disease or peripheral artery disease in the lower extremities (h), Multivessel coronary artery disease (current/prior) (i).
(a) Hospitalisation equals time 0 and is defined as first hospital contact with physical presence by the patient, where the patient is registered as actively present in the hospital system included but not restricted to waiting area, emergency room, coronary care unit, internal medicine or other department, depending on country/region.
(b) Angiographic signs supporting the clinical suspicion of a type 1 MI including but not limited to: A flow-limiting stenosis not present at the site of a prior stent. A relevant stenosis with features suggesting a thrombus/plaque rupture such as luminal irregularities, thrombus-looking appearance, or haziness. Type 1 MI excludes type 2 MI (including but not limited to significant gastrointestinal bleedings, anaemia and sepsis), and type 4 MI (a-c: periprocedural (PCI) MI, stent thrombosis and in-stent restenosis) and type 5 MI (periprocedural (CABG) MI). Interpretation of the above is at the discretion of the investigator.
(c) If the participant experienced a recent AMI (within 30 days) before the index AMI, investigator must ensure that the current index AMI is considered a new AMI i.e. in a different culprit vessel compared to the recent AMI. This must be confirmed based on angiographic findings. Comparisons of ECG findings between recent AMI and current index AMI is not considered sufficient for the evaluation.
(d) The sponsor may consider stopping recruitment of STEMI participants if these exceed 40% of the total expected study population
(e) Known before hospitalisation for index AMI.
(f) The documented presence of a coronary stent on the coronary angiogram performed for the current (index) AMI is acceptable to define prior coronary revascularisation.
(g) Defined as 1) previous formal diagnosis of CKD or 2) previous ≥ 2 results of consistently reduced GFR with supplementary information in records supporting that this was in a clinical setting without factors that could affect kidney function (i.e. and not limited to: acute or post-interventions situations or initiation of new medications).
(h) Carotid artery disease defined as 1) ≥50% stenosis in carotid artery documented by angiography, MR angiography, CT angiography or Doppler ultrasound or 2) prior carotid artery revascularization procedure. Peripheral artery disease in lower extremities defined as 1) ≥50% stenosis in peripheral artery in lower extremities documented by angiography, MR angiography, CT angiography or Doppler ultrasound, 2) prior peripheral artery revascularization procedure or 3) lower extremity amputation at or above ankle due to atherosclerotic disease (excluding e.g. trauma or osteomyelitis)
(i) Defined as ≥50% stenosis on 2 or more epicardial artery territories or the left main artery during a prior cardiac catheterisation or cardiac catheterisation during the current AMI, or prior percutaneous coronary intervention (PCI) and ≥50% stenosis of at least 1 epicardial artery territory different from the prior revascularised artery, or prior multivessel coronary bypass grafting.
ST-segment elevation myocardial infarction with all the following (d): Relevant onset of symptoms suggestive of cardiac ischaemia related to the index AMI, no longer than within 12 hours before hospitalisation, at the investigator's discretion. ECG-changes (in the absence of left ventricular hypertrophy or left bundle branch block): ST-segment elevation at the J point in at least two contiguous leads ≥0.25 mV in men <40 years, ≥0.2 mV in men ≥40 years, or ≥0.15 mV in women in leads V2-V3; and/or ≥0.1 mV in all other leads.
Or Non-ST-segment myocardial infarction with all the following: Relevant onset or worsening of symptoms suggestive of cardiac ischaemia related to the index AMI, no longer than within 24 hours before hospitalisation, at the investigator's discretion. Rise and/or fall in cardiac troponin I or T with at least one value above the 99th percentile upper reference limit.
Possibility for both randomisation and administration of the CCI of study intervention as early as possible after invasive procedure, and latest within 36 hours of hospitalisation (time 0) for STEMI, and latest within 72 hours of hospitalisation (time 0) for NSTEMI.
Age 18 years or above at the time of signing the informed consent.

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Exclusion Criteria

Use of fibrinolytic therapy for treatment of the current AMI.
History or evidence of untreated latent tuberculosis (TB) such as (but not limited to): History of a positive TB test or chest X-ray compatible with latent TB; and TB treatment initiated less than 28 days prior to randomisation. Participants with TB risk factors (see details in Section 8.2.6)but unwilling to undergo TB treatment if confirmed positive for latent TB based on central laboratory test at baseline (visit 2)
(a) Participants with increased levels of ALT ≤8 x ULN are eligible at the discretion of the investigator if the investigator considers the ALT elevations to be caused by the current AMI. In case the elevation is considered related to other reasons than the current AMI, participants should be excluded when ALT >2.5 x ULN.
(b) Endoscopic procedure for screening purposes such as gastroscopy and colonoscopy are allowed if there is no suspicion of malignant disease driving the referral.
(c) Screening for (acute and chronic) hepatitis B and C should focus on health status (reported by participant and clinical examination) and review of already available medical records including laboratory samples, defined as: For hepatitis B: positive HBsAg and/or positive anti-HBc with detectable HBV DNA. Note: participants with positive anti-HBc and undetectable HBV DNA can be enrolled and should, following central laboratory result, be handled according to Section ‎8.2.7.2. For hepatitis C: positive anti-HCV and detectable HCV RNA.
Chronic heart failure classified as being in New York Heart Association (NYHA) Class IV
Ongoing haemodynamic instability defined as any of the following: Killip Class III or IV, Sustained and/or symptomatic hypotension (systolic blood pressure <90 mmHg)
Severe kidney impairment defined as any of the following: eGFR <15 mL/min/1.73 m2, Chronic haemodialysis or peritoneal dialysis.
Known ALT >8 x ULN(a)
Severe hepatic disease defined as at least one of the following: Previously known or current hepatic encephalopathy (clinical evaluation), Previously known or current ascites (clinical evaluation), Jaundice (clinical evaluation), Previous oesophageal/gastric variceal bleeding, Known hepatic cirrhosis
Major cardiac surgical (including but not restricted to coronary artery bypass graft surgery [CABG]), non-cardiac surgical, or major endoscopic procedure(b) (thoracoscopic or laparoscopic) within the past 60 days or any major surgical procedure planned at the time of randomisation or as treatment for the current AMI (CABG). Deferred (staged) percutaneous coronary intervention for a non-culprit vessel identified during the current AMI is allowed.
Clinical evidence of, or suspicion of, active infection at the discretion of the investigator (c).
Known (acute or chronic) hepatitis B or hepatitis C (c)

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Bulgaria	Not Recruiting	15 Aug 2024	600
Czechia	Not Recruiting	15 Aug 2024	280
Denmark	Not Recruiting	15 Aug 2024	195
France	Not Recruiting	15 Aug 2024	277
Germany	Not Recruiting	15 Aug 2024	154
Greece	Not Recruiting	15 Aug 2024	380
Italy	Not Recruiting	15 Aug 2024	551
The Netherlands	Not Recruiting	15 Aug 2024	—
Poland	Not Recruiting	15 Aug 2024	838
Spain	Not Recruiting	15 Aug 2024	340