V-INITIATE: 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)

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Recruiting
• CT.gov ID: NCT04929249
• Collaborator: (none)
• Enrollment: 444
• Locations: 35
• Arms: 2
• Anticipated Duration (Months): 24.1
• Patients Per Site: 12.7
• Patients Per Site Per Month: 0.5

Study Details

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 40 US sites.

Study Design

• Study Type: Interventional
• Anticipated Enrollment: 444 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: randomized, two-arm, parallel-group, open-label, multicenter clinical trialrandomized, 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: Jun 25, 2021
• Anticipated Primary Completion Date: Jun 30, 2023
• Anticipated Study Completion Date: Jun 30, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Inclisiran First Inclisiran + usual care	Drug: Inclisiran; 284 mg liquid in prefilled syringe (PFS), 1.5 ml inclisiran sodium (300 mg); Other Names: Inclisiran First
No Intervention: Usual Care Usual care

Outcome Measures

Primary Outcome Measures

1. Percent change from baseline in LDL-C [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) [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 [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 [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 [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) [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) [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) [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) [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 [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 [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 [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 [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) [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 [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 [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) [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) [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) [Day 90 to Day 330]

    To assess visit-to-visit LDL-C variability from Day 90 until Day 330

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion 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

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:

10. 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

11. 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

12. 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

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

14. 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.

1. 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)

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

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

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

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

6. Participants who are unable to communicate or to cooperate with the investigator

7. 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)

8. 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)

9. 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

10. Persons directly involved in the conduct of the study

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

12. 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

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Little Rock	Arkansas	United States	72205
2	Novartis Investigative Site	Greenwich	Connecticut	United States	06830
3	Novartis Investigative Site	Stamford	Connecticut	United States	06905
4	Novartis Investigative Site	Fort Lauderdale	Florida	United States	33312
5	Novartis Investigative Site	Hialeah	Florida	United States	33012
6	Novartis Investigative Site	Jacksonville	Florida	United States	32209
7	Novartis Investigative Site	Jacksonville	Florida	United States	32216
8	Novartis Investigative Site	Kissimmee	Florida	United States	34741
9	Novartis Investigative Site	Jerseyville	Illinois	United States	62052
10	Novartis Investigative Site	Oak Brook	Illinois	United States	60523
11	Novartis Investigative Site	Winfield	Illinois	United States	60190
12	Novartis Investigative Site	Indianapolis	Indiana	United States	46202
13	Novartis Investigative Site	Davenport	Iowa	United States	52801
14	Novartis Investigative Site	Alexandria	Louisiana	United States	71301
15	Novartis Investigative Site	Baltimore	Maryland	United States	21218
16	Novartis Investigative Site	Baltimore	Maryland	United States	21239
17	Novartis Investigative Site	Kansas City	Missouri	United States	64108
18	Novartis Investigative Site	Saint Louis	Missouri	United States	63128
19	Novartis Investigative Site	Lincoln	Nebraska	United States	68506
20	Novartis Investigative Site	Elmer	New Jersey	United States	08318
21	Novartis Investigative Site	Linden	New Jersey	United States	07036
22	Novartis Investigative Site	Flushing	New York	United States	11355
23	Novartis Investigative Site	New York	New York	United States	10021
24	Novartis Investigative Site	Camp Hill	Pennsylvania	United States	17011
25	Novartis Investigative Site	Newport	Pennsylvania	United States	17074
26	Novartis Investigative Site	Yardley	Pennsylvania	United States	19067
27	Novartis Investigative Site	Nashville	Tennessee	United States	37203
28	Novartis Investigative Site	Cypress	Texas	United States	77429
29	Novartis Investigative Site	Houston	Texas	United States	77024
30	Novartis Investigative Site	Houston	Texas	United States	77036
31	Novartis Investigative Site	Houston	Texas	United States	77070
32	Novartis Investigative Site	Webster	Texas	United States	77598
33	Novartis Investigative Site	Lynchburg	Virginia	United States	24501
34	Novartis Investigative Site	Richmond	Virginia	United States	23294
35	Novartis Investigative Site	Morgantown	West Virginia	United States	26501

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT04929249
• Other Study ID Numbers: CKJX839A1US02
• First Posted: Jun 18, 2021
• Last Update Posted: Aug 12, 2022
• Last Verified: Aug 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: Hyperlipidemia; Secondary Cardiovascular Prevention; Atherosclerotic Cardiovascular Disease (ASCVD); Hypercholesterolemia; Lipid lowering therapies; Inclisiran
• Additional relevant MeSH terms: Cardiovascular Diseases; Atherosclerosis

Study Results

No Results Posted as of Aug 12, 2022