heart attack Myocardial Infarction
Conditions
Interventions
Participants will be randomized in a 2:2 1:1:1 ratio to receive, 150, or 400 mg
MEDI6570, subcutaneously (SC), or placebo, SC, every 4 weeks (Q4W) for 32 weeks
(9 doses in total). The randomization
Visit 3) and administration of study
intervention. During the follow up period, participants will also undergo an
echocardiogram and CTA scan. In addition, at least 200 participants group will
unde
Visit 9).
Intervention Groups and Duration: The study intervention is MEDI6570, a human
Immunoglobulin G1 lambda (IgG1*) triple mutation antibody that binds to human
lectin-like oxidized low densit
Sponsors
Astra Zeneca
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: 1 Participant must provide informed consent before any study specific activities are performed (Appendix A 3), must be able and willing to meet all requirements for randomization within 42 days after signing the full ICF, and must adhere to the schedules of activities. 2 Participant must be >= 40 years of age at the time of signing the ICF. 3 Participant must: (a) be 30 to 365 days after presumed type-1 (ie, due to plaque rupture or erosion) MI (either STEMI or NSTEMI) at the time of enrollment. (b) have persistent inflammation, defined as hs CRP >= 1 mg/L, as measured centrally at screening Visit 1. 4 Participant must have body mass index within the range 18 to 40 kg/m2 inclusive. 5 For female participants, the participant must not be pregnant or lactating and must be of non-childbearing potential, confirmed at screening Visit 1 by one of the following: (a) Postmenopausal, defined as amenorrhea for >= 12 months following cessation of all exogenous hormonal treatments, and with luteinizing hormone and follicle stimulating hormone levels in the postmenopausal range. (b) Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy. Tubal ligation is not considered as irreversible surgical sterilization. 6 Participant must have an evaluable, pre-randomization CTA with quantifiable, non calcified plaque, as confirmed by the core laboratory. Participants will be reassessed for study eligibility before study intervention is administered on Day 1 (Visit 3). Participants should be considered for a high-intensity statin based on existing guidelines for long-term management of patients after an MI. Participants should ideally be on a stable dose of lipid-lowering therapy throughout the treatment period of the study; therefore, efforts should be made to maximize statin intensity before randomization. The proportion of participants with an NT-proBNP value = 125 pg/mL will be required for inclusion in the study. During the study, randomization to an intervention group may also be capped within other specific participant subgroups. In addition to the inclusion criteria specified above, study participants may elect to take part in the Genomics Initiative; participants who chose to do this must provide written informed consent before samples are collected for the optional genetic research that supports the Genomics Initiative (Appendix D 2).
Exclusion criteria
Exclusion criteria: 1 History of any clinically important disease or disorder which, in the opinion of the investigator, may either put the participant at risk because of participation in the study, or influence the results or the participant*s ability to participate in the study. 2 Percutaneous coronary intervention [PCI] planned after screening Visit 1. Eligible participants who have a PCI planned after screening Visit 1 may be rescreened after the PCI has been performed (Section 5.4). 3 History of or planned coronary artery bypass grafting. 4 Documented episode of post-MI pericarditis (eg, Dressler*s Syndrome) in the 3 months before enrollment. 5 Ongoing New York Heart Association Class IV (severe) HF. 6 Increased risk of bleeding (a) Patients with history or presence of any bleeding disorder. (b) Active bleeding or high risk for major bleeding (eg, gastrointestinal pathology, malignancy with high risk of bleeding, active peptic ulcer). (c) Need for chronic anticoagulation therapy (prophylactic doses of heparin are allowed). (d) Known severe liver disease (eg, ascites and/or clinical signs of coagulopathy). 7 History or presence of any of the following: (a) Ongoing infection or febrile illness that in the opinion of the investigator may be the cause of elevated hs-CRP on screening (Visit 1). (b) Ongoing atrial fibrillation or flutter. (c) Cancer within 5 years before randomization (Day 1; Visit 3), with the exception of non melanoma skin cancer. (d) Alcohol or substance abuse within 6 months before randomization (Day 1; Visit 3), as judged by the investigator. (e) Known history of hypersensitivity reactions to other biologics, to human IgG preparations, or to any component of MEDI6570, or ongoing severe allergy as judged by the investigator. (f) Patients with active positive results on screening for serum hepatitis B surface antigen, hepatitis C antibody, or HIV. 8 Any clinically important abnormalities in clinical chemistry, hematology, coagulation parameters, as judged by the investigator, including but not limited to: (a) Aspartate transaminase (AST) > 2.0 × ULN. (b) Alanine transaminase (ALT) > 2.0 × ULN. (c) Total bilirubin (TBL) > 1.5 x ULN (unless due to Gilbert*s syndrome). (d) Platelet count 180 mmHg. (b) Diastolic BP > 100 mmHg. (c) Participants who are excluded based on elevated BP may be rescreened following adequate treatment. The eligibility assessment is based on measurements taken starting from after 5 minutes of rest; if the result is outside these limits, additional BP measurements can be taken over the following 5 minutes, ie, up to a total of 10 minutes of rest (repeated a maximum of 3 times). If the result is outside these limits during this period, the participant is considered a screen fail. 10 Participants with any of the following contraindications to CTA: (a) eGFR < 50 mL/min/1.73 m2 by the Chronic Kidney Disease Epidemiology Collaboration equation, or end stage renal disease treated with kidney transplant or renal replacement therapy. (b) Allergy to iodinated contrast. (c) History of contrast-induced nephropathy. (d) Contraindication to nitroglycerin. (e) Rapid heart rate that is uncontrolled by medical therapy. (f) Inability
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| To evaluate the effect of MEDI6570 on non-calcified coronary atherosclerotic plaques compared with placebo | — |
Secondary
| Measure | Time frame |
|---|---|
| Relative change from baseline to Day 253 in NT proBNP. Change from baseline to Day 253 in: • LVEF • GLS as measured by echocardiography Change from baseline to Day 253 in: • LVEF • GLS as measured by echocardiography Change from baseline to Day 253 in: • Global non-calcified plaque volume • Low attenuation plaque volume as measured by CTA imaging Change from baseline to Day 253 in: • FAI as measured by CTA imaging • ADA incidence • Titer as measured in serum during the intervention and follow-up periods • MEDI6570 as measured in serum during the intervention and follow up periods During the intervention and follow up periods: • AEs • Clinically important changes in: Vital signs ECGs Safety laboratory assessments Changes from baseline in: • hs-CRP • IL-6 • MPO • MMP9 • Free sLOX-1 as measured in plasma or serum during the intervention and follow up periods Changes from baseline to Day 253 in: • End-diastolic volume index • End-systolic volume index • Left atrial volume index • E/e* ratio as measured by echocardiography Change from baseline to Day 253 in: • Percent atheroma volume • High-risk plaque features (positive remodeling, napkin ring sign, spotty calcification and low attenuation plaque) as measured by CTA imaging Change from baseline to Day 253 in: • FRP as measured by CTA Time to MACE (composite of CV death, MI, stroke, or coronary revascularization) from randomization to Day 253. Time to CV death or HF hospitalization from randomization to Day 253. Change from baseline to Day 253 in: • Time spent in MVPA • Step count • Acceleration intensity (MMI) • Uninterrupted sleep time as measured by a continuously worn physical activity monitor | — |
Countries
Netherlands
Outcome results
None listed