PONE-D-20-35525

EFFICACY AND COST EFFECTIVENESS OF INTRAVENOUS FERRIC CARBOXYMALTOSE VERSUS IRON SUCROSE IN ADULT PATIENTS WITH IRON DEFICIENCY ANEMIA

PLOS ONE

Dear Dr. BASHA,

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.

As you can see, your manuscript received somewhat mixed reviews. Overall, I believe that it provides potentially useful data, but in its current form has multiple limitations. In particular, the selection of patients (inclusion/exlusion criteria), baseline characteristics, dosing strategy and many more need to be clearly described.

Please submit your revised manuscript by Feb 21 2021 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: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Pavel Strnad

Academic Editor

PLOS ONE

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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: No

Reviewer #2: Yes

Reviewer #3: Partly

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

Reviewer #1: I Don't Know

Reviewer #2: Yes

Reviewer #3: I Don't Know

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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: No

Reviewer #2: Yes

Reviewer #3: Yes

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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: No

Reviewer #2: Yes

Reviewer #3: Yes

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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: The study is certainly important for health care providers in Qatar but I believe that some major limitations in the study design warrant a work-over of the study.

Please specify outcome measures in the abstract. Improvement in laboratory levels is a meaningless statement.

The complete patient population is poorly defined. IDA is a disease spectrum. I recommend to clarify the patient selection (hemoglobin, ferritin concentration and transferrin saturation).

Was the iron deficit calculated using the Ganzoni formula? What kind of dosing strategy was used in the patient cohort? Was there a difference in total iron dose between groups?

Likewise, the exclusion criteria are poorly defended. How did the authors exclude other anemia causes? What kind of biochemical studies were routinely performed in the cohort?

Please provide a dedicated table of the baseline characteristics to show any differences between groups at baseline.

I have no experience in cost-effectiveness analyses and therefore cannot assess the statistical methods used.

Reviewer #2: Authors have here reported on the administration of two intra-venous iron formulations (ferric carboxy malthose and iron sucrose) in adult patients with iron deficiency anemia. This prospective study lasting 12 months is very interesting, well written and structured. Tables support the text. In detail this reviewer finds interesting the aspects related to RBC parameters improvement and cost (direct and indirect) analysis. O suggest to modify some aspects of the paper :

I think the variation in Hgb and other RBCs parameters for both treatments should be better highlighted by a specific figure where I suggest to report in detail only haemoglobin levels, MCV and ferritine.

I do not find useful reporting in table WBC and PLt counts, I do not see from data a particular high PLT count before treatment (reactive thrombocytosis) pre and post treatment values seem quite stable ,thus I think this should be just reported in the text. Further, it seems that patients treated with iron sucrose had baseline Hgb levels lower than patients treated with ferric carboxymalthose.

Could please authors better describe this aspect? Authors should alos better afford the issuesrelated to oral iron in comparison to iv iron.

References should be updated with a recently published article referring to the administration of iv iron vs oral iron(10.1007/s00277-020-04361-3)

Reviewer #3: In this study, the authors evaluate the efficacy and cost-effectiveness of ferric carboxymaltose compared to iron sucrose in adult patients with iron deficiency anemia.

Although clinically relevant due to the frequency of the disease and its impact, the work presents several major limitations:

- consider to reorganize the structure of the introduction (role of oral iron and intravenous iron) and include more References since many data are not supported by references (e.g., “Intravenous iron preparations have been used for treating IDA, with a promising result and making it possible to avoid blood transfusion and side effects of the oral iron preparation.” “Iron sucrose (IS) has been widely used for treating IDA that shows the potential result.”)

- The primary outcome, i.e., the treatment efficacy, is not well defined. Indeed, the authors consider hematological and iron parameters at a follow-up time point that was not clearly defined. “The post level was measured at least 2 weeks after the medication administration.” The authors do not specify the follow-up length (median or mean days of follow-up). This is relevant since the hemoglobin levels and iron parameters 2 weeks after the administration cannot be compared to values at a longer follow-up (e.g., 40 days). At least the follow-up between the two groups should be similar. Moreover, iron parameters at 2 weeks are still disrupted by the IV iron administration.

- The total amount of administered iron per patient in the two groups should be specified in order to compare the efficacy parameters.

- The two groups (FCM vs. IS) characteristics are not well defined: the total amount of iron administered per patient, causes of iron deficiency anemia, clinical symptoms. Moreover, their baseline hemoglobin levels are different. I suggest commenting on this difference and its potential impact on therapy choice. Nevertheless, since hemoglobin is the efficacy parameter, and hemoglobin increase is used for the cost-effectiveness evaluation, the authors should consider potential adjustments and comment on this.

- Adverse events data are not presented (even if not adverse events have been observed should be specified), while in the Methods section, there is a specific paragraph about the management of adverse reaction. Moreover, no data about hypophosphatemia have been presented. I would consider editing the part about drugs used to manage these reactions since the role of antihistaminic drugs is controversial.

Minor revisions:

- Introduction, page 4: the sentence “Anemia is the most common nutritional deficiency” should be revised. Indeed, iron deficiency is the most common nutritional deficiency.

- Introduction, page 4: “poor appetite” is not considered one of the most frequent symptoms of iron deficiency anemia

- Check all the abbreviations: some are spelled out many times, some are not spelled out

- “The acquisition cost of FCM is expensive but reported to have a better outcome.”: compared to?

- Units of measurements are not always specified in the tables

- Native English revision is required

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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

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.

PONE-D-20-35525R1

EFFICACY AND COST EFFECTIVENESS OF INTRAVENOUS FERRIC CARBOXYMALTOSE VERSUS IRON SUCROSE IN ADULT PATIENTS WITH IRON DEFICIENCY ANEMIA

PLOS ONE

Dear Dr. BASHA,

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.

As you can see, one of the reviewers has major concerns that have not yet been addressed and in fact recommended to reject the manuscript. Therefore, I strongly advise you to answer these comments as good as you can.

Please submit your revised manuscript by Jul 01 2021 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: http://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,

Pavel Strnad

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 #2: All comments have been addressed

Reviewer #3: (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 #2: Yes

Reviewer #3: Partly

**********

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

Reviewer #2: Yes

Reviewer #3: I Don't Know

**********

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

Reviewer #3: 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

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 #2: I have revised this version of the manuscript, I think it has been improved , all comments have been well adrressed. I think the paper can now be accepted for pubblication

Reviewer #3: Considering the authors' comments at first revision, some crucial points have not been addressed:

- The author did not specify the follow-up lenght and this dramatically affect the comparison of efficacy parameters

- The authors did not specify the mean/median amount of iron (in milligrams) administered in the two groups and this dramatically affect the efficacy outcomes.

- The different Hb baseline level could affect therapeutic decisions

- The conclusion that IS showed a higher increase in Hb is affected by the Hb baseline difference between the two groups

**********

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

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.

EFFICACY AND COST EFFECTIVENESS OF INTRAVENOUS FERRIC CARBOXYMALTOSE VERSUS IRON SUCROSE IN ADULT PATIENTS WITH IRON DEFICIENCY ANEMIA

PONE-D-20-35525R2

Dear Dr. BASHA,

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,

Pavel Strnad

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: