Trial to Evaluate the Effect of ALN-PCSSC Treatment on Low Density Lipoprotein Cholesterol (LDL-C)
Condition: Atherosclerotic Cardiovascular Disease; Familial Hypercholesterolemia; Diabetes
MeSH terms: Cardiovascular Diseases; Atherosclerosis; Hyperlipoproteinemia Type II; Hypercholesterolemia
Intervention: ALN-PCSSC; Normal Saline
Intervention description: ALN-PCSSC is a small interfering ribonucleic acid (RNA) that inhibits PCSK9 synthesis and is given as SC injections; Saline (sterile, normal, 0.9%) solution given as SC injections
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 501.0
Sex: All
Minimum age: 18 Years
Maximum age: 99 Years
Healthy volunteers: No

Summary:

      This study is a Phase II, placebo-controlled, double-blind, randomized trial in 480
      participants with atherosclerotic cardiovascular disease (ASCVD) or ASCVD-risk equivalents
      (for example, diabetes and familial hypercholesterolemia) and elevated LDL-C despite maximum
      tolerated dose of LDL-C lowering therapies to evaluate the efficacy, safety, and tolerability
      of ALN-PCSSC injection(s).
    

Eligibility criteria:

        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.