Evaluation of Laroprovstat (AZD0780) on Major Adverse Cardiovascular Events in Patients with Atherosclerotic Cardiovascular Disease or High ASCVD Risk
- Trial ID
- 2025-520519-14-00
- Protocol
- D7960C00015
- Sponsor
- AstraZeneca AB
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the effect of **AZD0780** compared to placebo in reducing the risk of MACE-PLUS, which is a composite endpoint including cardiovascular (CV) death, myocardial infarction (MI), ischaemic stroke, acute lower limb ischemia, major amputation of vascular aetiology, and urgent arterial revascularisation. This is clinically relevant as it addresses multiple severe outcomes associated with **atherosclerotic cardiovascular disease** (ASCVD), providing a comprehensive assessment of the treatment's potential benefits in a high-risk population.
Secondary objectives include:
- Comparing the effect of AZD0780 to placebo in reducing the risk of 3-point MACE, which includes CV death, MI, and ischaemic stroke.
- Evaluating the reduction in risk of MACE-PLUS in patients with a history of ASCVD.
- Assessing the reduction in risk of MI.
- Determining the effect on reducing the risk of urgent coronary revascularization.
- Comparing the reduction in risk of CV death.
- Evaluating the reduction in risk of major adverse limb events (MALE), including acute lower limb ischemia, major amputation of vascular aetiology, and urgent lower extremity revascularisation.
- Assessing the reduction in risk of all-cause mortality.
These secondary objectives aim to provide a detailed understanding of AZD0780's impact on various cardiovascular and related outcomes, which are critical for improving patient management and outcomes in those with or at high risk for ASCVD.
Participants
The clinical trial involves a total of **11,569 participants** diagnosed with **Atherosclerotic Cardiovascular Disease**. The study population includes both male and female subjects, with an age range starting from 18 years and above. Participants were selected based on their history of atherosclerotic cardiovascular events or increased risk of such events, with specific criteria related to LDL-C levels and additional risk factors such as Type 2 Diabetes Mellitus, age, and previous cardiovascular conditions. The trial includes individuals who are on a maximally tolerated lipid-lowering regimen, including statins, or those who have documented intolerance to statins. The population is characterized by a mix of general and vulnerable groups, ensuring a comprehensive assessment of the treatment's efficacy across diverse demographics. Lifestyle considerations such as current tobacco use and the presence of chronic kidney disease are also relevant to the study's inclusion criteria.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled**, parallel-group study to evaluate the efficacy of AZD0780 in reducing major adverse cardiovascular events (MACE-PLUS) in patients with established **atherosclerotic cardiovascular disease** (ASCVD) or those at high risk for a first ASCVD event. The trial will span an estimated duration from September 2025 to October 2029, with a maximum treatment period of 54 weeks for each participant. The study involves the administration of AZD0780 or a placebo, both in the form of film-coated tablets, via oral use.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific inclusion criteria, such as a history of ASCVD events or increased risk factors for a first ASCVD event. Following randomization, participants will attend regular follow-up visits to monitor their health status, adherence to the treatment regimen, and any adverse events. The primary endpoint is the time to the first event of any component of MACE-PLUS, with secondary endpoints including time to first event of 3P MACE, myocardial infarction, urgent coronary revascularization, cardiovascular death, major adverse limb events, and all-cause mortality.
The expected length of participant involvement is up to 54 weeks, with conditions for early termination including significant adverse reactions, non-compliance with the study protocol, or withdrawal of consent. Participants are required to be on a stable dose of lipid-lowering therapies before screening and must continue a maximally tolerated lipid-lowering regimen throughout the study. The trial aims to provide robust data on the efficacy of AZD0780 in reducing cardiovascular events, contributing to the understanding and management of ASCVD.
Treatment
The clinical trial involves the administration of **AZD0780**, an investigational medication, which is a synthetic molecule formulated as a **film-coated tablet**. The active substance in AZD0780 is **laroprovstat**, a chemical compound. The medication is administered orally, with the dosage expressed in milligrams per square meter (mg/m²). The maximum treatment period for AZD0780 is 54 weeks. The trial aims to evaluate the effect of AZD0780 on major adverse cardiovascular events in patients with established atherosclerotic cardiovascular disease or those at high risk for a first event. Participant compliance with the dosing schedule will be monitored throughout the study.
