Study Description
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.
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.
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 baseline visit.
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.
Worldwide Contacts
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