Dual PCSK9 Inhibition With Inclisiran and Alirocumab in Secondary Prevention

Official title

PCSK9-DUO Trial: Dual PCSK9 Inhibition With Inclisiran and Alirocumab in Patients With High Cardiovascular Risk in Secondary Prevention

Overview

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

• Drug Inclisiran
  Participants receive inclisiran 284 mg administered subcutaneously at baseline (Day 0) and at Month 3.
• Drug Alirocumab
  Participants receive alirocumab 300 mg administered subcutaneously every four weeks in a supervised clinical setting for 9 months.

Primary outcome measures

• Percent Change in LDL-C From Baseline [Time frame: 3 months and 9 months]

Secondary outcome measures (10)

• Trajectory of Percent Change in LDL-C From Baseline [Time frame: 1, 3, 6, and 9 months]
• Change From Baseline in LDL-C Concentration [Time frame: 1, 3, 6, and 9 months]
• Proportion of Participants Achieving LDL-C <1.4 mmol/L [Time frame: 1, 3, 6, and 9 months]
• Change in Apolipoprotein B From Baseline [Time frame: 1, 3, 6, and 9 months]
• Change in Non-HDL Cholesterol From Baseline [Time frame: 1, 3, 6, and 9 months]
• Change in Lipoprotein(a) From Baseline [Time frame: 1, 3, 6, and 9 months]
• Change From Baseline in Total Cholesterol, HDL Cholesterol, and Triglyceride Concentrations [Time frame: 1, 3, 6, and 9 months]
• Incidence of Adverse Events [Time frame: Up to 9 months]
• Treatment Discontinuation Due to Adverse Events [Time frame: Up to 9 months]
• Change in Circulating PCSK9 Concentration From Baseline [Time frame: 1, 3, 6, and 9 months]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Slovenia · 1 center

• University Medical Centre Ljubljana — Ljubljana

Publications

• Kafol J, Fras Z, Novakovic M, Sperling LS, Cevc M, Krevel B, Kafol L, Kelenc A, Kepic K, Vrbinc K, Svarc M, Groselj U, Jug B. Real-world effectiveness and cardiovascular outcomes of PCSK9 inhibitor therapy: a prospective registry study. Lipids Health Dis. 2026 Mar 5;25(1):106. doi: 10.1186/s12944-026-02897-3. PMID 41787544
• Mach F, Koskinas KC, Roeters van Lennep JE, Tokgozoglu L, Badimon L, Baigent C, Benn M, Binder CJ, Catapano AL, De Backer GG, Delgado V, Fabin N, Ference BA, Graham IM, Landmesser U, Laufs U, Mihaylova B, Nordestgaard BG, Richter DJ, Sabatine MS; ESC/EAS Scientific Document Group. 2025 Focused Update of the 2019 ESC/EAS Guidelines for the management of dyslipidaemias. Eur Heart J. 2025 Nov 7;46(42 PMID 40878289
• Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, Chapman MJ, De Backer GG, Delgado V, Ference BA, Graham IM, Halliday A, Landmesser U, Mihaylova B, Pedersen TR, Riccardi G, Richter DJ, Sabatine MS, Taskinen MR, Tokgozoglu L, Wiklund O; ESC Scientific Document Group. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur PMID 31504418
• Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna M, Stroes ES, Langslet G, Raal FJ, El Shahawy M, Koren MJ, Lepor NE, Lorenzato C, Pordy R, Chaudhari U, Kastelein JJ; ODYSSEY LONG TERM Investigators. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015 Apr 16;372(16):1489-99. doi: 10.1056/NEJMoa1501031. Epub 2015 Mar 15. PMID 25773378
• Wright RS, Raal FJ, Koenig W, Landmesser U, Leiter LA, Vikarunnessa S, Lesogor A, Maheux P, Talloczy Z, Zang X, Schwartz GG, Ray KK. Inclisiran administration potently and durably lowers LDL-C over an extended-term follow-up: the ORION-8 trial. Cardiovasc Res. 2024 Oct 14;120(12):1400-1410. doi: 10.1093/cvr/cvae109. PMID 38753448
• Ray KK, Wright RS, Kallend D, Koenig W, Leiter LA, Raal FJ, Bisch JA, Richardson T, Jaros M, Wijngaard PLJ, Kastelein JJP; ORION-10 and ORION-11 Investigators. Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol. N Engl J Med. 2020 Apr 16;382(16):1507-1519. doi: 10.1056/NEJMoa1912387. Epub 2020 Mar 18. PMID 32187462

Identifiers

NCT: NCT07581808 · UKC-PCSK9-DUO

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