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

Study Overview
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Brief Summary
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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).

Detailed Description
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Participants will be screened and 480 eligible participants will be randomized: 60 participants per each of six ALN-PCSSC dose groups plus 120 participants total across the placebo groups (20 participants each to match each of the six drug dose groups). Treatment allocation will be stratified by country and by current use of statins or other lipid-modifying therapies. Each participant will receive either one or two injections on Day 1 or a single injection on Day 1 and on Day 90 of blinded ALN-PCSSC or placebo. Formation of anti-drug antibodies (ADA) will be assessed on Day 1 (prior to and 4 hours after the injection) and on Days 30, 60, 90, 120, 150, 180 (Days 150 and 180 only in participants who receive a second dose of study drug), and 210 or until any ADA response becomes negative within the study duration. The independent Data Monitoring Committee (DMC) will review safety data beginning after the first 40 participants receive the first injection of ALN-PCSSC or placebo and complete the Day 14 follow-up visit. Thereafter, the DMC will review safety data every 2 months until the end of the trial. A recommendation may be taken to stop or amend the study at any of these reviews. On Day 1, all eligible participants will be randomized and receive the first subcutaneous (SC) administration of ALN-PCSSC or placebo. After the first study drug administration, the participant will be observed in the clinic for at least 4 hours post injection before being discharged. Participants will return at Day 14 and then at monthly intervals for 6 months. Participants randomized to receive a second dose of study drug will receive the second injection of ALN-PCSSC or placebo at the Day 90 visit. Efficacy assessments will include the measurement of the effects of ALN-PCSSC on levels of LDL-C lipids and lipoproteins including total cholesterol (TC), triglycerides, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, very low-density lipoprotein (VLDL), apolipoprotein A1 (Apo-AI), apolipoprotein B (Apo-B), lipoprotein (a) [Lp(a)], C-reactive protein (CRP), and proprotein convertase subtilisin/kexin type 9 (PCSK9). End of study (EOS) evaluations will be conducted at the EOS visit (Day 210). The expected duration of the participants' involvement in the study will be approximately 374 days, which includes screening, study drug administration, the course of single or multiple injections, and the follow-up period to Day 360. Participants completing the study to Day 210 will be given the opportunity to enroll in a separate long-term extension study. Any participants in whom LDL-C levels have not returned to >80% of baseline values will continue to be followed as part of this study until either this level has been reached or until a maximum of Day 360, at which point they will be given the opportunity to enroll in the long-term extension study. At each visit, LDL-C levels, adverse events, serious adverse events, concomitant medications, and safety laboratory assessments will be collected. Objectives: Primary: To evaluate the effect of ALN-PCSSC treatment on LDL-C levels at Day 180. Secondary: To evaluate the effect of ALN-PCSSC on the following: LDL-C at Day 90 LDL-C levels at other time points PCSK9 levels over time Other lipids, lipoproteins, apolipoproteins Proportion of participants achieving pre-specified global lipid guidelines Individual responsiveness to different doses Duration of lipid-lowering effect of different doses Safety and tolerability profile of ALN-PCSSC Exploratory: To collect/evaluate the effect of ALN-PCSSC on the following: Cardiovascular (CV) events such as CV death, non-fatal myocardial infarction, resuscitated cardiac arrest and non-fatal stroke (ischemic and hemorrhagic) Evaluation of ADA for the investigational product

Official Title
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A Placebo-controlled, Double-blind, Randomized Trial to Compare the Effect of Different Doses of ALN-PCSSC Given as Single or Multiple Subcutaneous Injections in Subjects With High Cardiovascular Risk and Elevated LDL-C

Conditions
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Atherosclerotic Cardiovascular Disease, Familial Hypercholesterolemia, Diabetes

