Overview

The purpose of this phase 3, randomized, placebo controlled, event-driven study is to assess the effect of AZD0780, an oral PCSK9 inhibitor, compared with placebo in reducing the risk of MACE-PLUS in patients with established ASCVD or at high risk for a first ASCVD event. The effect of AZD0780 vs placebo on the risk of MACE-PLUS will be evaluated from randomisation until the primary analysis censoring date (PACD). The Study Closure Visit will be scheduled to occur after the PACD and will be the final visit for each participant in the study.

Eligibility

Inclusion Criteria:

• Meets one of the following:
  1. Participants with history of an ASCVD event: Participants ≥ 18 years of age at the time of signing the ICF with a history of ASCVD defined as ACS within 1 to 12 months prior to randomisation, or large artery ischaemic stroke suspected to be due to atherosclerotic vascular disease within 1 to 12 months prior to randomisation, or revascularisation for symptomatic lower limb PAD, and LDL-C ≥ 60 mg/dL (≥ 1.55 mmol/L).

     Additional risk factors based on the level of the screening LDL-C:

     • Participants with an LDL-C ≥ 75 mg/dL (≥ 1.9 mmol/L) need to have at least one of the other additional risk factors below.
       • T2DM requiring ongoing medical therapy
       • Age ≥ 65 years
       • Previous above ankle amputation due to PAD
       • Previous diagnosis of non-end stage CKD
  2. Participants at increased risk of a first ASCVD event: Male participant ≥ 50

     years of age or female participant ≥ 55 years of age at the time of signing the ICF with LDL-C ≥ 100 mg/dL (≥ 2.6 mmol/L) and diagnostic evidence of at least one of the following disease categories (i, ii, or iii):

  3. Significant atherosclerotic artery disease

ii) High-risk Type 1 or Type 2 diabetes mellitus with manifestation of end-organ disease (diabetic nephropathy, retinopathy, neuropathy or an ABI outside the normal range [0.9 to 1.4])

iii) Documented atherosclerosis of less significance

For ii) and iii), participants need to have at least one of the additional risk factors below:

1. CKD with eGFR ≤ xx mL/min/1.73 m2
2. Current tobacco use
3. Age ≥ 65
4. T2DM (if included on the less significant atherosclerosis criterion iii)
   • Participant should be receiving a maximally tolerated lipid-lowering regimen including a maximally tolerated dose of a statin.
     1. Participants who are judged by the treating physician not to tolerate high-intensity statins (according to guidelines, typically, atorvastatin ≥ 40 mg once daily or rosuvastatin ≥ 20 mg once daily) may be included if treated with a low or moderate intensity statin dose.
     2. Participants not receiving any statins must have documented intolerable side effects to at least 2 different statins, including one at the lowest standard dose or on a chronic medication that would prohibit the use of a statin (according to the prescribing information for the statin in question).
     3. Participants must achieve a stable dose (> 28 days) of lipid-lowering therapies before screening.

Exclusion criteria:

• Any underlying known disease, or condition including homozygous familial hypercholesterolaemia, or LDL or plasma apheresis within 12 months prior to randomisation, that, in the opinion of the investigator, might interfere with the interpretation of the clinical study results.
• Any revascularisation procedure planned within the next 3 months.
• Available imaging assessment within the last 3 years showing either coronary calcium score of zero, or a coronary computed tomography angiography with no atherosclerosis.
• Calculated eGFR < 15 mL /min/1.73 m2
• Any laboratory values with the following deviations at screening:
  • AST or ALT > 3 × ULN
  • TBL > 2 × ULN (except for participants with Gilbert's syndrome where TBL 3 × ULN is acceptable provided direct bilirubin < 1.5 × ULN)
  • Fasting triglycerides ≥ 400 mg/dL (≥ 4.52 mmol/L).
  • Creatine kinase > 5 × ULN
  • Urine albumin/creatinine ratio ≥ 500 mg/g
• Uncontrolled T2DM defined as HbA1c ≥ 9.5% at screening.
• Inadequately treated hypothyroidism defined as TSH > 1.5 × ULN at screening or participants whose thyroid replacement therapy was initiated or modified within the last 3 months prior to screening.
• Use of mipomersen or lomitapide (cholesterol-lowering medications) within 12 months of screening or planned use during the study.
• Use of gemfibrozil within one week prior to the Screening Visit or planned use during the study.
• Use of PCSK9 inhibitors: evolocumab/alirocumab within 12 weeks of the Screening Visit or planned use during the study, or inclisiran within 18 months of the Screening Visit or planned use during the study, or any other approved PCSK9 inhibitor use within 5 half lives prior to the Screening Visit or planned use during the study.