VictORION-INCLUSION: Evaluating Inclisiran for Cholesterol Managment in Heart Disease

VictORION-INCLUSION (V-INCLUSION) seeks to evaluate the effectiveness of inclisiran as an innovative therapy with the potential to help bridge care gaps in historically understudied and undertreated populations by leveraging electronic health records (EHR) in multiple US Healthcare Systems (HCS) to systematically identify those at high risk for and already diagnosed with ASCVD for more expeditious achievement of LDL-C targets.

The trial consists of two parts. Part 1 is a randomized, controlled, multicenter, open-label two arm trial comparing inclisiran and usual care versus usual care alone in an inclusive study population identified by electronic health records. Part 2 is a single arm trial consisting of Part 1 usual care participants initiating inclisiran at Day 360, and receiving two additional doses on day 450 and 630 (dosed in similar fashion to inclisiran + UC arm in Part 1). Approximately 1440 participants will be randomized to either inclisiran + usual care or to usual care only. Eligible participants must be at high risk for or be diagnosed with established ASCVD (prior CAD, PAD, CeVD event) and LDL-C above treatment threshold despite treatment with statin therapy (or with documented statin intolerance).

The study population will consist of underrepresented and historically understudied male and female participants (at least 50% female, 70% underrepresented \[Black/African American, Hispanic/Latino, Asian, other\] and 10% rural participants of any sex or race/ethnicity) ≥18 years of age with a history of ASCVD (coronary artery disease, ischemic cerebrovascular disease or peripheral arterial disease) or ASCVD risk equivalent (HeFH, Type 2 DM, or 10 year ASCVD risk score ≥ 20%) who have elevated LDL-C (≥ 70 mg/dL or LDL-C ≥ 100 mg/dL) respectively) despite being treated with statin therapy. A total of approximately 1440 participants will be randomized to inclisiran + usual care or usual care in a 1:1 ratio at approximately 30 US healthcare systems.

Eligibility Criteria:
Inclusion Criteria: Must meet all criteria below.

1. Males and females \>= 18 years of age
2. Have clinical ASCVD or ASCVD risk equivalent diagnosis captured in EHR
3. Serum LDL-C ≥ 70 mg/dL for participants with ASCVD, or LDL-C ≥ 100 mg/dL for ASCVD risk equivalent participants, based on last recorded LDL-C value within the preceding eighteen (18) months without a subsequent change in lipid lowering therapy.
4. Willing and able to give informed consent before initiation of any study related procedures and willing to comply with all required study procedures.
5. On statin therapy, or have documented statin intolerance, as determined by the treating clinician.
6. From historically underrepresented populations in cardiovascular clinical research, including at least one of the following: female sex; Hispanic/Latino ethnicity; Black/African-American, Asian, or Native American race; rural dwelling based on the HRSA definition for determining rural grant eligibility.

Exclusion Criteria: Cannot meet any criteria below.

1. Planned use of other investigational products or devices during the course of the study.
2. Treatment with monoclonal antibodies directed towards PCSK9 within 90 days or with inclisiran within 180 days of pre-screening.
3. History of hypersensitivity to the study treatment or its excipients or to other siRNA drugs.
4. Pregnant or nursing (lactating) women.
5. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using basic methods of contraception during dosing of study treatment.
6. New York Heart Association (NYHA) class III or IV heart failure or last known left ventricular ejection fraction \<25%.
7. Significant cardiac arrhythmia within 3 months prior to randomization that is not controlled by medication or other methods (i.e. via ablation etc.) at the time of pre-screening.
8. Uncontrolled hypertension: systolic blood pressure \>180 mmHg or diastolic blood pressure \>110 mmHg prior to randomization despite antihypertensive therapy.
9. Active liver disease defined as any known current infectious, neoplastic, or metabolic pathology of the liver or alanine aminotransferase (ALT) elevation \>3x ULN, aspartate aminotransferase (AST) elevation \>3x ULN, or total bilirubin elevation \>2x ULN (except participants with Gilbert's syndrome) at pre-screening confirmed by a repeat measurement at least one week apart.
10. End-stage renal disease (ESRD)