The efficacy and safety of roxadustat for the treatment of anemia in non-dialysis dependent chronic kidney disease patients: An updated systematic review and meta-analysis of randomized clinical trials

Basel Abdelazeem; Joseph Shehata; Kirellos Said Abbas; Nahla Ahmed El-Shahat; Bilal Malik; Pramod Savarapu; Mostafa Eltobgy; Arvind Kunadi

doi:10.1371/journal.pone.0266243

Peer Review History

Original SubmissionNovember 8, 2021
6 Jan 2022 Decision Letter - Gianpaolo Reboldi, Editor PONE-D-21-35500The Efficacy and Safety of Roxadustat for the Treatment of Anemia in Non-dialysis Dependent Chronic Kidney Disease Patients: An Updated Systematic Review and Meta-Analysis of Randomized Clinical TrialsPLOS ONE Dear Dr. Eltobgy, 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 Feb 20 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. 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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. 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. [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: I Don't Know 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: No ****** 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: In this work, the Authors investigated by a systematic review and meta-analysis the effects and the safety of Roxadustat (ROX) in CKD patients not on dialysis therapy. Comments - Some further meta-analyses were recently published (Wang et al., Ann Palliat Med 2021, 10:4736–46; Qie et al., Int Urol Nephrol 2021, 53:985–97; Zhang et al., Aging 2021, 13:17914–29; Liu et al., Front Med 2021, 8: 724456) and should be added to the article. - The Authors report in the present work higher serious adverse events, hypertension, and deep venous thrombosis in ROX treated patients. By contrast, a recent meta-analysis (Liu, see above) showed that total adverse events were not significantly different between ROX and placebo as confirmed by trial sequential analysis, with increased risk of hyperkalemia events. A comment is welcomed. - Three phase 2 trials were included: may this decrease the level of evidence? - How were managed studies reporting data for more than one ROX dose? - The Authors report improved iron utilization parameters upon ROX treatment including decreases in ferritin and transferrin saturation and increases in TIBG and transferrin. These changes however also indicate a decrease in body’s iron storage and available iron, and suggest that patients were not receiving appropriate iron therapy for body iron requirement during ROX treatment. It appears that a stranded iron application is necessary in future studies to better characterize the effects of ROX on iron metabolism. Authors would comment on this issue. Reviewer #2: Abdelazeem and Colleagues, with this systematic review and meta-analysis, tried to extrapolate from the randomized studies available the efficacy and safety of Roxadustat on change in Hemoglobin and related parameters as well as on cardiovascular risk. The study is of interest and statistical analysis is overall of good quality. Moreover, this is an important topic from a clinical research perspective. However, I have several concerns to share with Authors: - Abstract: I would suggest Authors to change “efficacy and safety of ROX, especially on the cardiovascular system” into “efficacy and safety of ROX, especially on cardiovascular endpoints/risk”. The word system is too general. Moreover, please change “hat evaluated ROX NDD- CKD patients” with “hat evaluated ROX in NDD-CKD patients”; - English language should be improved throughout the manuscript. - Introduction is clearly written, and the aim is well depicted in my opinion. - Methodology is overall accurate in term of study selection and statistical tools used. However, I have a major concern namely the fact that studies were “intervention was ROX compared placebo or any other medications” were included in the meta-analysis. In this way Authors compared for example ROX with darbepoetin or ROX against no ESA. This can introduce a bias if the primary endpoint is the change in Hb levels. - Please also improve the quality of figures. Most of them are not clearly interpretable in the current form. - Some subgroup analyses/meta-analyses (for instance panel D of figure 4) included less then 5 studies and this confers low power to statistical finding. Please clarify this in the limitations if possible. ****** 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. 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Revision 1
27 Jan 2022 Author Response Mostafa Eltobgy, MD The Ohio State University 281 W Lane Ave, Columbus, OH 43210 Tel: 551-227-6556 E-mail: eltobgy.2@osu.edu January 27th, 2021 Dear Editor-in-Chief, We submit for the revision for our manuscript entitled “The efficacy and safety of roxadustat for the treatment of anemia in non-dialysis dependent chronic kidney disease patients: an updated systematic review and meta-analysis of randomized clinical trials” with ID PONE-D-21-35500 for consideration in your journal. Please see the reply to each of the reviewers’ comments below. Journal Requirements: When submitting your revision, we need you to adso much ess 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 https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf Reply: Thank you so much for your comments. We ensured that our manuscript met PLOS ONE's style requirements 2. 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 Reply: Thank you so much for your comments. We add captions for the Supporting Information files at the end of the manuscript and update any in-text citations to match accordingly as requested Reviewer #1: In this work, the Authors investigated by a systematic review and meta-analysis the effects and the safety of Roxadustat (ROX) in CKD patients not on dialysis therapy. 1. Some further meta-analyses were recently published (Wang et al., Ann Palliat Med 2021, 10:4736–46; Qie et al., Int Urol Nephrol 2021, 53:985–97; Zhang et al., Aging 2021, 13:17914–29; Liu et al., Front Med 2021, 8: 724456) and should be added to the article. Reply: Thank you so much for your suggestions, we added the suggested articles to our discussion except Wang et al. as it discussed dialysis dependent patients not non-dialysis dependent patients. And our target population is non-dialysis-dependent patients. 2. The Authors report in the present work higher serious adverse events, hypertension, and deep venous thrombosis in ROX treated patients. By contrast, a recent meta-analysis (Liu, see above) showed that total adverse events were not significantly different between ROX and placebo as confirmed by trial sequential analysis, with increased risk of hyperkalemia events. A comment is welcomed. Reply: Thank you so much for your comment, we added a comment on Liu et al. article in our discussion and commented about hyperkalemia as suggested. 3. Three phase 2 trials were included: may this decrease the level of evidence? Reply: Thanks for your comment. We did a subgroup analysis to investigate the effect of the trial phase on the Hb level. We found it did not affect the result. Please refer to Fig S1 in S1 File. 4. How were managed studies reporting data for more than one ROX dose? Reply: Thanks for your comment. The ROX doses were different between studies and we couldn’t do a subgroup analysis because multiple different doses were used in the included RCTs and there was no clear value that we can use to subgroup the ROX doses. We report that in the limitations. 5. The Authors report improved iron utilization parameters upon ROX treatment including decreases in ferritin and transferrin saturation and increases in TIBG and transferrin. These changes however also indicate a decrease in body’s iron storage and available iron, and suggest that patients were not receiving appropriate iron therapy for body iron requirement during ROX treatment. It appears that a stranded iron application is necessary in future studies to better characterize the effects of ROX on iron metabolism. Authors would comment on this issue. Reply: Thank you so much for your input, we added this to our discussion Reviewer #2: Abdelazeem and Colleagues, with this systematic review and meta-analysis, tried to extrapolate from the randomized studies available the efficacy and safety of Roxadustat on change in Hemoglobin and related parameters as well as on cardiovascular risk. The study is of interest and statistical analysis is overall of good quality. Moreover, this is an important topic from a clinical research perspective. However, I have several concerns to share with Authors: 1. Abstract: I would suggest Authors to change “efficacy and safety of ROX, especially on the cardiovascular system” into “efficacy and safety of ROX, especially on cardiovascular endpoints/risk”. The word system is too general. Moreover, please change “hat evaluated ROX NDD- CKD patients” with “hat evaluated ROX in NDD-CKD patients”; Reply: Thank you So much for your comments. We edited that in the revision. 2. English language should be improved throughout the manuscript. Reply: Thank you So much for your comments. We revised the whole manuscript grammatically and sent it for language editing by a professional. 3. Introduction is clearly written, and the aim is well depicted in my opinion. Reply: Thank you so much for your comment. 4. Methodology is overall accurate in term of study selection and statistical tools used. However, I have a major concern namely the fact that studies were “intervention was ROX compared placebo or any other medications” were included in the metaanalysis. In this way Authors compared for example ROX with darbepoetin or ROX against no ESA. This can introduce a bias if the primary endpoint is the change in Hb levels. Reply: Thank you so much for your comments. Only two studies used darbepoetin and the rest used placebo as the control group. We did a sensitivity analysis by omitting each study (Please refer to Table S2 in S1 File) and this didn’t affect the primary endpoint results. In addition that we did subgroup analysis ROX to placebo and ROX to darbepoetin alfa. We discussed the result in primary endpoint paragraph and the analysis can be seen in Fig S2 in S1 File. 5. Please also improve the quality of the figures. Most of them are not clearly interpretable in their current form. Reply: Thank you so much for your comments, We tried to improve the quality. The figures currently are in high-quality TIF format with 300 dpi. 6. Some subgroup analyses/meta-analyses (for instance panel D of figure 4) included less then 5 studies and this confers low power to statistical findings. Please clarify this in the limitations if possible. Reply: Thank you so much for your comments, we added this to our limitation as requested. *******End of review****** Please address all correspondence concerning this manuscript to me at eltobgy.2@osu.edu Thank you for your consideration of this manuscript. Sincerely, Mostafa Eltobgy, MD Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0266243.r002
17 Mar 2022 Decision Letter - Gianpaolo Reboldi, Editor The efficacy and safety of roxadustat for the treatment of anemia in non-dialysis dependent chronic kidney disease patients: An updated systematic review and meta-analysis of randomized clinical trials PONE-D-21-35500R1 Dear Dr. Eltobgy, 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 #1: All comments have been addressed 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 #1: (No Response) Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: (No Response) 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 #1: (No Response) 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: (No Response) 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 #1: (No Response) Reviewer #2: The article has been improved in term of methodology and presentation of results. I will thus suggest acceptance ****** 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:** Michele Provenzano https://doi.org/10.1371/journal.pone.0266243.r003
Formally Accepted
24 Mar 2022 Acceptance Letter - Gianpaolo Reboldi, Editor PONE-D-21-35500R1 The efficacy and safety of roxadustat for the treatment of anemia in non-dialysis dependent chronic kidney disease patients: An updated systematic review and meta-analysis of randomized clinical trials Dear Dr. Eltobgy: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. 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 plosone@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 Prof Gianpaolo Reboldi Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0266243.r004

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