Primary Hypercholesterolemia or Mixed Dyslipidemia
Conditions
Keywords
Inclisiran, LDL-C, monotherapy, atherosclerotic cardiovascular disease, atheroma, Atherosclerosis, lipid, lipid lowering therapy (LLT), cholesterol, hypercholesteremia, mixed dyslipidemia, TC (total cholesterol), Apo B, non HDL-C, Lp(a), PCSK9, PCSK9 inhibitor, siRNA, low ASCVD risk, moderate ASCVD risk
Brief summary
The purpose of this study was to evaluate the efficacy and safety of inclisiran as a monotherapy in Chinese adults with low or moderate atherosclerotic cardiovascular disease (ASCVD) risk and elevated low-density lipoprotein cholesterol (LDL-C) who were not on any lipid lowering therapy.
Detailed description
This study was designed as a randomized, double-blind, multi-center Phase III trial, with a placebo-controlled treatment period and an open label treatment period, to evaluate the efficacy and safety of inclisiran sodium 300 mg s.c. in participants aged 18 to 75 years with a low or moderate ASCVD risk and fasting LDL-C value of ≥ 130 mg/dL but \< 190 mg/dL who were not on any lipid lowering therapy. The study consisted of 3 parts: * Screening: the screening period was up to 14 days to allow adequate time for the eligibility evaluations. * Core Part: a double-blind, placebo-controlled treatment period of 180 days in which eligible participants were randomized 1:1 to receive either inclisiran sodium 300 mg s.c. (inclisiran group) or matching placebo s.c. (control group) on Day 1 and Day 90. The end of core part (EOC) visit was conducted on Day 180. The database lock for the core part was planned to occur after all randomized participants have completed the EOC visit (or have discontinued from the study before EOC). The primary analysis was conducted after the database lock for the core part. • Extension Part: an extended treatment period of 180 days. In the extension part, participants originally randomized to inclisiran in the core part were to continue the inclisiran treatment while participants initially randomized to placebo were to transit to the inclisiran. The extension part was to start from the Day 180 treatment dose (placebo in the inclisiran group and inclisiran for participants originally randomized to the control group).
Interventions
DRUGInclisiran
Inclisiran s.c
Matching s.c. placebo
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Sponsor Personnel participating in the study conduct were also blinded during the during core part of the study.
Intervention model description
Multi-center, randomized, double-blind, placebo-controlled, parallel groups
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Written informed consent must be obtained before any assessment is performed. * Fasting LDL-C of ≥ 130 mg/dL but \< 190 mg/dL * Triglycerides ≤ 400 mg/dL * Categorized as low or moderate ASCVD risk by the 2016 Chinese Guideline
Exclusion criteria
* Use of any LLT within 90 days prior to screening visit * History of ASCVD * Diabetes mellitus or fasting plasma glucose of ≥ 7.0 mmol/L or HbA1c ≥ 6.5% * Secondary hypercholesterolemia, e.g. hypothyroidism or nephrotic syndrome Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change in Low-density Lipoprotein Cholesterol (LDL-C) (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part | Baseline, Day 150 | Low-density lipoprotein cholesterol is a type of lipoprotein in the blood. Lipoproteins are particles made of lipids(fats) and proteins that carry fats through the bloodstream. Because of their structure, fats can't move through the blood on their own. So, lipoproteins carry fats to various cells in the body. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) (ng/mL) From Baseline at Day 150 - Core Analysis: Core Part | Baseline, Day 150 | Inclisiran is a double-stranded small interfering ribonucleic acid (siRNA) that causes degradation of protein convertase subtilisin/kexin type 9 (PCSK9) messenger RNA (mRNA) leading to the reduction of PCSK9 protein. The percentage change from baseline in PCSK9 at Day 150 was assessed. |
| Absolute Change in PCSK9 (ng/mL) From Baseline at Day 150 - Core Analysis: Core Part | Baseline, Day 150 | Inclisiran is a double-stranded small interfering ribonucleic acid (siRNA) that causes degradation of protein convertase subtilisin/kexin type 9 (PCSK9) messenger RNA (mRNA) leading to the reduction of PCSK9 protein. |
| Percentage Change in Total Cholesterol (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part | Baseline, Day 150 | Total cholesterol is a measure of all the cholesterol in the blood. It includes low-density lipoprotein (LDL), high-density lipoprotein (HDL) and a portion of triglycerides. |
| Absolute Change in Total Cholesterol (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part | Baseline, Day 150 | Total cholesterol is a measure of all the cholesterol in the blood. It includes low-density lipoprotein (LDL), high-density lipoprotein (HDL) and a portion of triglycerides. |
