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)

Study Overview
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Brief Summary
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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
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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.

Official Title
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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)

Conditions
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Atherosclerotic Cardiovascular Disease

Intervention / Treatment
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* Drug: Inclisiran


Participation Criteria
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Eligibility Criteria
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Participants eligible for inclusion in this study must meet all of the following criteria: Signed informed consent must be obtained prior to participation in the study Males and females ≥18 years of age 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 Serum LDL-C ≥70 mg/dL or non-HDL-C ≥100 mg/dL Fasting triglyceride <5.65 mmol/L (<500 mg/dL) at screening Calculated glomerular filtration rate >30 mL/min by estimated glomerular filtration rate (eGFR) using standardized local clinical methodology 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 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. 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 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 New York Heart Association (NYHA) class III or IV heart failure or last known left ventricular ejection fraction <30% Significant cardiac arrhythmia within 3 months prior to randomization that is not controlled by medication or via ablation at the time of screening Major adverse cardiovascular event within 6 months prior to randomization Uncontrolled severe hypertension: systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg prior to randomization despite antihypertensive therapy Severe concomitant non-cardiovascular disease that carries the risk of reducing life expectancy to less than 2 years 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 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. 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) Treatment with other investigational products or devices within 30 days or five half-lives of the screening visit, whichever is longer History of hypersensitivity to any of the study treatments or its excipients or to drugs of similar chemical classes Planned use of other investigational products or devices during the course of the study 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 Previous or current treatment (within 90 days of screening) with monoclonal antibodies directed towards PCSK9 or ezetimibe 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: randomized, two-arm, parallel-group, open-label, multicenter clinical trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Inclisiran First<br>Inclisiran + usual care | Drug: Inclisiran<br>* Inclisiran sodium 300 mg/1.5 ml (equivalent to 284 mg inclisiran liquid) in prefilled syringe (PFS).<br>* Other names: Inclisiran First;|
| No Intervention: Usual Care<br>Usual care | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent change from baseline in LDL-C | 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 | Day 330 | 
| Discontinuation of statin therapy (i.e., no statin use ≥ 30 days before the end-of-study visit) (yes, no) | To assess the non-inferiority of an inclisiran first implementation strategy compared to usual care on discontinuation of background statin therapy at Day 330 | Day 330 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute change from baseline in LDL-C | To assess the absolute change in LDL-C of an inclisiran first implementation strategy compared to usual care at Day 330 | Day 330 | 
| Average percent change from baseline in LDL-C levels to each post-baseline visit | To assess the average percent change in LDL-C of an inclisiran first implementation strategy compared to usual care to each post-baseline visit | Day 330 | 
| Average absolute change from baseline in LDL-C to each post-baseline visit | To assess the average absolute change in LDL-C of an inclisiran first implementation strategy compared to usual care to each post-baseline visit | Day 330 | 
| Achieving ≥ 50% reduction from baseline in LDL-C (yes, no) | 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 | Day 330 | 
| Achieving LDL-C < 100 mg/dL (among the subset of participants with LDL-C >100 mg/dL at baseline) (yes, no) | 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 | Day 330 | 
| Achieving LDL-C < 70 mg/dL (yes, no) | 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 | Day 330 | 
| Achieving LDL-C < 55 mg/dL (yes, no) | 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 | Day 330 | 
| Percent change and absolute change from baseline in apoB | To assess apoB in participants receiving an inclisiran first implementation strategy compared to usual care at Day 330 | Day 330 | 
| Percent change and absolute change from baseline in non-HDL-C | To assess non-HDL-C in participants receiving an inclisiran first implementation strategy compared to usual care at Day 330 | Day 330 | 
| Percent change and absolute change from baseline in VLDL-C | To assess VLDL-C in participants receiving an inclisiran first implementation strategy compared to usual care at Day 330 | Day 330 | 
| Percent change and absolute change from baseline in total cholesterol | To assess total cholesterol in participants receiving an inclisiran first implementation strategy compared to usual care at Day 330 | Day 330 | 
| Percent change and absolute change from baseline in Lp(a) | To assess Lp(a) in participants receiving an inclisiran first implementation strategy compared to usual care at Day 330 | Day 330 | 
| Percent change and absolute change from baseline in HDL-C | To assess HDL-C in participants receiving an inclisiran first implementation strategy compared to usual care at Day 330 | Day 330 | 
| Percent change and absolute change from baseline in triglycerides | To assess triglycerides in participants receiving an inclisiran first implementation strategy compared to usual care at Day 330 | Day 330 | 
| Intensity of lipid lowering therapy (decrease in dose, no change in dose, 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 | Day 330 | 
| 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) | To assess adherence to background lipid-lowering therapy in participants receiving an inclisiran first implementation strategy compared to usual care at Day 330 | Day 330 | 
| LDL-C measures of variability (standard deviation, coefficient of variation) | To assess visit-to-visit LDL-C variability from Day 90 until Day 330 | Day 90 to Day 330 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hyperlipidemia, Secondary Cardiovascular Prevention, Atherosclerotic Cardiovascular Disease (ASCVD), Hypercholesterolemia, Lipid lowering therapies, Inclisiran