PONE-D-20-30158

Prevention of tunneled cuffed catheter dysfunction with prophylactic use of a taurolidine urokinase locks: a prospective and randomized double-blind trial

PLOS ONE

Dear Dr. Wissing

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Pasqual Barretti, Ph.D., MD

Academic Editor

PLOS ONE

Additional Editor Comments:

The manuscript is interesting, well written and appropriate in relation to its methodology. However, reviewers 1 and 3 made important suggestions, which can greatly improve the final wording. So, my option is major revision

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2. During your revisions, please note that a simple title correction is required: the title in the manuscript file describes "use of a taurolidine urokinase lock", whereas the submission site describes "use of a tarolidine urokinase locks". Please update the online submission information to remove the "s" from "lock".

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4. Thank you for including your ethics statement:  This study was conducted according to the Helsinki Declaration of 1975 and approved by the central ethic committee of the Universitair Ziekenhuis Brussel (UZ Brussel) in Brussels, Belgium and each local participating ethic committee (B.U.N 143201523891)"

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: I have reviewed carefully the manuscript entitled “Prevention of tunneled cuffed catheter dysfunction with prophylactic use of a taurolidine urokinase locks: a prospective and randomized double-blind trial” (PONE-D-20-30158) by Florence Bonkain et al.

This multicentered, double-blinded randomized controlled study was conducted enrolling 68 hemodialysis patients (36 patients in the TaurolockU group and 32

patients in the control group) from eight Belgian hemodialysis units between May 2015 and June 2017.

After a follow-up of 9875 catheter days (5017 days for the TaurolockU group and 4858 days for the control group), the study demonstrated that prophylactic use of urokinase locks once per week is highly effective in reducing the number of thrombotic catheter dysfunctions without increasing total cost for patients with a history of recurring catheter dysfunction.

Generally speaking, this manuscript is a well-prepared work.

The study's theme is intriguing and clinically important.

The English writing, including the expression, fluency, and readability of this manuscript is good.

However, I have several minor comments

[Title]

# Is it necessary to add a term “prospective” in front of a “randomized double-blind trial?”

[Abstract]

# Some necessary components (ex: the source and number of participants, study place and period…etc.) are lacking in the abstract section

[Results]

# The control group has significantly longer “duration of dialysis” than the intervention group ((median, IQR) , 4.40 (1.8-8.3) versus 2.7 (1.1-4.5), p=0.01). I suggest that the authors make comment regarding the association between “duration of dialysis” and “dysfunction of catheter” in Discussion section.

Reviewer #2: The authors successfully define the study outcomes and gap in literature that their study addresses, with a a clear methodology, appropriate statistical analysis, and conclusions based on the data. Primary outcome, its measurement, time points at which measurements were taken for the primary outcome, and the analysis metric were all satisfactory according to the CONSORT criteria.

Sample size calculations were included taking in to account predicted rate of attrition. Recruitment and justification of the number of participants was satisfactory. The authors provide a reference to their published study protocol. Allocations within each arm of the study were done in a method which could not be predicted.

Statistical analysis supports the conclusions of the paper both within primary and secondary outcomes with statistical tests named and rationale described, as well as explaining cost-effectiveness between the 2 interventions was not significant in the context of the study and its implementation. The lack of adverse events was clearly addressed by the authors.

The authors have submitted a well-designed study which satisfies the CONSORT criteria, as well as satisfying its primary outcome measure. The null hypothesis can be rejected as the authors demonstrate that prophylactic use of taurolidine uorkinase lock in the defined group reduces the number

of thrombotic TCC dysfunction compared to taurolidine heparin locks, taking into account of other factors which may influence the outcomes.

It is the opinion of this reviewer that the study is suitable for publication.

Reviewer #3: This is a nice paper. The data are very interesting and relevant.

I have three concerns:

1. The statistical analysis performed do not take acount the misbalance between groups in regard of duration of dialysis. To this is required a generalized linear model.

2. In a cohort in which outcome may occur at many points of time, there is a need for Cox analysis regression that compares the hazard risk of outcome (catheter thrombosis), take account the time interval between the time zero to the event, and make survival curves adjusted to the misbalances between groups. In this case, bivariate analysis will be sufficient because groups were heterogeneous only in regard of the duration of dialysis.

2. Author should take into account the cost of waste of time to make thrombolysis in a catheter in the cost analysis.

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Reviewer #1: Yes: Chih-Chung Shiao

Reviewer #2: Yes: Habib Akbani

Reviewer #3: No

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Prevention of tunneled cuffed catheter dysfunction with prophylactic use of a taurolidine urokinase lock: a randomized double-blind trial

PONE-D-20-30158R1

Dear Dr. Wissing, 

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Pasqual Barretti, Ph.D., MD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

The manuscript can be accepted for publication, But, I strongly recommend the authors do the suggestion from the reviewer 4> Table 5 - is footnote 3 still required?

Figure 2 - is 1 patient missing from the figure? The N at risk are 32 and 35 for the groups - should be 36?

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

Reviewer #4: (No Response)

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: (No Response)

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: I thank my fellow reviewers for suggesting improvements upon the original manuscript. It is clear that the authors have done an excellent job in addressing their concerns, and I would like to in particular draw attention to the robust detail of statistical analysis that has been completed. My previous comments remain:

The authors successfully define the study outcomes and gap in the literature that their study addresses, with a clear methodology, appropriate statistical analysis, and conclusions based on the data. The primary outcome, its measurement, time points at which measurements were taken for the primary outcome, and the analysis metric were all satisfactory according to the CONSORT criteria.

Sample size calculations were included taking into account the predicted rate of attrition. Recruitment and justification of the number of participants were satisfactory. The authors provide a reference to their published study protocol. Allocations within each arm of the study were done in a method that could not be predicted.

The statistical analysis supports the conclusions of the paper both within primary and secondary outcomes with statistical tests named and rationale described, as well as explaining cost-effectiveness between the 2 interventions was not significant in the context of the study and its implementation. The lack of adverse events was clearly addressed by the authors.

The authors have submitted a well-designed study that satisfies the CONSORT criteria, as well as satisfying its primary outcome measure. The null hypothesis can be rejected as the authors demonstrate that prophylactic use of taurolidine UK in the defined group reduces the number

of thrombotic TCC dysfunction compared to taurolidine heparin locks, taking into account other factors which may influence the outcomes.

It is the opinion of this reviewer this manuscript remains suitable for publication and I thank the authors for making appropriate changes.

Reviewer #3: All questions were completely adressed. I want to greet the authors by the nice study. The answers were sactisfatory an the changes were made.

Reviewer #4: Table 5 - is footnote 3 still required?

Figure 2 - is 1 patient missing from the figure? The N at risk are 32 and 35 for the groups - should be 36?

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: Yes: Habib Akbani

Reviewer #3: No

Reviewer #4: No