https://orcid.org/0000-0003-1570-2323
Peer Review History
| Original SubmissionDecember 29, 2023 |
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PONE-D-23-43948Feasibility, safety and tolerability of estrogen and/or probiotics for improving vaginal health in Canadian African, Caribbean, and Black women: A pilot phase 1 clinical trialPLOS ONE Dear Dr. Kaushic 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 address commments of both reviewersPlease ensure that your decision is justified on PLOS ONE’s publication criteria and not, for example, on novelty or perceived impact. For Lab, Study and Registered Report Protocols: These article types are not expected to include results but may include pilot data. ============================== Please submit your revised manuscript by Mar 11 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. 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:
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, Alan Landay Academic 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 2. Thank you for stating in your Funding Statement: “This study was funded by CIHR Grants FRN#159229 and FRN#154047 (CK) and in kind contributions from CIHR HIV Clinical Trials Network (FS, CK). B.G was partially supported by a Post-doctoral Award from CIHR FRN#181875” Please provide an amended statement that declares *all* the funding or sources of support (whether external or internal to your organization) received during this study, as detailed online in our guide for authors at http://journals.plos.org/plosone/s/submit-now. Please also include the statement “There was no additional external funding received for this study.” in your updated Funding Statement. Please include your amended Funding Statement within your cover letter. We will change the online submission form on your behalf. 3. 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: GR developed the probiotic strains GR-1 and RC-14 but has had no financial interest in them for 15 years. GR consults for Seed, a company producing probiotic strains not used in this study. All the other authors have declared no conflict of interest.” We note that one or more of the authors are employed by a commercial company: Seed a. Please provide an amended Funding Statement declaring this commercial affiliation, as well as a statement regarding the Role of Funders in your study. If the funding organization did not play a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript and only provided financial support in the form of authors' salaries and/or research materials, please review your statements relating to the author contributions, and ensure you have specifically and accurately indicated the role(s) that these authors had in your study. You can update author roles in the Author Contributions section of the online submission form. Please also include the following statement within your amended Funding Statement. “The funder provided support in the form of salaries for authors [insert relevant initials], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.” If your commercial affiliation did play a role in your study, please state and explain this role within your updated Funding Statement. b. Please also provide an updated Competing Interests Statement declaring this commercial affiliation along with any other relevant declarations relating to employment, consultancy, patents, products in development, or marketed products, etc. Within your Competing Interests Statement, please confirm that this commercial affiliation 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 this adherence statement is not accurate and 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 both an updated Funding Statement and Competing Interests Statement in your cover letter. We will change the online submission form on your behalf. 4. Thank you for stating the following in the Acknowledgments Section of your manuscript: “This study was supported by CIHR Grants FRN# 159229 and #126019 (C.K.) and by in kind support from the CIHR Canadian HIV Trials Network (CTN 308). B.G was partially supported by a Post-doctoral Award from CIHR FRN#181875.” We note that you have provided additional information within the Acknowledgements Section that is not currently declared in your Funding Statement. Please note that funding information should not appear in the Acknowledgments 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 and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows: “This study was funded by CIHR Grants FRN#159229 and FRN#154047 (CK) and in kind contributions from CIHR HIV Clinical Trials Network (FS, CK). B.G was partially supported by a Post-doctoral Award from CIHR FRN#181875” Please include your amended statements within your cover letter; we will change the online submission form on your behalf. 5. 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. 6. 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 (if provided): Please address the comments of the reviewers [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: Yes Reviewer #2: Yes ********** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ********** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes ********** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ********** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: This paper reports the results of a prospective, randomized, open-label phase 1 clinical trial to determine the feasibility, safety, and tolerability of administering low-dose estrogen, probiotics, or both in combination to improve vaginal health and decrease HIV susceptibility. The manuscript if well written, easy to follow and straight forward. I am particularly pleased with the decision to focus enrollment on African, Caribbean, and Black women, who are historically underrepresented in research. I wholeheartedly agree that acceptance of formulation and delivery methods need to be considered when applying probiotics to different body sites and for diverse populations. I was a bit disappointed about the lack of biological outcome data in this paper, like for example displacement of anaerobic and BV-associated microbiota, normalizing vaginal pH, and decreasing genital inflammation along with clinical signs and symptoms of BV (it looks like this part will be published separately in the future). Unless there is a rationale for splitting the paper, I would prefer to see a complete story (this paper feels amputated). Other limitations include the small sample size limiting generalization (was acknowledged by the authors), lack of placebo arm (should be acknowledged by the authors). I was also surprised by the number of adverse events. Are those severe systemic effects (like nausea, light headedness, headache, cramps) expected with this type of intervention? It is hard to evaluate without a placebo arm. Importantly, do NOT use the word subject when referring to study participants (it is stigmatizing and not acceptable). Reviewer #2: This paper summarizes the safety, feasibility, and tolerability of innovative intervention regimens to improve vaginal health. It was a randomized phase 1 open label in which participants were randomized to one of 4 arms: Intravaginal estradiol (estring 7.5mg/day), vaginal probiotic 2x/day, estradiol + vaginal, estradiol + oral twice daily. Interventions were taken for 30 days. There was high and comparable adherence across arms. While the AE rate was high, they were primarily mild and resolved by end of study, with no SAEs. The results are sufficient to move forward with larger trials of these potential interventions. The paper is nicely written, and only minor clarifications are requested. Abstract: Concise and well-written. Results : could the authors please clarify what is the unit on adherence? E.g., is 0.93 --> 93% of doses were taken? Introduction - Well written and generally sufficient. There seems to be a jump in rationale explaining the selection of Lacticacseibacillus rhamnosus and Limosillactobacillus reuteri (lines 92-97). Could the authors please add a sentence or two about how these strains address the sentence (92-94), or the “properties” they are addressing in line 94? Reviewer notes later there are some mechanisms at lines 111-113 that may flow better above. - Lines 106-108, could authors clarify here whether the studies citing topical estrogen creams employed safely and well-tolerated were in pre-menopausal women? It may be there in the citations, but just a few words to clarify and save the reader from having to look something up. - Line 109. The use of the word “demonstrate” is confusing in this sentence: “we are testing an innovative strategy”? Materials and Methods - Line 135. Could the authors please specify the amount of compensation? - Lines 145-146. Could the authors please explain at least some of the inclusion and exclusion criteria in the text? To have none there is disruptive to reading. Or make this a table in the main paper (I don’t think Plos limits these?) because it’s disruptive to have to go to supplemental to read this. o Irregular menstrual cycle is listed as an exclusion criterion. Could the authors please explain how this was assessed? - Explanation of randomization process is clear. - Description of study visits and procedures are clear. Results - The CONSORT flow diagram is clear and nicely done. o Could the authors please explain why 4 participants withdrew consent? - Lines 227-229: Reviewer is confused on what is meant by “prematurely terminated the study” (dropped out? Stopped coming for study visits?) as they are then “considered non-adherent” (line 229) so it would be important to understand why they were non-adherent/prematurely terminated. - Line 239, it is unclear why “congenital anomaly” is listed as a potential SAE of this intervention? - Lines 288-290: Could the authors please clarify the adherence rate units – is tis 92% 93% 97% etc.? Are these adherence rates for all 50 women who were randomized or just those n=41 completing? It seems like it is for all based implication in lines 292-293. But this is somewhat confusing b/c the CONSORT diagram indicates that these “participants terminating study prematurely” (line 293) are not included in analyses. But then the safety markers are also analyzed across the 50 participants (368) - Kudos to investigators on the high adherence and completion rates! Were participants provided any incentives or reminders? Discussion - Well written and concise. Hits the main points. - As with comment above, wording in lines 416-418 is confusing use of “demonstrate” – “we demonstrate an innovative strategy”. “we evaluate? Test? Examine?” - Lines 421-422 – it seems something got cut out of this sentence. In what ways “more beneficial” for? ********** 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: 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. |
| Revision 1 |
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PONE-D-23-43948R1Feasibility, safety and tolerability of estrogen and/or probiotics for improving vaginal health in Canadian African, Caribbean, and Black women: A pilot phase 1 clinical trialPLOS ONE Dear Dr. Kaushic, 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 Jul 13 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. 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:
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, Alan Landay Academic Editor PLOS ONE Journal Requirements: Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #3: (No Response) ********** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #3: Yes ********** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #3: Yes ********** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #3: 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 #3: Yes ********** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #3: Comments: Statistically, this manuscript is pretty straightforward. For phase 1 safety trials, this is usually the case since the purpose and sample size are not conducive for performing more complicated analyses. Your stated goals of the trial in line 114 align with this and, as I see it, assessing "feasibility, safety, and tolerability" are more about estimating proportions and percentages than doing any sort of comparative analyses. That said, I am not sure about the sample sizes for the arms in this trial. I know there exists literature on calculating the sample size for phase 1 dose-finding trials, but I know less about safety trials. Logically, I would think that the sample size should be large enough to capture AEs (and especially SAEs) that occur with some frequency in the population being studied. For the overall numbers, I think you are ok. That's