Study setting {9}
This multi-institutional randomized controlled trial will be performed in five referral academic hospitals: (1) Ajou University Hospital, (2) Hanyang University Guri Hospital, (3) Ewha Women’s University Seoul Hospital, (4) Seoul National University Bundang Hospital, and (5) Incheon St. Mary’s Hospital, Catholic University of Korea.
Eligibility criteria {10}
Eligible patients are ≥18 years in an in-patient setting who require PICC insertion. Because diagnosis of CLABSI requires at least 48 hours of dwelling time, patients with pending discharge or transfer to another hospital within two days after catheterization will be excluded. Figure 1 shows the CONSORT flow chart of this study. Both tPICCs and cPICCs will be placed by one interventional radiologist at each institution designated for this study.
Who will take informed consent? {26a}
Informed consent will be obtained by investigators of each institution 1 day before PICC placement. In patients with urgent medical necessity, which will be decided by the referring physician, informed consent will be obtained within at least 6 hours of procedure. Investigators will provide information sheets to participants and will provide a detailed explanation of the study before obtaining informed consent.
Additional consent provisions for collection and use of participant data and biological specimens {26b}
Not applicable.
Interventions
Explanation for the choice of comparators {6b}
We hypothesize that using the subcutaneous tunnel for PICC insertion will reduce the CLABSI rate compared to conventional methods.
Intervention description {11a}
Participants will be allocated into two groups. The cPICC group will have PICC placement with the traditional method under ultrasonography and fluoroscopic guidance in an angiography suite. The tPICC group will undergo PICC placement in same manner and place with additional subcutaneous tunnelling. Most commercially available PICCs contain no tunnellers or Dacron cuffs. Thus, after vein puncture with the access needle, a Nitinol guidewire will be placed as usual. We will make a tunnel 2–3 cm distal to the initial venepuncture site using an additional 18-gauge needle, and the guidewire will be retrogradely passed through the needle. After resolution of the loop over the venepuncture site, a peel-away sheath will be placed over the wire. The catheter will be trimmed to the distance between the venepuncture site and cavoatrial junction plus the subcutaneous tunnel before being inserted in the usual manner. The initial venepuncture and exit-site wounds will be closed by applying a small amount of n-butyl-2-cyanoacrylate (Figure 2).
Criteria for discontinuing or modifying allocated interventions {11b}
Patients who do not want to participate in the trial or accidentally lose the PICC within 48 hours after the procedure will be excluded from the study. There are no criteria for modifying allocated intervention.
Strategies to improve adherence to interventions {11c}
This study includes one-time intervention during procedure and is a pragmatic study. There is no need to improve intervention adherence.
Relevant concomitant care permitted or prohibited during the trial {11d}
Not applicable.
Provisions for post-trial care {30}
Subcutaneous tunnelling is a widely used procedure for central venous catheter placement with no reported serious complications. However, investigators will try to attenuate any damage from the intervention. When it is impossible to recover from irreversible injury, an insurance program for this study will provide compensation. Patients will not be compensated for their participation in the study.
Outcomes {12}
The primary outcome is the effect of subcutaneous tunnelling in PICC placement on the rate of CLABSI. For this, we will use the National Healthcare Safety Network surveillance definition [14]. CLABSI will be defined as a laboratory-confirmed bloodstream infection where the PICC is in place more than 48 hours and must meet both of these criteria: participants have a recognized pathogen identified from one or more blood specimens by a culture- or non-culture-based microbiologic test, and organisms identified in the blood are not related to an infection at another origin (e.g., mucosal-barrier injury). CLABSI will be diagnosed by a board-certified infectionologist at each institution, who is independent to this study for blinding.
The secondary outcomes include rates of local infection and bleeding from exit sites, extra procedure time for subcutaneous tunnelling, and technical success defined as the rate of successful catheter tip placement to the cavoatrial junction. We will divide technical success into two categories. If there is a failure in puncturing the target vein or placing the catheter to the cavoatrial junction, we will define it as ‘impossible PICC’. In case of subcutaneous tunnelling failure after target vein puncture, we will define it as ‘impossible tunnelling’.
