Trial to Assess the Effect of Long Term Dosing of Inclisiran in Subjects With High CV Risk and Elevated LDL-C

Homozygous Familial Hypercholesterolemia Clinical Trial

— ORION-8  

Official title:

An Open-label Extension Trial of the Phase III Lipid-lowering Trials to Assess the Effect of Long Term Dosing of Inclisiran Given as Subcutaneous Injections in Subjects With High Cardiovascular Risk and Elevated LDL-C

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03814187
• Other study ID #: MDCO-PCS-17-05
• Secondary ID: CKJX839A12306B20
• Status: Completed
• Phase: Phase 3
• Start date: April 16, 2019
• Est. completion date: February 13, 2023

Study information

• Verified date: February 2024
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this extension study was to evaluate the efficacy, safety, and tolerability of long-term dosing of Inclisiran. The study was a global multicenter study.

Description:

This study was an open label, long term extension study in subjects with atherosclerotic cardiovascular disease (ASCVD), ASCVD-risk equivalents (eg, diabetes and familial hypercholesterolemia), or heterozygous familial hypercholesterolemia (HeFH) and elevated low density lipoprotein cholesterol (LDL-C) despite maximum tolerated dose of LDL-C lowering therapies who have completed the inclisiran Phase II trial MDCO-PCS-16-01 (ORION-3; NCT03060577), or any of the following Phase III lipid lowering studies: MDCO-PCS-17-03 (ORION-9; NCT03397121), MDCO-PCS-17-04 (ORION-10; NCT03399370), or MDCO-PCS-17-08 (ORION-11; NCT03400800).

The End of Study (EOS) visit in the previous feeder studies was Day 1 in this extension study.The duration that each subject participated in this study was a maximum of 3 years. However, for subjects from the Study ORION-3, the Sponsor decided to end the study prior to completion of their full 3-year of participation. It is recorded in the database as discontinuation was due to Sponsor's decision.

In this Phase III extension study, the same study drug of inclisiran sodium 300 mg (equivalent to 284 mg inclisiran) was administered as a single subcutaneous (SC) dose every 180 days from the last dose in previous feeder study (except for subjects newly initiating inclisiran, who received the first two doses 90 days apart) until the end of the study.

On Day 1 (EOS visit in the feeder study), subjects from the previous feeder studies received blinded study medication except subjects from Study ORION-3. Subjects who received placebo in the previous Phase III feeder study received blinded inclisiran and subjects who received inclisiran in the previous feeder study received blinded placebo at this visit, so that subjects previously on placebo received the correct dosing regime, i.e. a dose at Day 1, Day 90 and every 180-days thereafter. Subjects previously treated with inclisiran did not need a dose of inclisiran to maintain every 180-dosing regime and therefore, were given placebo in order to maintain the blinding of the feeder study. Subjects that moved over from ORION-3 received the first study medication at Day 90, as this study was already open-label.

On Day 90, all subjects received inclisiran sodium 300 mg. This is 180 days after the last injection in the previous feeder study for subjects that received inclisiran and was the second dose of inclisiran for the subjects that received placebo in the feeder study. The EOS visit occurred at Day 1080.

This extension study allowed subjects continued access to inclisiran treatment and allowed the collection of additional efficacy and safety data for long-term use beyond the end of the feeder studies.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 3275
• Est. completion date: February 13, 2023
• Est. primary completion date: February 13, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Completion on a previously qualifying inclisiran Phase II trial MDCO-PCS-16-01 (ORION-3), or Phase III lipid lowering ORION feeder study [MDCO-PCS-17-03 (ORION-9), MDCO-PCS-17-4 (ORION-10), or MDCO-PCS-17-08 (ORION-11)] meaning the subject received the last dose of study drug and completed the final study visit per applicable protocol.

2. On current lipid-lowering therapies (such as a statin and/or ezetimibe) from previous study with no planned medication or dose change during study participation.

3. Willing and able to give informed consent before initiation of any study-related procedures and willing to comply with all required study procedures.

Exclusion Criteria:

1. 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's) judgment] if he/she participates in the clinical study.

2. An underlying known disease, or surgical, physical, or medical condition that, in the opinion of the investigator (or delegate) might interfere with interpretation of the clinical study results.

3. Severe concomitant noncardiovascular disease that carries the risk of reducing life expectancy to less than 3 years,

4. 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 the upper limit of normal (ULN), or total bilirubin (TBIL) elevation >2x ULN at the last recorded visit in the feeder study prior to study entry visit.

5. Females who are pregnant or nursing, or who are of childbearing potential and unwilling to use at least one method of acceptable effective 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 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 randomization.

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

6. Planned use of other investigational medicinal products other than inclisiran or devices during the course of the study.

7. 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.

The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Related Conditions & MeSH terms

• ASCVD
• Elevated Cholesterol
• Heterozygous Familial Hypercholesterolemia
• Homozygous Familial Hypercholesterolemia
• Hypercholesterolemia
• Hyperlipoproteinemia Type II

Intervention

Drug:
• Inclisiran Sodium
Inclisiran is a small interfering ribonucleic acid (RNA) that inhibits PCSK9 synthesis.

Locations

Country	Name	City	State
Canada	Research Site 90011-005	Chicoutimi	Quebec
Canada	Research Site 90011-001	Montréal	Quebec
Canada	Research Site 90011-002	Québec	Quebec
Czechia	Research Site 11420-002	Chomutov
Czechia	Research Site 90420-001	Praha
Czechia	Research Site 90420-006	Praha
Czechia	Research Site 11420-003	Uherské Hradište
Denmark	Research Site 90045-001	Aalborg	Nordjylland
Denmark	Research Site 90045-004	Esbjerg
Denmark	Research Site 90045-003	Herning
Denmark	Research Site 90045-006	Hvidovre
Denmark	Research Site 90045-002	Roskilde
Denmark	Research Site 90045-005	Viborg
Germany	Research Site 11049-006	Berlin
Germany	Research Site 11049-002	Bochum
Germany	Research Site 11049-003	Frankfurt
Germany	Research Site 11049-001	Heidelberg
Germany	Research Site 11049-007	Heidelberg
Hungary	Research Site 11036-001	Budapest
Hungary	Research Site 11036-004	Debrecen
Hungary	Research Site 11036-002	Hatvan
Hungary	Research Site 11036-003	Zalaegerszeg
Netherlands	Research Site 90031-001	Amersfoort
Netherlands	Research Site 90031-003	Amsterdam
Netherlands	Research Site 90031-006	Goes
Netherlands	Research Site 90031-009	Hoorn
Netherlands	Research Site 90031-005	Utrecht
Poland	Research SIte 11048-016	Brzozowie
Poland	Research Site 11048-011	Bydgoszcz
Poland	Research Site 11048-018	Bydgoszcz
Poland	Research Site 11048-004	Gdansk
Poland	Research Site 11048-005	Gdynia
Poland	Research Site 11048-007	Katowice
Poland	Research SIte 11048-012	Katowice
Poland	Research Site 11048-003	Kraków
Poland	Research SIte 11048-014	Kraków
Poland	Research Site 11048-008	Lublin
Poland	Research Site 11048-001	Poznan
Poland	Research Site 11048-019	Ruda Slaska
Poland	Research SIte 11048-013	Rzeszów
Poland	Research SIte 11048-015	Tarnów
Poland	Research Site 11048-006	Warsaw
Poland	Research Site 11048-009	Warsaw
Poland	Research Site 11048-002	Wroclaw
Poland	Research Site 11048-010	Wroclaw
South Africa	Research Site 90027-008	Bellville	Cape Town
South Africa	Research Site 90027-003	Bloemfontein	Free State
South Africa	Research Site 90027-001	Cape Town	Western Cape
South Africa	Research Site 90027-010	Johannesburg	Gauteng
South Africa	Research Site 11027-005	Kempton Park	Gauteng
South Africa	Research Site 11027-007	Kuilsrivier	Western Cape
South Africa	Research Site 90027-007	Lyttelton	Cape Town
South Africa	Research Site 11027-013	Paarl	Western Cape
South Africa	Research Site 90027-006	Pretoria	Gauteng
South Africa	Research Site 90027-004	Somerset West	Western Cape
South Africa	Research Site 90027-005	Somerset West	Western Cape
South Africa	Research Site 90027-009	Witbank	Gauteng
Spain	Research Site 90034-005	Barcelona	Cataluna
Spain	Research Site 90034-006	Barcelona	Cataluna
Spain	Research Site 90034-004	Córdoba	Andalucia
Spain	Research Site 90034-003	La Coruña	Galicia
Spain	Research Site 90034-001	Reus	Cataluna
Spain	Research Site 90034-002	Zaragoza	Aragon
Sweden	Research Site 90046-002	Göteborg
Sweden	Research Site 90046-001	Stockholm
Sweden	Research Site 90046-003	Stockholm
Ukraine	Research Site 11380-005	Cherkasy
Ukraine	Research Site 11380-008	Kharkiv
Ukraine	Research Site 11380-001	Kyiv
Ukraine	Research Site 11380-002	Kyiv
Ukraine	Research Site 11380-003	Kyiv
