[Efficacy and safety of various doses of hybutimibe monotherapy or in combination with atorvastatin for primary hypercholesterolemia: a multicenter, randomized, double-blind, double-dummy, parallel-controlled phase Ⅲ clinical trial].

Objective: To evaluate the efficacy and safety of hybutimibe monotherapy or in combination with atorvastatin in the treatment of primary hypercholesterolemia. Methods: This was a multicenter, randomized, double-blind, double-dummy, parallel-controlled phase Ⅲ clinical trial of patients with untreated primary hypercholesterolemia from 41 centers in China between August 2015 and April 2019. Patients were randomly assigned, at a ratio of 1∶1∶1∶1∶1∶1, to the atorvastatin 10 mg group (group A), hybutimibe 20 mg group (group B), hybutimibe 20 mg plus atorvastatin 10 mg group (group C), hybutimibe 10 mg group (group D), hybutimibe 10 mg plus atorvastatin 10 mg group (group E), and placebo group (group F). After a dietary run-in period for at least 4 weeks, all patients were administered orally once a day according to their groups. The treatment period was 12 weeks after the first dose of the study drug, and efficacy and safety were evaluated at weeks 2, 4, 8, and 12. After the treatment period, patients voluntarily entered the long-term safety evaluation period and continued the assigned treatment (those in group F were randomly assigned to group B or D), with 40 weeks' observation. The primary endpoint was the percent change in low density lipoprotein cholesterol (LDL-C) from baseline at week 12. Secondary endpoints included the percent changes in high density lipoprotein cholesterol (HDL-C), triglyceride (TG), apolipoprotein B (Apo B) at week 12 and changes of the four above-mentioned lipid indicators at weeks 18, 24, 38, and 52. Safety was evaluated during the whole treatment period. Results: Totally, 727 patients were included in the treatment period with a mean age of (55.0±9.3) years old, including 253 males. No statistical differences were observed among the groups in demographics, comorbidities, and baseline blood lipid levels. At week 12, the percent changes in LDL-C were significantly different among groups A to F (all P<0.01). Compared to atorvastatin alone, hybutimibe combined with atorvastatin could further improve LDL-C, TG, and Apo B (all P<0.05). Furthermore, there was no significant difference in percent changes in LDL-C at week 12 between group C and group E (P=0.991 7). During the long-term evaluation period, there were intergroup statistical differences in changes of LDL-C, TG and Apo B at 18, 24, 38, and 52 weeks from baseline among the statins group (group A), hybutimibe group (groups B, D, and F), and combination group (groups C and E) (all P<0.01), with the best effect observed in the combination group. The incidence of adverse events was 64.2% in the statins group, 61.7% in the hybutimibe group, and 71.0% in the combination group during the long-term evaluation period. No treatment-related serious adverse events or adverse events leading to death occurred during the 52-week study period. Conclusions: Hybutimibe combined with atorvastatin showed confirmatory efficacy in patients with untreated primary hypercholesterolemia, which could further enhance the efficacy on the basis of atorvastatin monotherapy, with a good overall safety profile.目的： 评估海博麦布单药或联合阿托伐他汀治疗原发性高胆固醇血症的疗效及安全性。 方法： 本研究为多中心、随机、双盲、双模拟、平行对照Ⅲ期临床试验，于2015年8月至2019年4月纳入全国41个中心初次接受治疗的原发性高胆固醇血症患者，以1∶1∶1∶1∶1∶1的比例随机分配至阿托伐他汀10 mg组（A组）、海博麦布20 mg组（B组）、海博麦布20 mg+阿托伐他汀10 mg组（C组）、海博麦布10 mg组（D组）、海博麦布10 mg+阿托伐他汀10 mg组（E组）和安慰剂组（F组）。所有患者经4周膳食导入期后，均按1次/d口服对应药物。用药后12周内为治疗期，第2、4、8和12周评价其疗效和安全性。治疗期后，患者自愿进入40周的长期安全性评价期（长评期），继续服用相应组别药物（F组随机分配至B组或D组）。主要疗效指标为低密度脂蛋白胆固醇（LDL-C）第12周较基线的变化率，次要疗效指标包括高密度脂蛋白胆固醇（HDL-C）、甘油三酯（TG）和载脂蛋白B（Apo B）在12周的变化率以及上述4个血脂指标水平在第18、24、38和52周的变化。同时，评价在整个治疗过程中的药物安全性。 结果： 治疗期纳入727例患者，年龄（55.0±9.3）岁，男性253例。A至F组各组间人口学情况、合并症和血脂基线差异均无统计学意义。第12周A至F组的LDL-C较基线变化率的差异均具有统计学意义（P均<0.01）。海博麦布联合阿托伐他汀相比单用他汀可进一步降低患者的LDL-C、TG和Apo B水平（P均<0.05）。此外，C组与E组第12周LDL-C较基线变化率的差异无统计学意义（P=0.991 7）。长评期他汀组（A组）、海博麦布组（B组、D组和F组）和联合组（C组和E组）在第18、24、38和52周的LDL-C、TG和Apo B变化率组间差异有统计学意义（P均<0.01），且联合组更具治疗优势。长评期不良事件发生率为他汀组64.2%，海博麦布组61.7%，联合组71.0%，52周内未发生与药物有关的严重不良反应或导致死亡的不良事件。 结论： 海博麦布联合阿托伐他汀治疗原发性高胆固醇血症降低LDL-C疗效确切，可在他汀单药治疗基础上进一步提升疗效，并且总体安全性良好。.