Start up: A French program to support patients with pulmonary arterial hypertension during the adjustment of prostanoids to the individualized optimal dose

Emmanuel Bergot; Marie Fertin; Mélanie Gallant Dewavrin; Grégoire Prévot; Julia Meijer; Coralie Hakibilen; Laurette Gruand; Sophie Gauthier; Andreea Todea; Thamer Boukerzaza; Xavier Jaïs

doi:10.1371/journal.pone.0331008

Peer Review History

Original SubmissionFebruary 22, 2025
5 May 2025 Decision Letter - James Maloney, Editor PONE-D-25-06416Start Up: A French program to support patients with pulmonary arterial hypertension during the adjustment of prostanoids to the individualized optimal dosePLOS ONE Dear Dr. Bergot, 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 19 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. Thank you for stating in your Funding Statement: This is a patient program managed by Patientys and financially supported by Janssen Cilag. Patientys contributed to program design, interpretation of the data, writing of thereport, and decision to submit the paper for publication. Medical writing support wasfunded by Patientys.EB, MF, MGD for HTaPFrance, GP, and XJ report having been consultants forPatientys, and having received consulting fees, during the conduct of the study.AT and TB are employees of Janssen-Cilag. 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Additional Editor Comments: The manuscript offers useful information to PH centers that do not have an active selexipag titration protocol, and offers important insights on dose maximization. Please address all reviewer comments [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: Partly Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: N/A 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: No Reviewer #2: No ****** 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: Prostacyclin initiation and titration can be difficult and time consuming, so it is nice to see clinical study in this area. In the current paper, Bergot et al propose a “start-up program” during which patients would be supported by an external nurse during initiation. While there are a number of more rigorous questions that might have been attempted, the current paper is a bit superficial – there is no direct comparison group from the same patient population(s), either concurrent or historical. And the goal is nebulous – perhaps patient satisfaction, though if so the number completing surveys was low. Or perhaps number reaching their “maximally tolerated dose”, but this is not objectively defined and perhaps really can’t be. The study does provide some observational data describing demographics, type of AEs, how long the outside nurse spent on the phone, and what dose they reached, patient and physician satisfaction - but none of this other than the phone call durations and satisfaction rates are novel as similar information is present in RCTs and observational studies. And I am not sure that either of these more novel aspects move the field forward appreciably. More specific comments: While it appears the aims of the Start Up program may have been primarily convenience (particularly for clinicians) and support (particularly for patients), from a research perspective a few more details would be helpful. Were there any prespecified hypotheses or aims? If so, would add to abstract and methods. Even if not, consider adding as the last sentence of the introduction some sort of general aim or even just a “what this paper is about” sentence. Something like “In the current report, we describe…” For AE assessing / grading / reporting, as outlined in the methods, more detail is needed. During the phone calls, were patients asked only general question (how are you feeling / any problems) and then any spontaneous AEs were graded? Or were there specific queries focused on the most common prostanoid AEs such as GI side effects or headache? And was any sort of script utilized? Did the nurse who was on the phone grade the AEs, or was this done by a physician or researcher? For the discontinuation rates (for reasons other than death) – how does this compare across RCT and observational studies? What medications were utilized to treat AEs, if any (medications for headache, nausea, diarrhea, for example). Were these recommended by the nurse? Was there any sort of preplanned AE management in place? Consider a table with information on med use. Minor points - In the results section, avoid using terms such as “benefited” (patients “benefitted” from a phone call) and instead use more neutral terms such as received. - When referring to physicians on line 162, favor rewording to avoid the use of “him” in this context; perhaps “A systemic report was provided to the treating physicians, providing insight…” - Line 164 and 166, add s to patient - Line 267, add “of” before patients The patient satisfaction questionnaire completion rate (28%) is quite low – any comments? And what was the completion rate amongst health care providers? Reviewer #2: Thanks for the opportunity to review this paper re. follow-up a medication where side-effects often hinder optimal dosage. Some comments as they appear in the text. Page 2, line 27, write out the CTCAE v4.0. Page 5, line 71, write out HTaPFrance. Page 5, the timeline described in line 76-81 could be more easily described if Figure 1 is referenced. I may read badly, but the numbers do not fit with the description in results from line 146 onwards. Page 8, line 143, what is MR004 reference methodology (no reference given). Page 12, line 184-186, I miss the definition of high, medium, low in the Methods section. Were these cut-offs decided a priori? Page 16, “alert from the French drug regulatory agency”, please explain (not only in the footnote to Figure 1). Page 16, line 238, very few patients answered the rating, please discuss if the findings are representative with such a low response rate. Same page, what was the response rate amongst health professionals? LATER, I see the discussion under limitations on page 21. But the authors could speculate more any effect of biases. Figure 2, please give a explanatory footnote. As now, the figure is not understandable. Figure 4, what number is correct? In text, out of 302 reaching dose, 86 answered. In Figure 4, 249 questionnaires were sent. Please check and be careful with numbers and be consistent! ****** 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: Stefan Söderberg ******** [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.0331008.r001
Revision 1
19 Jun 2025 Author Response Dear PlosOne editor, dear reviewers, We would like to thank you for these constructive comments on our work. Please find below our responses to all of your concerns. Academic Editor comments: Style requirements: Requirements regarding style and file naming are now met in the updated version. Funding statement: All funding is declared in the funding statement. The statement “There was no additional external funding received for this study” has been added to the reviewed cover letter. Data accessibility: Data are issued from the Start Up patient support program developed by Patientys. Patient gave their written consent for the use of their data, however they did not agree specifically for public availability of their unaggregated data. To meet PlosOne requirements, data can be available upon request at privacy@patientys.com. The section has been updated in the submission form. Ethics statement: Our ethics statement has been updated in the methods section with complete information about the institutional body. Reference list: The reference list has been checked to ensure that it is complete and correct. Reviewer#1 comments Objective of the manuscript: The Start Up program was first designed to bring support to patients and their medical teams while initiating prostacyclin. The objective of the current study was to report the existence of such patient support program and give real world data supporting the hypothesis that an external support is beneficial to patients and physicians in treatment titration. Our data shows that the external nurse allows for a personalized titration pattern following AE reported by patients which may participate to a higher rate of patient reaching their optimal dose and a lower discontinuation rate. In addition, the time spent by the external nurse is time saving for medical teams and highly appreciated. AE assessing: During the phone calls, using guidelines determined by the scientific committee, the nurse drives the patient interview to identify and grade AEs. There is a specific focus on prostanoids associated AEs, in order to give insights to the medical team of the patient that will take decision regarding the treatment. The methods section has been detailed. Medications use: Medications to treat AEs were only manage by the medical team of the patient, in regard to the AEs declared by the patient. Some medical teams anticipated and gave to their patient a prescription for medication to treat AEs while introducing Selexipag. The PAH nurse of the Start Up program may solicit the physician to send a prescription if needed but do not take any medical decisions. The methods section has been detailed. Discontinuation rates compared to current literature In the Start Up program, 78 patients (19%) discontinued their treatment, before reaching their optimal treatment dose. Among them, 35 patients (9%) reported a treatment discontinuation due to adverse events during the titration phase. In the Phase 3 clinical trial (GRIPHON), 14,3% of patient reported a treatment discontinuation related to adverse event. Among the several real-world data studies, more relatable to the Start Up program, the discontinuation rate due to adverse events varies from 20% in the EXPOSURE study and 22% in the SPHERE registry study up to 32% in the GRIPHON open label study. However, they monitor discontinuation after the titration period, making a comparison more difficult with our study. We could only speculate that because adverse events occur more frequently during the dose-adjustment phase (Sitbon et al., 2015), treatment discontinuation may have been higher during the titration phase. Therefore, the discontinuation rate observed in the Start Up study may be lower than other real world data studies, supporting that the close patient monitoring may participate to less treatment discontinuation. � The discussion section has been detailed. Minor points: - “Benefited” � “Received”: modified - Avoid the use of “him” when referring to physician: modified - Line 164 and 166: Add “S” to patient: modified - Line 267: ass “of”: modified Patients’ satisfaction completion: The satisfaction questionnaire was only implemented later in 2018, as described in the Methods section and sent to 249 patients out of the 302 patients that reached their optimal dose. In addition, patients must fill-out the satisfaction questionnaire and send it using a prepaid envelope to the PAH nurse. This postal sent by the patient may explain the low completion rate. Completion rate of health care providers: Unfortunately, amongst healthcare providers, the distribution of the questionnaires was not controlled. While the questionnaire was sent by email to 64 physicians, we received answers from nurses and pharmacists suggesting email forwarding. We cannot therefore provide a response rate among healthcare professionals. Reviewer#2 comments Page 2, line 27, write out the CTCAE v4.0. � detailed Page 5, line 71, write out HTaPFrance. � detailed Page 5, the timeline described in line 76-81 could be more easily described if Figure 1 is referenced. I may read badly, but the numbers do not fit with the description in results from line 146 onwards. � Line 76-81 aimed to describe the 2 populations of patients that benefited or not of the additional follow-up of 1 year. Line 149 and followings describe the whole population and detail the patients that did not reached their individualized dose. For a better clarity the Methods section is detailed and figure 1 referenced. Page 8, line 143, what is MR004 reference methodology (no reference given). � detailed Page 12, line 184-186, I miss the definition of high, medium, low in the Methods section. Were these cut-offs decided a priori? � This is aligned to the GRIPHON study, Phase III trial for Selexipag. The Methods section has been detailed. Page 16, “alert from the French drug regulatory agency”, please explain (not only in the footnote to Figure 1). � Explained in the Results section Page 16, line 238, very few patients answered the rating, please discuss if the findings are representative with such a low response rate. Same page, what was the response rate amongst health professionals? LATER, I see the discussion under limitations on page 21. But the authors could speculate more any effect of biases. � Discussion more detailed. The low response rate among patients may be due to the data collection method for satisfaction. Patients had to return the questionnaire in a pre-stamped envelope. Unfortunately, amongst healthcare providers, the distribution of the questionnaires was not controlled. While the questionnaire was sent by email to 64 physicians, we received answers from nurses and pharmacists suggesting email forwarding. We cannot therefore provide a response rate among healthcare professionals. Figure 2, please give an explanatory footnote. As now, the figure is not understandable. � Detailed Figure 4, what number is correct? In text, out of 302 reaching dose, 86 answered. In Figure 4, 249 questionnaires were sent. Please check and be careful with numbers and be consistent! � Of the 302 patients that reached their optimal dose, the questionnaire was sent to 249 patients. This is due to the implementation of the satisfaction questionnaire later in the program resulting in early participants not filling the questionnaire. The results section has been detailed to be consistent. Attachments Attachment Submitted filename: Response to reviewers_Vf.docx https://doi.org/10.1371/journal.pone.0331008.r002
24 Jun 2025 Decision Letter - James Maloney, Editor PONE-D-25-06416R1Start Up: A French program to support patients with pulmonary arterial hypertension during the adjustment of prostanoids to the individualized optimal dosePLOS ONE Dear Dr. Bergot, 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 08 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, James P. Maloney, MD 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. Editor Comments: The manuscript provides valuable information on selexipag titration success rates, and the manuscript has improved after changes made in response to reviewers. However, several areas of the reviewer comments still need to be addressed, mostly related to industry-driven bias for the project and related statements in the manuscript. As the titration protocol appears proprietary, the implications of the project outside of France are unclear. The authors need to clarify what aspects of this program are proprietary and minimize industry bias. 1. Reviewer 1 asked for clarification of the purpose of the program, and for any hypotheses that accompanied this project. While the revision does not mention hypotheses, it does clarify intent - "objective to support them in taking their therapies targeting the prostacyclin pathway and determine the individualized optimal dose". However, the project is sponsored by two for profit companies, one the drug manufacturer, so the manuscript needs to clarify the role of these companies for this project in multiple sections (not just in the Funding statement). a) Is "Start Up" name copyrighted or is that being sought ? (or its equivalent in the EU). Is the name owned by someone? b) The title refers to this as a "French" program, and indeed Patientys and Janssen-Cilag are in France, but both are for-profit and Janssen is world-wide and publicly traded. Is there an intent to market this program outside of France? The manuscript says the program was developed by the French PH network - was it then sold or licensed to Patientys? Was Patientys involved in the genesis of the original version of the program? Who pays for the nurse coordinator in this project - Janssen or Patientys? The Patientys website is only in French, so the authors need to clarify more aspects of this company and if it is in part owned by Janssen. c) The term "external" is misleading (line 72), as the "external" nurse is employed by a for-profit company. Thus, this should be clarified to "an external nurse employed by Patientys, directly supported by Janssen." State if the nurse was a patientys or Janssen employee. The role and for-profit nature of the companies must be clear in the Methods section. d) the StartUp program thus appears proprietary and is owned/co-owned by two for-profit companies. Make clear that the details of the program/standard operating procedures (SOP)/counseling/etc are proprietary and are not part of the publication. The structure of the program is of interest to readers, if it can't be released then state so - that it is proprietary. If it can be released, add it as an appendix. e) Line 23, what does "supported by the French PH network" mean? Financially supported? Did the French PH network use its own nurses then, or were patientys/janssen involved from the start? If not, when did the transition occur? d) As 2 authors are from Janssen (AT and TB), then Janssen should appear in the text of the manuscript, not just in author and funding sections. Make it clear that Janssen is the drug manufacturer in the methods section. e) the weblink to the Janssen website is not relevant or helpful to the reader (it does not even go directly to selexipag information), thus remove it f) This program appears similar to programs such as BAYER that were designed to support riociguat use in the USA, so the program is not novel. Are there publications on the BAYER program for comparison? In the USA the FDA mandated nurse-assessed BP and side effect evaluations during riociguat titration. However, in the USA most, but not all commercial payers will cover the extra cost of the RN monitoring program during drug uptitration, while some insurers will not pay for the extra charges for the nurse-driven program. Selexipag does not have such a program in the USA, in USA PH centers the nurses and providers steer uptitration, without a defined SOP. How does this work in France? Outside of the StartUp program, how is selexipag uptitrated in France? Is the drug only uptitrated via StartUp? Including a discussion of other PH drug titration patient assistance programs, base don publicly available information, will be very helpful for context of the StartUp program. g): Getting to reviewer 1's comments, the authors now add more discussion of other selexipag trials and compare the apparently lower selexipag discontinuation rates. However, the authors need to add to the limitations paragraph a discussion that direct statistical comparison was not performed. h) correct BIAS: line 307-8, since no references are given, defend the statement included or remove it: "In contrast with existing PAH patient support programs, Start Up was supervised by a scientific medical committee". Does this team know that BAYER did not have a "scientific medical committee" for its program? As above, clarify when Patientys and Janssen came into the project - if they funded the French PH network from the start, say so. If the program was transitioned to Patientys at some stage, clarify that. Line 308 - the "scientific medical committee" makeup needs to be stated (even as an appendix, so the reader can ascertain the balance of French university-hospital based members versus industry members). 2) Why is data after 2022 not included? Did the program end - was it a pilot? 3) Line 175: the authors still do not clarify the nature of the selexipag patient alert requested by reviewers, and appear to purposely leave it out. Giving the website link is of little help as it is only in French. State the reason for the alert very specifically, even if Janssen co-authors view it adversely. 4) Line 254: BIAS - remove the position statement that the alert was "unsubstantiated". The reader cannot verify this statement, unless the French public oversight agency later retracted the alert and themselves used that word. 5) Strike much of line 337 as a cost analysis was not performed, so the authors cannot say the program is "profitable" which implies finances. The authors can only state "useful" in limiting drug discontinuation rates compared to RCTs, and base don survey data. Minor Comments - line 392: "representation" not "representability" - line 391: awkward, correct - line 404: their, not "her" 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.0331008.r003
Revision 2
25 Jul 2025 Author Response In response to editor's comments and requests on the manuscript the Response to reviewers has been updated. We clarified the specific status of the Start Up program in France which falls in the French regulation framework and the role of the for-profit organisations and non-profit organisation. The Start Up program has been initiated by the non profit organisation, constructed by a scientific committee, and implemented by Patientys, which acts as a trusted third party and operational organisation. Janssen is the institutionnal support of the project, allowing for patient and hospital to benefit from the PSP free of charge. The drug cost management is independant of the program as it is covered by the French healthcare system. I have downloaded an updated cover letter, manuscript and response to reviewers. Regards, Attachments Attachment Submitted filename: Response to reviewers.docx https://doi.org/10.1371/journal.pone.0331008.r004
30 Jul 2025 Decision Letter - James Maloney, Editor PONE-D-25-06416R2Start Up: A French program to support patients with pulmonary arterial hypertension during the adjustment of prostanoids to the individualized optimal dosePLOS ONE Dear Dr. Bergot, 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 (minor) version of the manuscript that addresses the points raised during the review process. Please submit your revised manuscript by Sep 13 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, James P. Maloney, MD 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: This revision is a better manuscript but it has new typo and grammar errors in sections the authors edited. These need to be fixed. 1. Line 339: "may represent", no need for S on the end 2. Line 393: should read "did not benefit" 3. Line 393: Should read "Nor is there a direct..." 4. line 503: representation 5. line 398: "suggest", not suppose 6. Line 399: should read "...the overall population..." 7. Line 402: should read "limited our rate of response....", remove 'satisfaction" [Note: HTML markup is below. Please do not edit.] [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.0331008.r005
Revision 3
5 Aug 2025 Author Response Dear Plos One Editor, Typo and grammar errors have been taken into account in the revised manuscript. The Manuscript, Manuscript with track changes and Responses to reviewers are uploaded. Kind regards, Attachments Attachment Submitted filename: Response_to_reviewers_auresp_3.docx https://doi.org/10.1371/journal.pone.0331008.r006
10 Aug 2025 Decision Letter - James Maloney, Editor Start Up: A French program to support patients with pulmonary arterial hypertension during the adjustment of prostanoids to the individualized optimal dose PONE-D-25-06416R3 Dear Dr. Bergot, 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, James P. Maloney, MD Academic Editor PLOS ONE Additional Editor Comments (optional): Grammar and typographical errors are now fixed. Reviewers' comments: None new https://doi.org/10.1371/journal.pone.0331008.r007
Formally Accepted
Acceptance Letter - James Maloney, Editor PONE-D-25-06416R3 PLOS ONE Dear Dr. Bergot, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset You will receive further instructions from the production team, including instructions on how to review your proof when it is ready. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few days to review your paper and let you know the next and final steps. Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. You will receive an invoice from PLOS for your publication fee after your manuscript has reached the completed accept phase. If you receive an email requesting payment before acceptance or for any other service, this may be a phishing scheme. Learn how to identify phishing emails and protect your accounts at https://explore.plos.org/phishing. If we can help with anything else, please email us at customercare@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. James P. Maloney Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0331008.r008

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