Dual PCSK9 Inhibition With Inclisiran and Alirocumab in Secondary Prevention

NCT07581808 | Recruiting Phase 4

• 1 other identifier: UKC-PCSK9-DUO
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

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.

Conditions

Atherosclerotic Cardiovascular Disease (ASCVD); Hypercholesterolemia

Keywords

Alirocumab; Inclisiran; LDL cholesterol; Secondary prevention; Statin intolerance

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (10)

• Trajectory of Percent Change in LDL-C From Baseline

  1, 3, 6, and 9 months

• Change From Baseline in LDL-C Concentration

  1, 3, 6, and 9 months

• Proportion of Participants Achieving LDL-C <1.4 mmol/L

  1, 3, 6, and 9 months

• Change in Apolipoprotein B From Baseline

  1, 3, 6, and 9 months

• Change in Non-HDL Cholesterol From Baseline

  1, 3, 6, and 9 months

Other Outcomes (3)

• Incidence of Injection-Site Reactions

  Up to 9 months

• Treatment Adherence

  Up to 9 months

• Major Adverse Cardiovascular Events

  Up to 9 months

Study Arms (3)

Inclisiran

EXPERIMENTAL

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

Alirocumab

EXPERIMENTAL

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

Inclisiran Plus Alirocumab

EXPERIMENTAL

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; Drug: Alirocumab

Interventions

Inclisiran DRUG

Participants receive inclisiran 284 mg administered subcutaneously at baseline (Day 0) and at Month 3.

Inclisiran; Inclisiran Plus Alirocumab

Alirocumab DRUG

Participants receive alirocumab 300 mg administered subcutaneously every four weeks in a supervised clinical setting for 9 months.

Alirocumab; Inclisiran Plus Alirocumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University Medical Centre Ljubljana: lead

Study Sites (1)

University Medical Centre Ljubljana

Ljubljana, 1000, Slovenia

RECRUITING

Related Publications (6)

• 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 BACKGROUND

• 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.

  PMID: 40878289 BACKGROUND

• 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.

  PMID: 31504418 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

MeSH Terms

Conditions

Hypercholesterolemia; Atherosclerosis

Interventions

ALN-PCS; alirocumab

Condition Hierarchy (Ancestors)

Hyperlipidemias; Dyslipidemias; Lipid Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Cardiovascular Diseases

Study Officials

• Zlatko Fras, MD, PhD

  University Medical Centre Ljubljana

  STUDY CHAIR

• Jan Kafol, MD

  University Medical Centre Ljubljana

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Zlatko Fras, MD, PhD

CONTACT

+386 1 522 25 62; zlatko.fras@kclj.si

Jan Kafol, MD

CONTACT

jan.kafol@kclj.si

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: May 5, 2026
• First Posted: May 12, 2026
• Study Start: May 18, 2026
• Primary Completion (Estimated): May 1, 2027
• Study Completion (Estimated): June 1, 2027
• Last Updated: June 2, 2026

Record last verified: 2026-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• 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.
• 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.

Locations

SL (1)