Advance care planning in multiple sclerosis (ConCure-SM): A multicenter single-arm pilot and feasibility study

Alessandra Solari; Ludovica De Panfilis; Roberta Martina Zagarella; Luca Ghirotto; Mariangela Farinotti; Alberto Gajofatto; Maria Grazia Grasso; Paola Kruger; Alessandra Lugaresi; Katia Mattarozzi; Sara Montepietra; Francesco Patti; Eugenio Pucci; Michela Rimondini; Claudio Solaro; Marta Perin; Andrea Giordano; Simone Veronese; on behalf of the ConCure-SM project

doi:10.1371/journal.pone.0331220

Peer Review History

Original SubmissionFebruary 1, 2025
25 Apr 2025 Decision Letter - Nayanatara Arun Kumar, Editor Dear Dr. Solari, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please submit your revised manuscript by Jun 09 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. 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We look forward to receiving your revised manuscript. Kind regards, Nayanatara Arun Kumar Academic Editor PLOS ONE Journal Requirements: 1. When submitting your revision, we need you to address these additional requirements.-->--> -->-->Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at -->-->https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and -->-->https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf-->--> -->-->2. Thank you for stating in your Funding Statement: -->-->The study was supported by FISM - Fondazione Italiana Sclerosi Multipla – cod. 2020/R-Multi/024 and financed or co-financed with the ‘5 per mille’ public funding to AS. The funding source had no role in study design, data collection, data analysis, data interpretation or report writing. 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FP received personal compensation for serving on advisory board and/or speaking activities by Almirall, Bayer, Biogen, Bristol Meyers & Squibb, Merck, Novartis Roche, Sanofi and TEVA; he further received research grants by Biogen Italy, Biogen Global, Merck, University of Catania, FISM and Reload Onlus Patients Association. AS received personal compensation for serving on advisory board and speaking activities by Almirall and Merck. All the other authors have no competing interests.-->--> -->-->We note that one or more of the authors are employed by a commercial company. -->--> -->-->a. Please provide an amended Funding Statement declaring this commercial affiliation, as well as a statement regarding the Role of Funders in your study. 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Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. Additional Editor Comments: Dear Authors Please go through the queries asked by the reviewer and do the corrections accordingly and resubmit for the editorial decision, All the best With regards and Best Wishes Dr. Nayanatara [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? Reviewer #1: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? -->?> Reviewer #1: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available??> The PLOS Data policy Reviewer #1: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes ****** Reviewer #1: The authors presented a pilot and feasibility study of advance care planning in Multiple sclerosis. The study was well planned, advanced statistical methods were used to analyse the data based on mixed method, but the sample size was not large enough. Being a pilot and feasibility study, small sample size can be acceptable. However, large sample statistics were used to analyse small sample and hence quantitative part of the analysis is not reliable. I have few other comments to make 1. The Letter “P” in P-values should be italic throughout 2. At the end of the methods section in the Abstract need to mention that a mixed method analysis was done. 3. So many outcome measures scales were used based on a small sample size, yet adjustment in p-values were not done for multiplicity. This is a big limitation needs to be corrected or mentioned as a limitation. 4. As the study could not recruit the desired number of patients, inferential statistics (p-values) based on quantitative results are not reliable as they are also affected by the multiple testing. 5. In line 203, it says that generalized estimating equations were used for secondary outcomes. GEE is also a large sample procedure and hence would not give reliable results. 6. In line 205, Section Statistics, says that multiple imputation of missing values was done. A bit more information needs to be presented to show the extent of the missing values. 7. Qualitative analyses are good. 8. As this is a pilot and feasibility study, all the limitations for quantitative analysis need to be mentioned in appropriate places. ****** 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: Dr Shah-Jalal Sarker ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/ . PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org https://doi.org/10.1371/journal.pone.0331220.r001
Revision 1
