Study protocol for a multicentre, randomised, controlled trial to assess the effectiveness of antimicrobial central venous catheters versus ordinary central venous catheters at reducing catheter related infections in critically ill Chinese patients

Introduction Catheter use is associated with many complications and is an iatrogenic source of morbidity and mortality in intensive care units (ICU). The catheter being studied (Certofix Protect) was developed to reduce the risk of catheter related infections. This clinical trial will compare the safety and efficiency of Certofix Protect with that of an ordinary Certofix catheter. Methods and analysis In this multicentre trial, we will randomly assigned dual lumen central venous catheterisation (≥5 ds) in patients in the adult ICU to the antimicrobial central venous catheter (CVC) group or the ordinary CVC group. We plan to recruit 12–16 medical centres in China. Our main objective is to assess the effectiveness of antimicrobial CVCs in reducing catheter related bloodstream infection (CRBSI), all cause mortality, catheter colonisation, catheter related thrombosis and other catheter related complications. The primary outcome is the incidence of CRBSI. Ethics and dissemination The ethics committee of West China Hospital of Sichuan University has granted ethics approval for this study (27 January 2015). The results will be published in peer reviewed journals and presented at conferences. Trial registration number NCT02645682.


Strengths and limitations of this study
This is the first multi-centre, randomized study to assess the effectiveness of Certofix® protect in critically ill Chinese adult patients and to determine the relationship between catheter-related bloodstream infections and catheter-related thrombosis. Because of differences in the two catheters being studied, it is not possible to blind the people conducting the research. Unfortunately, no study has provided evidence that antithrombotic therapy can prevent CRT.
A new antimicrobial CVC (Certofix® protect) has been developed by B. Braun Melsungen AG (Melsungen, Germany) to reduce the risk for catheter-related infections and CRT. A prospective, randomized, double-bind clinical trial (NCT00555282) conducted in the Czech Republic found that the blood stream infection rate was significantly lower in a protected CVC group compared with a standard CVC group (2.00% vs. 6.47%, p=0.008), and that the incidence of blood stream infections/1000 catheter-days was lower for coated catheters (3.21 vs. 8.30, p=0.036), but coated CVC had a similar incidence as standard CVC  Other objectives are to assess the effectiveness of Certofix® protect in reducing catheter colonization and CRT and the relationship between catheter-related infections and CRT.

Study design
The recruitment period of the study is 18   infections; (4) patients receiving an initial study catheter through guidewire exchange; (5) patients hospitalised for severe burn injuries; (6) patients with, in the opinion of the doctors, a situation that is not suitable for indwelling, including allergy to the material of the catheter, confirmed deep vein thrombosis, chronic inflammatory skin disorders at the catheter insertion site, coagulation dysfunction (such as antithrombotic prophylaxis), abnormal anatomical structure (enlargement of thyroid glands, cervical tumours, severe pneumonectasis, post-surgical changes of the insertion site); (7) patients who have been enrolled in the study before (during hospitalization); and (8) patients enrolled in another investigative trial in the past 3 months. Table 1 shows a schedule for participant enrolment, interventions, assessments, and visits. During treatment, doctors are required to collect data and samples from patients and arrange tests. All notices are provided in Supplemental File 1.

Study endpoints
The primary endpoint is CRBSI. CRBSI is defined as an isolate of an organism from a quantitative or semi-quantitative culture of a distal catheter segment and from a separate percutaneous blood culture, or an isolate of an organism from a blood culture from the catheter and from a separate percutaneous blood culture, with a time interval of two positive outcomes in more than 2 hours. Clinicians should make sure the infection cannot be from another identifiable source of infection. The secondary endpoints are catheter colonization; attack rate of CRT (insertion side or contralateral side); morbidity of CRT (insertion side or

Study population
The study sample size is calculated on the basis of an expected CRBSI rate of approximately 3% for the control group and 6% for the antiseptic catheter group. Allowing for a 10% dropout rate, 1818 patients are required to yield a study with 80% power at a statistical significance level of 0.05.

Participant selection and recruitment
Before identifying and screening patients for eligibility, informed consent must be obtained by the doctor in charge ( Figure 1). All information is to be transferred into an electronic database so that the trial office can monitor recruitment and refusal rates at each centre.

Randomization
For a patient who meets the required criteria, a researcher opens a randomized card that records the screening number and treatment allocation group for random allocation of the patients. To ensure that patients are randomly assigned at a 1:1 ratio at each study centre, the

Treatment allocation (blinding)
As the two kinds of CVC under investigation are different in some details, it is impossible to blind local investigative doctors. Outcome data assessment and analysis will be posted to participants by the coordinating centre, which will be blind.

