Atherosclerotic Cardiovascular Disease (ASCVD), Hypercholesterolemia
Conditions
Keywords
Alirocumab, Inclisiran, LDL cholesterol, Secondary prevention, Statin intolerance
Brief summary
This study will evaluate the effectiveness and safety of combining two different types of PCSK9 inhibitors, inclisiran and alirocumab, in patients with high cardiovascular risk who are unable to tolerate statins. Lowering low-density lipoprotein cholesterol (LDL-C) is essential to reduce the risk of cardiovascular events. While PCSK9 inhibitors are effective, many patients treated with a single agent do not reach recommended LDL-C targets, especially those who cannot take statins. Inclisiran and alirocumab reduce LDL-C through different mechanisms. Inclisiran decreases the production of PCSK9 in the liver, while alirocumab binds circulating PCSK9 in the blood. Combining these therapies may lead to a greater reduction in LDL-C levels. In this randomized, open-label clinical trial, approximately 60 patients in secondary prevention will be assigned to one of three groups: inclisiran alone, alirocumab alone, or a combination of both treatments. Patients will be followed for 9 months with regular clinical and laboratory assessments. The main goal of the study is to determine whether combination therapy leads to greater LDL-C reduction compared to each treatment alone. Secondary objectives include assessing the proportion of patients achieving target LDL-C levels and evaluating treatment safety and tolerability.
Detailed description
Atherosclerotic cardiovascular disease remains a leading cause of morbidity and mortality, with elevated low-density lipoprotein cholesterol (LDL-C) being a major modifiable risk factor. Despite the availability of effective lipid-lowering therapies, a substantial proportion of high-risk patients fail to achieve recommended LDL-C targets, particularly those with statin intolerance. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in regulating LDL receptor degradation and plasma LDL-C levels. Pharmacological inhibition of PCSK9 has emerged as an effective strategy to reduce LDL-C. Two distinct therapeutic approaches are currently available: monoclonal antibodies (such as alirocumab), which neutralize circulating PCSK9, and small interfering RNA therapies (such as inclisiran), which reduce hepatic production of PCSK9. Although both approaches have demonstrated efficacy, real-world data suggest that monotherapy may not be sufficient for many high-risk patients. The combination of these two mechanisms may provide additive or synergistic effects, leading to more profound LDL-C reduction. This study is designed as a prospective, randomized, open-label, monocentric clinical trial. Approximately 60 adult patients in secondary prevention with statin intolerance and elevated LDL-C (2.5-5.0 mmol/L) will be enrolled. Participants will be randomized in a 1:1:1 ratio to receive inclisiran, alirocumab, or a combination of both therapies. Inclisiran will be administered subcutaneously at baseline and at 3 months. Alirocumab will be administered subcutaneously at a dose of 300 mg every 4 weeks in a supervised clinical setting. Patients will be followed for 9 months, with study visits at baseline, 1 month, 3 months, 6 months, and 9 months. The primary endpoint is the percentage change in LDL-C from baseline at 3 and 9 months. Secondary endpoints include the proportion of patients achieving guideline-recommended LDL-C targets, changes in other lipid parameters, and safety outcomes including adverse events and treatment tolerability. This study aims to provide proof-of-concept evidence on the effectiveness and safety of dual PCSK9 inhibition using complementary mechanisms, with potential implications for improving lipid management in high-risk, statin-intolerant patients.
Interventions
DRUGInclisiran
Participants receive inclisiran 284 mg administered subcutaneously at baseline (Day 0) and at Month 3.
DRUGAlirocumab
Participants receive alirocumab 300 mg administered subcutaneously every four weeks in a supervised clinical setting for 9 months.
Sponsors
University Medical Centre Ljubljana
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
This is an open-label study. Due to differences in dosing schedules and administration frequency between inclisiran and alirocumab, blinding is not feasible. Laboratory measurements and outcome assessments are based on objective parameters.
