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Efficacy and safety of hybutimibe on primary hypercholesterolemia: a randomized, double-blinded, placebo and positive–controlled, parallel phase II study

Qi, Litong1; Zhao, Shuiping2; Chen, Jiyan3; Zhang, Mei4; Li, Xiaodong5; Dong, Yugang6; Guo, Xiaomei7; Huang, Kai8; Wang, Fang9; Huo, Yong1,∗; Ge, Junbo10,∗

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doi: 10.1097/CP9.0000000000000012
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Abstract

Introduction

Dyslipidemia includes hypercholesterolemia, hypertriglyceridemia, low high-density lipoproteinemia and mixed hyperlipidemia, among which, hypercholesterolemia is mainly manifested by increased low-density lipoprotein cholesterol. It is considered as the most important risk factor of atherosclerosis cardiovascular disease, including atherosclerotic cardiovascular disease (ASCVD), coronary heart disease, ischemic stroke, and peripheral artery disease[1]. Low-density lipoprotein cholesterol (LDL-C) is an independent risk factor for atherosclerosis and elevated levels of LDL-C significantly increase the risk of coronary heart disease. Each 30 mg/dL (0.8 mmol/L) increase is related to a 30% increase in the risk of coronary heart disease, and each 1 mmol/L reduction is related to a 20% elevation in cardiovascular disease (CVD) risk. Decreasing the LDL-C levels under 70 mg/dL (1.8 mmol/L) can effectively control the risk of cardiovascular events. Guidelines on blood lipid at home and abroad regard LDL-C as the preferred target, and the LDL-C goals also tend to be lower, requiring a reduction of 1.8 mmol/L or a reduction of ≥50%. The results of the second national survey of blood lipid treatment status in China showed that 61% of high-risk and 77% of very high-risk hypercholesterolemia patients did not reach the LDL-C target value[1,2].

Currently, the first-line drugs for lowering cholesterol and preventing atherosclerotic cardiovascular disease are statins, which reduce intracellular cholesterol synthesis by competitively inhibiting the rate-limiting enzyme in the process of cholesterol biosynthesis, and stimulate the increase in the number and activity of LDL receptors on the cell membrane surface to increase serum cholesterol clearance. These lead to a reduction in endogenous cholesterol levels. The “cholesterol escape” and the 6% decrease in LDL-C caused by doubling of statin dose, make it impossible to achieve lipid-lowering goals, however increase the incidence rate of adverse reactions, such as liver toxicity and myopathy[3]. Ezetimibe, the selective cholesterol absorption inhibitor when combined with statins has a dual inhibitory effect on cholesterol synthesis and absorption, and more effectively increases the cholesterol compliance rate. Combination of selective cholesterol absorption inhibitor and statins can reduce LDL-C levels more effectively, meanwhile, the combined therapy can significantly reduce total cholesterol (TC), non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (APO-B), and triacylglycerol (TG) levels, and significantly increase HDL-C and apolipoprotein A1 (APO-A1) levels[4,5]. Additionally, the combination therapy significantly alters the lipoprotein composition of patients with lipoproteinemia and lowers the cholesterol of residual granule-like lipoprotein particles than statin monotherapy, suggesting a stronger lipid-lowering effect. Moreover, the safety and patient tolerance are also greatly improved for combination therapy[6–8].

Hybutimibe, is a new type of lipid-lowering drug, obtained by breaking through the patent restrictions and modifying the structure on the basis of ezetimibe. Hybutimibe selectively inhibits cholesterol absorption by acting on the receptor of the cholesterol transporter NPC1L1 (Niemann-Pick C1-Like 1) on the surface of the intestine and liver cells. The novel structure of hybutimibe has never been listed globally. A randomized, double-blind, placebo-controlled, parallel-group, single-dose escalation phase I clinical study involving healthy participants in the United States and China showed that a single oral dose of 1–30 mg was safe and well-tolerated in healthy adults. Three dosages, 5, 10, and 20 mg of hybutimibe, are safe to be taken orally once daily by China and United States for 10 consecutive days, and the drugs were well tolerated. Pharmacokinetic data showed that the average maximum plasma concentration of hybutimibe and its active metabolite M1 increased proportionally as the dose of hybutimibe increased[9]. The State Food and Drug Administration (CFDA) (clinical batch number: 2014L00798/2014L00799) approved hybutimibe to undergo phase II and phase III clinical studies.

Therefore, to further evaluate the efficacy and safety of hybutimibe in the treatment of primary hypercholesterolemia, based on phase I clinical trial, a randomized, double-blind, double-simulation, multi-dose, and multi-center phase II clinical trial was designed. In the trial, with placebo and ezetimibe as comparators, three dosages of hybutimibe were included to explore its safety and efficacy which provides a basis for further phase III clinical trial.

Materials and methods

Study design and participants

This is a multi-center, randomized, double-blind, double-dummy, placebo and positive-drug controlled, multi-dosage, paralleled phase II study, to evaluate the efficacy and safety of hybutimibe in the treatment of hypercholesteremia. The protocol of the study was initiated by the investigators and reviewed by the ethics committees from 18 centers of China. The study complies with the relevant regulations and ethical requirements in the Declaration of Helsinki (as revised in 2013). The study was approved by Clinical Trial Ethics Committee of The First Hospital of Peking University [Ethic Review No. (2014) Drug Registration No. (30)] in August 19th 2014, and registered with the National Clinical Trial registry [NCT02087917 (March 14th 2014)]. All participants have signed informed consent forms.

From August 2014 to August 2015, a total of 244 patients with primary hypercholesterolemia from 15 centers were enrolled. The diagnostic criteria for patients with primary hypercholesterolemia referred to the 2007 guidelines for prevention and treatment of dyslipidemia in Chinese adults[10]: primary hypercholesterolemia, to undergo the diet control for at least 4 weeks, and the LDL-C levels ≥3.36 mmol/L (130 mg/dL) and ≤4.88 mmol/L (189 mg/dL); during the run-in feeding period, two LDL-C level measurement results remain stable and need to be within the range 3.36 mmol/L (130 mg/dL)–4.88 mmol/L (189 mg/dL), with an interval of at least 1 week, and the difference not >12% (the higher value is preferred); aged 18–70 years; without using other lipid-lowering medications within 6 weeks (including traditional Chinese medicines); able to understand and sign the informed consent form. According to the “2007 Guidelines for the Prevention and Treatment of Dyslipidemia in Chinese Adults,” we defined the lower limit of LDL levels ≥3.36 mmol/L (130 mg/dL)[10]. Considering including more high risk patients into this study, we used the upper limit refers to the 2013 American blood lipid guideline[11], which is 4.88 mmol/L, while for Chinese adults guideline it is 4.12 mmol/L. The exclusion criteria for the patients were homozygous familial hypercholesterolemia; severe heart, liver, lung, kidney, and other important organ diseases, such as kidney failure, lung cancer, and end-stage liver diseases; severe muscle abnormalities and neuropathy; serious endocrine disease that affects blood lipids or blood lipoproteins; history of ezetimibe intolerance; diabetes combined with hypertension patients with blood pressure ≥160/95 mm Hg; history of tumor within 5 years; any abnormality of the following laboratory tests: TG ≥ 3.99 mmol/L (350 mg/dL); fasting blood glucose ≥ 126 mg/dL (7.0 mmol/L); creatine kinase (CK)≥ 2 the upper limit of normal (ULN); AST, ALT (liver function) ≥1.5 times ULN; thyroid-stimulating hormone (TSH) is outside the normal range; creatinine exceeds ULN; with kidney injury, active liver disease, or unexplained elevated serum transaminase; participated in other clinical trials within 3 months before enrollment; or following conditions occurred before the screening: severe trauma or major surgery within 6 months before the study starts; severe cardiovascular events or surgery; pregnant, planning to become pregnant, or women taking oral contraceptives; patients allergic to the trial drugs or having other allergy histories which had effects on the study; positive for HCV, HIV, or hepatitis B surface antigen; under treatment of fabric acid derivatives, probucol, warfarin, systemic steroids, cyclosporine, or other immunosuppressive agents within 12 weeks before the study; other conditions inappropriate to this study.

Randomization and treatment

The identified patients, after a 4-week washout and run-in feeding period, were randomly assigned at a ratio of 1:1:1:1:1 to receive placebo ezetimibe, hybutimibe 5, 10, or 20 mg/day. All patients administered treatment drugs orally, once a day, four tablets each time, for eight consecutive weeks. To ensure the study was double-blind, the double-dummy technology was adopted; besides the assigned drugs, all patients also received three dummy agents whose dosage form, appearance, size, color, weight, etc. were exactly the same as those of treatment drugs. All study drugs, including hybutimibe and placebo drugs, were produced and provided by Zhejiang HISUN Pharmaceutical Co., Ltd.

The interactive web response system (IWRS) stratified block randomization with the stratified factors of age and gender. The serial numbers were sealed and stored by an independent third-party institute. The study drug and placebo were packaged in a blinded manner under the supervision of a biostatistician according to the drug's randomization number. During the entire study period, the participants, investigators, and research staff were blinded to the treatment group assignment until the end of the study.

Primary outcomes and assessments

The primary outcome was the changes calculated in LDL-C at week 8 from baseline (plasma LDL-C at week 8-LDL-C at baseline) and change rates calculated in LDL-C at week 8 from baseline LDL-C at week 8- LDL-C at baseline)/LDL-C at baseline. The secondary outcome included the change rates in LDL-C at weeks 1, 2, and 4 from baseline, and change rates in TC, TG, HDL-C, non-HDL-C, APO-B, APO-A1 levels at week 1, 2, 4, and 8 from baseline.

Baseline information includes demographic, medical history, the physical examination, lipid profile; dietary evaluation: diet score, the laboratory examination, clinical biochemistry, urine pregnancy test for women of childbearing age, serological screening, blood glucose, electrocardiogram, chest radiograph, concomitant medication, and so on.

The safety assessment, including adverse events (graded according to the 4.03 version of the NCI General Terminology Standard for Adverse Events), laboratory measurements, and other safety data, was done from the beginning of treatment to the end of treatment.

Statistical analysis

This is a phase II exploratory clinical trial. According to the data from previous clinical trials of Hybutimibe[9,12], considering the clinical difference of 10% in change rate between treatment groups and a dropout rate of 10%, a total of 244 patients were needed. Considering the ratio of patient number in five groups was 1:1:1:1:1 and the minimum number of 40 in each group was warranted.

Mean, standard deviation, median, minimum, and maximum were calculated for continuous variables; frequency and percentage for categorical variables were calculated. mITT, excluding patients without accepting any dose of treatment drugs and eliminating subjects with the minimum and reasonable method, was used for the analysis of primary outcome and used for comparison of the baseline characteristics. Paired t test was used to compare the change rates and changes in LDL-C after 8-week treatment and a two-factor analysis of variance was used for comparison among treatment groups.

The analysis of the secondary outcomes including change rates in LDL-C levels at week 1, 2, 4 from baseline and changes and change rates of LDL-C, TC, TG, non-HDL-C, HDL-C, APO-A1, and APO-B levels at weeks 1, 2, 4, and 8 from baseline was compared by paired t tests, and the comparison between treatment groups was performed by two-factor analysis of variance. Per-protocol set including patients compliant with the protocol was used as a supplementary analysis set of the primary outcomes. The missing values for the primary outcome were imputed by the last data carried forward. The missing values of baseline information and the secondary outcomes were not imputed, and the data obtained according to mITT were analyzed.

The safety evaluation included all patients receiving the study drug at least once. The present study calculated the number of adverse events and severity of adverse events, adverse events leading to withdrawal from the study, adverse events leading to death, and serious adverse events.

All statistical analyses were conducted by using SAS software (version 9.2; SAS Institute), and the two-side test with a P value <0.05 is considered statistically significant.

Results

Patients

A total of 244 patients with primary hypercholesterolemia were included and randomized (Figure 1). Among them, 2 patients (1 from placebo and 1 from hybutimibe 10 mg/day) did not receive any treatment drug, and 242 patients were included in the mITT. After treatment, 12 patients were dropout (4.92%), 7 patients excluded (2 did not meet the inclusion criteria, 2 without measurements of primary outcome, 2 used the contraindicated drugs, and 1 with poor compliance) from the study (2.87%), and finally 225 patients were included into the per-protocol (PP) dataset. Two hundred and forty-two patients administrating at least one dose of treatment drugs were included in the safety analysis.

F1
Figure 1:
CONSORT diagram for participant inclusion.

Two hundred and forty-four patients with an average age of 54 years (±1.28) and 70.66% of women were randomized. The patients in five groups were comparable in demographic, medical history, physical examination, and laboratory tests (P > 0.05) (Table 1). The baseline blood lipid profiles, including TC, TG, HDL-C, non-HDL-C, LDL-C, APO-A1, and APO-B in five groups were comparable (P > 0.05).

Table 1 - Baseline characteristics of the intention-to-treat population
Characteristics Placebo(n = 48) Ezetimibe (n = 45) Hybutimibe 20 mg/day (n = 51) Hybutimibe 10 mg/day (n = 48) Hybutimibe 5 mg/day (n = 50) P
Sex
 Males 16 (33.33) 15 (33.33) 16 (31.37) 11 (22.92) 13 (26.00) 0.7313
 Females 32 (66.67) 30 (66.67) 35 (68.63) 37 (77.08) 37 (74.00)
Age (year) 53.13 ± 10.25 53.33 ± 10.16 53.49 ± 10.61 56.27 ± 8.24 54.20 ± 8.16 0.4807
BMI (kg/m2) 24.45 ± 3.06 25.07 ± 2.77 24.93 ± 3.25 24.86 ± 3.34 24.72 ± 3.68 0.9124
Disease history
 Allergic history 4 (8.33) 6 (13.33) 10 (19.61) 7 (14.58) 9 (18.00) 0.5504
 History of surgery 21 (43.75) 20 (44.44) 18 (35.29) 14 (29.17) 22 (44.00) 0.4353
 Medication use 18 (37.50) 18 (40.00) 13 (26.00) 10 (21.74) 14 (28.57) 0.2705
Vital signs
 SBP (mm Hg) 122.31 ± 11.21 123.20 ± 11.05 121.16 ± 12.11 122.71 ± 10.42 123.36 ± 11.82 0.8779
 DBP (mm Hg) 77.90 ± 6.26 76.93 ± 7.44 76.37 ± 7.90 77.50 ± 7.08 77.30 ± 7.89 0.8736
 Heart rate (/min) 71.25 ± 8.20 72.44 ± 6.88 72.10 ± 6.76 73.08 ± 7.87 73.22 ± 7.83 0.7013
 Respiratory (/min) 18.06 ± 2.36 18.31 ± 2.20 17.96 ± 2.15 18.02 ± 2.47 17.84 ± 2.08 0.8924
 Temperature (°C) 36.41 ± 0.27 36.36 ± 0.31 36.35 ± 0.37 36.39 ± 0.25 36.38 ± 0.33 0.8613
Lipid profiles
 TCH (mmol/L) 6.50 ± 0.61 6.61 ± 0.55 6.48 ± 0.54 6.58 ± 0.54 6.61 ± 0.55 0.6677
 TG (mmol/L) 1.66 ± 0.67 1.94 ± 0.91 1.71 ± 0.62 1.59 ± 0.64 1.81 ± 0.75 0.1714
 HDL-C (mmol/L) 1.34 ± 0.27 1.29 ± 0.21 1.30 ± 0.18 1.38 ± 0.28 1.32 ± 0.25 0.4256
 Non-HDL-C (mmol/L) 5.16 ± 0.54 5.32 ± 0.51 5.18 ± 0.53 5.20 ± 0.49 5.30 ± 0.52 0.4519
LDL-C (mmol/L) 3.87 ± 0.33 4.01 ± 0.32 3.92 ± 0.38 3.99 ± 0.39 4.00 ± 0.39 0.2364
 APO-A1 (g/L) 1.36 ± 0.17 1.37 ± 0.15 1.35 ± 0.14 1.38 ± 0.16 1.36 ± 0.16 0.9565
 APO-B (g/L) 1.23 ± 0.12 1.26 ± 0.10 1.22 ± 0.13 1.24 ± 0.12 1.26 ± 0.12 0.5080
APO-A1: apo lipoprotein A-I; APO-B: apo lipoprotein B; BMI: body mass index; DBP: diastolic blood pressure; HDL-C: high density lipid cholesterol; SBP: systolic blood pressure; TCH: total cholesterol; TG: triglyceride.
Defined as those patients who had a surgery of coronary artery bypass, angioplasty, surgery for acute coronary syndrome and cerebrovascular accident, and other severe trauma or major surgery within 6 months before they enter into this study.
Referred to the drug use history within 6 weeks before enrollment but not the medications listed in the exclusion criteria.

Efficacy

After 8 weeks’ treatment, the LDL-C levels of patients receiving ezetimibe and hybutimibe (in mITT) were significantly reduced, compared with baseline (all P values < 0.05) (Table 2). Among them, the average change rate of LDL-C in the ezetimibe group was −20.01% for ezetimibe, −10.84% (95% CI: −14.67, −7.00) for hybutimibe 5 mg/day, −17.06% (95% CI: −20.83, −13.29) for hybutimibe 10 mg/day, and −17.04% (95% CI: −20.30, −13.79) for hybutimibe 20 mg/day change, respectively. Post hoc analyses showed that when compared with the placebo group, the LDL-C of patients in ezetimibe and three hybutimibe groups were significantly improved (all P values <0.05); the change rates of LDL-C in patients who received the 20 and 10 mg/day of hybutimibe were similar with those patients receiving ezetimibe (all P > 0.05), whereas the improvement rate of the 5 mg/day of hybutimibe was significantly lower (P < 0.05) (Figure 2). The results from per-protocol set were consistent with mITT.

Table 2 - LDL-C change rates of five treatment groups at 8 weeks from the baseline in the mITT set and PPS
Modified ITT Placebo(n = 48) Ezetimibe (n = 45) Hybutimibe 5 mg/day (n = 50) Hybutimibe 10 mg/day (n = 48) Hybutimibe 20 mg/day (n = 51)
Change rate (95% CI) −1.69 (−4.83, 1.45) −20.01 (−24.26, −15.76) −10.84 (−14.67, −7.00) −17.06 (−20.83, −13.29) −17.04 (−20.30, −13.79)
vs. baseline (P value) 0.2847 < 0.0001 < 0.0001 < 0.0001 < 0.0001
vs. placebo (P value) ≤ 0.05 ≤ 0.05 ≤ 0.05 ≤ 0.05
vs. Ezetimibe (P value) ≤ 0.05 ≤ 0.05 > 0.05 > 0.05
PPS Placebo(n = 47) Ezetimibe(n = 42) Hybutimibe5 mg/day (n = 46) Hybutimibe10 mg/day (n = 44) Hybutimibe20 mg/day (n = 46)
Change rate (95% CI) −1.76 (−4.97, 1.44) −19.32 (−23.50, −15.14) −10.82 (−14.91, −6.74) −17.4 (−21.41, −13.42) −17.99 (−21.32, −14.66)
8 weeks vs. baseline (P value) 0.2740 < 0.0001 < 0.0001 < 0.0001 < 0.0001
Other groups vs. placebo (P value) ≤ 0.05 ≤ 0.05 ≤ 0.05 ≤ 0.05
Other groups vs. Ezetimibe (P value) ≤ 0.05 ≤ 0.05 > 0.05 > 0.05
CI: confidence interval; LDL-C: low-density lipoprotein cholesterol; mITT: modified intention to treat; PPS: per-protocol set.

F2
Figure 2:
Circulating LDL-C change rate in patients with primary hypercholesterolemia after oral treatment drugs for consecutive 8 weeks in modified intention-to-treat dataset.

Compared with baseline, both ezetimibe and hybutimibe significantly improved TC, non-HDL-C, and APO-B at weeks 1, 2, 4, and 8 in both mITT and PP populations (all P < 0.05). The change rates of the above lipid profiles at weeks 1, 2, 4, and 8 in both ezetimibe and hybutimibe treatment groups were significantly higher than placebo (all P values <0.05) (Figure 3). Meanwhile, the efficacy of 20 mg/day hybutimibe was comparable to ezetimibe. By the end of week 8, there were no significant differences in HDL-C, TG, and APO-I in all groups (all P > 0.05). After 4 weeks’ treatment with 20 and 10 mg/day of hybutimibe, the lipid profile was significantly improved than those with 5 mg/day of hybutimibe. However, compared with baseline, the decrease and improvement rates of TG were not statistically significant at each time (all P > 0.05); the decrease levels of TG and improvement rate in both ezetimibe and hybutimibe groups were not significantly higher than those with placebo (all P > 0.05), and the results were consistent in mITT and per-protocol set population.

F3
Figure 3:
TC, TG, HDL-C, non-HDL-C, APO-A1, and APO-B change rates in patients with primary hypercholesterolemia after 8 consecutive weeks of treatment in mITT population.

Safety

Among 242 patients with at least one dose of treatment drugs, 25 patients reported a total of 75 adverse events, accounting for 10.33% of all patients. The primary adverse events were elevated ALT/AST, abnormalities in multi-lead ST-T, abdominal pain, bloating, diarrhea, constipation, poor bowel movements or decreased excretion, vertigo, fatigue, muscle aches, skin rash, hives, dizziness, headache, and gastrointestinal discomfort; among them, the incidence of diarrhea in the placebo group alone was 6.25%, and the incidence of other adverse events was <5% in each group. Most of the adverse events were grade 1 (n = 71), only 4 were grade 2. One grade 3 atrial flutters occurred in the hybutimibe 5 mg/day group, occurring 1 hour after the medication, which was defined as non-relating with hybutimibe (Table 3).

Table 3 - Adverse events reported in five treatment groups during the study period in safety set
Adverse events Placebo(n = 48) Ezetimibe (n = 45) Hybutimibe 5 mg/day (n = 50) Hybutimibe 10 mg/day (n = 48) Hybutimibe 20 mg/day (n = 51)
Live function 1
Elevated ALT 1 2 1
Elevated AST 1
ECG changes 1
Stomachache 1 2 2
Abdominal bloating 1 1 1
Diarrhea 3 1
Constipation 1 2
Decreases of stool volume 1
Dizzy 1
Fatigue 1
Myalgia 1
Rash 1 1
Dizziness, headache 1 1 1
Gastrointestinal discomfort 1 1
Total 9 5 6 8 5
Number of adverse events 12 14 19 16 14
Patients number with adverse events 6 4 5 6 4
ALT: alanine aminotransferase; AST: aspartate aminotransferase; ECG: electrocardiogram. Elevated ALT and AST: the ALT and AST levels were higher than three times of the upper limits of the reference values.

There were six adverse events requiring discontinuation of the study drugs: three in the placebo group, one for stomachache, one for fever, one for low back pain; two in the hybutimibe 5 mg/day group, one for frequent urination and decrease in urine output and one for atrial flutter; one pruritus in hybutimibe 20 mg/day group. There was no significant difference in the incidence of various adverse reactions in five groups.

Discussion

This randomized, double-blind, double-dummy, multi-center phase II study showed that hybutimibe 5, 10, and 20 mg/day effectively reduced the LDL-C levels of patients with primary hypercholesterolemia, and also had benefits on other blood lipid profiles, such as TC, non-HDL-C, and APO-B. The adverse effects were also well tolerable.

The same target drug, ezetimibe, can be used for the treatment of primary hypercholesterolemia, homozygous familial hypercholesterolemia, and homozygous sitosterolemia. According to the Guidelines for Clinical Research of Drugs for Treatment of Lipid Metabolism Disorders, LDL-C reduction as the primary endpoint in patients with primary hypercholesterolemia can support the indications of hypercholesterolemia or mixed hyperlipidemia Additionally, considering that this is a phase II exploratory clinical study and the incidence rate of primary hypercholesterolemia, homozygous familial hypercholesterolemia is low, the primary hypercholesterolemia was selected as an indication for this study. This phase II study aimed to explore the dosage of hybutimibe, so according to the Guidelines, a randomized, placebo-controlled, and double-blind study should be conducted. The lipid-lowering efficacy of hybutimibe at different dosages were compared with the positive comparator, ezetimibe, which has come to market in China. Moreover, in mechanism, hybutimibe is a new selective intestinal cholesterol absorption inhibitor, which reduces the absorption of cholesterol, plant sterols, and the reabsorption of bile cholesterol by inhibiting the cholesterol absorption protein NPCILI of intestinal epithelial cells, thereby reducing plasma cholesterol levels. The structure and mechanism of hybutimibe are similar to those of ezetimibe approved by the U.S. FDA in 2002. Therefore, it is relatively reasonable in mechanism and structure to use ezetimibe as a positive control drug.

After 8 weeks of treatment, the LDL-C levels of patients in hybutimibe (20, 10, and 5 mg/day) groups were reduced by 17.99%, 17.42%, and 10.82%, compared with the placebo group and there was a non-significant difference in the LDL-C reduction of two high dosage groups and ezetimibe group. Compared with placebo, hybutimibe significantly improved the TC, non-HDL-C, and APO-B at weeks 1, 2, and 4, presenting a very similar efficacy with ezetimibe. However, non-significant effects on TG, HDL-C, and APO-A1 benefits were observed. Our results reconfirmed the conclusions of the previous phase I study. Consistent with the results from the phase II study of ezetimibe, after 8 weeks of treatment, the LDL-C levels in 20, 10, and 5 mg/day of hybutimibe were reduced by 17.99%, 17.42%, 10.82%, respectively, compared with that in placebo. Additionally, we also found that LDL-C reduction by hybutimibe 10 and 20 mg/day were similar with ezetimibe, suggesting that 20 mg/day might be a potential benefits dosage of hybutimibe for LDL-C. Compared with enzetimibe, hybutimibe have several characteristics. Hybutimibe absorbs and reaches its peak more quickly than enzetimibe, and the fastest time of peak plasma concentration was 0.5 h after taking the drug, while it is 4 h for ezetimibe[9]. The binding rate of hybutimibe glucuronic acid conjugate with plasma protein is 94.5%, which is significantly higher than that of ezetimibe (88–92%), showing the stable plasma concentrations of hybutimibe in human body[9,12]. Also, the overall clearance rate of hybutimibe was 93%, which was higher than that of enzetimibe, which was 89%[9,13].

Our findings suggested that hybutimibe is relatively safe with low-grade adverse events. Most patients with adverse events could recover on their own without any treatment, and only a small number of adverse events could recover after stopping the study drug, combined with other drugs, or non-drug treatment to recover. The incidence of adverse events in the hybutimibe groups did not increase as the dosages increased. The more common adverse effects of hybutimibe were ALT elevation, gastrointestinal reaction, dizziness, and headache. The adverse effects that may be related to hybutimibe were not severe and can recover on their own without treatment. Compared with the adverse effects of ezetimibe, the frequency and extent of adverse effects of hybutimibe were generally the same, and no new adverse effects occurred[14,15]. Common adverse effects of ezetimibe include upper respiratory tract infection (9%), headache (8%), back pain (5%), skeletal muscle pain (5%), arthralgia (4%), 95% of which are mild and moderate; and the incidence of adverse effects of ezetimibe was similar with that of placebo. That creatine kinase and liver enzymes increased by more than three times the upper limit of the normal range are only seen in a very small number of patients[15], and the tolerance of patients were well accepted. Adverse effects such as creatine kinase, myalgia, transaminase, and drug allergic reactions have not been reported in our study, and need to be continuously observed in a further large-scaled phase III study.

This study has several limitations. First, the sample size is relatively small, which is less potent to detect the differences in multiple groups. Second, because of the limitation of sample size, the subgroup analyses were not performed and the possible efficacy and safety of hybutimibe in different subpopulations were not explored. Third, all the participants were Chinese, there may be restrictions when extending our conclusion to other populations. Finally, the efficacy and safety of hybutimibe in the treatment of primary hypercholesterolemia still need to be further confirmed by a large-scale phase III study.

Our randomized double-blind, double-dummy, multi-dosage, and multi-center phase II clinical trial study found that three dosages of hybutimibe effectively reduced LDL-C levels in patients with primary hyperlipidemia. TC, non-HDL-C, and APO-B levels were also significantly improved; however, hybutimibe has non-significant effects on TG, APO-A1, and HDL-C. Overall, the efficacy of 20 mg/day of hybutimibe was very similar to that of ezetimibe. In the meantime, hybutimibe were safe, and no serious adverse reactions occurred. The application of hybutimibe in the treatment of primary hypercholesterolemia needs to be further confirmed its effectiveness and safety by a phase III clinical trial with larger sample size.

Funding

This study was supported by National Science and Technology major projects- new drugs creation and development [grant number No. 2013ZX09402101].

Author contributions

LQ contributed to concept and design of the study. SZ, JC, and MZ contributed to acquisition of data. XL, YD, and XG contributed to statistical analysis. KH and FW contributed to analysis and interpretation of data. YH contributed to drafting of the manuscript. JG contributed to revising of the manuscript. The manuscript was reviewed and approved by all authors. The requirements for authorship have been met. Each author attests to the integrity of the work.

Conflict of interest statement

Yong Huo and Junbo Ge are the Editorial Board members of Cardiology Plus. The article was subject to the journal's standard procedures, with peer review handled independently of this Editorial Board member and their research groups.

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Keywords:

APO-B; Hybutimibe; Hypercholesterolemia; LDL-C

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