-->PONE-D-25-67189-->-->Study on The Safety Evaluation of Latent Tuberculosis Treatment in High‑Risk Groups for Tuberculosis Development : Study Protocol for a Multi‑center Prospective Observational Cohort Study in Korea (STEP-TB)-->-->PLOS One

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“The STEP-TB cohort is supported by the Korea National Institute of Health (KNIH) through the Research Program on the “Study on the safety evaluation of latent tuberculosis treatment in high risk groups for tuberculosis development” (2025E200100). The funder has no role in the design of the study, data collection, analysis, interpretation, or the decision to submit the manuscript for publication.”

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Authors receiving funding: JM, Grant number: 2025ER200600 Funder: Korea Disease Control and Prevention Agency (KDCA), Funder website: https://www.kdca.go.kr The funder had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.”

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1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

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Reviewer #1: Yes

Reviewer #2: Yes

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-->2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.-->

Reviewer #1: Yes

Reviewer #2: Partly

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-->3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.-->

Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: No

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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 and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

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Reviewer #1: The protocol is well-written overall. However, I recommend elaborating on several items to ensure clarity and reproducibility:

1. Follow-up Procedures: Could you clarify the methodology for monitoring adverse events (AEs) and TB incidence during follow-up? Specifically:

o Will you rely solely on symptom assessment or include routine laboratory tests?

o Will national TB registers (where available) be cross-referenced to ascertain cases?

2. Adverse Event Analysis: Regarding the regression analysis, which AEs will be evaluated?

o Are you including all AEs regardless of severity, or focusing on Grade 3/4 events?

o Please specify if a standard grading system (e.g., CTCAE) will be used to assess severity.

3. Adherence and Completion: How will treatment adherence be measured (e.g., pill counts, self-reports, or pharmacy records), and what is your specific clinical definition of "treatment completion"?

4. Definition of CKD: Please provide the specific diagnostic criteria or staging used to define Chronic Kidney Disease (CKD) in this study.

5. Structural Flow: The fact that CKD is the primary exposure variable only becomes clear in the analysis section. I recommend flagging this—along with its scientific rationale—much earlier in the Introduction.

6. Submission Requirements: I have reviewed the PLOS submission guidelines; it remains unclear whether a formal Discussion section is mandatory for protocol manuscripts. I am happy to defer to the Editor’s guidance on this.

Reviewer #2: PONE 25-67189 Review

Interesting and valuable study, that is already funded and ongoing. As such hard to know how much can be changed. Suggestions to add for clarity of paper, if done. If not done authors can consider adding to study procedures, if feasible.

1. Objectives. The paper would be clearer if there was a clear statement of objectives at the end of the Intro, or start of methods. It appears the primary objective, based on statements made in the sample size section, is to compare the rate of adverse events in persons with CKD, but this is not stated anywhere until near the end of the methods section. The title mentions ‘safety evaluation in high risk persons’ but does not specify CKD. Hence, consistency and clarity is needed

2. Population. The primary objective is safety, so one expects the study population will be those treated. At times (Line 81) the study population is all those with a positive TB infection test. But in other places – the TBI test negative persons, and the Test positive but not treated – are also studied. So a listing summarizing the various study populations to be included, and for what objectives and analyses would also be helpful. As well, some sense of the larger population from those referred for TBI testing is drawn would be useful, for later generalizing of results.

3. Cascade analysis. Not stated, but should be possible with the design is a cascade analysis from ‘contemplating TB infection testing’ to completed TPT. This would be interesting, especially if they can compare characteristics of those who are lost at each step (not tested vs tested, test negative vs test positive, not treated vs start TPT, not completed vs completed TPT).

4. Procedures and outcome definitions: Completion of TPT – how will that be measured, and when. How will completion be defined? Same for Adverse events – how will they be detected, investigated and then defined. Grading? Using what grading system? Serious? Drug discontinuation? What about type of AE, and relationship to TPT regimen?

5. Terminology – a minor point, but WHO now recommends thew terms: TB infection (instead of “latent TB infection” – introduced by CDC/ATS in 2000), and TB disease (instead of ‘active TB’). For consideration.

6. Excluding participants. Line 181 – they suggest that persons who are lost to Follow-up will be excluded. But, this is an outcome, and such participants should not be excluded.

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Reviewer #1: Yes: Yohhei Hamada

Reviewer #2: Yes: dick Menzies

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Study on The Safety Evaluation of Latent Tuberculosis Treatment in High‑Risk Groups for Tuberculosis Development: Study Protocol for a Multi‑center Prospective Observational Cohort Study in Korea (STEP-TB)

PONE-D-25-67189R1

Dear Dr. Jinsoo Min,

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,

Violet Chihota

Academic Editor

PLOS One

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