A Randomized Study to Evaluate the Effect of an "Inclisiran First" Implementation Strategy Compared to Usual Care in Patients With Atherosclerotic Cardiovascular Disease and Elevated LDL-C Despite Receiving Maximally Tolerated Statin Therapy (VICTORION-INITIATE)

NCT ID: NCT04929249

Last Updated: 2025-05-16

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 450 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-06-25
• Study Completion Date: 2023-09-15

Brief Summary

The purpose of this study was to assess the effectiveness of an "inclisiran first" implementation strategy (addition of inclisiran to maximally tolerated statin therapy immediately upon failure to achieve acceptable LDL-C with maximally tolerated statin therapy alone) compared to usual care in an atherosclerotic cardiovascular disease (ASCVD) population.

Detailed Description

The study design was a randomized, two-arm, parallel-group, open-label, multicenter, clinical trial comparing an "inclisiran first" implementation strategy to usual care (1:1 randomization) with established ASCVD and elevated LDL-C (or non-HDL-C) despite treatment with maximally tolerated statin therapy.

Eligible patients had established ASCVD and elevated LDL-C levels ≥ 70 mg/dL (or non-HDL-C ≥ 100 mg/dL) despite treatment with maximally tolerated statin therapy.

In the "inclisiran first" implementation strategy group post-randomization, addition of other non-statin LDL-C lowering therapies (e.g., ezetimibe or bempedoic acid, excluding PCSK9 inhibiting monoclonal antibodies) were allowed to reach acceptable LDL-C levels. In the "inclisiran first" implementation strategy group, inclisiran was administered initially at randomization, 90 days later, and six months, thereafter.

Conditions

Atherosclerotic Cardiovascular Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Inclisiran First

Inclisiran sodium 300 mg 1.5 ml (equivalent to 284 mg of inclisiran) + usual care

Group Type: EXPERIMENTAL

Inclisiran

Intervention Type: DRUG

Inclisiran sodium 300 mg/1.5 ml (equivalent to 284 mg inclisiran liquid) in prefilled syringe (PFS).

Usual Care

Treating physicians were recommended to treat patients in accordance with the 2018 ACC/AHA guidelines

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

Inclisiran

Inclisiran sodium 300 mg/1.5 ml (equivalent to 284 mg inclisiran liquid) in prefilled syringe (PFS).

Intervention Type: DRUG

Other Intervention Names

Inclisiran First

Eligibility Criteria

Inclusion Criteria

1. Signed informed consent must be obtained prior to participation in the study

2. Males and females ≥18 years of age

3. History of ASCVD, documented by hospital records, claims data and/or prior laboratory/imaging assessments a Coronary heart disease (CHD):

• Prior myocardial infarction
• Prior coronary revascularization (PCI or CABG)
• Angiographic or CT-imaging (e.g., MDCT/CTA) evidence of coronary atherosclerosis (>70% stenosis in at least one major epicardial coronary artery) b Cerebrovascular disease:
• Prior ischemic stroke confirmed by a brain imaging study, CT or MRI; thought not to be caused by atrial fibrillation, valvular heart disease or mural thrombus
• Carotid artery stenosis >70% on prior angiography or ultrasound
• History of prior percutaneous or surgical carotid artery revascularization c Peripheral arterial disease (PAD):
• Prior documentation of a resting ankle-brachial index ≤0.85
• History of prior percutaneous or surgical revascularization of an iliac, femoral, or popliteal artery or aortic aneurysm
• Prior non-traumatic amputation of a lower extremity due to peripheral artery disease

4. Serum LDL-C ≥70 mg/dL or non-HDL-C ≥100 mg/dL

5. Fasting triglyceride <5.65 mmol/L (<500 mg/dL) at screening

6. Calculated glomerular filtration rate >30 mL/min by estimated glomerular filtration rate (eGFR) using standardized local clinical methodology

7. Participants should be on maximally tolerated statin therapy, as determined by the investigator, with no immediate plans to modify lipid lowering therapies. Statin intolerant patients are eligible if they had documented side effects on at least 2 different statins, including one at the lowest standard dose

8. Participants must be 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

Participants meeting any of the following criteria are not eligible for inclusion in this study.

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] 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. New York Heart Association (NYHA) class III or IV heart failure or last known left ventricular ejection fraction <30%

4. Significant cardiac arrhythmia within 3 months prior to randomization that is not controlled by medication or via ablation at the time of screening

5. Major adverse cardiovascular event within 6 months prior to randomization

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

7. Severe concomitant non-cardiovascular disease that carries the risk of reducing life expectancy to less than 2 years

8. History of malignancy that required surgery (excluding local and wide-local excision), radiation therapy and/or systemic therapy during the two years prior to randomization

9. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using basic methods of contraception during dosing of investigational drug. Basic contraception methods include:

1. Total abstinence (when this is in line with the preferred and usual lifestyle of the participant. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception

2. Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking investigational drug. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment

3. Male sterilization (at least 6 m prior to screening). For female participants in the study, the vasectomized male partner should be the sole partner for that participant

4. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps)

5. Use of oral (estrogen and progesterone), injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS) In case of use of oral contraception, women should have been stable on the same pill for a minimum of 3 months before taking investigational drug.

Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.