Patient termination and withdrawal criteria
Participants and their authorised surrogates will participate in the study voluntarily, therefore, they may withdraw from the trial at any time for any reason. Patients may also be withdrawn from the study for: (1) severe adverse events; or (2) violating or deviating from the protocol.
If a patient is withdrawn for one of the two reasons mentioned, they should proceed to security analysis.  12 data quality (incomplete case report forms); or (4) investigators make changes without informing the lead researchers. Each investigator should be qualified and be approved by the lead researchers. As a 10% dropout rate is allowed, there will be no need to add new patients when an existing participant withdraws from the trial.

Data collection and inspection
Data collection begins on the day a participant signs the informed consent and continues until the participant is discharged or transferred to another hospital. Data are collected using a paper-based case report form and an electronic database.
Investigators follow a schedule to collect data, including: (1) screening data, informed consent, demographic data, inclusion and exclusion criteria, and enrolment data; (2) baseline information on catheterization, vascular ultrasound of veins at the insertion site and contralateral site, and CVC catheterization; (3) CVC removal data, peripheral blood cultures, catheter blood cultures, catheter tip cultures, and vascular ultrasound of veins at the insertion site and contralateral site; and (4) prognosis, date of transferring out of the intensive care unit, and date of discharge/death, whichever comes first.

Follow-up data
Statistical analysis plan A detailed statistical analysis plan setting out full details of the proposed analyses will be completed before the trial database is locked for analyses. If researchers make adjustments to the protocol before the statistical analysis plan is determined, the amendment will be added to the plan.

Analysis sets
There will be a full analysis set, a per protocol set, and a safety set.

Proposed interim analysis
An interim analysis will be conducted in the middle of the recruitment period to evaluate the effectiveness of the main indexes and to determine whether it is necessary/possible to terminate the trial early. An independent data safety monitoring board has been established to oversee the safety of the trial participants and may suggest terminating the study when the  Table 2 shows the alpha spending functions and cutoff values.

Principles
All statistical tests will be two tailed and will be analysed using SAS statistical analysis software (ver. 9.4; SAS Institute, Cary, NC). Quantitative variables will be analysed by calculating the mean, standard deviation, median, minimum value, maximum value, lower quartile (Q1), and upper quartile (Q3). Categorical variables will be described using cases and percentages for each category. The significance of differences between two groups will be determined using the chi-square test or Fisher's exact test for categorical data, the group t-test or Wilcoxon rank sum test for continuous data, and the Wilcoxon rank sum test or the Cochran-Mantel-Haenszel chi-square test for ranked data.

Proposed primary analysis
The incidence rates of CRBSI in the two groups will be compared using the Cochran-Mantel-Haenszel chi-square test. For the interim analysis, the size of the test for α 1 is 0.003, and we will also calculate (1-α 1 ) × 100% confidence intervals. If the result rejects H 0 , then the antimicrobial CVC group is superior to the ordinary CVC group. If the interim analysis shows no statistical significance or if the data safety monitoring board decides to complete the next stage of the trial, then we will complete the final analysis (α 2 = 0.049, CI (1-α 2 ) × 100%). If the result rejects H 0 , then the antimicrobial CVC group is superior to the ordinary CVC group. The proposed primary analysis is based on the final analysis set and the per protocol set.

Other planned analyses
Catheter colonization, rate of CRT, and hospital mortality in the two groups will be compared using the chi-square test or Fisher's exact test. Analyses of the other indicators follows the process described under "Principles" above. Analyses of the secondary indicators is based on the full analysis set and the per protocol set.

Missing data
Worst-case imputation will be used to evaluate missing data in the full analysis set. Dropout rates will be obtained and for each group we will determine if the dropout rate is higher than the difference in event rates between the two groups using the worst-case scenario model.

Author independence
The study authors affiliated with the West China Hospital and the Peking Union Medical College Hospital designed the study. The authors have full independence in decisions

Safety evaluation
The proportion of abnormal cases after treatment will be determined, as will the number of cases/incidence of adverse events and severe adverse events. We will also describe the clinical manifestations, degrees of all adverse events, and the relationship between these factors and the catheters in detail. Changes in indexes will be described using a crosstab grid.
All safety evaluations will be based on the safety set.

Definitions
An adverse event is defined as a patient who develops clinical features such as discomfort or laboratory abnormalities that are not related to the expected therapeutic effects during central venous catheterization.
The catheter-associated adverse events to be recorded are: (1) a broken or cracked catheter; (2) hematoma at the insertion site; (3) chylothorax, pneumothorax, haemothorax, or pleural effusion caused by mispuncture or malposition; (4) arrhythmia or rupture of the atrium caused by malposition, endocarditis because of mechanical stimulation, thrombophlebitis, or injury to the atrium, thoracic duct, brachial plexus, or phrenic nerve because of mispucture. The severe adverse events (definitely related or possibly related) to be recorded are: (1) death as the result of an adverse event. Medical conditions resulting in death need to be comprehensively reported, such as an underlying disease or an accident; (2) life-threatening events. Life-threatening events are those events that put the patient at risk for death at the time. This is distinct from an event that may become more serious in the future and put the patient at risk for death; (3) events requiring hospitalization or prolong the time of hospitalization. Hospitalization in this context means more than 1 calendar day; (4) events leading to permanent damage, or medical intervention that must be taken to avoid permanent damage.
An event may meet more than one criteria. If the event could results in harm to a patient or clinician, intervention should be taken to prevent the event, and this adverse event should be recorded as a severe adverse event.

Recording and reporting
Researchers must record adverse events and severe adverse events in the corresponding case report form, including signs and symptoms, date, disappearance date (duration), severity or strength, relationship with therapy, measurements, and outcomes. If the interim analysis finds that the morbidity of some type of adverse event or severe adverse event and its severity increases significantly, researchers must report the adverse event in a timely manner. All severe adverse events must be reported to the drug administration department and the ethics committee within 24 hours (one working day), and the production enterprise must be  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60   F  o  r  p  e  e  r  r  e  v  i  e  w  o  n  l  y   18 informed at the same time.

Follow-up
Researchers must follow-up all adverse events and severe adverse events during the trial.
Follow-up will continue until the adverse event or the severe adverse event disappears or becomes stable. All adverse events are to be kept in the case report form until the last observation date.

Quality control
Quality control is defined as "a part of quality management focused on fulfilling quality requirements" [10]. This approach places an emphasis on three aspects: (1) Elements: such as controls, job management, defined and well-managed processes [11], performance and integrity criteria, and identification of records; (2) Competence: such as knowledge, skills, experience, and qualifications; (3) Soft resources: such as personnel, integrity, confidence, organizational culture, motivation, team spirit, and quality relationships. In study management, quality control requires that the project manager and the team inspect the work to ensure its alignment with the project scope [12].  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60   F  o  r  p  e  e  r  r  e  v  i  e  w  o  n  l  y   19 Authorised and qualified researchers will visit the research centres to verify adherence to the protocol and regulations, ensure original data, and to assist research activities according to the inspection plan.

Ethics and dissemination
The protocol has been registered at the ClinicalTrials.gov registry. Any revisions to the protocol will be documented in the ClinicalTrials.gov registry. Written informed consent will be obtained from all participants. We will publish the results of this trial in peer-reviewed clinical journals and present the findings at conferences for widespread dissemination of the results.

3) Remove catheters
At removal, the site was again disinfected by povidone iodine or chlorhexidine to make sure that the skin around the catheter was clean.

4) Indication of removal
No need for CVC in patients; Occlusion of catheter; Suspected or confirmed deep vein thrombosis of insertion site; Patients with highly suspected CRBSI and meeting one of the following criteria, haemodynamic instability, bacteremia; or the doctor in charge insisting to remove the catheter after 5 days' observation.

5)Tests
Blood culture For the dual-lumen catheter, blood samples were taken from both lumens separately.
Researchers should insert percutaneously to take sample from peripheral blood vessels. Aerobic culture and anaerobic culture were needed for each blood sample.

Cultures of CVC
The entire catheter was removed aseptically, and 4-cm segment was cut from the catheter tip, which was semi-quantitatively cultured using the roll-plate method.

Vein ultrasound
It is used to diagnose or to exclude deep vein thrombosis (DVT Dr Minming Wu and Dr Yao Chen contributed to the study design and development.

Competing interests
The authors declare that they have no competing financial interests.

Funding
This work is supported by B. Braun Melsungen AG (Melsungen, Germany) through individual research contracts with participating institutions. The funding source has no role in the design or conduct of the trial, data collection, analyses, or manuscript preparation.

Strengths and limitations of this study
This is the first multi-centre, randomized study to assess the effectiveness of Certofix® protect in critically ill Chinese adult patients and to determine the relationship between catheter-related bloodstream infections and catheter-related thrombosis. Because of differences in the two catheters being studied, it is not possible to blind the people conducting the research. Whether the local physician use the ultrasound as guidance may influence major outcomes even though we recommend experienced operators to conduct the insertion. It's difficult to distinguish and exclude patients whose expected survival less than one month cause their condition are constantly changing. What's more, ICU patients suffer from many underlying diseases which makes difficult to judge from the source of infection.  Critically ill patients with CRBSI are more likely to get CRT [19,20]. Although many studies on antimicrobial catheters, CRT and relationship between them have been conducted, research in China is limited.
We conducted this multi-centre study to assess the effectiveness of Certofix® protect (supplemental appendix -study catheter) at reducing CRBSI, catheter colonization and CRT in critically ill Chinese adult patients. We also try to find out the relationship between catheter-related infections and CRT.  The intervention group is those patients that undergo catheterization with Certofix® protect.

