This study will be a proof-of-concept, placebo-controlled, double-blind, randomized trial in participants with a recent acute coronary syndrome (ACS) to evaluate the efficacy, pharmacokinetics, safety, tolerability, disease progression measures by IVUS, and pharmacodynamics of MDCO-216 infusion. Eligible participants will be randomized to receive 5 infusions of MDCO-216 20 milligrams/kilogram (mg/kg) or placebo in a 1:1 ratio.

Inclusion Criteria:

• Have experienced a recent ACS event within 14 days of screening that requires a clinically indicated coronary angiogram.

• A qualifying ACS event will be defined as follows: a diagnosis of a qualifying myocardial infarction (MI) event will be defined by abnormal levels of cardiac biomarkers (troponin I or T or creatine kinase myoglobin [CK-MB] mass) with at least one determination greater than the 99th percentile or upper limits of normal (ULN) for the laboratory and at least one of the following: chest discomfort or symptoms of myocardial ischemia (≥10 minutes) at rest within 24 hours prior to hospitalization for MI and/or new electrocardiogram (ECG) findings (or presumed new if no prior ECG available) indicative of acute myocardial ischemia in absence of left ventricular hypertrophy (LVH) and left bundle branch block (LBB).

• Baseline coronary angiogram must meet all of the following criteria for IVUS interrogation of target artery:

  • Target artery must be accessible to the IVUS catheter
  • Target artery must have a stenotic area of ≥20% and <50% in lumen diameter by angiographic visual estimation within the length of the native coronary artery ("target segment") for imaging by IVUS
  • Target artery has not undergone prior percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery (CABG)
  • Target artery is not currently a candidate for intervention or a likely candidate for intervention over the treatment phase of the study and until the second IVUS interrogation at Day 36; the target artery may not be a bypass graft
  • Target artery may not be the culprit vessel for a previous MI.

The target artery may have the following:

• A lesion of up to 60% stenosis, distal to the target segment, provided that this area is not a target for PCI or CABG
• A single branch of the "target vessel" may have a narrowing ≤70% by visual estimation, provided that the branch in question is not a target for PCI or CABG.
• Willing and able to give informed consent before initiation of any study-related procedures and willing to comply with all required study procedures.

Exclusion Criteria:

• Baseline IVUS not completed due to non-qualifying coronary angiogram as demonstrated by a greater than 50% reduction in lumen of the left main coronary artery by visual estimation, or extensive coronary artery disease (CAD) with no target vessel for IVUS interrogation.
• Baseline IVUS interrogation determined to be unacceptable by the Atherosclerosis Imaging Core Laboratory.
• ST-segment elevation myocardial infarction (STEMI) within the last 90 days
• Clinically significant heart disease which, in the opinion of the Investigator, is likely to require CABG, PCI cardiac transplantation, surgical or percutaneous valve repair, and/or replacement following index IVUS imaging (does not apply to PCI that occurs as a result of initial screening angiogram and completed prior to index IVUS imaging).
• New York Heart Failure Association Class III or IV heart failure or last known left ventricular ejection fraction <30%.
• Coronary artery bypass surgery <6 weeks prior to the qualifying IVUS.
• Cardiac arrhythmia within 3 months prior to randomization that is not controlled by medication.
• Uncontrolled severe hypertension: systolic blood pressure >180 millimeters of mercury (mmHg) or diastolic blood pressure >110 mmHg prior to randomization despite anti-hypertensive therapy.
• Poorly controlled diabetes mellitus and a hemoglobin A1c (HbA1c) >10.0% prior to randomization.
• Active liver disease defined as any known current infectious, neoplastic, or metabolic pathology of the liver or alanine aminotransferase, aspartate aminotransferase elevation >2 x ULN or total bilirubin elevation >1.5 x ULN at screening confirmed by a repeat measurement at least one week apart.
• Fasting triglyceride value >400 milligrams/deciliter (mg/dL).
• Impaired kidney function defined as calculated glomerular filtration rate <60 mL/minute by estimated glomerular filtration rate. In addition, participants with a 0.3 mg/dL or 25% increase in serum creatinine in the initial 3 to 5 days following angiography will be excluded from the study.
• Serious comorbid disease in which the life expectancy of the participant is shorter than the duration of the trial (such as, acute systemic infection, cancer, or other serious illnesses). This includes all cancers with the exception of treated basal-cell carcinoma occurring >3 years before screening.
• Body weight >120 kg.
• Females who are pregnant or nursing, or who are of childbearing potential and unwilling to use at least 2 methods of contraception (oral contraceptives, barrier methods, approved contraceptive implant, long-term injectable contraception, intrauterine device or tubal litigation). Women who are >2 years postmenopausal defined as ≥1 year since last menstrual period and are <55 years old with a negative pregnancy test within 24 hours of randomization or surgically sterile are exempt from this exclusion.
• Males who are unwilling to use an acceptable method of birth control during the entire study period (such as, condom with spermicide).
• Previous participation (enrollment and randomization) in this study or any preceding study with ETC-216 (predecessor compound of MDCO-216), MDCO-216, or similar investigational medicines containing apolipoprotein A-I (ApoA-I) proteins.
• Known allergy to the phospholipid or any other component of the investigational product (dimeric recombinant ApoA-IM, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, or mannitol and sucrose in phosphate buffer).
• Treatment with other investigational medicinal products or devices within 30 days or 5 half˗lives, whichever is longer.
• Known history of alcohol and/or drug abuse.
• Use of other investigational medicinal products or devices during the course of the study, excluding Post-Marketing Registries.
• Any condition that according to the investigator could interfere with the conduct of the study.