Ukraine	Research Site 11380-004	Kyiv
Ukraine	Research Site 11380-006	Úzhgorod
Ukraine	Research Site 11380-009	Zaporizhzhya
United Kingdom	Research Site 11044-028	Bollington	Cheshire
United Kingdom	Research Site 11044-026	Bury
United Kingdom	Research Site 11044-024	Cheadle Hulme
United Kingdom	Research Site 11044-014	Chorley
United Kingdom	Research Site 11044-012	Cornwell
United Kingdom	Research Site 11044-010	Derby
United Kingdom	Research Site 11044-006	Edgbaston
United Kingdom	Research Site 11044-009	Exeter
United Kingdom	Research Site 11044-001	Glasgow
United Kingdom	Research Site 11044-008	Hexham
United Kingdom	Research SIte 11044-020	Macclesfield
United Kingdom	Research Site 11044-005	Manchester
United Kingdom	Research Site 11044-025	Manchester
United Kingdom	Research Site 11044-027	Manchester
United Kingdom	Research Site 11044-029	Manchester
United Kingdom	Research Site 11044-019	Plymouth
United Kingdom	Research Site 11044-003	Reading
United Kingdom	Research Site 11044-022	Sale
United Kingdom	Research Site 11044-023	Sale
United Kingdom	Research Site 11044-002	Stockton-on-Tees
United Kingdom	Research Site 11044-021	Timperley
United Kingdom	Research Site 11044-007	Wales
United Kingdom	Research Site 11044-004	Waterloo
United States	Research Site 10001-016	Akron	Ohio
United States	Research Site 10001-054	Albany	New York
United States	Research Site 10001-100	Amarillo	Texas
United States	Research Site 10001-001	Anderson	South Carolina
United States	Research Site 10001-059	Arlington Heights	Illinois
United States	Research Site 10001-146	Athens	Tennessee
United States	Research Site 10001-069	Atlanta	Georgia
United States	Research Site 10001-087	Austin	Texas
United States	Research Site 10001-117	Austin	Texas
United States	Research Site 10001-073	Beverly Hills	California
United States	Research Site 10001-122	Binghamton	New York
United States	Research Site 10001-015	Birmingham	Alabama
United States	Research Site 90001-047	Boca Raton	Florida
United States	Research Site 90001-004	Boston	Massachusetts
United States	Research Site 10001-060	Bridgewater	New Jersey
United States	Research Site 90001-012	Butte	Montana
United States	Research Site 10001-050	Canoga Park	California
United States	Research Site 10001-011	Carlsbad	California
United States	Research Site 10001-063	Cary	North Carolina
United States	Research Site 10001-013	Chandler	Arizona
United States	Research Site 10001-158	Chicago	Illinois
United States	Research Site 10001-010	Cincinnati	Ohio
United States	Research Site 10001-120	Cincinnati	Ohio
United States	Research Site 10001-134	Cincinnati	Ohio
United States	Research Site 90001-002	Cincinnati	Ohio
United States	Research Site 10001-084	Clearwater	Florida
United States	Research Site 10001-099	Clearwater	Florida
United States	Research Site 10001-155	Clearwater	Florida
United States	Research Site 10001-014	Columbus	Ohio
United States	Research Site 10001-144	Crowley	Louisiana
United States	Research Site 10001-009	Dallas	Texas
United States	Research Site 10001-141	Dayton	Ohio
United States	Research Site 10001-127	Daytona Beach	Florida
United States	Research Site 10001-137	Dunwoody	Georgia
United States	Research Site 10001-018	Edina	Minnesota
United States	Research Site 10001-068	Edinburg	Texas
United States	Research Site 10001-065	El Cajon	California
United States	Research Site 10001-128	Endwell	New York
United States	Research Site 10001-036	Evanston	Illinois
United States	Research Site 10001-093	Falls Church	Virginia
United States	Research Site 10001-119	Fleming Island	Florida
United States	Research Site 10001-024	Flint	Michigan
United States	Research Site 10001-138	Foley	Alabama
United States	Research Site 10001-070	Fort Lauderdale	Florida
United States	Research Site 10001-095	Grandville	Michigan
United States	Research Site 10001-064	Greensboro	North Carolina
United States	Research Site 10001-006	Greer	South Carolina
United States	Research Site 10001-075.	Greer	South Carolina
United States	Research Site 10001-067	Hialeah	Florida
United States	Research Site 10001-031	Houston	Texas
United States	Research Site 10001-032	Houston	Texas
United States	Research Site 10001-061	Houston	Texas
United States	Research Site 10001-088	Houston	Texas
United States	Research Site 10001-091	Houston	Texas
United States	Research Site 10001-113	Huntsville	Alabama
United States	Research Site 10001-028	Hutchinson	Kansas
United States	Research Site 10001-082	Indianapolis	Indiana
United States	Research Site 10001-039	Jacksonville	Florida
United States	Research Site 10001-098	Jacksonville	Florida
United States	Research Site 10001-139	Jacksonville	Florida
United States	Research Site 10001-130	Kingsport	Tennessee
United States	Research Site 10001-106	Knoxville	Tennessee
United States	Research Site 10001-118	Knoxville	Tennessee
United States	Research Site 10001-041	Lake Charles	Louisiana
United States	Research Site 10001-124	Las Vegas	Nevada
United States	Research Site 90001-112	Las Vegas	Nevada
United States	Research Site 10001-005	Layton	Utah
United States	Research Site 10001-108	Lexington	Kentucky
United States	Research Site 10001-125	Lexington	Kentucky
United States	Research Site 10001-150	Los Angeles	California
United States	Research Site 10001-092	Macon	Georgia
United States	Research Site 10001-085	Manassas	Virginia
United States	Research Site 10001-148	Marion	Ohio
United States	Research Site 10001-077	Mesa	Arizona
United States	Research Site 10001-030	Miami	Florida
United States	Research Site 10001-081	Miami	Florida
United States	Research Site 10001-116	Miami	Florida
United States	Research Site 10001-140	Miami	Florida
United States	Research Site 10001-142	Miami	Florida
United States	Research Site 10001-080	Miami Springs	Florida
United States	Research Site 10001-094	Midlothian	Virginia
United States	Research Site 90001-005	Mission Viejo	California
United States	Research Site 10001-058	Mobile	Alabama
United States	Research Site 10001-101	Monroe	Louisiana
United States	Research Site 10001-037	Montgomery	Alabama
United States	Research Site 10001-145	Mooresville	North Carolina
United States	Research Site 10001-111	Myrtle Beach	South Carolina
United States	Research Site 10001-057	New Braunfels	Texas
United States	Research Site 10001-042	New Windsor	New York
United States	Research Site 10001-022	Northridge	California
United States	Research Site 10001-043	Northridge	California
United States	Research Site 10001-021	Omaha	Nebraska
United States	Research Site 10001-053	Omaha	Nebraska
United States	Research Site 10001-107	Owensboro	Kentucky
United States	Research Site 10001-133	Pelzer	South Carolina
United States	Research Site 10001-027	Pembroke Pines	Florida
United States	Research Site 10001-048	Pembroke Pines	Florida
United States	Research Site 10001-115	Pembroke Pines	Florida
United States	Research Site 10001-147	Pembroke Pines	Florida
United States	Research Site 10001-136	Phoenix	Arizona
United States	Research Site 10001-003	Pinellas Park	Florida
United States	Research Site 10001-104	Ponte Vedra	Florida
United States	Research Site 10001-129	Poughkeepsie	New York
United States	Research Site 10001-103	Rapid City	South Dakota
United States	Research Site 10001-023	Richmond	Virginia
United States	Research Site 10001-079	Round Rock	Texas
United States	Research Site 10001-033	Sacramento	California
United States	Research Site 10001-090	Saint Augustine	Florida
United States	Research Site 10001-007	Saint Louis	Missouri
United States	Research Site 10001-156	Saint Louis	Missouri
United States	Research Site 90001-056	Saint Paul	Minnesota
United States	Research Site 10001-102	Saint Petersburg	Florida
United States	Research Site 10001-002	Salt Lake City	Utah
United States	Research Site 10001-052	Salt Lake City	Utah
United States	Research Site 10001-071	San Antonio	Texas
United States	Research Site 10001-105	San Ramon	California
United States	Research Site 10001-008	Santa Rosa	California
United States	Research Site 10001-076	Saraland	Alabama
United States	Research Site 10001-123	Sarasota	Florida
United States	Research Site 10001-083	Schertz	Texas
United States	Research Site 10001-149	Shavano Park	Texas
United States	Research Site 10001-046	Shelby	North Carolina
United States	Research Site 10001-153	Spring Valley	California
United States	Research Site 90001-015	Stanford	California
United States	Research Site 10001-078	Sterling Heights	Michigan
United States	Research Site 10001-029	Suffolk	Virginia
United States	Research Site 90001-014	Summit	New Jersey
United States	Research Site 10001-051	Surprise	Arizona
United States	Research Site 10001-114	Tacoma	Washington
United States	Research Site 10001-143	Tampa	Florida
United States	Research Site 10001-045	Tomball	Texas
United States	Research Site 10001-044	Torrance	California
United States	Research Site 10001-034	Troy	Michigan
United States	Research Site 10001-004	Tucson	Arizona
United States	Research Site 10001-019	Tucson	Arizona
United States	Research Site 10001-132	Tucson	Arizona
United States	Research Site 10001-040	Valparaiso	Indiana
United States	Research Site 10001-055	Warren	New Jersey
United States	Research Site 10001-074	West Des Moines	Iowa
United States	Research Site 10001-110	Williamsville	New York
United States	Research Site 10001-109	Wyomissing	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Canada,  Czechia,  Denmark,  Germany,  Hungary,  Netherlands,  Poland,  South Africa,  Spain,  Sweden,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Proportion of Subjects Achieving Global Lipid Targets for Their Level of ASCVD Risk	The primary objective of the study is to evaluate the effect of inclisiran treatment on the proportion of subjects achieving prespecified LDL-C targets at end of study (EOS).; Target is <70 mg/dL for atherosclerotic cardiovascular disease (ASCVD) subjects and <100 mg/dL for ASCVD risk equivalent subjects.; Risk equivalent subjects are defined as either type 2 diabetes, familial hypercholesterolemia or a 10-year risk of a cardiovascular event =20% as assessed by the Framingham Risk Score or equivalent; without a medical history of coronary heart disease , cerebrovascular disease or peripheral artery disease.	From ORION-8 Day 1 to the end of study (up to 1080 days)
Primary	Incidence of Treatment-emergent Adverse Events (TEAEs)	Safety assessments include adverse events and serious adverse events until the end of study.; End of study visit occured at least 90 days following the last inclisiran dose once a decision was made to end the study (either by the subject, investigator or sponsor). For subjects prematurely and permanently discontinued from study treatment, who were not willing to return within the 90 day timeframe, the EOS visit was scheduled as soon as possible, or if decision to discontinue and not return was made at a specific visit, this visit became the EOS visit.	From ORION-8 Day 1 to the end of study (up to 1080 days)
Secondary	Absolute Change in LDL-C From the Initial Feeder Study Baseline	Absolute change from baseline in low density lipoprotein cholesterol (LDL-C) was calculated to evaluate the effect of inclisiran on LDL-C levels.	Feeder study baseline, ORION-8 baseline, Day 1080/EOS (ORION-8) (up to a maximum of 2340 days)
Secondary	Percentage Change in LDL-C From the Initial Feeder Study Baseline	Percentage change from baseline in low density lipoprotein cholesterol (LDL-C) was calculated to evaluate the effect of inclisiran on LDL-C levels.	Feeder study baseline, ORION-8 baseline, Day 1080/EOS (ORION-8) (up to a maximum of 2340 days)
Secondary	Absolute Change From the Initial Feeder Study Baseline in Total Cholesterol, Triglycerides and HDL-C	Absolute change from baseline in total cholesterol, triglycerides and high density lipoprotein cholesterol (HDL-C) was calculated to evaluate the effect of inclisiran on other lipids and lipoproteins.	Feeder study baseline, ORION-8 baseline, Day 1080/EOS (ORION-8) (up to a maximum of 2340 days)
Secondary	Percentage Change From the Initial Feeder Study Baseline in Total Cholesterol, Triglycerides and HDL-C	Percentage change from baseline in total cholesterol (TC), triglycerides and high density lipoprotein cholesterol (HDL-C) was calculated to evaluate the effect of inclisiran on other lipids and lipoproteins.	Feeder study baseline, ORION-8 baseline, Day 1080/EOS (ORION-8) (up to a maximum of 2340 days)