Participant timeline {13}
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STUDY PERIOD
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Enrolment
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Allocation
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Post-allocation
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Close-out
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TIMEPOINT**
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-1-3 days
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0
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Until catheter removal or hospital discharge
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After catheter removal or hospital discharge
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ENROLMENT:
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Eligibility screen
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X
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Informed consent
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X
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Demographic information
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X
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Allocation
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X
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INTERVENTIONS:
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Conventional PICC
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X
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Tunnelled PICC
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X
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ASSESSMENTS:
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Demographics
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X
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Laboratory test
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X
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Procedure details
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X
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Procedure-associated complications
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X
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Delayed complications
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X
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Sample size {14}
According to previous reports about PICC, infection rates range from 0.6 to 7.4% [1, 3-5]. In a previous retrospective study, the CLABSI rate of tPICC was 2.6% [13]. Sample size was calculated by assuming the same infection rate in this trial to verify the prior retrospective study result. In this trial, 2 677 participants are needed to prove a reduction of the infection rate from 6.2% to 2.6% for the primary outcome, at a two-sided α level of 0.05 and statistical power of 90%. A total of 1694 participants will be included in this study to account for a 20% of dropout rate (PASS, version 16, NCSS statistical software). Data will be analysed on an intention-to-treat basis according to their originally assigned group.
Recruitment {15}
All hospitalized patients requesting PICC will be potential candidates in this study according to the inclusion and exclusion criteria. When obtaining informed consent, there will be respectful discussions with each candidate to ensure prudent decisions of the patients. A total of 339 patients will be enrolled from each of the five institutes by non-competitive recruitment.
Assignment of interventions: allocation
Sequence generation {16a}
Randomization numbers will be generated by R program (blockrand function in the package “blockrand”) using a 1:2 to 1:6 random block. Multiple datasets were generated by an independent statistician, and an independent research organizer (Medsoft, Hwasung Gyeonggi, Korea) will apply one of the datasets to the electronic Case Report Form (e-CRF) while blinded.
Concealment mechanism {16b}
Just before the procedure and after aseptic skin preparation, a circulating nurse who is not part of this trial will access the secure, password-protected, online-randomized database. The nurse will inform the investigator that the subject is in the cPICC or tPICC group.
Implementation {16c}
The computer-generated block randomization list will be created by an independent statistician. All hospitalized patients who will access PICC and are referred to department of interventional radiology where investigators invited them to participate in this trial. Participants will be sent to the angiography suite and randomly assigned to a group immediately before the procedure by an independent circulating nurse in the angiography suite.
Assignment of interventions: Blinding
Who will be blinded {17a}
There is unavoidable risk of bias in this type of randomized controlled trial where the intervention cannot be blinded to interventionists, participants, or care providers. However, this study has a single-blind characteristics due to following reasons. Participants can only presume their procedure on the grounds of their scar, but they cannot be assured about their group because procedures will be performed under aseptic drapes that screen the patient’s visual confirmation. It is difficult to know whether a tunnel is made or not because they are subcutaneous, and multiple skin incisions can also be made for conventional PICC. Furthermore, the interventionist will not confirm their group. As for care providers, mainly ward nurses can also presume the group but cannot be assured of the allocations for the same reasons as the participants. Outcome assessors will be blinded to allocation. The e-CRF on allocation will not be accessible to outcome assessors. Data analysts will be blinded until the end of study.
Procedure for unblinding if needed {17b}
This study is unblinded.
Data collection and management
Plans for assessment and collection of outcomes {18a}
In line with pragmatic study, the participants will be treated for their own condition according to the initial treatment plan. Daily physical examination and laboratory tests will be performed on a treatment schedule. When the participants have a symptom or sign of infection, blood culture and laboratory testing will be performed as usual management. Laboratory tests include white blood cell count with differentiation, erythrocyte sedimentation rate, and C-reactive protein level.
Plans to promote participant retention and complete follow-up {18b}
This study plans to enrol hospitalized patients, and adverse events (AEs) will be evaluated during hospitalization. We have no plan to promote retention.
Data management {19}
All data will be secured in independent online server (Medsoft) outside of the hospitals. The investigators will be responsible for all data entry and management. All data will be checked by at least two investigators.
Confidentiality {27}
All collected data will be coded with a code number and this will be the only reference to participants identification during the study period to maintain anonymity. Informed consent forms will be secured in a locked cabinet in a password locked secure place in each hospital. Data will be stored for 3 years after end of this study according to Enforcement Decree of the Bioethics and Safety Act of Korea. All data will be destroyed after that period, but data storage extension will be possible with Institutional Review Board (IRB) permission.
Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
No laboratory evaluation or biological specimen collection is needed in this study.
Statistical methods
Statistical methods for primary and secondary outcomes {20a}
Independent sample t-tests or Mann-Whitney U tests (continuous variables) and Chi-square tests (categorical variables) will be used to compare the two study groups. The infection rate (CLABSI) will be multiplied by 1000 and divided by total catheter-days [15]. Binary logistic regression will be used to predict infection and infection-related death, adjusting for patient-, device-, and provider-level characteristics. Cox proportional hazards regression will be performed used to estimate adjusted hazard ratios and 95% confidence intervals (CIs) for ‘time to infection’. Odds ratios with 95% CIs will be estimated for every complication. A p value less than 0.05 will be considered significant.
Methods for additional analyses (e.g., subgroup analyses) {20b}
Subgroups will be divided according to their accompanying diseases including diabetes mellitus, malignant tumour (or haematologic malignancy), immune insufficiency (human immunodeficiency virus infection or organ transplantation), end-stage renal disease, or comorbidity of more than one of those conditions.
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
Data produced following protocol non-adherence will not be included in the study and will be disclosed. An effort will be made to reduce missing date to a minimum. We will handle missing data with multiple imputation (MICE Package, R ver. 4.0.3, The R Foundation for Statistical Computing, Vienna, Austria).
Plans to give access to the full protocol, participant level-data, and statistical code {31c}
The full protocol will be available at the registry website and is published here.
Oversight and monitoring
Composition of the coordinating centre and trial steering committee {5d}
The five authors (one from each institute) take full responsibility for scientific validity, study quality, study conduction, procedures, patient management after AEs and quality of final study result and reports. All five authors share information through periodic meetings and discuss the study and appropriate management when problems occur.
Composition of the data monitoring committee, its role, and reporting structure {21a}
Data monitoring will be held by each monitoring members in each institute. During monitoring, a data monitoring committee (DMC) will check whether the source document for the subject is appropriate, confirm that the consent acquisition process and storage are appropriate, review the overall trial performance, conduct e-CRF review, review the researcher's binder, collect any AEs from the subject, and follow. The committee is planning to monitor through verification of safety evaluation and data collection.
Any catheter-related AEs will be checked during the follow-up period and will be recorded at e-CRF. In case of more than grade II AEs, it will be reported to the principal investigator (DJ Shim) within 24 hours. Each DMC member will judge whether the AE is associated with the procedure, and any related AE will be immediate reported to the IRB and principal investigator. Each researcher should report any severe AE (≥ grade III) and any other unexpected problems to the IRB within 15 days.
Three independent members will be appointed to the data and safety monitoring board (DSMB; Seungjae Lee [Department of Applied Bioengineering, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Korea], Young Seo Cho [Department of Radiology, Hanyang University Guri Hospital, Guri-si, Gyeonggi-do, Republic of Korea], Minuk Kim [Department of Radiology, Seoul Metropolitan Government-Seoul National University Boramae Medical Center]).
Adverse event reporting and harms {22}
AEs will be classified according to the Common Terminology Criteria for Adverse Events (CTCAE) guideline [16]. If more than three minor AEs (< grade III) occur at one site, the investigator of that site will report the AEs to the DSMB. In case of one severe AE (CTCAE III, IV or V), a DSMB meeting will be held for safety evaluation. Daily checks for each case will be held by the research team of each institution, and will be communicated with the other research teams.
Frequency and plans for auditing trial conduct {23}
Patient monitoring by an independent monitor will take place until each of the new 200 cases are collected or every 3 months if cases do not reach 200. The inspection centre of each institution appointed inspectors to conduct systematic inspections of trial-related activities and documents. Evaluation of the patients and data will be totally independent from the investigators of each institution and the trial sponsors.
Interim analyses {21b}
Interim analyses will not be performed.
Plans for communicating important protocol amendments to relevant parties (e.g., trial participants, ethical committees) {25}
Any change of this trial protocol will be reported to the IRB of each institute and trial registry.
Dissemination plans {31a}
The results of this study will be published in a peer-reviewed medical journal.