PONE-D-21-08923Predictive factors requiring high-dose evocalcet in hemodialysis patients with secondary hyperparathyroidismPLOS ONE

Dear Dr. Tokumoto,

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 note that both referees raised several issues (see their reports below) that should be addressed thoroughly. Besides, reviewer #2 was somewhat skeptic about the robustness of the statistical analysis and the rationale of some analyses. I'd suggest addressing these comments specifically. 

Please submit your revised manuscript by Apr 09 2022 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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We look forward to receiving your revised manuscript.

Kind regards,

Gianpaolo Reboldi, MD, MSc, PhD

Academic Editor

PLOS ONE

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2. Thank you for stating the following in the Competing Interests section: "MT received consulting fees from KKC and Ono Pharmaceutical, and lecture fees from KKC, Chugai Pharmaceutical, Bayer, Kissei Pharmaceutical, Torii Pharmaceutical, Fuso Pharmaceutical, and Ono Pharmaceutical. ST, SA, and YE are employees of KKC. NK received lecture fees and travel grants for research meetings from KKC, which are not connected to this research. MF received consulting fees from KKC and Ono Pharmaceutical, lecture fees from KKC, Bayer, Torii Pharmaceutical and Ono Pharmaceutical, and grants from KKC and Bayer. TA received consulting fees from KKC, Astellas Pharma, Bayer, Fuso Pharmaceutical, Japan Tobacco, Ono Pharmaceutical, Sanwa Chemical, Otsuka, GSK, and NIPRO, and lecture fees from KKC, Chugai Pharmaceutical, Bayer, Kissei Pharmaceutical, Torii Pharmaceutical, and Ono Pharmaceutical."

We note that you received funding from a commercial source: Kyowa Kirin Co., Ltd, Ono Pharmaceutical, Chugai Pharmaceutical, Bayer, Kissei Pharmaceutical, Torii Pharmaceutical, and Fuso Pharmaceutical

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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: No

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: No

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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: No

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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: No

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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: General comments:

This is a post-hoc analysis of a phase 3 randomized clinical trial which compared head-to-head the efficacy and safety of oral cinacalcet hydrochloride to evocalcet. The post-hoc analysis included 313 hemodialysis patients and looked at the baseline clinical and biochemical parameters determining the response and the use of higher doses of the oral calcimimetic evocalcet. The authors found that at the end of study, median serum PTH level was higher and achievement ratio of the Japanese Society for Dialysis Therapy target range was lower in the high-dose subgroup (216 pg/mL, 58%, respectively) than other subgroups (low: 149 pg/mL, 79%; medium: 149 pg/mL, 73%, respectively). Younger age, prior cinacalcet use, higher levels of serum PTH, corrected calcium, procollagen type 1 N-terminal propeptide, intact fibroblast growth factor-23, and larger maximum parathyroid gland volume were significantly associated with high dose evocalcet (p < 0.05 in all cases).

The authors should consider the following comments and questions.

Specific comments:

1- Was the calcium concentration in the dialysate kept stable during the study? It would be of interest knowing which was the mean (median) calcium concentration in the dialysate fluid for each one of the patient groups.

2- How was the compliance to cinacalcet and evocalcet evaluated?

3- Circulating levels of 25OHD3 have been demonstrated to be associated with the response to oral cinacalcet. Did the authors assess circulating levels of 25OD3 in this trial?

Reviewer #2: Here is a list of specific comments. Note: line and page numbering in reviews and comments is based on ruler applied in Editorial Manager-generated PDF.

1. Page 4, lines 59–60: This phrase inferred causality. Because the post-hoc analysis lost the benefit of randomization, I suggest using ‘associate’ instead of using “predict”.

2. Page 6, lines 99–101: I suggest indicating the categorized evocalcet dose at week 28 was the primary exposure of interest.

3. Page 7, line 110: Because the primary exposure of interest was determined at week 28, I suggest clarifying in the manuscript that the baseline for endpoints was week 28.

4. Page 7, lines 110–111: I suggest not mentioning “in each subgroup stratified by evocalcet dose range” in the Endpoints section.

5. Page 7, lines 111–112: This sentence was also irrelevant in the Endpoints section.

6. Page 7, lines 122–126: I suggest clarifying which characteristics were collected at week 28. If a characteristic was collected at week 28, I suggest referring the week-28 value as the “baseline” value.

