Dual PCSK9 Inhibition With Inclisiran and Alirocumab in Secondary Prevention (PCSK9-DUO)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Hypercholesterolemia; Atherosclerotic Cardiovascular Disease (ASCVD)
• Intervention / Treatment: Drug: Inclisiran; Drug: Alirocumab

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.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Zlatko Fras, MD, PhD; Phone Number: +386 1 522 25 62; Email: zlatko.fras@kclj.si
• Study Contact Backup: Name: Jan Kafol, MD; Email: jan.kafol@kclj.si

Study Locations

• Slovenia
  • Ljubljana, Slovenia, 1000
    • Recruiting
    • University Medical Centre Ljubljana
    • Contact: Zlatko Fras, MD, PhD; Phone Number: +386 1 522 25 62; Email: zlatko.fras@kclj.si
    • Contact: Jan Kafol, MD; Email: jan.kafol@kclj.si
    • Principal Investigator: Jan Kafol, MD
    • Sub-Investigator: Zlatko Fras, MD, PhD
    • Sub-Investigator: Borut Jug, MD, PhD
    • Sub-Investigator: Marko Novakovic, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Inclisiran; Participants receive inclisiran 284 mg administered subcutaneously at baseline and at 3 months. Patients will be followed for 9 months with scheduled clinical and laboratory assessments.	Drug: Inclisiran; Participants receive inclisiran 284 mg administered subcutaneously at baseline (Day 0) and at Month 3.
Experimental: Alirocumab; Participants receive alirocumab 300 mg administered subcutaneously every four weeks in a supervised clinical setting for 9 months. Patients will be followed with regular clinical and laboratory assessments.	Drug: Alirocumab; Participants receive alirocumab 300 mg administered subcutaneously every four weeks in a supervised clinical setting for 9 months.
Experimental: Inclisiran Plus Alirocumab; Participants receive inclisiran 284 mg administered subcutaneously at baseline and at 3 months, in combination with alirocumab 300 mg administered subcutaneously every four weeks in a supervised clinical setting for 9 months. Patients will be followed with scheduled clinical and laboratory assessments.	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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change in LDL-C From Baseline	Percent change in low-density lipoprotein cholesterol (LDL-C) from baseline at 3 months and 9 months, comparing inclisiran, alirocumab, and combination therapy.	3 months and 9 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Trajectory of Percent Change in LDL-C From Baseline	Percent change in LDL-C from baseline at each scheduled follow-up visit to assess early response and durability of treatment effect.	1, 3, 6, and 9 months
Proportion of Participants Achieving LDL-C <1.4 mmol/L	Proportion of participants achieving LDL-C below 1.4 mmol/L at each scheduled follow-up visit.	1, 3, 6, and 9 months
Change in Apolipoprotein B From Baseline	Absolute and percent change in apolipoprotein B from baseline.	1, 3, 6, and 9 months
Change in Non-HDL Cholesterol From Baseline	Absolute and percent change in non-HDL cholesterol from baseline.	1, 3, 6, and 9 months
Change in Lipoprotein(a) From Baseline	Absolute and percent change in lipoprotein(a) from baseline.	1, 3, 6, and 9 months
Incidence of Adverse Events	Number and proportion of participants experiencing any adverse event during the study.	Up to 9 months
Treatment Discontinuation Due to Adverse Events	Proportion of participants who discontinue assigned study treatment because of adverse events.	Up to 9 months
Change in Circulating PCSK9 Concentration From Baseline	Absolute and percent change in circulating PCSK9 concentration to assess pharmacodynamic effects of treatment.	1, 3, 6, and 9 months
Change From Baseline in LDL-C Concentration	Absolute change in LDL-C concentration compared with baseline at each scheduled follow-up visit.	1, 3, 6, and 9 months
Change From Baseline in Total Cholesterol, HDL Cholesterol, and Triglyceride Concentrations	Change in serum total cholesterol, HDL cholesterol, and triglyceride concentrations compared with baseline values.	1, 3, 6, and 9 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Injection-Site Reactions	Number and proportion of participants experiencing injection-site reactions.	Up to 9 months
Treatment Adherence	Adherence to assigned therapy assessed by documented administration of inclisiran and alirocumab.	Up to 9 months
Major Adverse Cardiovascular Events	Exploratory assessment of cardiovascular death, myocardial infarction, stroke, urgent coronary revascularization, or hospitalization for unstable angina.	Up to 9 months

Collaborators and Investigators

• Sponsor: University Medical Centre Ljubljana
• Investigators: Study Chair: Zlatko Fras, MD, PhD, University Medical Centre Ljubljana; Principal Investigator: Jan Kafol, MD, University Medical Centre Ljubljana

Publications and helpful links

General Publications

• 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.
• 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.
• 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 Heart J. 2020 Jan 1;41(1):111-188. doi: 10.1093/eurheartj/ehz455. No abstract available.
• 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.
• 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):4359-4378. doi: 10.1093/eurheartj/ehaf190. No abstract available.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): May 18, 2026
• Primary Completion (Estimated): May 1, 2027
• Study Completion (Estimated): June 1, 2027

Study Registration Dates

• First Submitted: May 5, 2026
• First Submitted That Met QC Criteria: May 5, 2026
• First Posted (Actual): May 12, 2026

Study Record Updates

• Last Update Posted (Actual): June 2, 2026
• Last Update Submitted That Met QC Criteria: May 28, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Secondary prevention; Inclisiran; LDL cholesterol; Alirocumab; Statin intolerance
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Metabolic Diseases; Hyperlipidemias; Dyslipidemias; Lipid Metabolism Disorders; Arteriosclerosis; Arterial Occlusive Diseases; Nutritional and Metabolic Diseases; Hypercholesterolemia; Atherosclerosis; alirocumab; ALN-PCS
• Other Study ID Numbers: UKC-PCSK9-DUO

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual participant data (IPD) underlying the results reported in this study will be made available upon reasonable request to qualified researchers. Data sharing will be subject to approval by the study investigators and institutional policies, and will require a data use agreement to ensure appropriate use and protection of participant confidentiality.
• IPD Sharing Time Frame: Individual participant data and supporting documents will be available beginning 6 months following publication of the primary results and ending 5 years after publication.
• IPD Sharing Access Criteria: De-identified individual participant data, study protocol, statistical analysis plan, and informed consent form will be made available to qualified researchers who provide a methodologically sound research proposal. Data access will be subject to approval by the study investigators and the sponsoring institution. A data use agreement will be required to ensure appropriate use of the data and protection of participant confidentiality. Requests for access should be directed to the principal investigator.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No