Evaluating the Impact of Maridebart Cafraglutide on Cardiovascular Outcomes in Participants With Atherosclerotic Cardiovascular Disease and Overweight or Obesity

• Maridebart Cafraglutide (Drug), also known as AMG 133, MariTide: Maridebart cafraglutide will be administered SC.
• Placebo (Drug): Placebo will be administered SC.

Primary outcomes

• Time to First Occurrence of a Composite Endpoint Consisting of: CV Death, Myocardial Infarction (MI), or Ischemic Stroke (3-point Major Adverse Cardiac Events [3-P MACE]) [Up to approximately 35 months]
• Time to First Occurrence of a Composite Endpoint Consisting of: All-cause Death, MI, Ischemic Stroke, Coronary Revascularization, or Heart Failure (HF) Event (5-point MACE) [Up to approximately 35 months]

Secondary outcomes

• Time to First Occurrence of a Composite Endpoint Consisting of: CV Death, MI, Ischemic Stroke, or HF Event [Up to approximately 35 months]
• Time to First Occurrence of a Composite Endpoint Consisting of: CV Death, MI, Ischemic Stroke or Coronary Revascularization [Up to approximately 35 months]
• Time to First MI [Up to approximately 35 months]
• Time to First Ischemic Stroke [Up to approximately 35 months]
• Time to CV Death [Up to approximately 35 months]
• Time to All-cause Death [Up to approximately 35 months]
• Time to First Coronary Revascularization [Up to approximately 35 months]
• Time to First HF Event [Up to approximately 35 months]
• Time to First HF Event or CV Death [Up to approximately 35 months]
• Time to First Unstable Angina Requiring Hospitalization [Up to approximately 35 months]
• Time to First Occurrence of MI or CV Death [Up to approximately 35 months]
• Time to First Occurrence of MI, Ischemic Stroke or All-cause Death [Up to approximately 35 months]
• Total Major Ischemic Events (Time to First and Recurrent MI or Ischemic Stroke) [Up to approximately 35 months]
• Total All-cause Hospitalizations (Time to First and Recurrent Event) [Up to approximately 35 months]
• Time to Onset of Type 2 Diabetes Mellitus (T2DM) in Participants with Prediabetes at Baseline [Up to approximately 35 months]
• Time to Onset of T2DM in Participants without T2DM at Baseline [Up to approximately 35 months]
• Change from Baseline in Systolic Blood Pressure (SBP) at Week 72 [Baseline and Week 72]
• Change from Baseline in Diastolic Blood Pressure (DBP) at Week 72 [Baseline and Week 72]
• Change from Baseline in Body Mass Index (BMI) at Week 72 [Baseline and Week 72]
• Change from Baseline in Waist Circumference at Week 72 [Baseline and Week 72]
• Change from Baseline in Urine Albumin-to-creatinine Ratio (uACR) at Week 72 [Baseline and Week 72]
• Change from Baseline in Hemoglobin A1c (HbA1c) at Week 72 [Baseline and Week 72]
• Change from Baseline in Fasting Plasma Glucose at Week 72 [Baseline and Week 72]
• Percent Change from Baseline in High-sensitivity C-reactive protein (hs-CRP) at Week 72 [Baseline and Week 72]
• Percent Change from Baseline in Body Weight at Week 72 [Baseline and Week 72]
• Percent Change from Baseline in Total Cholesterol at Week 72 [Baseline and Week 72]
• Percent Change from Baseline in High-density Lipoprotein Cholesterol (HDL-C) at Week 72 [Baseline and Week 72]
• Percent Change from Baseline in Low-density Lipoprotein Cholesterol (LDL-C) at Week 72 [Baseline and Week 72]
• Percent Change from Baseline in Triglycerides (TG) at Week 72 [Baseline and Week 72]
• Number of Participants at Week 72 with HbA1c < 6.5% (48 mmol/mol) in Participants with T2DM at Baseline [Baseline and Week 72]
• Number of Participants at Week 72 with HbA1c < 6.0% (42 mmol/mol) in Participants with T2DM at Baseline [Baseline and Week 72]
• Number of Participants at Week 72 with HbA1c < 5.7% (39 mmol/mol) in Participants with T2DM at Baseline [Baseline and Week 72]
• Number of Participants at Week 72 with HbA1c < 6.5% (48 mmol/mol) in Participants Without T2DM at Baseline [Baseline and Week 72]
• Number of Participants at Week 72 with HbA1c < 6.0% (42 mmol/mol) in Participants Without T2DM at Baseline [Baseline and Week 72]
• Number of Participants at Week 72 with HbA1c < 5.7% (39 mmol/mol) in Participants Without T2DM at Baseline [Baseline and Week 72]
• Number of Participants at Week 72 with HbA1c < 5.7% (39 mmol/mol) in Participants with HbA1c ≥ 5.7% and < 6.5% at Baseline [Baseline and Week 72]
• Change from Baseline in Short Form 36 Health Survey Acute Version 2 (SF-36 v2) Physical Function Domain Score at Week 48 [Baseline and Week 48]
• Time to First Event of a Composite Nephropathy Endpoint [Up to approximately 35 months]: Composite endpoint consists of onset of persistent macroalbuminuria, persistent ≥ 40% reduction in estimated glomerular filtration rate (eGFR), onset of persistent eGFR < 15 mL/min/1.73 m\^2, initiation of chronic renal replacement therapy (dialysis or transplantation), CV or renal death.
• Change in eGFR (total slope) for the period from baseline to the final follow up visit [Baseline up to approximately 35 months]
• Change in eGFR (chronic slope) for the period from 4 months to the final follow-up visit [From 4 months up to approximately 35 months]
• Time to First Occurrence of a Major Adverse Limb Event (MALE) Defined as Acute Limb Ischemia, Urgent Peripheral Revascularization, Major Amputation Due to a Vascular Etiology or Chronic Limb-threatening Ischemia Requiring Revascularization [Up to approximately 35 months]
• Total Arterial (Coronary, Cerebrovascular, and Peripheral) Revascularization Procedures (Time to First and Recurrent Event) [Up to approximately 35 months]
• Time to First Occurrence of a Composite Endpoint Consisting of: CV Death, MI, Ischemic Stroke, MALE, or Arterial Revascularization [Up to approximately 35 months]
• Time to First Occurrence of a Composite Endpoint Consisting of: CV Death, MI, Ischemic Stroke, or Acute Limb Ischemia [Up to approximately 35 months]
• Time to First Occurrence of a Composite Endpoint Consisting of CV Death, MI, Ischemic Stroke, Acute Limb Ischemia, or Urgent Arterial Revascularization Procedure (Coronary, Cerebrovascular or Peripheral) [Up to approximately 35 months]
• Number of Participants with Treatment-emergent Adverse Events [Up to approximately 35 months]
• Number of Participants with Serious Adverse Events [Up to approximately 35 months]
• Plasma Concentration of Maridebart Cafraglutide at Week 72 [Week 72]

