laroprovstat for Atherosclerotic cardiovascular disease

Inclusion criteria

• {"criterion_text":"- 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)"}
• {"criterion_text":"- 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

• {"criterion_text":"- 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.\n- 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.\n- Any revascularisation procedure planned within the next 3 months.\n- Available imaging assessment within the last 3 years showing either coronary calcium score of zero, or a coronary computed tomography angiography with no atherosclerosis.\n- Calculated eGFR < 15 mL/min/1.73 m2 (CKD-EPI formula; Delgado et al 2022, Inker et al 2021) at screening.\n- 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\n- Uncontrolled T2DM defined as HbA1c ≥ 9.5% at screening.\n- 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.\n- Use of mipomersen or lomitapide (cholesterol-lowering medications) within 12 months of screening or planned use during the study.\n- Use of gemfibrozil within one week prior to the Screening Visit or planned use during the study."}

Primary endpoints

• {"endpoint_text":"- Time to first event of any component of MACE PLUS","definition_or_measurement_approach":"Time-to-event (time to first occurrence) of the composite MACE-PLUS (cardiovascular death, myocardial infarction, ischaemic stroke, acute lower limb ischaemia, major amputation of a vascular aetiology, and urgent arterial revascularisation)."}

Secondary endpoints

• {"endpoint_text":"- Time to first event of any component of 3P MACE","definition_or_measurement_approach":"Time-to-event to first occurrence of 3-point MACE (3P-MACE), defined as the composite of cardiovascular death, myocardial infarction (MI), and ischaemic stroke."}
• {"endpoint_text":"- Time to first event of any component of MACE PLUS in participants with a prior history of ASCVD","definition_or_measurement_approach":"Time-to-event to first occurrence of MACE-PLUS (see primary endpoint definition) in the subgroup of participants with prior ASCVD."}
• {"endpoint_text":"- Time to first event of MI","definition_or_measurement_approach":"Time-to-event to first occurrence of myocardial infarction (MI)."}
• {"endpoint_text":"- Time to first event of urgent coronary revascularisation","definition_or_measurement_approach":"Time-to-event to first occurrence of urgent coronary revascularisation."}
• {"endpoint_text":"- Time to CV death","definition_or_measurement_approach":"Time-to-event to cardiovascular death."}
• {"endpoint_text":"- Time to first event of MALE","definition_or_measurement_approach":"Time-to-event to first occurrence of major adverse limb event (MALE) – composite of acute lower limb ischemia, major amputation of vascular aetiology, and urgent lower extremity revascularisation."}
• {"endpoint_text":"- Time to all-cause mortality","definition_or_measurement_approach":"Time-to-event to death from any cause."}

Methods

• Printed pamphlets/leaflets (K2_Recruitment material Pamphlet / Leaflet) – patient-facing recruitment materials referenced in multiple country submissions.
• Local advertisements/posters (K2 local advertisement / Local Advertisement files).
• GP/physician invitation letters and site letters to participants (K2_Recruitment material_PI letter to participant; Patient Letter).
• Site-specific recruitment materials and clinic flyers (multiple 'Site' and 'Pamphlet' documents per country).
• Digital recruitment: website postings, social media (Instagram posts, Reels), text posts and online study listings (documents: Social Media, Website, Text Post, Reels, Study Listing, POSSIBIA Social Media materials).
• Pre-screening tools and online prescreen questionnaires (POSSIBIA Pre screening; Pratia/Velocity pre-screening tools).
• Study listing on clinic and CRO websites and privacy policy information for online recruitment (Study Listing, Privacy Policy documents).
• Patient organisation / community outreach (patient organisation listed as a trial site in Germany).

Primary sponsor

Full Name

AstraZeneca AB

Organisation Type

Pharmaceutical company

Country Of Registered Address

Sweden