Methods
The control group is those patients that undergo catheterization with Certofix®. Patients are prospectively followed from the day of CVC insertion for at least 5 days or up until CVC removal, whichever comes first.

Study endpoints
The primary endpoint is CRBSI. CRBSI [21] is defined as CVC-tip colonization by quantitative or semi-quantitative method and at least one peripheral blood culture positive for the same microorganism or differential time to positivity (>120 min from central and

Study population
The study sample size is calculated on the basis of an expected CRBSI rate of approximately 6% for the control group and 3% for the antiseptic catheter group. Allowing for a 10% dropout rate, 1818 patients are required to yield a study with 80% power at a statistical significance level of 0.05.

Participant selection and recruitment
Before identifying and screening patients for eligibility, informed consent (supplemental file) must be obtained by the doctor in charge. All information is to be transferred into an electronic database so that the trial office can monitor recruitment and refusal rates at each centre.

Randomization
Each research centre will receive sequentially numbered containers used to implement the random allocation sequence. And the treatment allocation group is hiding beyond the coated card. To ensure that patients are randomly assigned at a 1:1 ratio at each study centre, the randomized cards was protected using a block design (each block includes 4 random allocation sequence). For a patient who meets the required criteria, the local investigator opens a randomized card that records the screening number and treatment allocation group.
Then, physician in charge of the patient will obtain the right study catheter and complete catheterization. So that treatment allocation is concealed.

Patient termination and withdrawal criteria
Participants and their authorised surrogates will participate in the study voluntarily, therefore, they may withdraw from the trial at any time for any reason. Patients may also be withdrawn from the study for: (1) severe adverse events; or (2) violating or deviating from the protocol. If a patient is withdrawn for one of the two reasons mentioned, they should proceed to security analysis. data quality (incomplete case report forms); or (4) investigators make changes without informing the lead researchers. Each investigator should be qualified and be approved by the lead researchers. As a 10% dropout rate is allowed, there will be no need to add new patients when an existing participant withdraws from the trial.

Data collection and inspection
Principal investigators will centralize all the data monthly and send a newsletter to each centre to promote data quality and process of the trial. Data collection begins on the day a participant signs the informed consent and continues until the participant is discharged or transferred to another hospital. Data are collected using a paper-based case report form (supplemental file, data collection form) and an electronic database.
Investigators follow a schedule to collect data, including: (1) screening data, informed

Follow-up data
Statistical analysis plan

Hypothesis
The study hypothesis is: Where π represents the incidence of CRBSI. There will be a full analysis set, a per protocol set, and a safety set (supplemental appendixsupplemental method).

Principles
All statistical tests will be two tailed and will be analysed using SAS statistical analysis software (ver. 9.4; SAS Institute, Cary, NC). Quantitative variables will be analysed by calculating the mean, standard deviation, median, minimum value, maximum value, lower quartile (Q1), and upper quartile (Q3). Categorical variables will be described using cases and percentages for each category. The significance of differences between two groups will be determined using the chi-square test or Fisher's exact test for categorical data, the group t-test or Wilcoxon rank sum test for continuous data, and the Wilcoxon rank sum test or the Cochran-Mantel-Haenszel chi-square test for ranked data.

Proposed primary analysis
The incidence density of CRBSI in the two groups will be compared using the   Table 2 shows the alpha spending functions and cut-off values.

Secondary analysis
Incidence density of Catheter-tip colonization, CRT, and hospital mortality in the two groups will be compared using the chi-square test or Fisher's exact test, or random-intercept logistic regression. Analyses of the other indicators follows the process described under "Principles" above. Analyses of the secondary indicators is based on the full analysis set and the per protocol set.

Subgroup analysis
Subgroup analyses will be conducted for predefined factors such as insertion site, catheter durations, antibiotic therapy, anticoagulation therapy, underlying diseases, BMI, SOFA score,

Safety analysis
The proportion of abnormal cases after treatment will be determined, as will the number of cases/incidence of adverse events and severe adverse events. We will also describe the clinical manifestations, degrees of all adverse events, and the relationship between these factors and the catheters in detail. Changes in indexes will be described using a crosstab grid.
All safety evaluations will be based on the safety set.