| Percentage Change in High-density Lipoprotein Cholesterol (HDL-C) (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part | Baseline, Day 150 | HDL-C stands for high-density lipoprotein cholesterol, often referred to as the good cholesterol. This is because HDL cholesterol helps remove other forms of cholesterol from the bloodstream. It picks up excess cholesterol in the blood and carries it back to the liver, where it is broken down and flushed out of the body. |
| Absolute Change in HDL-C (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part | Baseline, Day 150 | HDL-C stands for high-density lipoprotein cholesterol, often referred to as the good cholesterol. This is because HDL cholesterol helps remove other forms of cholesterol from the bloodstream. It picks up excess cholesterol in the blood and carries it back to the liver, where it is broken down and flushed out of the body. |
| Percentage Change in Non-HDL-C (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part | Baseline, Day 150 | Non-HDL cholesterol is a measure of all the bad types of cholesterol in the blood, excluding HDL cholesterol. It is calculated by subtracting HDL cholesterol from total cholesterol. Non-HDL cholesterol includes all the types of cholesterol other than HDL cholesterol, and higher levels of non-HDL cholesterol can increase the risk of cardiovascular disease. |
| Absolute Change in Non-HDL-C (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part | Baseline, Day 150 | Non-HDL cholesterol is a measure of all the bad types of cholesterol in the blood, excluding HDL cholesterol. It is calculated by subtracting HDL cholesterol from total cholesterol. Non-HDL cholesterol includes all the types of cholesterol other than HDL cholesterol, and higher levels of non-HDL cholesterol can increase the risk of cardiovascular disease. |
| Percentage Change in Apolipoprotein B (ApoB) (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part | Baseline, Day 150 | Apolipoprotein B (ApoB) is a protein that helps carry fat and cholesterol through the body. It is encoded by the APOB gene. ApoB attaches to negative types of cholesterol that cause plaque buildup in blood vessels, which can lead to damage and heart disease. |
| Absolute Change in ApoB (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part | Baseline, Day 150 | Apolipoprotein B (ApoB) is a protein that helps carry fat and cholesterol through the body. It is encoded by the APOB gene. ApoB attaches to negative types of cholesterol that cause plaque buildup in blood vessels, which can lead to damage and heart disease. |
| Absolute Change in LDL-C (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part | Baseline, Day 150 | Low-density lipoprotein cholesterol is a type of lipoprotein in the blood. Lipoproteins are particles made of lipids(fats) and proteins that carry fats through the bloodstream. Because of their structure, fats can't move through the blood on their own. So, lipoproteins carry fats to various cells in the body. |
| Absolute Change in ApoA-1 (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part | Baseline, Day 150 | Apolipoprotein A1 (ApoA1) is the primary protein associated with high-density lipoprotein (HDL) particles, and plays a central role in reverse cholesterol transport. HDL cholesterol (HDL-C) and ApoA1 concentrations are inversely related to the risk for coronary artery disease (CAD). |
| Percentage Change in Lipoprotein (a) (Lp(a)) (Nmol/L) From Baseline at Day 150 - Core Analysis: Core Part | Baseline, Day 150 | Often referred to as Lp(a), lipoprotein (a) is a type of lipoprotein that is genetically inherited and in high levels is a common independent risk factor for heart disease. |
| Absolute Change in Log-transformed Lp(a) (Nmol/L) From Baseline at Day 150 - Core Analysis: Core Part | Baseline, Day 150 | Often referred to as Lp(a), lipoprotein (a) is a type of lipoprotein that is genetically inherited and in high levels is a common independent risk factor for heart disease. |
| Percentage Change in Triglyceride (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part | Baseline, Day 150 | Triglycerides are fats from the food we eat. Most of the fats we eat (like butter) are in triglyceride form. Extra calories, alcohol and sugar in the body turn into triglycerides. The body stores them in fat cells throughout the body. |
| Absolute Change in Triglyceride (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part | Baseline, Day 150 | Triglycerides are fats from the food we eat. Most of the fats we eat (like butter) are in triglyceride form. Extra calories, alcohol and sugar in the body turn into triglycerides. The body stores them in fat cells throughout the body. |
| Percentage Change in LDL-C (mg/dL) From Baseline at Day 330 - Final Analysis: Core Part + Extension Part | Baseline, Day 330 | Low-density lipoprotein cholesterol is a type of lipoprotein in the blood. Lipoproteins are particles made of lipids(fats) and proteins that carry fats through the bloodstream. Because of their structure, fats can't move through the blood on their own. So, lipoproteins carry fats to various cells in the body. |
