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)
- Registration Number
- NCT04929249
- Lead Sponsor
- Novartis Pharmaceuticals
- 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.
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 450
Not provided
Participants meeting any of the following criteria are not eligible for inclusion in this study.
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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
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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
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New York Heart Association (NYHA) class III or IV heart failure or last known left ventricular ejection fraction <30%
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Significant cardiac arrhythmia within 3 months prior to randomization that is not controlled by medication or via ablation at the time of screening
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Major adverse cardiovascular event within 6 months prior to randomization
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Uncontrolled severe hypertension: systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg prior to randomization despite antihypertensive therapy
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Severe concomitant non-cardiovascular disease that carries the risk of reducing life expectancy to less than 2 years
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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
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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:
- 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
- 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
- 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
- Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps)
- 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.
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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)
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Treatment with other investigational products or devices within 30 days or five half-lives of the screening visit, whichever is longer
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History of hypersensitivity to any of the study treatments or its excipients or to drugs of similar chemical classes
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Planned use of other investigational products or devices during the course of the study
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Any condition that according to the investigator could interfere with the conduct of the study, such as but not limited to:
- 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 (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)
- 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
- Persons directly involved in the conduct of the study
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Previous or current treatment (within 90 days of screening) with monoclonal antibodies directed towards PCSK9 or ezetimibe
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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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Inclisiran First Inclisiran Inclisiran sodium 300 mg 1.5 ml (equivalent to 284 mg of inclisiran) + usual care
- Primary Outcome Measures
Name Time Method Percent Change From Baseline in LDL-C Baseline, Day 330 Percent change from baseline in Low-Density Lipoprotein Cholesterol (LDL-C) of an "inclisiran first" implementation strategy compared to usual care at Day 330.
Percentage of Participants Who Discontinued Statin Therapy Day 330 Percentage of patients who discontinued statin therapy ≥ 30 days before the end-of-study visit of an "inclisiran first" implementation strategy compared to usual care, for patients in the FAS excluding those with a medical history of statin intolerance.
- Secondary Outcome Measures
Name Time Method Absolute Change From Baseline in LDL-C Baseline, Day 330 Absolute change in Low-Density Lipoprotein Cholesterol (LDL-C) of an "inclisiran first" implementation strategy compared to usual care at Day 330
Average Percent Change From Baseline in LDL-C Levels Across Visits Up to 330 Days Average percent change in Low-Density Lipoprotein Cholesterol (LDL-C) of an "inclisiran first" implementation strategy compared to usual care across visits.
Calculated by averaging the observed post-baseline values (percent change) for each participant across analysis visits.Average Absolute Change From Baseline in LDL-C Levels Across Visits Up to 330 days Average absolute change in Low-Density Lipoprotein Cholesterol (LDL-C) of an "inclisiran first" implementation strategy compared to usual care across visits.
Calculated by averaging the observed post-baseline values (absolute change) for each participant across analysis visits.Percentage of Participants Achieving ≥ 50% Reduction From Baseline in LDL-C Baseline, Day 330 Percentage of patients achieving a ≥ 50% reduction from baseline in Low-Density Lipoprotein Cholesterol (LDL-C) levels of an "inclisiran first" implementation strategy compared to usual care at Day 330.
Missing data is imputed using "non-responder" (i.e., "negative" outcome) imputation.Percentage of Participants Achieving LDL-C < 100 mg/dL. Day 330 Percentage of participants achieving Low-Density Lipoprotein Cholesterol (LDL-C) \< 100 mg/dL (among the subset of participants with LDL-C \>=100 mg/dL at baseline) of an "inclisiran first" implementation strategy compared to usual care at Day 330.
Missing data is imputed using "non-responder" (i.e., "negative" outcome) imputation.Percentage of Participants Achieving LDL-C < 70 mg/dL Day 330 Percentage of participants achieving Low-Density Lipoprotein Cholesterol (LDL-C) \< 70 mg/dL of an "inclisiran first" implementation strategy compared to usual care at Day 330.
Missing data is imputed using "non-responder" (i.e., "negative" outcome) imputation.Percentage of Participants Achieving LDL-C < 55 mg/dL Day 330 Percentage of participants achieving Low-Density Lipoprotein Cholesterol (LDL-C) \< 55 mg/dL of an "inclisiran first" implementation strategy compared to usual care at Day 330.
Missing data is imputed using "non-responder" (i.e., "negative" outcome) imputation.Percent Change in Lipids and Other Lipoproteins From Baseline Baseline, Day 330 Percent change in plasma lipids, lipoproteins and triglycerides in participants receiving an "inclisiran first" implementation strategy compared to usual care at Day 330
Absolute Change in Lipids and Other Lipoproteins From Baseline Baseline, Day 330 Absolute change in plasma lipids, lipoproteins and triglycerides in participants receiving an "inclisiran first" implementation strategy compared to usual care at Day 330
Percentage of Participants by Intensity of Lipid Lowering Therapy Baseline, Day 330 Percentage of participants with decrease in dose, no change in dose or increase in dose to assess changes in background lipid-lowering therapy in participants receiving an "inclisiran first" implementation strategy compared to usual care at Day 330
Proportion of Days Covered by Medication Up to 330 Days Proportion of days covered refers to the total number of days on either statin, ezetimibe, bempedoic acid or PCSK9 inhibiting monoclonal antibody therapies taken during the study divided by total number of study days, calculated for each participant; If a participant did not take any of the four medications then the total number of days will be assumed to be zero.
LDL-C Measures of Variability - Standard Deviation Day 90, Day 180, Day 270 and Day 330 Visit-to-visit LDL-C variability from Day 90 until Day 330 of an "inclisiran first" implementation strategy compared to usual care. It was assessed using two measures of variability: standard deviation and coefficient of variation.
LDL-C Measures of Variability - Coefficient of Variation Day 90, Day 180, Day 270 and Day 330 Visit-to-visit LDL-C variability from Day 90 until Day 330 of an "inclisiran first" implementation strategy compared to usual care. It was assessed using two measures of variability: standard deviation and coefficient of variation.
Trial Locations
- Locations (43)
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
Montefiore Hospital .
🇺🇸Bronx, New York, 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
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