10. Known history of alcohol and/or drug abuse within the last 5 years (occasional casual users of illicit drugs in the opinion of the investigators are not excluded)

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

12. History of hypersensitivity to any of the study treatments or its excipients or to drugs of similar chemical classes

13. Planned use of other investigational products or devices during the course of the study

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

1. Participants 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 participants whose cooperation is doubtful due to drug abuse or alcohol dependency)

3. Unlikely to comply with the protocol requirements, instructions, and study-related restrictions (e.g., uncooperative attitude, inability to return for follow-up visits, and improbability of completing the study - including potential participants who indicate that their participation is contingent on receiving inclisiran)

4. Have any medical or surgical condition, which in the opinion of the investigator would put the participant at increased risk from participating in the study

5. Persons directly involved in the conduct of the study

15. Previous or current treatment (within 90 days of screening) with monoclonal antibodies directed towards PCSK9 or ezetimibe

16. Active liver disease defined as any known current infectious, neoplastic, or metabolic pathology of the liver or alanine aminotransferase (ALT) elevation >3x ULN, aspartate aminotransferase (AST) elevation >3x ULN, or total bilirubin elevation >2x ULN (except patients with Gilbert's syndrome) at screening confirmed by a repeat measurement at least one week apart

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Novartis Pharmaceuticals

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Novartis Pharmaceuticals

Role: STUDY_DIRECTOR

Novartis Pharmaceuticals

Locations

ARcare Center for Clinical Research .

Little Rock, Arkansas, United States

ARcare Center for Clinical Research

Little Rock, Arkansas, United States

Keck Medical Center USC .

Los Angeles, California, United States

d-b-a Greenwich Cardio Assoc CLCZ696BUS08

Greenwich, Connecticut, United States

Cardiology Ass of Fairfield County .

Stamford, Connecticut, United States

Integrative Research Associates Inc

Fort Lauderdale, Florida, United States

Elite Cardiac Research Center .

Hialeah, Florida, United States

University of Florida Health Science Center .

Jacksonville, Florida, United States

Jacksonville Ctr for Clin Rea Encore Research Group

Jacksonville, Florida, United States

Internal Medicine and Cardiology

Kissimmee, Florida, United States

Gateway Cardiology PC CACZ885M2301_Younis

Jerseyville, Illinois, United States

Affinity Health Corp

Oak Brook, Illinois, United States

Northwestern Medicine Northwestern University .

Winfield, Illinois, United States

Indiana University Health

Indianapolis, Indiana, United States

St Elizabeth Healthcare .

Edgewood, Kentucky, United States

Alexandria Cardiology Clinic .

Alexandria, Louisiana, United States

Medstar Health Research Institute .

Baltimore, Maryland, United States

MedStar Good Samaritan Hospital

Baltimore, Maryland, United States

Bryan LGH Heart Inst Intigrated Cardiology Group .

Lincoln, Nebraska, United States

Inspira Health Network The Heart House

Elmer, New Jersey, United States

New Jersey Heart

Linden, New Jersey, United States

New York Presbyterian Queens .

Flushing, New York, United States

New York Presbyterian Hospital .

New York, New York, United States

State Uni of NY at Stony Brook .

Stony Brook, New York, United States

Montefiore Hospital .

The Bronx, New York, United States

Milton S Hershey Medical Center

Hershey, Pennsylvania, United States

Capital Area Research LLC Suite 330

Newport, Pennsylvania, United States

Capital Area Research

Newport, Pennsylvania, United States

Cardiology Consultants of Philadelphia

Yardley, Pennsylvania, United States

Alliance for Multispecialty Res LLC

Nashville, Tennessee, United States

Cypress Heart and Vascular Center

Cypress, Texas, United States

NW Houston Neuro Comp Sleep Med Ctr

Cypress, Texas, United States

Primecare Medical Group

Houston, Texas, United States

Synergy Group Medical LLC .

Houston, Texas, United States

Synergy Group Medical LLC

Houston, Texas, United States

Northwest Houston Cardiology PA .

Houston, Texas, United States

Synergy Groups Medical LLC

Missouri City, Texas, United States

Bay Area Heart Ace Clinical Resh Gp .

Webster, Texas, United States

Centra Health .

Lynchburg, Virginia, United States

National Clinical Research .

Richmond, Virginia, United States

Exemplar Research Inc .

Morgantown, West Virginia, United States

Marshfield Medical Clinic .

Marshfield, Wisconsin, United States

Marshfield Clinic Health System

Weston, Wisconsin, United States

Countries

United States

References

Koren MJ, Rodriguez F, East C, Toth PP, Watwe V, Abbas CA, Sarwat S, Kleeman K, Kumar B, Ali Y, Jaffrani N. An "Inclisiran First" Strategy vs Usual Care in Patients With Atherosclerotic Cardiovascular Disease. J Am Coll Cardiol. 2024 May 21;83(20):1939-1952. doi: 10.1016/j.jacc.2024.03.382. Epub 2024 Apr 7.

Reference Type: DERIVED

PMID: 38593947 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

https://www.novctrd.com/ctrdweb/patientsummary/patientsummaries?patientSummaryId=2304

A Plain Language Trial Summary is available on www.novctrd.com

Other Identifiers

CKJX839A1US02

Identifier Type: -

Identifier Source: org_study_id