PONE-D-24-44048 Study protocol: The effect of a low-carbohydrate enteral nutrition formula on postoperative hyperglycemia in non-diabetic patients with esophageal cancer: a randomized exploratory phase II trial (ENLICHE study) PLOS ONE

Dear Dr. Imamura,

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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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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: The authors present a study protocol to i investigate the impact of a low-carbohydrate EN

formula on hyperglycemic control during perioperative nutritional management of

esophageal cancer. They plan to recruit 50 patients to enroll in a single-center, randomized phase II trial with two arms (standard vs low-carbohydrate EN). Sample will be stratified by operation time and HbA1c. The primary outcome is the mean time-in-range across the 48 hours from postoperative day 1 to 2.

1. Line 6. Should more information, such as sex, diabetic status, etc, be collected at the enrollment as well?

2. Line 6. Please clarify when the enrollment for this study is, pre-operation or post-operation.

3. Line 18. The stratification is also based on HbA1c levels. Please clarify when this level is measured, enrollment, pre-operation, post-operation, or?

4. Line 23. “alternative formulations or reduce the dosage….” Will these participants be still included in the study? If so, how to deal with different treatments for different participants within the same group?

5. Line 15. “approximately 120 esophagectomies are performed annually.” Please clarify whether this refers to non-diabetic patients.

Reviewer #2: This study tackles an important but often overlooked issue in postoperative care—glycemic control in non-diabetic patients undergoing esophagectomy. The randomized controlled trial design gives it a solid foundation, but a few areas could be refined to improve clarity and real-world applicability. One key aspect that needs more attention is how preoperative metabolic variability and dietary habits might influence outcomes. Continuous glucose monitoring is a useful addition, but it would help to acknowledge its potential limitations, including sensor accuracy immediately after surgery and possible interference from perioperative medications. The stratification strategy based on operative time and HbA1c levels makes sense, but the decision to exclude pacemaker patients’ needs a clearer explanation. If it’s due to concerns about device interference or physiological differences, that should be explicitly stated.

This protocol has the potential to shape postoperative nutrition strategies for non-diabetic patients, an area where clear guidelines are still lacking. The manuscript makes a strong case for why glycemic management matters in this population, but widening the discussion to include other surgical contexts would make the findings even more relevant. While the hypothesis is well-reasoned, it would be helpful to consider real-world barriers to implementation, particularly in settings where specialized enteral formulas aren’t readily available.

Methodologically, the study is well-structured, with clear stratification criteria that improve comparability. The enteral nutrition protocol aligns with clinical practice, and safety measures for managing hypo- and hyperglycemia are well detailed. That said, the single-center design raises concerns about how generalizable the findings will be, and the open-label approach introduces potential bias. The authors should discuss how they plan to minimize these effects. The study also focuses narrowly on glucose control, but low carbohydrate enteral nutrition could have broader metabolic consequences, particularly on lipid metabolism and gut microbiota, which deserve at least a mention.

The statistical framework is solid, with time-in-range (TIR) as a meaningful primary outcome. The use of least squares mean difference and confidence intervals is appropriate, though it would be helpful to clarify how multiple comparisons are being handled. Given the likelihood of postoperative complications, a more detailed plan for managing missing data is needed. Subgroup analyses based on HbA1c levels or operative time could also add depth to the findings.

The manuscript is well-organized and follows transparency standards, with the SPIRIT checklist reinforcing protocol clarity. Minor refinements in the statistical methods section would improve readability. Ethical considerations are clearly addressed, with documented IRB approval and trial registration, which strengthens the study’s credibility.

While the authors acknowledge key limitations, they could go further in discussing long-term follow-up plans. The mention of a future phase III trial is promising, but it would be helpful to explain how this study’s results will shape that trial’s design. Addressing cost-effectiveness and practical barriers to using low carbohydrate enteral nutrition in routine care would also make the findings more applicable.

To strengthen this manuscript, the authors should clarify the rationale for excluding pacemaker patients, expand the discussion on metabolic effects beyond glucose control, provide a clearer strategy for handling missing data, and consider real-world implementation challenges. Refining statistical explanations and improving language precision would also enhance the manuscript.

Overall, this is a well-conceived and clinically relevant study. With a few revisions, it has strong potential for publication.

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Reviewer #1: No

Reviewer #2: No

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Study protocol: The effect of a low-carbohydrate enteral nutrition formula on postoperative hyperglycemia in non-diabetic patients with esophageal cancer: a randomized exploratory phase II trial (ENLICHE study)

PONE-D-24-44048R1

Dear Dr. Imamura,

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.

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Kind regards,

Steven E. Wolf, MD

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: Thanks for your appropriately addressing all the raised comments and concerns with updated manuscript. This reviewer has no further concerns.

Reviewer #2: The authors have satisfactorily addressed all of my prior concerns and clarified all points raised in my 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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