Clinical trial NCT06431763: A Study to Investigate LDL-cholesterol Lowering With Inclisiran Compared to Bempedoic Acid in Patients With Atherosclerotic Cardiovascular Disease.
Official title: A Randomized, Multicenter, Open-label Trial Comparing the Effectiveness of Inclisiran to Bempedoic Acid on LDL Cholesterol (LDL-C) Lowering in Participants With Atherosclerotic Cardiovascular Disease (VICTORION-CHALLENGE)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Hypercholesterolemia
Keywords: LDL-cholesterol
atherosclerotic cardiovascular disease
Inclisiran
bempedoic acid
BPA
PCSK9 inhibitor
head-to-head comparison
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2024-05-29
Enrollment: 400
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study is a phase IV, open-label, randomized study designed to evaluate the efficacy of Inclisiran vs. bempedoic acid (BPA) in 400 adult subjects (≥ 18 years) at very high and high risk for cardiovascular events as defined by the cardiovascular risk categories in the 2019 ESC/EAS guidelines for the management of dyslipidemias (Mach et al 2020) and elevated levels of LDL-C (≥ 70 mg/dL) despite being on a maximally tolerated high-intensity (HI) statin dose (+/- Ezetimibe). Currently, BPA is recommended ahead of injectables by German HTA body (GBA). A head-to-head trial is proposed to provide robust scientific data on the superiority of Inclisiran vs. BPA and to support the early use of Inclisiran.

Detailed description: During the screening period study eligibility will be assessed and the participants' individual LDL-C target according to guideline (Mach et al., 2020) will be determined. Among other criteria, at screening, a participant must be on a stable maximally tolerated dose of a HI statin with either atorvastatin ≥40 mg once a day (QD) or rosuvastatin ≥20 mg QD (+/- Ezetimibe \[10mg\]) for ≥ 4 weeks with which, however, a target LDL-C of \< 70 mg/dL is not reached.

During the open-label treatment period, all participants, who fulfill the inclusion/exclusion criteria, will be randomized at V1 (Day 1) in a 1:1 open-label fashion to either Inclisiran sodium 300 mg s.c. (administered at Day 1 and Day 90) or to BPA tablets 180 mg p.o. (given once daily). Participants will be required to maintain their background lipid-lowering treatment (maximally tolerated statin dose +/- Ezetimibe) unchanged for the duration of the study. The end of treatment (EOT) is reached at day 150.

A Safety-Follow-up call will be conducted 30 days after EOT visit (Day 180).

The overall study duration is approximately 190 days but can vary depending on individual screening and the visit windows allowed for the treatment period and EOS visit.

Eligibility criteria: Inclusion Criteria:

1. Fasting LDL-C ≥ 70 mg/dL at screening
2. Participants must be on a stable (≥ 4 weeks) and well-tolerated lipid-lowering regimen (with or without Ezetimibe \[10mg\]) that must include a high-intensity statin therapy with either atorvastatin ≥40 mg QD or rosuvastatin ≥20 mg QD in a maximally tolerated or maximally approved dose at screening
3. Participants categorized as very high or high CV risk, as defined below:

   * Very high risk participants with at least one of the following:

     * Documented ASCVD: ACS: Unstable angina or myocardial infarction, Stable angina, Coronary revascularization, Unequivocally documented ASCVD upon prior imaging, Stroke and Transient Ischaemic Attack (TIA), Peripheral artery disease (PAD)
     * Diabetes mellitus (DM) with target organ damage (defined as microalbuminuria, retinopathy, or neuropathy), or at least ≥ 3 major risk factors, or early onset of Type 1 DM of long duration (\< 20 years)
     * A calculated SCORE2 ≥ 7.5 % for age \< 50 years; SCORE2 ≥ 10 % for age 50-69 years; SCORE2-OP ≥ 15 % for age ≥ 70 years to estimate 10-year risk of fatal and non-fatal CVD
     * Pre-existing diagnosis of heterozygous familial hyper-cholesterolemia (HeFH) with ASCVD or with another major risk factor OR
   * High risk participants with at least one of the following:

     * Markedly elevated single risk factors, in particular total cholesterol \> 310 mg/dL, LDL-C \> 190 mg/dL, or blood pressure ≥ 180/110 mmHg
     * Pre-existing diagnosis of HeFH without other major risk factors
     * DM without target organ damage (defined as microalbuminuria, retinopathy, or neuropathy), with DM duration ≥ 10 years or other additional risk factor
     * Moderate chronic kidney disease (eGFR 30-59 mL/min/1.73m2)
     * A calculated SCORE2 2.5 to \< 7.5 % for age \< 50 years; SCORE2 5 to \< 10 % for age 50-69 years; SCORE2-OP 7.5 to \< 15 % for age ≥ 70 years to estimate 10-year risk of fatal and non-fatal CVD as defined by the cardiovascular risk categories in the 2019 ESC/EAS guideline (Mach et al 2020), and updated SCORE2 and SCORE2-OP (Hageman et al 2021, de Vries et al 2021, Visseren et al 2021). Further details for documented ASCVD will be provided in the protocol.
4. Fasting triglyceride \< 400 mg/dL at screening

Exclusion Criteria:

1. Acute coronary syndrome, ischemic stroke, peripheral arterial revascularization procedure or amputation due to atherosclerotic disease \< 4 months prior to screening visit or V1.
2. Planned or expected cardiac, cerebrovascular or peripheral artery surgery or coronary re-vascularization within 6 months after screening visit.
3. Heart failure NYHA class IV at screening or V1.
4. Participants on more than one other lipid-lowering drug on top of statin at screening visit.
5. Previous treatment with a mAb directed towards PCSK9 (e.g., evolocumab, alirocumab) or planned use after screening visit.
6. Previous treatment prior to screening with BPA within 90 days
7. Previous exposure to Inclisiran or any other non-mAb PCSK9-targeted therapy, either as an investigational or marketed drug.

Primary outcomes:
measure: Percent change from baseline in LDL-C levels
timeFrame: Baseline, Day 150
Secondary outcomes:
measure: Percent change from baseline in LDL-C levels in patients without Ezetimibe
timeFrame: Baseline, Day 150
measure: Percent change from baseline in LDL-C levels in patients with Ezetimibe
timeFrame: Baseline, Day 150
measure: Number of participants by individual responsiveness
timeFrame: Day 150
measure: Absolute change from Baseline in LDL-C
timeFrame: Day 150
measure: Percent change from Baseline in LDL-C levels
timeFrame: Baseline, from Day 30 up to Day 150
measure: Percent change from Baseline in LDL-C levels
timeFrame: Between Day 90 and Day 150
measure: Mean change from baseline in MMAS-8 over time
timeFrame: From Baseline up to Day 150
measure: Mean change from Baseline in TSQM over time
timeFrame: From Baseline up to Day 150
measure: Mean change from Baseline in SF-BPI over time
timeFrame: From Baseline up to Day 150
measure: Proportion of participants with clinically significant change from Baseline in SF-BPI
timeFrame: At day 150
Other outcomes:
Locations:
city: Konstanz
country: Germany
facility: Novartis Investigative Site
state: Baden Wuerttemberg
city: Mannheim
country: Germany
facility: Novartis Investigative Site
state: Baden Wuerttemberg
city: Regensburg
country: Germany
facility: Novartis Investigative Site
state: Bavaria
city: Frankfurt Am Main
country: Germany
facility: Novartis Investigative Site
state: Hessen
city: Frankfurt am Main
country: Germany
facility: Novartis Investigative Site
state: Hessen
city: Frankfurt Am Main
country: Germany
facility: Novartis Investigative Site
state: Hessen
city: Goettingen
country: Germany
facility: Novartis Investigative Site
state: Niedersachsen
city: Essen
country: Germany
facility: Novartis Investigative Site
state: Nordrhein Westfalen
city: Kaiserslautern
country: Germany
facility: Novartis Investigative Site
state: Rhineland-Palatinate
city: Dresden
country: Germany
facility: Novartis Investigative Site
state: Sachsen
city: Aachen
country: Germany
facility: Novartis Investigative Site
city: Bad Homburg
country: Germany
facility: Novartis Investigative Site
city: Bad Krozingen
country: Germany
facility: Novartis Investigative Site
city: Bad Oeynhausen
country: Germany
facility: Novartis Investigative Site
city: Bamberg
country: Germany
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Bochum
country: Germany
facility: Novartis Investigative Site
city: Bochum
country: Germany
facility: Novartis Investigative Site
city: Bremen
country: Germany
facility: Novartis Investigative Site
city: Dessau-Rosslau
country: Germany
facility: Novartis Investigative Site
city: Dresden
country: Germany
facility: Novartis Investigative Site
city: Erfurt
country: Germany
facility: Novartis Investigative Site
city: Essen
country: Germany
facility: Novartis Investigative Site
city: Essen
country: Germany
facility: Novartis Investigative Site
city: Falkensee
country: Germany
facility: Novartis Investigative Site
city: Gladbeck
country: Germany
facility: Novartis Investigative Site
city: Greifswald
country: Germany
facility: Novartis Investigative Site
city: Guetersloh
country: Germany
facility: Novartis Investigative Site
city: Hamburg
country: Germany
facility: Novartis Investigative Site
city: Hamburg
country: Germany
facility: Novartis Investigative Site
city: Hamburg
country: Germany
facility: Novartis Investigative Site
city: Hannover
country: Germany
facility: Novartis Investigative Site
city: Hoyerswerda
country: Germany
facility: Novartis Investigative Site
city: Jena
country: Germany
facility: Novartis Investigative Site
city: Kassel
country: Germany
facility: Novartis Investigative Site
city: Kiel
country: Germany
facility: Novartis Investigative Site
city: Koeln-Nippes
country: Germany
facility: Novartis Investigative Site
city: Leipzig
country: Germany
facility: Novartis Investigative Site
city: Lichtenfels
country: Germany
facility: Novartis Investigative Site
city: Loehne
country: Germany
facility: Novartis Investigative Site
city: Ludwigshafen
country: Germany
facility: Novartis Investigative Site
city: Magdeburg
country: Germany
facility: Novartis Investigative Site
city: Markkleeberg
country: Germany
facility: Novartis Investigative Site
city: Meissen
country: Germany
facility: Novartis Investigative Site
city: Muehldorf
country: Germany
facility: Novartis Investigative Site
city: Muenster
country: Germany
facility: Novartis Investigative Site
city: Offenbach Am Main
country: Germany
facility: Novartis Investigative Site
city: Papenburg
country: Germany
facility: Novartis Investigative Site
city: Pirna
country: Germany
facility: Novartis Investigative Site
city: Potsdam
country: Germany
facility: Novartis Investigative Site
city: Ruedersdorf
country: Germany
facility: Novartis Investigative Site
city: Saint Ingbert Oberwuerzbach
country: Germany
facility: Novartis Investigative Site
city: Stuttgart
country: Germany
facility: Novartis Investigative Site
city: Sulzbach Rosenberg
country: Germany
facility: Novartis Investigative Site
city: Ulm
country: Germany
facility: Novartis Investigative Site
city: Voelklingen
country: Germany
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: