Study protocol of the ASTOP trial: A multicenter, randomized, double-blind, placebo-controlled trial of presurgical aspirin administration for the prevention of thromboembolic complications of coil embolization for ruptured aneurysms

Sakyo Hirai; Kyohei Fujita; Shoko Fujii; Satoru Takahashi; Keigo Shigeta; Jun Karakama; Yukiko Enomoto; Yohei Sato; Masataka Yoshimura; Shin Hirota; Tatsuya Mizoue; Yoshikazu Yoshino; Yoshihisa Kawano; Toshihiro Yamamura; Shinya Kohyama; Masaru Hirohata; Shinichi Yoshimura; Yosuke Ishii; Toshihiro Yamauchi; Naoki Taira; Yoshiki Obata; Makoto Sakamoto; Masato Inoue; Motoshige Yamashina; So Tokunaga; Toshio Higashi; Kana Sawada; Hidetoshi Mochida; Keisuke Ido; Masataka Takeuchi; Tomoji Takigawa; Yasushi Takagi; Masafumi Morimoto; Masataka Nanto; Kazunori Miki; Kouichi Misaki; Koichi Arimura; Yoshiki Hanaoka; Mutsuya Hara; Shoko Hara; Kota Yokoyama; Jun Ooyama; Ryoichi Hanazawa; Hiroyuki Sato; Akihiro Hirakawa; Megumi Ishiguro; Shigeru Nemoto; Kazutaka Sumita

doi:10.1371/journal.pone.0310906

Peer Review History

Original SubmissionJuly 29, 2024
5 Aug 2024 Decision Letter - Cem Bilgin, Editor PONE-D-24-27147Study protocol of the ASTOP trial: a multicenter, randomized, double-blind, placebo-controlled trial of presurgical aspirin administration for the prevention of thromboembolic complications of coil embolization for ruptured aneurysmsPLOS ONE Dear Dr. Sumita, 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 Sep 19 2024 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. 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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 confirming that IRB approval was not provided by each study center. Please provide a list of the names of each center enrolled in the study as a Supplementary File. Please also correct the statement in the Methods and Design section of the manuscript (L138-139) "The ethics committee of each center approved this study" if IRB approval documents cannot be provided for each study center. 3. Please note that funding information should not appear in any section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form. Please remove any funding-related text from the manuscript. 4. We note that the grant information you provided in the ‘Funding Information’ and ‘Financial Disclosure’ sections do not match. When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for your study in the ‘Funding Information’ section. 5. Thank you for stating the following financial disclosure: "This study has been funded by a grant from the Japanese Society of Neuroendovascular Therapy and crowdfunding." 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. 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. 7. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. 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? Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible. 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 aim to evaluate whether pre-operative aspirin application can improve thromboembolic complications in patients with ruptured aneurysms treated with coil embolization, which is a significant question for neurointerventionalists. The study protocol is well-designed with sufficient statistical background and planned with reasonable follow-up modalities (MRI, CT, clinical examinations, and etc.). -Abstract: The abstract clearly summarizes the study protocol. The endovascular treatment modality (coil embolization) can also be added to the abstract to be clearer of the treatment method. -Methods and Design: The study has been recruiting patients over 20 years of age; however, the age criteria in Figure 1 was written as ≤20. Please correct the Figure 1 accordingly. -Discussion section reiterates the need for a randomized clinical trial and its potential effect on future clinical applications of aspirin before endovascular treatment of ruptured aneurysms. -Discussion: On page 22, line 371, the sentence states that 495 patients will be registered. However, in the methods section, the target sample size was determined as 484 patients. Please correct the number in the discussion accordingly. Reviewer #2: This trial investigates the efficacy and safety of preoperative aspirin administration in preventing thromboembolic complications during coil embolization for ruptured cerebral aneurysms. The trial involves 484 patients who will be randomly assigned to receive either 200 mg of aspirin or a placebo prior to the procedure. The primary outcomes include the incidence of intraoperative thromboembolic complications and symptomatic ischemic lesions, while secondary outcomes focus on the incidence of cerebral ischemic events, all bleeding events within 14 days, and functional outcomes at 90 days post-enrollment. The manuscript presents a well-designed study protocol with clear objectives and a robust methodology. Addressing the deficiencies and providing additional details in certain sections below will significantly enhance the quality of the protocol. 1) Can you provide a more detailed explanation of the statistical methods used to determine the sample size? 2) What specific measures will be taken to ensure the blinding of participants and investigators throughout the trial? 3) How will you handle any potential adverse effects of aspirin administration, especially concerning bleeding risks? ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: Yes: Atakan Orscelik ******** [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.0310906.r001
Revision 1
15 Aug 2024 Author Response Dear academic editor and reviewers. We thank the referees for valuable suggestions. We have revised our manuscript on the basis of the editor and reviewer's comments as follows. We look forward to a publication of our manuscript in PLOS ONE. Sincerely, Kazutaka Sumita Our responses to the comments are as follows: The academic editor: 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. Following the PLOS ONE style, “Abstract”, “Introduction”, “Discussion”, “Acknowledgements”, and “References” sections have been revised as Level 1 Headings. P8L134 Methods and design → Materials and methods This has been corrected as Level 1 Heading. Materials and methods section “Patient population”, “Randomization”, “Intervention”, “Data monitoring body”, “Sample size estimates”, “Statistical analyses” sections have been revised as Level 2 Headings. P14L232 "Outcome" has been added as a Level 2 Heading, and "Primary outcomes," "Secondary outcomes," and "Exploratory outcomes" have been revised as Level 3 Headings. P22L399 Summary and conclusions → Conclusions This has been corrected as Level 1 Heading. P24L460 “Supporting information” section has been added as a Level 1 Heading. 2. Thank you for confirming that IRB approval was not provided by each study center. Please provide a list of the names of each center enrolled in the study as a Supplementary File. The list of research facilities has been uploaded as “S5 file” to the Supporting information. Please also correct the statement in the Methods and Design section of the manuscript (L138-139) "The ethics committee of each center approved this study" if IRB approval documents cannot be provided for each study center. Since this study was approved centrally by the CRB and approval by each facility's IRB was not required, the sentence "The ethics committee of each center approved this study" has been deleted in accordance your comments. P9L141 The ethic committee of each center approved this study → delete 3. Please note that funding information should not appear in any section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form. Please remove any funding-related text from the manuscript. We have deleted the funding information in the manuscript as shown below. P21L360 Study organization and funding ASTOP is an investigator-initiated study. Coordination and project management will be provided by an author. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article in Funding statement section. → Delete P23L415 Sources of funding ASTOP has been funded by a grant from the Japanese Society of Neuroendovascular Therapy and crowdfunding for ASTOP. The ASTOP study was registered with the Japan Registry of Clinical Trials (identifier: jRCTs031210421). Declaration of conflicts of interest The authors declare that there is no conflict of interest. → Delete 4. We note that the grant information you provided in the ‘Funding Information’ and ‘Financial Disclosure’ sections do not match. When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for your study in the ‘Funding Information’ section. Funding for this research is provided by Japanese Society of Neuroendovascular Therapy and crowdfunding. I listed these in the funding information on the submission site. Crowdfunding does not have a grant number, so I left it blank. 5. Thank you for stating the following financial disclosure: "This study has been funded by a grant from the Japanese Society of　Neuroendovascular Therapy and crowdfunding." 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. The following sentence has been added to the cover letter: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript." 6. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. The following supporting information has been added to the end of the manuscript. P24L476 Supporting information S1 File. SPIRIT check list S2 File. Study Protocol in English S3 File. The original version of the CRB approval document in English S4 File. The latest version of the CRB approval document in English S5 File. List of research facilities 7. 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. I checked the reference list. Following the reviewer's suggestions, I simplified the discussion and deleted two references (reference No. 11 and No. 12 in the original manuscript). I have renumbered and corrected the reference list. Reviewer #1: -Abstract: The abstract clearly summarizes the study protocol. The endovascular treatment modality (coil embolization) can also be added to the abstract to be clearer of the treatment method. Thank you for your valuable suggestion. To make it easier to understand what kind of endovascular treatment was performed, we added the information that coil embolization was performed in the Abstract section in accordance your comments. Abstract section P6L97 A total of 484 patients with ruptured cerebral aneurysms receiving endovascular treatment within 72 h of onset will be randomly assigned 1:1 to receive 200 mg of aspirin or placebo before the procedure. → A total of 484 patients with ruptured cerebral aneurysms receiving coil embolization within 72 h of onset will be randomly assigned 1:1 to receive 200 mg of aspirin or placebo before the procedure. -Methods and Design: The study has been recruiting patients over 20 years of age; however, the age criteria in Figure 1 was written as ≤20. Please correct the Figure 1 accordingly. Thank you for pointing out the mistake. We will correct it as follows. Figure.1 Main eligibility criteria 3) Age at the time of onset is ≤20 years → 3) Age at the time of onset is ≥20 years -Discussion section reiterates the need for a randomized clinical trial and its potential effect on future clinical applications of aspirin before endovascular treatment of ruptured aneurysms. As you pointed out, the discussion section contains some overlapping content with that stated in the introduction. I have removed the overlapping content and simplified the content. In addition, I have removed two references, and changed the numbering of the references in the discussion section. Discussion section P21L362 The primary objective of the ASTOP study is to assess whether the administration of antiplatelet agents before EVT for RAs in the acute phase can reduce thromboembolic complications during the procedure and symptomatic ischemic lesions on MRI-DWI. The use of preoperative dual antiplatelet therapy, mainly with aspirin and clopidogrel, to prevent perioperative thromboembolic complications has become a common clinical practice in the field of neuro-EVT, especially for unruptured cerebral aneurysms and carotid artery stenting procedures. However, these practices are not based on scientific evidence proven through RCTs. → Delete -Discussion: On page 22, line 371, the sentence states that 495 patients will be registered. However, in the methods section, the target sample size was determined as 484 patients. Please correct the number in the discussion accordingly. Thank you for pointing out the mistake. We will correct it as follows. Discussion section P22L396 Recruitment will continue until the registration of 495 patients is completed. → Recruitment will continue until the registration of 484 patients is completed. Reviewer #2: 1) Can you provide a more detailed explanation of the statistical methods used to determine the sample size? Thank you for your valuable opinion. We have added the following information to the statistical method used to determine the sample size so that it is easier for non-statisticians to understand. Abstract section P6L92 a sample size of 484 will be required to detect a 10% improvement with aspirin administration with 90% power using a two-sided hypothetical test at a significance level of 2.5% for each primary outcome → a sample size of 484 will be required to detect a 10% improvement with aspirin administration with 90% power using the Pearson's chi-square test at a two-sided significance level of 2.5% for each primary outcome Sample size estimates P17L301 Under these assumptions, a sample size of 460 patients (230 patients in each group) will be required to achieve 90% power for each intergroup comparison of the primary outcomes, using a two-sided significance level of 0.025. → Under these assumptions, a sample size of 460 patients (230 patients in each group) will be required to achieve 90% power for each intergroup comparison of the primary outcomes using the Pearson’s chi-square test at a two-sided significance level of 0.025. 2) What specific measures will be taken to ensure the blinding of participants and investigators throughout the trial? The study coordinators, other than the investigators responsible for the patient care, will create a correspondence table of the study drugs, either aspirin or placebo, and their respective drug numbers. Each drug will be stored in bags that cannot be inspected internally from the outside. At the time of endovascular treatment, the investigators will hand over the bags containing the drug numbers presented by the allocation system to the anesthesiologist or the assigned nurse. These drugs will be administered to the patient via a nasogastric tube after the induction of general anesthesia, without the investigators being present. This ensures the double-blind status of both the study participants and the investigators. We have added the following information about the blinding process: Randomization　P11L191 The study coordinators, other than the investigators responsible for the intervention, prepare the test drug and create a correspondence table of the trial drugs, either aspirin or placebo, and their respective drug numbers. Each drug is stored in a bag that cannot be seen from outside. Intervention P12L204 This ensures the double-blind status of both the study participants and the investigators. 3) How will you handle any potential adverse effects of aspirin administration, especially concerning bleeding risks? Thank you for your important comment. We have added the following sentences regarding how to respond in the event of a serious adverse event for which a causal relationship with the study drug or study procedures cannot be denied. Intervention　P13L222 In the event of adverse events, including hemorrhagic complications, the best possible medical care will be provided. If a serious adverse event occurs that cannot be ruled out as being related to the study drug or procedure, it will be reported to the administrator of the implementing medical institution and subsequently to the Certified Review Board of Tokyo Medical and Dental University for further review and consideration. Attachments Attachment Submitted filename: response to reviewer.docx https://doi.org/10.1371/journal.pone.0310906.r002
9 Sep 2024 Decision Letter - Cem Bilgin, Editor Study protocol of the ASTOP trial: a multicenter, randomized, double-blind, placebo-controlled trial of presurgical aspirin administration for the prevention of thromboembolic complications of coil embolization for ruptured aneurysms PONE-D-24-27147R1 Dear Dr. Sumita, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Cem Bilgin Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0310906.r003
Formally Accepted
17 Sep 2024 Acceptance Letter - Cem Bilgin, Editor PONE-D-24-27147R1 PLOS ONE Dear Dr. Sumita, 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 If revisions are needed, the production department will contact you directly to resolve them. If no revisions are needed, you will receive an email when the publication date has been set. At this time, we do not offer pre-publication proofs to authors during production of the accepted work. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few weeks to review your paper and let you know the next and final steps. Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. If we can help with anything else, please email us at customercare@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Cem Bilgin Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0310906.r004

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