Missing data
Worsts Observation Carried Forward will be used to evaluate missing data in the full analysis set. Dropout rates will be obtained and for each group we will determine if the dropout rate is higher than the difference in event rates between the two groups using the worst-case scenario model.

Proposed interim analysis
An interim analysis will be conducted in the middle of the recruitment period to evaluate the effectiveness of the main indexes and to determine whether it is necessary/possible to damage.
An event may meet more than one criteria. If the event could result in harm to a patient or clinician, intervention should be taken to prevent the event, and this adverse event should be recorded as a severe adverse event.
Recording and reporting Researchers must record adverse events and severe adverse events in the corresponding case report form, including signs and symptoms, date, disappearance date (duration), severity or strength, relationship with therapy, measurements, and outcomes. If the interim analysis finds that the morbidity of some type of adverse event or severe adverse event and its severity increases significantly, researchers must report the adverse event in a timely manner. All severe adverse events must be reported to the drug administration department and the ethics committee within 24 hours (one working day), and the production enterprise must be informed at the same time.

Follow-up
Researchers must follow-up all adverse events and severe adverse events during the trial.
Follow-up will continue until the adverse event or the severe adverse event disappears or

Quality control
Quality control is defined as "a part of quality management focused on fulfilling quality requirements" (ISO 9000:2005, Clause 3.2.10). This approach places an emphasis on three aspects: (1) Elements: such as controls, job management, defined and well-managed processes [22], performance and integrity criteria, and identification of records; (2) Competence: such as knowledge, skills, experience, and qualifications; (3) Soft resources: such as personnel, integrity, confidence, organizational culture, motivation, team spirit, and quality relationships. In study management, quality control requires that the project manager and the team inspect the work to ensure its alignment with the project scope [23].
An independent data safety monitoring committee (consist of principal investigators, chief doctors of each centre) has been established to oversee the safety of the trial participants and may suggest terminating the study when the outcome of the interim analysis reaches the determined threshold. Principal investigators will centralize all the data monthly and send a newsletter (a newsletter reports inclusion cases and completed cases of each centre) to participating centre to promote data quality and process of the trial. Authorised and qualified researchers will visit the research centres to verify adherence to the protocol and regulations, ensure original data, and to assist research activities according to the inspection plan.

Ethics and dissemination
The protocol has been registered at the ClinicalTrials.gov registry (Protocol ID: HC-I-H 1503; ClinicalTrials.gov ID: NCT02645682.). Any revisions to the protocol will be documented in the ClinicalTrials.gov registry. Written informed consent will be obtained from all participants. All the inclusion patients will be able to have access and correct the data. In case of additional studies from database, all the investigators should keep the results confidential until these are publicly available, and they couldn't give publication related to database without the approval of the principle investigator. We will publish the results of this trial in peer-reviewed clinical journals and present the findings at conferences for widespread dissemination of the results.

Author independence
The study authors affiliated with the West China Hospital and the Peking Union Medical College Hospital designed the study. The authors have full independence in decisions regarding the reporting of results and the content of the reported study.

2.1) Procedures for insertion
First doctors chose a proper insertion site, and then used maximal barrier precautions during insertion (the operator was required to wear masks, sterile gloves, and surgical gowns and use large sterile drapes). After disinfected with povidone iodine or chlorhexidine, the catheter was inserted percutaneously using Seldinger technique. It was not allowed to exchange the catheter over a guidewire into an old site. Sites were dressed with hyalo-dressing.

2.2) Care of the catheter during indwelling catheterization
Twice a week or according to routine procedures, perform the follows: the dressing removed; the site inspected and cleaned with povidone-iodine or chlorhexidine; and the new dressing applied.

2.3) Remove catheters
At removal, the site was again disinfected by povidone iodine or chlorhexidine to make sure that the skin around the catheter was clean.

2.5) Tests
Blood culture For the dual-lumen catheter, blood samples were taken from both lumens separately.
Researchers should insert percutaneously to take sample from peripheral blood vessels. Aerobic culture and anaerobic culture were needed for each blood sample.

Cultures of CVC-tip
The entire catheter was removed aseptically, and 4-cm segment was cut from the catheter tip, which was semi-quantitatively cultured using the roll-plate method.

Vein ultrasound
It is used to diagnose or to exclude deep vein thrombosis (DVT). If the insertion site is femoral vein, doctors will screen iliac vein and femoral vein on both sides for DVT. While in the jugular vein, bilateral jugular veins should be inspected. Ultrasound is needless only in case of catheterization in subclavian vein. Ultrasound will be arranged before insertion and after withdrawal of catheter (within 48h).

