A Study of Inclisiran in Participants With Homozygous Familial Hypercholesterolemia (HoFH)

Study Overview
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Brief Summary
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This study was a Phase III,A two-part (double-blind placebo-controlled/open-label) multicenter study to evaluate safety, tolerability, and efficacy of inclisiran in subjects with homozygous familial hypercholesterolemia (HoFH).

Detailed Description
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This study had two sequential parts: Part 1: 6-month double-blind period in which subjects were randomized to receive either inclisiran or placebo Part 2: 18-month open-label follow-up period; placebo-treated subjects from Part 1 were transitioned to inclisiran at Day 180 and all subjects who participated in an open-label follow-up period of inclisiran only

Official Title
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A Two-Part (Double-Blind Placebo Controlled/Open-Label) Multicenter Study to Evaluate Safety, Tolerability, and Efficacy of Inclisiran in Subjects With Homozygous Familial Hypercholesterolemia (Hofh) (ORION-5)

Conditions
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Homozygous Familial Hypercholesterolemia

Intervention / Treatment
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* Drug: Inclisiran Sodium for injection
* Drug: Placebo
* Drug: Placebos


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of HoFH by genetic confirmation or a clinical diagnosis based on a history of an untreated LDL-C concentration >500 mg/dL (13 mmol/L) together with either xanthoma before 10 years of age or evidence of heterozygous familial hypercholesterolemia in both parents Stable on a low-fat diet. Subjects on statins should be receiving a maximally tolerated dose. Maximum tolerated dose is defined as the maximum dose of statin that can be taken on a regular basis without intolerable adverse events. Subjects not receiving statins must have documented evidence of intolerance to at least two different statins. Subjects on lipid-lower therapies (such as 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. Fasting central laboratory LDL-C concentration ≥130 mg/dL (3.4 mmol/L). Triglyceride concentration <400 mg/dL (4.5 mmol/L) No current or planned renal dialysis or renal transplantation Subjects on a documented regimen of LDL or plasma apheresis will be allowed to continue the apheresis during the study, if needed. Subjects must be willing and able to give written informed consent before initiation of any study-related procedures. The subject should be willing to comply with all required study procedures. Willing to follow all study procedures including adherence to dietary guidelines, study visits, fasting blood draws, and compliance with study treatment regimens. Exclusion Criteria: Use of Mipomersen or Lomitapide therapy within 5 months of screening Treatment (within 90 days of screening) with monoclonal antibodies directed towards PCSK9 New York Heart Association (NYHA) class IV heart failure or last known left ventricular ejection fraction <25% Major adverse cardiovascular event within 3 months prior to randomization Planned cardiac surgery or revascularization Uncontrolled severe hypertension: systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg prior to randomization despite anti-hypertensive therapy Active liver disease defined as any known current infectious, neoplastic, or metabolic pathology of the liver or unexplained alanine aminotransferase (ALT), aspartate aminotransferase (AST), elevation >3x ULN, or total bilirubin >2x upper limit of normal (ULN) at screening confirmed by a repeat measurement at least 1 week apart Severe concomitant noncardiovascular disease that carries the risk of reducing life expectancy to less than the duration of the trial History of malignancy that required surgery (excluding local and wide-local excision), radiation therapy and/or commencement of systemic therapy as treatment during the 3 years prior to randomization Females who are pregnant or nursing, or who are of childbearing potential and unwilling to use at least one acceptable effective method of contraception (eg, oral contraceptives, barrier methods, approved contraceptive implant, long- term injectable contraception, intrauterine device) for the entire duration of the study. Exemptions from this criterion: Women >2 years postmenopausal (defined as 1 year or longer since their last menstrual period) AND more than 55 years of age Postmenopausal women (as defined above) and less than 55 years of age with a negative pregnancy test within 24 hours of enrolment Women who are surgically sterilized at least 3 months prior to enrolment Known history of alcohol and/or drug abuse within 5 years Any condition that according to the investigator could interfere with the conduct of the study, such as but not limited to: Subjects who are unable to communicate or to cooperate with the investigator. Unable to understand the protocol requirements, instructions and study-related restrictions, the nature, scope, and possible consequences of the study (including subjects whose cooperation is doubtful due to drug abuse or alcohol dependency) Unlikely to comply with the protocol requirements, instructions, and study-related restrictions (eg, uncooperative attitude, inability to return for follow-up visits, and improbability of completing the study) Have any medical or surgical condition, which in the opinion of the investigator would put the subject at increased risk from participating in the study Persons directly involved in the conduct of the study Any uncontrolled or serious disease, or any medical or surgical condition, that may either interfere with participation in the clinical study, and/or put the subject at significant risk (according to investigator's [or delegate] judgment) if he/she participates in the clinical study Any underlying known disease, or surgical, physical, or medical condition that, in the opinion of the Investigator, might interfere with the interpretation of clinical study results Treatment with other investigational medicinal products or devices within 30 days or 5 half-lives of the screening visit, whichever is longer Previous participation in the study Hypersensitivity to any of the ingredients of Inclisiran The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 - Inclisiran<br>Participants who received a dose of 300 milligram (mg) inclisiran sodium for injection administered by SC injection on Day 1 and Day 90. | Drug: Inclisiran Sodium for injection<br>* Inclisiran is a synthetic, chemically modified small interfering ribonucleic acid (siRNA) targeting proprotein convertase subtilisin kexin type 9 (PCSK9) messenger ribonucleic acid (mRNA) with a covalently attached triantennary N-acetylgalactosamine (GalNAc) ligand.<br>* Other names: ALN-PCSSC;|
| Placebo Comparator: Part 1 - Placebo<br>Participants who received a dose of placebos administered by SC injection on Day 1 and Day 90. | Drug: Placebo<br>* Sterile normal saline (0.9% sodium chloride in water for injection)<br>Drug: Placebos<br>* Sterile normal saline (0.9% sodium chloride in water for injection)<br>|
| Experimental: Part 2 - Inclisiran<br>Participants who received a dose of 300 mg inclisiran sodium for injection administered by SC injection on Day 270, Day 450 and Day 630. In addition, participants who were assigned to the placebo arm in Part 1 will receive a dose of 300 mg inclisiran sodium administered by SC injection on Day 180 after completion of Part 1. | Drug: Inclisiran Sodium for injection<br>* Inclisiran is a synthetic, chemically modified small interfering ribonucleic acid (siRNA) targeting proprotein convertase subtilisin kexin type 9 (PCSK9) messenger ribonucleic acid (mRNA) with a covalently attached triantennary N-acetylgalactosamine (GalNAc) ligand.<br>* Other names: ALN-PCSSC;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change in Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Day 150 | Percentage Change in LDL-C levels from Baseline to Day 150 | Baseline, Day 150 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute Change in Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Day 150 | Absolute Change in LDL-C levels (mg/dL) from baseline to Day 150 | Baseline, Day 150 | 
| Percent Change in Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Subsequent Visits up to Day 180 | Percentage Change in LDL-C levels from baseline to subsequent visits on Days 90, 150, and 180 | Baseline, Days 90, 150, 180 | 
| Percent Change in Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Subsequent Visits up to Day 720 | Percentage Change in LDL-C levels from baseline to subsequent visits up to Day 720 | Baseline, Days 270, 330, 450, 510, 630, 690, and 720 | 
| Absolute Change in Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Subsequent Visits up to Day 180 | Absolute change in LDL-C levels (mg/dL) from baseline to subsequent visits on Days 90, 150 and 180 based on the | Baseline, Days 90, 150, 180 | 
| Absolute Change in Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Subsequent Visits up to Day 720 | Absolute change in LDL-C levels from Baseline to Subsequent Visits up to Day 720 | Baseline, Days 270, 330, 450, 510, 630, 690, and 720 | 
| Percent Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) From Baseline to Subsequent Visits up to Day 180 | Percentage Change in PCSK9 from baseline to subsequent visits up to Day 180 | Baseline, Days 90, 150, 180 | 
| Percent Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) From Baseline to Subsequent Visits up to Day 720 | Percentage Change in PCSK9 from baseline to subsequent visits up to Day 720 | Baseline, Days 270, 330, 450, 510, 630, 690, and 720 | 
| Absolute Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) From Baseline to Subsequent Visits up to Day 180 | Absolute Change in PCSK9 from baseline to subsequent visits up to Day 180 | Baseline, Days 90, 150, 180 | 
| Absolute Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) From Baseline to Subsequent Visits up to Day 720 | Absolute Change in PCSK9 from baseline to subsequent visits up to Day 720 | Baseline, Days 270, 330, 450, 510, 630, 690, and 720 | 
| Percent Change in Total Cholesterol From Baseline to Subsequent Visits up to Day 180 | Percentage change in total cholesterol from baseline to subsequent visits up to Day 180 | Baseline, Days 90, 150 and 180 | 
| Absolute Change in Total Cholesterol From Baseline to Subsequent Visits up to Day 180 | Absolute Change in total cholesterol from baseline to subsequent visits up to Day 180 | Baseline, Days 90, 150, 180 | 
| Percent Change in Total Cholesterol From Baseline to Subsequent Visits up to Day 720 | Percentage change in total cholesterol from baseline to subsequent visits up to Day 720 | Baseline, Days 270, 330, 450, 510, 630, 690, and 720 | 
| Absolute Change in Total Cholesterol From Baseline to Subsequent Visits up to Day 720 | Absolute Change in total cholesterol from baseline to subsequent visits up to Day 720 | Baseline, Days 270, 330, 450, 510, 630, 690, and 720 | 
| Percent Change in Apolipoprotein B (apoB) From Baseline to Subsequent Visits up to Day 180 | Percentage change in Apolipoprotein B (apoB) from baseline to subsequent visits up to Day 180 demonstrated by Mixed Model Repeated Measures statisitical method. | Baseline, Days 90, 150, 180 | 
| Percent Change in Apolipoprotein B (apoB) From Baseline to Subsequent Visits up to Day 720 | Percentage Change in Apolipoprotein B (apoB) from baseline to subsequent visits up to Day 720 | Baseline, Days 270, 330, 450, 510, 630, 690, and 720 | 
| Absolute Change in Apolipoprotein B (apoB) From Baseline to Subsequent Visits up to Day 180 | Absolute change in Apolipoprotein B (apoB) from baseline to subsequent visits up to Day 180 | Baseline, Days 90, 150, 180 | 
| Absolute Change in Apolipoprotein B (Apo B) From Baseline to Subsequent Visits up to Day 720 | Absolute Change in Apolipoprotein B (Apo B) from baseline to subsequent visits up to Day 720 | Baseline, Days 270, 330, 450, 510, 630, 690, and 720 | 
| Percent Change in Non-HDL Cholesterol (Non-HDL-C) From Baseline to Subsequent Visits up to Day 180 | Percentage change in non-HDL-C levels from baseline to subsequent visits up to Day 180 | Baseline, Days 90, 150, 180 | 
| Percent Change in Non-HDL Cholesterol (Non-HDL-C) From Baseline to Subsequent Visits up to Day 720 | Percentage Change in non-HDL-C from Baseline to subsequent visits up to Day 720 | Baseline, Days 270, 330, 450, 510, 630, 690, and 720 | 
| Absolute Change in Non-HDL Cholesterol (Non-HDL-C) From Baseline to Subsequent Visits up to Day 180 | Absolute change in non-HDL-C levels from Baseline to subsequent visits up to Day 180 | Baseline, Days 90, 150, 180 | 
| Absolute Change in Non-HDL Cholesterol (Non-HDL-C) From Baseline to Subsequent Visits up to Day 720 | Absolute Change in non-HDL Cholesterol (non-HDL-C) from Baseline to Subsequent Visits up to Day 720 | Baseline, Days 270, 330, 450, 510, 630, 690, and 720 | 
| Individual Responsiveness of Subjects: Part 1 | Individual Responsiveness of Subjects defined as the number of subjects reaching on treatment LDL-C levels of <25 mg/dL, <50 mg/dL, <70 mg/dL, and <100 mg/dL up to Day 180 | Days 150, 180 | 
| Individual Responsiveness of Subjects: Part 2 | Individual Responsiveness of Subjects defined as the number of subjects reaching on treatment LDL-C levels of <25 mg/dL, <50 mg/dL, <70 mg/dL, and <100 mg/dL up to Day 720 | Days 330, 510, 690 and 720 | 
| Proportional Responsiveness: Part 1 | Number of participants in each group who attain global lipid targets for their indication | Days 150, 180 | 
| Proportional Responsiveness of Subjects: Part 2 | Number of participants in each group who attain global lipid targets for their indication | Days 330, 510, 690 and 720 | 
| LDL-C Reduction ≥20% or ≥30% From Baseline: Part 1 | Proportion of subjects in each group with ≥20% or ≥30% LDL-C reduction from Baseline in Part 1 (Days 90, 150, 180) | Baseline, Days 90, 150, 180 | 
| LDL-C Reduction ≥20% or ≥30% From Baseline: Part 2 | Proportion of subjects in each group with ≥20% or ≥30% LDL-C reduction from Baseline in Part 2 (Days 330, 510, 690, and 720) | Baseline, Days 330, 510, 690, and 720 | 
| Percent Change in High-Density Lipoprotein Cholesterol Levels (HDL-C) From Baseline to Subsequent Visits up to Day 180 | Percentage Change in HDL-C levels (mg/dL) from baseline to subsequent visits on Day 90, 150, and 180 | Baseline, Days 90, 150, 180 | 
| Percent Change in High-Density Lipoprotein Cholesterol Levels (HDL-C) From Baseline to Subsequent Visits up to Day 720 | Percentage change in LDL-C levels from Baseline to Subsequent Visits up to Day 720 | Baseline, Days 330, 450, 510, 630, 690, and 720 | 
| Absolute Change in High-Density Lipoprotein Cholesterol Levels (HDL-C) From Baseline to Subsequent Visits up to Day 180 | Absolute Change in HDL-C levels (mg/dL) from baseline to subsequent visits on Day 90, 150, and 180 | Baseline, Days 90, 150, 180 | 
| Absolute Change in High-Density Lipoprotein Cholesterol Levels (HDL-C) From Baseline to Subsequent Visits up to Day 720 | Absolute change in LDL-C levels from Baseline to Subsequent Visits up to Day 720 | Baseline, Days 330, 450, 510, 630, 690, and 720 | 
| Absolute Change in Very-Low-Density Lipoprotein Cholesterol (VLDL-C) From Baseline to Subsequent Visits up to Day 180 | Absolute Change in VLDL-C levels from baseline to subsequent visits on Days 90, 150, and 180 | Baseline, Days 90, 150, 180 | 
| Absolute Change in Very-Low-Density-Lipoprotein Cholesterol Levels (VLDL-C) From Baseline to Subsequent Visits up to Day 720 | Absolute change in VLDL-C levels from Baseline to Subsequent Visits up to Day 720 | Baseline, Days 330, 450, 510, 630, 690, and 720 | 
| Percent Change in Very-Low-Density Lipoprotein Cholesterol (VLDL-C) From Baseline to Subsequent Visits up to Day 180 | Percentage Change in VLDL-C levels (mg/dL) from baseline to subsequent visits on Days 90, 150, and 180 | Baseline, Days 90, 150, 180 | 
| Percent Change in Very-Low-Density-Lipoprotein Cholesterol Levels (VLDL-C) From Baseline to Subsequent Visits up to Day 720 | Percentage change in VLDL-C levels from Baseline to Subsequent Visits up to Day 720 | Baseline, Days 330, 450, 510, 630, 690, and 720 | 
| Absolute Change in Apolipoprotein A-1 (Apo-A1) mg/dL From Baseline to Subsequent Visits up to Day 180 | Absolute Change in Apolipoprotein A-1 (Apo-A1) from baseline to subsequent visits on Days 90, 150, and 180 | Baseline, Days 90, 150, 180 | 
| Absolute Change Apolipoprotein A-1 (Apo-A1) From Baseline to Subsequent Visits up to Day 720 | Absolute change in Apolipoprotein A-1 (Apo-A1) from Baseline to Subsequent Visits up to Day 720 | Baseline, Days 330, 450, 510, 630, 690, and 720 | 
| Percent Change in Apolipoprotein A-1 (Apo-A1) From Baseline to Subsequent Visits up to Day 180 | Percentage Change in Apolipoprotein A-1 (Apo-A1) from baseline to subsequent visits on Day 90, 150, and 180 | Baseline, Days 90, 150, 180 | 
| Percent Change Apolipoprotein A-1 (Apo-A1) From Baseline to Subsequent Visits up to Day 720 | Percentage change in Apolipoprotein A-1 (Apo-A1) from Baseline to Subsequent Visits up to Day 720 | Baseline, Days 330, 450, 510, 630, 690, and 720 | 
| Percent Change in Lipoprotein(a) [Lp(a)] From Baseline to Subsequent Visits up to Day 180 | Percentage Change in Lp(a) from Baseline to Subsequent Visits up to Day 180 | Baseline, Days 90, 150, 180 | 
| Percent Change in Lipoprotein(a) [Lp(a)] From Baseline to Subsequent Visits up to Day 720 | Percentage change in Lp(a) from Baseline to Subsequent Visits up to Day 720 | Baseline, Days 330, 450, 510, 630, 690, and 720 | 
| Absolute Change in Lipoprotein(a) [Lp(a)] From Baseline to Subsequent Visits up to Day 180 | Absolute Change in Lp(a) from baseline to subsequent visits up to Day 180 | Baseline, Days 90, 150, 180 | 
| Absolute Change in Lipoprotein(a) [Lp(a)] From Baseline to Subsequent Visits up to Day 720 | Absolute change in Lp(a) from Baseline to Subsequent Visits up to Day 720 | Baseline, Days 330, 450, 510, 630, 690, and 720 | 
| Percent Change in High-Sensitivity C-Reactive Protein (hsCRP) From Baseline to Subsequent Visits up to Day 180: Part 1 | Percent change in hsCRP from Baseline to subsequent visits up to Day 180 | Baseline, Days 90, 150, 180 | 
| Percent Change in High-Sensitivity C-Reactive Protein (hsCRP) From Baseline to Subsequent Visits up to Day 720: Part 2 | Percentage change in hsCRP from baseline to subsequent visits up to Day 720 | Baseline, Days 330, 510 ,690, 720 | 
| Absolute Change in High-Sensitivity C-Reactive Protein (hsCRP) From Baseline to Subsequent Visits up to Day 180: Part 1 | Absolute Change in High-Sensitivity C-Reactive Protein (hsCRP) from Baseline to subsequent visits up to Day 180 | Baseline, Days 90, 150, 180 | 
| Absolute Change in High-Sensitivity C-Reactive Protein (hsCRP) From Baseline to Subsequent Visits up to Day 720: Part 2 | Absolute Change in High-Sensitivity C-Reactive Protein (hsCRP) from baseline to subsequent visits up to Day 720 | Baseline, Days 330, 510, 690, 720 | 
| Percent Change in Apo-B From Baseline to Day 150 | Percentage change in Apo-B from baseline to Day 150 as demonstrated using the ANCOVA statisitical model. | Baseline, Day 150 | 
| Percent Change in Non-HDL-C From Baseline to Day 150 | Percentage Change in non-HDL-C from baseline to Day 150 as demonstrated using the ANCOVA statisitical model. | Baseline, Day 150 | 
| Percent Change in Total Cholesterol From Baseline to Day 150 | Percentage change in total cholesterol from baseline to Day 150 as demonstrated using the ANCOVA statisitical model. | Baseline, Day 150 | 
| Proportion of Subjects With ≥30% LDL-C Reduction of From Baseline at Day 150 | Number of participants in each group with ≥30% LDL-C reduction from baseline at Day 150 using the Regression Logistic Statistical Model | Baseline, Day 150 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HoFH