通化东宝利拉鲁肽注射液对比诺和力^(®)治疗2型糖尿病的有效性及安全性研究:一项多中心、随机、开放、平行对照、Ⅲ期临床研究

Efficacy and safety of Tonghua Dongbao liraglutide injection versus Victoza in the treatment of type 2 diabetes mellitus:a multicenter,randomized,open,parallel controlled,phaseⅢclinical study

目的探讨通化东宝利拉鲁肽注射液(统博力)对比诺和力^(®)治疗2型糖尿病(T2DM)的有效性及安全性。方法为多中心、随机、开放、平行、阳性药物对照的Ⅲ期临床研究,等效设计。纳入2019年4月19日至2021年3月19日来自国内39家研究中心的应用二甲双胍、磺脲类药物或两者联合治疗均血糖控制不佳的T2DM患者为受试者,根据研究前口服降糖药治疗分层,按照1∶1的比例采用分层区组随机将其随机分配至统博力组和诺和力^(®)组。治疗26周后,比较两组受试者治疗前后糖化血红蛋白(HbA_(1c))、FPG、7点自测血糖的变化、低血糖事件和不良事件发生率、抗药物抗体(ADA)的发生率。有效性指标分析采用修订的意向性治疗(mITT)人群和符合方案集(PPS),安全性分析采用安全性数据集(SS)。采用配对t检验比较治疗前后相应指标的差异,采用独立样本t检验、Wilcoxon秩和检验、χ^(2)检验或Fisher精确检验进行组间比较,采用重复测量混合效应模型(MMRM)分别比较两组受试者第26周HbA_(1c)、FPG、7点自测血糖相对其基线变化的差异。采用Cochran-Mantel-Haenzel检验比较两组第26周时HbA_(1c)<7%的比例,并计算两组率差的95%CI。采用Pearsonχ2检验比较两组间治疗期间的不良事件(TEAE)、低血糖事件、ADA的发生率。结果共524例受试者随机入组,共482例受试者完成研究(统博力组243例,诺和力^(®)组239例)。所有524例受试者均被纳入mITT人群,434例受试者被纳入PPS,262例患者纳入SS。经过26周的治疗,统博力组和诺和力^(®)组受试者的HbA_(1c)分别下降1.640%±1.011%和1.620%±1.106%,两组间变化值的最小二乘均值之差(95%CI)为0(-0.18%~0.18%),差异在±0.4%的预定范围内,认为统博力与诺和力^(®)等效。两组第26周FPG分别下降(2.137±2.489)mmol/L和(2.004±2.331)mmol/L,两组间变化值的最小二乘均值之差(95%CI)为0.080(-0.280~0.439)mmol/L,差异无统计学意义(P=0.663)。两组分别有49.6%(130/262)和50.8%(133/262)的受试者达到了HbA_(1c)<7%的目标,两组间HbA_(1c)<7%比例的率差(95%CI)为-0.01%(-0.10%~0.07%,P=0.801)。两组TEAE的发生率分别为82.1%(215/262)和79.0%(207/262),差异无统计学意义(χ^(2)=0.78,P=0.377),两组低血糖事件和ADA的发生率差异均无统计学意义(P>0.05)。结论统博力和诺和力^(®)控制血糖的总体疗效相当,具有良好的安全性,在临床上有应用价值。

Objective To explore the efficacy and safety of Tonghua Dongbao(TD)liraglutide injection(Tongboli)versus Victoza in the treatment of type 2 diabetes mellitus(T2DM).Methods This was a multicenter,randomized,open-label,parallel,positive drug controlled phaseⅢclinical study with an equivalent design.Patients with T2DM who received metformin,sulfonylureas or a combination of metformin and sulfonylureas from 39 research centres in China from April 19,2019 to March 19,2021 were included.They were randomly assigned to TD liraglutide(Tongboli)group and Victoza group according to the ratio of 1∶1.After 26 weeks of treatment,the changes of glycated hemoglobin A_(1c)(HbA_(1c)),venous fasting plasma glucose(FPG),7-point self-monitored blood glucose,incidence of hypoglycemic events and adverse events,and the incidence of anti-drug antibody(ADA)were compared between the two groups before and after treatment.The modified intention-to-treat(mITT)population and per protocol set(PPS)were used for efficacy index analysis,and the safety data set(SS)was used for safety analysis.Paired t-test was used to compare the differences in the respective before and after treatment indicatiors.Independent sample t-test,Wilcoxon rank sum test,χ^(2) test or Fisher exact test were used to compare the differences between groups.Repeated-measures mixed-effect model(MMRM)was used to compare the changes in HbA_(1c),FPG and 7-point self-monitored blood glucose from baseline at the 26th week.The Cochran-Mantel-Haenzel test was used to compare the proportions of HbA_(1c)<7%in the two groups at the 26th week,and the 95%CI of the rate difference between the two groups was calculated.Pearsonχ^(2) test was used to compare the incidence of treatment emergency adverse event(TEAE),hypoglycemic events and ADA between the two groups during treatment.Results A total of 524 subjects were randomly enrolled and 482 subjects completed the study cases in the Tongboli group(n=243)and Victoza group(n=239).All 524 subjects were included in the mITT population,434 subjects were included in PPS,and 262 patients were included in SS.After 26 weeks of treatment,the HbA_(1c)of the two groups decreased by 1.640%±1.011%and 1.620%±1.106%in Tongboli group and Victoza,respectively.The difference in the least squares mean(95%CI)between the two groups was 0(-0.18%-0.18%),and the difference was within the predetermined range of±0.4%.Tongboli and Victoza can be considered equivalent.At the 26th week,FPG decreased by(2.137±2.489)mmol/L and(2.004±2.331)mmol/L in the two groups,respectively.The difference in the least squares mean value(95%CI)between the two groups was 0.080(-0.280-0.439)mmol/L,which was not statistically significant(P=0.663).There were 49.6%(130/262)and 50.8%(133/262)subjects in the two groups who achieved the target of HbA_(1c)<7%,respectively.The difference in the rate(95%CI)between the two groups was-0.01%(-0.10%-0.07%,P=0.801).The incidence of TEAE in the two groups was 82.1%(215/262)and 79.0%(207/262),respectively,with no significant difference(χ^(2)=0.78,P=0.377).There was no significant difference in the incidence of hypoglycemic events and ADA between the two groups(P>0.05).ConclusionThe overall therapeutic effect of Tongboli and Victoza in controlling blood glucose is comparable,with good safety and clinical application value.