Prolonged Intravenous Infusion of β-lactam Antibiotics in Early Septic Patients
Phase: NA
Conditions: Sepsis
Sponsor: Qilu Hospital of Shandong University

 
 
 
 
 
 
Official title: Prolonged Intravenous Infusion of β-lactam Antibiotics in Early Septic Patients 
(PROBES) 
NCT number: NCT ID not yet assigned 
Document date:21/8/2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Study protocol: 
(1) Experimental: prolonged intravenous infusion of β-lactams Antibiotics 
Administer according to the PK/PD optimized regimen with the goal of increasing T>MIC. (1) 
Carbapenems: Calculate the daily dose according to the creatinine clearance rate and divide it into 
3 times. Each time, the dose is injected intravenously at 1/2 dose for 15 minutes, and the 
remaining 1/2 dose is injected at a constant rate for 3 hours. (2) Cephalosporins: calculate the 
allowable daily dose according to the creatinine clearance rate, inject at a uniform rate within 24 
hours. (3) β-lactams and β-lactamase inhibitor compound: the daily dose is calculated according to 
the creatinine clearance rate and injected at a uniform rate within 24 hours. 
(2) No Intervention: short-term intravenous infusion of β-lactams Antibiotics: 
The daily allowable dose is calculated according to the creatinine clearance rate. The 
carbapenems, cephalosporins and β-lactamase inhibitor compound preparations are administered 
in accordance with the dosage and usage required by the instructions, and the injection is 
generally 30 minutes. 
Timetable： 
Each research center is divided into 3 research phases, and the first 4 weeks of each research 
phase is the wash-out period. 12 weeks is a research phase, and they are randomly assigned to the 
participating centers of the prolonged intravenous infusion of β-lactams Antibiotics group. All 
infected patients admitted after the start of the research phase are subjected to a prolonged 
intravenous infusion of β-lactams Antibiotics regimen; and the other centers randomly assigned to 
enter the short-term intravenous infusion group. The participating centers will implement a routine 
30-minute infusion program for all infected patients admitted after the start of the research phase. 
After the 12-week study period and a 4-week wash-out period is over, the newly admitted cases 
will be administered according to the method of the next study period. After the 4-week wash-out 
period is over, it enters the second research phase. In the second research phase, each participating 
center automatically crosses into another program group, that is, the unit that executes the 
prolonged intravenous infusion of β-lactams Antibiotics program in the first phase automatically 
executes the conventional short-term intravenous infusion program, and vice versa. The 
participation period of each center is at least one year, in order to cover the difference in the 
incidence of different pathogenic infections in different seasons throughout the year. 

Patients who had been admitted to the hospital and started taking medication before the start of this 
study were still taking medication according to the original schedule during the washout period and 
were not included in this study. The dosing regimen of all enrolled cases is based on the group of 
the research center on the day of enrollment, and the regimen must be strictly implemented until the 
end of the treatment, regardless of whether the antibiotic treatment of the case crosses the research 
phase. The researcher should ensure the completeness and authenticity of the research data record. 
 
Statistical analysis plan: 
(1) 
Statistical software: All statistical analysis is mainly conducted by SAS 9.4 and R 3.6.0. 
(2) 
 
1) Full analysis set (FAS): includes cases that have been randomly assigned to the group, have 
used the study medication at least once, and have follow-up records. 
2) Per-Protocol set (PPS): it is a subset of the ITT data set, that is, all those who complete 
relevant observations according to the requirements of the plan and meet the following 
conditions, refer to those whose compliance is between 80% and 120%, Did not seriously 
violate the research plan, completed all the visits, and completed the CRF, the main evaluation 
indicators and most other evaluation indicators are not missing. 
3) Safety set (SS): All groups who have been randomized and used study drugs at least once 
constitute the safety set of this study. All safety information records from the subjects will be 
evaluated, including adverse events, serious adverse events, and abnormal changes in safety 
indicators that have clinical significance. 
4) The efficacy indicators were analyzed by FAS and PPS population respectively. Safety 
analysis adopts SS population analysis. 
5) Stratified analysis: According to the subject’s SOFA score (2-7 points; 8 -13 points), stratified 
analysis is carried out on the 28-day survival rate, and PK/PD-guided optimized antibiotic 
regimens are explored for pus Related effects on the prognosis of patients with toxicosis. 
（3）Statistical analysis content 
Statistical analysis content 
  
1). General principles of statistical analysis 

All statistical tests use two-sided tests. After P value is adjusted by FDT, Q value ≤ 0.05 will 
be considered as statistically significant (unless otherwise specified). The description of quantitative 
indicators will calculate the mean, standard deviation, median, minimum, maximum, lower quartile 
(Q1), upper quartile (Q3), and classification indicators to describe the number of cases and 
percentages of each category. The general comparison of the two groups will be analyzed by 
appropriate methods according to the types of indicators. The comparison of quantitative data 
between groups will be based on the data distribution using group t test (homogeneity of variance, 
normal distribution) or Wilcoxon rank sum test, classification The data uses the chi-square test or 
the exact probability method (if the chi-square test is not applicable), and the rank data uses the 
Wilcoxon rank sum test or the CMH test. Kaplan–Meier description, Log-rank test and Cox 
regression were used for the survival time data of the study subjects. The research results of each 
research center are evaluated by meta-analysis to evaluate the heterogeneity and the overall research 
merger effect. The potential confounding bias (treatment, service, management, etc.) of each 
research center is analyzed using a multi-layered mixed model. 
2). Baseline and demographic characteristics 
Summarize the number of enrollment and make a list of dropped cases. The size of the data set 
in each group, the distribution of cases in each center, the comparison of the total dropout rate, and 
a detailed list of the reasons for termination. 
The demographic characteristics (age, sex, height, body mass index, vital signs, etc.), history 
of allergies, etc. of the subjects were statistically described. According to the numerical 
characteristics of the variables, the t-test/Wilcoxon rank sum test was used to compare the 
quantitative data of the two groups of subjects such as age, height, and body mass index; the chi-
square test/exact probability method was used to determine the gender of the subjects, post medical 
history, allergy history and other categorical variables for comparison. 
Analysis of dropped cases: Cases that meet the criteria for dropped cases and the subjects 
withdrew from the study should be included in the dropped case analysis. The total dropout rate 
between groups and the dropout due to adverse events were compared using the chi-square test. 
3). Effectiveness analysis 
(1) Baseline index: Describe the baseline of each curative effect index, refer to general 
statistical methods for the comparison method between groups. A stratified analysis was performed 

based on the subjects’ SOFA score. 
(2) Main efficacy indicators: The clinical efficacy is evaluated by the survival rate in the ICU 
and the survival rate on the 28th day after enrollment. Simultaneous FAS analysis and PPS analysis. 
(3) Secondary curative effect index 
① Stratified analysis of clinical effectiveness; 
 ②Bacterial clearance rate; 
 ③Infection recurrence rate; 
④Isolation rate of new resistant bacteria; 
⑤ Infection rate of newly emerging drug-resistant bacteria; 
⑥Total cost of living in ICU; 
⑦Total hospitalization expenses; 
⑧DDD is used for antibiotics in hospital. 
For all the outcome indicators, first conduct independent evaluation in each research center in 
accordance with general principles. Then meta-analyze the research results of each research center. 
Assess the heterogeneity and the combined effect of the overall study. Finally, a multivariate 
stratified mixed model was used to adjust the potential bias.