Ignite Creation Date:
2024-05-06 @ 8:26 PM
Last Modification Date:
2024-10-26 @ 3:27 PM
Study NCT ID:
NCT06381947
Status:
NOT_YET_RECRUITING
Last Update Posted:
2024-04-24
First Post:
2024-03-15
Brief Title:
Efficacy and Safety of Bempedoic Acid in Association With Anti-PCSK9 and Ezetimibe in Statin-intolerant Patients
Sponsor:
University of Salerno
Organization:
University of Salerno
Study Overview
Official Title:
Efficacy and Safety of Bempedoic Acid in Association With Anti-PCSK9 and Ezetimibe in Statin-intolerant Patients a Randomized Crossover Trial
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
BESAFE
Brief Summary:
Statin intolerance occurs in up to 15-20 of treated patients The combined use of Proprotein Convertase SubtilisinKexin 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 36 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
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 ESCEAS 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 11 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 P1-0and 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
Eligible participants as per the inclusion criteria will be randomized with 11 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 P1-0and 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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None