ZILTIVEKIMAB for Acute myocardial infarction (type 1)

Inclusion criteria

• {"criterion_text":"- Hospitalisation (a) for acute myocardial infarction with evidence of type 1 MI (b) by invasive angiography performed at site with PCI capabilities (c).\n- (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)\n- (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.\n- 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.\n- 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.\n- 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.\n- Age 18 years or above at the time of signing the informed consent.\n- 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).\n- (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.\n- (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.\n- (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.\n- (d) The sponsor may consider stopping recruitment of STEMI participants if these exceed 40% of the total expected study population\n- (e) Known before hospitalisation for index AMI.\n- (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.\n- (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)."}

Exclusion criteria

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

Primary endpoints

• {"endpoint_text":"- 5.Time to first occurrence of non-fatal MI (a,c)","definition_or_measurement_approach":"Time-to-first event analysis for non-fatal myocardial infarction. (See note (c) and (a) in protocol for event definitions and adjudication.)"}
• {"endpoint_text":"- 7.Time to first occurrence of non-fatal stroke (a,d)","definition_or_measurement_approach":"Time-to-first event for non-fatal stroke; includes ischaemic, haemorrhagic and undetermined strokes per note (d)."}
• {"endpoint_text":"- 10.(a) Based on EAC-confirmed events","definition_or_measurement_approach":"Events are adjudicated by an Event Adjudication Committee (EAC); primary analyses based on EAC-confirmed events."}
• {"endpoint_text":"- 11.(b) including undetermined cause of death","definition_or_measurement_approach":"All-cause or cardiovascular death endpoints include deaths of undetermined cause as specified (note b)."}
• {"endpoint_text":"- 12.(c) acute MI only","definition_or_measurement_approach":"Where indicated, MI endpoint limited to acute myocardial infarction events only (note c)."}
• {"endpoint_text":"- 13.(d) including ischaemic, haemorrhagic and undetermined stroke","definition_or_measurement_approach":"Stroke endpoint includes ischaemic, haemorrhagic and undetermined stroke types per note (d)."}
• {"endpoint_text":"- 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","definition_or_measurement_approach":"Time-to-first event composite of 4-component MACE; components are adjudicated (a) and include CV death (including undetermined cause per b), non-fatal MI (per c), non-fatal stroke (per d), and ischaemia-driven coronary revascularisation."}
• {"endpoint_text":"- 2.Number of CV death (a,b), non-fatal MI, non-fatal stroke or ischaemia-driven coronary revascularisation","definition_or_measurement_approach":"Event counts of the listed cardiovascular events; based on adjudicated events where specified."}
• {"endpoint_text":"- 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","definition_or_measurement_approach":"Time-to-first event composite using all-cause mortality and adjudicated non-fatal cardiovascular events."}
• {"endpoint_text":"- 4.Number of all-cause mortality (a,b), non-fatal MI (a,c), non-fatal stroke (a,d) or ischaemia-driven coronary revascularisation","definition_or_measurement_approach":"Counts of events (all-cause death, non-fatal MI, non-fatal stroke, ischaemia-driven revascularisation); adjudication per protocol."}
• {"endpoint_text":"- 6.Time to first occurrence of MI (c)","definition_or_measurement_approach":"Time-to-first myocardial infarction (as defined in note c)."}
• {"endpoint_text":"- 8.Time to first occurrence of stroke (d)","definition_or_measurement_approach":"Time-to-first stroke event including ischaemic, haemorrhagic and undetermined stroke (note d)."}
• {"endpoint_text":"- 9.Time to first occurence of ischaemia-driven coronary revascularisation","definition_or_measurement_approach":"Time-to-first ischaemia-driven coronary revascularisation (clinical decision-driven revascularisation)."}

Secondary endpoints

• {"endpoint_text":"- 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","definition_or_measurement_approach":"Time-to-first event for 3-component coronary MACE; components adjudicated."}
• {"endpoint_text":"- 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)","definition_or_measurement_approach":"Time-to-first event for expanded 5-component MACE including heart failure hospitalisation or urgent heart-failure visit."}
• {"endpoint_text":"- 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)","definition_or_measurement_approach":"Time-to-first heart failure composite endpoint including outpatient HF visits."}
• {"endpoint_text":"- 9.Time to occurrence of CV death (a,b)","definition_or_measurement_approach":"Time-to-event for cardiovascular death (including undetermined cause per note b)."}
• {"endpoint_text":"- 10.Time to occurrence of all-cause death (a,b)","definition_or_measurement_approach":"Time-to-event for death from any cause; adjudication notes (a) apply."}
• {"endpoint_text":"- 11.(a) Based on EAC-confirmed events","definition_or_measurement_approach":"Indicates secondary endpoints where analyses are restricted to events confirmed by the Event Adjudication Committee."}
• {"endpoint_text":"- 12.(b) including undetermined cause of death","definition_or_measurement_approach":"Specifies inclusion of deaths of undetermined cause in certain mortality endpoints."}
• {"endpoint_text":"- 13.(c) acute MI only","definition_or_measurement_approach":"Indicates analyses restricted to acute MI events only as per note c."}
• {"endpoint_text":"- 14.(d) including ischaemic, haemorrhagic and undetermined stroke","definition_or_measurement_approach":"Specifies stroke types included (ischaemic, haemorrhagic, undetermined) for relevant endpoints."}
• {"endpoint_text":"- 8.Time to first occurrence of a 2-component HF enpoint comprising: CV death (a, b), HF hospitalisation (a) or urgent HF visit (a)","definition_or_measurement_approach":"Time-to-first event for 2-component heart failure endpoint."}
• {"endpoint_text":"- 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)","definition_or_measurement_approach":"Time-to-first event for 3-component MACE including CV death, non-fatal MI and non-fatal stroke."}
• {"endpoint_text":"- 2.Number of CV death (a,b), non-fatal MI (a,c) or non-fatal stroke (a,d)","definition_or_measurement_approach":"Counts of adjudicated cardiovascular events (CV death, non-fatal MI, non-fatal stroke)."}
• {"endpoint_text":"- 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)","definition_or_measurement_approach":"Time-to-first event for composite MACE with all-cause mortality and adjudicated non-fatal events."}
• {"endpoint_text":"- 4.Number of all-cause mortality (a,b), non-fatal MI (a,c) or non-fatal stroke (a,d)","definition_or_measurement_approach":"Counts of all-cause death and adjudicated non-fatal cardiovascular events."}

Methods

• Direct-to-Patient (DTP) approach (third party: Marken Limited noted with duty 'Direct to Patient').
• Site-based recruitment at participating hospitals/clinics (country-specific site lists provided).
• Digital advertisement materials (country-specific digital adverts referenced in recruitment documents for multiple MSCs).
• Physical materials: posters and trifold brochures (country-specific recruitment advertisement poster and trifold documents exist for multiple MSCs).
• Participant-facing information materials including participant study booklets, device instruction storyboards and study intro movie scripts (country-specific subject information packages available).

Primary sponsor

Full Name

Novo Nordisk A/S

Organisation Type

Pharmaceutical company

Country Of Registered Address

Denmark

Contract research organisations

Name

Icon Clinical Research Limited

Responsibilities

Listed as third party with sponsor duties (codes present); role includes event adjudication supplier and other CRO-like responsibilities (specific textual duty values not fully detailed).

Name

4G Clinical B.V.

Responsibilities

RTSM/IWRS supplier

Name

Oracle Danmark ApS / Oracle Corp.

Responsibilities

Provider of ARGUS service

Name

Q Squared Solutions LLC

Responsibilities

Special laboratory- PK and ADA

Third parties

• {"country":"Netherlands","full_name":"Stichting EuroQol Research Foundation","duties_or_roles":"PRO-Copyright holder for EQ-5D-5L","organisation_type":"Patient organisation/association"}
• {"country":"United Kingdom","full_name":"Marken Limited","duties_or_roles":"Direct to Patient","organisation_type":"Pharmaceutical company"}
• {"country":"Denmark","full_name":"Oracle Danmark ApS","duties_or_roles":"provider of ARGUS service","organisation_type":"Non-Pharmaceutical company"}
• {"country":"Greece","full_name":"Affidea Piraeus Biopathological","duties_or_roles":"Ophthalmological examinations","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Ireland","full_name":"Icon Clinical Research Limited","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Oracle Corp.","duties_or_roles":"","organisation_type":"Non-Pharmaceutical company"}
• {"country":"Netherlands","full_name":"4G Clinical B.V.","duties_or_roles":"RTSM/IWRS supplier","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"Q Squared Solutions LLC","duties_or_roles":"Special laboratory- PK and ADA","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Duke Clinical And Translational Science Institute","duties_or_roles":"Academic Research Organization","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"Ireland","full_name":"Icon Clinical Research Limited","duties_or_roles":"Event Adjudication supplier","organisation_type":"Pharmaceutical company"}
• {"country":"Belgium","full_name":"International Drug Development Institute","duties_or_roles":"","organisation_type":"Laboratory/Research/Testing facility"}