Clinical trial NCT03060577: An Extension Trial of Inclisiran in Participants With Cardiovascular Disease and High Cholesterol
Official title: An Open Label, Active Comparator Extension Trial to Assess the Effect of Long Term Dosing of Inclisiran and Evolocumab Given as Subcutaneous Injections in Participants With High Cardiovascular Risk and Elevated LDL-C (ORION-3)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Atherosclerotic Cardiovascular Disease
Symptomatic Atherosclerosis
Type2 Diabetes
Familial Hypercholesterolemia
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2017-02-23
Enrollment: 382
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This clinical study was designed to assess the efficacy, safety, and tolerability of long-term dosing of inclisiran and evolocumab given as subcutaneous injections in participants with high cardiovascular risk and elevated low-density lipoprotein cholesterol (LDL-C).

Detailed description: MDCO-PCS-16-01 (ORION-3) was a Phase II, open-label, multicenter, non-randomized, active comparator long term extension study. Total study duration was 4 years from first participant enrolled to the last subject completed. The study consisted of three study periods:

Screening Period: Participants completing study MDCO-PCS-15-01 (ORION-1) were screened for all inclusion and exclusion criteria of study ORION-3.

Treatment Period: Participants fulfilling all eligibility criteria of ORION-3 were enrolled. Participants who received inclisiran in ORION-1 received inclisiran sodium throughout this study up to 4 years (Group 1; Inclisiran-only arm), and participants who received placebo in ORION-1 received evolocumab as open-label comparator up to Day 336, and then transitioned to inclisiran on Day 360 and every 180 days thereafter for up to 4 years (Group 2; Switching arm).

Safety follow up: Participants were followed up for safety during 4 weeks after the last dose of study treatment. Including the Screening Period, the total study duration for a participant was up to 4 years.

Eligibility criteria: Inclusion Criteria:

1. Completion of Study MDCO-PCS-15-01 and no contraindication to receiving inclisiran or evolocumab.
2. Willing and able to give written and informed consent before initiation of any study related procedures and willing to comply with all required study procedures.
3. Willing to self-inject.

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 participant at significant risk (according to investigator's \[or delegate's\] judgment).
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. Serious comorbid disease in which the life expectancy of the participant is shorter than the duration of the trial (for example, acute systemic infection, cancer, or other serious illnesses).
4. Active liver disease defined as any known current infectious, neoplastic, or metabolic pathology of the liver; unexplained alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevation greater than 2 times upper limit of normal (ULN); or total bilirubin elevation greater than 1.5 times ULN at study entry visit.
5. Females who are pregnant or nursing, or who are of childbearing potential and unwilling to use at least two methods of contraception (for example, oral contraceptives, barrier methods, approved contraceptive implant, long-term injectable contraception, intrauterine device) for the entire duration of the study. Exemptions from this criterion are

   * 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 old with a negative pregnancy test within 24 hours of enrollment
   * Women who are surgically sterilized at least 3 months prior to enrollment
6. Males who are unwilling to use an acceptable method of birth control during the entire study period (that is, condom with spermicide).
7. Treatment with investigational medicinal products other than inclisiran or devices within 30 days or five half˗lives, whichever is longer.
8. Planned use of investigational medicinal products other than inclisiran or devices during the course of the study.
9. Participants with a history of a serious hypersensitivity reaction to evolocumab or any of the excipients
10. Previous or current treatment (within 90 days of study entry) with monoclonal antibodies directed towards PCSK9.
11. Any condition that according to the investigator could interfere with the conduct of the study, such as but not limited to:

    * Inappropriate for this study, including participants 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 participants whose cooperation is doubtful due to drug abuse or alcohol dependency).
    * Unlikely to comply with the protocol requirements, instructions, and study-related restrictions (for example, uncooperative attitude, inability to return for follow-up visits, and improbability of completing the study).
    * Involved with, or a relative of, someone directly involved in the conduct of the study.
    * Any known cognitive impairment (for example, Alzheimer's Disease).

