Efficacy, safety AND tolerability of add on Bempedoic Acid vs increased dose of Atorvastatin, in patients already on moderate dose of atorvastatin without achieving target LDL-C - A single blind randomised control trial

Objective:

In patients already on moderate dose of Atorvastatin(20mg) but not reaching the target LDL level(<70mg/dl), the objectives are-

·       1. To compare the Efficacy of add on Bempedoic acid(180mg) to moderate dose of Atorvastatin(20mg) vs increased dose of Atorvastatin(40mg).

·       2. To compare the Safety between the two groups.

·       3. To compare the Tolerability between the two groups.

 Background:

Elevated blood cholesterol is a strong atherosclerotic cardiovascular disease (ASCVD) risk factor. Worldwide, high cholesterol levels are estimated to cause 56% of ischemic heart disease and 18% of strokes, causing more than 4 million deaths annually. Lowering of low-density lipoprotein cholesterol (LDL-C) in blood is a beneficial factor for this condition. Statin therapy along with lifestyle modification is still the essential therapy for hypercholesterolemia.

Bempedoic acid is a non-statin drug which targets the cholesterol biosynthesis pathway in the liver, lowers the LDL cholesterol level. Whereas statins like Atorvastatin inhibit HMG CoA reductase, bempedoic acid inhibits ATP-citrate lyase (ACL), two steps upstream of HMG CoA reductase. The lack of active metabolites of bempedoic acid in skeletal muscles makes it a good alternative for patients with statin-associated muscle symptoms (SAMS).

Methodology:

Study design:

It is a parallel group single blind analytical randomized controlled clinical trial study.

**Study setting:**Burdwan Medical college and Hospital, Department of General Medicine and Pharmacology & Therapeutics

**Time Line:**From October 2023 to April 2025, 18 months period

Place of study: Medicine Outpatient Department of Burdwan Medical College & Hospital and Department of Pharmacology & Therapeutics, Burdwan Medical College.

Study period:

The total study period is 18 months. It will be divided into 3 phases- A. preparatory phase, B. Data collection, C. Data analysis and report writing.

Study population:

Hypercholesterolemia patients having uncontrolled LDL-C with moderate dose of Atorvastatin(20mg) for at least 3 months, attending Medicine OPD.

 Data collection and procedure:

After receiving Institutional Ethics Committee approval and proper informed consent from the patients, the study will be started in the Medicine OPD. All the patients attending the OPD will be analysed according to inclusion and exclusion criteria. Then the selected patients will be randomized by computer generated random number table 1:1 and will be distributed in two groups. One group will be prescribed high dose Atorvastatin (40mg) once daily by the physician and the other group will be prescribed add on Bempedoic Acid (180mg) along with Atorvastatin (20mg). The study will be single blind (participant blind). To comply with the single blinding procedure, the required medicine will be dispensed according to the randomization and the participants will not know which drug they are receiving. All the drugs will be pre-acquired before the commencement of the study and will be kept under care and observation. The drugs will be kept in two boxes which will be marked as Drug A and Drug B. Box drug A will be containing Atorvastatin 40mg and drug B will be containing Atorvastatin 20mg+ Bempedoic Acid 180mg. The drugs will be dispensed in adequate amount to the patients upto the next follow up visit. In the follow up visit, after routine check up by the physician, the required medications will be again dispensed to the patients till the end of the study period. The investigator will also look for the general history, blood reports (efficacy and safety variables) and adverse events. After the study period, all the patients will be prescribed with the best possible medication from the hospital.

SCREENING VISIT

After proper informed consent from the patients, all the patients will be screened according to inclusion and exclusion criteria. Clinical evaluation will be done by the attending OPD physician. Selected patients will be examined for blood for LDL, HDL, non HDL cholesterol, hs CRP, Serum creatinine, eGFR, SGOT, SGPT, creatine phosphokinase. ECG and body weight measurement will also be recorded. All the medications other than allowed ones should be stopped and 7 days wash out period will be allowed.

 BASELINE VISIT:

Baseline visit will be scheduled 7 days after the screening visit. All the patients will be given either drug A or drug B according to the randomization. The type of medicine the patient will be receiving, will not be discussed with the patient or patient party during medicine disposal.

 1st FOLLOW UP VISIT (12 WEEKS):

The patients will be examined for blood for LDL, HDL-C, non HDL cholesterol, hs CRP, Serum creatinine, eGFR, SGOT, SGPT, creatine phosphokinase. ECG and body weight measurement will also be recorded. Any adverse effects reported by them will also be recorded in the adverse events checklist. After that, the required medication will be dispersed in adequate amount.

 END OF THE STUDY VISIT(24 WEEKS):

The patients will be examined for blood for LDL, HDL, non HDL cholesterol, hs CRP, Serum creatinine, eGFR, SGOT, SGPT, creatine phosphokinase. ECG and body weight measurement will also be recorded. Any adverse effects reported by them will also be recorded in the adverse events checklist.

After the end of the study, all the patients will be continued with the best possible treatment from the hospital.

The patients will be advised to address the investigator freely, even through telephonic communication regarding any study related issue or adverse events at any time during the study period.

 Expected outcome:

It is expected that Bempedoic Acid and Atorvastatin combination group will show more efficacy, safety (with lesser adverse effects) and tolerability compared to High dose of Atorvastatin group.

Statistical Analysis plan:

Between the group analysis will be done by using unpaired t-test or Mann-Whitney U test. Repeated measures ANOVA or Friedman’s ANOVA will be used for comparing within the group participants. Adverse events will be analyzed by using Chi Square test. All the statistical analysis will be done with the help of Excel(version 21) and SPSS(version 18).