| Absolute Change in LDL-C (mg/dL) From Baseline at Day 330 - Final Analysis: Core Part + Extension Part | Baseline, Day 330 | Low-density lipoprotein cholesterol is a type of lipoprotein in the blood. Lipoproteins are particles made of lipids(fats) and proteins that carry fats through the bloodstream. Because of their structure, fats can't move through the blood on their own. So, lipoproteins carry fats to various cells in the body. |
| Number of Participants With Adverse Events (AEs) During Core Part | Core part, from treatment start (Day 1) to Day 150 | An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a subject or clinical investigation subject |
| Number of Participants With Adverse Events (AEs) During Extension Part | Extension part, from Day 181, up to Day 360 | An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a subject or clinical investigation subject |
| Number of Participants With Adverse Events (AEs) - Cumulative Data (Core + Extension Part) | AEs are reported from first dose of study treatment until end of study treatment plus 30 days after the last study visit (or 90 days after the last administration of study drug, whichever is longer) up to a maximum timeframe of approximately 360 days | An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a subject or clinical investigation subject |
| Percentage Change in Apolipoprotein A-1 (ApoA-1) (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part | Baseline, Day 150 | Apolipoprotein A1 (ApoA1) is the primary protein associated with high-density lipoprotein (HDL) particles, and plays a central role in reverse cholesterol transport. HDL cholesterol (HDL-C) and ApoA1 concentrations are inversely related to the risk for coronary artery disease (CAD). |
Countries
China
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Inclisiran - Inclisiran Inclisiran sodium 300 mg (equivalent to 284 mg inclisiran) s.c administered on Days 1, 90, and 270, and with matching placebo s.c administered on Day 180 | 103 |
| Placebo- Inclisiran Placebo s.c administered on Days 1 and 90 and Inclisiran sodium 300 mg (equivalent to 284 mg inclisiran) s.c administered on Days 180 and 270 | 104 |
| Total | 207 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Participant decision | 3 | 3 |
Baseline characteristics
| Characteristic | Placebo- Inclisiran | Total | Inclisiran - Inclisiran |
|---|---|---|---|
| Age, Continuous | 47.7 years STANDARD_DEVIATION 10.63 | 47.9 years STANDARD_DEVIATION 10.28 | 48.0 years STANDARD_DEVIATION 9.97 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 104 Participants | 207 Participants | 103 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 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 | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 63 Participants | 121 Participants | 58 Participants |
| Sex: Female, Male Male | 41 Participants | 86 Participants | 45 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 103 | 0 / 104 | 0 / 100 | 0 / 101 |
| other Total, other adverse events | 40 / 103 | 27 / 104 | 25 / 100 | 20 / 101 |
| serious Total, serious adverse events | 5 / 103 | 3 / 104 | 1 / 100 | 2 / 101 |
Outcome results
Primary
Percentage Change in Low-density Lipoprotein Cholesterol (LDL-C) (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part
Low-density lipoprotein cholesterol is a type of lipoprotein in the blood. Lipoproteins are particles made of lipids(fats) and proteins that carry fats through the bloodstream. Because of their structure, fats can't move through the blood on their own. So, lipoproteins carry fats to various cells in the body.
Time frame: Baseline, Day 150
Population: Full analysis set - all treated participants
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Inclisiran - Inclisiran | Percentage Change in Low-density Lipoprotein Cholesterol (LDL-C) (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part | -45.87 % change in LDL-C |
| Placebo- Inclisiran | Percentage Change in Low-density Lipoprotein Cholesterol (LDL-C) (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part | 1.62 % change in LDL-C |
p-value: <0.000195% CI: [-52.35, -42.65]ANCOVA
Secondary
Absolute Change in ApoA-1 (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part
Apolipoprotein A1 (ApoA1) is the primary protein associated with high-density lipoprotein (HDL) particles, and plays a central role in reverse cholesterol transport. HDL cholesterol (HDL-C) and ApoA1 concentrations are inversely related to the risk for coronary artery disease (CAD).
Time frame: Baseline, Day 150
Population: Full analysis set - all treated participants
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Inclisiran - Inclisiran | Absolute Change in ApoA-1 (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part | 6.44 mg/dL |
| Placebo- Inclisiran | Absolute Change in ApoA-1 (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part | 3.31 mg/dL |
p-value: 0.240395% CI: [-2.09, 8.35]ANCOVA
Secondary
Absolute Change in ApoB (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part
Apolipoprotein B (ApoB) is a protein that helps carry fat and cholesterol through the body. It is encoded by the APOB gene. ApoB attaches to negative types of cholesterol that cause plaque buildup in blood vessels, which can lead to damage and heart disease.
Time frame: Baseline, Day 150
Population: Full analysis set - all treated participants
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Inclisiran - Inclisiran | Absolute Change in ApoB (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part | -42.64 mg/dL |
| Placebo- Inclisiran | Absolute Change in ApoB (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part | -0.76 mg/dL |
p-value: <0.000195% CI: [-46.28, -37.47]ANCOVA
Secondary
Absolute Change in HDL-C (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part
HDL-C stands for high-density lipoprotein cholesterol, often referred to as the good cholesterol. This is because HDL cholesterol helps remove other forms of cholesterol from the bloodstream. It picks up excess cholesterol in the blood and carries it back to the liver, where it is broken down and flushed out of the body.
Time frame: Baseline, Day 150
Population: Full analysis set - all treated participants
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Inclisiran - Inclisiran | Absolute Change in HDL-C (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part | 4.66 mg/dL |
| Placebo- Inclisiran | Absolute Change in HDL-C (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part | 3.60 mg/dL |
p-value: 0.422895% CI: [-1.54, 3.68]ANCOVA
Secondary
Absolute Change in LDL-C (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part
Low-density lipoprotein cholesterol is a type of lipoprotein in the blood. Lipoproteins are particles made of lipids(fats) and proteins that carry fats through the bloodstream. Because of their structure, fats can't move through the blood on their own. So, lipoproteins carry fats to various cells in the body.
Time frame: Baseline, Day 150
Population: Full analysis set - all treated participants
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Inclisiran - Inclisiran | Absolute Change in LDL-C (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part | -69.05 mg/dL |
| Placebo- Inclisiran | Absolute Change in LDL-C (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part | 0.68 mg/dL |
p-value: <0.000195% CI: [-76.6, -62.86]ANCOVA
Secondary
Absolute Change in LDL-C (mg/dL) From Baseline at Day 330 - Final Analysis: Core Part + Extension Part
Low-density lipoprotein cholesterol is a type of lipoprotein in the blood. Lipoproteins are particles made of lipids(fats) and proteins that carry fats through the bloodstream. Because of their structure, fats can't move through the blood on their own. So, lipoproteins carry fats to various cells in the body.
Time frame: Baseline, Day 330
Population: Full analysis set - all treated participants in the Inclisiran - Inclisiran group
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Inclisiran - Inclisiran | Absolute Change in LDL-C (mg/dL) From Baseline at Day 330 - Final Analysis: Core Part + Extension Part | -67.55 mg/dL |
Secondary
Absolute Change in Log-transformed Lp(a) (Nmol/L) From Baseline at Day 150 - Core Analysis: Core Part
Often referred to as Lp(a), lipoprotein (a) is a type of lipoprotein that is genetically inherited and in high levels is a common independent risk factor for heart disease.
Time frame: Baseline, Day 150
Population: Full analysis set - all treated participants
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Inclisiran - Inclisiran | Absolute Change in Log-transformed Lp(a) (Nmol/L) From Baseline at Day 150 - Core Analysis: Core Part | 0.68 nmol/L |
| Placebo- Inclisiran | Absolute Change in Log-transformed Lp(a) (Nmol/L) From Baseline at Day 150 - Core Analysis: Core Part | 1.01 nmol/L |
p-value: <0.000195% CI: [0.6, 0.76]ANCOVA
Secondary
Absolute Change in Non-HDL-C (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part
Non-HDL cholesterol is a measure of all the bad types of cholesterol in the blood, excluding HDL cholesterol. It is calculated by subtracting HDL cholesterol from total cholesterol. Non-HDL cholesterol includes all the types of cholesterol other than HDL cholesterol, and higher levels of non-HDL cholesterol can increase the risk of cardiovascular disease.
Time frame: Baseline, Day 150
Population: Full analysis set - all treated participants
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Inclisiran - Inclisiran | Absolute Change in Non-HDL-C (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part | -73.48 mg/dL |
| Placebo- Inclisiran | Absolute Change in Non-HDL-C (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part | -1.14 mg/dL |
p-value: <0.000195% CI: [-79.56, -65.13]ANCOVA
Secondary
Absolute Change in PCSK9 (ng/mL) From Baseline at Day 150 - Core Analysis: Core Part
Inclisiran is a double-stranded small interfering ribonucleic acid (siRNA) that causes degradation of protein convertase subtilisin/kexin type 9 (PCSK9) messenger RNA (mRNA) leading to the reduction of PCSK9 protein.
Time frame: Baseline, Day 150
Population: Full analysis set - all treated participants
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Inclisiran - Inclisiran | Absolute Change in PCSK9 (ng/mL) From Baseline at Day 150 - Core Analysis: Core Part | -217.14 ng/mL |
| Placebo- Inclisiran | Absolute Change in PCSK9 (ng/mL) From Baseline at Day 150 - Core Analysis: Core Part | 9.47 ng/mL |
p-value: <0.000195% CI: [-244.77, -208.45]ANCOVA
Secondary
Absolute Change in Total Cholesterol (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part
Total cholesterol is a measure of all the cholesterol in the blood. It includes low-density lipoprotein (LDL), high-density lipoprotein (HDL) and a portion of triglycerides.
Time frame: Baseline, Day 150
Population: Full analysis set - all treated participants
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Inclisiran - Inclisiran | Absolute Change in Total Cholesterol (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part | -68.82 mg/dL |
| Placebo- Inclisiran | Absolute Change in Total Cholesterol (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part | 2.64 mg/dL |
p-value: <0.000195% CI: [-79.24, -63.69]ANCOVA
Secondary
Absolute Change in Triglyceride (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part
Triglycerides are fats from the food we eat. Most of the fats we eat (like butter) are in triglyceride form. Extra calories, alcohol and sugar in the body turn into triglycerides. The body stores them in fat cells throughout the body.
Time frame: Baseline, Day 150
Population: Full analysis set - all treated participants
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Inclisiran - Inclisiran | Absolute Change in Triglyceride (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part | -15.32 mg/dL |
| Placebo- Inclisiran | Absolute Change in Triglyceride (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part | -7.36 mg/dL |
p-value: 0.501995% CI: [-31.17, 15.26]ANCOVA
Secondary
Number of Participants With Adverse Events (AEs) - Cumulative Data (Core + Extension Part)
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a subject or clinical investigation subject
Time frame: AEs are reported from first dose of study treatment until end of study treatment plus 30 days after the last study visit (or 90 days after the last administration of study drug, whichever is longer) up to a maximum timeframe of approximately 360 days
Population: Final analysis - all treated participants (Core + Extension part)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Inclisiran - Inclisiran | Number of Participants With Adverse Events (AEs) - Cumulative Data (Core + Extension Part) | -Adverse events Treatment-related | 18 Participants |
| Inclisiran - Inclisiran | Number of Participants With Adverse Events (AEs) - Cumulative Data (Core + Extension Part) | -Fatal SAEs Treatment-related | 0 Participants |
| Inclisiran - Inclisiran | Number of Participants With Adverse Events (AEs) - Cumulative Data (Core + Extension Part) | -SAEs Treatment-related | 0 Participants |
| Inclisiran - Inclisiran | Number of Participants With Adverse Events (AEs) - Cumulative Data (Core + Extension Part) | AEs leading to treatment discontinuation | 0 Participants |
| Inclisiran - Inclisiran | Number of Participants With Adverse Events (AEs) - Cumulative Data (Core + Extension Part) | Adverse events | 85 Participants |
| Inclisiran - Inclisiran | Number of Participants With Adverse Events (AEs) - Cumulative Data (Core + Extension Part) | -Treatment-related | 0 Participants |
| Inclisiran - Inclisiran | Number of Participants With Adverse Events (AEs) - Cumulative Data (Core + Extension Part) | Fatal SAEs | 0 Participants |
| Inclisiran - Inclisiran | Number of Participants With Adverse Events (AEs) - Cumulative Data (Core + Extension Part) | AEs requiring additional therapy | 65 Participants |
| Inclisiran - Inclisiran | Number of Participants With Adverse Events (AEs) - Cumulative Data (Core + Extension Part) | SAEs | 6 Participants |
| Placebo- Inclisiran | Number of Participants With Adverse Events (AEs) - Cumulative Data (Core + Extension Part) | AEs requiring additional therapy | 63 Participants |
| Placebo- Inclisiran | Number of Participants With Adverse Events (AEs) - Cumulative Data (Core + Extension Part) | Adverse events | 81 Participants |
| Placebo- Inclisiran | Number of Participants With Adverse Events (AEs) - Cumulative Data (Core + Extension Part) | -Adverse events Treatment-related | 18 Participants |
| Placebo- Inclisiran | Number of Participants With Adverse Events (AEs) - Cumulative Data (Core + Extension Part) | SAEs | 5 Participants |
| Placebo- Inclisiran | Number of Participants With Adverse Events (AEs) - Cumulative Data (Core + Extension Part) | -SAEs Treatment-related | 0 Participants |
| Placebo- Inclisiran | Number of Participants With Adverse Events (AEs) - Cumulative Data (Core + Extension Part) | Fatal SAEs | 0 Participants |
| Placebo- Inclisiran | Number of Participants With Adverse Events (AEs) - Cumulative Data (Core + Extension Part) | -Fatal SAEs Treatment-related | 0 Participants |
| Placebo- Inclisiran | Number of Participants With Adverse Events (AEs) - Cumulative Data (Core + Extension Part) | AEs leading to treatment discontinuation | 0 Participants |
| Placebo- Inclisiran | Number of Participants With Adverse Events (AEs) - Cumulative Data (Core + Extension Part) | -Treatment-related | 0 Participants |
Secondary
Number of Participants With Adverse Events (AEs) During Core Part
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a subject or clinical investigation subject
Time frame: Core part, from treatment start (Day 1) to Day 150
Population: Safety set - all treated participants in the core part
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Inclisiran - Inclisiran | Number of Participants With Adverse Events (AEs) During Core Part | Serious adverse events (SAEs) | 5 Participants |
| Inclisiran - Inclisiran | Number of Participants With Adverse Events (AEs) During Core Part | -Fatal SAEs Treatment-related | 0 Participants |
| Inclisiran - Inclisiran | Number of Participants With Adverse Events (AEs) During Core Part | -Adverse events Treatment-related | 14 Participants |
| Inclisiran - Inclisiran | Number of Participants With Adverse Events (AEs) During Core Part | AEs leading to treatment discontinuation | 0 Participants |
| Inclisiran - Inclisiran | Number of Participants With Adverse Events (AEs) During Core Part | -SAEs Treatment-related | 0 Participants |
| Inclisiran - Inclisiran | Number of Participants With Adverse Events (AEs) During Core Part | -Treatment-related | 0 Participants |
| Inclisiran - Inclisiran | Number of Participants With Adverse Events (AEs) During Core Part | Fatal SAEs | 0 Participants |
| Inclisiran - Inclisiran | Number of Participants With Adverse Events (AEs) During Core Part | AEs requiring additional therapy | 52 Participants |
| Inclisiran - Inclisiran | Number of Participants With Adverse Events (AEs) During Core Part | Adverse events (AEs) | 73 Participants |
| Placebo- Inclisiran | Number of Participants With Adverse Events (AEs) During Core Part | AEs requiring additional therapy | 50 Participants |
| Placebo- Inclisiran | Number of Participants With Adverse Events (AEs) During Core Part | -SAEs Treatment-related | 0 Participants |
| Placebo- Inclisiran | Number of Participants With Adverse Events (AEs) During Core Part | Adverse events (AEs) | 70 Participants |
| Placebo- Inclisiran | Number of Participants With Adverse Events (AEs) During Core Part | -Adverse events Treatment-related | 4 Participants |
| Placebo- Inclisiran | Number of Participants With Adverse Events (AEs) During Core Part | Serious adverse events (SAEs) | 3 Participants |
| Placebo- Inclisiran | Number of Participants With Adverse Events (AEs) During Core Part | Fatal SAEs | 0 Participants |
| Placebo- Inclisiran | Number of Participants With Adverse Events (AEs) During Core Part | -Fatal SAEs Treatment-related | 0 Participants |
| Placebo- Inclisiran | Number of Participants With Adverse Events (AEs) During Core Part | AEs leading to treatment discontinuation | 0 Participants |
| Placebo- Inclisiran | Number of Participants With Adverse Events (AEs) During Core Part | -Treatment-related | 0 Participants |
Secondary
Number of Participants With Adverse Events (AEs) During Extension Part
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a subject or clinical investigation subject
Time frame: Extension part, from Day 181, up to Day 360
Population: Final analysis - all treated participants in the extension part
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Inclisiran - Inclisiran | Number of Participants With Adverse Events (AEs) During Extension Part | Serious adverse events (SAEs) | 1 Participants |
| Inclisiran - Inclisiran | Number of Participants With Adverse Events (AEs) During Extension Part | -Fatal SAEs Treatment-related | 0 Participants |
| Inclisiran - Inclisiran | Number of Participants With Adverse Events (AEs) During Extension Part | Adverse events (AEs) | 52 Participants |
| Inclisiran - Inclisiran | Number of Participants With Adverse Events (AEs) During Extension Part | AEs leading to treatment discontinuation | 0 Participants |
| Inclisiran - Inclisiran | Number of Participants With Adverse Events (AEs) During Extension Part | -SAEs Treatment-related | 0 Participants |
| Inclisiran - Inclisiran | Number of Participants With Adverse Events (AEs) During Extension Part | -Treatment-related | 0 Participants |
| Inclisiran - Inclisiran | Number of Participants With Adverse Events (AEs) During Extension Part | -Adverse events Treatment-related | 9 Participants |
| Inclisiran - Inclisiran | Number of Participants With Adverse Events (AEs) During Extension Part | AEs requiring additional therapy | 36 Participants |
| Inclisiran - Inclisiran | Number of Participants With Adverse Events (AEs) During Extension Part | Fatal SAEs | 0 Participants |
| Placebo- Inclisiran | Number of Participants With Adverse Events (AEs) During Extension Part | AEs requiring additional therapy | 28 Participants |
| Placebo- Inclisiran | Number of Participants With Adverse Events (AEs) During Extension Part | -Adverse events Treatment-related | 15 Participants |
| Placebo- Inclisiran | Number of Participants With Adverse Events (AEs) During Extension Part | Serious adverse events (SAEs) | 2 Participants |
| Placebo- Inclisiran | Number of Participants With Adverse Events (AEs) During Extension Part | -SAEs Treatment-related | 0 Participants |
| Placebo- Inclisiran | Number of Participants With Adverse Events (AEs) During Extension Part | Fatal SAEs | 0 Participants |
| Placebo- Inclisiran | Number of Participants With Adverse Events (AEs) During Extension Part | -Fatal SAEs Treatment-related | 0 Participants |
| Placebo- Inclisiran | Number of Participants With Adverse Events (AEs) During Extension Part | AEs leading to treatment discontinuation | 0 Participants |
| Placebo- Inclisiran | Number of Participants With Adverse Events (AEs) During Extension Part | -Treatment-related | 0 Participants |
| Placebo- Inclisiran | Number of Participants With Adverse Events (AEs) During Extension Part | Adverse events (AEs) | 47 Participants |
Secondary
Percentage Change in Apolipoprotein A-1 (ApoA-1) (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part
Apolipoprotein A1 (ApoA1) is the primary protein associated with high-density lipoprotein (HDL) particles, and plays a central role in reverse cholesterol transport. HDL cholesterol (HDL-C) and ApoA1 concentrations are inversely related to the risk for coronary artery disease (CAD).
Time frame: Baseline, Day 150
Population: Full analysis set - all treated participants
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Inclisiran - Inclisiran | Percentage Change in Apolipoprotein A-1 (ApoA-1) (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part | 5.11 % change in apolipoprotein A-1 |
| Placebo- Inclisiran | Percentage Change in Apolipoprotein A-1 (ApoA-1) (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part | 3.06 % change in apolipoprotein A-1 |
p-value: 0.301195% CI: [-1.84, 5.93]ANCOVA
Secondary
Percentage Change in Apolipoprotein B (ApoB) (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part
Apolipoprotein B (ApoB) is a protein that helps carry fat and cholesterol through the body. It is encoded by the APOB gene. ApoB attaches to negative types of cholesterol that cause plaque buildup in blood vessels, which can lead to damage and heart disease.
Time frame: Baseline, Day 150
Population: Full analysis set - all treated participants
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Inclisiran - Inclisiran | Percentage Change in Apolipoprotein B (ApoB) (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part | -36.63 % change in apolipoprotein B |
| Placebo- Inclisiran | Percentage Change in Apolipoprotein B (ApoB) (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part | 0.21 % change in apolipoprotein B |
p-value: <0.000195% CI: [-40.72, -32.96]ANCOVA
Secondary
Percentage Change in High-density Lipoprotein Cholesterol (HDL-C) (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part
HDL-C stands for high-density lipoprotein cholesterol, often referred to as the good cholesterol. This is because HDL cholesterol helps remove other forms of cholesterol from the bloodstream. It picks up excess cholesterol in the blood and carries it back to the liver, where it is broken down and flushed out of the body.
Time frame: Baseline, Day 150
Population: Full analysis set - all treated participants
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Inclisiran - Inclisiran | Percentage Change in High-density Lipoprotein Cholesterol (HDL-C) (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part | 12.24 % change in HDL-C |
| Placebo- Inclisiran | Percentage Change in High-density Lipoprotein Cholesterol (HDL-C) (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part | 9.30 % change in HDL-C |
p-value: 0.374395% CI: [-3.55, 9.42]ANCOVA
Secondary
Percentage Change in LDL-C (mg/dL) From Baseline at Day 330 - Final Analysis: Core Part + Extension Part
Low-density lipoprotein cholesterol is a type of lipoprotein in the blood. Lipoproteins are particles made of lipids(fats) and proteins that carry fats through the bloodstream. Because of their structure, fats can't move through the blood on their own. So, lipoproteins carry fats to various cells in the body.
