ASCVD, Elevated Cholesterol, Risk Factor, Cardiovascular
Conditions
Keywords
Inclisiran sodium, ASCVD, LDL-C
Brief summary
This is a Phase III, placebo-controlled, double-blind, randomized study in participants with ASCVD or ASCVD-Risk equivalents and elevated LDL-C despite maximum tolerated dose of LDL-C lowering therapies to evaluate the efficacy, safety, and tolerability of subcutaneous (SC) inclisiran injection(s). The study will be an international multicenter study (non-United States).
Interventions
Inclisiran is a small interfering ribonucleic acid (RNA) that inhibits PCSK9 synthesis.
DRUGPlacebo
Placebo will be supplied as sterile normal saline (0.9% sodium chloride in water for injection).
Sponsors
The Medicines Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Caregiver)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Participants may be included if they meet all of the following inclusion criteria prior to randomization: 1. Male or female participants ≥18 years of age. 2. History of ASCVD (coronary heart disease \[CHD\], cardiovascular disease \[CVD\], or peripheral arterial disease \[PAD\]). 3. Serum LDL-C ≥1.8 millimole (mmol)/liter (L) (≥70 mg/dL). 4. Fasting triglyceride \<4.52 mmol/L (\<400 mg/dL) at screening. 5. Calculated glomerular filtration rate \>30 mL/min by estimated glomerular filtration rate (eGFR) using standardized clinical methodology 6. Participants on statins should be receiving a maximally tolerated dose. 7. Participants not receiving statins must have documented evidence of intolerance to all doses of at least 2 different statins. 8. Subjects on lipid-lower therapies (such as a 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. 9. Subjects were 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
Participants will be excluded from the study if any of the following
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Percentage Change in LDL-C From Baseline to Day 510 | Baseline, Day 510 |
| Time-adjusted Percent Change in LDL-C Levels From Baseline After Day 90 and up to Day 540 | Baseline, Day 90 to Day 540 |
Secondary
| Measure | Time frame |
|---|---|
| Absolute Change In LDL-C From Baseline To Day 510 | Baseline, Day 510 |
| Time-adjusted Absolute Change in LDL-C From Baseline After Day 90 and up to Day 540 | Baseline, Day 90 to Day 540 |
| Percentage Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) From Baseline to Day 510 | Baseline, Day 510 |
| Percentage Change in Total Cholesterol From Baseline to Day 510 | Baseline, Day 510 |
| Percentage Change in Apolipoprotein B (ApoB) From Baseline to Day 510 | Baseline, Day 510 |
| Percentage Change in Non-HDL-C From Baseline to Day 510 | Baseline, Day 510 |
Countries
Czechia, Germany, Hungary, Poland, South Africa, Ukraine, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Inclisiran Inclisiran sodium 300 milligrams (mg) (equivalent to 284 mg inclisiran) in 1.5 milliliters (mL) will be administered as a SC injection on Day 1, Day 90, and then every 6 months
Inclisiran Sodium: Inclisiran is a small interfering ribonucleic acid (RNA) that inhibits PCSK9 synthesis. | 810 |
| Placebo Placebo (1.5 mL) will be administered as a SC injection of saline solution on Day 1, Day 90, and then every 6 months
Placebo will be supplied as sterile normal saline (0.9% sodium chloride in water for injection). | 807 |
| Total | 1,617 |
Baseline characteristics
| Characteristic | Inclisiran | Total | Placebo |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 443 Participants | 884 Participants | 441 Participants |
| Age, Categorical Between 18 and 65 years | 367 Participants | 733 Participants | 366 Participants |
| Age, Continuous | 64.8 years STANDARD_DEVIATION 8.29 | 64.8 years STANDARD_DEVIATION 8.48 | 64.8 years STANDARD_DEVIATION 8.68 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 6 Participants | 8 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 12 Participants | 20 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 791 Participants | 1587 Participants | 796 Participants |
| Region of Enrollment Czechia | 10 participants | 21 participants | 11 participants |
| Region of Enrollment Germany | 42 participants | 83 participants | 41 participants |
| Region of Enrollment Hungary | 52 participants | 104 participants | 52 participants |
| Region of Enrollment Poland | 360 participants | 717 participants | 357 participants |
| Region of Enrollment South Africa | 60 participants | 121 participants | 61 participants |
| Region of Enrollment Ukraine | 55 participants | 109 participants | 54 participants |
| Region of Enrollment United Kingdom | 231 participants | 462 participants | 231 participants |
| Sex: Female, Male Female | 231 Participants | 457 Participants | 226 Participants |
| Sex: Female, Male Male | 579 Participants | 1160 Participants | 581 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 14 / 811 | 15 / 804 |
| other Total, other adverse events | 331 / 811 | 319 / 804 |
| serious Total, serious adverse events | 181 / 811 | 181 / 804 |
Outcome results
Primary
Percentage Change in LDL-C From Baseline to Day 510
Time frame: Baseline, Day 510
Population: ITT population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Inclisiran | Percentage Change in LDL-C From Baseline to Day 510 | -49.3 Percent change |
| Placebo | Percentage Change in LDL-C From Baseline to Day 510 | 4.2 Percent change |
p-value: <0.000195% CI: [-56.66, -50.35]ANCOVA
Primary
Time-adjusted Percent Change in LDL-C Levels From Baseline After Day 90 and up to Day 540
Time frame: Baseline, Day 90 to Day 540
Population: ITT population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Inclisiran | Time-adjusted Percent Change in LDL-C Levels From Baseline After Day 90 and up to Day 540 | -45.82 Percent change |
| Placebo | Time-adjusted Percent Change in LDL-C Levels From Baseline After Day 90 and up to Day 540 | 3.35 Percent change |
p-value: <0.000195% CI: [-51.57, -46.77]ANCOVA
Secondary
Absolute Change In LDL-C From Baseline To Day 510
Time frame: Baseline, Day 510
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Inclisiran | Absolute Change In LDL-C From Baseline To Day 510 | -50.91 mg/dL |
| Placebo | Absolute Change In LDL-C From Baseline To Day 510 | 0.96 mg/dL |
p-value: <0.000195% CI: [-55.01, -48.72]ANCOVA
Secondary
Percentage Change in Apolipoprotein B (ApoB) From Baseline to Day 510
Time frame: Baseline, Day 510
Population: ITT Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Inclisiran | Percentage Change in Apolipoprotein B (ApoB) From Baseline to Day 510 | -38.15 Percent change |
| Placebo | Percentage Change in Apolipoprotein B (ApoB) From Baseline to Day 510 | 0.79 Percent change |
p-value: <0.000195% CI: [-41.21, -36.67]ANCOVA
Secondary
Percentage Change in Non-HDL-C From Baseline to Day 510
Time frame: Baseline, Day 510
Population: ITT Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Inclisiran | Percentage Change in Non-HDL-C From Baseline to Day 510 | -41.16 Percent change |
| Placebo | Percentage Change in Non-HDL-C From Baseline to Day 510 | 2.15 Percent change |
p-value: <0.000195% CI: [-46.04, -40.6]ANCOVA
Secondary
Percentage Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) From Baseline to Day 510
Time frame: Baseline, Day 510
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Inclisiran | Percentage Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) From Baseline to Day 510 | -63.64 Percent change |
| Placebo | Percentage Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) From Baseline to Day 510 | 15.62 Percent change |
p-value: <0.000195% CI: [-81.97, -76.57]ANCOVA
Secondary
Percentage Change in Total Cholesterol From Baseline to Day 510
Time frame: Baseline, Day 510
Population: ITT Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Inclisiran | Percentage Change in Total Cholesterol From Baseline to Day 510 | -28.00 Percent change |
| Placebo | Percentage Change in Total Cholesterol From Baseline to Day 510 | 1.79 Percent change |
p-value: <0.000195% CI: [-31.78, -27.81]ANCOVA
Secondary
Time-adjusted Absolute Change in LDL-C From Baseline After Day 90 and up to Day 540
Time frame: Baseline, Day 90 to Day 540
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Inclisiran | Time-adjusted Absolute Change in LDL-C From Baseline After Day 90 and up to Day 540 | -48.63 mg/dL |
| Placebo | Time-adjusted Absolute Change in LDL-C From Baseline After Day 90 and up to Day 540 | 0.31 mg/dL |
p-value: <0.000195% CI: [-51.39, -46.48]ANCOVA