Hypercholesterolemia
Conditions
Keywords
inclisiran, ezetimibe, LDL-C, monotherapy, primary hypercholesterolemia
Brief summary
CKJX839D12304 was a research study to determine if the study treatment, called inclisiran, in comparison to placebo and ezetimibe effectively reduces Low-Density Lipoprotein Cholesterol (LDL-C) as measured by percentage change from baseline to Day 150. This study was conducted in eligible participants with primary hypercholesterolemia not receiving any lipid-lowering therapy (LLT), with a 10-year Atherosclerotic Cardiovascular Disease (ASCVD) risk of less than 7.5%.
Detailed description
This study was a randomized, double-blind, placebo- and active comparator-controlled, multicenter study in 350 adult participants with primary hypercholesterolemia not receiving any LLT with a 10-year ASCVD risk score of less than 7.5%. This study evaluated the efficacy and safety of inclisiran sodium 300 mg, administered as a monotherapy in comparison to ezetimibe and placebo. The study consisted of: * a screening period of up to 14 days; * a double-blind treatment period of 150+/- 5 days during which participants were randomly assigned to either the inclisiran arm, the ezetimibe arm or the placebo arm in a 2:1:1 ratio; and * a safety follow-up / End of Study visit conducted 30+5 days after the Day 150 visit. The overall study duration was approximately 190 days.
Interventions
DRUGInclisiran
284 mg (equivalent to 300 mg inclisiran sodium) subcutaneous injection given on Day 1 and Day 90
DRUGEzetimibe
10 mg over-encapsulated tablet taken once a day from Day 1 through Day 149
0mg placebo injection solution for subcutaneous injection on Day 1 and Day 90
DRUGMatching Placebo for Ezetimibe
0mg over-encapsulated placebo tablet taken once a day from Day 1 through Day 149
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Sponsor Personnel participating in the study conduct were also be blinded.
Intervention model description
Multi-center, randomized, double-blind, placebo- and active comparator-controlled, parallel groups
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
at screening: * informed consent signed prior to participation in study * fasting LDL-C of \>= 100 mg/dL but \< 190 mg/dL * fasting triglycerides \<= 400 mg/dL * 10-year ASCVD risk score \< 7.5% * not on any lipid-lowering therapy within 90 days of screening Key
Exclusion criteria
* history of ASCVD * diabetes mellitus or fasting plasma glucose of \>= 7.0 mmol/L or HbA1c \>= 6.5% * secondary hypercholesterolemia, e.g. hypothyroidism (TSH above upper limit of normal)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change in Low-density Lipoprotein Cholesterol (LDL-C) From Baseline to Day 150 | Baseline, Day 150 | Percentage change in LDL-C from Baseline (day 1) to Day 150, Inclisiran arm versus Ezetimibe and placebo. There were two estimands of interest in comparing efficacy of inclisiran as monotherapy against that of placebo or ezetimibe that differ on the treatment of interest used for each and the management of intercurrent events as follows: * Monotherapy Estimand: Inclisiran as monotherapy compared to the use of comparator. This estimand uses a hypothetical strategy where participants who permanently discontinued treatment, died or used other LLTs were handled in a hypothetical scenario of what would have happened if the intercurrent event did not happen. * Treatment-policy Estimand: Inclisiran as monotherapy compared to the use of comparator with or without other lipid lowering therapies (LLTs) added. This estimand ignored the use of other LLTs and treatment discontinuation. Deaths (if any) were handled as an unfavorable outcome using a composite variable strategy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) From Baseline to Day 150 | Baseline, Day 150 | Percentage change in PCSK9 from Baseline (Day 1) to Day 150 , Inclisiran arm versus Ezetimibe and placebo. There were two estimands of interest in comparing efficacy of inclisiran as monotherapy against that of placebo or ezetimibe that differ on the treatment of interest used for each and the management of intercurrent events as follows: * Monotherapy Estimand: Inclisiran as monotherapy compared to the use of comparator. This estimand uses a hypothetical strategy where participants who permanently discontinued treatment, died or used other LLTs were handled in a hypothetical scenario of what would have happened if the intercurrent event did not happen. * Treatment-policy Estimand: Inclisiran as monotherapy compared to the use of comparator with or without other lipid lowering therapies (LLTs) added. This estimand ignored the use of other LLTs and treatment discontinuation. Deaths (if any) were handled as an unfavorable outcome using a composite variable strategy. |
| Percentage Change in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) From Baseline to Day 150 | Baseline, Day 150 | Percentage change in non-HDL-C from Baseline (Day 1) to Day 150, Inclisiran arm versus Ezetimibe and placebo. There were two estimands of interest in comparing efficacy of inclisiran as monotherapy against that of placebo or ezetimibe that differ on the treatment of interest used for each and the management of intercurrent events as follows: * Monotherapy Estimand: Inclisiran as monotherapy compared to the use of comparator. This estimand uses a hypothetical strategy where participants who permanently discontinued treatment, died or used other LLTs were handled in a hypothetical scenario of what would have happened if the intercurrent event did not happen. * Treatment-policy Estimand: Inclisiran as monotherapy compared to the use of comparator with or without other lipid lowering therapies (LLTs) added. This estimand ignored the use of other LLTs and treatment discontinuation. Deaths (if any) were handled as an unfavorable outcome using a composite variable strategy. |
| Percentage Change in Total Cholesterol (TC)/HDL-C Ratio From Baseline to Day 150 | Baseline, Day 150 | Percentage change in total cholesterol/HDL-C ratio from Baseline (Day1) to Day 150, Inclisiran arm versus Ezetimibe and placebo. There were two estimands of interest in comparing efficacy of inclisiran as monotherapy against that of placebo or ezetimibe that differ on the treatment of interest used for each and the management of intercurrent events as follows: * Monotherapy Estimand: Inclisiran as monotherapy compared to the use of comparator. This estimand uses a hypothetical strategy where participants who permanently discontinued treatment, died or used other LLTs were handled in a hypothetical scenario of what would have happened if the intercurrent event did not happen. * Treatment-policy Estimand: Inclisiran as monotherapy compared to the use of comparator with or without other lipid lowering therapies (LLTs) added. This estimand ignored the use of other LLTs and treatment discontinuation. Deaths (if any) were handled as an unfavorable outcome using a composite variable strate |
| Absolute Change in LDL-C From Baseline to Day 150 | Baseline, Day 150 | Absolute change in LDL-C from Baseline (Day 1) to Day 150, Inclisiran arm versus Ezetimibe and placebo. There were two estimands of interest in comparing efficacy of inclisiran as monotherapy against that of placebo or ezetimibe that differ on the treatment of interest used for each and the management of intercurrent events as follows: * Monotherapy Estimand: Inclisiran as monotherapy compared to the use of comparator. This estimand uses a hypothetical strategy where participants who permanently discontinued treatment, died or used other LLTs were handled in a hypothetical scenario of what would have happened if the intercurrent event did not happen. * Treatment-policy Estimand: Inclisiran as monotherapy compared to the use of comparator with or without other lipid lowering therapies (LLTs) added. This estimand ignored the use of other LLTs and treatment discontinuation. Deaths (if any) were handled as an unfavorable outcome using a composite variable strategy. |
| Percentage Change in Apo B/Apo A-1 Ratio From Baseline to Day 150 | Baseline, Day 150 | Percentage change in Apo B/Apo A-1 ratio from baseline (Day 1) to Day 150, Inclisiran arm versus Ezetimibe and placebo. There were two estimands of interest in comparing efficacy of inclisiran as monotherapy against that of placebo or ezetimibe that differ on the treatment of interest used for each and the management of intercurrent events as follows: * Monotherapy Estimand: Inclisiran as monotherapy compared to the use of comparator. This estimand uses a hypothetical strategy where participants who permanently discontinued treatment, died or used other LLTs were handled in a hypothetical scenario of what would have happened if the intercurrent event did not happen. * Treatment-policy Estimand: Inclisiran as monotherapy compared to the use of comparator with or without other lipid lowering therapies (LLTs) added. This estimand ignored the use of other LLTs and treatment discontinuation. Deaths (if any) were handled as an unfavorable outcome using a composite variable strategy. |
| Change in Lipoprotein (a) [Lp(a)] From Baseline to Day 150 | Baseline, Day 150 | Day 150 / Baseline ratio in Lp(a) in Inclisiran arm versus Ezetimibe and placebo. There were two estimands of interest in comparing efficacy of inclisiran as monotherapy against that of placebo or ezetimibe that differ on the treatment of interest used for each and the management of intercurrent events as follows: * Monotherapy Estimand: Inclisiran as monotherapy compared to the use of comparator. This estimand uses a hypothetical strategy where participants who permanently discontinued treatment, died or used other LLTs were handled in a hypothetical scenario of what would have happened if the intercurrent event did not happen. * Treatment-policy Estimand: Inclisiran as monotherapy compared to the use of comparator with or without other lipid lowering therapies (LLTs) added. This estimand ignored the use of other LLTs and treatment discontinuation. Deaths (if any) were handled as an unfavorable outcome using a composite variable strategy. |
| Incidence of Treatment Emergent Adverse Events (TEAE) and Serious Adverse Events (SAE) | From first dose of study treatment on Day 1 up to Day 180 | Incidence of TEAEs (regardless of seriousness) and SAEs by treatment group, including changes in laboratory results qualifying and reported as AEs. |
| Percentage Change in Apolipoprotein B (Apo B) From Baseline to Day 150 | Baseline, Day 150 | Percentage change in Apo B from Baseline (Day 1) to Day 150, Inclisiran arm versus Ezetimibe and placebo. There were two estimands of interest in comparing efficacy of inclisiran as monotherapy against that of placebo or ezetimibe that differ on the treatment of interest used for each and the management of intercurrent events as follows: * Monotherapy Estimand: Inclisiran as monotherapy compared to the use of comparator. This estimand uses a hypothetical strategy where participants who permanently discontinued treatment, died or used other LLTs were handled in a hypothetical scenario of what would have happened if the intercurrent event did not happen. * Treatment-policy Estimand: Inclisiran as monotherapy compared to the use of comparator with or without other lipid lowering therapies (LLTs) added. This estimand ignored the use of other LLTs and treatment discontinuation. Deaths (if any) were handled as an unfavorable outcome using a composite variable strategy. |
Countries
Colombia, Germany, Hungary, Mexico, United States
Participant flow
Recruitment details
Participants were enrolled at 42 investigative sites in 5 countries
Pre-assignment details
There was a 14 day screening period
Participants by arm
| Arm | Count |
|---|---|
| Inclisiran Inclisiran s.c and Placebo p.o | 174 |
| Ezetimibe Placebo s.c. and Ezetimibe p.o. | 89 |
| Placebo Placebo s.c. and Placebo p.o. | 87 |
| Total | 350 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 |
| Overall Study | Lost to Follow-up | 4 | 1 | 2 |
| Overall Study | Subject decision | 5 | 2 | 1 |
Baseline characteristics
| Characteristic | Inclisiran | Total | Ezetimibe | Placebo |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 6 Participants | 13 Participants | 3 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 168 Participants | 337 Participants | 86 Participants | 83 Participants |
| Age, Continuous | 45.7 years STANDARD_DEVIATION 11.74 | 46.1 years STANDARD_DEVIATION 11.46 | 46.3 years STANDARD_DEVIATION 10.9 | 46.7 years STANDARD_DEVIATION 11.55 |
| Baseline Low-Density Lipoprotein Cholesterol (LDL-C) | 135.8 mg/dL STANDARD_DEVIATION 27.01 | 135.4 mg/dL STANDARD_DEVIATION 27.07 | 134.4 mg/dL STANDARD_DEVIATION 25.82 | 135.4 mg/dL STANDARD_DEVIATION 28.69 |
| Race (NIH/OMB) American Indian or Alaska Native | 10 Participants | 29 Participants | 10 Participants | 9 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 20 Participants | 37 Participants | 7 Participants | 10 Participants |
| Race (NIH/OMB) More than one race | 4 Participants | 5 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 140 Participants | 278 Participants | 71 Participants | 67 Participants |
| Sex: Female, Male Female | 104 Participants | 219 Participants | 56 Participants | 59 Participants |
| Sex: Female, Male Male | 70 Participants | 131 Participants | 33 Participants | 28 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 / 174 | 0 / 89 | 0 / 87 | 0 / 350 |
| other Total, other adverse events | 19 / 174 | 18 / 89 | 13 / 87 | 50 / 350 |
| serious Total, serious adverse events | 1 / 174 | 0 / 89 | 0 / 87 | 1 / 350 |
Outcome results
Primary
Percentage Change in Low-density Lipoprotein Cholesterol (LDL-C) From Baseline to Day 150
Percentage change in LDL-C from Baseline (day 1) to Day 150, Inclisiran arm versus Ezetimibe and placebo. There were two estimands of interest in comparing efficacy of inclisiran as monotherapy against that of placebo or ezetimibe that differ on the treatment of interest used for each and the management of intercurrent events as follows: * Monotherapy Estimand: Inclisiran as monotherapy compared to the use of comparator. This estimand uses a hypothetical strategy where participants who permanently discontinued treatment, died or used other LLTs were handled in a hypothetical scenario of what would have happened if the intercurrent event did not happen. * Treatment-policy Estimand: Inclisiran as monotherapy compared to the use of comparator with or without other lipid lowering therapies (LLTs) added. This estimand ignored the use of other LLTs and treatment discontinuation. Deaths (if any) were handled as an unfavorable outcome using a composite variable strategy.
Time frame: Baseline, Day 150
Population: Full Analysis Set, all randomized participants.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Inclisiran | Percentage Change in Low-density Lipoprotein Cholesterol (LDL-C) From Baseline to Day 150 | LS Mean (Treatment Policy estimand) | -46.54 Percentage change from baseline |
| Inclisiran | Percentage Change in Low-density Lipoprotein Cholesterol (LDL-C) From Baseline to Day 150 | LS Mean (Monotherapy estimand) | -49.37 Percentage change from baseline |
| Ezetimibe | Percentage Change in Low-density Lipoprotein Cholesterol (LDL-C) From Baseline to Day 150 | LS Mean (Treatment Policy estimand) | -11.17 Percentage change from baseline |
| Ezetimibe | Percentage Change in Low-density Lipoprotein Cholesterol (LDL-C) From Baseline to Day 150 | LS Mean (Monotherapy estimand) | -11.92 Percentage change from baseline |
| Placebo | Percentage Change in Low-density Lipoprotein Cholesterol (LDL-C) From Baseline to Day 150 | LS Mean (Treatment Policy estimand) | 1.37 Percentage change from baseline |
| Placebo | Percentage Change in Low-density Lipoprotein Cholesterol (LDL-C) From Baseline to Day 150 | LS Mean (Monotherapy estimand) | -1.53 Percentage change from baseline |
Comparison: Treatment Policy Estimandp-value: <0.000195% CI: [-40.88, -29.86]ANCOVA
Comparison: Treatment Policy Estimandp-value: <0.000195% CI: [-53.62, -42.2]ANCOVA
Comparison: Monotherapy Estimandp-value: <0.000195% CI: [-42.63, -32.26]ANCOVA
Comparison: Monotherapy Estimandp-value: <0.000195% CI: [-56.51, -45.28]ANCOVA
Secondary
Absolute Change in LDL-C From Baseline to Day 150
Absolute change in LDL-C from Baseline (Day 1) to Day 150, Inclisiran arm versus Ezetimibe and placebo. There were two estimands of interest in comparing efficacy of inclisiran as monotherapy against that of placebo or ezetimibe that differ on the treatment of interest used for each and the management of intercurrent events as follows: * Monotherapy Estimand: Inclisiran as monotherapy compared to the use of comparator. This estimand uses a hypothetical strategy where participants who permanently discontinued treatment, died or used other LLTs were handled in a hypothetical scenario of what would have happened if the intercurrent event did not happen. * Treatment-policy Estimand: Inclisiran as monotherapy compared to the use of comparator with or without other lipid lowering therapies (LLTs) added. This estimand ignored the use of other LLTs and treatment discontinuation. Deaths (if any) were handled as an unfavorable outcome using a composite variable strategy.
Time frame: Baseline, Day 150
Population: Full Analysis Set, all randomized participants.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Inclisiran | Absolute Change in LDL-C From Baseline to Day 150 | LS Mean (Treatment Policy estimand) | -64.86 mg/dL |
| Inclisiran | Absolute Change in LDL-C From Baseline to Day 150 | LS Mean (Monotherapy estimand) | -68.57 mg/dL |
| Ezetimibe | Absolute Change in LDL-C From Baseline to Day 150 | LS Mean (Treatment Policy estimand) | -17.55 mg/dL |
| Ezetimibe | Absolute Change in LDL-C From Baseline to Day 150 | LS Mean (Monotherapy estimand) | -18.52 mg/dL |
| Placebo | Absolute Change in LDL-C From Baseline to Day 150 | LS Mean (Treatment Policy estimand) | -1.29 mg/dL |
| Placebo | Absolute Change in LDL-C From Baseline to Day 150 | LS Mean (Monotherapy estimand) | -1.07 mg/dL |
Comparison: Treatment Policy Estimandp-value: <0.000195% CI: [-53.91, -40.72]ANCOVA
Comparison: Treatment Policy Estimandp-value: <0.000195% CI: [-70.28, -56.87]ANCOVA
Comparison: Monotherapy Estimandp-value: <0.000195% CI: [-56.16, -43.94]ANCOVA
Comparison: Monotherapy Estimandp-value: <0.000195% CI: [-74.09, -60.92]ANCOVA
Secondary
Change in Lipoprotein (a) [Lp(a)] From Baseline to Day 150
Day 150 / Baseline ratio in Lp(a) in Inclisiran arm versus Ezetimibe and placebo. There were two estimands of interest in comparing efficacy of inclisiran as monotherapy against that of placebo or ezetimibe that differ on the treatment of interest used for each and the management of intercurrent events as follows: * Monotherapy Estimand: Inclisiran as monotherapy compared to the use of comparator. This estimand uses a hypothetical strategy where participants who permanently discontinued treatment, died or used other LLTs were handled in a hypothetical scenario of what would have happened if the intercurrent event did not happen. * Treatment-policy Estimand: Inclisiran as monotherapy compared to the use of comparator with or without other lipid lowering therapies (LLTs) added. This estimand ignored the use of other LLTs and treatment discontinuation. Deaths (if any) were handled as an unfavorable outcome using a composite variable strategy.
Time frame: Baseline, Day 150
Population: Full Analysis Set, all randomized participants with a valid assessment for the outcome measure.
| Arm | Measure | Group | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Inclisiran | Change in Lipoprotein (a) [Lp(a)] From Baseline to Day 150 | LS Mean (Treatment Policy estimand) | 0.690 Ratio from baseline |
| Inclisiran | Change in Lipoprotein (a) [Lp(a)] From Baseline to Day 150 | LS Mean (Monotherapy estimand) | 0.687 Ratio from baseline |
| Ezetimibe | Change in Lipoprotein (a) [Lp(a)] From Baseline to Day 150 | LS Mean (Treatment Policy estimand) | 0.911 Ratio from baseline |
| Ezetimibe | Change in Lipoprotein (a) [Lp(a)] From Baseline to Day 150 | LS Mean (Monotherapy estimand) | 0.912 Ratio from baseline |
| Placebo | Change in Lipoprotein (a) [Lp(a)] From Baseline to Day 150 | LS Mean (Treatment Policy estimand) | 0.923 Ratio from baseline |
| Placebo | Change in Lipoprotein (a) [Lp(a)] From Baseline to Day 150 | LS Mean (Monotherapy estimand) | 0.922 Ratio from baseline |
Comparison: Treatment Policy Estimandp-value: 0.000295% CI: [0.65, 0.882]ANCOVA
Comparison: Treatment Policy Estimandp-value: 0.00195% CI: [0.622, 0.898]ANCOVA
Comparison: Monotherapy Estimandp-value: <0.000195% CI: [0.652, 0.871]ANCOVA
Comparison: Monotherapy Estimandp-value: 0.000895% CI: [0.622, 0.893]ANCOVA
Secondary
Incidence of Treatment Emergent Adverse Events (TEAE) and Serious Adverse Events (SAE)
Incidence of TEAEs (regardless of seriousness) and SAEs by treatment group, including changes in laboratory results qualifying and reported as AEs.
Time frame: From first dose of study treatment on Day 1 up to Day 180
Population: Safety Analysis Set, all participants who received at least one dose of study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Inclisiran | Incidence of Treatment Emergent Adverse Events (TEAE) and Serious Adverse Events (SAE) | Fatal SAEs | 0 Participants |
| Inclisiran | Incidence of Treatment Emergent Adverse Events (TEAE) and Serious Adverse Events (SAE) | SAEs | 1 Participants |
| Inclisiran | Incidence of Treatment Emergent Adverse Events (TEAE) and Serious Adverse Events (SAE) | AEs related to s.c. treatment (Inclisiran or s.c. matching placebo) | 11 Participants |
| Inclisiran | Incidence of Treatment Emergent Adverse Events (TEAE) and Serious Adverse Events (SAE) | SAEs related to p.o. treatment (ezetimibe or p.o. matching placebo) | 0 Participants |
| Inclisiran | Incidence of Treatment Emergent Adverse Events (TEAE) and Serious Adverse Events (SAE) | SAEs related to s.c. treatment (Inclisiran or s.c. matching placebo) | 0 Participants |
| Inclisiran | Incidence of Treatment Emergent Adverse Events (TEAE) and Serious Adverse Events (SAE) | AEs | 54 Participants |
| Inclisiran | Incidence of Treatment Emergent Adverse Events (TEAE) and Serious Adverse Events (SAE) | AEs leading to treatment discontinuation of inclisiran or s.c. matching placebo | 3 Participants |
| Inclisiran | Incidence of Treatment Emergent Adverse Events (TEAE) and Serious Adverse Events (SAE) | AEs related to p.o. treatment (ezetimibe or p.o. matching placebo) | 3 Participants |
| Inclisiran | Incidence of Treatment Emergent Adverse Events (TEAE) and Serious Adverse Events (SAE) | AEs leading to treatment discontinuation of ezetimibe or p.o. matching placebo | 4 Participants |
| Ezetimibe | Incidence of Treatment Emergent Adverse Events (TEAE) and Serious Adverse Events (SAE) | AEs leading to treatment discontinuation of inclisiran or s.c. matching placebo | 0 Participants |
| Ezetimibe | Incidence of Treatment Emergent Adverse Events (TEAE) and Serious Adverse Events (SAE) | AEs | 27 Participants |
| Ezetimibe | Incidence of Treatment Emergent Adverse Events (TEAE) and Serious Adverse Events (SAE) | AEs related to s.c. treatment (Inclisiran or s.c. matching placebo) | 4 Participants |
| Ezetimibe | Incidence of Treatment Emergent Adverse Events (TEAE) and Serious Adverse Events (SAE) | AEs related to p.o. treatment (ezetimibe or p.o. matching placebo) | 2 Participants |
| Ezetimibe | Incidence of Treatment Emergent Adverse Events (TEAE) and Serious Adverse Events (SAE) | SAEs | 0 Participants |
| Ezetimibe | Incidence of Treatment Emergent Adverse Events (TEAE) and Serious Adverse Events (SAE) | SAEs related to s.c. treatment (Inclisiran or s.c. matching placebo) | 0 Participants |
| Ezetimibe | Incidence of Treatment Emergent Adverse Events (TEAE) and Serious Adverse Events (SAE) | SAEs related to p.o. treatment (ezetimibe or p.o. matching placebo) | 0 Participants |
| Ezetimibe | Incidence of Treatment Emergent Adverse Events (TEAE) and Serious Adverse Events (SAE) | Fatal SAEs | 0 Participants |
| Ezetimibe | Incidence of Treatment Emergent Adverse Events (TEAE) and Serious Adverse Events (SAE) | AEs leading to treatment discontinuation of ezetimibe or p.o. matching placebo | 0 Participants |
| Placebo | Incidence of Treatment Emergent Adverse Events (TEAE) and Serious Adverse Events (SAE) | SAEs related to p.o. treatment (ezetimibe or p.o. matching placebo) | 0 Participants |
| Placebo | Incidence of Treatment Emergent Adverse Events (TEAE) and Serious Adverse Events (SAE) | AEs related to p.o. treatment (ezetimibe or p.o. matching placebo) | 2 Participants |
| Placebo | Incidence of Treatment Emergent Adverse Events (TEAE) and Serious Adverse Events (SAE) | AEs leading to treatment discontinuation of ezetimibe or p.o. matching placebo | 0 Participants |
| Placebo | Incidence of Treatment Emergent Adverse Events (TEAE) and Serious Adverse Events (SAE) | Fatal SAEs | 0 Participants |
| Placebo | Incidence of Treatment Emergent Adverse Events (TEAE) and Serious Adverse Events (SAE) | AEs related to s.c. treatment (Inclisiran or s.c. matching placebo) | 0 Participants |
| Placebo | Incidence of Treatment Emergent Adverse Events (TEAE) and Serious Adverse Events (SAE) | AEs leading to treatment discontinuation of inclisiran or s.c. matching placebo | 0 Participants |
| Placebo | Incidence of Treatment Emergent Adverse Events (TEAE) and Serious Adverse Events (SAE) | SAEs related to s.c. treatment (Inclisiran or s.c. matching placebo) | 0 Participants |
| Placebo | Incidence of Treatment Emergent Adverse Events (TEAE) and Serious Adverse Events (SAE) | SAEs | 0 Participants |
| Placebo | Incidence of Treatment Emergent Adverse Events (TEAE) and Serious Adverse Events (SAE) | AEs | 25 Participants |
Secondary
Percentage Change in Apo B/Apo A-1 Ratio From Baseline to Day 150
Percentage change in Apo B/Apo A-1 ratio from baseline (Day 1) to Day 150, Inclisiran arm versus Ezetimibe and placebo. There were two estimands of interest in comparing efficacy of inclisiran as monotherapy against that of placebo or ezetimibe that differ on the treatment of interest used for each and the management of intercurrent events as follows: * Monotherapy Estimand: Inclisiran as monotherapy compared to the use of comparator. This estimand uses a hypothetical strategy where participants who permanently discontinued treatment, died or used other LLTs were handled in a hypothetical scenario of what would have happened if the intercurrent event did not happen. * Treatment-policy Estimand: Inclisiran as monotherapy compared to the use of comparator with or without other lipid lowering therapies (LLTs) added. This estimand ignored the use of other LLTs and treatment discontinuation. Deaths (if any) were handled as an unfavorable outcome using a composite variable strategy.
Time frame: Baseline, Day 150
Population: Full Analysis Set, all randomized participants.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Inclisiran | Percentage Change in Apo B/Apo A-1 Ratio From Baseline to Day 150 | LS Mean (Treatment Policy estimand) | -37.79 Percentage change from baseline |
| Inclisiran | Percentage Change in Apo B/Apo A-1 Ratio From Baseline to Day 150 | LS Mean (Monotherapy estimand) | -40.03 Percentage change from baseline |
| Ezetimibe | Percentage Change in Apo B/Apo A-1 Ratio From Baseline to Day 150 | LS Mean (Treatment Policy estimand) | -7.55 Percentage change from baseline |
| Ezetimibe | Percentage Change in Apo B/Apo A-1 Ratio From Baseline to Day 150 | LS Mean (Monotherapy estimand) | -7.69 Percentage change from baseline |
| Placebo | Percentage Change in Apo B/Apo A-1 Ratio From Baseline to Day 150 | LS Mean (Treatment Policy estimand) | -2.65 Percentage change from baseline |
| Placebo | Percentage Change in Apo B/Apo A-1 Ratio From Baseline to Day 150 | LS Mean (Monotherapy estimand) | -2.65 Percentage change from baseline |
Comparison: Treatment Policy Estimandp-value: <0.000195% CI: [-41.18, -29.12]ANCOVA
Comparison: Monotherapy Estimandp-value: <0.000195% CI: [-39.1, -25.59]ANCOVA
Comparison: Treatment Policy Estimandp-value: <0.000195% CI: [-36.92, -23.57]ANCOVA
Comparison: Monotherapy Estimandp-value: <0.000195% CI: [-43.44, -31.31]ANCOVA
Secondary
Percentage Change in Apolipoprotein B (Apo B) From Baseline to Day 150
Percentage change in Apo B from Baseline (Day 1) to Day 150, Inclisiran arm versus Ezetimibe and placebo. There were two estimands of interest in comparing efficacy of inclisiran as monotherapy against that of placebo or ezetimibe that differ on the treatment of interest used for each and the management of intercurrent events as follows: * Monotherapy Estimand: Inclisiran as monotherapy compared to the use of comparator. This estimand uses a hypothetical strategy where participants who permanently discontinued treatment, died or used other LLTs were handled in a hypothetical scenario of what would have happened if the intercurrent event did not happen. * Treatment-policy Estimand: Inclisiran as monotherapy compared to the use of comparator with or without other lipid lowering therapies (LLTs) added. This estimand ignored the use of other LLTs and treatment discontinuation. Deaths (if any) were handled as an unfavorable outcome using a composite variable strategy.
Time frame: Baseline, Day 150
Population: Full Analysis Set, all randomized participants.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Inclisiran | Percentage Change in Apolipoprotein B (Apo B) From Baseline to Day 150 | LS Mean (Treatment Policy estimand) | -37.39 Percentage change from baseline |
| Inclisiran | Percentage Change in Apolipoprotein B (Apo B) From Baseline to Day 150 | LS Mean (Monotherapy estimand) | -39.36 Percentage change from baseline |
| Ezetimibe | Percentage Change in Apolipoprotein B (Apo B) From Baseline to Day 150 | LS Mean (Treatment Policy estimand) | -8.41 Percentage change from baseline |
| Ezetimibe | Percentage Change in Apolipoprotein B (Apo B) From Baseline to Day 150 | LS Mean (Monotherapy estimand) | -9.20 Percentage change from baseline |
| Placebo | Percentage Change in Apolipoprotein B (Apo B) From Baseline to Day 150 | LS Mean (Treatment Policy estimand) | -0.73 Percentage change from baseline |
| Placebo | Percentage Change in Apolipoprotein B (Apo B) From Baseline to Day 150 | LS Mean (Monotherapy estimand) | -0.58 Percentage change from baseline |
Comparison: Monotherapy Estimandp-value: <0.000195% CI: [-34.08, -26.23]ANCOVA
Comparison: Monotherapy Estimandp-value: <0.000195% CI: [-43.12, -34.43]ANCOVA
Comparison: Treatment Policy Estimandp-value: <0.000195% CI: [-33.3, -24.65]ANCOVA
Comparison: Treatment Policy Estimandp-value: <0.000195% CI: [-41.1, -32.22]ANCOVA
Secondary
Percentage Change in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) From Baseline to Day 150
Percentage change in non-HDL-C from Baseline (Day 1) to Day 150, Inclisiran arm versus Ezetimibe and placebo. There were two estimands of interest in comparing efficacy of inclisiran as monotherapy against that of placebo or ezetimibe that differ on the treatment of interest used for each and the management of intercurrent events as follows: * Monotherapy Estimand: Inclisiran as monotherapy compared to the use of comparator. This estimand uses a hypothetical strategy where participants who permanently discontinued treatment, died or used other LLTs were handled in a hypothetical scenario of what would have happened if the intercurrent event did not happen. * Treatment-policy Estimand: Inclisiran as monotherapy compared to the use of comparator with or without other lipid lowering therapies (LLTs) added. This estimand ignored the use of other LLTs and treatment discontinuation. Deaths (if any) were handled as an unfavorable outcome using a composite variable strategy.
Time frame: Baseline, Day 150
Population: Full Analysis Set, all randomized participants.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Inclisiran | Percentage Change in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) From Baseline to Day 150 | LS Mean (Treatment Policy estimand) | -40.45 Percentage change from baseline |
| Inclisiran | Percentage Change in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) From Baseline to Day 150 | LS Mean (Monotherapy estimand) | -42.82 Percentage change from baseline |
| Ezetimibe | Percentage Change in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) From Baseline to Day 150 | LS Mean (Treatment Policy estimand) | -9.97 Percentage change from baseline |
| Ezetimibe | Percentage Change in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) From Baseline to Day 150 | LS Mean (Monotherapy estimand) | -10.84 Percentage change from baseline |
| Placebo | Percentage Change in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) From Baseline to Day 150 | LS Mean (Treatment Policy estimand) | 1.88 Percentage change from baseline |
| Placebo | Percentage Change in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) From Baseline to Day 150 | LS Mean (Monotherapy estimand) | 2.04 Percentage change from baseline |
Comparison: Treatment Policy Estimandp-value: <0.000195% CI: [-34.98, -25.98]ANCOVA
Comparison: Treatment Policy Estimandp-value: <0.000195% CI: [-47.83, -36.82]ANCOVA
Comparison: Monotherapy Estimandp-value: <0.000195% CI: [-36.07, -27.89]ANCOVA
Comparison: Monotherapy Estimandp-value: <0.000195% CI: [-50.28, -39.44]ANCOVA
Secondary
Percentage Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) From Baseline to Day 150
Percentage change in PCSK9 from Baseline (Day 1) to Day 150 , Inclisiran arm versus Ezetimibe and placebo. There were two estimands of interest in comparing efficacy of inclisiran as monotherapy against that of placebo or ezetimibe that differ on the treatment of interest used for each and the management of intercurrent events as follows: * Monotherapy Estimand: Inclisiran as monotherapy compared to the use of comparator. This estimand uses a hypothetical strategy where participants who permanently discontinued treatment, died or used other LLTs were handled in a hypothetical scenario of what would have happened if the intercurrent event did not happen. * Treatment-policy Estimand: Inclisiran as monotherapy compared to the use of comparator with or without other lipid lowering therapies (LLTs) added. This estimand ignored the use of other LLTs and treatment discontinuation. Deaths (if any) were handled as an unfavorable outcome using a composite variable strategy.
Time frame: Baseline, Day 150
Population: Full Analysis Set, all randomized participants with a valid assessment for the outcome measure.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Inclisiran | Percentage Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) From Baseline to Day 150 | LS Mean (Treatment Policy estimand) | -67.12 Percentage change from baseline |
| Inclisiran | Percentage Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) From Baseline to Day 150 | LS Mean (Monotherapy estimand) | -71.31 Percentage change from baseline |
| Ezetimibe | Percentage Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) From Baseline to Day 150 | LS Mean (Treatment Policy estimand) | 6.04 Percentage change from baseline |
| Ezetimibe | Percentage Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) From Baseline to Day 150 | LS Mean (Monotherapy estimand) | 5.56 Percentage change from baseline |
| Placebo | Percentage Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) From Baseline to Day 150 | LS Mean (Treatment Policy estimand) | 7.82 Percentage change from baseline |
| Placebo | Percentage Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) From Baseline to Day 150 | LS Mean (Monotherapy estimand) | 8.16 Percentage change from baseline |
Comparison: Treatment Policy Estimandp-value: <0.000195% CI: [-81.76, -64.56]ANCOVA
Comparison: Treatment Policy Estimandp-value: <0.000195% CI: [-84.51, -65.37]ANCOVA
Comparison: Monotherapy Estimandp-value: <0.000195% CI: [-85.12, -68.62]ANCOVA
Comparison: Monotherapy Estimandp-value: <0.000195% CI: [-88.77, -70.17]ANCOVA
Secondary
Percentage Change in Total Cholesterol (TC)/HDL-C Ratio From Baseline to Day 150
Percentage change in total cholesterol/HDL-C ratio from Baseline (Day1) to Day 150, Inclisiran arm versus Ezetimibe and placebo. There were two estimands of interest in comparing efficacy of inclisiran as monotherapy against that of placebo or ezetimibe that differ on the treatment of interest used for each and the management of intercurrent events as follows: * Monotherapy Estimand: Inclisiran as monotherapy compared to the use of comparator. This estimand uses a hypothetical strategy where participants who permanently discontinued treatment, died or used other LLTs were handled in a hypothetical scenario of what would have happened if the intercurrent event did not happen. * Treatment-policy Estimand: Inclisiran as monotherapy compared to the use of comparator with or without other lipid lowering therapies (LLTs) added. This estimand ignored the use of other LLTs and treatment discontinuation. Deaths (if any) were handled as an unfavorable outcome using a composite variable strate
Time frame: Baseline, Day 150
Population: Full Analysis Set, all randomized participants.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Inclisiran | Percentage Change in Total Cholesterol (TC)/HDL-C Ratio From Baseline to Day 150 | LS Mean (Treatment Policy estimand) | -31.54 Percentage change from baseline |
| Inclisiran | Percentage Change in Total Cholesterol (TC)/HDL-C Ratio From Baseline to Day 150 | LS Mean (Monotherapy estimand) | -33.56 Percentage change from baseline |
| Ezetimibe | Percentage Change in Total Cholesterol (TC)/HDL-C Ratio From Baseline to Day 150 | LS Mean (Treatment Policy estimand) | -6.70 Percentage change from baseline |
| Ezetimibe | Percentage Change in Total Cholesterol (TC)/HDL-C Ratio From Baseline to Day 150 | LS Mean (Monotherapy estimand) | -6.98 Percentage change from baseline |
| Placebo | Percentage Change in Total Cholesterol (TC)/HDL-C Ratio From Baseline to Day 150 | LS Mean (Treatment Policy estimand) | 2.31 Percentage change from baseline |
| Placebo | Percentage Change in Total Cholesterol (TC)/HDL-C Ratio From Baseline to Day 150 | LS Mean (Monotherapy estimand) | 2.51 Percentage change from baseline |
Comparison: Treatment Policy Estimandp-value: <0.000195% CI: [-30.32, -19.36]ANCOVA
Comparison: Treatment Policy Estimandp-value: <0.000195% CI: [-41.27, -26.44]ANCOVA
Comparison: Monotherapy Estimandp-value: <0.000195% CI: [-32.07, -21.09]ANCOVA
Comparison: Monotherapy Estimandp-value: <0.000195% CI: [-43.46, -28.67]ANCOVA