Low-methoxy pectin-containing enteral nutrition in critical care for intestinal tolerance (LOME-PECT): Study protocol for a randomized controlled trial

Shizuka Kashiwagi; Shunsuke Takaki; Yasufumi Oi; Hiroshi Honzawa; Ryo Yamamoto; Ikutaro Yamashita; Izumi Ohki; Shigeki Fujitani; Akiyoshi Nagatomi; Yuki Ohshima; Minoru Yoshida; Hideki Yoshida; Miyuki Kurisu; Yuji Takahashi; Hideki Hashimoto; Yasuaki Koyama; Junji Hatakeyama; Satoru Shinoda; Nobuyuki Yokoyama; Kensuke Nakamura

doi:10.1371/journal.pone.0326582

Peer Review History

Original SubmissionDecember 11, 2024
22 Apr 2025 Decision Letter - Belgin Sever, Editor Dear Dr. Nakamura, 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. Please submit your revised manuscript by Jun 06 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. 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We look forward to receiving your revised manuscript. Kind regards, Belgin Sever, Ph.D. Academic Editor PLOS ONE Journal Requirements: When submitting your revision, we need you to address these additional requirements. 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf . 2. Thank you for stating in your Funding Statement: “This trial is supported by grants from Otsuka Pharmaceutical Co., Ltd. (No. MF23-2)” Please provide an amended statement that declares all the funding or sources of support (whether external or internal to your organization) received during this study, as detailed online in our guide for authors at http://journals.plos.org/plosone/s/submit-now. Please also include the statement “There was no additional external funding received for this study.” in your updated Funding Statement. Please include your amended Funding Statement within your cover letter. We will change the online submission form on your behalf. 3. Thank you for stating the following in the Acknowledgments Section of your manuscript: “The LOME-PECT trial is supported by grants from Otsuka Pharmaceutical Co., Ltd. (No. MF23-2)” We note that you have provided additional information within the Acknowledgements Section that is not currently declared in your Funding Statement. Please note that funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form. Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows: “This trial is supported by grants from Otsuka Pharmaceutical Co., Ltd. (No. MF23-2)” Please include your amended statements within your cover letter; we will change the online submission form on your behalf. 4. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information. 5. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. Additional Editor Comments (if provided): [Note: HTML markup is below. Please do not edit.] 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? Reviewer #1: 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??> Reviewer #1: Yes ****** 3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable??> Reviewer #1: 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 Reviewer #1: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes ****** 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. Reviewer #1: The authors present a protocol for a randomized control trial comparing to enteric nutrition (EN) formulas in critically ill patients in the ICU requiring EN in Japan. The manuscript will be strengthened if the authors consider the following points. 1. Line 305-306: authors state there is no time limit between enrollment and initiation of EN, but is there a typical time window in which they expect this to be started? It might be helpful to provide a typical range of time. 2. Will any comparisons of the groups be made to assess how well randomization balanced the groups? It would be important to know if there are any differences at "baseline". 3. line 453: authors refer to subgroup analyses, but they include some continuous variables in the list of variables that will be considered for sub-groups. The protocol (in supplemental material) includes more specific sub-groups for age, BMI, and SOFA, which would be helpful to include in the manuscript. SOFA should also be defined. The protocol also includes subcategories of diseases for the sub-groups, so that should also be included in the manuscript. 4. Further details should be provided for the analysis of the secondary outcomes. There is no mention of how comparisons between groups will be made and there are different types of outcomes included as secondary outcomes than the primary outcome, so analytic techniques will presumably be different. 5. Lines 570-571: authors state that written informed consent will be obtained from all potential participants - is this really feasible for someone in the ICU? ****** 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 ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/ . PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org https://doi.org/10.1371/journal.pone.0326582.r001
Revision 1
