Efficacy and Safety of Bempedoic Acid in Association With Anti-PCSK9 and Ezetimibe in Statin-intolerant Patients

NCT06381947 | Not Yet Recruiting Phase 4 DMC

• 1 other identifier: 19092023
• Study Type: interventional
• Target: 130
• Locations: 0 countries
• Sites: N/A

Brief Summary

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.

Conditions

Dyslipidemias; Statin Adverse Reaction; Cardiovascular Diseases; Lipid Metabolism Disorders

Keywords

Dyslipidemias; Statin intolerance; PCSK9 inhibitors; Ezetimibe; Bempedoic acid; Cardiovascular risk control

Outcome Measures

Primary Outcomes (1)

• Mean percentage change in LDL-C after 12 weeks of treatment

  The primary outcome is the mean percentage change in LDL-C after 12 weeks of treatment

  0 - 12 weeks

Secondary Outcomes (18)

• Mean absolute change from baseline to week 12 in low-density lipoprotein cholesterol

  0 - 12 weeks

• Percentage of patients reaching the recommended LDL-C target

  0 - 28 weeks

• Changes in plasmatic levels of total cholesterol after 12 weeks of treatment

  0 - 12 weeks

• Changes in plasmatic levels of HDL cholesterol after 12 weeks of treatment

  0 - 12 weeks

• Changes in plasmatic levels of non-HDL cholesterol after 12 weeks of treatment

  0 - 12 weeks

Study Arms (2)

PCSK9 inhibitors plus ezetimibe and bempedoic acid

EXPERIMENTAL

Patients in therapy with PCSK9 inhibitors, bempedoic acid and ezetimibe

Drug: Lipid-lowering therapy combination with PCSK9 inhibitors, bempedoic acid and ezetimibe

PCSK9 inhibitors plus ezetimibe

EXPERIMENTAL

Patients in therapy with PCSK9 inhibitors and ezetimibe

Drug: Lipid-lowering therapy combination with PCSK9 inhibitors and ezetimibe

Interventions

Lipid-lowering therapy combination with PCSK9 inhibitors, bempedoic acid and ezetimibe DRUG

Evaluation of therapy of bempedoic acid with PCSK9 inhibitors and ezetimibe in reducing LDL-C in statin-intolerant patients.

Also known as: PCSK9 inhibitors, bempedoic acid, ezetimibe, Praluent, Repatha, Nilemdo, Nustendi, Absorcol

PCSK9 inhibitors plus ezetimibe and bempedoic acid

Lipid-lowering therapy combination with PCSK9 inhibitors and ezetimibe DRUG

Evaluation of therapy of PCSK9 inhibitors with ezetimibe in reducing LDL-C in statin-intolerant patients.

Also known as: PCSK9 inhibitors, ezetimibe, Praluent, Repatha, Absorcol

PCSK9 inhibitors plus ezetimibe

Eligibility Criteria

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

You may qualify if:

• High- or very-high-risk patients who do not reach the recommended LDL-C target despite lipid-lowering pharmacological therapy for primary or secondary prevention (≤70 mg/dl in high-risk patients, ≤55 mg/dl in very-high-risk patients and ≤40 mg/dl in patients with 2 major cardiovascular events within 2 years)
• Patients treated with PCSK9 inhibitors plus ezetimibe for at least 12 weeks
• Patients with statin intolerance, defined as inability to tolerate at least two statins, one at the lowest starting daily dose and another at any daily dose, either due to objectionable symptoms (real or perceived) or abnormal laboratory analysis, temporally related to statin treatment, reversible upon statin discontinuation, reproducible by rechallenge (restarting medication), and excluding other known factors)
• Age ≥18 years

You may not qualify if:

• Fasting blood triglycerides greater than or equal to 500 mg/dL
• Body Mass Index (BMI) greater than or equal to 50 kg/m2
• Severe chronic kidney disease (GFR\< 30 ml/min) or glomerular nephropathy
• Recent history (\<4 weeks) of clinically significant cardiovascular disease or planning to undergo a major surgical or interventional procedure
• Statin assumption (including low/medium dose and low/medium intensity statins)
• Uncontrolled hypertension
• Uncontrolled hypothyroidism or hyperthyroidism
• Liver disease or dysfunction (Child-Pugh B)
• Gastrointestinal conditions or procedures that could affect drug absorption
• Active malignancy
• Unexplained creatine kinase elevations \>3 times the upper limit of normal
• Lipid-modifying therapies prohibited: mipomersen within 6 months of screening, lomitapide, or apheresis within 3 months of screening, inhibitor cholesterol ester transfer protein inhibitors within 2 years of screening (with the exception of evacetrapib, which must have been discontinued ≥3 months prior to screening); and red yeast rice extract and berberine-containing products within 2 weeks of screening
• Participation in other studies
• Unavailable to sign the informed consent

Sponsors & Collaborators

• University of Salerno: lead

Related Publications (26)

• Alonso R, Cuevas A, Cafferata A. Diagnosis and Management of Statin Intolerance. J Atheroscler Thromb. 2019 Mar 1;26(3):207-215. doi: 10.5551/jat.RV17030. Epub 2019 Jan 19.

  PMID: 30662020 BACKGROUND

• Nissen SE, Stroes E, Dent-Acosta RE, Rosenson RS, Lehman SJ, Sattar N, Preiss D, Bruckert E, Ceska R, Lepor N, Ballantyne CM, Gouni-Berthold I, Elliott M, Brennan DM, Wasserman SM, Somaratne R, Scott R, Stein EA; GAUSS-3 Investigators. Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin Intolerance: The GAUSS-3 Randomized Clinical Trial. JAMA. 2016 Apr 19;315(15):1580-90. doi: 10.1001/jama.2016.3608.

  PMID: 27039291 BACKGROUND

• Cannon CP, Cariou B, Blom D, McKenney JM, Lorenzato C, Pordy R, Chaudhari U, Colhoun HM; ODYSSEY COMBO II Investigators. Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial. Eur Heart J. 2015 May 14;36(19):1186-94. doi: 10.1093/eurheartj/ehv028. Epub 2015 Feb 16.

  PMID: 25687353 BACKGROUND

• Moriarty PM, Thompson PD, Cannon CP, Guyton JR, Bergeron J, Zieve FJ, Bruckert E, Jacobson TA, Kopecky SL, Baccara-Dinet MT, Du Y, Pordy R, Gipe DA; ODYSSEY ALTERNATIVE Investigators. Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: The ODYSSEY ALTERNATIVE randomized trial. J Clin Lipidol. 2015 Nov-Dec;9(6):758-769. doi: 10.1016/j.jacl.2015.08.006. Epub 2015 Aug 29.

  PMID: 26687696 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

• Roth EM, McKenney JM. ODYSSEY MONO: effect of alirocumab 75 mg subcutaneously every 2 weeks as monotherapy versus ezetimibe over 24 weeks. Future Cardiol. 2015;11(1):27-37. doi: 10.2217/fca.14.82.

  PMID: 25606700 BACKGROUND

• Fala L. Repatha (Evolocumab): Second PCSK9 Inhibitor Approved by the FDA for Patients with Familial Hypercholesterolemia. Am Health Drug Benefits. 2016 Mar;9(Spec Feature):136-9. No abstract available.

  PMID: 27668060 BACKGROUND

• Honigberg MC, Natarajan P. Bempedoic Acid for Lowering LDL Cholesterol. JAMA. 2019 Nov 12;322(18):1769-1771. doi: 10.1001/jama.2019.16598. No abstract available.

  PMID: 31714973 BACKGROUND

• Ray KK, Bays HE, Catapano AL, Lalwani ND, Bloedon LT, Sterling LR, Robinson PL, Ballantyne CM; CLEAR Harmony Trial. Safety and Efficacy of Bempedoic Acid to Reduce LDL Cholesterol. N Engl J Med. 2019 Mar 14;380(11):1022-1032. doi: 10.1056/NEJMoa1803917.

  PMID: 30865796 BACKGROUND

• Laufs U, Banach M, Mancini GBJ, Gaudet D, Bloedon LT, Sterling LR, Kelly S, Stroes ESG. Efficacy and Safety of Bempedoic Acid in Patients With Hypercholesterolemia and Statin Intolerance. J Am Heart Assoc. 2019 Apr 2;8(7):e011662. doi: 10.1161/JAHA.118.011662.

