Trial Outcomes & Findings for Trial to Assess the Effect of Long Term Dosing of Inclisiran in Subjects With High CV Risk and Elevated LDL-C (NCT NCT03814187)

Last Updated: 2024-03-06

Results Overview

The primary objective of the study is to evaluate the effect of inclisiran treatment on the proportion of subjects achieving prespecified LDL-C targets at end of study (EOS). Target is \<70 mg/dL for atherosclerotic cardiovascular disease (ASCVD) subjects and \<100 mg/dL for ASCVD risk equivalent subjects. Risk equivalent subjects are defined as either type 2 diabetes, familial hypercholesterolemia or a 10-year risk of a cardiovascular event ≥20% as assessed by the Framingham Risk Score or equivalent; without a medical history of coronary heart disease , cerebrovascular disease or peripheral artery disease.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

3275 participants

Primary outcome timeframe

From ORION-8 Day 1 to the end of study (up to 1080 days)

Results posted on

2024-03-06

Participant Flow

268 centers in 13 countries: United States(145), Canada(8), Czechia(4), Denmark(6), Germany(9), Hungary(4), Netherlands(12), Poland(18), South Africa(12), Spain(6), Sweden(3), Ukraine(8), United Kingdom(33)

Participants completed a qualifying Phase II lipid lowering trial \[MDCO-PCS-16-01 (ORION-3)\] or Phase III lipid-lowering ORION feeder study \[MDCO-PCS-17-03 (ORION-9), MDCO-PCS-17-04 (ORION-10), or MDCO-PCS-17-08 (ORION-11) \] meaning the subject received the last dose of study drug and completed the final study visit per applicable protocol.

Participant milestones

Participant milestones
Measure	Phase III Inclisiran-Inclisiran Subjects who received inclisiran (actual treatment) in studies ORION-9/ ORION-10/ORION-11	Phase III Placebo-Inclisiran subjects who received placebo (actual treatment) in ORION-9/ORION-10/ORION-11	ORION-3 Rollover Subjects rolling over from ORION-3 Phase II study
Overall Study STARTED	1513	1478	284
Overall Study Safety Population	1512	1478	284
Overall Study COMPLETED	1246	1200	0
Overall Study NOT COMPLETED	267	278	284

Reasons for withdrawal

Reasons for withdrawal
Measure	Phase III Inclisiran-Inclisiran Subjects who received inclisiran (actual treatment) in studies ORION-9/ ORION-10/ORION-11	Phase III Placebo-Inclisiran subjects who received placebo (actual treatment) in ORION-9/ORION-10/ORION-11	ORION-3 Rollover Subjects rolling over from ORION-3 Phase II study
Overall Study Sponsor's Administrative Decision	0	0	272
Overall Study Death	80	81	4
Overall Study Withdrew Consent	77	78	2
Overall Study Lost to Follow-up	47	52	1
Overall Study Adverse Event	22	23	0
Overall Study Physician Decision	7	4	2
Overall Study Initiation Of Protocol-Prohibited Approved PCSK9 Inhibitor	0	0	1
Overall Study Other reasons	34	40	2

Baseline Characteristics

Trial to Assess the Effect of Long Term Dosing of Inclisiran in Subjects With High CV Risk and Elevated LDL-C

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Phase III Inclisiran-Inclisiran n=1512 Participants Subjects who received inclisiran (actual treatment) in studies ORION-9/ ORION-10/ORION-11	Phase III Placebo-Inclisiran n=1478 Participants subjects who received placebo (actual treatment) in ORION-9/ORION-10/ORION-11	ORION-3 Rollover n=284 Participants Subjects rolling over from ORION-3 Phase II study	Total n=3274 Participants Total of all reporting groups
Age, Continuous	64.7 years STANDARD_DEVIATION 9.83 • n=5 Participants	64.6 years STANDARD_DEVIATION 9.82 • n=7 Participants	67.7 years STANDARD_DEVIATION 9.97 • n=5 Participants	64.9 years STANDARD_DEVIATION 9.88 • n=4 Participants
Sex: Female, Male Female	482 Participants n=5 Participants	476 Participants n=7 Participants	100 Participants n=5 Participants	1058 Participants n=4 Participants
Sex: Female, Male Male	1030 Participants n=5 Participants	1002 Participants n=7 Participants	184 Participants n=5 Participants	2216 Participants n=4 Participants
Race/Ethnicity, Customized American Indian/Alaska Native	3 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants	7 Participants n=4 Participants
Race/Ethnicity, Customized Asian	17 Participants n=5 Participants	7 Participants n=7 Participants	3 Participants n=5 Participants	27 Participants n=4 Participants
Race/Ethnicity, Customized Black/African American	103 Participants n=5 Participants	78 Participants n=7 Participants	7 Participants n=5 Participants	188 Participants n=4 Participants
Race/Ethnicity, Customized Native Hawaiian/Other Pacific Islander	6 Participants n=5 Participants	4 Participants n=7 Participants	0 Participants n=5 Participants	10 Participants n=4 Participants
Race/Ethnicity, Customized White	1383 Participants n=5 Participants	1387 Participants n=7 Participants	271 Participants n=5 Participants	3041 Participants n=4 Participants
Race/Ethnicity, Customized Missing	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants

PRIMARY outcome

Timeframe: From ORION-8 Day 1 to the end of study (up to 1080 days)

Population: Safety Population: All ORION-3 rollover subjects who signed the informed consent to Study ORION-8, and all ORION-9/ORION-10/ORION-11 rollover subjects with at least one study drug administration in Study. Only participants with valid LDL-C measurements at Day 1080/EOS were included in the analysis.

Outcome measures

Outcome measures
Measure	Phase III Inclisiran-Inclisiran n=1251 Participants Subjects who received inclisiran (actual treatment) in studies ORION-9/ ORION-10/ORION-11	Phase III Placebo-Inclisiran n=1204 Participants subjects who received placebo (actual treatment) in ORION-9/ORION-10/ORION-11	ORION-3 Rollover n=276 Participants Subjects rolling over from ORION-3 Phase II study	Total n=2731 Participants Total
Proportion of Subjects Achieving Global Lipid Targets for Their Level of ASCVD Risk % of subjects Who Attain Global Lipid Targets at Day 1080 / EOS	78.18 Percentage of participants Interval 75.8 to 80.4	79.07 Percentage of participants Interval 76.7 to 81.3	76.81 Percentage of participants Interval 71.4 to 81.6	78.43 Percentage of participants Interval 76.8 to 80.0
Proportion of Subjects Achieving Global Lipid Targets for Their Level of ASCVD Risk % of ASCVD subjects Who Attain Global Lipid Targets of <70 mg/dL at Day 1080 / EOS	79.34 Percentage of participants Interval 76.8 to 81.7	79.96 Percentage of participants Interval 77.4 to 82.4	76.70 Percentage of participants Interval 70.0 to 82.5	79.41 Percentage of participants Interval 77.7 to 81.1
Proportion of Subjects Achieving Global Lipid Targets for Their Level of ASCVD Risk % of ASCVD Risk Equivalent subjects Who Attain Global Lipid Targets of <100 mg/dL at Day 1080 / EOS	72.56 Percentage of participants Interval 66.1 to 78.3	74.88 Percentage of participants Interval 68.6 to 80.5	77.00 Percentage of participants Interval 67.7 to 84.7	74.33 Percentage of participants Interval 70.4 to 78.0

PRIMARY outcome

Timeframe: From ORION-8 Day 1 to the end of study (up to 1080 days)

Population: Safety Population: All ORION-3 rollover subjects who signed the informed consent to Study Orion-8, and all ORION-9/ORION-10/ORION-11 rollover subjects with at least one study drug administration in Study

Safety assessments include adverse events and serious adverse events until the end of study. End of study visit occured at least 90 days following the last inclisiran dose once a decision was made to end the study (either by the subject, investigator or sponsor). For subjects prematurely and permanently discontinued from study treatment, who were not willing to return within the 90 day timeframe, the EOS visit was scheduled as soon as possible, or if decision to discontinue and not return was made at a specific visit, this visit became the EOS visit.

Outcome measures

Outcome measures
Measure	Phase III Inclisiran-Inclisiran n=1512 Participants Subjects who received inclisiran (actual treatment) in studies ORION-9/ ORION-10/ORION-11	Phase III Placebo-Inclisiran n=1478 Participants subjects who received placebo (actual treatment) in ORION-9/ORION-10/ORION-11	ORION-3 Rollover n=284 Participants Subjects rolling over from ORION-3 Phase II study	Total n=3274 Participants Total
Incidence of Treatment-emergent Adverse Events (TEAEs) Adverse events	1197 Participants	1170 Participants	181 Participants	2548 Participants
Incidence of Treatment-emergent Adverse Events (TEAEs) Adverse events :Treatment-related	133 Participants	148 Participants	16 Participants	297 Participants
Incidence of Treatment-emergent Adverse Events (TEAEs) SAEs	464 Participants	482 Participants	43 Participants	989 Participants
Incidence of Treatment-emergent Adverse Events (TEAEs) SAEs: Treatment-related	2 Participants	2 Participants	1 Participants	5 Participants
Incidence of Treatment-emergent Adverse Events (TEAEs) Fatal SAEs	80 Participants	81 Participants	4 Participants	165 Participants
Incidence of Treatment-emergent Adverse Events (TEAEs) Fatal SAEs: Treatment-related	0 Participants	0 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Feeder study baseline, ORION-8 baseline, Day 1080/EOS (ORION-8) (up to a maximum of 2340 days)

Absolute change from baseline in low density lipoprotein cholesterol (LDL-C) was calculated to evaluate the effect of inclisiran on LDL-C levels.

Outcome measures

Outcome measures
Measure	Phase III Inclisiran-Inclisiran n=1512 Participants Subjects who received inclisiran (actual treatment) in studies ORION-9/ ORION-10/ORION-11	Phase III Placebo-Inclisiran n=1478 Participants subjects who received placebo (actual treatment) in ORION-9/ORION-10/ORION-11	ORION-3 Rollover n=284 Participants Subjects rolling over from ORION-3 Phase II study	Total Total
Absolute Change in LDL-C From the Initial Feeder Study Baseline Day 1080 / EOS	-55.81 mg/dL Interval -58.0 to -53.6	-54.70 mg/dL Interval -56.9 to -52.5	-64.31 mg/dL Interval -69.0 to -59.7	—
Absolute Change in LDL-C From the Initial Feeder Study Baseline ORION-8 Baseline	-55.21 mg/dL Interval -56.9 to -53.5	0.46 mg/dL Interval -1.4 to 2.3	-61.58 mg/dL Interval -66.4 to -56.8	—

SECONDARY outcome

Timeframe: Feeder study baseline, ORION-8 baseline, Day 1080/EOS (ORION-8) (up to a maximum of 2340 days)

Percentage change from baseline in low density lipoprotein cholesterol (LDL-C) was calculated to evaluate the effect of inclisiran on LDL-C levels.

Outcome measures

Outcome measures
Measure	Phase III Inclisiran-Inclisiran n=1512 Participants Subjects who received inclisiran (actual treatment) in studies ORION-9/ ORION-10/ORION-11	Phase III Placebo-Inclisiran n=1478 Participants subjects who received placebo (actual treatment) in ORION-9/ORION-10/ORION-11	ORION-3 Rollover n=284 Participants Subjects rolling over from ORION-3 Phase II study	Total Total
Percentage Change in LDL-C From the Initial Feeder Study Baseline ORION-8 Baseline	-50.02 Percentage change in LDL-C Interval -51.3 to -48.8	3.10 Percentage change in LDL-C Interval 1.4 to 4.9	-48.22 Percentage change in LDL-C Interval -51.2 to -45.2	—
Percentage Change in LDL-C From the Initial Feeder Study Baseline Day 1080 / EOS	-48.96 Percentage change in LDL-C Interval -50.5 to -47.4	-49.69 Percentage change in LDL-C Interval -51.3 to -48.0	-49.95 Percentage change in LDL-C Interval -52.6 to -47.3	—

SECONDARY outcome

Timeframe: Feeder study baseline, ORION-8 baseline, Day 1080/EOS (ORION-8) (up to a maximum of 2340 days)

Absolute change from baseline in total cholesterol, triglycerides and high density lipoprotein cholesterol (HDL-C) was calculated to evaluate the effect of inclisiran on other lipids and lipoproteins.

Outcome measures

Outcome measures
Measure	Phase III Inclisiran-Inclisiran n=1512 Participants Subjects who received inclisiran (actual treatment) in studies ORION-9/ ORION-10/ORION-11	Phase III Placebo-Inclisiran n=1478 Participants subjects who received placebo (actual treatment) in ORION-9/ORION-10/ORION-11	ORION-3 Rollover n=284 Participants Subjects rolling over from ORION-3 Phase II study	Total Total
Absolute Change From the Initial Feeder Study Baseline in Total Cholesterol, Triglycerides and HDL-C ORION-8 Baseline Total Cholesterol (TC)	-59.05 mg/dL Interval -61.0 to -57.1	-0.07 mg/dL Interval -2.2 to 2.1	-63.11 mg/dL Interval -68.3 to -57.9	—
Absolute Change From the Initial Feeder Study Baseline in Total Cholesterol, Triglycerides and HDL-C Day 1080 / EOS Total Cholesterol (TC)	-58.48 mg/dL Interval -61.0 to -55.9	-57.08 mg/dL Interval -59.6 to -54.6	-65.43 mg/dL Interval -70.5 to -60.3	—
Absolute Change From the Initial Feeder Study Baseline in Total Cholesterol, Triglycerides and HDL-C ORION-8 Baseline Triglycerides	-21.50 mg/dL Interval -25.1 to -17.9	-5.74 mg/dL Interval -9.5 to -2.0	-14.43 mg/dL Interval -23.7 to -5.1	—
Absolute Change From the Initial Feeder Study Baseline in Total Cholesterol, Triglycerides and HDL-C Day 1080 / EOS Triglycerides	-19.58 mg/dL Interval -23.7 to -15.4	-22.12 mg/dL Interval -26.3 to -17.9	-21.32 mg/dL Interval -30.3 to -12.4	—
Absolute Change From the Initial Feeder Study Baseline in Total Cholesterol, Triglycerides and HDL-C ORION-8 Baseline HDL Cholesterol	3.37 mg/dL Interval 2.9 to 3.9	0.59 mg/dL Interval 0.1 to 1.1	3.41 mg/dL Interval 2.2 to 4.6	—
Absolute Change From the Initial Feeder Study Baseline in Total Cholesterol, Triglycerides and HDL-C Day 1080 / EOS HDL Cholesterol	3.60 mg/dL Interval 3.0 to 4.2	4.39 mg/dL Interval 3.8 to 5.0	5.27 mg/dL Interval 3.8 to 6.7	—

SECONDARY outcome

Timeframe: Feeder study baseline, ORION-8 baseline, Day 1080/EOS (ORION-8) (up to a maximum of 2340 days)

Percentage change from baseline in total cholesterol (TC), triglycerides and high density lipoprotein cholesterol (HDL-C) was calculated to evaluate the effect of inclisiran on other lipids and lipoproteins.

Outcome measures

Outcome measures
Measure	Phase III Inclisiran-Inclisiran n=1512 Participants Subjects who received inclisiran (actual treatment) in studies ORION-9/ ORION-10/ORION-11	Phase III Placebo-Inclisiran n=1478 Participants subjects who received placebo (actual treatment) in ORION-9/ORION-10/ORION-11	ORION-3 Rollover n=284 Participants Subjects rolling over from ORION-3 Phase II study	Total Total
Percentage Change From the Initial Feeder Study Baseline in Total Cholesterol, Triglycerides and HDL-C ORION-8 Baseline Total Cholesterol (TC)	-30.64 Percentage change Interval -31.5 to -29.7	1.28 Percentage change Interval 0.1 to 2.4	-29.49 Percentage change Interval -31.6 to -27.4	—
Percentage Change From the Initial Feeder Study Baseline in Total Cholesterol, Triglycerides and HDL-C Day 1080 / EOS Total Cholesterol (TC)	-29.34 Percentage change Interval -30.5 to -28.2	-29.53 Percentage change Interval -30.7 to -28.4	-30.44 Percentage change Interval -32.4 to -28.5	—
Percentage Change From the Initial Feeder Study Baseline in Total Cholesterol, Triglycerides and HDL-C ORION-8 Baseline Triglycerides	-7.84 Percentage change Interval -10.0 to -5.7	3.03 Percentage change Interval 0.8 to 5.2	-0.20 Percentage change Interval -7.6 to 7.2	—
Percentage Change From the Initial Feeder Study Baseline in Total Cholesterol, Triglycerides and HDL-C Day 1080 / EOS Triglycerides	-3.90 Percentage change Interval -6.5 to -1.3	-6.85 Percentage change Interval -9.2 to -4.5	-3.18 Percentage change Interval -9.2 to 2.8	—
Percentage Change From the Initial Feeder Study Baseline in Total Cholesterol, Triglycerides and HDL-C ORION-8 Baseline HDL Cholesterol	9.28 Percentage change Interval 8.2 to 10.4	3.48 Percentage change Interval 2.4 to 4.6	8.13 Percentage change Interval 5.7 to 10.5	—
Percentage Change From the Initial Feeder Study Baseline in Total Cholesterol, Triglycerides and HDL-C Day 1080 / EOS HDL Cholesterol	9.91 Percentage change Interval 8.7 to 11.2	11.75 Percentage change Interval 10.3 to 13.2	12.16 Percentage change Interval 9.3 to 15.0	—

Adverse Events

Phase III Inclisiran-Inclisiran

Serious events: 464 serious events

Other events: 1110 other events

Deaths: 80 deaths

Phase III Placebo-Inclisiran

Serious events: 482 serious events

Other events: 1073 other events

Deaths: 81 deaths

ORION-3 Rollover

Serious events: 43 serious events

Other events: 169 other events

Deaths: 4 deaths

Total

Serious events: 989 serious events

Other events: 2352 other events

Deaths: 165 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: + 1 862 778 8300

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial.
Publication restrictions are in place

Restriction type: OTHER