PONE-D-22-1613Biperiden for prevention of post-traumatic epilepsy: a protocol of a double-blinded placebo-controlled randomized clinical trial (BIPERIDEN trial)PLOS ONE

Dear Dr. Mello,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

We believe that the authors will easily answer the reviewers' comments, but I would also require some clarifications regarding the primary outcome:-I would like to be sure that any event (mortality, hospitalization, disability etc...) during a 2 year period after inclusion, will be regarded as positive for the primary outcome. -Is there rationale that an early a short prevention of epilepsy will affect re-hospitalisation for any cause (for example infection)-Would it be relevant to focus on death/rehospitalization related to neurologic issue / epilepsy?-As these events are the primary endpoint, please provide a definition of life-trheatening event, prolonged hospitalisation, disability, permanent damage-Please clarify why congenital birth/defect is in the primary endpoint because it looks more like a safety endpoint to me

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Raphael Cinotti, MD, PhD

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

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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

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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

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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

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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

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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 authors,

Thank you for giving me the Opportunity to review your study protocol entitled "Biperiden for prevention of post-traumatic epilepsy: a protocol of a double-blinded placebo-controlled randomized clinical trial".

It is a well-written manuscript and I read it with great interests.

Here are my comments in order to improve the manuscript.

1- Line 211: sentence "... with the advantage of having a great degree of safety..."

I would nuance this sentence because safety is one of the stakes in this RCT. I suggest to replace this part of the sentence by a formulation, as an example, like "and will confirm the great safety of the drug"

2- Line 242: "...will be conduct by specialized personnel."

Does it mean that this staff is trained to administer questionnaires on Quality of Life?

Minor remark: maybe the word staff would be more appropriate instead of personnel (line 234)

Kind regards

Reviewer #2: This is an interesting study protocol that will address a significant medical issue. The scientific rationale is well described, I have just a few comments regarding the study design

- Ethic. Inclusion can be made without consent due to the clinical situation, but it is not clear if the consent of the patient will be sought after the first 48 hours. It seems important since a 2-year follow-up is planned

- Standard of care. A better description of the anti-epileptic treatment of the control group is required: are preventive treatments completely forbidden? In case of prolonged sedation in comatose patients, are benzodiazepines allowed?

- Intervention period. A description of the treatment of epilepsy in the case of cloni during the first 6 days period of treatment is needed.

- End of treatment. Can the treatment be stopped in patients with epilepsy and not yet controlled ?

- Follow-up. In the case of patients with difficult-to-treat intracranial hypertension, or protracted comatose states, what is the policy to rule out a status epilepticus.

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Reviewer #1: Yes: Yoann Launey

Reviewer #2: Yes: Roquilly

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Attachments

Attachment

Submitted filename: PONE-D-22-16132_reviewer.pdf

Biperiden for prevention of post-traumatic epilepsy: a protocol of a double-blinded placebo-controlled randomized clinical trial (BIPERIDEN trial)

PONE-D-22-16132R1

Dear Dr. Mello,

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,

Hugh Cowley

Staff 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

**********

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

**********

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

**********

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

**********

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

**********

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 for having adressed the reviewer's comments. I have no supplementary coments and think the manuscript can go further in the publication process

Reviewer #2: The authors have appropriately responded to my comments and I congratulate them for promoting such a study

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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: Yoann Launey, MD, PhD

Reviewer #2: Yes: Antoine Roquilly

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