Intervention model description
Participants will be randomized in a 1:1:1 ratio to one of three parallel treatment groups: inclisiran monotherapy, alirocumab monotherapy, or combined inclisiran and alirocumab therapy. Randomization will be stratified by baseline LDL-C (\<3.6 vs ≥3.6 mmol/L) and background ezetimibe use (yes/no) using permuted block randomization.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adults aged ≥18 years * Established atherosclerotic cardiovascular disease (secondary prevention), defined as prior cardiovascular events or imaging-confirmed atherosclerosis (e.g., coronary artery disease on angiography or CT, carotid plaque on ultrasound, or peripheral arterial disease). * Eligible for PCSK9 inhibitor therapy according to national clinical criteria * Fasting LDL cholesterol ≥2.5 mmol/L and ≤5.0 mmol/L at screening * Documented statin intolerance or contraindication to statin therapy * On stable background lipid-lowering therapy (including ezetimibe if applicable) for at least 4 weeks prior to enrollment * Able and willing to provide written informed consent
Exclusion criteria
* Eligibility for PCSK9 inhibitor therapy solely based on elevated lipoprotein(a) \>1000 mg/L with LDL-C below inclusion threshold * Prior use of any PCSK9 inhibitor (alirocumab, evolocumab or inclisiran) before enrollment * Planned initiation or modification of lipid-lowering therapy during the study period * Known homozygous familial hypercholesterolemia * Active liver disease or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \>3× upper limit of normal * Severe renal impairment (eGFR \<30 mL/min/1.73 m²) * Active malignancy or life expectancy \<1 year * Pregnancy, breastfeeding, or women of childbearing potential not using effective contraception * Known hypersensitivity to inclisiran, alirocumab, or any of their excipients * Participation in another interventional clinical trial within 30 days prior to enrollment * Any condition that, in the opinion of the investigator, would interfere with study participation or interpretation of results
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in LDL-C From Baseline | 3 months and 9 months | Percent change in low-density lipoprotein cholesterol (LDL-C) from baseline at 3 months and 9 months, comparing inclisiran, alirocumab, and combination therapy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Trajectory of Percent Change in LDL-C From Baseline | 1, 3, 6, and 9 months | Percent change in LDL-C from baseline at each scheduled follow-up visit to assess early response and durability of treatment effect. |
| Change From Baseline in LDL-C Concentration | 1, 3, 6, and 9 months | Absolute change in LDL-C concentration compared with baseline at each scheduled follow-up visit. |
| Proportion of Participants Achieving LDL-C <1.4 mmol/L | 1, 3, 6, and 9 months | Proportion of participants achieving LDL-C below 1.4 mmol/L at each scheduled follow-up visit. |
| Change in Apolipoprotein B From Baseline | 1, 3, 6, and 9 months | Absolute and percent change in apolipoprotein B from baseline. |
| Change in Non-HDL Cholesterol From Baseline | 1, 3, 6, and 9 months | Absolute and percent change in non-HDL cholesterol from baseline. |
| Change in Lipoprotein(a) From Baseline | 1, 3, 6, and 9 months | Absolute and percent change in lipoprotein(a) from baseline. |
| Change From Baseline in Total Cholesterol, HDL Cholesterol, and Triglyceride Concentrations | 1, 3, 6, and 9 months | Change in serum total cholesterol, HDL cholesterol, and triglyceride concentrations compared with baseline values. |
| Incidence of Adverse Events | Up to 9 months | Number and proportion of participants experiencing any adverse event during the study. |
| Treatment Discontinuation Due to Adverse Events | Up to 9 months | Proportion of participants who discontinue assigned study treatment because of adverse events. |
| Change in Circulating PCSK9 Concentration From Baseline | 1, 3, 6, and 9 months | Absolute and percent change in circulating PCSK9 concentration to assess pharmacodynamic effects of treatment. |
Countries
Slovenia
Contacts
CONTACTZlatko Fras, MD, PhD
CONTACTJan Kafol, MD
STUDY_CHAIRZlatko Fras, MD, PhD
University Medical Centre Ljubljana
PRINCIPAL_INVESTIGATORJan Kafol, MD
University Medical Centre Ljubljana
Outcome results
None listed