PONE-D-24-29935The effect of an additional pre-extubational loading dose of caffeine citrate on mechanically ventilated preterm infants (NEOKOFF trial): study protocol for a multicenter randomized clinical trialPLOS ONE

Dear Dr. Gasparics,

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Hasan Tolga Celik, M.D.

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

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4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. 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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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 #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Dear Author,

It has been a real challenge to determine the guidelines for caffeine therapy in preterm infants. Therefore, I would like to thank you for your contribution, which I find very important. However, I would kindly request that you address these points below:

- Please clarify the extubation criteria that are used in the study.

- Please state the criteria for extubation failure used in the study that further leads to reintubation.

- Would the chronological age on the day of extubation be important? Could you please comment on this matter?

Yours sincerely.

Reviewer #2: Important note: This review pertains only to ‘statistical aspects’ of the study and so ‘clinical aspects’ [like medical importance, relevance of the study, ‘clinical significance and implication(s)’ of the whole study, etc.] are to be evaluated [should be assessed] separately/independently. Further please note that any ‘statistical review’ is generally done under the assumption that study specific methodological [as well as execution] issues are perfectly taken care of by the investigator(s). This review is not an exception to that and so does not cover clinical aspects {however, seldom comments are made only if those issues are intimately / scientifically related & intermingle with ‘statistical aspects’ of the study}. Agreed that ‘statistical methods’ are used as just tools here, however, they are vital part of methodology [and so should be given due importance]. I look at the manuscript in/with statistical view point, other reviewer(s) look(s) at it with different angle so that in totality the review is very comprehensive. However, there should be efforts from authors side to improve (may be by taking clues from reviewer’s comments). Therefore, please do not limit the revision only (with respect) to comments made here.

COMMENTS: Although there is no major flaw in the study/manuscript [and it is on very vital/important topic {namely “Extubation which involves removal of an endotracheal tube (ETT) from the trachea. Early and successful extubation can reduce complications such as ventilation acquired pneumonia (VAP)}], I have different opinion / observations/concerns or rather questions regarding a few issues which are given below:

Please refer to section on ‘Sample size’. As stated in line 119, “The calculated sample size is 226 patients (113 participants/arm)” is perfectly right, however, you need to adjust (inflate by 10% at least) the required sample size in the light of the fact that the proposed Chi-square test is ‘non-parametric’. Instead, one can/should apply continuity-corrected Z test and then the required sample size is Total 248 (124 in A, 124 in B). Moreover, note the Chi-square test is always two tailed [alternative hypothesis is two sided], whereas, you are interested in one sided alternative hypothesis (which may not matter much in this case, however, one should keep this thermotical point in mind. See the screen-shot below [from software ‘COMPRE2’ module of WIN-PEPI].

In line 202 you stated ‘’ drop-out rate is expected to be minimal due to the one-time intervention” seems to be incorrect [of doubtful value] as one-time intervention could be one of reasons of keeping the drop-out rate to the minimal level [it is not due]. Your claim perhaps sound diffently. As stated in lines 212-214 (Continuous variables will be compared using the t-test or Mann-Whitney test, whereas the χ2 test or Fisher’s exact test will be used for dichotomous outcomes.) following notes are pasted [in this context] from one famous standard textbook on ‘Medical Research Methodology’ {though I am sure that the authors already know these things}.

1. Though few variables are continuous in appearance they are likely to yield data that are in [at the most] ‘ordinal’ level of measurement [and not in ratio level of measurement for sure]. Then application of suitable non-parametric (or distribution free) test(s) is/are indicated/advisable then [even if distribution may be ‘Gaussian’ (also called ‘normal’)]. Agreed that there is/are no non-parametric test(s)/technique(s) available to be used as alternative in all situation(s), but should be used whenever/wherever they are available. Therefore, in short use suitable non-parametric test(s)/technique(s) while dealing with data that are in ‘ordinal’ level of measurement even if [despite that] the distribution may be ‘Gaussian’.

2.

the Fisher’s exact test’ [which is commonly available in many software] is applicable to 2x2 tables only [for larger tables Exact Chi-square test is available – reference ‘A network algorithm for performing Fisher's exact test in r× c contingency tables’ Cyrus R Mehta, Nitin R Patel, Journal of the American Statistical Association, 1983, Volume: 78, Issue: 382, Pages 427-434].

Kindly provide more convincing explanation (give details) of the statement in lines 224-5: Due to the nature of the study population, participants do not need to be blinded and neither those performing the intervention nor treating clinicians will be blinded. Why you say that “participants do not need to be blinded” is not clear. You may be [most likely be] 100% correct (considering age & status of the subjects). What about ‘equipoise’ principle? Kindly remember [please excuse me for such a harsh comment/statement] that this is a scientific/academic document and so all details should be clearly/correctly communicated (do not take reader’s for granted).

It is appreciable that in line 47-8 you stated “Preterm infants in the control group will receive the standard dosing regimen” and later lines 142-3 that “The control group will receive the above-mentioned routine dosing regimens” as it is very important that the control group should receive the routine (present standard of care) dosing regimens [/ active controls] in such trials. I suggest to mention this fact [handling of the control group] more prominently (as these are the only two occasions).

Good that Supporting information includes [S1 File:] SPIRIT checklist. But referring to CONSORT guidelines is also desirable. It is well-known that while reporting {findings from and even planning} ‘Clinical Trial’ one should follow CONSORT guidelines. Since your article type is protocol of ‘Clinical Trial’, you are supposed to cover these items in the report or even in ‘Protocol’ (even if you may not use them)]. Surprisingly, any information is not proposed to be displayed in tables. All important information is planned to be included only as ‘Supporting information’ and not in the main text [highly desirable].

Limitations (if any) of the study are not mentioned/listed anywhere. Does that mean {according to authors} there are none? As pointed out in ‘important note’ above “This review pertains only to ‘statistical aspects’ of the study and so ‘clinical aspects’ should be assessed separately/independently. In my opinion, to make this article more (completely) acceptable (which is quite possible and easy), a small amount of re-vision (re-drafting) may be needed. ‘Minor revision’ is recommended.

Reviewer #3: I had the pleasure to review the article titled “The effect of an additional pre-extubational loading dose of caffeine citrate on mechanically ventilated preterm infants (NEOKOFF trial): study protocol for a multicenter randomized clinical trials”.

The authors aim to investigate whether administering an additional loading dose of caffeine citrate one hour prior to extubation improves the success of extubation. The article is presented as a multicenter randomized clinical trial protocol.

Abstract:

- Aim: The specific aim or objective of the study should be explicitly stated in the abstract to clarify the central research question.

Methods:

- Inclusion Criteria: It would be helpful to specify whether there is a threshold for chronological age among the participants.

- Randomization: The randomization procedure mentions an allocation ratio of 1:1, but it would be beneficial to provide more clarity on how this will be achieved or operationalized within the trial.

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Reviewer #1: Yes: Alper Aykanat

Reviewer #2: No

Reviewer #3: No

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Attachments

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Submitted filename: renamed_1016f.docx

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Submitted filename: review_10.24.docx

The effect of an additional pre-extubational loading dose of caffeine citrate on mechanically ventilated preterm infants (NEOKOFF trial): study protocol for a multicenter randomized clinical trial

PONE-D-24-29935R1

Dear Dr. Amos Gasparics,

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,

Hasan Tolga Celik, M.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Yes

Reviewer #2: Partly

Reviewer #3: Yes

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3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. 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

**********

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 #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Thank you very much for your comments, which I find very comprehensive and adequate.

I am looking forward to see the final results of your study.

Reviewer #2: COMMENTS: All most all the comments made on earlier draft are/were considered positively & are attended {however not all reasons/arguments are very convincing}. Nevertheless, I recommend the acceptance.

Kindly note that statement [in one of the responses] “…given reasoning was accepted by the competent authority, and we received the ethical approval” is not sufficient/adequate (rather undesirable).

Reviewer #3: The authors have addressed all my comments thoroughly and to my satisfaction, demonstrating a clear effort to enhance the quality of the work.

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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 #1: Yes: Alper Aykanat

Reviewer #2: No

Reviewer #3: No

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