Evaluation of Efficacy and Safety of Early in Hospital Initiation of Inclisiran Treatment in Patients With Acute Coronary Syndromes

This is a multicenter, prospective, randomized, double-blind, placebo-controlled, two arms, parallel groups clinical trial in participants experiencing an ACS (STEMI or NSTEMI) of recent onset. The study drug treatment (inclisiran/placebo) will be initiated at randomization (Day 1) and before discharge.

The study consists of:

• Screening visit within 7 days (≤ 7 days) from hospital admission. Screening visit might happen at hospital admission day or any time after hospital admission and before randomization (Day 1).
• Randomization/Baseline visit (Day 1) within 7 days (≤ 7 days) from hospital admission and before or at day of discharge.

The discharge can happen any time after randomization and first study drug administration (Day 1).

• Double-blinded treatment period (150 days).
• Scheduled safety calls in between visits during the double-blind treatment period (they do not replace on-site visits)
• Safety Follow-up call (30 days after EOS visit)

Screening and randomization visits must happen during the in-hospital phase, within 7 days (≤ 7 days), and before discharge. The Screening period, of no more than 6 days after the date of hospital admission, will be used to determine if patients qualify to enter the double-blind treatment phase of the study. Screening and Randomization/Day 1 visits cannot occur on the same day. The overall study duration is 150 days.

Inclusion criteria

Participant eligible for inclusion in this study must meet all the following criteria:

At Screening:

• Signed informed consent must be obtained prior to participation in the study.
• Males and females, ≥18 years of age at the time of providing written informed consent.
• Ability to understand study's requirements and provide informed consent and comply with all required study procedures.
• Hospitalization for a ACS event (STEMI or NSTEMI).
• Receiving treatment for the qualifying ACS event, according to clinical judgement, by means of medical treatment alone or percutaneous coronary revascularization.
• Had a successful PCI (with or without stent) for the qualifying event if a PCI was required.
• LDL-C value at the Screening visit measured by the local lab of:

• LDL-C ≥70 mg/dL in participant previously treated with high-intensity statin (atorvastatin ≥40 mg/day or rosuvastatin ≥20 mg/day) or equivalent as per national guidelines and local regulation for at least 4 weeks before screening or
• LDL-C ≥100 mg/dL in participant previously treated with low/moderate-intensity statin for at least 4 weeks before screening or
• LDL-C ≥125 mg/dL in participant previously not treated with statins for at least 4 weeks before screening, or who never received statins (including statin intolerant participants).

At Randomization:

• The participant must have a Baseline fasting LDL-C ≥70 mg/dL (local lab assessment) to be eligible for randomization.
• Randomization within 7 days (≤ 7 days) following hospital admission for the qualifying ACS event and before/at discharge.

Exclusion criteria

Participant meeting any of the following criteria is not eligible for inclusion in this study.

Only for Japan: For exclusion criteria 6, investigator judgment should be documented in the source data document.

• Participant who is clinically unstable during hospitalization for the qualifying ACS event, defined by any of the following events within 24 hours prior to randomization:

• Hemodynamic instability: hypotension, defined as sustained systolic blood pressure of <90 mmHg due to cardiac failure with associated symptoms requiring inotropes
• Arrhythmic events: Ventricular storm (e.g., torsade, ventricular tachycardia, ventricular flutter)
• Cardiogenic shock or mechanical complication of myocardial infarction
• New York Heart Association (NYHA) class IV heart failure
• Left ventricular ejection fraction <20% at randomization (after all treatment procedures, based on the latest assessment of the LVEF using invasive or non-invasive assessment modalities)
• Uncontrolled severe hypertension: systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg prior to randomization despite antihypertensive therapy.
• Participant who has undergone or is scheduled to undergo CABG for treatment of the qualifying ACS event.
• Active liver disease defined as: (i) any known current infectious, neoplastic, or metabolic pathology of the liver or (ii) alanine aminotransferase (ALT) elevation >3x ULN or aspartate aminotransferase (AST) elevation >3x ULN, or total bilirubin elevation >2x ULN (except participant with Gilbert's syndrome) at the Screening visit, in the context of an ACS, and assessed as related to the index event and/or treatment procedures (such as PCI). Eligibility will be based on Investigator's judgement for participant who will be randomized.
• Renal insufficiency (eGFR <30 mL/min/1.73m2) at the Screening visit.
• Fasting triglycerides value >400 mg/dL (4.52 mmol/L; assessed by local labs) at randomization visit.
• Participant, who based on the Investigator's judgement, could reach the LDL-C target value of <55 mg/dL after 4 weeks on statin treatment only.
• Secondary hypercholesterolemia (based on medical history).
• Homozygous familial hypercholesterolemia (based on medical history).
• Participant on apheresis at the Screening visit.
• Ongoing or medical history of myopathy at the Screening visit.
• CK values ≥5x ULN at Screening visit and confirmed by repeat test during Screening (local lab) , in the context of an ACS, and assessed as related to the index event and/or treatment procedures (such as PCI) eligibility will be based on Investigator's judgement for participant who will be randomized (who will be switched to or initiated on the protocol-specified dose of high-intensity statin of atorvastatin ≥40 mg QD or rosuvastatin ≥20 mg QD). Unless a more stringent CK value threshold is mandated by a local regulatory authority (e.g., ≥3x ULN in Korea according to MFDS internal guideline).