2.6) Analysis set Full analysis set (FAS)
The basic intention-to-treat (ITT) principle is that participants in the trials should be analyzed in the groups to which they are randomized, regardless of whether they receive or adhere to the allocated intervention. Based on ITT principle, FAS represents remaining participants after eliminating the least number of patients with reasonable way, including all the patients who are randomized and receive study catheters.

Per protocol set (PPS)
PPS can only be restricted to the participants who fulfill the protocol in the terms of the eligibility, interventions, and outcome assessment. Also, the PPS restricts the comparison of the treatments to the ideal patients, that is, those who adhere perfectly to the clinical trial instructions as stipulated in the protocol. [6]

Methods: Assignment of interventions (for controlled trials)
Allocation: Sequence generation 16a Method of generating the allocation sequence (eg, computergenerated random numbers), and list of any factors for stratification.
To reduce predictability of a random sequence, details of any planned restriction (eg, blocking) should be provided in a separate document that is unavailable to those who enrol participants or assign interventions 9 16b Mechanism of implementing the allocation sequence (eg, central telephone; sequentially numbered, opaque, sealed envelopes), describing any steps to conceal the sequence until interventions are assigned 9 Implementation 16c Who will generate the allocation sequence, who will enrol participants, and who will assign participants to interventions 9 Blinding (masking) 17a Who will be blinded after assignment to interventions (eg, trial participants, care providers, outcome assessors, data analysts), and how

Strengths and limitations of this study
• We include large samples from 12-16 medical centres across different provinces which make results better represent of Chinese ICU patients. • Different puncture skill may influence the risk of mechanical and infectious complications. While our study didn't collect this part of data.  Critically ill patients with CRBSI are more likely to get CRT [19,20]. Although many studies on antimicrobial catheters, CRT and relationship between them have been conducted, research in China is limited.
We conducted this multi-centre study to assess the effectiveness of Certofix® protect (supplemental appendix -study catheter) at reducing CRBSI, catheter colonization and CRT in critically ill Chinese adult patients. We also try to find out the relationship between catheter-related infections and CRT.

Study endpoints
The primary endpoint is CRBSI. CRBSI [21] is defined as CVC-tip colonization by quantitative or semi-quantitative method and at least one peripheral blood culture positive

Study population
The study sample size is calculated on the basis of an expected CRBSI rate of approximately 6% for the control group and 3% for the antiseptic catheter group. Allowing for a 10% dropout rate, 1818 patients are required to yield a study with 80% power at a statistical significance level of 0.05.

Participant selection and recruitment
Before identifying and screening patients for eligibility, informed consent (supplemental file) must be obtained by the doctor in charge. All information is to be transferred into an electronic database so that the trial office can monitor recruitment and refusal rates at each centre.

Randomization
Each research centre will receive sequentially numbered containers used to implement the random allocation sequence. And the treatment allocation group is hiding beyond the coated card. To ensure that patients are randomly assigned at a 1:1 ratio at each study centre, the randomized cards was protected using a block design (each block includes 4 random allocation sequence). For a patient who meets the required criteria, the local investigator opens a randomized card that records the screening number and treatment allocation group.

Patient termination and withdrawal criteria
Participants and their authorised surrogates will participate in the study voluntarily, therefore, they may withdraw from the trial at any time for any reason. Patients may also be withdrawn from the study for: (1) severe adverse events; or (2) violating or deviating from the protocol.
If a patient is withdrawn for one of the two reasons mentioned, they should proceed to security analysis.

Research centre termination and withdrawal criteria
A research centre must terminate their involvement in the clinical trial if: (1) the researchers do not obey the rules of the International Conference on Harmonisation Guidelines for Good Clinical Practice or local regulations; (2) the research centre intentionally submits incorrect or incomplete data to inspectors; (3) the requirements of the protocol are not met, including poor data quality (incomplete case report forms); or (4) investigators make changes without informing the lead researchers. Each investigator should be qualified and be approved by the lead researchers. As a 10% dropout rate is allowed, there will be no need to add new patients when an existing participant withdraws from the trial.  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60   F  o  r  p  e  e  r  r  e  v  i  e  w  o  n  l  y 12 Principal investigators will centralize all the data monthly and send a newsletter to each centre to promote data quality and process of the trial. Data collection begins on the day a participant signs the informed consent and continues until the participant is discharged or transferred to another hospital. Data are collected using a paper-based case report form (supplemental file, data collection form) and an electronic database.

Analysis sets
There will be a full analysis set, a per protocol set, and a safety set (supplemental appendixsupplemental method).