7. Page 7, line 127: Did ratios refer to percentages? If so, I suggest replacing ratios with percentages.

8. Page 7, lines 127–128: I suggest removing “and summary statistics were calculated for continuous data” because it was redundant given the following sentence.

9. Page 7, line 129: Please write ‘were calculated for continuous data’.

10. Page 8, line 131: Following Comment #3 above, I suggest limiting to the time points after week 28.

11. Page 8, line 133: Following Comment #3 above, I suggest starting from week 28.

12. Page 8, lines 136–140: I did not understand the rationale of this analysis. The evocalcet categories were previously defined and described as the primary exposure of interest. However, the multinomial logistic used the evocalcet categories as the outcome without any justification.

13. Page 8, lines 141–143: Similarly, the safety endpoints and follow-up time should start from week 28 to week 30.

14. Page 8, lines 144–146: I suggest relocating this sentence to the end of the second paragraph of this section.

15. Page 8, lines 150–151: I suggest including a figure depicting the patient flow from the randomization to the safety and full analysis sets.

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Reviewer #1: No

Reviewer #2: No

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PONE-D-21-08923R1Predictive factors requiring high-dose evocalcet in hemodialysis patients with secondary hyperparathyroidismPLOS ONE

Dear Dr. Tokumoto,

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.  While reviewer #1 was satisfied by the revised version, reviewer #2 remarked issues regarding the the design and analysis plan that must be addressed (see details below).

Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised by reviewer #2

Please submit your revised manuscript by Jun 16 2022 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,

Gianpaolo Reboldi, MD, MSc, PhD

Academic Editor

PLOS ONE

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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 #1: All comments have been addressed

Reviewer #2: (No Response)

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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 #1: Yes

Reviewer #2: Partly

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: No

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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 #1: Yes

Reviewer #2: No

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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

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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 #1: They have properly answered to my main questions. The manuscript has been significantly improved.

I do not have further comments.

Reviewer #2: Here is a list of specific comments. Note: line and page numbering in reviews and comments is based on ruler applied in Editorial Manager-generated PDF.

1. Page 6, lines 103–106: I suggest reserving ‘this study’ for the post-hoc analysis and referring the previous phase 3 head-to-head comparison study as ‘the parent study’.

2. Page 6, line 104:

(2a) My apologies for misinterpreting the role of the evocalcet categories in Comment #2 of the previous review.

(2b) There were two roles of the evocalcet categories in this study: (1) as an outcome in identifying factors associated with the evocalcet categories; and (2) as a stratification factor in evaluating efficacy and safety of evocalcet.

(2c) For the second role, stratifying patients based on a post-baseline factor was likely to introduce bias. In this case, the evocalcet categories was not determined until Week 28 whereas the factors that were evaluated were measured at baseline, Week 0. I suggest considering a more careful analytic plan.

(2d) To avoid the aforementioned bias, you may treat Week 28 as baseline. This means that only efficacy and safety endpoints that were measured and collected after Week 28 will be treated as outcomes. Everything collected at or prior to Week 28 could be consider as baseline factor. In this case, the stratified analysis would be OK as long as the outcomes were collected after Week 28.

3. Page 7, line 115: These endpoints were the outcomes for the second role of the evocalcet categories (see Comment #2b above). For the first role, the outcome would be the evocalcet categories. I suggest explicitly defining the outcome for the first role.

4. Page 7, lines 124–127:

(4a) Comment #15 of the previous review was meant to clarify the full analysis set and the safety analysis set in this study. The figure in the response was for the parent study. I suggest including a patient flow diagram for this study even if it would be a copy of the left-hand side of the original figure.

(4b) In addition, the full analysis and safety sets were with regard to the second role of the evocalcet categories (see Comment #2b above).

5. Page 8, lines 134–136: Given Comment #2c above, these comparisons would not be performed unless there was another stratified variable that was defined at baseline. Otherwise, this sentence could be removed.

6. Page 8, lines 143–147: This was only for the first role of the evocalcet categories (see Comment #2b above). The analytic plan for the efficacy endpoints were not included.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Pablo URENA TORRES

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.

Predictive factors requiring high-dose evocalcet in hemodialysis patients with secondary hyperparathyroidism

PONE-D-21-08923R2

Dear Dr. Tokumoto,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Gianpaolo Reboldi, MD, MSc, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

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

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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

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

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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: No

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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

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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: (No Response)

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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

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