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) (V-INITIATE)

• ClinicalTrials.gov Identifier: NCT04929249
• Recruitment Status: Completed
• First Posted: June 18, 2021
• Last Update Posted: December 20, 2023
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Study Description

Brief Summary:

The purpose of this study is 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 ASCVD population.

Condition or disease	Intervention/treatment	Phase
Atherosclerotic Cardiovascular Disease	Drug: Inclisiran	Phase 3

Detailed Description:

The study design will be a randomized, two-arm, parallel-group, open-label, multicenter, clinical trial comparing an "inclisiran first" implementation strategy to usual care in approximately 444 participants (1:1 randomization) with established ASCVD and elevated LDL-C (or non-HDL-C) despite treatment with maximally tolerated statin therapy.

The study will include male and female participants ≥18 years of age with a history of ASCVD (coronary heart disease, ischemic cerebrovascular disease or peripheral arterial disease) who have elevated LDL-C (≥70 mg/dL) or non-HDL-C (≥100 mg/dL) despite being treated with maximally tolerated statin therapy. A total of approximately 444 participants will be randomized to the "inclisiran first" implementation strategy or usual care in a 1:1 ratio at approximately 50 US sites.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 450 participants
• Allocation: Randomized
• Intervention Model: Single Group Assignment
• Intervention Model Description: randomized, two-arm, parallel-group, open-label, multicenter clinical trial
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized, Multicenter, Open-label Trial Comparing the Effectiveness of an "Inclisiran First" Implementation Strategy to Usual Care on LDL Cholesterol (LDL-C) in Patients With Atherosclerotic Cardiovascular Disease and Elevated LDL-C (≥70 mg/dL) Despite Receiving Maximally Tolerated Statin Therapy (VICTORION-INITIATE)
• Actual Study Start Date: June 25, 2021
• Actual Primary Completion Date: September 15, 2023
• Actual Study Completion Date: September 15, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Inclisiran First; Inclisiran + usual care	Drug: Inclisiran; Inclisiran sodium 300 mg/1.5 ml (equivalent to 284 mg inclisiran liquid) in prefilled syringe (PFS).; Other Name: Inclisiran First
No Intervention: Usual Care; Usual care

Outcome Measures

Primary Outcome Measures :

1. Percent change from baseline in LDL-C [ Time Frame: Day 330 ]
   To assess the effect on LDL-C of an "inclisiran-first" implementation strategy compared to usual care at Day 330 in participants with ASCVD and an LDL-C ≥70 mg/dL despite maximally tolerated statin therapy
2. Discontinuation of statin therapy (i.e., no statin use ≥ 30 days before the end-of-study visit) (yes, no) [ Time Frame: Day 330 ]
   To assess the non-inferiority of an "inclisiran first" implementation strategy compared to usual care on discontinuation of background statin therapy at Day 330

Secondary Outcome Measures :

1. Absolute change from baseline in LDL-C [ Time Frame: Day 330 ]
   To assess the absolute change in LDL-C of an "inclisiran first" implementation strategy compared to usual care at Day 330
2. Average percent change from baseline in LDL-C levels to each post-baseline visit [ Time Frame: Day 330 ]
   To assess the average percent change in LDL-C of an "inclisiran first" implementation strategy compared to usual care to each post-baseline visit
3. Average absolute change from baseline in LDL-C to each post-baseline visit [ Time Frame: Day 330 ]
   To assess the average absolute change in LDL-C of an "inclisiran first" implementation strategy compared to usual care to each post-baseline visit
4. Achieving ≥ 50% reduction from baseline in LDL-C (yes, no) [ Time Frame: Day 330 ]
   To assess the proportion of participants reaching pre-specified LDL-C targets among those receiving an "inclisiran first" implementation strategy compared to usual care at Day 330
5. Achieving LDL-C < 100 mg/dL (among the subset of participants with LDL-C >100 mg/dL at baseline) (yes, no) [ Time Frame: Day 330 ]
   To assess the proportion of participants reaching pre-specified LDL-C targets among those receiving an "inclisiran first" implementation strategy compared to usual care at Day 330
6. Achieving LDL-C < 70 mg/dL (yes, no) [ Time Frame: Day 330 ]
   To assess the proportion of participants reaching pre-specified LDL-C targets among those receiving an "inclisiran first" implementation strategy compared to usual care at Day 330
7. Achieving LDL-C < 55 mg/dL (yes, no) [ Time Frame: Day 330 ]
   To assess the proportion of participants reaching pre-specified LDL-C targets among those receiving an "inclisiran first" implementation strategy compared to usual care at Day 330
8. Percent change and absolute change from baseline in apoB [ Time Frame: Day 330 ]
   To assess apoB in participants receiving an "inclisiran first" implementation strategy compared to usual care at Day 330
9. Percent change and absolute change from baseline in non-HDL-C [ Time Frame: Day 330 ]
   To assess non-HDL-C in participants receiving an "inclisiran first" implementation strategy compared to usual care at Day 330
10. Percent change and absolute change from baseline in VLDL-C [ Time Frame: Day 330 ]
    To assess VLDL-C in participants receiving an "inclisiran first" implementation strategy compared to usual care at Day 330
11. Percent change and absolute change from baseline in total cholesterol [ Time Frame: Day 330 ]
    To assess total cholesterol in participants receiving an "inclisiran first" implementation strategy compared to usual care at Day 330
12. Percent change and absolute change from baseline in Lp(a) [ Time Frame: Day 330 ]
    To assess Lp(a) in participants receiving an "inclisiran first" implementation strategy compared to usual care at Day 330
13. Percent change and absolute change from baseline in HDL-C [ Time Frame: Day 330 ]
    To assess HDL-C in participants receiving an "inclisiran first" implementation strategy compared to usual care at Day 330
14. Percent change and absolute change from baseline in triglycerides [ Time Frame: Day 330 ]
    To assess triglycerides in participants receiving an "inclisiran first" implementation strategy compared to usual care at Day 330
15. Intensity of lipid lowering therapy (decrease in dose, no change in dose, increase in dose) [ Time Frame: Day 330 ]
    To assess changes in background lipid-lowering therapy in participants receiving an "inclisiran first" implementation strategy compared to usual care at Day 330
16. Proportion of days covered (total number of days on either statin, ezetimibe, bempedoic acid or PCSK9 inhibiting monoclonal antibody therapies divided by total number of study days) [ Time Frame: Day 330 ]
    To assess adherence to background lipid-lowering therapy in participants receiving an "inclisiran first" implementation strategy compared to usual care at Day 330
17. LDL-C measures of variability (standard deviation, coefficient of variation) [ Time Frame: Day 90 to Day 330 ]
    To assess visit-to-visit LDL-C variability from Day 90 until Day 330

