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)

Atherosclerotic Cardiovascular Disease Clinical Trial

— V-INITIATE  

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04929249
• Other study ID #: CKJX839A1US02
• Status: Completed
• Phase: Phase 3
• Start date: June 25, 2021
• Est. completion date: September 15, 2023

Study information

• Verified date: December 2023
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 450
• Est. completion date: September 15, 2023
• Est. primary completion date: September 15, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Atherosclerosis
• Atherosclerotic Cardiovascular Disease
• Cardiovascular Diseases

Intervention

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

Locations

Country	Name	City	State
United States	Novartis Investigative Site	Alexandria	Louisiana
United States	Novartis Investigative Site	Baltimore	Maryland
United States	Novartis Investigative Site	Baltimore	Maryland
United States	Novartis Investigative Site	Bronx	New York
United States	Novartis Investigative Site	Cypress	Texas
United States	Novartis Investigative Site	Edgewood	Kentucky
United States	Novartis Investigative Site	Elmer	New Jersey
United States	Novartis Investigative Site	Flushing	New York
United States	Novartis Investigative Site	Fort Lauderdale	Florida
United States	Novartis Investigative Site	Greenwich	Connecticut
United States	Novartis Investigative Site	Hershey	Pennsylvania
United States	Novartis Investigative Site	Hialeah	Florida
United States	Novartis Investigative Site	Houston	Texas
United States	Novartis Investigative Site	Houston	Texas
United States	Novartis Investigative Site	Houston	Texas
United States	Novartis Investigative Site	Indianapolis	Indiana
United States	Novartis Investigative Site	Jacksonville	Florida
United States	Novartis Investigative Site	Jacksonville	Florida
United States	Novartis Investigative Site	Jerseyville	Illinois
United States	Novartis Investigative Site	Kissimmee	Florida
United States	Novartis Investigative Site	Lincoln	Nebraska
United States	Novartis Investigative Site	Linden	New Jersey
United States	Novartis Investigative Site	Little Rock	Arkansas
United States	Novartis Investigative Site	Los Angeles	California
United States	Novartis Investigative Site	Lynchburg	Virginia
United States	Novartis Investigative Site	Marshfield	Wisconsin
United States	Novartis Investigative Site	Missouri City	Texas
United States	Novartis Investigative Site	Morgantown	West Virginia
United States	Novartis Investigative Site	Nashville	Tennessee
United States	Novartis Investigative Site	New York	New York
United States	Novartis Investigative Site	Newport	Pennsylvania
United States	Novartis Investigative Site	Oak Brook	Illinois
United States	Novartis Investigative Site	Richmond	Virginia
United States	Novartis Investigative Site	Stamford	Connecticut
United States	Novartis Investigative Site	Stony Brook	New York
United States	Novartis Investigative Site	Webster	Texas
United States	Novartis Investigative Site	Weston	Wisconsin
United States	Novartis Investigative Site	Winfield	Illinois
United States	Novartis Investigative Site	Yardley	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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