PONE-D-25-27081 Evaluation effect of umbilical cord blood serum drops in the treatment of severe dry eye in patients with Sjogren's syndrome and mustard gas chemical veterans: Protocol for a randomized clinical trial PLOS ONE

Dear Dr. rostami,

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Yu-Chi Liu, MD, PhD

Academic Editor

PLOS ONE

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Additional Editor Comments (if provided):

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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: Partly

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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: Partly

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: No

Reviewer #2: No

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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

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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: As the statistical reviewer I will focus on methods and reporting. Overall the approaches are appropriate and clearly reported.

Major

1) I would recommend regression based modeling to estimate ORs and SEs for the outcomes of interest, so they can be used in power calculations (as opposed to p-values)

2) Please follow the CONSORT statement.

3) linked to point 1, please clarify how findings will inform future power calculations and for which outcome.

4) clarify how you will deal with missing data in the trial. multiple imputation?

5) I don't understand why participants are not blinded - a clear justification is needed since this is a major limitation for the primary (self-reported) outcome.

Minor

1) justify the selected sample, is it just down to feasibility? resources?

2) Can you clarify where and how data will be shared?

Reviewer #2: This study protocol addresses a clinically relevant problem, and the use of human umbilical cord blood serum drops represents an innovative approach. This therapy may offer an effective treatment option for severe dry eye in patients with Sjögren’s syndrome and chemical ocular injury by using biologically active components with regenerative potential. However, several methodological and reporting issues need clarification and refinement to strengthen the protocol.

Study design: The trial includes two distinct populations, Sjögren’s patients and mustard gas–exposed veterans. The rationale for including both groups is not clearly explained. Based on the methods, it appears that the analyses for the two populations will be conducted independently. A clearer justification for this hybrid design is needed, and the background section should better support the inclusion of mustard gas–exposed patients.

Title: The current title is somewhat confusing. The study combines a between group RCT (Group A and B) with a within-subject paired-eye design (group C). However, the primary comparison is not directly between the Sjogren's syndrome and mustard gas chemical injury. Consider revising the title to more accurately reflect the study design and objectives.

Sample size: No sample size calculation is provided. The protocol would be strengthened by using preliminary or pilot data to estimate the number of participants needed per group, along with the expected effect size, power, and significance level. Without this information, it is difficult to assess feasibility and statistical robustness.

Follow-up duration: The proposed 60-day follow-up may be too short to capture sustained treatment effects, particularly in chronic conditions such as Sjögren’s syndrome and chemical injury–related dry eye. A longer follow-up period should be considered if feasible.

Outcome measures: The current outcome set is limited to conventional clinical and patient-reported measures. Including additional objective endpoints, such as in vivo confocal microscopy (IVCM), could provide valuable insight into corneal nerve changes and ocular surface regeneration, thereby strengthening the study’s conclusions.

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Reviewer #1: No

Reviewer #2: Yes: Chang Liu

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Evaluation of umbilical cord blood serum eye drops for severe dry eye in two distinct populations—Sjögren’s syndrome and mustard gas–induced ocular injury: Protocol for a pilot randomized clinical trial

PONE-D-25-27081R1

Dear Dr. rostami,

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,

Yu-Chi Liu, MD, PhD

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

**********

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: I am satisfied with the authors' responses and the resulting changes to the paper. Nothing else to add.

Reviewer #2: Thank you for the authors’ revisions. The authors have addressed and explained my previous comments, and the manuscript has been improved. As a study protocol, I have no further major concerns and recommend the manuscript for publication after minor editorial review.

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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: No

Reviewer #2: No

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