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Participants eligible for inclusion in this study must meet all of the following 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

Contacts and Locations

Locations

United States, Arkansas

Novartis Investigative Site

Little Rock, Arkansas, United States, 72205

United States, California

Novartis Investigative Site

Los Angeles, California, United States, 90033

United States, Connecticut

Novartis Investigative Site

Greenwich, Connecticut, United States, 06830

Novartis Investigative Site

Stamford, Connecticut, United States, 06905

United States, Florida

Novartis Investigative Site

Fort Lauderdale, Florida, United States, 33312

Novartis Investigative Site

Hialeah, Florida, United States, 33012

Novartis Investigative Site

Jacksonville, Florida, United States, 32209

Novartis Investigative Site

Jacksonville, Florida, United States, 32216

Novartis Investigative Site

Kissimmee, Florida, United States, 34741

United States, Illinois

Novartis Investigative Site

Jerseyville, Illinois, United States, 62052

Novartis Investigative Site

Oak Brook, Illinois, United States, 60523

Novartis Investigative Site

Winfield, Illinois, United States, 60190

United States, Indiana

Novartis Investigative Site

Indianapolis, Indiana, United States, 46202

United States, Kentucky

Novartis Investigative Site

Edgewood, Kentucky, United States, 41017

United States, Louisiana

Novartis Investigative Site

Alexandria, Louisiana, United States, 71301

United States, Maryland

Novartis Investigative Site

Baltimore, Maryland, United States, 21218

Novartis Investigative Site

Baltimore, Maryland, United States, 21239

United States, Nebraska

Novartis Investigative Site

Lincoln, Nebraska, United States, 68506

United States, New Jersey

Novartis Investigative Site

Elmer, New Jersey, United States, 08318

Novartis Investigative Site

Linden, New Jersey, United States, 07036

United States, New York

Novartis Investigative Site

Bronx, New York, United States, 10467 2490

Novartis Investigative Site

Flushing, New York, United States, 11355

Novartis Investigative Site

New York, New York, United States, 10021

Novartis Investigative Site

Stony Brook, New York, United States, 11794-3362

United States, Pennsylvania

Novartis Investigative Site

Hershey, Pennsylvania, United States, 17033

Novartis Investigative Site

Newport, Pennsylvania, United States, 17074

Novartis Investigative Site

Yardley, Pennsylvania, United States, 19067

United States, Tennessee

Novartis Investigative Site

Nashville, Tennessee, United States, 37203

United States, Texas

Novartis Investigative Site

Cypress, Texas, United States, 77429

Novartis Investigative Site

Houston, Texas, United States, 77024

Novartis Investigative Site

Houston, Texas, United States, 77061

Novartis Investigative Site

Houston, Texas, United States, 77070

Novartis Investigative Site

Missouri City, Texas, United States, 77459

Novartis Investigative Site

Webster, Texas, United States, 77598

United States, Virginia

Novartis Investigative Site

Lynchburg, Virginia, United States, 24501

Novartis Investigative Site

Richmond, Virginia, United States, 23294

United States, West Virginia

Novartis Investigative Site

Morgantown, West Virginia, United States, 26501

United States, Wisconsin

Novartis Investigative Site

Marshfield, Wisconsin, United States, 54449

Novartis Investigative Site

Weston, Wisconsin, United States, 54476

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

More Information

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT04929249
• Other Study ID Numbers: CKJX839A1US02
• First Posted: June 18, 2021
• Last Update Posted: December 20, 2023
• Last Verified: December 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes

Plan Description

Novartis is committed to sharing access to patient-level data and supporting clinical documents from eligible studies with qualified external researchers. Requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to protect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

Hyperlipidemia; Secondary Cardiovascular Prevention; Atherosclerotic Cardiovascular Disease (ASCVD); Hypercholesterolemia; Lipid lowering therapies; Inclisiran

Additional relevant MeSH terms:

Cardiovascular Diseases; Atherosclerosis; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases