ASCVD, Elevated Cholesterol
Conditions
Keywords
Inclisiran sodium, ASCVD, LDL-C
Brief summary
This is a Phase III, placebo-controlled, double-blind, randomized study in participants with ASCVD 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 a multicenter study in the 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
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. Participants on statins should be receiving a maximally tolerated dose. 6. Participants not receiving statins must have documented evidence of intolerance to all doses of at least 2 different statins. 7. 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.
Exclusion criteria
1. New York Heart Association (NYHA) class IV heart failure. 2. Uncontrolled cardiac arrhythmia 3. Uncontrolled severe hypertension 4. Active liver disease 5. Females who are pregnant or nursing, or who are of childbearing potential and unwilling to use at least 2 methods of highly effective contraception (failure rate less than 1% per year) (for example, combined oral contraceptives, barrier methods, approved contraceptive implant, long-term injectable contraception, or intrauterine device) for the entire duration of the study. Exemptions from this criterion: 1. Women \>2 years postmenopausal (defined as 1 year or longer since last menstrual period) and more than 55 years of age. 2. Postmenopausal women (as defined above) and less than 55 years of age with a negative pregnancy test within 24 hours of randomization. 3. Women who are surgically sterilized at least 3 months prior to enrollment. 6. Males who are unwilling to use an acceptable method of birth control during the entire study period (such as condom with spermicide). 7. Treatment with other investigational products or devices within 30 days or 5 half-lives of the screening visit, whichever is longer. 8. Treatment (within 90 days of screening) with monoclonal antibodies directed towards PCSK9 The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change in LDL-C From Baseline to Day 510 | Baseline, Day 510 | — |
| Time-adjusted Percentage Change in LDL-C Levels From Baseline After Day 90 and up to Day 540 | Baseline, Day 90 to Day 540 | Assessments performed at Baseline, Day 90, Day 540, time-adjusted percent change at Day 540 reported |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | — |
| Absolute Change in LDL-C From Baseline to Day 510 | Baseline, Day 510 | — |
| Percentage Change in Non-HDL-C From Baseline to Day 510 | Baseline, Day 510 | — |
| Percentage Change in Apolipoprotein B (ApoB) 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 | Assessments performed at Baseline, Day 90, Day 540, time-adjusted percent change at Day 540 reported |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Inclisiran Inclisiran sodium 300 milligrams (mg) will be administered as a SC injection on Day 1, Day 90, then every 6 months.
Inclisiran Sodium: Inclisiran is a small interfering ribonucleic acid (RNA) that inhibits PCSK9 synthesis. | 781 |
| Placebo Placebo will be administered as a SC injection of saline solution on Day 1, Day 90, then every 6 months.
Placebo will be supplied as sterile normal saline (0.9% sodium chloride in water for injection). | 780 |
| Total | 1,561 |
Baseline characteristics
| Characteristic | Placebo | Total | Inclisiran |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 447 Participants | 931 Participants | 484 Participants |
| Age, Categorical Between 18 and 65 years | 333 Participants | 630 Participants | 297 Participants |
| Age, Continuous | 65.7 years STANDARD_DEVIATION 8.89 | 66.0 years STANDARD_DEVIATION 8.9 | 66.4 years STANDARD_DEVIATION 8.9 |
| Race (NIH/OMB) American Indian or Alaska Native | 4 Participants | 6 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 10 Participants | 9 Participants |
| Race (NIH/OMB) Black or African American | 87 Participants | 197 Participants | 110 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 3 Participants | 10 Participants | 7 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 685 Participants | 1338 Participants | 653 Participants |
| Region of Enrollment United States | 780 participants | 1561 participants | 781 participants |
| Sex: Female, Male Female | 232 Participants | 478 Participants | 246 Participants |
