Efficacy and Safety of Bempedoic Acid in Association With Anti-PCSK9 and Ezetimibe in Statin-intolerant Patients: a Randomized Crossover Trial
Phase: PHASE4
Conditions: Dyslipidemias, Statin Adverse Reaction, Cardiovascular Diseases, Lipid Metabolism Disorders
Sponsor: University of Salerno

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Efficacy and safety of bempedoic acid in association with anti-PCSK9 
and ezetimibe in statin-intolerant patients:  
a randomized crossover trial 
 
 
 
 
 
Principal Investigator (PI)             Prof. Gennaro Galasso 1,2       
 
Steering Committee                
Dott. Angelo Silverio1, Dott. Michele Bellino1, Prof. Carmine 
Vecchione1,2, Prof. Ciro Indolfi3, Prof. Pasquale Perrone 
Filardi 
 
Data Management/Analysis 
Dott. Giovanni Granata 1 
 
 
 
 
1 Dipartimento di Medicina, Chirurgia ed Odontoiatria, Università degli Studi di Salerno, Baronissi, Italia 
2 Clinica cardiologica Universitaria, Dipartimento Cardio-Toraco-Vascolare, A.O.U. San Giovanni di Dio e Ruggi 
d’Aragona, Salerno, Italia 
3 Laboratorio di Cardiologica Molecolare e Cellulare, Dipartimento di Clinica Medica e Sperimentale, Università della 
Magna Graecia, Catanzaro, Italia 
4 Dipartimento di Scienze Biomediche, Università Federico II di Napoli, Napoli, Italia. 
 
 
 
 
 
Promoter of the study 
 
Università degli Studi di Salerno                     
 
 
Coordinator Center 
 
Università degli Studi di Salerno 
 
 
 
 
 
 
 

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Background 
Statin intolerance occurs in up to 15-20% of treated patients, appearing as muscle aches, pains, 
weakness, cramps, or because of abnormalities in serum markers of liver or muscle function.1, 2 These 
conditions are associated with treatment discontinuation, increased low-density lipoprotein 
cholesterol (LDL-C) value and higher risk of cardiovascular events.2  
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%.3-5 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.6 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.5, 7 The full dose of 
Evolocumab (420 mg every two weeks),  was approved only in the setting of homozygous familiar 
hypercholesterolemia.8 
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.9  
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.10 
In the CLEAR Serenity study, bempedoic acid showed a safe and effective profile compared with 
placebo in patients with statin intolerance.11 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.12  
 

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Rational 
PCSK9 is a secreted glycoprotein which modulates the circulating levels of LDL-C through 
downregulation of the expression of low density lipoprotein receptor (LDL-R). PCSK9 synthesis is 
transcriptionally regulated by the intracellular cholesterol pool.13  
Statins decrease hepatic intracellular cholesterol and induce the nuclear translocation of sterol-
regulatory element binding protein-2 (SREBP-2), which increase PCSK9 expression as well as its 
circulating levels.14-16 The synergistic effect of PCSK9 inhibitors when combined with statins has 
been previously demonstrated and has been associated with an additional mean reduction of LDL-C 
of -14.2%.4, 17-20 Conversely, PCSK9 inhibitors up-titration reduced the mean LDL-C level of only 
3% in most of the patient not receiving statins.5, 7 
Bempedoic acid, by regulating the same metabolic pathway of statin, might increase the expression 
of PCSK9 and exert a synergistic effects with PCSK9 inhibitors. Bempedoic acid reduces cholesterol 
synthesis through inhibition of ATP-citrate lyase, an enzyme upstream from 3-hydroxy-3-
methylglutaryl-coenzyme A determining an increased expression of SREBP-2 and PCSK9 in mice.9, 
21 Moreover Bempedoic acid has been demonstrated to increase the expression of mRNA encoding 
PCSK9 of about 1.5 fold in human hepatocytes.21 Hence, bempedoic acid mimic the biological effect 
of statins in terms of overexpression and increased hepatocellular secretion of PCSK9, and might 
enhance the effect of PCSK-9 in term of LDL-C reduction.  
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.22 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.  
We 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.  

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Study design 
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 (Tables 1 and 2).6 The patients enrolled have 
to be intolerant to statin and have not changed their hypolipidemic therapy within 6 weeks prior 
recruitment. 
The study design is depicted in Figure 1. 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, we assumed the absence of any 
carryover effect after the washout period of 4 weeks. Moreover, we 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-Treament B (AB Group) sequence or to a 
Treatment B-Treatment A (BA Group) sequence. 

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We 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. 
 
Inclusion Criteria: 
• High- or very-high-risk patients (Table 1) who do not reach the recommended LDL-C target 
(Table 2) 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)6 
• 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 
 
Exclusion Criteria: 
• 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 

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• 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 cholestrerol 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 informed consent 
 
Primary endpoint 
• The primary endpoint is the mean percentage change in LDL-C after 12 weeks of treatment 
 
Secondary endpoints 
Beside the safety and the efficacy in reducing LDL-C, secondary objectives of this study are the 
evaluation of PCSK9 serum levels, lipid and inflammatory profile, and glucose metabolism 
parameters in statin-intolerant patients treated with bempedoic acid, PCSK9 inhibitors and ezetimibe.   
Indeed, no previous studies have evaluated changes of PCSK9 serum levels in humans during 
treatment with bempedoic acid, especially in absence of statin. This information would increase 

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current knowledge on the mechanisms of action and may corroborate the hypothesis of a synergistic 
effect of bempedoic acid and PCSK9 inhibitors. 
Insulin resistance (IR) is a leading mechanism in the pathophysiology of type 2 diabetes mellitus, 
hypertension, dyslipidaemia, atherosclerotic vascular disease, and has been associated with the risk 
of coronary heart disease and stroke.23 A recent meta-analysis of five studies and 3,629 patients 
showed that the use of bempedoic acid significantly reduces the risk of new onset or worsening 
diabetes.24 No previous studies have investigated about the effects of bempedoic acid on insulin 
resistance in human, especially in patients not treated with statins, which may act as a potential 
confounder. IR, sensitivity and beta cell function can be non-invasively measured by using the 
homeostasis model assessment (HOMA) calculations based on fasting glucose, fasting insulin, and/or 
C-peptide levels.25, 26 
 
On this basis, the following secondary endpoints will be considered for this study: 
• The mean absolute change from baseline to week 12 in low-density lipoprotein cholesterol 
• Percentage of patients reaching the recommended LDL-C target 
• Changes in plasmatic levels of total cholesterol, high-density lipoprotein cholesterol (HDL-
C), non-HDL cholesterol, lipoprotein(a), apolipoprotein B, fasting glucose, glycated 
haemoglobin (HbA1c), fasting insulinemia, homeostatic model assessment (HOMA) index, 
high-sensitivity C-reactive protein (hs-CRP) after 12 weeks of treatment 
• Changes in PCSK9 serum levels before starting the treatment and after 12 weeks of treatment 
• 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 
• The number and type of adverse events 
• MACE, rehospitalization and death at 12 and 28 weeks 
 

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Visit schedule and assessments 
Subjects considered eligible for this study will be included if they meet all inclusion criteria and none 
of the exclusion criteria, after signing the informed consent. The study protocol assessments will be 
done according to the schedule of assessments reported in Table 3. 
Blood samples for protocol assessments will be collected and send to the central laboratory. 
Unscheduled visits for safety evaluation will be permitted for the entire duration of the study. 
 
Study measures 
- Subject demographics and medical history: year of birth, age, and sex. 
- Cardiovascular risk factors: hypertension, diabetes, and tobacco use. 
- Comorbidities: heterozygous familial hypercholesterolemia, atherosclerotic cardiovascular disease 
(ASCVD), prior myocardial infarction, prior percutaneous coronary intervention, prior coronary 
artery bypass graft, and heart failure. 
- Height (cm), weight (kg), and BMI (kg/m2). 
- Lipid-lowering drugs: fibrates, nicotinic acid, bile acid sequestrant, and others.  
- Concomitant pharmacological therapy. 
- Serum levels of LDL-C, total cholesterol, HDL-C, non-HDL-C, triglicerides, lp(a), APO-B, fasting 
glucose, fasting insulinemia, HbA1c, hsCRP, PCSK9, creatinine, uric acid, ALT, AST, and CK 
- Clinical events: rehospitalization and death. 
 
Sample size 
A sample size of 130 randomized patients was expected to provide a 95% power to detect a difference 
of 15% in the percent change from baseline to week 12 in LDL-C between treatments. This 
calculation was based on a two-tailed t test for matched pairs at the 5% level of significance, and a 
common standard deviation of 25, with a potential dropout rate of 10%. 
 

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Statistical Analysis 
All participants who will receive at least one dose of each intervention will be included in the study 
analysis. An intention-to-treat analysis will be performed. 
Comparisons between Treatment A vs Treatment B will be made within patients. A within patient 
comparison takes into account the correlation between measurements for each participant because 
they act as their own control, therefore measurements are not independent. The value of measurement 
on treatment A minus measurement on treatment B separately for each participant will be evaluated. 
Participant baseline and follow-up data will be analysed using descriptive statistics. For the primary 
and secondary outcome measures, continuous variables will be analysed using paired samples t test.27 
The effect estimates will be expressed in mean difference and standard error. Categorical variables 
will be analysed using Mainland-Gart test.28 A p value of <0.05 will be considered as statistically 
significant. 
Statistical analyses will be carried out using RStudio software (RStudio Team (2020). RStudio: 
Integrated Development for R. RStudio, PBC, Boston, MA URL http://www.rstudio.com/.) 
 
 
 
 
 
 
 
 
 
 
 
 

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Laufs U, Banach M, Mancini GBJ, Gaudet D, Bloedon LT, Sterling LR, Kelly S and Stroes ESG. 
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Ballantyne CM, Banach M, Mancini GBJ, Lepor NE, Hanselman JC, Zhao X and Leiter LA. 
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Mayne J, Dewpura T, Raymond A, Cousins M, Chaplin A, Lahey KA, Lahaye SA, Mbikay M, Ooi 
TC and Chrétien M. Plasma PCSK9 levels are significantly modified by statins and fibrates in humans. 
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Berge KE, Ose L and Leren TP. Missense mutations in the PCSK9 gene are associated with 
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Pinkosky SL, Newton RS, Day EA, Ford RJ, Lhotak S, Austin RC, Birch CM, Smith BK, Filippov S, 
Groot PHE, Steinberg GR and Lalwani ND. Liver-specific ATP-citrate lyase inhibition by bempedoic 
acid decreases LDL-C and attenuates atherosclerosis. Nat Commun. 2016;7:13457. 
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PCSK9 Inhibitor Therapy. https://clinicaltrials.gov/ct2/show/study/NCT03193047 (Accessed on 
November 24, 2020). 
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24. 
Masson W, Lobo M, Lavalle-Cobo A, Masson G and Molinero G. Effect of bempedoic acid on 
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model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin 
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Tripathy D, Almgren P, Tuomi T and Groop L. Contribution of insulin-stimulated glucose 
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27. 
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TABLE 1. Cardiovascular risk categories 
VERY HIGH RISK 
 
People with any of the following:  
Ø Documented ASCVD, either clinical or unequivocal on imaging. 
Ø Documented ASCVD includes previous ACS (MI or unstable angina), 
stable angina, coronary revascularization (PCI, CABG, and other arterial 
revascularization procedures), stroke and TIA, and peripheral arterial 
disease.  
Ø Unequivocally documented ASCVD on imaging includes those findings 
that are known to be predictive of clinical events, such as significant 
plaque on coronary angiography or CT scan (multivessel coronary disease 
with two major epicardial arteries having >50% stenosis), or on carotid 
ultrasound. 
Ø DM with target organ damagea, or at least three major risk factors, or 
early onset of T1DM of long duration (>20 years) 
Ø Severe CKD (eGFR <30 mL/min/1.73 m2) 
Ø A calculated SCORE  ≥ 10% for 10-year risk of fatal CVD 
Ø FH with ASCVD or with another major risk factor 
HIGH RISK 
People with: 
Ø Markedly elevated single risk factors, in particular TC>8 mmol/L (>310 
mg/dL), LDL-C >4.9 mmol/L (>190 mg/dL), or BP ≥ 180/110 mmHg. 
Ø Patients with FH without other major risk factors. 
Ø Patients with DM without target organ damagea, with DM duration ≥ 10 
years or another additional risk factor 
Ø Moderate CKD (eGFR 30-59 mL/min/1.73 m2) 
Ø A calculated SCORE ≥ 5% and <10% for 10-year risk of fatal CVD 
 
ASCVD, atherosclerotic cardiovascular disease; ACS, acute coronary syndrome; BP, blood pressure; 
CABG, coronary artery bypass graft surgery; CKD, chronic kidney disease; CT, computed 
tomography; CVD, cardiovascular disease; DM, diabetes mellitus; eGFR, estimated glomerular 
filtration rate; FH, familial hypercholesterolaemia; LDL-C, low-density lipoprotein cholesterol; MI, 
myocardial infarction; PCI, percutaneous coronary intervention; SCORE, Systematic Coronary Risk 
Estimation; T1DM, type 1 DM; TC, total cholesterol; TIA, transient ischaemic attack. 
a Target organ damage is defined as microalbuminuria, retinopathy, or neuropathy. 
 
 

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TABLE 2. Treatment goals for low-density lipoprotein cholesterol 
CARDIOVASCULAR RISK 
LDL-C TARGET 
VERY HIGH 
• 
Reduction of ≥ 50% from baseline and an LDL-C goal: <1.4 
mmol/L (<55 mg/dL) 
• 
For patients with ASCVD who experience a second vascular 
event within 2 years (not necessarily of the same type as the 
first event) while taking maximally tolerated statin-based therapy, 
an LDL-C goal: <1.0 mmol/L (<40 mg/dL) 
HIGH 
• 
Reduction of ≥ 50% from baseline and an LDL-C goal: <1.8 
mmol/L (<70 mg/dL) 
 
ASCVD, atherosclerotic cardiovascular disease; LDL-C, low-density lipoprotein cholesterol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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TABLE 3. Schedule of assessments 
 
 
Phase 1 
Phase 2 
 
Screening and 
randomization 
P1-0 
(0 weeks) 
P1-4 
(4 weeks) 
P1-12 
(12 weeks) 
P2-0 
(16 weeks) 
P2-4 
(20 weeks) 
P2-12 
(28 weeks) 
Inclusion and exclusion criteria 
R 
- 
- 
- 
- 
- 
- 
Informed consent 
R 
- 
- 
- 
- 
- 
- 
Demographics 
- 
R 
- 
- 
- 
- 
- 
Height 
- 
R 
- 
- 
- 
- 
- 
Weight 
- 
R 
- 
- 
R 
- 
- 
Medical history 
- 
R 
- 
- 
- 
- 
- 
Lipid-lowering drugs 
- 
R 
- 
- 
- 
- 
- 
Concomitant medications 
- 
R 
- 
- 
- 
- 
- 
Blood for LDL-C 
- 
R 
R 
R 
R 
R 
R 
Blood for PCSK9 
 
R 
R 
R 
R 
R 
R 
Blood for creatinine 
- 
R 
- 
R 
R 
- 
R 
Blood for total cholesterol, HDL-
C, non-HDL-C, triglicerides, 
lp(a), APO-B, fasting glucose, 
fasting insulinemia, HbA1c, 
hsCRP 
- 
R 
- 
R 
R 
- 
R 
Blood for uric acid, ALT, AST, 
and CK 
- 
R 
R 
R 
R 
R 
R 
Clinical events 
- 
R 
R 
R 
R 
R 
R 
 
APO-B, apolipoprotein B; HbA1C, glycosylated hemoglobin; HDL-C, high-density lipoprotein 
cholesterol; LDL-C, low-density lipoprotein cholesterol; hs-CRP, high-sensitivity C-reactive protein; 
OxPL, oxidized phospholipids; PCSK9, Proprotein Convertase Subtilisin/Kexin type 9; R, required. 
 
 
 
 
 
 

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FIGURE 1. Study design