because, if we assume that the probability of an AE is 0.1, then, using the binomial distribution, the probability that you would not detect that AE in 41 people is 0.01. So, only a 1% chance that it would be missed. On the other hand, if we use a sample size of 13 people, that jumps to 0.25 (and 0.31 for 11 people). That's a pretty high probability and I think is too high for comfort. There are no power analyses reported in this manuscript. I think that is a negative, but that can't be changed retrospectively. I am struggling the most with PLOS publication criterion number 3 (https://journals.plos.org/plosone/s/criteria-for-publication) since I think the product-specific sample sizes are too low to be robust. I think the conclusions inferred by product, such as lines 384-386, are too strong given the small sample size. I think a greater focus on the overall results and softening the language around the product-specific conclusions is needed. Specific comments: 1. (lines 146-9) Please reference the computer program used for randomization. 2. (Table 4) I believe the overall sample size for Visit 5 is a typo and should read 41 instead of 4. ********** 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 #3: 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. |
| Revision 2 |
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PONE-D-23-43948R2Feasibility, safety and tolerability of estrogen and/or probiotics for improving vaginal health in Canadian African, Caribbean, and Black women: A pilot phase 1 clinical trialPLOS ONE Dear Dr. Kaushic, 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 Oct 21 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. 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:
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, Kazunori Nagasaka 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. Additional Editor Comments: Dear Authors, Thank you for submitting your research in Plos One. Please revise the manuscript according to the reviewers comments. We look forward to your revised manuscript. Sincerely, Kazunkori Nagasaka [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #3: (No Response) Reviewer #4: All comments have been addressed Reviewer #5: (No Response) ********** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #3: No Reviewer #4: Yes Reviewer #5: Yes ********** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #3: No Reviewer #4: Yes Reviewer #5: Yes ********** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #3: Yes Reviewer #4: Yes Reviewer #5: 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 #3: Yes Reviewer #4: Yes Reviewer #5: Yes ********** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #3: Thank you for your thorough consideration of my comments. That said, I am still coming to the same conclusions as my previous review. Based on your response, specifically this: "This study was designed as a pilot Phase I clinical trial study with the purpose was to examine the feasibility of recruitment, randomization, retention, assessment procedures, and implementation of an novel intervention." safety is not a part of this study's purpose. And yet the title and abstract seem to report safety findings. Demonstration projects are important and I can understand the argument that such a project is needed to assess the feasibility of testing an intervention and data collection systems. But, the way this manuscript is structured it still looks heavily like you are reporting the results of a safety trial and that safety is one of the objectives of this manuscript. I think it is unreasonable to expect a phase 1 trial to capture an extremely rare event, such as a 1:1000 event. But, I think it is reasonable for a phase 1 trial to capture a 1:100, which I don't see as an extreme case. Thus, I still feel the sample sizes are not large enough to produce robust results and that criterion #3 (https://journals.plos.org/plosone/s/criteria-for-publication) has not been met. Reviewer #4: The authors have addressed all issues, and I believe the manuscript is ready for publication in its current form. Reviewer #5: This is an important manuscript addressing a key research question – understanding and mitigating modifiable risk factors for HIV transmission in a high-risk population. The introduction adequately lays out the scientific rationale for the feasibility trial and underlying clinical question being discussed, including current data gaps – need for research to better prevent/treat BV in order to reduce biological susceptibility to HIV, and lack of safety data on use of oral probiotics combined with estrogen vaginally for longer than 5 days. The primary and secondary outcomes are clearly defined, and the study design which includes randomization and intention to treat analysis is sound. The methods section is well laid out and use a schedule events make it easy to follow. A few thing can be further clarified to strengthen the interpretation of results and support the study’s conclusions: 1) Adherence assessment: - How was adherence measured exactly, in the participants who completed the trial? - The manuscript states ‘adherence metrics were determined according to either the ratio of probiotics consumed relative to the total dispensed, or the number of days the estring was used relative to the study duration.” – was this all based on self-report, or were there any objective measures of assessing adherence? The manuscript states that participants kept a diary – what exactly did they note? E.g., those using a probiotics twice a day, did they indicate date/time each probiotic was used for the full 30 days, and how was this assessed/graded to give an adherence score of close to 1 (perfect adherence)? It is often difficult for patients to take a daily pill for 30 days, and we expect it would be difficult to do so twice daily for 30 days, so how was this assessed to give the high adherence scores noted? This needs to be justified further - Can an addendum of a sample study diary that is filled out be included in the appendix to show an example of ‘good’ adherence (assuming filled out daily), vs non-ideal adherence? What data did the authors use to back the statement “diary completion across all visits and interventions was 100% among those who completed the study,” and can the authors more explicitly address how this method of assessing diary completion gives them confidence that the participants used the capsules twice daily, which then strengthens the safety conclusions of the trial? This is important, because non-optimal adherence affects the safety outcomes which are important for the trial. If the authors cannot confidently state that the intervention was not used twice daily for 30 days, then this should be included in the limitations to inform interpretation of the AEs noted. 2) Adverse event evaluation - What scale was used to grade the AEs, and is it a standardized scale/one used previously in similar studies? What differentiated a mild from moderate AE? If a standardized grading scale was not used, consider noting this as a limitation as it may reduce reproducibility 3) Completion of sexual history questionnaire as adherence assessments - Can the authors please clarify how completion of a the sexual history questionnaire is used as an adherence assessment method? What is the rationale for this? Has this been validated previously or used in similar studies? ********** 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 #3: No Reviewer #4: No Reviewer #5: 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. |
| Revision 3 |
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PONE-D-23-43948R3Feasibility, safety and tolerability of estrogen and/or probiotics for improving vaginal health in Canadian African, Caribbean, and Black women: A pilot phase 1 clinical trialPLOS ONE Dear Dr. Kaushic, 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 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. 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:
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, Kazunori Nagasaka 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. Additional Editor Comments: Dear Authors, We apologize for the delay in the peer review process of your paper and thank you for your inquiry regarding the status of your submission. We acknowledge your research environment and appreciate your patience. However, our reviewers have identified significant concerns regarding the content of your paper, which prevent us from accepting it at this time. They have highlighted critical statistical issues, particularly concerning the sample size. We encourage you to discuss these points with the biostatistician on your research team and seek guidance on each of the concerns raised. We understand that your time is limited, but we would greatly appreciate your attention to these issues and a response addressing the reviewers' comments. Thank you for your understanding. Plos One Kazunori Nagasaka [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #3: (No Response) ********** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #3: No ********** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #3: No ********** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #3: 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 #3: Yes ********** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #3: I think I understand better where you are coming from, but I still believe the statement you have added, "2-5% chance of missing 1:100 AE, based on sample size" is not correct. In lines 334-366, the numbers reported there are all based on N=29. Assuming an event with a probability of 0.001 or 0.1%, we can calculate the probability of observing exactly zero events in 29 people using the binomial distribution. I'm using R. > pbinom(0,29,0.001) [1] 0.9714024 That's a 97% chance of observing exactly zero events, i.e., a 97% chance of missing that event. I'm ok with that because I think it is unreasonable to expect a phase 1 trial to detect such a rare event. Using the same approach, we can see what the probability is of observing exactly zero events when the probability is 0.01: > pbinom(0,29,0.01) [1] 0.7471721 That says there is approximately a 75% chance of missing an event, which is far greater than the 2-5% in your statement. If you want to get down to your 2-5%, you need to up the probability by an order of magnitude: > pbinom(0,29,0.10) [1] 0.04710129 Thus, you can feel confident about observing an AE in your trial if it occurs in approximately 10% of people. My contention is that is not good enough. I suspect different fields have different standards, so maybe standards are lower in your field. For instance, I can find a paper that suggests sample sizes have been increasing over time (https://doi.org/10.1093/jnci/dju163) and that your sample size would be on the lower end for studies performed approximately 35 years ago. But maybe those trials are different and there are differences between your field and theirs. ********** 7. 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| Revision 4 |
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Feasibility, safety and tolerability of estrogen and/or probiotics for improving vaginal health in Canadian African, Caribbean, and Black women: A pilot phase 1 clinical trial PONE-D-23-43948R4 Dear Dr. Kaushic, 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, Kazunori Nagasaka Academic Editor PLOS ONE Additional Editor Comments (optional): Dear Authors, Thank you for submitting your manuscript to Plos One. We now get two reviewer's comment. Our reviewers have recommended that the manuscript is ready for publication. Congratulations on your manuscript and we look forward to receiving your future studies. Sincerely, Kazunori Nagasaka Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #2: All comments have been addressed ********** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #2: Yes ********** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #2: Yes ********** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #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 #2: Yes ********** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #2: The authors have addressed all issues, and I believe the manuscript is ready for publication in its current form. ********** 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 #2: No ********** |
| Formally Accepted |
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PONE-D-23-43948R4 PLOS ONE Dear Dr. Kaushic, 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 Professor Kazunori Nagasaka Academic Editor PLOS ONE |
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