Principles
All statistical tests will be two tailed and will be analysed using SAS statistical analysis software (ver. 9.4; SAS Institute, Cary, NC). Quantitative variables will be analysed by calculating the mean, standard deviation, median, minimum value, maximum value, lower quartile (Q1), and upper quartile (Q3). Categorical variables will be described using cases and percentages for each category. The significance of differences between two groups will be determined using the chi-square test or Fisher's exact test for categorical data, the group t-test or Wilcoxon rank sum test for continuous data, and the Wilcoxon rank sum test or the Cochran-Mantel-Haenszel chi-square test for ranked data.  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  The incidence density of CRBSI in the two groups will be compared using the Cochran-Mantel-Haenszel chi-square test and stratified analysis based on the time CRBSI occurs. For the interim analysis, the size of the test for α 1 is 0.003, and we will also calculate (1-α 1 ) × 100% confidence intervals. If the result rejects H 0 , then the antimicrobial CVC group is superior to the ordinary CVC group. If the interim analysis shows no statistical significance or if the data safety monitoring board decides to complete the next stage of the trial, then we will complete the final analysis (α 2 = 0.049, CI (1-α 2 ) × 100%). The proposed primary analysis is based on the final analysis set and the per protocol set. Table 2 shows the alpha spending functions and cut-off values.

Secondary analysis
Incidence density of Catheter-tip colonization, CRT, and hospital mortality in the two groups above. Analyses of the secondary indicators is based on the full analysis set and the per protocol set.

Subgroup analysis
Subgroup analyses will be conducted for predefined factors such as insertion site, catheter durations, antibiotic therapy, anticoagulation therapy, underlying diseases, BMI, SOFA score, APACHE2 score, etc. Other exploratory subgroup analyses will be eventually conducted.

Safety analysis
The proportion of abnormal cases after treatment will be determined, as will the number of cases/incidence of adverse events and severe adverse events. We will also describe the clinical manifestations, degrees of all adverse events, and the relationship between these factors and the catheters in detail. Changes in indexes will be described using a crosstab grid.
All safety evaluations will be based on the safety set.
Missing data Worsts Observation Carried Forward will be used to evaluate missing data in the full analysis set. Dropout rates will be obtained and for each group we will determine if the dropout rate is higher than the difference in event rates between the two groups using the worst-case scenario model.

Proposed interim analysis
An interim analysis will be conducted in the middle of the recruitment period to evaluate the effectiveness of the main indexes and to determine whether it is necessary/possible to terminate the trial early.

Definitions
An adverse event is defined as a patient who develops clinical features such as discomfort or laboratory abnormalities that are not related to the expected therapeutic effects during central venous catheterization.
The catheter-associated adverse events according to the modified CTCAE V.4 classification [22] to be recorded are: (1) a broken or cracked catheter; (2) hematoma at the insertion site; (3) chylothorax, pneumothorax, haemothorax, or pleural effusion caused by mispuncture or  An event may meet more than one criteria. If the event could result in harm to a patient or clinician, intervention should be taken to prevent the event, and this adverse event should be recorded as a severe adverse event.

Recording and reporting
Researchers must record adverse events and severe adverse events in the corresponding case report form, including signs and symptoms, date, disappearance date (duration), severity or strength, relationship with therapy, measurements, and outcomes. If the interim analysis finds that the morbidity of some type of adverse event or severe adverse event and its severity increases significantly, researchers must report the adverse event in a timely manner. All severe adverse events must be reported to the drug administration department and the ethics committee within 24 hours (one working day), and the production enterprise must be informed at the same time.

Follow-up
Researchers must follow-up all adverse events and severe adverse events during the trial.
Follow-up will continue until the adverse event or the severe adverse event disappears or becomes stable. All adverse events are to be kept in the case report form until the last observation date.

Quality control
Quality control is defined as "a part of quality management focused on fulfilling quality requirements" (ISO 9000:2005, Clause 3.2.10). This approach places an emphasis on three aspects: (1) Elements: such as controls, job management, defined and well-managed processes [23], performance and integrity criteria, and identification of records; (2) Competence: such as knowledge, skills, experience, and qualifications; (3) Soft resources: such as personnel, integrity, confidence, organizational culture, motivation, team spirit, and quality relationships. In study management, quality control requires that the project manager and the team inspect the work to ensure its alignment with the project scope [24].  19 An independent data safety monitoring committee (consist of experts of each centre who are not investigators) has been established to oversee the safety of the trial participants and may suggest terminating the study when the outcome of the interim analysis reaches the determined threshold. Principal investigators will centralize all the data monthly and send a newsletter (a newsletter reports inclusion cases and completed cases of each centre) to participating centre to promote data quality and process of the trial.

Study inspection
Authorised and qualified researchers will visit the research centres to verify adherence to the protocol and regulations, ensure original data, and to assist research activities according to the inspection plan.

Ethics and dissemination
The protocol has been registered at the ClinicalTrials.gov registry (Protocol ID: HC-I-H 1503; ClinicalTrials.gov ID: NCT02645682.). Any revisions to the protocol will be documented in the ClinicalTrials.gov registry. Written informed consent will be obtained from all participants. All the inclusion patients will be able to have access and correct the data. In case of additional studies from database, all the investigators should keep the results confidential until these are publicly available, and they couldn't give publication related to database without the approval of the principle investigator. We will publish the results of this trial in

Author independence
The study authors affiliated with the West China Hospital and the Peking Union Medical College Hospital designed the study. The authors have full independence in decisions regarding the reporting of results and the content of the reported study.

2.1) Procedures for insertion
First doctors chose a proper insertion site, and then used maximal barrier precautions during insertion (the operator was required to wear masks, sterile gloves, and surgical gowns and use large sterile drapes). After disinfected with povidone iodine or chlorhexidine, the catheter was inserted percutaneously using Seldinger technique. It was not allowed to exchange the catheter over a guidewire into an old site. Sites were dressed with hyalo-dressing.

2.2) Care of the catheter during indwelling catheterization
Twice a week or according to routine procedures, perform the follows: the dressing removed; the site inspected and cleaned with povidone-iodine or chlorhexidine; and the new dressing applied.

2.5) Tests
Blood culture For the dual-lumen catheter, blood samples were taken from both lumens separately.
Researchers should insert percutaneously to take sample from peripheral blood vessels. Aerobic culture and anaerobic culture were needed for each blood sample.

Cultures of CVC-tip
The entire catheter was removed aseptically, and 4-cm segment was cut from the catheter tip, which was semi-quantitatively cultured using the roll-plate method.

Vein ultrasound
It is used to diagnose or to exclude deep vein thrombosis (DVT). If the insertion site is femoral vein, doctors will screen iliac vein and femoral vein on both sides for DVT. While in the jugular vein, bilateral jugular veins should be inspected. Ultrasound is needless only in case of catheterization in subclavian vein. Ultrasound will be arranged before insertion and after withdrawal of catheter (within 48h).

4) Supplementary Appendix References
Role of study sponsor and funders, if any, in study design; collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication, including whether they will have ultimate authority over any of these activities

Introduction
Background and rationale Time schedule of enrolment, interventions (including any run-ins and washouts), assessments, and visits for participants. A schematic diagram is highly recommended (see Figure) 7 Sample size 14 Estimated number of participants needed to achieve study objectives and how it was determined, including clinical and statistical assumptions supporting any sample size calculations 9 Recruitment 15 Strategies for achieving adequate participant enrolment to reach target sample size 9

Methods: Assignment of interventions (for controlled trials)
Allocation: Sequence generation 16a Method of generating the allocation sequence (eg, computergenerated random numbers), and list of any factors for stratification.
To reduce predictability of a random sequence, details of any planned restriction (eg, blocking) should be provided in a separate document that is unavailable to those who enrol participants or assign interventions 9 16b Mechanism of implementing the allocation sequence (eg, central telephone; sequentially numbered, opaque, sealed envelopes), describing any steps to conceal the sequence until interventions are assigned 9 Implementation 16c Who will generate the allocation sequence, who will enrol participants, and who will assign participants to interventions 9 Blinding (masking) 17a Who will be blinded after assignment to interventions (eg, trial participants, care providers, outcome assessors, data analysts), and how None 17b If blinded, circumstances under which unblinding is permissible, and procedure for revealing a participant's allocated intervention during the trial None

Methods: Data collection, management, and analysis
Data collection methods 18a Plans for assessment and collection of outcome, baseline, and other trial data, including any related processes to promote data quality (eg, duplicate measurements, training of assessors) and a description of study instruments (eg, questionnaires, laboratory tests) along with their reliability and validity, if known. Reference to where data collection forms can be found, if not in the protocol 10, 11,17, 18 18b Plans to promote participant retention and complete follow-up, including list of any outcome data to be collected for participants who discontinue or deviate from intervention protocols 11, 17 Data management 19 Plans for data entry, coding, security, and storage, including any related processes to promote data quality (eg, double data entry; range checks for data values). Reference to where details of data management procedures can be found, if not in the protocol 10 Statistical methods 20a Statistical methods for analysing primary and secondary outcomes. Reference to where other details of the statistical analysis plan can be found, if not in the protocol 13 20b Methods for any additional analyses (eg, subgroup and adjusted analyses) 14 20c Definition of analysis population relating to protocol non-adherence (eg, as randomised analysis), and any statistical methods to handle missing data (eg, multiple imputation) 14