Sex: All, ages: 45 Years to 99 Years

Inclusion Criteria

* Age ≥ 45 years at screening.
* BMI of ≥ 27.0 kg/m\^2 at screening.
* History of Atherosclerotic Cardiovascular Disease (ASCVD) with a documented history of at least one of the following:

  * Prior MI (presumed atherothrombotic event due to plaque rupture/erosion).
  * Prior ischemic stroke (presumed due to atherosclerosis; may include ischemic stroke with hemorrhagic transformation).
  * Symptomatic peripheral arterial disease (PAD), as evidenced by intermittent claudication with ankle-brachial index (ABI) < 0.9 (at rest), or peripheral arterial revascularization procedure, or amputation due to atherosclerotic disease.

Exclusion Criteria

* History of any of the following within 60 days before screening or between screening and randomization: MI, hospitalization for unstable angina, arterial revascularization (eg, coronary, cerebrovascular or peripheral) major cardiovascular surgery, stroke, or transient ischemic attack (TIA).
* New York Heart Association (NYHA) class IV HF during screening or hospitalization for HF within 60 days before screening or between screening and randomization.
* Type 1 DM, or any other type of diabetes with the exception of T2DM or prior gestational diabetes. Participants with a history of gestational diabetes should be stratified according to their current diabetes classification.
* For participants with T2DM (including those without a prior history of T2DM but with a HbA1c ≥ 6.5% during screening):

  * HbA1c > 10.0% (86 mmol/mol) at screening.
  * History of diabetic ketoacidosis or hyperosmolar state/coma within 12 months before randomization.
  * One or more episodes of severe hypoglycemia within 6 months before randomization and/or history of hypoglycemia unawareness.
  * History of proliferative diabetic retinopathy, diabetic maculopathy, severe non-proliferative diabetic retinopathy, or currently receiving or planning to receive treatment for diabetic retinopathy and/or diabetic macular edema.
* Use of any glucagon-like peptide-1 receptor agonist (GLP-1 RA), glucose-dependent insulinotropic polypeptide (GIP) agonists or antagonists, or amylin analogs within 90 days before randomization or planned use during the conduct of the trial.
* History of chronic pancreatitis or history of acute pancreatitis in the 180 days before screening or between screening and randomization.
* Family (first-degree relative\[s\]), or personal history of medullary thyroid carcinoma (MTC), or multiple endocrine neoplasia syndrome type 2 (MEN-2).
* Calcitonin ≥ 50 ng/L (pg/mL) at screening.
* Acute or chronic hepatitis; signs and symptoms of any liver disease other than metabolic dysfunction-associated steatotic liver disease, or alanine aminotransferase (ALT) > 3.0 x the upper limit of normal (ULN) during screening, or total bilirubin (TBL) > 1.8 x ULN during screening (for participants with a known diagnosis of Gilbert syndrome, direct bilirubin should be used instead of TBL).
* History of malignancy within the last 5 years before screening or between screening and randomization (except for the following treated with curative intent: non-melanoma skin cancer, breast ductal carcinoma in situ, cervical carcinoma in situ, or prostate cancer in situ).
* Participants of childbearing potential planning to become pregnant while on study or unwilling to use protocol-specified methods of contraception during treatment.

683 more sites not listed.

• MD, Study director, Amgen