Effectiveness and safety of an absorbable modified polymer starch powder hemostat versus usual care in gynecology procedures: A prospective, multi-center, and randomized study

Jordi Ponce; Amparo García-Tejedor; Marc  Barahona; Serena Cappuccio; Barbara Costantini; Camilla Fedele; Lola  Marti-Cardona; Giovanni Scambia

doi:10.1371/journal.pone.0331376

Peer Review History

Original SubmissionJanuary 18, 2025
21 Mar 2025 Decision Letter - Hideto Sano, Editor PONE-D-25-02293Effectiveness and safety of an absorbable modified polymer starch powder hemostat versus usual care in gynecology procedures: A prospective, multi-center, and randomized study.PLOS ONE Dear Dr. Garcia-Tejedor, 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 May 05 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. 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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. We note that the grant information you provided in the ‘Funding Information’ and ‘Financial Disclosure’ sections do not match. When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for your study in the ‘Funding Information’ section. 3. Thank you for stating the following financial disclosure: [Cryolife, Europe Baxter (Founded Medical writing)]. Please state what role the funders took in the study. If the funders had no role, please state: ""The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."" If this statement is not correct you must amend it as needed. Please include this amended Role of Funder statement in your cover letter; we will change the online submission form on your behalf. 4. Thank you for stating the following in the Competing Interests section: [Barbara Costantini, Jordi Ponce and Giovanni Scambia served as speakers for Baxter and have received speaker honoraria according to fair market value.]. Please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials, by including the following statement: ""This does not alter our adherence to PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests). If there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared. Please include your updated Competing Interests statement in your cover letter; we will change the online submission form on your behalf. 5. We note that you have indicated that there are restrictions to data sharing for this study. For studies involving human research participant data or other sensitive data, we encourage authors to share de-identified or anonymized data. However, when data cannot be publicly shared for ethical reasons, we allow authors to make their data sets available upon request. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. Before we proceed with your manuscript, please address the following prompts: a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information, data are owned by a third-party organization, etc.) and who has imposed them (e.g., a Research Ethics Committee or Institutional Review Board, etc.). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent. b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of recommended repositories, please see https://journals.plos.org/plosone/s/recommended-repositories. You also have the option of uploading the data as Supporting Information files, but we would recommend depositing data directly to a data repository if possible. Please update your Data Availability statement in the submission form accordingly. 6. 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. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: No Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: No Reviewer #2: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). 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 ****** 4. 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 ****** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: The study lacks a statistically valid sample size justification. That could not be found in the protocol, either. The paper mentions that 90 subjects are needed as per the protocol. How was that calculated? This reviewer found no valid statistical design section in the protocol unless it is under another section. One should not have to search for this information. Section 9.0 (Statistical Considerations) of the protocol is totally inadequate. All it mentions is an ITT and per protocol strategy. Where or what was the intended non inferiority margin? Since non inferiority was mentioned in the manuscript, it should have been incorporated into the design of the study. Apparently the ITT and per protocol results compare as they are the same as noted in Table 3. However, even though the groups look fairly balanced was there any attempt to look at covariate association for achieving hemostasis along with treatment in a multivariate setting such as the logistic regression? The investigation does seem incomplete, unless other possible associative factors with hemostasis are examined in a more rigorous statistical setting. The statistical handling of this data (design and analysis) is obviously incomplete. Reviewer #2: I found the manuscript, to be of high quality. The methodology is sound, the data are presented clearly, and the discussion is insightful. The authors have effectively addressed the research question, and the article is well-designed for publication ****** 6. 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: Yes: Selim Misirlioglu ******** [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 . Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0331376.r001
Revision 1
25 Apr 2025 Author Response Response to the reviewers, manuscript PONE-D-25-02293, entitled “Effectiveness and safety of an absorbable modified polymer starch powder hemostat versus usual care in gynecology procedures: A prospective, multi-center, and randomized study”. Dear Editor-in-Chief, I have considered the comments made by the reviewers and I hope that the paper improves greatly thanks to these comments. I am sending you the revised manuscript and the rebuttal letter providing a point-by-point response to each of the numbered reviewer comments. #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. We note that the grant information you provided in the ‘Funding Information’ and ‘Financial Disclosure’ sections do not match. When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for your study in the ‘Funding Information’ section. It was corrected. No specific numbers have been assigned to the Grants received. 3. Thank you for stating the following financial disclosure: [Cryolife, Europe Baxter (Founded Medical writing)]. Please state what role the funders took in the study. If the funders had no role, please state: ""The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."" If this statement is not correct you must amend it as needed. Please include this amended Role of Funder statement in your cover letter; we will change the online submission form on your behalf. Thank you very much indeed for the comment, we highly appreciate it. The following sentence was added in the Funding section and in the cover letter: “Cryolife was involved in study funding, study design, provision of study materials, data collection and analysis”. “Baxter was involved in medical writing funding, preparation of the manuscript, decision to publish”. 4. Thank you for stating the following in the Competing Interests section: [Barbara Costantini, Jordi Ponce and Giovanni Scambia served as speakers for Baxter and have received speaker honoraria according to fair market value.]. Please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials, by including the following statement: ""This does not alter our adherence to PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests). If there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared. Please include your updated Competing Interests statement in your cover letter; we will change the online submission form on your behalf. The following sentence was added in the “Conflict of Interests” section and in the cover letter: “This does not alter our adherence to PLOS ONE policies on sharing data and materials.” 5. We note that you have indicated that there are restrictions to data sharing for this study. For studies involving human research participant data or other sensitive data, we encourage authors to share de-identified or anonymized data. However, when data cannot be publicly shared for ethical reasons, we allow authors to make their data sets available upon request. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. Before we proceed with your manuscript, please address the following prompts: a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information, data are owned by a third-party organization, etc.) and who has imposed them (e.g., a Research Ethics Committee or Institutional Review Board, etc.). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent. b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of recommended repositories, please see https://journals.plos.org/plosone/s/recommended-repositories. You also have the option of uploading the data as Supporting Information files, but we would recommend depositing data directly to a data repository if possible. Please update your Data Availability statement in the submission form accordingly. The following sentence was added in the Data Availability Statement: “Our study utilizes third-party data that are the property of Artivion, formerly known as CryoLife Europa. As these data are proprietary, they cannot be publicly shared. However, interested researchers may contact Artivion directly to inquire about potential access to the data (https://artivion.com/; 1655 Roberts Blvd., NW; Kennesaw, GA 30144 USA.”. 6. 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. It was corrected. Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: No Reviewer #2: Yes 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: No Reviewer #2: Yes 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). 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 4. 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 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters). Reviewer #1: 1. The study lacks a statistically valid sample size justification. That could not be found in the protocol, either. The paper mentions that 90 subjects are needed as per the protocol. How was that calculated? This reviewer found no valid statistical design section in the protocol unless it is under another section. One should not have to search for this information. Section 9.0 (Statistical Considerations) of the protocol is totally inadequate. All it mentions is an ITT and per protocol strategy. Where or what was the intended non inferiority margin? Since non inferiority was mentioned in the manuscript, it should have been incorporated into the design of the study. Thank you very much indeed for the comment, we highly appreciate it. We fully agree with the reviewer about the limitation of the lack of statistically valid sample size justification. This was added as a study limitation. The current study was a Phase IV, observational (post-market) study designed to provide descriptive and exploratory data rather than confirmatory evidence. As stated in the study protocol, the sample size was not determined to achieve a specific statistical power to detect differences between the PerClot and Standard of Care (SoC) patient populations. Instead, this study followed an observational, case-controlled design, in which patients were grouped based on treatment exposure rather than through true randomization, which is characteristic of experimental studies such as randomized controlled trials (RCTs). The PerClot group represented the case study cohort, while the SoC group served as the control, allowing for comparative assessment of specific clinical characteristics between the two cohorts. Given the exploratory nature of this study, our primary objective was to gather preliminary evidence rather than to definitively establish non-inferiority. Although prospective sample size calculation is the preferred methodological approach, as the reviewer correctly noted, a post-hoc analysis was conducted to estimate the number of patients required to detect significant differences based on the observed results. This analysis provided valuable insights into the potential adequacy of the study’s sample size, reinforcing the descriptive and hypothesis-generating role of this investigation. The following paragraph was added as a study limitation: “Another important limitation of this study is the lack of a statistically valid sample size justification. While a prospective sample size calculation would have been the ideal approach, a post-hoc analysis was performed to estimate the number of patients required to detect significant differences based on the observed results. With an alpha risk of 0.05 in a two-sided test and sample sizes of 44 patients in the AMP group and 46 in the SC group, the statistical power to detect the observed differences as significant was only 16%. Furthermore, to achieve a power of 80% with an alpha of 0.05, a total of 353 patients per group would have been required for the observed differences in the proportion of patients achieving hemostasis within 10 minutes to reach statistical significance”. 2. Apparently the ITT and per protocol results compare as they are the same as noted in Table 3. However, even though the groups look fairly balanced was there any attempt to look at covariate association for achieving hemostasis along with treatment in a multivariate setting such as the logistic regression? The investigation does seem incomplete, unless other possible associative factors with hemostasis are examined in a more rigorous statistical setting. The statistical handling of this data (design and analysis) is obviously incomplete. Thank you for your insightful comment. We fully acknowledge the importance of examining potential covariate associations with hemostasis in a more rigorous statistical framework, such as logistic regression, to strengthen the analysis. Unfortunately, we do not have access to the original dataset but only to the statistical report provided by the study promoter, which limits our ability to perform additional multivariate analyses. Consequently, we are unable to explore potential confounding factors that may influence hemostasis outcomes. While our study primarily focused on comparing ITT and per-protocol results, we recognize that a more comprehensive statistical approach could provide further insights. We appreciate your valuable suggestion and acknowledge this as a limitation of our study. The following sentence was added as a limitation of the study: “Additionally, the absence of a multivariate analysis to assess potential covariate associations with hemostasis, which could have offered a more detailed statistical evaluation, may be considered a limitation of the study”. Reviewer #2: I found the manuscript, to be of high quality. The methodology is sound, the data are presented clearly, and the discussion is insightful. The authors have effectively addressed the research question, and the article is well-designed for publication. Thank you very much indeed for this insightful comment; we truly appreciate it. Attachments Attachment Submitted filename: Rebuttal letter PerClot PlosOne R1 1.1.docx https://doi.org/10.1371/journal.pone.0331376.r002
19 Jun 2025 Decision Letter - Hideto Sano, Editor PONE-D-25-02293R1Effectiveness and safety of an absorbable modified polymer starch powder hemostat versus usual care in gynecology procedures: A prospective, multi-center, and randomized study.PLOS ONE Dear Dr. Garcia-Tejedor, 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 Aug 03 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. Please include the following items when submitting your revised manuscript: 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'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols . We look forward to receiving your revised manuscript. Kind regards, Hideto Sano Academic Editor PLOS ONE Journal Requirements: 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. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: All comments have been addressed Reviewer #3: (No Response) Reviewer #4: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: (No Response) Reviewer #3: No Reviewer #4: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: (No Response) Reviewer #3: No Reviewer #4: N/A ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). 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 Response) Reviewer #3: No Reviewer #4: 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: (No Response) Reviewer #3: Yes Reviewer #4: Yes ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: (No Response) Reviewer #3: In this revised submission, Dr. Garcia-Tejedor and colleagues compare the use of absorbable modified polymer starch powder hemostat (AMP-SPH) compared to standard of care (SC). The submission could be improved with respect to technique, data, and statistics by the following: 1. The bleeding severity descriptions provided suggest that AMP-SPH may have been used outside of its approved labeling. Providing an explanation of why this was permitted would be useful. 2. Achieving hemostasis at 10 minutes was the primary endpoint, but 10 minutes is considered long for the primary endpoint in time to hemostasis studies in the current environment. Supplying a table with the results for the degree of hemostasis at all observed time points would be helpful. 3. The bleeding severity score use was only semi-quantitative. Providing a discussion of why a quantitative bleeding severity score was not employed, what such scores exist, and how not using one may effect results would be appropriate. 4. Addition to the discussion of how electrocautery was the SC when AMP-SPH is approved for use when conventional treatments are ineffective or impractical. Explaining why it would not have been more appropriate to use another established hemostat (for example a flowable) as the SC in all SC subjects should be discussed. 5. Reporting of the incidence of rebleeding after 10 minutes intraoperatively. 6. Explanation of what were the pre-analysis criteria for statistical non-inferiority. 7. Clarification as to why all subjects were not able to be included in the final analysis. 8. Discussion of why there was a trend toward more hematomas in the AMP-SPH group. 9. In the abstract as well as on page 2 line 44-45 and page 16, line 357-9, the word “observed” could be added for the comparison on amount of blood transfusions being less in the AMP-SPH group as this difference was not statistically significant. Reviewer #4: The authors of the manuscript have properly addresed all the Reviewer´s comments and concerns. Congratulations. ****** 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 #3: No Reviewer #4: 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 . Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0331376.r003
Revision 2
8 Jul 2025 Author Response Response to the reviewers, manuscript PONE-D-25-02293R1, entitled “Effectiveness and safety of an absorbable modified polymer starch powder hemostat versus usual care in gynecology procedures: A prospective, multi-center, and randomized study”. Dear Editor-in-Chief, I have considered the comments made by the reviewers and I hope that the paper improves greatly thanks to these comments. I am sending you the revised manuscript and the rebuttal letter providing a point-by-point response to each of the numbered reviewer comments. # Journal Requirements: 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. Reference list has been reviewed. # Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: (No Response) Reviewer #3: In this revised submission, Dr. Garcia-Tejedor and colleagues compare the use of absorbable modified polymer starch powder hemostat (AMP-SPH) compared to standard of care (SC). The submission could be improved with respect to technique, data, and statistics by the following: 1. The bleeding severity descriptions provided suggest that AMP-SPH may have been used outside of its approved labeling. Providing an explanation of why this was permitted would be useful. According to the study protocol, and the intraoperative inclusion criteria: Subject experiences generalized oozing or mild to moderate bleeding which is consistent with the requirement for a hemostatic agent. Bleeding was defined and documented in the CRF as: • Oozing - The rate of bleeding is slow. This is what one may expect from capillary, venular, or arteriolar bleeding. • Mild bleeding - The rate of bleeding is slightly faster than oozing. There is no pulsatile flow present. This is what one may expect from capillary, venular, or arteriolar bleeding. • Moderate bleeding. There may be a weak pulsatile flow present. If there is a pulsatile flow, the rate of blood flow is similar to the rate of flow for mild bleeding. If there is no pulsatile flow, the rate of blood flow is faster than mild bleeding. • Severe bleeding. For the most part, pulsatile flow is present. If there is no pulsatile flow, then the rate of blood flow is extremely rapid. If we were to apply the Vibe Scale (Lewis KM, Li Q, Jones DS, Corrales JD, Du H, Spiess PE, Lo Menzo E, DeAnda A Jr. Development and validation of an intraoperative bleeding severity scale for use in clinical studies of hemostatic agents. Surgery. 2017 Mar;161(3):771-781. doi: 10.1016/j.surg.2016.09.022.) to these definitions for bleeding in this chart: • Oozing - Vibe 1 >1-5ml/min • Mild - Vibe 2 >5-10ml/min • Moderate - Vibe 2-3 • Severe - Vibe 3 >10-50ml/min (not Vibe 4) Except for the 1 outlier that was reported to have severe bleeding; All the patients bleeding did fall into the labeling. Probably this severe bleeding patient should have been excluded from the study as this patient is an outlier - although, this patient apparently did not meet the specific criteria to be excluded by the surgeon - according to the blood loss classification of the ATLS classification chart. The patient was not a Class II-IV. Intraoperative Exclusion Criteria: Subject has any major intraoperative bleeding incidences (i.e., American College of Surgeons Advanced Trauma Life Support Class II, III or IV Hemorrhage [2013]) ATLS classification of blood loss is classified into four classes based on the estimated percentage of blood volume loss. Class I involves up to 15% blood loss (750ml), Class II involves 15-30% (750-1500ml), Class III involves 30-40% (1500-2000ml), and Class IV involves >40% blood loss (>2000ml). These classifications correlate with changes in vital signs like heart rate and blood pressure. (Spahn, D.R., Bouillon, B., Cerny, V. et al. Management of bleeding and coagulopathy following major trauma: an updated European guideline. Crit Care 17, R76 (2013). https://doi.org/10.1186/cc12685). 2. Achieving hemostasis at 10 minutes was the primary endpoint, but 10 minutes is considered long for the primary endpoint in time to hemostasis studies in the current environment. Supplying a table with the results for the degree of hemostasis at all observed time points would be helpful. While 10 minutes may not represent the current clinical study bleeding assessment criteria, this study was started in 2015. If we apply the Vibe bleeding scale rates (Lewis KM, Li Q, Jones DS, Corrales JD, Du H, Spiess PE, Lo Menzo E, DeAnda A Jr. Development and validation of an intraoperative bleeding severity scale for use in clinical studies of hemostatic agents. Surgery. 2017 Mar;161(3):771-781. doi: 10.1016/j.surg.2016.09.022.) to the bleeding scale established for this study the majority of patients would bleed 1-10ml/min so over 10 minutes that would be 10-100mls max. None of these patients even meet criteria of Class 1 of 750ml in the STS ATLS Trauma bleeding scale. While we do not have this data available, we provide in the article the data for time to hemostasis: The time required to achieve hemostasis was lower in the AMP group (1.91±1.15 minutes) than in the SC group (2.28±2.09 minutes), although not significant (p=.309). 3. The bleeding severity score use was only semi-quantitative. Providing a discussion of why a quantitative bleeding severity score was not employed, what such scores exist, and how not using one may affect results would be appropriate. For this study the investigators decided to devise a study specific bleeding severity score because in 2015 there were no validated quantitative bleeding scales published and peer reviewed. The only validated quantifiable bleeding chart available at the time was the STS ATLS Trauma bleeding scale from 2013. There were bleeding scales used in many clinical trials. We acknowledge that they are ⦁ “Subjective” description of bleeding ⦁ Valid for investigators only within a particular clinical specialty ⦁ Valid for only a particular type of intervention For example: Oz et al used a bleeding scale in cardiovascular surgery in 2000 to describe the initial level of bleeding so as to evaluate the efficacy of a flowable hemostat. The bleeding severity at each site was characterized as "oozing" or "heavy bleeding" (flowing or spurting). They considered success at 3 minutes and at 10 minutes by severity of bleeding. (Oz MC, Cosgrove DM 3rd, Badduke BR, Hill JD, et al. Controlled clinical trial of a novel hemostatic agent in cardiac surgery. The Fusion Matrix Study Group. Ann Thorac Surg. 2000 May;69(5):1376-82.) Izzo et al used a bleeding scale for hepatic surgery in 2008 to measure and evaluate the efficacy of a hemostatic matrix before and after treatment. A hemostatic matrix was applied directly to areas of bleeding. The severity of bleeding before and after application was graded on a 5-point scale (0 = no bleeding, 1 = oozing, 2 = moderate blood flow, 3 = heavy blood flow, 4 = spurting blood). The time to complete hemostasis was also recorded. After application of the gelatin matrix, bleeding severity was assessed at 1-min intervals until hemostasis was complete. (Izzo F, Di Giacomo R, Falco P, Piccirillo M, et al. Efficacy of a hemostatic matrix for the management of bleeding in patients undergoing liver resection: results from 237 cases. Curr Med Res Opin. 2008 Apr;24(4):1011-5.) The first quantitative validated bleeding scale for intraoperative bleeding is the one published by Lewis KM et al. in 2017 (Lewis KM, Li Q, Jones DS, Corrales JD, Du H, Spiess PE, Lo Menzo E, DeAnda A Jr. Development and validation of an intraoperative bleeding severity scale for use in clinical studies of hemostatic agents. Surgery. 2017 Mar;161(3):771-781. doi: 10.1016/j.surg.2016.09.022.), but as previously mentioned this study started before it was published. 4. Addition to the discussion of how electrocautery was the SC when AMP-SPH is approved for use when conventional treatments are ineffective or impractical. Explaining why it would not have been more appropriate to use another established hemostat (for example a flowable) as the SC in all SC subjects should be discussed. Electrocautery has long been recognized as a standard method for achieving hemostasis in various surgical procedures. Its widespread use and acceptance in clinical practice make it a relevant control for evaluating new hemostatic agents. Electrocautery is effective for controlling bleeding in many situations, particularly in cases of minor to moderate bleeding, and is often the first-line approach in surgical settings. The primary aim of our study was to assess the efficacy of AMP-SPH in situations where conventional treatments may be insufficient. While AMP-SPH is approved for use when conventional methods are ineffective or impractical, it is essential to establish its effectiveness against a widely accepted standard. The choice of electrocautery as the control group reflects real-world clinical scenarios where surgeons often rely on this method. By comparing AMP-SPH to electrocautery, we can provide insights into its potential advantages in practice, particularly in complex cases where bleeding control is critical. While flowable hemostatic agents are indeed established alternatives, they may not be universally applicable in all surgical contexts. The choice of hemostatic agent often depends on the specific surgical procedure, the nature of the bleeding, and the surgeon's preference. Additionally, many flowable hemostatic devices also contain thrombin making the device an “Active” hemostatic device which is in a different category than AMP-SPH which is considered a “Passive” hemostat. Electrocautery remains a versatile tool that can be employed in a variety of situations, making it a suitable control for our study. We acknowledge the importance of exploring the comparative effectiveness of AMP-SPH against other established hemostatic agents in future studies. This could provide a more comprehensive understanding of its role in the surgical armamentarium and help refine guidelines for hemostatic management in various clinical settings. 5. Reporting of the incidence of rebleeding after 10 minutes intraoperatively. In the AMP-SPH group, only 1 patient did not achieve hemostasis within 10 minutes. Bleeding was controlled after the 10 min by other methods (not described). In the SC group, 3 patients did not achieve hemostasis within 10 minutes. Bleeding was controlled in 1 patient with AMP-SPH, in another with sutures, and in the last one by other methods not described by the investigator. During this study, no other rebleeding events were described intraoperatively and no patients required reintervention for post- operative bleeding. The following paragraph was added in the results section: “In the AMP-SPH group, hemostasis within 10 minutes was achieved in all but one patient; bleeding in this case was subsequently controlled by unspecified methods. In the SC group, three patients failed to achieve hemostasis within 10 minutes. Bleeding was controlled in these cases using AMP-SPH (n=1), sutures (n=1), and unspecified methods (n=1). No intraoperative rebleeding events or postoperative reinterventions for bleeding were reported during the study”. 6. Explanation of what were the pre-analysis criteria for statistical non-inferiority. We acknowledge the study limitation of the lack of statistically valid sample size justification. This was added as a study limitation. The current study was a Phase IV, observational (post-market) study designed to provide descriptive and exploratory data rather than confirmatory evidence. As stated in the study protocol, the sample size was not determined to achieve a specific statistical power to detect differences between the AMP-SPH and Standard of Care (SoC) patient populations. Instead, this study followed an observational, case-controlled design, in which patients were grouped based on treatment exposure rather than through true randomization, which is characteristic of experimental studies such as randomized controlled trials (RCTs). The AMP-SPH group represented the case study cohort, while the SoC group served as the control, allowing for comparative assessment of specific clinical characteristics between the two cohorts. Given the exploratory nature of this study, our primary objective was to gather preliminary evidence rather than to definitively establish non-inferiority. Although prospective sample size calculation is the preferred methodological approach, as the reviewer correctly noted, a post-hoc analysis was conducted to estimate the number of patients required to detect significant differences based on the observed results. This analysis provided valuable insights into the potential adequacy of the study’s sample size, reinforcing the descriptive and hypothesis-generating role of this investigation. The following paragraph was added as a study limitation: “Another important limitation of this study is the lack of a statistically valid sample size justification. While a prospective sample size calculation would have been the ideal approach, a post-hoc analysis was performed to estimate the number of patients required to detect significant differences based on the observed results. With an alpha risk of 0.05 in a two-sided test and sample sizes of 44 patients in the AMP-SPH group and 46 in the SC group, the statistical power to detect the observed differences as significant was only 16%. Furthermore, to achieve a power of 80% with an alpha of 0.05, a total of 353 patients per group would have been required for the observed differences in the proportion of patients achieving hemostasis within 10 minutes to reach statistical significance. 7. Clarification as to why all subjects were not able to be included in the final analysis. The Per Protocol (PP) population includes all subjects who were randomized and treated with PerClot, and had no major protocol deviations, where major protocol deviations are defined as: • Failure to meet any preoperative inclusion/exclusion criteria; • Failure to meet any intraoperative inclusion/exclusion criteria; or • Any informed consent violation. The patients excluded from the PP population had major protocol deviations. Four (4) deviations were determined to be subjects not meeting the Inclusion Criteria or meeting the Exclusion Criteria of the study and the remaining deviations were Informed Consent Form deviations. All subjects were consented to the study, but there were various deviations for the method and/or process of consenting, which included signing the wrong version of the informed consent, the incorrect person dating the consent, or an unauthorized Investigator signing the consent. It was verified that the changes in the different versions of the informed consent were minor and would not have impacted the safety of the patient. 8. Discussion of why there was a trend toward more hematomas in the AMP-SPH group. In our study, the most commonly reported AE in the AMP group was hematoma, which occurred in 5 cases: 2 cases of pelvic hematoma (one with vaginal spotting); 1 Douglas hematoma; 1 vaginal cuff hematoma; and 1 cupula hematoma. There was one occurrence of hematoma in the SC group. This translated into an incidence of 11.4% in the AMP group and 2.2% in the SC group, but despite this, the difference was not statistically significant. The following paragraph was added in the discussion section: “The incidence of hematoma formation following pelvic gynecological surgery is highly variable, ranging from Attachments Attachment Submitted filename: Rebuttal letter PerClot PlosOne R2 1.1.docx https://doi.org/10.1371/journal.pone.0331376.r004
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Revision 3
25 Jul 2025 Author Response Response to the reviewers, manuscript PONE-D-25-02293R2, entitled “Effectiveness and safety of an absorbable modified polymer starch powder hemostat versus usual care in gynecology procedures: A prospective, multi-center, and randomized study”. Dear Editor-in-Chief, I have considered the comments made by the reviewers and I hope that the paper improves greatly thanks to these comments. I am sending you the revised manuscript and the rebuttal letter providing a point-by-point response to each of the numbered reviewer comments. # Review Comments to the Author Reviewer #1: (No Response) Reviewer #2: WELL DESIGNED AND WRITTEN STUDY REGARDING HEMOSTATIC AGENTS WHICH DO HAVE PROFOUND IMPACT IN OUR DAILY PRACTICE Thank you very much indeed for the comment, we highly appreciate it. Reviewer #3: In this second revision of the submission, Dr. Garcia-Tejedor and colleagues have contrasted the use of absorbable modified polymer starch powder hemostat (AMP-SPH) compared to standard of care (SC). The submission has been significantly improved. An additional modification would further strengthen the submission. 1. Provide the time span over which patient enrollment occurred in terms of chronological dates. The following paragraph was added in the results section: “A total of 90 patients were enrolled across two study sites between November 2015 and July 2017. Screening concluded in July 2017 upon reaching the target enrollment. The study duration was 21 months, from the first patient’s initial visit to the last patient’s final visit. Of the 90 enrolled participants, 44 (48.9%) were assigned to the AMP group and 46 (51.1%) to the SC group (Figure 1).” Reviewer #4: The authors of the manuscript have addressed all possible reviewers concerns. Nothing else to comment Thank you very much indeed for the comment, we highly appreciate it. Attachments Attachment Submitted filename: Rebuttal letter PerClot PlosOne R3 1.0.docx https://doi.org/10.1371/journal.pone.0331376.r006
15 Aug 2025 Decision Letter - Hideto Sano, Editor Effectiveness and safety of an absorbable modified polymer starch powder hemostat versus usual care in gynecology procedures: A prospective, multi-center, and randomized study. PONE-D-25-02293R3 Dear Dr. Garcia-Tejedor, 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. 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Formally Accepted
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