Primary outcomes:
measure: Percentage Change in LDL-C From Baseline of the ORION-1 Study to Day 210 in ORION-3 (Inclisiran Arm)
timeFrame: Baseline (ORION-1) and Day 210 (ORION-3) (up to 570 days total)
Secondary outcomes:
measure: Percentage Change in LDL-C From Baseline of the ORION-1 Study (Inclisiran Arm)
timeFrame: Baseline (ORION-1) and Days 30, 360, 720, 1080 and 1440 (ORION-3) (up to 390, 720, 1080, 1440 and 1800 days total, respectively)
measure: Absolute Change in LDL-C From Baseline of the ORION-1 Study (Inclisiran Arm)
timeFrame: Baseline (ORION-1) and Days 30, 360, 720, 1080 and 1440 (ORION-3) (up to 390, 720, 1080, 1440 and 1800 days total, respectively)
measure: Percentage Change in PCSK9 Levels From Baseline of the ORION-1 Study (Inclisiran Arm)
timeFrame: Baseline (ORION-1) and Days 30, 360, 720 and 1440 (ORION-3) (up to 390, 720, 1080 and 1800 days total, respectively)
measure: Absolute Change in PCSK9 Levels From Baseline of the ORION-1 Study (Inclisiran Arm)
timeFrame: Baseline (ORION-1) and Days 30, 360, 720 and 1440 (ORION-3) (up to 390, 720, 1080 and 1800 days total, respectively)
measure: Percentage Change in Triglycerides From Baseline of the ORION-1 Study (Inclisiran Arm)
timeFrame: Baseline (ORION-1) and Days 30, 210 and 1440 (ORION-3) (up to 390, 570 and 1800 days total, respectively)
measure: Absolute Change in Triglycerides From Baseline of the ORION-1 Study (Inclisiran Arm)
timeFrame: Baseline (ORION-1) and Days 30, 210 and 1440 (ORION-3) (up to 390, 570 and 1800 days total, respectively)
measure: Percentage Change in Apolipoprotein B From Baseline of the ORION-1 Study (Inclisiran Arm)
timeFrame: Baseline (ORION-1) and Days 30, 210 and 1440 (ORION-3) (up to 390, 570 and 1800 days total, respectively)
measure: Absolute Change in Apolipoprotein B From Baseline of the ORION-1 Study (Inclisiran Arm)
timeFrame: Baseline (ORION-1) and Days 30, 210 and 1440 (ORION-3) (up to 390, 570 and 1800 days total, respectively)
measure: Percentage Change in Lipoprotein-a From Baseline of the ORION-1 Study (Inclisiran Arm)
timeFrame: Baseline (ORION-1) and Days 30, 210 and 1440 (ORION-3) (up to 390, 570 and 1800 days total, respectively)
measure: Absolute Change in Lipoprotein-a From Baseline of the ORION-1 Study (Inclisiran Arm)
timeFrame: Baseline (ORION-1) and Days 30, 210 and 1440 (ORION-3) (up to 390, 570 and 1800 days total, respectively)
measure: Number of Participants With ≥50% LDL-C Reduction From Baseline of the ORION-1 Study (Inclisiran Arm)
timeFrame: Baseline (ORION-1) and Days 30, 360, 720 and 1440 (ORION-3) (up to 390, 720, 1080 and 1800 days total, respectively)
measure: Number of Participants Reaching on Treatment LDL-C Levels of <25 mg/dL, <50 mg/dL, <70 mg/dL, and <100 mg/dL (Inclisiran Arm)
timeFrame: From the start of treatment in ORION-3 to 90 days after end of treatment, assessed up to maximum duration of 4 years
Other outcomes:
Locations:
city: Jacksonville
country: United States
facility: Novartis Investigative Site
state: Florida
city: Indianapolis
country: United States
facility: Novartis Investigative Site
state: Indiana
city: New York
country: United States
facility: Novartis Investigative Site
state: New York
city: Cincinnati
country: United States
facility: Novartis Investigative Site
state: Ohio
city: Cincinnati
country: United States
facility: Novartis Investigative Site
state: Ohio
city: Greenville
country: United States
facility: Novartis Investigative Site
state: Tennessee
city: Amarillo
country: United States
facility: Novartis Investigative Site
state: Texas
city: Richmond
country: United States
facility: Novartis Investigative Site
state: Virginia
city: Vancouver
country: Canada
facility: Novartis Investigative Site
state: British Columbia
city: Winnipeg
country: Canada
facility: Novartis Investigative Site
state: Manitoba
city: Brampton
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: London
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Chicoutimi
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Sherbrooke
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Quebec
country: Canada
facility: Novartis Investigative Site
city: Quebec
country: Canada
facility: Novartis Investigative Site
city: St Johns
country: Canada
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Essen
country: Germany
facility: Novartis Investigative Site
city: Frankfurt
country: Germany
facility: Novartis Investigative Site
city: Heidelberg
country: Germany
facility: Novartis Investigative Site
city: Munich
country: Germany
facility: Novartis Investigative Site
city: Rotterdam
country: Netherlands
facility: Novartis Investigative Site
state: The Netherlands
city: Leiden
country: Netherlands
facility: Novartis Investigative Site
state: Zuid-Holland
city: Amsterdam
country: Netherlands
facility: Novartis Investigative Site
city: Den Haag
country: Netherlands
facility: Novartis Investigative Site
city: Deventer
country: Netherlands
facility: Novartis Investigative Site
city: Eindhoven
country: Netherlands
facility: Novartis Investigative Site
city: Goes
country: Netherlands
facility: Novartis Investigative Site
city: Hoogeveen
country: Netherlands
facility: Novartis Investigative Site
city: Hoogezand
country: Netherlands
facility: Novartis Investigative Site
city: Hoorn
country: Netherlands
facility: Novartis Investigative Site
city: Utrecht
country: Netherlands
facility: Novartis Investigative Site
city: Utrecht
country: Netherlands
facility: Novartis Investigative Site
city: Venlo
country: Netherlands
facility: Novartis Investigative Site
city: Zwijndrecht
country: Netherlands
facility: Novartis Investigative Site
city: Fowey
country: United Kingdom
facility: Novartis Investigative Site
state: Cornwall
city: Liskeard
country: United Kingdom
facility: Novartis Investigative Site
state: Cornwall
city: Penzance
country: United Kingdom
facility: Novartis Investigative Site
state: Cornwall
city: St Austell
country: United Kingdom
facility: Novartis Investigative Site
state: Cornwall
city: Torpoint
country: United Kingdom
facility: Novartis Investigative Site
state: Cornwall
city: Birmingham
country: United Kingdom
facility: Novartis Investigative Site
city: Edinburgh
country: United Kingdom
facility: Novartis Investigative Site
city: Exeter
country: United Kingdom
facility: Novartis Investigative Site
city: High Wycombe
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: Manchester
country: United Kingdom
facility: Novartis Investigative Site
city: Newcastle Upon Tyme
country: United Kingdom
facility: Novartis Investigative Site
city: Plymouth
country: United Kingdom
facility: Novartis Investigative Site
city: Worcester
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Imperial College London
name: Kausik Ray, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Warden 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.