16 May 2025 Author Response Responses to the Reviewers Reviewer(s)' Comments to the Author: Journal Requirements: 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf. Our response: According to the style requirements, we changed the font size and file name and moved the figure caption. 2. Thank you for stating in your Funding Statement: “This trial is supported by grants from Otsuka Pharmaceutical Co., Ltd. (No. MF23-2)” Please provide an amended statement that declares all the funding or sources of support (whether external or internal to your organization) received during this study, as detailed online in our guide for authors at http://journals.plos.org/plosone/s/submit-now. Please also include the statement “There was no additional external funding received for this study.” in your updated Funding Statement. Please include your amended Funding Statement within your cover letter. We will change the online submission form on your behalf. Our response: We provided an amended Funding Statement. We also added in the cover letter that we received no additional external funding for this study. 3. Thank you for stating the following in the Acknowledgments Section of your manuscript: “The LOME-PECT trial is supported by grants from Otsuka Pharmaceutical Co., Ltd. (No. MF23-2)” We note that you have provided additional information within the Acknowledgements Section that is not currently declared in your Funding Statement. Please note that funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form. Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows: “This trial is supported by grants from Otsuka Pharmaceutical Co., Ltd. (No. MF23-2)” Please include your amended statements within your cover letter; we will change the online submission form on your behalf. Our response: In accordance with the journal’s requirement, we have removed the section entitled ”Competing Interests” and “Source of Funding” from the manuscript to exclude funding sources in the manuscript. We have also amended funding statement in the cover letter. 4. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information. Our response: We added supporting information section to the manuscript and added supporting files including SPIRIT checklist. 5. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. Our response: We have verified that the references are complete and correct. Reviewer #1: Reviewer #1: The authors present a protocol for a randomized control trial comparing to enteric nutrition (EN) formulas in critically ill patients in the ICU requiring EN in Japan. The manuscript will be strengthened if the authors consider the following points. Our response: We wish to express our appreciation to the reviewer for careful review and insightful comments on our paper. 1. Line 305-306: authors state there is no time limit between enrollment and initiation of EN, but is there a typical time window in which they expect this to be started? It might be helpful to provide a typical range of time. Our response: We appreciate the reviewer’s insightful comment. As noted, there is no strict time limit between enrollment and initiation of EN. However, in practice, EN is typically initiated within 24 hours following enrollment. Moreover, in order to minimize cases where EN could not be commenced post-enrollment, we take care to initiate EN immediately after the enrollment. We have clarified these points in the revised manuscript as follows. Lines: 308-312 There is no time limit between enrollment and the initiation of EN. However, there are minimal practical barriers to starting EN in the enrolled patients, and efforts to align enrollment timing with EN initiation are encouraged in order to minimize cases where EN could not be commenced post-enrollment. Therefore, EN is expected to be initiated within 24 hours. 2. Will any comparisons of the groups be made to assess how well randomization balanced the groups? It would be important to know if there are any differences at "baseline". Our response: We appreciate the reviewer’s insightful comment. We will collect background factors of enrolled patients and calculate summary statistics. However, between-group comparisons will not be conducted, as the aim is to characterize the overall study sample rather than to test for group differences. To clarify this point, we have revised the manuscript and added a supplemental table for background data to be collected. Accordingly, we have added abbreviations. Lines 431-437 Baseline data to be collected consist of background characteristics, disease category, Sequential Organ Failure Assessment (SOFA), nutrition screening based on the Malnutrition Screening Tool (MUST), laboratory test, and gastrointestinal symptoms including Bristol scale. Details of these items are shown in S1Table. Descriptive statistics will be calculated to summarize these variables. Between-group inferential statistical comparisons will not be conducted, as these analyses are intended for descriptive purpose only. 3. line 453: authors refer to subgroup analyses, but they include some continuous variables in the list of variables that will be considered for sub-groups. The protocol (in supplemental material) includes more specific sub-groups for age, BMI, and SOFA, which would be helpful to include in the manuscript. SOFA should also be defined. The protocol also includes subcategories of diseases for the sub-groups, so that should also be included in the manuscript. Our response: We appreciated the Reviewer’s comment on this point. We revised the details of subgroup analyses as follows. We also cited an article which refers to SOFA. Lines: 477-482 To examine the interaction effect, subgroup analyses will be performed with the following subgroups: sex, age (<70 years old/ ≥70 years old), BMI (≤20/ 20< BMI ≤30/ ≥30), SOFA scores (less than 2 points in one or more items/others), and disease category (infectious disease, heart failure, respiratory failure, stroke, renal or metabolic diseases, postoperative, post-cardioplumonary resuscitation, trauma, other). 4. Further details should be provided for the analysis of the secondary outcomes. There is no mention of how comparisons between groups will be made and there are different types of outcomes included as secondary outcomes than the primary outcome, so analytic techniques will presumably be different. Our response: We appreciate the reviewer’s insightful comment. We revised the manuscript as follows for the secondary outcomes analysis method. Lines 475-497 Frequencies will be calculated for binary data, including the incidence of diarrhea, the rate of EN failure, and the survival rate on Day 28. Continuous variables assumed to follow a normal distribution, such as age, height, and weight, will be presented as means and standard deviations. Variables not assumed to follow a normal distribution, such as ICU stay, hospital stay, and ventilator days, will be reported as medians and interquartile ranges. Pearson’s chi-square test will be employed to compare groups for the primary endpoint. In principle, a two-tailed test is conducted with a significance level of 5% and CI of 95%. To examine the interaction effect, subgroup analyses will be performed with the following subgroups: sex, age (<70 years old/ ≥70 years old), BMI (≤20/ 20< BMI ≤30/ ≥30), SOFA scores (less than 2 points in one or more items/others)(12), and disease category (infectious disease, heart failure, respiratory failure, stroke, renal or metabolic diseases, postoperative, post-cardioplumonary resuscitation, trauma, other). Regarding secondary endpoints and adverse events, between-group comparisons for binary outcomes will be analyzed using confidence intervals for differences in population proportions, while continuous outcomes will be analyzed by confidence intervals in means or medians. Additionally, as a post-hoc analysis, a subgroup analysis will be conducted based on the above results. 5. Lines 570-571: authors state that written informed consent will be obtained from all potential participants - is this really feasible for someone in the ICU? Our response: We appreciated the Reviewer’s comment. As the reviewer pointed out, because this study involves ICU patients, it is often not possible to obtain consent directly from participants. In such cases, written informed consent will be sought from the participant’s legally authorized representatives including parents, siblings, or children. Additionally, due to the nature of ICU admissions, particularly during holidays or nighttime hours, it may not be feasible to obtain consent from all potential participants immediately. We revised the manuscript to clarify this point and ensure consistency Lines 612-614 Written informed consent will be sought from all potential participants or their representatives. Attachments Attachment Submitted filename: responseletter_PLOS_ONE_20250514SK.docx https://doi.org/10.1371/journal.pone.0326582.r002
3 June 2025 Decision Letter - Belgin Sever, Editor <p>Low-methoxy pectin-containing enteral nutrition in critical care for intestinal tolerance (LOME-PECT): study protocol for a randomized controlled trial. PONE-D-24-55750R1 Dear Dr. Nakamura, 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. An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Belgin Sever, Ph.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? Reviewer #1: 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??> Reviewer #1: Yes ****** 3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable??> Reviewer #1: 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 Reviewer #1: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes ****** 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. Reviewer #1: The authors have adequately addressed all of my earlier comments, so I have no further comments to add. ****** 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 ******** https://doi.org/10.1371/journal.pone.0326582.r003
Formally Accepted
Acceptance Letter - Belgin Sever, Editor PONE-D-24-55750R1 PLOS ONE Dear Dr. Nakamura, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset You will receive further instructions from the production team, including instructions on how to review your proof when it is ready. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few days to review your paper and let you know the next and final steps. Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. If we can help with anything else, please email us at customercare@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Assoc. Prof. Dr. Belgin Sever Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0326582.r004

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