DyslipidemiasPhase 4BESAFENCT06381947
Efficacy and Safety of Bempedoic Acid in Association With Anti-PCSK9 and Ezetimibe in Statin-intolerant Patients
A Phase 4 study testing Lipid-lowering therapy combination with PCSK9 inhibitors, bempedoic acid and ezetimibe and Lipid-lowering therapy combination with PCSK9 inhibitors and ezetimibe in people with Dyslipidemias and Statin Adverse Reaction, run by University of Salerno.
Trial 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%. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Dyslipidemias, Statin Adverse Reaction, Cardiovascular Diseases
- What is being tested?
- Lipid-lowering therapy combination with PCSK9 inhibitors, bempedoic acid and ezetimibe and Lipid-lowering therapy combination with PCSK9 inhibitors and ezetimibe
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 130 participants
- Where
- No sites listed yet
- Study dates
- 1 May 2024to 30 Jun 2025
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 14Show fewer
- 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
Trial locations and contacts
No sites are listed yet.
About this study
Official title: Efficacy and Safety of Bempedoic Acid in Association With Anti-PCSK9 and Ezetimibe in Statin-intolerant Patients: a Randomized Crossover Trial
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.
Read more
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.
Read the detailed description
This is an investigator-initiated, phase 4, open-label, multicentre, 2-way crossover trial. The study will enlist statin-intolerant patients at high-risk and very high-risk of cardiovascular events, not reaching the LDL-C goal recommended by the 2019 ESC/EAS Guidelines for management of dyslipidaemias based on their individual risk estimate. The patients enrolled have to be intolerant to statin and have not changed their hypolipidemic therapy within 6 weeks prior recruitment.
Eligible participants as per the inclusion criteria will be randomized with 1:1 allocation ratio, without restrictions, into two treatment sequences of 12 weeks, respectively, separated by a washout period of 4 weeks.
Being the inclusion criteria of this study highly selective, the rationale behind the crossover design is the lower sample size needed, and the shorter times to complete the enrolment. Furthermore, since the patients will serve as their own controls, the influence by confounders will be reduced. Being the primary endpoint of this study result of laboratory measurements, the investigators assumed the absence of any carryover effect after the washout period of 4 weeks. Moreover, the investigators assumed the absence of any period effect on the study endpoint.
The phase 1 will start at week 0 (P1-0)and stop at week 12 (P1-12); the phase 2 will start at week 16 (P2-0), after the washout period, and stop at week 28 (P2-12).
The two study treatments will be:
- PCSK9 inhibitors (Evolocumab 140 mg or Alirocumab 75 mg or Alirocumab 150 mg) plus Ezetimibe 10 mg plus Bempedoic acid (Treatment A)
- PCSK9 inhibitors (Evolocumab 140 mg or Alirocumab 75 mg or Alirocumab 150 mg) plus Ezetimibe 10 mg (Treatment B) All patients will be randomly assigned to a Treatment A-Treatment B (AB Group) sequence or to a Treatment B-Treatment A (BA Group) sequence.
The investigators will record laboratory and clinical variables at study visits scheduled for weeks 0, 4, 12, 16, 20, 28. Blood samples will be collected and stored at each visit by the participating centres, and analysed by a central core laboratory (University of Salerno).
At the end of the study, the decision to continue or not treatment with bempedoic acid, as well as any other therapeutic decision, will be left to the treating physician.
- Conditions
- Dyslipidemias, Statin Adverse Reaction, Cardiovascular Diseases, Lipid Metabolism Disorders
- Being tested
- Lipid-lowering therapy combination with PCSK9 inhibitors, bempedoic acid and ezetimibe, Lipid-lowering therapy combination with PCSK9 inhibitors and ezetimibe
- Keywords
- Dyslipidemias, Statin intolerance, PCSK9 inhibitors, Ezetimibe, Bempedoic acid, Cardiovascular risk control
- Medical subject headings
- Dyslipidemias, Cardiovascular Diseases, Lipid Metabolism Disorders
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Lipid-lowering therapy combination with PCSK9 inhibitors, bempedoic acid and ezetimibeDrug
Also called PCSK9 inhibitors, bempedoic acid, ezetimibe, Praluent, Repatha, Nilemdo, Nustendi, Absorcol
Evaluation of therapy of bempedoic acid with PCSK9 inhibitors and ezetimibe in reducing LDL-C in statin-intolerant patients.
