Retrospective Analysis Of Elevation Rates Of Transaminases And Triglyceride In 20 Phase Ⅰ Clinical Trials

Objectives:Assess the elevation rates of transaminases and triglyceride in healthy subjects treated with placebo and experimental drugs in phase I clinical trials.And discuss the correlation between the elevations rate and baseline characteristics(body mass index,sex,age and fatty liver),baseline value,length of hospitalization days,activity and other risk factors.Provide theoretical basis for the analysis of causes of the elevations of transaminases and triglyceride caused by drug-related or non-drug-related factors.Methods:A retrospective analysis was used for the data from 20 randomized and placebo-controlled trials of phase I clinical trial laboratory in The First Hospital of Jilin University.In the meta-analysis of 20 placebo-controlled trials,we calculated the rate of elevations of aspartate aminotransferase(AST)、alanine aminotransferase(ALT)and triglyceride(TG)bounded by the upper limit of the normal value(ULN)in placebo treatment.Statistical tests were used to compare those with significant changes of ALT,AST and TG during the experimental drugs therapy.The chi-square test is performed for the elevation rates of transaminases and triglyceride in experimental drugs treatment and placebo treatment.Correlation analysis between baseline values 、 length of hospitalization days、activity、body mass index(BMI),sex,age,fatty liver were normal after treatment and those elevated after treatment,such as chi-square、independent-sample T test and logistic regression analysis.ROC test was used to predict the abnormal cut off value of AST、ALT and TG baseline levels of placebo group.In the study,all adverse events were classified strictly accordance with CTCAE 4.03.SAS 9.4 is used for statistical analysis.Results:(1)There are 1029 healthy subjects were included in this study from 20 phase I clinical trials.No physical activity requirements in the process of hospitalization for 12 trials,and the other 8 trials required the subjects 1-3hours of walking activities in groups every day.The length of hospitalization days varied from 3 to 25 days.There were no significant differences in height,weight,other demographic characteristics,baseline clinical data such as transaminases and triglycerides,except for the weak statistical differences in age(P=0.04)between the placebo group and the experimental drug group.Except for baseline level of TG(P=0.01),there were no significant differences in height,weight,demographic characteristics,baseline clinical data such as transaminase between the physically activity and non-physically activity subjects.(2)In this study,all abnormal increases of AST,ALT and TG were mild and adaptive,and all slowly returned to baseline without drug intervention.(3)The elevation rates of AST,ALT and TG were 1.41% vs 3.27%(P =0.23),4.93% vs 6.31%(P = 0.53),28.57% vs 34.37%(P = 0.18)in placebo group and experimental drug group.We divided the highest detection values of AST,ALT and TG into [1ULN,2ULN),[2ULN,3ULN)and ≥ 3ULN,and then conduct statistical analysis.There were no statistical differences between the placebo group and the experimental drug group in the highest levels of AST,ALT and TG.(4)Elevation rates of AST,ALT and TG were significantly correlated with their own baseline levels,length of hospitalization days and gender(P<0.05);Elevation rates of AST and ALT were significantly correlated with physical activity of hospitalization(P<0.05);And elevation rates of TG were significantly correlated with baseline BMI(P<0.05).In other words,the higher the baseline level,the longer the hospitalization days,the male subjects,the physical activity during hospitalization(AST,ALT risk factors),and the higher the baseline BMI(TG risk factors),the more likely the subjects were to have the abnormal increase in above indicators.(5)The cut off values of AST,ALT and TG in the total and placebo groups were 25.55U/L VS 31.5U/L,20.75 U/L VS 30.2 U/L,and 1.08 mmol/L VS 1.35 mmol/L,respectively.The overall level of ROC tests for AST(P<0.001),ALT(P<0.002)and TG(P<0.003)were statistical significance.But only ALT(P=0.02)and TG(P=0.00)were statistical significance in the placebo group.Conclusions:(1)The elevation rates of AST,ALT and TG in the placebo control group are slightly lower than that in the experimental drugs group,but there is no significant statistical differences.The elevation of abnormal indicators after treatment in most Phase Ⅰ clinical trials may not be caused by adverse reactions of experimental drugs.(2)The Phase Ⅰ clinical trial effects exist indeed.The occurrence of this effect is related to various factors,including baseline level,length of hospitalization days,gender,Physical activity,etc.(3)Safety results from phase I clinical trials should be interpreted cautiously.Reducing the elevation of transaminases by controlling interferingfactors,which will help provide a context for interpretation of safety judgment in early phase clinical trials.