PONE-D-21-10573

COMPARISON OF BIOSIMILAR TIGERASE® AND PULMOZYME® IN LONG-TERM SYMPTOMATIC THERAPY OF PATIENTS WITH CYSTIC FIBROSIS AND SEVERE PULMONARY IMPAIRMENT

PLOS ONE

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Academic Editor

PLOS ONE

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Dear Authors,

please make corrections to your manuscript according to suggestions and comments made by the reviewers or write a detailed rebuttal.

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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: Partly

Reviewer #3: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: 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

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: Yes

Reviewer #2: No

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 paper is technically sound, and the conclusions are in accordance with the presented data. The statistical analysis was done correctly. The authors make all data available completely without restriction. The topic of the paper is addressed in a comprehensible way and in standard English.

I have some minor objections:

- I am not sure if “The St. George's Respiratory Questionnaire”, a respiratory disease specific questionnaire, is optimal for assessing the quality of life of patients with cystic fibrosis in trials involving the effect of the drug only on lung disease, considering that CF is not just lung disease.

Please could the authors look into the details stated below and make the needed corrections:

- Page 8:

NCI CTCAE - The National Cancer 175 Institute Common Terminology Criteria for Adverse Events - is not stated in the list of abbreviation

- Page 16:

329 3.3.2. Incidence of ADRs – ADR is not stated in the list of abbreviations, only AR. This should be synchronized.

- Page 20:

404 Tigerase® or Tigeraza® What is correct?

Reviewer #2: This is a very interesting studying evaluating the efficacy of dornase alfa in people with cystic fibrosis. In a subgroup of people from the main randomised controlled trial.

The major comment is the manuscript would benefit from the some restructuring as it is hard to follow-up the various section. Its only when you keep reading when you realize that this is a subgroup analyses.

They are some comments worth mentioning for the authors attention.

1) Can the ‘background’ in the abstract include the main objective of the study.

2) Can the title indicate that this is subgroup analysis, (see comment number 5 below) of a Phase III randomised open-label trial. Clarity is needed.

3) The authors should restructure the methods section, so that its easier to follow-up. For example, having a sub heading of subgroup analysis under materials and heading is very confusing as this this should come after the main analysis section. Although it looks like the subgroup analysis relates to inclusion/exclusion criteria, this should be made clear.

4) Also details relating on registration should really be in the methods section not the introduction section. i.e line 124.

5) Line 152/182 suggests this is a subgroup analysis study, based on a main RCT. This again needs to made clear in the intro objective and methods section.

6) Line 177 “The study” assuming this is based on the main RCT, this again should be made clear.

7) Is line 142 to 151 about the main study and in relation to the subgroup population used in this analysis?

8) Under the statistical analysis section with such few patients and the models fitted, were the assumption checked?

9) What was the rationale for the inclusion of gender, patients (is this age at baseline?), number of concomitant disease in the model, was this decided as priory?

10) Different populations have been stated in the manuscript, FAS, ITT PP and safety. It would help the reader if this placed in section with an explicit statement about which population is being considered in the subgroup analysis e.g. line 211 mentions included in the PP. results present results stratified by populations. Planned presentation of results should also be mentioned in the methods section.

11) Perhaps with such few patients in each of the groups descriptive statistics might suffice.

12) In the discussion, any mention of limitations?

13) Figure 2, is the x-axis observation time from randomisation? This should labelled so. And the y-axis the label is not clear “proportion of patients without”?

Reviewer #3: In the manuscript; PONE-D-21-10573

COMPARISON OF BIOSIMILAR TIGERASE® AND PULMOZYME® IN LONG-TERM SYMPTOMATIC THERAPY OF PATIENTS WITH CYSTIC FIBROSIS AND SEVERE PULMONARY IMPAIRMENT, the authors describes post hoc sub-analysis of a larger comparative study (phase III open label, prospective, multi-centre, randomized study) of a generic version of recombinant human DNase Tigerase® to the only comparable drug, Pulmozyme®. In the analyses included subgroup of 46 severe pulmonary impairment patients with baseline FEV1 level 40-60% of predicted (23 patients in each treatment group), and comapred efficacy endpoints (FEV1, FVC, number and time of exacerbations, body weight, St.George's Respiratory Questionnaire) as well as safety parameters (AEs, SAEs, anti-drug antibody) within 24 treatment weeks.

I suggest to the authors the following clarifications and additions;

- state the strengths and weaknesses of this publication in the discussion

- explain why they analyzed the efficacy and safety of dornase alpha only in the group of patients with cystic fibrosis and severe pulmonary impairment with baseline FEV1 level 40-60% of prediced, and whether the results have already been published in an earlier publication (reference 24)?

-explain why the average age of the included subjects was approximately 30 (group I), vs 25.6 years (group II), ie what was the share of patients with delta F508 mutation among them.

-present the rate of exacerbations requiring antibiotics.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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COMPARISON OF BIOSIMILAR TIGERASE® AND PULMOZYME® IN LONG-TERM SYMPTOMATIC THERAPY OF PATIENTS WITH CYSTIC FIBROSIS AND SEVERE PULMONARY IMPAIRMENT (subgroup analysis of a Phase III randomized open-label clinical trial (NCT04468100))

PONE-D-21-10573R1

Dear Dr. Akhtyamova-Givirovskaya,

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,

Davor Plavec, MD, MSc, PhD, Prof.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Based on the decisions of reviewers the manuscript is now ready for publication in its current form.

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

Reviewer #3: 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: (No Response)

Reviewer #2: Yes

Reviewer #3: Yes

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

Reviewer #1: (No Response)

Reviewer #2: Yes

Reviewer #3: 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 #1: (No Response)

Reviewer #2: No

Reviewer #3: 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: (No Response)

Reviewer #2: Yes

Reviewer #3: 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: (No Response)

Reviewer #2: (No Response)

Reviewer #3: The authors have adequately addressed my comments raised in a previous round of review and I feel that this manuscript is now acceptable for publication.

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Reviewer #1: Yes: dr. Dorian Tjesic-Drinkovic

Reviewer #2: No

Reviewer #3: No