A Study to Investigate LDL-cholesterol Lowering With Inclisiran Compared to Bempedoic Acid in Patients With Atherosclerotic Cardiovascular Disease.

Phase 4CompletedNCT06431763

Novartis Pharmaceuticals402 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Eligibility

Sex: ALLMin age: 18 YearsMax age: 99 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

Percent change from baseline in LDL-C levels

To demonstrate superiority of Inclisiran compared to BPA, in combination with standard of care (maximally tolerated HI statin dose +/- Ezetimibe) in reducing relative LDL-C levels at Day 150.

Time frame: Baseline, Day 150

Secondary Outcomes

Percent change from baseline in LDL-C levels in patients without Ezetimibe

To demonstrate superiority of Inclisiran compared to BPA, in patients on maximally tolerated HI statin dose without Ezetimibe in relative reduction of LDL-C levels at Day 150.

Time frame: Baseline, Day 150

Percent change from baseline in LDL-C levels in patients with Ezetimibe

To demonstrate superiority of Inclisiran compared to BPA, in patients on maximally tolerated HI statin dose with Ezetimibe in reducing relative LDL-C levels at Day 150.

Time frame: Baseline, Day 150

Number of participants by individual responsiveness

Number of patients who qualify for 'sufficient response' based on their individual risk class, defined through on treatment LDL-C levels. For patients classified as 'very high risk', responsiveness is 'achieved' once the LDL-C drops below 55mg/dL, and for patients classified as 'high risk' responsiveness is 'achieved' once the LDL-C \< 70 mg/dL at Day 150.

Time frame: Day 150

Absolute change from Baseline in LDL-C

Assess efficacy of Inclisiran compared to BPA in reducing LDL-C (absolute reduction).

Time frame: Day 150

Percent change from Baseline in LDL-C levels

Assess efficacy of Inclisiran compared to BPA in reducing LDL-C \[time-adjusted percent change\] starting Day 30 and up to Day 150.

Time frame: Baseline, from Day 30 up to Day 150

Percent change from Baseline in LDL-C levels

Assess efficacy of Inclisiran compared to BPA in reducing LDL-C \[time-adjusted percent change\] between Day 90 and Day 150.

Time frame: Between Day 90 and Day 150

Mean change from baseline in MMAS-8 over time

Assess adherence to lipid-lowering therapy over time in participants receiving Inclisiran compared to BPA on top of maximally tolerated HI statins (+/- Ezetimibe) using the Morisky 8-Item Medication Adherence Scale (MMAS-8). The Morisky Medication Adherence Scale is an assessment tool used to measure non-adherence in patient populations. It consists of seven yes/no questions and one 5-point Likert scale with a sum score ranging between 0 and 8 points. The higher score indicates higher adherence.

Time frame: From Baseline up to Day 150

Mean change from Baseline in TSQM over time

Assess effect of Inclisiran compared to BPA regarding treatment satisfaction using the Treatment Satisfaction Questionnaire for Medication (TSQM v. II). The TSQM (version II) comprises 11 items across four domains focusing on effectiveness (two items), side effects (four items), convenience (three items), and global satisfaction (two item) of the medication over the previous weeks, or since the patient's last use. With the exception of item 3 (presence of side effects; yes or no), all items have five or seven responses, scored from one (least satisfied) to five or seven (most satisfied). The 7-item scales had a nonneutral midpoint, such that there were more positive response options than negative response options, to allow for precise information to be obtained at the upper end of the score distribution. Item scores are summed to give four domain scores, which are in turn transformed to a scale of 0-100. Higher scores indicating higher patient satisfaction with medication.

Time frame: From Baseline up to Day 150

Mean change from Baseline in SF-BPI over time

Assess the effect of Inclisiran compared to BPA regarding pain-related quality of life using the Short Form Brief Pain Inventory (SF-BPI). The SF-BPI is a self-administered standardized fifteen items questionnaire that assesses how pain interferes with or influences a participant's life. The SF-BPI includes two main scores: a pain severity score and a pain interference score. The pain severity score combines the information of the four items about pain intensity, which are rated from 0, no pain, to 10, pain as bad as you can imagine. To derive the pain severity score the average of the four items will be taken. The pain interference is calculated similarly using the seven items regarding pain interference, which are rated from 0, does not interfere, to 10, completely interferes. The pain interference score will be the average of these seven items. Both scores will be between 0 and 10. Higher scores correspond to a poorer condition of the participant.

Time frame: From Baseline up to Day 150

Proportion of participants with clinically significant change from Baseline in SF-BPI

Proportion of participants with clinically significant change from Baseline \[Minimal clinically important difference of 2 points\] in SF-BPI, to assess the effect of Inclisiran compared to BPA regarding pain-related quality of life using the Short Form Brief Pain Inventory (SF-BPI).

Time frame: At day 150

NCT06431763 - A Study to Investigate LDL-cholesterol Lowering With Inclisiran Compared to Bempedoic Acid in Patients With Atherosclerotic Cardiovascular Disease. | Crick | Crick