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

28. maj 2026 opdateret af: University Medical Centre Ljubljana

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.

Studieoversigt

Status

Rekruttering

Betingelser

Intervention / Behandling

Detaljeret beskrivelse

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.

Undersøgelsestype

Interventionel

Tilmelding (Anslået)

60

Fase

  • Fase 4

Kontakter og lokationer

Dette afsnit indeholder kontaktoplysninger for dem, der udfører undersøgelsen, og oplysninger om, hvor denne undersøgelse udføres.

Studiekontakt

Undersøgelse Kontakt Backup

Studiesteder

  • Slovenien
      • Ljubljana, Slovenien, 1000
        • Rekruttering
        • University Medical Centre Ljubljana
        • Kontakt:
        • Kontakt:
        • Ledende efterforsker:
          • Jan Kafol, MD
        • Underforsker:
          • Zlatko Fras, MD, PhD
        • Underforsker:
          • Borut Jug, MD, PhD
        • Underforsker:
          • Marko Novakovic, MD, PhD

Deltagelseskriterier

Forskere leder efter personer, der passer til en bestemt beskrivelse, kaldet berettigelseskriterier. Nogle eksempler på disse kriterier er en persons generelle helbredstilstand eller tidligere behandlinger.

Berettigelseskriterier

Aldre berettiget til at studere

  • Voksen
  • Ældre voksen

Tager imod sunde frivillige

Ingen

Beskrivelse

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

Studieplan

Dette afsnit indeholder detaljer om studieplanen, herunder hvordan undersøgelsen er designet, og hvad undersøgelsen måler.

Hvordan er undersøgelsen tilrettelagt?

Design detaljer

  • Primært formål: Behandling
  • Tildeling: Randomiseret
  • Interventionel model: Parallel tildeling
  • Maskning: Ingen (Åben etiket)

Våben og indgreb

Deltagergruppe / Arm
Intervention / Behandling
Eksperimentel: 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.
Medicin: Inclisiran
Participants receive inclisiran 284 mg administered subcutaneously at baseline (Day 0) and at Month 3.
Eksperimentel: 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.
Medicin: Alirocumab
Participants receive alirocumab 300 mg administered subcutaneously every four weeks in a supervised clinical setting for 9 months.
Eksperimentel: 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.
Medicin: Inclisiran
Participants receive inclisiran 284 mg administered subcutaneously at baseline (Day 0) and at Month 3.
Medicin: Alirocumab
Participants receive alirocumab 300 mg administered subcutaneously every four weeks in a supervised clinical setting for 9 months.

Hvad måler undersøgelsen?

Primære resultatmål

Resultatmål
Foranstaltningsbeskrivelse
Tidsramme
Percent Change in LDL-C From Baseline
Tidsramme: 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.
3 months and 9 months

Sekundære resultatmål

Resultatmål
Foranstaltningsbeskrivelse
Tidsramme
Trajectory of Percent Change in LDL-C From Baseline
Tidsramme: 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.
1, 3, 6, and 9 months
Proportion of Participants Achieving LDL-C <1.4 mmol/L
Tidsramme: 1, 3, 6, and 9 months
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
Tidsramme: 1, 3, 6, and 9 months
Absolute and percent change in apolipoprotein B from baseline.
1, 3, 6, and 9 months
Change in Non-HDL Cholesterol From Baseline
Tidsramme: 1, 3, 6, and 9 months
Absolute and percent change in non-HDL cholesterol from baseline.
1, 3, 6, and 9 months
Change in Lipoprotein(a) From Baseline
Tidsramme: 1, 3, 6, and 9 months
Absolute and percent change in lipoprotein(a) from baseline.
1, 3, 6, and 9 months
Incidence of Adverse Events
Tidsramme: Up to 9 months
Number and proportion of participants experiencing any adverse event during the study.
Up to 9 months
Treatment Discontinuation Due to Adverse Events
Tidsramme: Up to 9 months
Proportion of participants who discontinue assigned study treatment because of adverse events.
Up to 9 months
Change in Circulating PCSK9 Concentration From Baseline
Tidsramme: 1, 3, 6, and 9 months
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
Tidsramme: 1, 3, 6, and 9 months
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
Tidsramme: 1, 3, 6, and 9 months
Change in serum total cholesterol, HDL cholesterol, and triglyceride concentrations compared with baseline values.
1, 3, 6, and 9 months

Andre resultatmål

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

Samarbejdspartnere og efterforskere

Det er her, du vil finde personer og organisationer, der er involveret i denne undersøgelse.

Sponsor

University Medical Centre Ljubljana

Efterforskere

  • Studiestol: Zlatko Fras, MD, PhD, University Medical Centre Ljubljana
  • Ledende efterforsker: Jan Kafol, MD, University Medical Centre Ljubljana

Publikationer og nyttige links

Den person, der er ansvarlig for at indtaste oplysninger om undersøgelsen, leverer frivilligt disse publikationer. Disse kan handle om alt relateret til undersøgelsen.

Generelle publikationer

Datoer for undersøgelser

Disse datoer sporer fremskridtene for indsendelser af undersøgelsesrekord og resumeresultater til ClinicalTrials.gov. Studieregistreringer og rapporterede resultater gennemgås af National Library of Medicine (NLM) for at sikre, at de opfylder specifikke kvalitetskontrolstandarder, før de offentliggøres på den offentlige hjemmeside.

Studer store datoer

Studiestart (Faktiske)

18. maj 2026

Primær færdiggørelse (Anslået)

1. maj 2027

Studieafslutning (Anslået)

1. juni 2027

Datoer for studieregistrering

Først indsendt

5. maj 2026

Først indsendt, der opfyldte QC-kriterier

5. maj 2026

Først opslået (Faktiske)

12. maj 2026

Opdateringer af undersøgelsesjournaler

Sidste opdatering sendt (Faktiske)

2. juni 2026

Sidste opdatering indsendt, der opfyldte kvalitetskontrolkriterier

28. maj 2026

Sidst verificeret

1. maj 2026

Mere information

Begreber relateret til denne undersøgelse

Nøgleord

Yderligere relevante MeSH-vilkår

Andre undersøgelses-id-numre

  • UKC-PCSK9-DUO

Plan for individuelle deltagerdata (IPD)

Planlægger du at dele individuelle deltagerdata (IPD)?

JA

IPD-planbeskrivelse

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-delingstidsramme

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-delingsadgangskriterier

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-deling Understøttende informationstype

  • STUDY_PROTOCOL
  • SAP
  • ICF

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