30 Apr 2025 Author Response RESPONSE TO REVIEWERS 1. The authors presented a pilot and feasibility study of advance care planning in Multiple sclerosis. The study was well planned, advanced statistical methods were used to analyse the data based on mixed method, but the sample size was not large enough. Being a pilot and feasibility study, small sample size can be acceptable. However, large sample statistics were used to analyse small sample and hence quantitative part of the analysis is not reliable. R: We agree with the reviewer that the quantitative analysis findings should be interpreted with caution. We have mentioned this in the Discussion, as follows: “Study limitations. Although useful for assessing the feasibility and potential of a larger study, pilot and feasibility studies are typically underpowered. Additionally, we did not reach the target number of participants and used (as from the study protocol) advanced statistical methods (i.e., mixed-method analysis and generalized estimating equations). Finally, we assessed several secondary outcome measures, without adjusting for multiplicity testing. Therefore, the results of the quantitative analysis should be interpreted with caution.” 2. The Letter “P” in P-values should be italic throughout. R: We have made changes following reviewer’s suggestion. 3. At the end of the methods section in the Abstract need to mention that a mixed method analysis was done. R: We have revised the Abstract as suggested. 4. So many outcome measures scales were used based on a small sample size, yet adjustment in p-values were not done for multiplicity. This is a big limitation needs to be corrected or mentioned as a limitation. R: See our response to point 1 above. 5. As the study could not recruit the desired number of patients, inferential statistics (p-values) based on quantitative results are not reliable as they are also affected by the multiple testing. R: See our response to point 1 above. 6. In line 203, it says that generalized estimating equations were used for secondary outcomes. GEE is also a large sample procedure and hence would not give reliable results. R: See our response to point 1 above. 7. In line 205, Section Statistics, says that multiple imputation of missing values was done. A bit more information needs to be presented to show the extent of the missing values. R: This information is provided in the Results, section “Adverse Events and Attrition” (lines 261-269). 8. As this is a pilot and feasibility study, all the limitations for quantitative analysis need to be mentioned in appropriate places. R: In addition to the Discussion (see our response to point 1 above) we have mentioned these limitations in the Results (section “Other outcome measures”, lines 93-95), and in the Box. https://doi.org/10.1371/journal.pone.0331220.r002
15 Jul 2025 Decision Letter - Nayanatara Arun Kumar, Editor Dear Dr. Solari, Please do the needful, please address each comments Please submit your revised manuscript by Aug 29 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. 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 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, Nayanatara Arun Kumar Academic Editor PLOS ONE Journal Requirements: If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. Additional Editor Comments: Dear Authors I have gone through the revision file as suggested by the respectable reviewers , based on this the manuscript is accepted for publication . Congratulations to all the authors [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author Reviewer #1: (No Response) ******** 2. Is the manuscript technically sound, and do the data support the conclusions??> Reviewer #1: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? -->?> Reviewer #1: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available??> The PLOS Data policy Reviewer #1: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes ****** Reviewer #1: In the section of other outcome measures in the Results: These findings should be interpreted with caution (see Discussion, ‘Study limitations’ section). Please add, "due to small sample size and multiplicity problem". ****** 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: Dr Shah-Jalal Sarker ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/ . PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org https://doi.org/10.1371/journal.pone.0331220.r003
Revision 2
16 Jul 2025 Author Response RESPONSE TO REVIEWER #1 In the section of other outcome measures in the Results: These findings should be interpreted with caution (see Discussion, ‘Study limitations’ section). Please add, "due to small sample size and multiplicity problem". R: We have added the phrase, as suggested. Attachments Attachment Submitted filename: Response to reviewers.docx https://doi.org/10.1371/journal.pone.0331220.r004
13 Aug 2025 Decision Letter - Nayanatara Arun Kumar, Editor Advance care planning in multiple sclerosis (ConCure-SM): A multicenter single-arm pilot and feasibility study PONE-D-25-03850R2 Dear Dr. Solari We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. For questions related to billing, please contact billing support . 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, Nayanatara Arun Kumar Academic Editor PLOS ONE Additional Editor Comments (optional): Dear Authors Congratulations to you and move forward with more in depth research regards Dr, Nayanatara Arun kumar Reviewers' comments: Reviewer's Responses to Questions Comments to the Author Reviewer #1: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions??> Reviewer #1: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? -->?> Reviewer #1: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available??> The PLOS Data policy Reviewer #1: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes ****** Reviewer #1: (No Response) ****** 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: Dr Shah-Jalal Sarker ******** https://doi.org/10.1371/journal.pone.0331220.r005
Formally Accepted
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