| Sex: Female, Male Male | 548 Participants | 1083 Participants | 535 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 12 / 781 | 11 / 778 |
| other Total, other adverse events | 247 / 781 | 219 / 778 |
| serious Total, serious adverse events | 175 / 781 | 205 / 778 |
Outcome results
Primary
Percentage Change in LDL-C From Baseline to Day 510
Time frame: Baseline, Day 510
Population: Intent-to-treat (ITT) population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Inclisiran | Percentage Change in LDL-C From Baseline to Day 510 | -56.34 percent change |
| Placebo | Percentage Change in LDL-C From Baseline to Day 510 | 1.30 percent change |
p-value: <0.000195% CI: [-60.86, -54.43]ANCOVA
Primary
Time-adjusted Percentage Change in LDL-C Levels From Baseline After Day 90 and up to Day 540
Assessments performed at Baseline, Day 90, Day 540, time-adjusted percent change at Day 540 reported
Time frame: Baseline, Day 90 to Day 540
Population: Intent-to-treat (ITT) population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Inclisiran | Time-adjusted Percentage Change in LDL-C Levels From Baseline After Day 90 and up to Day 540 | -51.27 percent change |
| Placebo | Time-adjusted Percentage Change in LDL-C Levels From Baseline After Day 90 and up to Day 540 | 2.51 percent change |
p-value: <0.000195% CI: [-56.23, -51.33]ANCOVA
Secondary
Absolute Change in LDL-C From Baseline to Day 510
Time frame: Baseline, Day 510
Population: Intent-to-treat (ITT) population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Inclisiran | Absolute Change in LDL-C From Baseline to Day 510 | -56.18 mg/dL |
| Placebo | Absolute Change in LDL-C From Baseline to Day 510 | -2.06 mg/dL |
p-value: <0.000195% CI: [-57.37, -50.88]ANCOVA
Secondary
Percentage Change in Apolipoprotein B (ApoB) From Baseline to Day 510
Time frame: Baseline, Day 510
Population: Intent-to-treat (ITT) population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Inclisiran | Percentage Change in Apolipoprotein B (ApoB) From Baseline to Day 510 | -44.81 percent change |
| Placebo | Percentage Change in Apolipoprotein B (ApoB) From Baseline to Day 510 | -1.72 percent change |
p-value: <0.000195% CI: [-45.5, -40.67]ANCOVA
Secondary
Percentage Change in Non-HDL-C From Baseline to Day 510
Time frame: Baseline, Day 510
Population: Intent-to-treat (ITT) population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Inclisiran | Percentage Change in Non-HDL-C From Baseline to Day 510 | -47.41 percent change |
| Placebo | Percentage Change in Non-HDL-C From Baseline to Day 510 | -0.05 percent change |
p-value: <0.000195% CI: [-50.25, -44.47]ANCOVA
Secondary
Percentage Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) From Baseline to Day 510
Time frame: Baseline, Day 510
Population: Intent-to-treat (ITT) population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Inclisiran | Percentage Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) From Baseline to Day 510 | -69.78 percent change |
| Placebo | Percentage Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) From Baseline to Day 510 | 13.52 percent change |
p-value: <0.000195% CI: [-89.25, -77.34]ANCOVA
Secondary
Percentage Change in Total Cholesterol From Baseline to Day 510
Time frame: Baseline, Day 510
Population: Intent-to-treat (ITT) population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Inclisiran | Percentage Change in Total Cholesterol From Baseline to Day 510 | -33.56 percent change |
| Placebo | Percentage Change in Total Cholesterol From Baseline to Day 510 | -0.42 percent change |
p-value: <0.000195% CI: [-35.3, -30.97]ANCOVA
Secondary
Time-adjusted Absolute Change in LDL-C From Baseline After Day 90 and up to Day 540
Assessments performed at Baseline, Day 90, Day 540, time-adjusted percent change at Day 540 reported
Time frame: Baseline, Day 90 to Day 540
Population: Intent-to-treat (ITT) population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Inclisiran | Time-adjusted Absolute Change in LDL-C From Baseline After Day 90 and up to Day 540 | -53.66 mg/dL |
| Placebo | Time-adjusted Absolute Change in LDL-C From Baseline After Day 90 and up to Day 540 | -0.39 mg/dL |
p-value: <0.000195% CI: [-55.75, -50.8]ANCOVA