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

• Register: ClinicalTrials.gov
• Last refreshed on: 6 February 2023
• Main ID: NCT03851705
• Date of registration: 07/02/2019
• Prospective Registration: No
• Primary sponsor: Novartis Pharmaceuticals
• Public title: A Study of Inclisiran in Participants With Homozygous Familial Hypercholesterolemia (HoFH) ORION-5
• Scientific 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)
• Date of first enrolment: February 6, 2019
• Target sample size: 56
• Recruitment status: Completed
• URL: https://clinicaltrials.gov/show/NCT03851705
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: Double (Participant, Investigator).
• Phase: Phase 3

Countries of recruitment

Czechia, Hong Kong, Israel, Russian Federation, Serbia, South Africa, Taiwan, Turkey, Ukraine

Key inclusion & exclusion criteria

Inclusion Criteria:

1. 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

2. Stable on a low-fat diet.

3. 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.

4. Subjects not receiving statins must have documented evidence of intolerance to at
least two different statins.

5. 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.

6. Fasting central laboratory LDL-C concentration =130 mg/dL (3.4 mmol/L).

7. Triglyceride concentration <400 mg/dL (4.5 mmol/L)

8. No current or planned renal dialysis or renal transplantation

9. Subjects on a documented regimen of LDL or plasma apheresis will be allowed to
continue the apheresis during the study, if needed.

10. 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.

11. Willing to follow all study procedures including adherence to dietary guidelines,
study visits, fasting blood draws, and compliance with study treatment regimens.

Exclusion Criteria:

1. Use of Mipomersen or Lomitapide therapy within 5 months of screening

2. Treatment (within 90 days of screening) with monoclonal antibodies directed towards
PCSK9

3. New York Heart Association (NYHA) class IV heart failure or last known left
ventricular ejection fraction <25%

4. Major adverse cardiovascular event within 3 months prior to randomization

5. Planned cardiac surgery or revascularization

6. Uncontrolled severe hypertension: systolic blood pressure >180 mmHg or diastolic blood
pressure >110 mmHg prior to randomization despite anti-hypertensive therapy

7. 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

8. Severe concomitant noncardiovascular disease that carries the risk of reducing life
expectancy to less than the duration of the trial

9. 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

10. 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:

1. Women >2 years postmenopausal (defined as 1 year or longer since their last
menstrual period) AND more than 55 years of age

2. Postmenopausal women (as defined above) and less than 55 years of age with a
negative pregnancy test within 24 hours of enrolment

3. Women who are surgically sterilized at least 3 months prior to enrolment

11. Known history of alcohol and/or drug abuse within 5 years

12. Any condition that according to the investigator could interfere with the conduct of
the study, such as but not limited to:

1. Subjects who are unable to communicate or to cooperate with the investigator.

2. 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)

3. 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)

4. 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

5. Persons directly involved in the conduct of the study

13. 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

14. 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

15. Treatment with other investigational medicinal products or devices within 30 days or 5
half-lives of the screening visit, whichever is longer

16. Previous participation in the study

17. 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.



Age minimum: 18 Years
Age maximum: 80 Years
Gender: All

Health Condition(s) or Problem(s) studied

Homozygous Familial Hypercholesterolemia

Intervention(s)

Drug: Placebo

Drug: Inclisiran Sodium for injection

Drug: Placebos

Primary Outcome(s)

Percent Change in Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Day 150 [Time Frame: Baseline, Day 150]

Secondary Outcome(s)

Absolute Change in High-Sensitivity C-Reactive Protein (hsCRP) From Baseline to Subsequent Visits up to Day 180: Part 1 [Time Frame: Baseline, Days 90, 150, 180]

Absolute Change in Lipoprotein(a) [Lp(a)] From Baseline to Subsequent Visits up to Day 720 [Time Frame: Baseline, Days 330, 450, 510, 630, 690, and 720]

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]

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 720 [Time Frame: Baseline, Days 270, 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 in High-Sensitivity C-Reactive Protein (hsCRP) From Baseline to Subsequent Visits up to Day 180: Part 1 [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 Lipoprotein(a) [Lp(a)] 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]

Proportion of Subjects With =30% LDL-C Reduction of From Baseline at Day 150 [Time Frame: Baseline, Day 150]

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 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 Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) From Baseline to Subsequent Visits up to Day 180 [Time Frame: Baseline, Days 90, 150, 180]

LDL-C Reduction =20% or =30% From Baseline: Part 1 [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 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]

Percent Change in Lipoprotein(a) [Lp(a)] From Baseline to Subsequent Visits up to Day 720 [Time Frame: Baseline, Days 330, 450, 510, 630, 690, and 720]

LDL-C Reduction =20% or =30% From Baseline: Part 2 [Time Frame: Baseline, Days 330, 510, 690, and 720]

Percent Change in High-Sensitivity C-Reactive Protein (hsCRP) From Baseline to Subsequent Visits up to Day 720: Part 2 [Time Frame: Baseline, Days 330, 510 ,690, 720]

Percent Change in Non-HDL-C From Baseline to Day 150 [Time Frame: Baseline, Day 150]

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]

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]

Proportional Responsiveness of Subjects: Part 2 [Time Frame: Days 330, 510, 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]

Absolute Change in High-Sensitivity C-Reactive Protein (hsCRP) From Baseline to Subsequent Visits up to Day 720: Part 2 [Time Frame: Baseline, Days 330, 510, 690, 720]

Absolute Change in Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Day 150 [Time Frame: Baseline, Day 150]

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]

Absolute Change in Total Cholesterol From Baseline to Subsequent Visits up to Day 180 [Time Frame: Baseline, Days 90, 150, 180]

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]

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 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 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 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]

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 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 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 Lipoprotein(a) [Lp(a)] From Baseline to Subsequent Visits up to Day 180 [Time Frame: Baseline, Days 90, 150, 180]

Absolute Change in Apolipoprotein B (apoB) From Baseline to Subsequent Visits up to Day 180 [Time Frame: Baseline, Days 90, 150, 180]

Percent Change in Total Cholesterol From Baseline to Day 150 [Time Frame: Baseline, Day 150]

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 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 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 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 Apo-B From Baseline to Day 150 [Time Frame: Baseline, Day 150]

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 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 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]

Proportional Responsiveness: Part 1 [Time Frame: Days 150, 180]

Secondary ID(s)

CKJX839A12302

MDCO-PCS-17-02

2018-000893-31

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Results

• Results available: Yes
• Date Posted: 10/11/2022
• URL: https://clinicaltrials.gov/ct2/show/results/NCT03851705