Time frame: Baseline, Day 330
Population: Full analysis set - all treated participants in the Inclisiran - Inclisiran group
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Inclisiran - Inclisiran | Percentage Change in LDL-C (mg/dL) From Baseline at Day 330 - Final Analysis: Core Part + Extension Part | -45.45 % change in LDL-C |
Secondary
Percentage Change in Lipoprotein (a) (Lp(a)) (Nmol/L) From Baseline at Day 150 - Core Analysis: Core Part
Often referred to as Lp(a), lipoprotein (a) is a type of lipoprotein that is genetically inherited and in high levels is a common independent risk factor for heart disease.
Time frame: Baseline, Day 150
Population: Full analysis set - all treated participants
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Inclisiran - Inclisiran | Percentage Change in Lipoprotein (a) (Lp(a)) (Nmol/L) From Baseline at Day 150 - Core Analysis: Core Part | -23.84 % change in lipoprotein (a) |
| Placebo- Inclisiran | Percentage Change in Lipoprotein (a) (Lp(a)) (Nmol/L) From Baseline at Day 150 - Core Analysis: Core Part | 6.43 % change in lipoprotein (a) |
p-value: <0.000195% CI: [-40.58, -19.95]ANCOVA
Secondary
Percentage Change in Non-HDL-C (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part
Non-HDL cholesterol is a measure of all the bad types of cholesterol in the blood, excluding HDL cholesterol. It is calculated by subtracting HDL cholesterol from total cholesterol. Non-HDL cholesterol includes all the types of cholesterol other than HDL cholesterol, and higher levels of non-HDL cholesterol can increase the risk of cardiovascular disease.
Time frame: Baseline, Day 150
Population: Full analysis set - all treated participants
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Inclisiran - Inclisiran | Percentage Change in Non-HDL-C (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part | -40.71 % change in non-HDL-C |
| Placebo- Inclisiran | Percentage Change in Non-HDL-C (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part | -0.14 % change in non-HDL-C |
p-value: <0.000195% CI: [-44.57, -36.57]ANCOVA
Secondary
Percentage Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) (ng/mL) From Baseline at Day 150 - Core Analysis: Core Part
Inclisiran is a double-stranded small interfering ribonucleic acid (siRNA) that causes degradation of protein convertase subtilisin/kexin type 9 (PCSK9) messenger RNA (mRNA) leading to the reduction of PCSK9 protein. The percentage change from baseline in PCSK9 at Day 150 was assessed.
Time frame: Baseline, Day 150
Population: Full analysis set - all treated participants
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Inclisiran - Inclisiran | Percentage Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) (ng/mL) From Baseline at Day 150 - Core Analysis: Core Part | -71.95 % change in PCSK9 |
| Placebo- Inclisiran | Percentage Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) (ng/mL) From Baseline at Day 150 - Core Analysis: Core Part | 5.88 % change in PCSK9 |
p-value: <0.000195% CI: [-85.86, -69.8]ANCOVA
Secondary
Percentage Change in Total Cholesterol (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part
Total cholesterol is a measure of all the cholesterol in the blood. It includes low-density lipoprotein (LDL), high-density lipoprotein (HDL) and a portion of triglycerides.
Time frame: Baseline, Day 150
Population: Full analysis set - all treated participants
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Inclisiran - Inclisiran | Percentage Change in Total Cholesterol (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part | -29.88 % change in total cholesterol |
| Placebo- Inclisiran | Percentage Change in Total Cholesterol (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part | 1.61 % change in total cholesterol |
p-value: <0.000195% CI: [-34.91, -28.07]ANCOVA
Secondary
Percentage Change in Triglyceride (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part
Triglycerides are fats from the food we eat. Most of the fats we eat (like butter) are in triglyceride form. Extra calories, alcohol and sugar in the body turn into triglycerides. The body stores them in fat cells throughout the body.
Time frame: Baseline, Day 150
Population: Full analysis set - all treated participants
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Inclisiran - Inclisiran | Percentage Change in Triglyceride (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part | 3.49 % change in Triglyceride |
| Placebo- Inclisiran | Percentage Change in Triglyceride (mg/dL) From Baseline at Day 150 - Core Analysis: Core Part | 0.48 % change in Triglyceride |
p-value: 0.587795% CI: [-7.88, 13.91]ANCOVA