  PMID: 30922146 BACKGROUND

• Ballantyne CM, Banach M, Mancini GBJ, Lepor NE, Hanselman JC, Zhao X, Leiter LA. Efficacy and safety of bempedoic acid added to ezetimibe in statin-intolerant patients with hypercholesterolemia: A randomized, placebo-controlled study. Atherosclerosis. 2018 Oct;277:195-203. doi: 10.1016/j.atherosclerosis.2018.06.002. Epub 2018 Jun 12.

  PMID: 29910030 BACKGROUND

• Mayne J, Dewpura T, Raymond A, Cousins M, Chaplin A, Lahey KA, Lahaye SA, Mbikay M, Ooi TC, Chretien M. Plasma PCSK9 levels are significantly modified by statins and fibrates in humans. Lipids Health Dis. 2008 Jun 11;7:22. doi: 10.1186/1476-511X-7-22.

  PMID: 18547436 BACKGROUND

• Berge KE, Ose L, Leren TP. Missense mutations in the PCSK9 gene are associated with hypocholesterolemia and possibly increased response to statin therapy. Arterioscler Thromb Vasc Biol. 2006 May;26(5):1094-100. doi: 10.1161/01.ATV.0000204337.81286.1c. Epub 2006 Jan 19.

  PMID: 16424354 BACKGROUND

• Welder G, Zineh I, Pacanowski MA, Troutt JS, Cao G, Konrad RJ. High-dose atorvastatin causes a rapid sustained increase in human serum PCSK9 and disrupts its correlation with LDL cholesterol. J Lipid Res. 2010 Sep;51(9):2714-21. doi: 10.1194/jlr.M008144. Epub 2010 Jun 5.

  PMID: 20525997 BACKGROUND

• Davignon J, Dubuc G. Statins and ezetimibe modulate plasma proprotein convertase subtilisin kexin-9 (PCSK9) levels. Trans Am Clin Climatol Assoc. 2009;120:163-73.

  PMID: 19768174 BACKGROUND

• Kastelein JJ, Ginsberg HN, Langslet G, Hovingh GK, Ceska R, Dufour R, Blom D, Civeira F, Krempf M, Lorenzato C, Zhao J, Pordy R, Baccara-Dinet MT, Gipe DA, Geiger MJ, Farnier M. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur Heart J. 2015 Nov 14;36(43):2996-3003. doi: 10.1093/eurheartj/ehv370. Epub 2015 Sep 1.

  PMID: 26330422 BACKGROUND

• Kereiakes DJ, Robinson JG, Cannon CP, Lorenzato C, Pordy R, Chaudhari U, Colhoun HM. Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab among high cardiovascular risk patients on maximally tolerated statin therapy: The ODYSSEY COMBO I study. Am Heart J. 2015 Jun;169(6):906-915.e13. doi: 10.1016/j.ahj.2015.03.004. Epub 2015 Mar 13.

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Related Links

• Related Info

MeSH Terms

Conditions

Dyslipidemias; Cardiovascular Diseases; Lipid Metabolism Disorders

Interventions

PCSK9 Inhibitors; 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid; Ezetimibe; alirocumab; evolocumab

Condition Hierarchy (Ancestors)

Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Anticholesteremic Agents; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Serine Proteinase Inhibitors; Protease Inhibitors; Enzyme Inhibitors; Lipid Regulating Agents; Therapeutic Uses; Azetidines; Azetines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Central Study Contacts

Gennaro Galasso, Prof.

CONTACT

+39 3497441225; ggalasso@unisa.it

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: This is an investigator-initiated, phase 4, open-label, multicentre, 2-way crossover trial

Study Record Dates

• First Submitted: March 15, 2024
• First Posted: April 24, 2024
• Study Start: May 1, 2024
• Primary Completion: June 30, 2025
• Study Completion: June 30, 2025
• Last Updated: April 24, 2024

Record last verified: 2024-04

Data Sharing

• IPD Sharing: Will not share