Trial to Evaluate the Effect of ALN-PCSSC Treatment on Low Density Lipoprotein Cholesterol (LDL-C) (ORION-1)

This is an interventional treatment trial for Atherosclerotic Cardiovascular Disease Read More

Inclusion Criteria:

1. Male or female participants ≥18 years of age.
2. History of ASCVD or ASCVD-risk equivalents (symptomatic atherosclerosis, Type 2 diabetes, familial hypercholesterolemia, including participants whose 10-year risk of a CV event assessed by Framingham Risk Score (Framingham Risk Score >20%) or equivalent has a target LDL-C of <100 mg/deciliter [dL]).
3. Serum LDL-C ≥1.8 millimole (mmol)/liter (L) (≥70 mg/dL) for ASCVD participants or ≥2.6 mmol/L (≥100 mg/dL) for ASCVD-risk equivalent participants at screening.
4. Fasting triglyceride <4.52 mmol/L (<400 mg/dL) at screening.
5. Calculated glomerular filtration rate 30 mL/min or higher by estimated glomerular filtration rate (eGFR) using standardized local clinical methodology.
6. Participants on statins should be receiving a maximally tolerated dose (investigator's discretion).
7. Participants on lipid-lower therapies (such as statin and/or ezetimibe) should be on a stable dose for ≥30 days before screening with no planned medication or dose change during study participation.
8. Willing and able to give informed consent before initiation of any study-related procedures and willing to comply with all required study procedures.

Exclusion Criteria:

1. Any uncontrolled or serious disease, or any medical or surgical condition, that may either interfere with participation in the clinical study, and/or put the participant at significant risk (according to investigator's [or delegate] judgment) if he/she participates in the clinical study.
2. An underlying known disease, or surgical, physical, or medical condition that, in the opinion of the investigator (or delegate), might interfere with interpretation of the clinical study results.
3. New York Heart Association (NYHA) class II, III, or IV heart failure or last known left ventricular ejection fraction <30%.
4. Cardiac arrhythmia within 3 months prior to randomization that is not controlled by medication or via ablation.
5. Any history of hemorrhagic stroke.
6. Major adverse cardiac event within 6 months prior to randomization.
7. Uncontrolled severe hypertension: systolic blood pressure >180 millimeters of mercury (mmHg) or diastolic blood pressure >110 mmHg prior to randomization despite anti-hypertensive therapy.
8. Poorly controlled Type 2 diabetes, such as, glycated hemoglobin A1c (HbA1c)>10.0% prior to randomization.
9. Active liver disease defined as any known current infectious, neoplastic, or metabolic pathology of the liver or unexplained alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevation >2x the upper limit of normal (ULN), or total bilirubin elevation >1.5x ULN at screening confirmed by a repeat measurement at least 1 week apart.
10. Serious comorbid disease in which the life expectancy of the participant is shorter than the duration of the trial (for example, acute systemic infection, cancer, or other serious illnesses). This includes all cancers with the exception of treated basal-cell carcinoma occurring >5 years before screening.
11. Females who are pregnant or nursing, or who are of childbearing potential and unwilling to use at least two methods of contraception (oral contraceptives, barrier methods, approved contraceptive implant, long-term injectable contraception, intrauterine device or tubal litigation) for the entire duration of the study. Women who are >2 years postmenopausal defined as ≥1 year since last menstrual period and if less than 55 years old with a negative pregnancy test within 24 hours of randomization or surgically sterile are exempt from this exclusion.
12. Males who are unwilling to use an acceptable method of birth control during the entire study period (such as, condom with spermicide).
13. Known history of alcohol and/or drug abuse within the last 5 years.
14. Treatment with other investigational medicinal products or devices within 30 days or five half˗lives, whichever is longer.
15. Use of other investigational medicinal products or devices during the course of the study.

16. Any condition that according to the investigator could interfere with the conduct of the study, such as but not limited to the following:

    • Inappropriate for this study, including participants who are unable to communicate or to cooperate with the investigator.
    • Unable to understand the protocol requirements, instructions and study-related restrictions, the nature, scope, and possible consequences of the study (including participants whose cooperation is doubtful due to drug abuse or alcohol dependency).
    • Unlikely to comply with the protocol requirements, instructions, and study-related restrictions (for example, uncooperative attitude, inability to return for follow-up visits, and improbability of completing the study).
    • Have any medical or surgical condition, which in the opinion of the investigator would put the participants at increased risk from participating in the study.
    • Involved with, or a relative of, someone directly involved in the conduct of the study.
    • Any known cognitive impairment (for example, Alzheimer's disease)
17. Previous or current treatment (within 90 days of screening) with monoclonal antibodies directed at PCSK9.