Intervention / Treatment
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* Drug: ALN-PCSSC
* Drug: Normal Saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female participants ≥18 years of age. 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]). 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. Fasting triglyceride <4.52 mmol/L (<400 mg/dL) at screening. Calculated glomerular filtration rate 30 mL/min or higher by estimated glomerular filtration rate (eGFR) using standardized local clinical methodology. Participants on statins should be receiving a maximally tolerated dose (investigator's discretion). 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. 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: 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. 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. New York Heart Association (NYHA) class II, III, or IV heart failure or last known left ventricular ejection fraction <30%. Cardiac arrhythmia within 3 months prior to randomization that is not controlled by medication or via ablation. Any history of hemorrhagic stroke. Major adverse cardiac event within 6 months prior to randomization. Uncontrolled severe hypertension: systolic blood pressure >180 millimeters of mercury (mmHg) or diastolic blood pressure >110 mmHg prior to randomization despite anti-hypertensive therapy. Poorly controlled Type 2 diabetes, such as, glycated hemoglobin A1c (HbA1c)>10.0% prior to randomization. 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. 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. 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. Males who are unwilling to use an acceptable method of birth control during the entire study period (such as, condom with spermicide). Known history of alcohol and/or drug abuse within the last 5 years. Treatment with other investigational medicinal products or devices within 30 days or five half˗lives, whichever is longer. Use of other investigational medicinal products or devices during the course of the study. 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) Previous or current treatment (within 90 days of screening) with monoclonal antibodies directed at PCSK9.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ALN-PCSSC 200 mg (bi-annual dosing)<br>ALN-PCSSC 200 milligram (mg) SC administration once at Day 1 | Drug: ALN-PCSSC<br>* ALN-PCSSC is a small interfering ribonucleic acid (RNA) that inhibits PCSK9 synthesis and is given as SC injections<br>* Other names: Inclisiran;|
| Experimental: ALN-PCSSC 300 mg (bi-annual dosing)<br>ALN-PCSSC 300 mg SC administration once at Day 1 | Drug: ALN-PCSSC<br>* ALN-PCSSC is a small interfering ribonucleic acid (RNA) that inhibits PCSK9 synthesis and is given as SC injections<br>* Other names: Inclisiran;|
| Experimental: ALN-PCSSC 500 mg (bi-annual dosing)<br>ALN-PCSSC 500 mg SC administration once at Day 1 | Drug: ALN-PCSSC<br>* ALN-PCSSC is a small interfering ribonucleic acid (RNA) that inhibits PCSK9 synthesis and is given as SC injections<br>* Other names: Inclisiran;|
| Placebo Comparator: Normal Saline (bi-annual dosing)<br>Saline SC administration once at Day 1 | Drug: Normal Saline<br>* Saline (sterile, normal, 0.9%) solution given as SC injections<br>|
| Experimental: ALN-PCSSC 100 mg (quarterly dosing)<br>ALN-PCSSC 100 mg SC administration twice at Day 1 and Day 90 | Drug: ALN-PCSSC<br>* ALN-PCSSC is a small interfering ribonucleic acid (RNA) that inhibits PCSK9 synthesis and is given as SC injections<br>* Other names: Inclisiran;|
| Experimental: ALN-PCSSC 200 mg (quarterly dosing)<br>ALN-PCSSC 200 mg SC administration twice at Day 1 and Day 90 | Drug: ALN-PCSSC<br>* ALN-PCSSC is a small interfering ribonucleic acid (RNA) that inhibits PCSK9 synthesis and is given as SC injections<br>* Other names: Inclisiran;|
| Experimental: ALN-PCSSC 300 mg (quarterly dosing)<br>ALN-PCSSC 300 mg SC administration twice at Day 1 and Day 90 | Drug: ALN-PCSSC<br>* ALN-PCSSC is a small interfering ribonucleic acid (RNA) that inhibits PCSK9 synthesis and is given as SC injections<br>* Other names: Inclisiran;|
| Placebo Comparator: Normal Saline (quarterly dosing)<br>Saline SC administration twice at Day 1 and Day 90 | Drug: Normal Saline<br>* Saline (sterile, normal, 0.9%) solution given as SC injections<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage Change in LDL-C From Baseline to Day 180 | Percent Change in LDL-C (beta-quantification) from Baseline to Day 180 in MITT Population | Baseline to 180 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage Change in LDL-C From Baseline to Day 90 | Percent Change in LDL-C (beta-quantification) from Baseline to Day 90 in MITT Population | Baseline to 90 days | 
| Percent Change From Baseline In LDL-C Levels At Day 60, Day 120, and Day 210 | This outcome measure evaluated the effects of both single- and double-dose inclisiran on LDL-C levels in the mITT population from baseline to Day 60, Day 120, and Day 210. | Baseline, Day 60, Day 120, and Day 210 | 
| Number of Participants With an LDL-C Greater Than 80% of the Baseline Value at Day 180 and Day 210 | This outcome measure evaluated the number of participants (single and double dose) in the mITT population with an LDL-C greater than 80% of the baseline value at Day 180 and Day 210. | Baseline, Day 180, Day 210 | 
| Number of Participants With Individual Responsiveness as Measured By LDL-C Levels at Day 90 and Day 180 | This outcome measure evaluated the individual responsiveness of participants to inclisiran (single and double dose) in the mITT population as defined by an LDL-C level of <25 mg/deciliter [dL] at Day 90 and Day 180. | Day 90, Day 180 | 
| Number of Participants With Greater Or Equal To 50% LDL-C Reduction From Baseline At Day 180 | This outcome measure evaluated the number of participants (single and double dose) in the mITT population with an LDL-C reduction greater than 50% of the baseline value at Day 180. | Baseline, Day 180 | 
| Percentage Change in PCSK9 Levels From Baseline at Day 180 | This outcome measure evaluated the percent change in proprotein convertase subtilisin/kexin type 9 (PCSK9) from baseline to Day 180 in participants (single and double dose) in the mITT population. | Baseline, Day 180 | 
| Percentage Change in Other Lipids and Apolipoproteins From Baseline to Day 180 | This outcome measure evaluated the percent change from baseline to Day 180 in cholesterol (total, high-density lipoprotein [HDL], non-HDL) and apolipoproteins (B, A1) in participants (single and double dose) in the mITT population. | Baseline, Day 180 | 
| Number of Participants Who Attained Global Lipid Modification Targets for Level of Atherosclerotic Cardiovascular Disease Risk | This outcome measure evaluated the proportion of participants (single and double dose) in the mITT population who attained a global lipid modification target by baseline cardiovascular risk group, looking specifically at LDL-C levels (mg/dL) in the category of cardiovascular disease (CVD). CVD was defined as a participant who had at least 1 of the following: prior myocardial infarction, prior percutaneous coronary intervention, prior coronary artery bypass graft, prior stroke, prior transient ischemic attack, peripheral artery disease. | Baseline, Day 180 | 
| Percentage Change in Other Lipids and Inflammatory Markers From Baseline to Day 180 | This outcome measure evaluated the percent change from baseline to Day 180 in triglycerides, very-low-density lipoprotein (VLDL) cholesterol, lipoprotein(a), and high sensitivity C-reactive protein (hsCRP) in participants (single and double dose) in the mITT population. | Baseline, Day 180 |