ARTEMIS - A research study to look at how ziltivekimab works compared to placebo in people who have had a heart attack

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Novo Nordisk A/S

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

1 Aug 2024 → ongoing

Decision date (initial)

2024-07-30

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Novo Nordisk A/S

External identifiers

EU CT number

2023-506876-28-00

WHO UTN

U1111-1294-3473

ClinicalTrials.gov

NCT06118281

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To demonstrate the superiority of a CCI of ziltivekimab CCI s.c. vs placebo followed by ziltivekimab CCI s.c. once monthly versus placebo, both added to standard of care, in reducing the risk of 4-component MACE in participants with AMI

Secondary objectives 4

1. 1.To demonstrate the superiority of a CCI of ziltivekimab CCI s.c. vs placebo followed by ziltivekimab CCI s.c. Once-monthly versus placebo, both added to standard of care, in reducing the risk of 3-component MACE in participants with AMI
2. 3.To demonstrate the superiority of a CCI ziltivekimab CCI s.c. vs placebo followed by ziltivekimab CCI s.c. once monthly versus placebo, both added to standard of care, in reducing the risk of heart failure (HF) in participants with AMI.
3. 4.To demonstrate the superiority of a CCI of ziltivekimab CCI s.c. vs placebo followed by ziltivekimab CCI s.c. once monthly versus placebo, both added to standard of care, in reducing mortality in participants with AMI.
4. 2.To demonstrate the superiority of a CCI of ziltivekimab CCI s.c. vs placebo followed by ziltivekimab CCI s.c. oncemonthly versus placebo, both added to standard of care, in reducing the risk of coronary MACE and expanded MACE in participants with AMI.

Conditions and MedDRA coding

The medical condition we are investigating is type 1 AMI (STEMI and NSTEMI). Ziltivekimab is a human monoclonal antibody directed against the interleukin-6 (IL-6) ligand, and currently available clinical data support that ziltivekimab once-monthly reduces inflammation as measured by highsensitivity C-reactive protein (hs-CRP). With the recent proof-of-concept that hs-CRP reduction through inhibition of an upstream pathway leads to reduction in cardiovascular events, it is reasonable to expect that similar inhibition of IL-6 with ziltivekimab also reduces CV risk.The aim of the current study is to demonstrate the efficacy and safety of ziltivekimab in reducing the risk of major adverse cardiovascular events when initiated as early as possible in adult patients with ST-elevation and non-ST-elevation myocardial infarction

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-002840-PIP01-20

Plan to share IPD

No

IPD plan description

N/A

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 15

1. Hospitalisation (a) for acute myocardial infarction with evidence of type 1 MI (b) by invasive angiography performed at site with PCI capabilities (c).
2. 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).
3. (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.
4. (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.
5. (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.
6. (d) The sponsor may consider stopping recruitment of STEMI participants if these exceed 40% of the total expected study population
7. (e) Known before hospitalisation for index AMI.
8. (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.
9. (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).
10. (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)
11. (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.
12. 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.
13. 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.
14. 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.
15. Age 18 years or above at the time of signing the informed consent.

Exclusion criteria 13

1. Use of fibrinolytic therapy for treatment of the current AMI.
2. 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)
3. (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.
4. (b) Endoscopic procedure for screening purposes such as gastroscopy and colonoscopy are allowed if there is no suspicion of malignant disease driving the referral.
5. (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.
6. Chronic heart failure classified as being in New York Heart Association (NYHA) Class IV
7. Ongoing haemodynamic instability defined as any of the following: Killip Class III or IV, Sustained and/or symptomatic hypotension (systolic blood pressure <90 mmHg)
8. Severe kidney impairment defined as any of the following: eGFR <15 mL/min/1.73 m2, Chronic haemodialysis or peritoneal dialysis.
9. Known ALT >8 x ULN(a)
10. 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
11. 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.
12. Clinical evidence of, or suspicion of, active infection at the discretion of the investigator (c).
13. Known (acute or chronic) hepatitis B or hepatitis C (c)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 13

1. 5.Time to first occurrence of non-fatal MI (a,c)
2. 7.Time to first occurrence of non-fatal stroke (a,d)
3. 10.(a) Based on EAC-confirmed events
4. 11.(b) including undetermined cause of death
5. 12.(c) acute MI only
6. 13.(d) including ischaemic, haemorrhagic and undetermined stroke
7. 1. Time to first occurence of a 4-component MACE endpoint comprising: CV death (a,b), Non-fatal MI (a,c), Non-fatal stroke (a,d), Ischaemia-driven coronary revascularisation
8. 2.Number of CV death (a,b), non-fatal MI, non-fatal stroke or ischaemia-driven coronary revascularisation
9. 3.Time to first occurrence of a composite MACE endpoint consisting of: All-cause mortality (a,b), Non-fatal MI (a,c), Non-fatal stroke (a,d), Ischaemia-driven coronary revascularisation
10. 4.Number of all-cause mortality (a,b), non-fatal MI (a,c), non-fatal stroke (a,d) or ischaemia-driven coronary revascularisation
11. 6.Time to first occurrence of MI (c)
12. 8.Time to first occurrence of stroke (d)
13. 9.Time to first occurence of ischaemia-driven coronary revascularisation

Secondary endpoints 14

1. 5.Time to first occurrence of a 3-component coronary MACE endpoint comprising: CV death (a,b), Non-fatal MI (a,c), Ischaemia-driven coronary revascularisation
2. 6.Time to first occurrence of a 5-component expanded MACE endpoint comprising: CV death (a,b), non-fatal MI (a,c), non-fatal stroke (a,d), Ischaemia-driven coronary revacularisation, HF hospitalisation (a) or urgent HF visit (a)
3. 7.Time to first occurrence of a 3-component HF endpoint comprising: CV death (a,b), HF hospitalisation (a) or urgent HF visit (a), Outpatient HF visit (a)
4. 9.Time to occurrence of CV death (a,b)
5. 10.Time to occurrence of all-cause death (a,b)
6. 11.(a) Based on EAC-confirmed events
7. 12.(b) including undetermined cause of death
8. 13.(c) acute MI only
9. 14.(d) including ischaemic, haemorrhagic and undetermined stroke
10. 8.Time to first occurrence of a 2-component HF enpoint comprising: CV death (a, b), HF hospitalisation (a) or urgent HF visit (a)
11. 1.Time to first occurrence of a 3-component MACE endpoint comprising: CV death (a,b), Non-fatal MI (a,c), Non-fatal stroke (a,d)
12. 2.Number of CV death (a,b), non-fatal MI (a,c) or non-fatal stroke (a,d)
13. 3.Time to first occurrence of a composite MACE endpoint consisting of: All-cause mortality (a,b), Non-fatal MI (a,c), Non-fatal stroke (a,d)
14. 4.Number of all-cause mortality (a,b), non-fatal MI (a,c) or non-fatal stroke (a,d)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Novo Nordisk A/S

Sponsor organisation

Novo Nordisk A/S

Address

Novo Alle 1

City

Bagsvaerd

Postcode

2880

Country

Denmark

Scientific contact point

Organisation

Novo Nordisk A/S

Contact name

EU submission Hub

Public contact point

Organisation

Novo Nordisk A/S

Contact name

EU submission Hub

Third parties 11

Locations

10 EU/EEA countries · 233 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 142 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications