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

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)

Sponsors

Lead Sponsor: Novartis Pharmaceuticals

Source Novartis
Brief Summary

This study is 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 has two sequential parts:

- Part 1: 6-month double-blind period in which subjects will be randomized to receive either inclisiran or placebo

- Part 2: 18-month open-label follow-up period; placebo-treated subjects from Part 1 will be transitioned to inclisiran at Day 180 and all subjects will participate in an open-label follow-up period of inclisiran only

Overall Status Active, not recruiting
Start Date February 6, 2019
Completion Date September 2021
Primary Completion Date March 2, 2020
Phase Phase 3
Study Type Interventional
Primary Outcome
Measure Time Frame
Percent Change in Low-Density Lipoprotein Cholesterol (LDL-C) from Baseline to Day 150 Baseline, Day 150
Secondary Outcome
Measure Time Frame
Absolute Change in Low-Density Lipoprotein Cholesterol (LDL-C) 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 720 Baseline, Days 90, 150, 180, 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 720 Baseline, Days 90, 150, 180, 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 720 Baseline, Days 90, 150, 180, 330, 510, 690, and 720
Absolute Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) from Baseline to Subsequent Visits up to Day 720 Baseline, Days 90, 150, 180, 330, 510, 690, and 720
Percent Change in Total Cholesterol from Baseline to Subsequent Visits up to Day 720 Baseline to Days 150, 180, 330, 510, 690, and 720
Absolute Change in Total Cholesterol from Baseline to Subsequent Visits up to Day 720 Baseline to Days 150, 180, 330, 510, 690, and 720
Percent Change in Apolipoprotein B (apoB) from Baseline to Subsequent Visits up to Day 720 Baseline to Days 150, 180, 330, 510, 690, and 720
Absolute Change in Apolipoprotein B (apoB) from Baseline to Subsequent Visits up to Day 720 Baseline to Days 150, 180, 330, 510, 690, and 720
Percent Change in non-HDL Cholesterol (non-HDL-C) from Baseline to Subsequent Visits up to Day 720 Baseline to Days 150, 180, 330, 510, 690, and 720
Absolute Change in non-HDL Cholesterol (non-HDL-C) from Baseline to Subsequent Visits up to Day 720 Baseline to Days 150, 180, 330, 510, 690, and 720
Individual Responsiveness of Subjects Baseline, Days 150, 180, 330, 510, 690 and 720
Proportional Responsiveness of Subjects Baseline, Days 150, 180, 330, 510, 690 and 720
LDL-C reduction ≥ 20% or ≥30% Baseline, Days 150, 180, 330, 510, 690, and 720
Percent Change in High-Density Lipoprotein Cholesterol Levels (HDL-C) from Baseline to Subsequent Visits up to Day 720 Baseline, Days 150, 180, 330, 510, 690, and 720
Absolute Change in High-Density Lipoprotein Cholesterol Levels (HDL-C) from Baseline to Subsequent Visits up to Day 720 Baseline, Days 150, 180, 330, 510, 690, and 720
Percent Change in Very-Low-Density Lipoprotein Cholesterol (VLDL-C) from Baseline to Subsequent Visits up to Day 720 Baseline, Days 150, 180, 330, 510, 690, and 720
Absolute Change in Very-Low-Density Lipoprotein Cholesterol (VLDL-C) from Baseline to Subsequent Visits up to Day 720 Baseline, Days 150, 180, 330, 510, 690, and 720
Percent Change in Apolipoprotein A-1 (Apo-A1) from Baseline to Subsequent Visits up to Day 720 Baseline, Days 150, 180, 330, 510, 690, and 720
Absolute Change in Apolipoprotein A-1 (Apo-A1) from Baseline to Subsequent Visits up to Day 720 Baseline, Days 150, 180, 330, 510, 690, and 720
Percent Change in Lipoprotein(a) [Lp(a)] from Baseline to Subsequent Visits up to Day 720 Baseline, Days 150, 180, 330, 510, 690, and 720
Absolute Change in Lipoprotein(a) [Lp(a)] from Baseline to Subsequent Visits up to Day 720 Baseline, Days 150, 180, 330, 510, 690, and 720
Percent Change in High-Sensitivity C-Reactive Protein (hsCRP) from Baseline to Subsequent Visits up to Day 720 Baseline, Days 150, 180, 330, 510, 690, and 720
Absolute Change in High-Sensitivity C-Reactive Protein (hsCRP) from Baseline to Subsequent Visits up to Day 720 Baseline, Days 150, 180, 330, 510, 690, and 720
Percent Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) from Baseline to Subsequent Visits up to Day 720 Baseline, Days 150, 180, 330, 510, 690, and 720
Absolute Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) from Baseline to Subsequent Visits up to Day 720 Baseline, Days 150, 180, 330, 510, 690, and 720
Enrollment 56
Condition
Intervention

Intervention Type: Drug

Intervention Name: Inclisiran for injection

Description: 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.

Other Name: ALN-PCSSC

Intervention Type: Drug

Intervention Name: Placebos

Description: Sterile normal saline (0.9% sodium chloride in water for injection)

Arm Group Label: Part 1 - Placebo

Eligibility

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.

Gender: All

Minimum Age: 18 Years

Maximum Age: 80 Years

Healthy Volunteers: Accepts Healthy Volunteers

Overall Official
Last Name Role Affiliation
John P. Kastelein, MD Principal Investigator The Familial Hypercholesterolemia Foundation
Location
Facility:
(50852-001) Queen Mary Hospital | Hong Kong, Hong Kong
(50972-001) Hadassah Hospital Lipid Research Ein Kerem | Jerusalem, 91120, Israel
(50007-001) Research Institute of Complex Issues of Cardiovascular Diseases | Kemerovo, 650002, Russian Federation
(50007-003) National Medical Research Centre of Cardiology | Moscow, 121552, Russian Federation
(50007-002) Hospital for War Veterans | Saint Petersburg, 193079, Russian Federation
(50381-001) Clinical Center of Serbia | Belgrad, 11000, Serbia
(50027-001) Johannesburg Hospital | Johannesburg, 2193, South Africa
(50886-001) Taipei Veterans General Hospital | Taipei, 11217, Taiwan
(50090-002) University of Health Sciences | Etlik, 06010, Turkey
(50090-003) Istanbul University | Istanbul, 34093, Turkey
(50090-001) Ege Universitesi | İzmir, 35040, Turkey
(50380-002) IMunicipal Non-commercial Enterprise "Ivano-Frankivsk Regional Clinical Cardiology Center Ivano-Frankivsk Regional Council" | Ivano-Frankivs'k, 76018, Ukraine
(50380-001) National Scientific Center | Kyiv, 03680, Ukraine
Location Countries

Hong Kong

Israel

Russian Federation

Serbia

South Africa

Taiwan

Turkey

Ukraine

Verification Date

September 2020

Responsible Party

Type: Sponsor

Keywords
Has Expanded Access No
Condition Browse
Number Of Arms 3
Arm Group

Label: Part 1 - Inclisiran

Type: Experimental

Description: Participants will receive a dose of 300 milligram (mg) Inclisiran for injection administered by SC injection on Day 1 and Day 90.

Label: Part 1 - Placebo

Type: Placebo Comparator

Description: Participants will receive a dose of placebos administered by SC injection on Day 1 and Day 90.

Label: Part 2 - Inclisiran

Type: Experimental

Description: All participants will receive a dose of 300 mg inclisiran for injection administered by SC injection on Day 270, Day 450 and Day 630.

Acronym ORION-5
Patient Data Undecided
Study Design Info

Allocation: Randomized

Intervention Model: Parallel Assignment

Primary Purpose: Treatment

Masking: Double (Participant, Investigator)

Masking Description: Double-blind

Source: ClinicalTrials.gov