Trial to Evaluate the Effect of Inclisiran Treatment on Low Density Lipoprotein Cholesterol (LDL-C) in Subjects With Heterozygous Familial Hypercholesterolemia (HeFH)

Conditions

Elevated Cholesterol, Heterozygous Familial Hypercholesterolemia

Keywords

HeFH, LDL-C, Inclisiran

Brief summary

This is a Phase III, placebo-controlled, double-blind, randomized study in participants with HeFH and elevated LDL-C to evaluate the efficacy, safety, and tolerability of subcutaneous (SC) injection(s) of inclisiran. The study will be multicenter and international.

Dutta S, Shah R, Singhal S, Singh S, Piparva K, Katoch CDS.

2023-12-194 citations

10.1080/14740338.2023.2293201

Efficacy, Safety, and Tolerability of Inclisiran in Patients With Homozygous Familial Hypercholesterolemia: Results From the ORION-5 Randomized Clinical Trial

Frederick J. Raal, Ronen Durst, Ran Bi, Zsolt Talloczy, Pierre Maheux et al. (8 authors)

Circulation2023-10-1869 citations

10.1161/circulationaha.122.063460

EFFICACY AND SAFETY OF INCLISIRAN BY BASELINE BODY MASS INDEX: A POST HOC POOLED ANALYSIS OF THE ORION-9, ORION-10 AND ORION-11 PHASE III RANDOMIZED CONTROLLED TRIALS

Lawrence A. Leiter, David Kallend, Wolfgang Köenig, Ulf Landmesser, Kausik K. Ray et al. (10 authors)

American Journal of Preventive Cardiology2023-01-211 citations

10.1016/j.ajpc.2022.100403

Abstract 11143: Efficacy and Safety of Inclisiran by Baseline Body Mass Index: A Post Hoc Pooled Analysis of the ORION-9, ORION-10 and ORION-11 Phase III Randomized Controlled Trials

Lawrence A. Leiter, David Kallend, Wolfgang Köenig, Ulf Landmesser, Kausik K. Ray et al. (10 authors)

Circulation2021-11-16

10.1161/circ.144.suppl_1.11143

Efficacy and safety of inclisiran in patients with established cerebrovascular disease: pooled, post hoc analysis of the ORION-9, ORION-10 and ORION-11, phase 3 randomised clinical trials

Wolfgang Köenig, Kausik K. Ray, D G Kallend, Ulf Landmesser, L. A. Leiter et al. (10 authors)

European Heart Journal2021-10-013 citations

10.1093/eurheartj/ehab724.2026

Efficacy and safety of inclisiran in patients with polyvascular disease: pooled, post hoc analysis of the ORION-9, ORION-10 and ORION-11, phase 3 randomised controlled trials

Wolfgang Köenig, Kausik K. Ray, D G Kallend, Ulf Landmesser, L. A. Leiter et al. (10 authors)

European Heart Journal2021-10-012 citations

10.1093/eurheartj/ehab724.2025

Inclisiran for the Treatment of Heterozygous Familial Hypercholesterolemia

Frederick J. Raal, David Kallend, Kausik K. Ray, Traci Turner, Wolfgang Köenig et al. (11 authors)

New England Journal of Medicine2020-03-18752 citations

10.1056/nejmoa1913805

Interventions

DRUGInclisiran

Inclisiran is a small interfering ribonucleic acid (RNA) that inhibits PCSK9 synthesis.

DRUGPlacebo

Placebo will be supplied as sterile normal saline (0.9% sodium chloride in water for injection).

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Caregiver)

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

No

Inclusion criteria

Participants may be included if they meet all of the following inclusion criteria prior to randomization: 1. Male or female participants ≥18 years of age. 2. History of HeFH with a diagnosis of HeFH by genetic testing; and/or a documented history of untreated LDL-C of \>190 mg/dL, and a family history of familial hypercholesterolemia, elevated cholesterol or early heart disease that may indicate familial hypercholesterolemia. 3. Serum LDL-C ≥2.6 millimoles (mmol)/liter (L) (≥100 mg/dL) at screening. 4. Fasting triglyceride \<4.52 mmol/L (\<400 mg/dL) at screening. 5. Participants on statins should be receiving a maximally tolerated dose. 6. Participants not receiving statins must have documented evidence of intolerance to all doses of at least 2 different statins. 7. Participants on lipid-lowering therapies (such as a statin and/or ezetimibe) should be on a stable dose for ≥30 days before screening with no planned medication or dose change during study participation.

Exclusion criteria

Participants will be excluded from the study if any of the following

Design outcomes

Primary

Measure	Time frame	Description
Percent Change in LDL-C From Baseline To Day 510	Baseline, Day 510	—
Time-adjusted Percent Change in LDL-C From Baseline After Day 90 and up to Day 540	Baseline, Day 90	Assessments performed at Baseline, Day 90, Day 540, time-adjusted percent change at Day 90 reported

Secondary

Measure	Time frame	Description
Absolute Change in LDL-C From Baseline to Day 510	Baseline, Day 510	—
Time-adjusted Absolute Change in LDL-C From Baseline After Day 90 and up to Day 540	Baseline, Day 90	Assessments performed at Baseline, Day 90, Day 540, absolute change at Day 90 reported
Percentage Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) From Baseline to Day 510	Baseline, Day 510	—
Percentage Change in Total Cholesterol From Baseline to Day 510	Baseline, Day 510	—
Percent Change in Apolipoprotein B (Apo-B) From Baseline To Day 510	Baseline, Day 510	—
Percent Change in Non-high-density Lipoprotein (HDL)-C From Baseline To Day 510	Baseline, Day 510	—

Countries

Canada, Czechia, Denmark, Netherlands, South Africa, Spain, Sweden, United States

Participant flow

Participants by arm

Arm	Count
Inclisiran Inclisiran sodium 300 milligrams (mg) will be administered as a SC injection on Day 1, Day 90 then every 6 months. Inclisiran: Inclisiran is a small interfering ribonucleic acid (RNA) that inhibits PCSK9 synthesis.	242
Placebo Placebo will be administered as SC injections of saline solution on Day 1, Day 90 then every 6 months. Placebo: Placebo will be supplied as sterile normal saline (0.9% sodium chloride in water for injection).	240
Total	482

Baseline characteristics

Characteristic	Inclisiran	Total	Placebo
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	53 Participants	108 Participants	55 Participants
Age, Categorical Between 18 and 65 years	189 Participants	374 Participants	185 Participants
Age, Continuous	54.4 years STANDARD_DEVIATION 12.48	54.7 years STANDARD_DEVIATION 12.14	55.0 years STANDARD_DEVIATION 11.81
Ethnicity (NIH/OMB) Hispanic or Latino	7 Participants	15 Participants	8 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	235 Participants	467 Participants	232 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants	1 Participants	0 Participants
Race (NIH/OMB) Asian	7 Participants	12 Participants	5 Participants
Race (NIH/OMB) Black or African American	8 Participants	15 Participants	7 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	1 Participants	1 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	226 Participants	453 Participants	227 Participants
Region of Enrollment Canada	12 participants	23 participants	11 participants
Region of Enrollment Czechia	7 participants	12 participants	5 participants
Region of Enrollment Denmark	23 participants	49 participants	26 participants
Region of Enrollment Netherlands	19 participants	38 participants	19 participants
Region of Enrollment South Africa	88 participants	177 participants	89 participants
Region of Enrollment Spain	42 participants	84 participants	42 participants
Region of Enrollment Sweden	18 participants	34 participants	16 participants
Region of Enrollment United States	33 participants	65 participants	32 participants
Sex: Female, Male Female	130 Participants	255 Participants	125 Participants
Sex: Female, Male Male	112 Participants	227 Participants	115 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	1 / 241	1 / 240
other Total, other adverse events	96 / 241	67 / 240
serious Total, serious adverse events	18 / 241	33 / 240

Outcome results

Primary

Percent Change in LDL-C From Baseline To Day 510

Time frame: Baseline, Day 510

Population: ITT (intent-to-treat) Population

Arm	Measure	Value (LEAST_SQUARES_MEAN)
Inclisiran	Percent Change in LDL-C From Baseline To Day 510	-41.15 percent change
Placebo	Percent Change in LDL-C From Baseline To Day 510	8.37 percent change

p-value: <0.000195% CI: [-55.04, -43.99]ANCOVA

Primary

Time-adjusted Percent Change in LDL-C From Baseline After Day 90 and up to Day 540

Assessments performed at Baseline, Day 90, Day 540, time-adjusted percent change at Day 90 reported

Time frame: Baseline, Day 90

Population: ITT (intent-to-treat) Population

Arm	Measure	Value (LEAST_SQUARES_MEAN)
Inclisiran	Time-adjusted Percent Change in LDL-C From Baseline After Day 90 and up to Day 540	-38.08 percent change
Placebo	Time-adjusted Percent Change in LDL-C From Baseline After Day 90 and up to Day 540	6.22 percent change

p-value: <0.000195% CI: [-48.48, -40.12]ANCOVA

Secondary

Absolute Change in LDL-C From Baseline to Day 510

Time frame: Baseline, Day 510

Population: ITT (intent-to-treat) Population

Arm	Measure	Value (LEAST_SQUARES_MEAN)
Inclisiran	Absolute Change in LDL-C From Baseline to Day 510	-58.95 mg/dL
Placebo	Absolute Change in LDL-C From Baseline to Day 510	9.94 mg/dL

p-value: <0.000195% CI: [-77.11, -60.67]ANCOVA

Secondary

Percentage Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) From Baseline to Day 510

Time frame: Baseline, Day 510

Population: ITT (intent-to-treat) Population

Arm	Measure	Value (LEAST_SQUARES_MEAN)
Inclisiran	Percentage Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) From Baseline to Day 510	-60.68 percent change
Placebo	Percentage Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) From Baseline to Day 510	17.66 percent change

p-value: <0.000195% CI: [-83.65, -73.04]ANCOVA

Secondary

Percentage Change in Total Cholesterol From Baseline to Day 510

Time frame: Baseline, Day 510

Population: ITT (intent-to-treat) Population

Arm	Measure	Value (LEAST_SQUARES_MEAN)
Inclisiran	Percentage Change in Total Cholesterol From Baseline to Day 510	-25.11 percent change
Placebo	Percentage Change in Total Cholesterol From Baseline to Day 510	6.66 percent change

p-value: <0.000195% CI: [-35.59, -27.94]ANCOVA

Secondary

Percent Change in Apolipoprotein B (Apo-B) From Baseline To Day 510

Time frame: Baseline, Day 510

Population: ITT (intent-to-treat) Population

Arm	Measure	Value (LEAST_SQUARES_MEAN)
Inclisiran	Percent Change in Apolipoprotein B (Apo-B) From Baseline To Day 510	-33.14 percent change
Placebo	Percent Change in Apolipoprotein B (Apo-B) From Baseline To Day 510	2.93 percent change

p-value: <0.000195% CI: [-39.99, -32.14]ANCOVA

Secondary

Percent Change in Non-high-density Lipoprotein (HDL)-C From Baseline To Day 510

Time frame: Baseline, Day 510

Population: ITT (intent-to-treat) Population

Arm	Measure	Value (LEAST_SQUARES_MEAN)
Inclisiran	Percent Change in Non-high-density Lipoprotein (HDL)-C From Baseline To Day 510	-34.93 percent change
Placebo	Percent Change in Non-high-density Lipoprotein (HDL)-C From Baseline To Day 510	7.43 percent change

p-value: <0.000195% CI: [-47.32, -37.4]ANCOVA

Secondary

Time-adjusted Absolute Change in LDL-C From Baseline After Day 90 and up to Day 540

Assessments performed at Baseline, Day 90, Day 540, absolute change at Day 90 reported

Time frame: Baseline, Day 90

Population: ITT (intent-to-treat) Population

Arm	Measure	Value (LEAST_SQUARES_MEAN)
Inclisiran	Time-adjusted Absolute Change in LDL-C From Baseline After Day 90 and up to Day 540	-56.58 mg/dL
Placebo	Time-adjusted Absolute Change in LDL-C From Baseline After Day 90 and up to Day 540	6.17 mg/dL

p-value: <0.000195% CI: [-69.01, -56.48]ANCOVA

Trial to Evaluate the Effect of Inclisiran Treatment on Low Density Lipoprotein Cholesterol (LDL-C) in Subjects With Heterozygous Familial Hypercholesterolemia (HeFH)

Conditions

Keywords

Brief summary

Related papers

Interventions

Sponsors

Study design

Eligibility

Inclusion criteria

Exclusion criteria

Design outcomes

Primary

Secondary

Countries

Participant flow

Participants by arm

Baseline characteristics

Adverse events

Outcome results

Percent Change in LDL-C From Baseline To Day 510

Time-adjusted Percent Change in LDL-C From Baseline After Day 90 and up to Day 540

Absolute Change in LDL-C From Baseline to Day 510

Percentage Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) From Baseline to Day 510

Percentage Change in Total Cholesterol From Baseline to Day 510

Percent Change in Apolipoprotein B (Apo-B) From Baseline To Day 510

Percent Change in Non-high-density Lipoprotein (HDL)-C From Baseline To Day 510

Time-adjusted Absolute Change in LDL-C From Baseline After Day 90 and up to Day 540