protocolSection identificationModule nctId: NCT06381947, orgStudyIdInfo id: 19092023, briefTitle: Efficacy and Safety of Bempedoic Acid in Association With Anti-PCSK9 and Ezetimibe in Statin-intolerant Patients, acronym: BESAFE, statusModule overallStatus: NOT_YET_RECRUITING, startDateStruct date: 2024-05-01, primaryCompletionDateStruct date: 2025-06-30, completionDateStruct date: 2025-06-30, studyFirstPostDateStruct date: 2024-04-24, lastUpdatePostDateStruct date: 2024-04-24, sponsorCollaboratorsModule leadSponsor name: University of Salerno, class: OTHER, descriptionModule briefSummary: Statin intolerance occurs in up to 15-20% of treated patients. The combined use of Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) inhibitors with ezetimibe is commonly performed in these patients, and has been associated with an estimated LDL-C reduction of 65-70%. This drug combination may be insufficient to reach the LDL-C target in high- and very-high-risk patients with statin intolerance, also considering the goals recommended by the current international guidelines. Also, PCSK9 inhibitor dosage escalations frequently fail to achieve the target. Doubling the dosage of alirocumab from 75 mg to 150 mg, when administrated as monotherapy, determines a further reduction of only 3,6% of LDL-C serum level. The full dose of Evolocumab (420 mg every two weeks), was approved only in the setting of homozygous familiar hypercholesterolemia.Bempedoic acid is an oral, once-daily prodrug, metabolized in the liver to an active inhibitor of ATP-citrate lyase, blocking cholesterol synthesis upstream of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and thereby increasing hepatic expression of the LDL receptor and decreasing circulating LDL-C levels.The CLEAR (Cholesterol Lowering via Bempedoic acid, an ACL-Inhibiting Regimen) Harmony trial demonstrated that bempedoic acid in addition to maximally tolerated statin therapy did not lead to a higher incidence of adverse events compared to placebo and significantly lowered LDL-C levels. In the CLEAR Serenity study, bempedoic acid showed a safe and effective profile compared with placebo in patients with statin intolerance. In the CLEAR Tranquility, it provided an oral therapeutic option complementary to ezetimibe in patients intolerant to high-dose statins who required additional LDL-C lowering.The synergistic effect of bempedoic acid plus PCSK9 inhibitors has been investigated by one phase 2 trial (NCT03193047), which showed a statistical superiority of bempedoic acid plus evolocumab strategy versus placebo plus evolocumab in terms of percent change in LDL-C up to 2 months. To date, no randomized phase 3 clinical trial have evaluated the effect of bempedoic acid in association with anti-PCSK9 and ezetimibe in statin-intolerant patients not attaining the recommended LDL-C target.The investigators hypothesized that the association of bempedoic acid with PCSK9 inhibitors and ezetimibe may be safe and effective in reducing LDL-C in statin-intolerant patients., conditionsModule conditions: Dyslipidemias, conditions: Statin Adverse Reaction, conditions: Cardiovascular Diseases, conditions: Lipid Metabolism Disorders, designModule studyType: INTERVENTIONAL, phases: PHASE4, designInfo allocation: RANDOMIZED, interventionModel: CROSSOVER, interventionModelDescription: This is an investigator-initiated, phase 4, open-label, multicentre, 2-way crossover trial, primaryPurpose: PREVENTION, maskingInfo masking: NONE, enrollmentInfo count: 130, type: ESTIMATED, armsInterventionsModule interventions name: Lipid-lowering therapy combination with PCSK9 inhibitors, bempedoic acid and ezetimibe, interventions name: Lipid-lowering therapy combination with PCSK9 inhibitors and ezetimibe, outcomesModule primaryOutcomes measure: Mean percentage change in LDL-C after 12 weeks of treatment, secondaryOutcomes measure: Mean absolute change from baseline to week 12 in low-density lipoprotein cholesterol, secondaryOutcomes measure: Percentage of patients reaching the recommended LDL-C target, secondaryOutcomes measure: Changes in plasmatic levels of total cholesterol after 12 weeks of treatment, secondaryOutcomes measure: Changes in plasmatic levels of HDL cholesterol after 12 weeks of treatment, secondaryOutcomes measure: Changes in plasmatic levels of non-HDL cholesterol after 12 weeks of treatment, secondaryOutcomes measure: Changes in plasmatic levels of fasting glucose after 12 weeks of treatment, secondaryOutcomes measure: Changes in plasmatic levels of glycated haemoglobin after 12 weeks of treatment, secondaryOutcomes measure: Changes in plasmatic levels of fasting insulinemia after 12 weeks of treatment, secondaryOutcomes measure: Changes in plasmatic levels of HOMA index after 12 weeks of treatment, secondaryOutcomes measure: Changes in plasmatic levels of hs-CRP after 12 weeks of treatment, secondaryOutcomes measure: Changes in plasmatic levels of lipoprotein(a) after 12 weeks of treatment, secondaryOutcomes measure: Changes in plasmatic levels of apolipoprotein B after 12 weeks of treatment, secondaryOutcomes measure: Changes in PCSK9 serum levels before starting the treatment and after 12 weeks of treatment, secondaryOutcomes measure: Number of participants with abnormal uric acid level, abnormal AST/ALT level, ALT or AST >3x ULN, and/or unexplained creatine kinase (CK) >3x ULN, secondaryOutcomes measure: The number and type of adverse events, secondaryOutcomes measure: MACE at 12 and 28 weeks, secondaryOutcomes measure: Rehospitalization at 12 and 28 weeks, secondaryOutcomes measure: Death at 12 and 28 weeks, eligibilityModule sex: ALL, minimumAge: 18 Years, stdAges: ADULT, stdAges: OLDER_ADULT, contactsLocationsModule, documentSection largeDocumentModule largeDocs typeAbbrev: Prot_SAP, hasProtocol: True, hasSap: True, hasIcf: False, label: Study Protocol and Statistical Analysis Plan, date: 2023-05-02, uploadDate: 2024-04-08T09:09, filename: Prot_SAP_000.pdf, size: 452473, largeDocs typeAbbrev: ICF, hasProtocol: False, hasSap: False, hasIcf: True, label: Informed Consent Form, date: 2023-05-02, uploadDate: 2024-04-08T09:09, filename: ICF_001.pdf, size: 193521, hasResults: False