Ziltivekimab to reduce plaque in heart arteries after a heart attack

Effects of Ziltivekimab Versus Placebo on Coronary Atherosclerosis in Patients With Acute Myocardial Infarction. A Serial, Multivessel, Intravascular Ultrasound, Near-infrared Spectroscopy and Optical Coherence Tomography Imaging Study

This trial will test whether ziltivekimab can reduce plaque in the heart's blood vessels in adults who recently had a heart attack.

Quick facts

• Phase: PHASE3
• Study type: Interventional
• Enrollment: 332 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Novo Nordisk A/S (industry)
• Drugs / interventions: methotrexate, ziltivekimab
• Locations: 20 sites (Vienna and 19 other locations)
• Trial ID: NCT07301034 on ClinicalTrials.gov

What this trial studies

This randomized, double-blind, placebo-controlled Phase 3 trial gives adults who recently had an acute myocardial infarction either ziltivekimab or a matching placebo and follows them for about 15 months. Eligible participants must have had at least one coronary segment (the culprit lesion) treated with percutaneous coronary intervention (PCI) and will undergo imaging to measure changes in atherosclerotic plaque. Treatment is assigned by chance and both participants and investigators are blinded to assignment. The study is sponsored by Novo Nordisk and is conducted at multiple academic sites in Europe.

Who should consider this trial

Good fit: Adults aged 18 or older who recently experienced an acute myocardial infarction and had at least one culprit lesion treated with PCI would be the ideal candidates for this trial.

Not a fit: People who did not have a recent heart attack, who lack measurable coronary plaque, or who do not meet the PCI or ECG timing criteria are unlikely to benefit from this trial.

Why it matters

Potential benefit: If successful, ziltivekimab could reduce coronary plaque burden and potentially lower the risk of future heart attacks.

How similar studies have performed: Prior anti-inflammatory cardiovascular trials (for example targeting IL-1β) have shown benefit on events, and earlier ziltivekimab studies produced large reductions in inflammatory markers, but direct evidence for plaque reduction with ziltivekimab is still being tested.

Eligibility criteria

Inclusion Criteria:

* Informed consent obtained before any study-related activities. Study-related activities are any procedures that are carried out as part of the study, including activities to determine suitability for the study.
* Age 18 years or above at the time of providing informed consent.
* Acute myocardial infarction, with at least one coronary segment (culprit lesion) treated with percutaneous coronary intervention (PCI):

  a. Acute ST-segment elevation myocardial infarction (STEMI) with all of the following: i. Onset of relevant pain suggestive of cardiac ischemia within less than or equal to (=\<) 24h of index angiography.

ii. Electrocardiogram (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 greater than or equal to (\>=) 0.25 millivolts (mV) in men less than (\<) 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.

Non-ST segment elevation myocardial infarction (NSTEMI), with rise and/or fall in cardiac troponin I or T with at least one value above the 99th percentile upper reference limit.

* At least two major native coronary arteries ‡ ("study vessels") each meeting the following criteria for intracoronary imaging immediately following the qualifying PCI procedure:

  1. Angiographic evidence of a reduction in lumen diameter between \>20 and \<50 percent (%) by angiographic visual estimation.
  2. Study vessel deemed to be accessible to imaging catheters and suitable for intracoronary imaging in the proximal (50 millimeter \[mm\]) segment ("study segment").
  3. Study vessel may not be a bypass (saphenous vein or arterial) graft or a bypassed native vessel.
  4. Study vessel must not have undergone previous PCI within the study segment.
  5. A vessel which is candidate for intervention at the time of qualifying PCI or over the following 6 months in the judgment of the Investigator, cannot be a study vessel.

     5\. Hemodynamic stability (as assessed by the treating physician) allowing the repetitive administration of nitroglycerine during the study specific imaging procedure.

     6\. Ability to understand the requirements of the study and to provide informed consent 7. Willingness to undergo follow-up intracoronary imaging. 8. Possibility for randomisation and administration of the loading dose as early as possible after invasive procedure and latest within 48 hours after index PCI.

     Two study segments may be obtained in the same vessel (e.g. two study segments in the Right Coronary Artery \[RCA\] or Left Circumflex Artery \[LCX\]), at the investigators discretion, considering vessel anatomy (e.g. left or right dominance), and where suitable landmarks between segments are at least 40 mm apart and with vessel wall irregularities.

     Exclusion Criteria:
* Known or suspected hypersensitivity to study intervention(s) or related products.
* Known allergy to contrast medium, heparin, aspirin, ticagrelor or prasugrel.
* Previous participation in this study. Participation is defined as randomisation.
* Female of childbearing potential.
* Participation in any other interventional or imaging clinical study within the past 30 days, or as parallel inclusion during the index hospitalization.
* Any condition, which in the investigator's opinion might jeopardise participant's safety or compliance with the protocol.
* Left-main disease, defined as \>=50 percent (%) reduction in lumen diameter of the left main coronary artery by angiographic visual estimation
* Three-vessel disease, defined as the presence of severe or significant coronary artery disease (CAD) on the basis of angiography, imaging, or physiology, in all three major epicardial territories (including major branches) that have an indication for revascularization or are too advanced to be treated.
* History of coronary artery bypass surgery
* Thrombolysis In Myocardial Infarction (TIMI) flow \<2 of the infarct-related artery after PCI
* Unstable clinical status (hemodynamic or electrical instability. Hemodynamic instability defined as any of the following:

Killip Class III or IV. Sustained and/or symptomatic hypotension (as assessed by the treating physician).

* Significant coronary calcification or tortuosity deemed to preclude Intra-Vascular Ultrasound (IVUS), Near Infrared Spectroscopy (NIRS) and Optical Coherence Tomography (OCT) evaluation.
* Uncontrolled cardiac arrhythmia, defined as recurrent and symptomatic ventricular tachycardia or atrial fibrillation with rapid ventricular response not controlled by medications in the past 3 months prior to screening.
* Severe kidney impairment defined as any of the following:

Previous or current estimated glomerular filtration rate \<30 milliliters per minute (ml/min) /1.73 square meter (m\^2) Chronic haemodialysis or peritoneal dialysis.

\- Active liver disease or hepatic dysfunction 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 hepatitis cirrhosis

* Current use of anti-interleukin (IL)-6 products or anticipated use of such drugs any time during the study.
* Use of systemic immunosuppressive drugs (both small molecules and biologics) or disease modifying anti-rheumatic drugs (DMARDs including both biologic DMARDs like anti- TNFalpha and conventional DMARDs like methotrexate) or anticipated chronic use of such drugs any time during the study. (Note: Use of otic, ophthalmic, inhaled, and topical corticosteroids or local corticosteroid injections are not exclusionary. Furthermore, temporary systemic immunosuppressive treatment of e.g., chronic obstructive pulmonary disease \[COPD\] exacerbations is allowed).
* Known, or suspicion of, active infection or major hematologic, metabolic, or endocrine dysfunction in the judgment of the Investigator.
* History of recurrent serious infections (infections leading to hospitalization or use of intravenous (i.v.) antibiotics) within the past 12 months, at the discretion of the investigator.
* Use of preventive systemic antibiotics, systemic antivirals, or systemic antifungals (Note: "Systemic" is defined as oral or i.v. drugs that are absorbed into the circulation. Antibiotics used to treat latent TB are exempted).
* Absolute neutrophil count \<2x10 10\^9/L
* Absolute platelet count \< 120 x10\^9/L
* Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \>8 × upper limit of normal. Participants with increased levels of ALT or AST \<=8 x upper limit of normal (ULN) are eligible at the discretion of the investigator if the investigator considers the ALT or AST 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 or AST \>2.5 x(ULN).
* Known (acute or chronic) hepatitis B or hepatitis C
* Planned surgery within 12 months from the time of screening.
* History of cancer within the past 5 years, except for adequately treated basal cell skin cancer, squamous cell skin cancer, in situ cervical cancer, low risk prostate cancer, or carcinoma in situ/high grade prostatic intraepithelial neoplasia (PIN) at the discretion of the investigator.
* Estimated life expectancy less than 2 years
* Presence of risk factors for tuberculosis (TB) or history or evidence of latent TB such as (but not limited to):

History or evidence of a positive TB test or chest X-ray compatible with latent TB and TB treatment initiated less than 28 days prior to randomisation.

* Diagnosis of human immunodeficiency virus (HIV).
* History of gastrointestinal perforation (Note: History of perforated appendicitis more than 5 years old is not exclusionary).
* History of active diverticulitis within the past 5 years.
* History of inflammatory bowel disease that has been clinically active within the past 12 months.
* History of bone marrow or solid organ transplant or anticipated to receive an organ transplant during the study.
* Received a live or attenuated-live vaccine product within 4 weeks of study intervention administration or expected to receive a live or attenuated-live vaccine product during the treatment period.
* Major cardiac surgical (including but not restricted to coronary artery bypass graft surgery \[CABG\]), non-cardiac surgical, or major endoscopic procedure (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).

Where this trial is running

Vienna and 19 other locations

• Medizinische Universität Wien — Vienna, Austria (NOT_YET_RECRUITING)
• Aalborg Universitetshospital Hjertemedicinsk Afdeling — Gistrup, Denmark (NOT_YET_RECRUITING)
• Rigshospitalet - Kardiologisk Forskningsenhed — København Ø, Denmark (NOT_YET_RECRUITING)
• Azienda Ospedaliera San Giovanni Addolorata — Rome, Lazio, Italy (NOT_YET_RECRUITING)
• Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII — Bergamo, Lombardy, Italy (NOT_YET_RECRUITING)
• DAI Scienze Mediche - UOC Endocrinologia — Messina, Sicily, Italy (NOT_YET_RECRUITING)
• Presidio Ospedaliero di Rivoli — Rivoli, To, Italy (NOT_YET_RECRUITING)
• Ospedale Policlinico San Martino — Genova, Italy (NOT_YET_RECRUITING)
• AOU Maggiore della Carità di Novara - Dipartimento Toraco-Cardio-Vascolare - SCDU Cardiologia — Novara, Italy (NOT_YET_RECRUITING)
• Azienda Ospedaliera Universitaria San Luigi Gonzaga - S.C.D.O. Microcitemie e malattie rare ematologiche — Orbassano, Italy (NOT_YET_RECRUITING)
• Fondazione Policlinico Universitario Agostino Gemelli IRCS — Rome, Italy (NOT_YET_RECRUITING)
• IRCCS Policlinico San Donato — San Donato Milanese, Italy (NOT_YET_RECRUITING)
• Radboudumc — Nijmegen, Netherlands (NOT_YET_RECRUITING)
• Erasmus MC — Rotterdam, Netherlands (NOT_YET_RECRUITING)
• Hospital Universitario de la Princesa — Madrid, Spain (NOT_YET_RECRUITING)
• Hospital Universitario Marqués de Valdecilla — Santander, Spain (NOT_YET_RECRUITING)
• Universitäres Herzzentrum — Basel, Switzerland (RECRUITING)
• Inselspital-Universitätsklinik für Kardiologie — Bern, Switzerland (RECRUITING)
• HUG-Service de Cardiologie — Geneva, Switzerland (NOT_YET_RECRUITING)
• LUKS-Herzzentrum — Lucerne, Switzerland (RECRUITING)

Study contacts

• Study coordinator: Novo Nordisk

Conditions: Myocardial Infarction