Lipid-lowering therapy combination with PCSK9 inhibitors and ezetimibeDrug
Also called PCSK9 inhibitors, ezetimibe, Praluent, Repatha, Absorcol
Evaluation of therapy of PCSK9 inhibitors with ezetimibe in reducing LDL-C in statin-intolerant patients.
| Study group | Role | What they receive |
|---|---|---|
| PCSK9 inhibitors plus ezetimibe and bempedoic acid | Experimental | Patients in therapy with PCSK9 inhibitors, bempedoic acid and ezetimibe Receives: 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 Receives: Drug: Lipid-lowering therapy combination with PCSK9 inhibitors and ezetimibe |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 0 - 12 weeks
Secondary outcomes (18)
Mean absolute change from baseline to week 12 in low-density lipoprotein cholesterol
Secondary outcome measure
Measured: 0 - 12 weeks
Percentage of patients reaching the recommended LDL-C target
Secondary outcome measure
Measured: 0 - 28 weeks
Changes in plasmatic levels of total cholesterol after 12 weeks of treatment
Secondary outcome measure
Measured: 0 - 12 weeks
Changes in plasmatic levels of HDL cholesterol after 12 weeks of treatment
Secondary outcome measure
Measured: 0 - 12 weeks
Changes in plasmatic levels of non-HDL cholesterol after 12 weeks of treatment
Secondary outcome measure
Measured: 0 - 12 weeks
Changes in plasmatic levels of fasting glucose after 12 weeks of treatment
Secondary outcome measure
Measured: 0 - 12 weeks
Changes in plasmatic levels of glycated haemoglobin after 12 weeks of treatment
Secondary outcome measure
Measured: 0 - 12 weeks
Changes in plasmatic levels of fasting insulinemia after 12 weeks of treatment
Secondary outcome measure
Measured: 0 - 12 weeks
Changes in plasmatic levels of HOMA index after 12 weeks of treatment
Secondary outcome measure
Measured: 0 - 12 weeks
Changes in plasmatic levels of hs-CRP after 12 weeks of treatment
Secondary outcome measure
Measured: 0 - 12 weeks
Changes in plasmatic levels of lipoprotein(a) after 12 weeks of treatment
Secondary outcome measure
Measured: 0 - 12 weeks
Changes in plasmatic levels of apolipoprotein B after 12 weeks of treatment
Secondary outcome measure
Measured: 0 - 12 weeks
Changes in PCSK9 serum levels before starting the treatment and after 12 weeks of treatment
Secondary outcome measure
Measured: 0 - 12 weeks
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
Secondary outcome measure
Measured: 0 - 28 weeks
The number and type of adverse events
Secondary outcome measure
Measured: 0 - 28 weeks
MACE at 12 and 28 weeks
Secondary outcome measure intending as MACE "major adverse cardiovascular events"
Measured: 0 - 28 weeks
Rehospitalization at 12 and 28 weeks
Secondary outcome measure intending as MACE "major adverse cardiovascular events"
Measured: 0 - 28 weeks
Death at 12 and 28 weeks
Secondary outcome measure intending as MACE "major adverse cardiovascular events"
Measured: 0 - 28 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Apr 2024
- Study start1 May 2024 (estimated)
- Primary completion30 Jun 2025 (estimated)
- Study completion30 Jun 2025 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (26)Papers the sponsor has linked to this study.
- Other trials for DyslipidemiasStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- This is an investigator-initiated, phase 4, open-label, multicentre, 2-way crossover trial
- Masking
- None (open label)
- Enrolment
- 130 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Salerno
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Gennaro Galasso, University of Salerno
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06381947
- Sponsor's protocol ID
- 19092023
- Acronym
- BESAFE
- Status last verified
- Apr 2024
- First submitted
- 15 Mar 2024
- Last updated
- 24 Apr 2024
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 30662020Nissen 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.
PubMed 27039291Cannon 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.
PubMed 25687353Moriarty 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.
PubMed 26687696Mach 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.
PubMed 31504418Roth 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.
PubMed 25606700Fala 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.
PubMed 27668060Honigberg 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.
PubMed 31714973Ray 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.
PubMed 30865796Laufs 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.
PubMed 30922146Ballantyne 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.
PubMed 29910030Mayne 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.
PubMed 18547436Berge 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.
PubMed 16424354Welder 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.
PubMed 20525997Davignon J, Dubuc G. Statins and ezetimibe modulate plasma proprotein convertase subtilisin kexin-9 (PCSK9) levels. Trans Am Clin Climatol Assoc. 2009;120:163-73.
PubMed 19768174
Study at a glance
From the registry record, last updated by the sponsor on 24 Apr 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Efficacy and Safety of Bempedoic Acid in Association With Anti-PCSK9 and Ezetimibe in Statin-intolerant Patients: a Randomized Crossover Trial
- ClinicalTrials.gov ID
- NCT06381947
- Acronym / sponsor ID
- BESAFE / 19092023
- Conditions
- Dyslipidemias, Statin Adverse Reaction, Cardiovascular Diseases, Lipid Metabolism Disorders
- Keywords
- Dyslipidemias, Statin intolerance, PCSK9 inhibitors, Ezetimibe, Bempedoic acid, Cardiovascular risk control
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 130 participants (estimated)
- Lead sponsor
- University of SalernoUniversity, hospital or other
- Study start
- 1 May 2024 (estimated)
- Primary completion
- 30 Jun 2025 (estimated)
- Study completion
- 30 Jun 2025 (estimated)
- First posted
- 24 Apr 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
This is an investigator-initiated, phase 4, open-label, multicentre, 2-way crossover trial. The study will enlist statin-intolerant patients at high-risk and very high-risk of cardiovascular events, not reaching the LDL-C goal recommended by the 2019 ESC/EAS Guidelines for management of dyslipidaemias based on their individual risk estimate. The patients enrolled have to be intolerant to statin and have not changed their hypolipidemic therapy within 6 weeks prior recruitment.
Eligible participants as per the inclusion criteria will be randomized with 1:1 allocation ratio, without restrictions, into two treatment sequences of 12 weeks, respectively, separated by a washout period of 4 weeks.
Being the inclusion criteria of this study highly selective, the rationale behind the crossover design is the lower sample size needed, and the shorter times to complete the enrolment. Furthermore, since the patients will serve as their own controls, the influence by confounders will be reduced. Being the primary endpoint of this study result of laboratory measurements, the investigators assumed the absence of any carryover effect after the washout period of 4 weeks. Moreover, the investigators assumed the absence of any period effect on the study endpoint.
The phase 1 will start at week 0 (P1-0)and stop at week 12 (P1-12); the phase 2 will start at week 16 (P2-0), after the washout period, and stop at week 28 (P2-12).
The two study treatments will be:
- PCSK9 inhibitors (Evolocumab 140 mg or Alirocumab 75 mg or Alirocumab 150 mg) plus Ezetimibe 10 mg plus Bempedoic acid (Treatment A)
- PCSK9 inhibitors (Evolocumab 140 mg or Alirocumab 75 mg or Alirocumab 150 mg) plus Ezetimibe 10 mg (Treatment B) All patients will be randomly assigned to a Treatment A-Treatment B (AB Group) sequence or to a Treatment B-Treatment A (BA Group) sequence.
The investigators will record laboratory and clinical variables at study visits scheduled for weeks 0, 4, 12, 16, 20, 28. Blood samples will be collected and stored at each visit by the participating centres, and analysed by a central core laboratory (University of Salerno).
At the end of the study, the decision to continue or not treatment with bempedoic acid, as well as any other therapeutic decision, will be left to the treating physician.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- This is an investigator-initiated, phase 4, open-label, multicentre, 2-way crossover trial
| Arm | Type | Receives |
|---|---|---|
| PCSK9 inhibitors plus ezetimibe and bempedoic acid | Experimental | Drug: Lipid-lowering therapy combination with PCSK9 inhibitors, bempedoic acid and ezetimibePatients in therapy with PCSK9 inhibitors, bempedoic acid and ezetimibe |
| PCSK9 inhibitors plus ezetimibe | Experimental | Drug: Lipid-lowering therapy combination with PCSK9 inhibitors and ezetimibePatients in therapy with PCSK9 inhibitors and ezetimibe |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- 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
Key exclusion criteria (14 listed)
- 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)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Lipid-lowering therapy combination with PCSK9 inhibitors, bempedoic acid and ezetimibeAlso: PCSK9 inhibitors, bempedoic acid, ezetimibe, Praluent, Repatha, Nilemdo, Nustendi, AbsorcolEvaluation of therapy of bempedoic acid with PCSK9 inhibitors and ezetimibe in reducing LDL-C in statin-intolerant patients. | Drug | PCSK9 inhibitors plus ezetimibe and bempedoic acid |
| Lipid-lowering therapy combination with PCSK9 inhibitors and ezetimibeAlso: PCSK9 inhibitors, ezetimibe, Praluent, Repatha, AbsorcolEvaluation of therapy of PCSK9 inhibitors with ezetimibe in reducing LDL-C in statin-intolerant patients. | Drug | PCSK9 inhibitors plus ezetimibe |
Primary outcome
Mean percentage change in LDL-C after 12 weeks of treatment
Time frame: 0 - 12 weeks
The primary outcome is the mean percentage change in LDL-C after 12 weeks of treatment
18 secondary outcomes
Mean absolute change from baseline to week 12 in low-density lipoprotein cholesterol
Time frame: 0 - 12 weeks
Percentage of patients reaching the recommended LDL-C target
Time frame: 0 - 28 weeks
Changes in plasmatic levels of total cholesterol after 12 weeks of treatment
Time frame: 0 - 12 weeks
Changes in plasmatic levels of HDL cholesterol after 12 weeks of treatment
Time frame: 0 - 12 weeks
Changes in plasmatic levels of non-HDL cholesterol after 12 weeks of treatment
Time frame: 0 - 12 weeks
Changes in plasmatic levels of fasting glucose after 12 weeks of treatment
Time frame: 0 - 12 weeks
Changes in plasmatic levels of glycated haemoglobin after 12 weeks of treatment
Time frame: 0 - 12 weeks
Changes in plasmatic levels of fasting insulinemia after 12 weeks of treatment
Time frame: 0 - 12 weeks
Changes in plasmatic levels of HOMA index after 12 weeks of treatment
Time frame: 0 - 12 weeks
Changes in plasmatic levels of hs-CRP after 12 weeks of treatment
Time frame: 0 - 12 weeks
Changes in plasmatic levels of lipoprotein(a) after 12 weeks of treatment
Time frame: 0 - 12 weeks
Changes in plasmatic levels of apolipoprotein B after 12 weeks of treatment
Time frame: 0 - 12 weeks
Changes in PCSK9 serum levels before starting the treatment and after 12 weeks of treatment
Time frame: 0 - 12 weeks
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
Time frame: 0 - 28 weeks
The number and type of adverse events
Time frame: 0 - 28 weeks
MACE at 12 and 28 weeks
Time frame: 0 - 28 weeks
Rehospitalization at 12 and 28 weeks
Time frame: 0 - 28 weeks
Death at 12 and 28 weeks
Time frame: 0 - 28 weeks
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 24 Apr 2024.
- Background: PubMed 30662020Alonso 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.
- Background: PubMed 27039291Nissen 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.
- Background: PubMed 25687353Cannon 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.
- Background: PubMed 26687696Moriarty 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.
- Background: PubMed 31504418Mach 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.
- Background: PubMed 25606700Roth 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.
- Background: PubMed 27668060Fala 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.
- Background: PubMed 31714973Honigberg 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.
- Background: PubMed 30865796Ray 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.
- Background: PubMed 30922146Laufs 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.
- Background: PubMed 29910030Ballantyne 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.
- Background: PubMed 18547436Mayne 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.
- Related InfoLink provided by the sponsor.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Lipid-lowering therapy combination with PCSK9 inhibitors, bempedoic acid and ezetimibe and Lipid-lowering therapy combination with PCSK9 inhibitors and ezetimibe in people with Dyslipidemias and Statin Adverse Reaction, run by University of Salerno.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 24 Apr 2024. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Gennaro Galasso, Prof. (+39 3497441225, ggalasso@unisa.it), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Mean percentage change in LDL-C after 12 weeks of treatment (time frame: 0 - 12 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT06381947, which also lists 26 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Apr 2024.