Homozygous Familial HypercholesterolemiaPhase 3ORION-5NCT03851705
A Study of Inclisiran in Participants With Homozygous Familial Hypercholesterolemia (HoFH)
A Phase 3 study testing Inclisiran Sodium for injection in people with Homozygous Familial Hypercholesterolemia, run by Novartis Pharmaceuticals at 13 sites in 8 countries.
Trial summary
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). Read more about this study
- Who is it for?
- Ages 18 to 80 yearsHealthy volunteers can take part
- Conditions the study is for
- Homozygous Familial Hypercholesterolemia
- What is being tested?
- Inclisiran Sodium for injection
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 56 participants
- Where
- 13 sitesin 8 countries
- Study dates
- 6 Feb 2019to 9 Sep 2021
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 80 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- 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).
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- 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.
Who cannot join
- 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
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- 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.
Trial locations and contacts
13 sites in 8 countries.
13 sites in 8 countries
Russia3 sites
(50007-001) Research Institute of Complex Issues of Cardiovascular Diseases
Kemerovo, 650002
(50007-003) National Medical Research Centre of Cardiology
Moscow, 121552
(50007-002) Hospital for War Veterans
Saint Petersburg, 193079
Turkey (Türkiye)3 sites
(50090-002) University of Health Sciences
Etlik, 06010
(50090-003) Istanbul University
Istanbul, 34093
(50090-001) Ege Universitesi
Izmir, 35040
Ukraine2 sites
(50380-002) IMunicipal Non-commercial Enterprise "Ivano-Frankivsk Regional Clinical Cardiology Center Ivano-Frankivsk Regional Council"
Ivano-Frankivsk, 76018
(50380-001) National Scientific Center
Kyiv, 03680
Israel1 site
(50972-001) Hadassah Hospital Lipid Research Ein Kerem
Jerusalem, 91120
About this study
Official title: 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)
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).
Read the detailed description
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
- Conditions
- Homozygous Familial Hypercholesterolemia
- Being tested
- Inclisiran Sodium for injection, Placebo, Placebos
- Keywords
- HoFH
- Medical subject headings
- Homozygous Familial Hypercholesterolemia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Inclisiran Sodium for injectionDrug
Also called ALN-PCSSC; KJX839, ALN-PCSSC
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.
PlaceboDrug
Sterile normal saline (0.9% sodium chloride in water for injection)
PlacebosDrug
Sterile normal saline (0.9% sodium chloride in water for injection)
| Study group | Role | What they receive |
|---|---|---|
| Part 1 - Inclisiran | Experimental | Participants who received a dose of 300 milligram (mg) inclisiran sodium for injection administered by SC injection on Day 1 and Day 90. Receives: Drug: Inclisiran Sodium for injection |
| Part 1 - Placebo | Placebo comparator | Participants who received a dose of placebos administered by SC injection on Day 1 and Day 90. Receives: Drug: Placebo; Drug: Placebos |
| Part 2 - Inclisiran | Experimental | 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. Receives: Drug: Inclisiran Sodium for injection |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: Baseline, Day 150
Secondary outcomes (51)
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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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.
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: Days 330, 510, 690 and 720
Proportional Responsiveness: Part 1
Number of participants in each group who attain global lipid targets for their indication
Measured: Days 150, 180
Proportional Responsiveness of Subjects: Part 2
Number of participants in each group who attain global lipid targets for their indication
Measured: 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)
Measured: 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)
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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
Measured: Baseline, Day 150
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Feb 2019
- Study start6 Feb 2019
- Primary completion2 Mar 2020
- Study completion9 Sep 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Homozygous Familial HypercholesterolemiaStudies of the same condition, open and under way.
- More trials run by Novartis PharmaceuticalsThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 56 participants (actual)
Sponsor and investigators
- Lead sponsor
- Novartis Pharmaceuticals
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03851705
- Sponsor's protocol ID
- MDCO-PCS-17-02
- Other IDs
- CKJX839A12302, 2018-000893-31, 2018
- Acronym
- ORION-5
- Status last verified
- Jan 2023
- First submitted
- 7 Feb 2019
- Last updated
- 30 Jan 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com.
Publications
Raal F, Durst R, Bi R, Talloczy Z, Maheux P, Lesogor A, Kastelein JJP; ORION-5 Study Investigators. Efficacy, Safety, and Tolerability of Inclisiran in Patients With Homozygous Familial Hypercholesterolemia: Results From the ORION-5 Randomized Clinical Trial. Circulation. 2024 Jan 30;149(5):354-362. doi: 10.1161/CIRCULATIONAHA.122.063460. Epub 2023 Oct 18.
PubMed 37850379Warden BA, Duell PB. Inclisiran: A Novel Agent for Lowering Apolipoprotein B-containing Lipoproteins. J Cardiovasc Pharmacol. 2021 Aug 1;78(2):e157-e174. doi: 10.1097/FJC.0000000000001053.
PubMed 33990512
Study at a glance
From the registry record, last updated by the sponsor on 30 Jan 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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)
- ClinicalTrials.gov ID
- NCT03851705
- Acronym / sponsor ID
- ORION-5 / MDCO-PCS-17-02
- Conditions
- Homozygous Familial Hypercholesterolemia
- Keywords
- HoFH
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 56 participants (actual)
- Lead sponsor
- Novartis PharmaceuticalsIndustry (pharma, biotech, devices)
- Study start
- 6 Feb 2019 (actual)
- Primary completion
- 2 Mar 2020 (actual)
- Study completion
- 9 Sep 2021 (actual)
- First posted
- 22 Feb 2019 (actual)
- Results
- Posted 10 Nov 2022
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
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
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Part 1 - Inclisiran | Experimental | Drug: Inclisiran Sodium for injectionParticipants who received a dose of 300 milligram (mg) inclisiran sodium for injection administered by SC injection on Day 1 and Day 90. |
| Part 1 - Placebo | Placebo comparator | Drug: Placebo, Drug: PlacebosParticipants who received a dose of placebos administered by SC injection on Day 1 and Day 90. |
| Part 2 - Inclisiran | Experimental | Drug: Inclisiran Sodium for injectionParticipants 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. |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (11 listed)
- 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.
Key exclusion criteria (26 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Inclisiran Sodium for injectionAlso: ALN-PCSSC; KJX839, ALN-PCSSCInclisiran 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. | Drug | Part 1 - Inclisiran, Part 2 - Inclisiran |
| PlaceboSterile normal saline (0.9% sodium chloride in water for injection) | Drug | Part 1 - Placebo |
| PlacebosSterile normal saline (0.9% sodium chloride in water for injection) | Drug | Part 1 - Placebo |
Primary outcome
Percent Change in Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Day 150
Time frame: Baseline, Day 150
Percentage Change in LDL-C levels from Baseline to Day 150
51 secondary outcomes
Absolute Change in Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Day 150
Time frame: Baseline, Day 150
Percent Change in Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Subsequent Visits up to Day 180
Time frame: Baseline, Days 90, 150, 180
Percent Change in Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Subsequent Visits up to Day 720
Time frame: 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
Time frame: Baseline, Days 90, 150, 180
Absolute Change in Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Subsequent Visits up to Day 720
Time frame: 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
Time frame: Baseline, Days 90, 150, 180
Percent Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) From Baseline to Subsequent Visits up to Day 720
Time frame: 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
Time frame: Baseline, Days 90, 150, 180
Absolute Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) From Baseline to Subsequent Visits up to Day 720
Time frame: Baseline, Days 270, 330, 450, 510, 630, 690, and 720
Percent Change in Total Cholesterol From Baseline to Subsequent Visits up to Day 180
Time frame: Baseline, Days 90, 150 and 180
Absolute Change in Total Cholesterol From Baseline to Subsequent Visits up to Day 180
Time frame: Baseline, Days 90, 150, 180
Percent Change in Total Cholesterol From Baseline to Subsequent Visits up to Day 720
Time frame: Baseline, Days 270, 330, 450, 510, 630, 690, and 720
Absolute Change in Total Cholesterol From Baseline to Subsequent Visits up to Day 720
Time frame: 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
Time frame: Baseline, Days 90, 150, 180
Percent Change in Apolipoprotein B (apoB) From Baseline to Subsequent Visits up to Day 720
Time frame: 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
Time frame: Baseline, Days 90, 150, 180
Absolute Change in Apolipoprotein B (Apo B) From Baseline to Subsequent Visits up to Day 720
Time frame: 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
Time frame: Baseline, Days 90, 150, 180
Percent Change in Non-HDL Cholesterol (Non-HDL-C) From Baseline to Subsequent Visits up to Day 720
Time frame: 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
Time frame: Baseline, Days 90, 150, 180
Absolute Change in Non-HDL Cholesterol (Non-HDL-C) From Baseline to Subsequent Visits up to Day 720
Time frame: Baseline, Days 270, 330, 450, 510, 630, 690, and 720
Individual Responsiveness of Subjects: Part 1
Time frame: Days 150, 180
Individual Responsiveness of Subjects: Part 2
Time frame: Days 330, 510, 690 and 720
Proportional Responsiveness: Part 1
Time frame: Days 150, 180
Proportional Responsiveness of Subjects: Part 2
Time frame: Days 330, 510, 690 and 720
LDL-C Reduction ≥20% or ≥30% From Baseline: Part 1
Time frame: Baseline, Days 90, 150, 180
LDL-C Reduction ≥20% or ≥30% From Baseline: Part 2
Time frame: 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
Time frame: Baseline, Days 90, 150, 180
Percent Change in High-Density Lipoprotein Cholesterol Levels (HDL-C) From Baseline to Subsequent Visits up to Day 720
Time frame: 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
Time frame: Baseline, Days 90, 150, 180
Absolute Change in High-Density Lipoprotein Cholesterol Levels (HDL-C) From Baseline to Subsequent Visits up to Day 720
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: Baseline, Days 90, 150, 180
Absolute Change Apolipoprotein A-1 (Apo-A1) From Baseline to Subsequent Visits up to Day 720
Time frame: 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
Time frame: Baseline, Days 90, 150, 180
Percent Change Apolipoprotein A-1 (Apo-A1) From Baseline to Subsequent Visits up to Day 720
Time frame: 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
Time frame: Baseline, Days 90, 150, 180
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 30 Jan 2023.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 37850379Raal F, Durst R, Bi R, Talloczy Z, Maheux P, Lesogor A, Kastelein JJP; ORION-5 Study Investigators. Efficacy, Safety, and Tolerability of Inclisiran in Patients With Homozygous Familial Hypercholesterolemia: Results From the ORION-5 Randomized Clinical Trial. Circulation. 2024 Jan 30;149(5):354-362. doi: 10.1161/CIRCULATIONAHA.122.063460. Epub 2023 Oct 18.
- Derived from this study: PubMed 33990512Warden BA, Duell PB. Inclisiran: A Novel Agent for Lowering Apolipoprotein B-containing Lipoproteins. J Cardiovasc Pharmacol. 2021 Aug 1;78(2):e157-e174. doi: 10.1097/FJC.0000000000001053.
- A Plain Language Trial Summary is available on novctrd.comLink provided by the sponsor.
- Individual participant dataSharing planned: Yes. Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
13 sites in 8 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Inclisiran Sodium for injection in people with Homozygous Familial Hypercholesterolemia, run by Novartis Pharmaceuticals at 13 sites in 8 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 11 inclusion and 26 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 30 Jan 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 13 sites in Russia, Turkey (Türkiye), Ukraine, Hong Kong, Israel and 3 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 10 Nov 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Percent Change in Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Day 150 (time frame: Baseline, Day 150). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03851705, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Jan 2023.