PONE-D-24-14937Tolerability and efficacy of switching anti-fibrotic treatment from nintedanib to pirfenidone for idiopathic pulmonary fibrosisPLOS 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: Yes

Reviewer #2: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

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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: Yes

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Reviewer #1: Yes

Reviewer #2: 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: Author submitted an interesting manuscript about switching anti-fibrotics. I have several concerns for author.

1. You showed two patterns of elderly IPF patients in Table 3. Which threshold is better for considering elderly IPF patients based on your cohort ?

2. Regarding adverse effect of anti-fibrotics, we also consider the possibility of interaction of other medication especially in elderly patients with polypharmacy. How about the possibility of drug interaction of each case ?

3. When you commence PFD in your cohort, did you do any specific management especially in nintedanib intolerance patients not disease progression ?

4. Which kind of disease progression of your switching anti-fibrotics such as FVC decline with worsening symptoms, progression of HRCT imaging of fibrosis and DLco decline ? We would like to know more detailed information.

5. How about the smoking effect of discontinuation of anti-fibrotics ?

6. Secondary PH is also crucial comorbidity in IPF patients. Could you show us the incidence of PH of both continuation and discontinuation group ?

7. How about the change of body weight when did you switch anti-fibrotics ?

Reviewer #2: 1. General comment

This manuscript is well written and well presented.

2. Major comments

・In the present study, 72.4% continued nintedanib for 1 year. Real-world data showed that about 50% of Japanese IPF patients discontinued nintedanib treatment within the first year (Ref 23. Ogura et al.). Probably, IPF management in the author’s hospital have been well managed to prevent adverse events of nintedanib itself.

On the other hand, when it comes to deciding whether disease progression or adverse event (e.g., appetite loss, fatigue), it’s hard to know where to draw the line?

・A post-marketing surveillance study that included Japanese IPF patients treated with nintedanib showed that older age, male sex, small body surface area, severe IPF, and lower %FVC predicted at baseline were associated with an increased risk of early discontinuation of nintedanib treatment. The present study showed similar results (i.

e., lower BMI, and lower initial %FVC, higher GAP stage). However, no significant difference was observed in the nintedanib discontinuation rate between elderly and non-elderly patients. This is because many patients were preserved physique, not limited to mild IPF)

・Which reference do authors define disease progression? Please mention.

・In results paragraph, authors mentioned “Next, 80 patients (65%) had to reduce the NT dose because of the following reason:・・・”. During 1 year or whole follow-up period?

・Initial NT dosage in all patients was 150mg×2/day? During follow-up, the patients increasing the dosage halfway was none?

・In table 4, higher GAP stage was risk factors for discontinuing NT within 12 months. On the other hand, a lower BMI was most significant predictor of deterioration after switching from NT to PFD, not higher GAP stage. Although I predicted the similar results in the above two analyses, how should I interpret it?

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Reviewer #1: No

Reviewer #2: No

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Tolerability and efficacy of switching anti-fibrotic treatment from nintedanib to pirfenidone for idiopathic pulmonary fibrosis

PONE-D-24-14937R1

Dear Dr. Sugino,

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.

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Kind regards,

Yoshiaki Zaizen, MD, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

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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: 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 #1: Yes

Reviewer #2: Yes

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

Reviewer #1: Yes

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: Yes

Reviewer #2: Yes

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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: Author responded my questions properly. It is informative for chest physician. Current status will be acceptable for publication.

Reviewer #2: The authors revised the manuscript to address almost my questions and concerns. I think the revised manuscript has been properly fixed.

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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

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