Core warming of coronavirus disease 2019 (COVID-19) patients undergoing mechanical ventilation—A protocol for a randomized controlled pilot study

Nathaniel Bonfanti; Emily Gundert; Anne M. Drewry; Kristina Goff; Roger Bedimo; Erik Kulstad

doi:10.1371/journal.pone.0243190

Peer Review History

Original SubmissionJune 19, 2020
19 Jun 2020 Author Response Transfer Alert This paper was transferred from another journal. As a result, its full editorial history (including decision letters, peer reviews and author responses) may not be present. Attachments Attachment Submitted filename: PLoS response to editor.docx https://doi.org/10.1371/journal.pone.0243190.r001
9 Sep 2020 Decision Letter - Richard Hodge, Editor PONE-D-20-12959 Core warming of coronavirus disease 2019 (COVID-19) patients undergoing mechanical ventilation: protocol for a randomized controlled pilot study PLOS ONE Dear Dr. Kulstad, 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. Specifically, both reviewers raised overlapping concerns about the proposed study design and the statistical methodology. Please submit your revised manuscript by Oct 22 2020 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: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols We look forward to receiving your revised manuscript. Kind regards, Richard Hodge Associate 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. At this time, we ask that you please specifically state that the protocol was reviewed and approved by the Institutional Review Board of Washington University 3. We note that you have stated that you will provide repository information for your data at acceptance. Should your manuscript be accepted for publication, we will hold it until you provide the relevant accession numbers or DOIs necessary to access your data. If you wish to make changes to your Data Availability statement, please describe these changes in your cover letter and we will update your Data Availability statement to reflect the information you provide. 4. Thank you for stating the following financial disclosure: "EK declares equity interest in Attune Medical." 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. 5. Thank you for stating the following in the Competing Interests section: "I have read the journal's policy and the authors of this manuscript have the following competing interests: EK declares equity interest in Attune Medical." 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. Please know it is PLOS ONE policy for corresponding authors to declare, on behalf of all authors, all potential competing interests for the purposes of transparency. PLOS defines a competing interest as anything that interferes with, or could reasonably be perceived as interfering with, the full and objective presentation, peer review, editorial decision-making, or publication of research or non-research articles submitted to one of the journals. Competing interests can be financial or non-financial, professional, or personal. Competing interests can arise in relationship to an organization or another person. Please follow this link to our website for more details on competing interests: http://journals.plos.org/plosone/s/competing-interests 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. 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: No ******** 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: No ****** 3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable? Reviewer #1: Yes Reviewer #2: No ****** 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: No ******** 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: This study looks to carry out a small pilot project of 20 severely ill and ventilated COVID-19 patients equally randomised into one of two arms a) raising body temperature to an elevated degree but below 40C b) treatment as usual. The study aims to generate data regarding important clincial parameters in order to design a definitive clinical trial at a later date. They have already registered the trial at https://clinicaltrials.gov/ct2/show/NCT04426344. I think the analysis would be enhanced if the authors state that they will produce Kaplan-Meier plots of important time to event outcomes/measures eg death, time on ventilation etc. Further I would like to see mention of a sceening log for this trial and a sentence of how they will report on this in order to give a fuller picture of what they will do/have done. Furthermore given the need for this to be an unblinded study, being able to compare who did and did not get entered into the study and to which arm, if entered, would be useful. I'd also like to see the 1st Exclusion removed as this is simply a negation of the last Inlcusion criteria, furthermore it doesnt exist on the kindly provided CRF. They may also wish to slightly amend their introduction about there being no treatment in light of the RECOVERY trial result https://www.medrxiv.org/content/10.1101/2020.06.22.20137273v1 and https://www.nejm.org/doi/10.1056/NEJMoa2021436 (full disclosure my brother is a co-author on these reports) Reviewer #2: The authors outline a protocol for a randomized controlled pilot study of core temperature warming in mechanically ventilated patients with COVID-19 and its effects on viral load in the endotracheal tube (primary outcome) and several additional clinical outcomes including disease severity, hospital and intensive care unit length of stay, duration of mechanical ventilation, and 30-day mortality. Though the rationale for the study is plausible, and certainly should be explored further, the manuscript does not provide adequate information on several key areas outlined below. Please note, it is very difficult to make comments on the manuscript without page numbers or line numbers. 1. Why was the viral load in the endotracheal tube chosen as the primary outcome? There is data on nasal/NP viral kinetics, but very little in endotracheal samples, and there is a high probability that this measurement will not demonstrate an appreciable difference between groups. 2. There is no description of the sample size calculation relative to the outcomes. Given the small sample size proposed, a more realistic outcome would be feasibility. 3. Duration of the study seems way too short to assess the outcomes being investigated – especially hospitalization duration and mortality. 4. There is no consideration for the duration of mechanical ventilation at the time of enrollment – there will be a meaningful difference in ability to assess outcomes depending on time since illness onset and time since ventilation. ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: Yes:** Greg Fegan Reviewer #2: 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.0243190.r002
Revision 1
15 Sep 2020 Author Response Thank you for the opportunity to submit our revised manuscript, PONE-D-20-12959, Core warming of coronavirus disease 2019 (COVID-19) patients undergoing mechanical ventilation: protocol for a randomized controlled pilot study. 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. We believe we now meet your style requirements. 2. At this time, we ask that you please specifically state that the protocol was reviewed and approved by the Institutional Review Board of Washington University We have added this to the manuscript under the Methods section. 3. We note that you have stated that you will provide repository information for your data at acceptance. Should your manuscript be accepted for publication, we will hold it until you provide the relevant accession numbers or DOIs necessary to access your data. If you wish to make changes to your Data Availability statement, please describe these changes in your cover letter and we will update your Data Availability statement to reflect the information you provide. We are happy to provide our data, however it obviously will not be available for quite some time, since the study still has to be performed and completed. We hope that this protocol paper can nevertheless be published prior to completion of the study and analysis of the data. 4. Thank you for stating the following financial disclosure: "EK declares equity interest in Attune Medical." 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. This amended role of funder statement is now included. 5. Thank you for stating the following in the Competing Interests section: "I have read the journal's policy and the authors of this manuscript have the following competing interests: EK declares equity interest in Attune Medical." 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. Please know it is PLOS ONE policy for corresponding authors to declare, on behalf of all authors, all potential competing interests for the purposes of transparency. PLOS defines a competing interest as anything that interferes with, or could reasonably be perceived as interfering with, the full and objective presentation, peer review, editorial decision-making, or publication of research or non-research articles submitted to one of the journals. Competing interests can be financial or non-financial, professional, or personal. Competing interests can arise in relationship to an organization or another person. Please follow this link to our website for more details on competing interests: http://journals.plos.org/plosone/s/competing-interests Updated competing interests statement is now included. 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. These have been added. 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: No 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: No 3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable? Reviewer #1: Yes Reviewer #2: No 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: No 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: This study looks to carry out a small pilot project of 20 severely ill and ventilated COVID-19 patients equally randomised into one of two arms a) raising body temperature to an elevated degree but below 40C b) treatment as usual. The study aims to generate data regarding important clincial parameters in order to design a definitive clinical trial at a later date. They have already registered the trial at https://clinicaltrials.gov/ct2/show/NCT04426344. I think the analysis would be enhanced if the authors state that they will produce Kaplan-Meier plots of important time to event outcomes/measures eg death, time on ventilation etc. Further I would like to see mention of a sceening log for this trial and a sentence of how they will report on this in order to give a fuller picture of what they will do/have done. Furthermore given the need for this to be an unblinded study, being able to compare who did and did not get entered into the study and to which arm, if entered, would be useful. I'd also like to see the 1st Exclusion removed as this is simply a negation of the last Inlcusion criteria, furthermore it doesnt exist on the kindly provided CRF. They may also wish to slightly amend their introduction about there being no treatment in light of the RECOVERY trial result https://www.medrxiv.org/content/10.1101/2020.06.22.20137273v1 and https://www.nejm.org/doi/10.1056/NEJMoa2021436 (full disclosure my brother is a co-author on these reports) Thank you for your review and resulting suggestions for improvement. We have specified that Kaplan-Meier plots will be produced. We have now included the use of a formal screening log, and our plans to report on screening results, as well as entry versus non-entry into the clinical study. We have removed the first exclusion criteria as suggested. We have now amended the abstract, and modified the introduction to include the mention of this treatment option. Reviewer #2: The authors outline a protocol for a randomized controlled pilot study of core temperature warming in mechanically ventilated patients with COVID-19 and its effects on viral load in the endotracheal tube (primary outcome) and several additional clinical outcomes including disease severity, hospital and intensive care unit length of stay, duration of mechanical ventilation, and 30-day mortality. Though the rationale for the study is plausible, and certainly should be explored further, the manuscript does not provide adequate information on several key areas outlined below. Please note, it is very difficult to make comments on the manuscript without page numbers or line numbers. Thank you for your review and suggestions for improvement. We have now included page numbers and line numbers. 1. Why was the viral load in the endotracheal tube chosen as the primary outcome? There is data on nasal/NP viral kinetics, but very little in endotracheal samples, and there is a high probability that this measurement will not demonstrate an appreciable difference between groups. As further clarification, we do not plan samples from the endotracheal tube itself, but rather lower respiratory tract samples, which have been shown to be more reliable and sensitive than upper airway samples. We have provided further references on this topic in the manuscript. 2. There is no description of the sample size calculation relative to the outcomes. Given the small sample size proposed, a more realistic outcome would be feasibility. We do not intend to power this pilot for superiority. We have further emphasized the feasibility aspect of this study. 3. Duration of the study seems way too short to assess the outcomes being investigated – especially hospitalization duration and mortality. We have utilized standard intensive care measures, where ICU, hospital, and 28 or 30 day mortality is most common. Because most severity of illness scoring systems are based on either in-hospital or 30 day mortality, we believe that deviating from this standard may introduce further interpretability challenges. 4. There is no consideration for the duration of mechanical ventilation at the time of enrollment – there will be a meaningful difference in ability to assess outcomes depending on time since illness onset and time since ventilation. Yes, we agree. We expect that randomizatioin may help balance differences in duration of mechanical ventilation at the time of enrollment; however, we have now specified that patients will be screened only if undergoing mechanical ventilation for three days or less. 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: Yes: Greg Fegan Reviewer #2: No Attachments Attachment Submitted filename: Response to Reviewers - Core warming.docx https://doi.org/10.1371/journal.pone.0243190.r003
26 Oct 2020 Decision Letter - Steven Eric Wolf, Editor PONE-D-20-12959R1 Core warming of coronavirus disease 2019 (COVID-19) patients undergoing mechanical ventilation: protocol for a randomized controlled pilot study PLOS ONE Dear Dr. Kulstad, 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 Dec 10 2020 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: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols We look forward to receiving your revised manuscript. Kind regards, Steven Eric Wolf, MD Academic Editor PLOS ONE Additional Editor Comments (if provided): Editor - Thank you for resubmitting your paper. As promised, I sent it back to the original referees who are now almost completely satisfied save a few minor issues. Please carefully consider the comments below and reply directly to each in a cover letter with appropriate marked and linked changes to the manuscript. I look forward to receiving the next version which I will handle personally for timeliness. [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? 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 ******** 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: Partly ****** 3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable? 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: The authors have satisfactorily accommodated all my previous request. This is the 2nd time I have seen this paper and I am happy with the paper to go ahead. Reviewer #2: Thank you for your response. You have addressed my comments but there remain a few points that require additional thought/consideration: 1. I am still concerned about the primary endpoint – will any lower respiratory tract specimen be used? There are data suggesting differences between BAL, endotracheal tube aspirates, and sputum. What is a patient is no longer intubated at 72 hours? Will their BAL/endotracheal aspirate be compared to a sputum sample at 72 hrs? Sample type appears to be a confounder for interpretation of the results. Additionally, in line 159 the endpoint is still listed as endotracheal aspirate. 2. There is no discussion of how administration of antiviral therapy may affect the virologic endpoint. The population of interest (mechanically ventilated adults) would not uniformly receive remdesivir given current guidelines, however, some may either before study enrollment or after. Stratification could be an option. ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: Yes:** Greg Fegan Reviewer #2: 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.0243190.r004
Revision 2
26 Oct 2020 Author Response Thank you for the opportunity to submit our revised manuscript, PONE-D-20-12959, Core warming of coronavirus disease 2019 (COVID-19) patients undergoing mechanical ventilation: protocol for a randomized controlled pilot study. Reviewer #2: Thank you for your response. You have addressed my comments but there remain a few points that require additional thought/consideration: Thank you for your review and suggestions for improvement. 1. I am still concerned about the primary endpoint – will any lower respiratory tract specimen be used? There are data suggesting differences between BAL, endotracheal tube aspirates, and sputum. What is a patient is no longer intubated at 72 hours? Will their BAL/endotracheal aspirate be compared to a sputum sample at 72 hrs? Sample type appears to be a confounder for interpretation of the results. Additionally, in line 159 the endpoint is still listed as endotracheal aspirate. We have not attempted to limit lower respiratory tract specimens, since some sites may prefer a BAL, others a mini BAL, etc. The key point will be that the same approach will be used in both arms, such that this will not be a confounder. Because the typical duration of mechanical ventilation for this patient population is between 8 to 10 days, we do not expect a large number of patients to be extubated before 72 hours. Nevertheless, if there are unexpected quicker recoveries, we would expect this to balance out between the two groups, barring a miraculous effect from the experimental treatment. We have corrected the terminology in line 159. 2. There is no discussion of how administration of antiviral therapy may affect the virologic endpoint. The population of interest (mechanically ventilated adults) would not uniformly receive remdesivir given current guidelines, however, some may either before study enrollment or after. Stratification could be an option. Because the treatment of this patient population is undergoing constant change, with different approaches emerging, and previous treatments being found to have essentially no effect (for example, remdesivir), we have avoided making explicit requirements for treatment. We instead rely on the fact that over the duration of the study, the specific treatments provided (and the changes in treatments that occur as new data or treatments emerge), will occur essentially equivalently between the two randomized groups. If there is a substantial imbalance, additional stratification will then likely be necessary. We expect that this pilot will give valuable baseline information in this regard. Attachments Attachment Submitted filename: Response to Reviewers - Second revisions.docx https://doi.org/10.1371/journal.pone.0243190.r005
18 Nov 2020 Decision Letter - Steven Eric Wolf, Editor Core warming of coronavirus disease 2019 (COVID-19) patients undergoing mechanical ventilation: protocol for a randomized controlled pilot study PONE-D-20-12959R2 Dear Dr. Kulstad, 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 for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, 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, Steven Eric 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? 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: No further comments to add as I had said when I looked at the 1st revision. My understanding of this work is to simply check what warming of severely sick COVID-19 patients may do in a small feasibility/pilot study. Reviewer #2: The authors have adequately addressed all of my comments and I have no further concerns for publication. ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: Yes:** Greg Fegan Reviewer #2: No https://doi.org/10.1371/journal.pone.0243190.r006
Formally Accepted
20 Nov 2020 Acceptance Letter - Steven Eric Wolf, Editor PONE-D-20-12959R2 Core warming of coronavirus disease 2019 (COVID-19) patients undergoing mechanical ventilation – a protocol for a randomized controlled pilot study Dear Dr. Kulstad: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. 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 plosone@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 Dr. Steven Eric Wolf Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0243190.r007

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