In addition to the experimental treatment, a **placebo** is used as a comparator in this double-blind, placebo-controlled study. The placebo is also administered in the form of a tablet and is indistinguishable from the active medication in appearance. It is administered orally, following the same dosing schedule as AZD0780, to maintain the study's blinding integrity. The placebo serves as a control to assess the efficacy and safety of AZD0780 in reducing the risk of major adverse cardiovascular events.
Efficacy
The efficacy of the investigational product AZD0780 will be assessed in a Phase III, randomized, double-blind, placebo-controlled, parallel-group study. The primary endpoint for evaluating efficacy is the time to the first event of any component of **MACE PLUS** (Major Adverse Cardiovascular Events), which includes cardiovascular death, myocardial infarction, ischemic stroke, acute lower limb ischemia, major amputation of a vascular etiology, and urgent arterial revascularization. Secondary endpoints include the time to the first event of any component of 3P MACE, time to the first event of any component of MACE PLUS in participants with a prior history of ASCVD, time to the first event of myocardial infarction, time to the first event of urgent coronary revascularization, time to cardiovascular death, time to the first event of major adverse limb events (MALE), and time to all-cause mortality.
The efficacy parameters will be measured and collected at specified timepoints throughout the study duration, which is estimated to conclude by October 26, 2029. The analysis of these endpoints will be conducted using appropriate statistical methods to determine the effect of AZD0780 compared to placebo in reducing the risk of MACE PLUS in patients with established atherosclerotic cardiovascular disease (ASCVD) or those at high risk for a first ASCVD event. The study will ensure that all data collection and analysis adhere to the highest standards of clinical research to provide reliable and valid results.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Meets one of the following: (a) 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 ≥ 1 month to ≤ 12 months prior to randomisation, ischaemic stroke suspected to be due to atherosclerotic vascular disease ≥ 1 month to ≤ 12 months prior to randomisation, or revascularisation for symptomatic lower limb PAD any time prior to screening Additional risk factors based on the level of the LDL-C: o Participants with an LDL-C ≥ 75 mg/dL (≥ 1.9 mmol/L) need to have at least one of the other additional risk factors (i to viii) below. i) T2DM requiring ongoing medical therapy ii) Age ≥ 65 years v) Previous above ankle amputation due to PAD vi) Previous diagnosis of non-end stage CKD (b) 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): i) 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: a) CKD with eGFR x mL/min/1.73 m2 b) Current tobacco use c) Age ≥ 65 d) T2DM (if included on the less significant atherosclerosis criterion iii)
- Participants should receive a background lipid lowering regimen anticipated to achieve at least a ~50% reduction in LDL-C. Except in cases of intolerance, the regimen should include a high intensity statin therapy or lower intensity statin therapy in combination with an oral agent with proven outcome benefit (eg, ezetimibe and/or bempedoic acid). Participants must achieve a stable background lipid lowering therapy > 28 days 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 (CKD-EPI formula; Delgado et al 2022, Inker et al 2021) at screening.
- 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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Bulgaria | Recruiting | 01 Sept 2025 | 258 |
 Czechia | Recruiting | 01 Sept 2025 | 271 |
 Denmark | Recruiting | 01 Sept 2025 | 150 |
 France | Recruiting | 01 Sept 2025 | 129 |
 Germany | Recruiting | 01 Sept 2025 | 812 |
 Greece | Recruiting | 01 Sept 2025 | 137 |
 Hungary | Recruiting | 01 Sept 2025 | 568 |
 Italy | Recruiting | 01 Sept 2025 | 153 |
 Poland | Recruiting | 01 Sept 2025 | 303 |
 Romania | Recruiting | 01 Sept 2025 | 161 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
AZD0780 | Test | FILM-COATED TABLET | ORAL USE | 0 | 54 | PRD10648575 |
AZD0780 placebo | Placebo | N/A | ORAL USE | — | 54 | N/A |