PONE-D-21-32897Prehabilitation to Improve outcomes afteR Autologous sTem cEll transplantation (PIRATE): A pilot randomised controlled trial protocolPLOS ONE

Dear Dr. Dennett,

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.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

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: No

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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: No

Reviewer #2: No

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4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. 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

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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 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.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This manuscript is very well-written. I would like to congratulate the authors for proposing this interesting topic. I only have a few minor concerns:

1) The authors mentioned that this is a “pilot randomized trial” in the title. However, I do not think this is a pilot study since the interventions and outcomes are well-defined. They might need to have a second look or provide a clear rationale and justifications for their methodology choice.

2) It is not clear to me why the authors decided to measure self-efficacy. I think they need to explain why it is important for this population. The short definition presented in table 2 is not enough to convince the reader of its relevance in this study. They would need to discuss self-efficacy and other outcomes somewhere in the methods section or maybe in the introduction.

3) The authors will do a great job recording reasons for non-participation in exercise (or non-adherence to exercise program) which is very important. However, they are planning to report only medical-related reasons, and my question is, why did they ignore psychosocial reasons for non-adherence? I think self-efficacy is also can be a reason for non-adherence as well. It is unnecessary (and not feasible) to report all reasons for non-adherence, but they need to discuss these issues since this is a study protocol paper. They need to be clear about this, and if they are interested only in medical reasons for non-completion or non-adherence, they should mention this explicitly in the methods section.

4) Finally, the validity of the outcome measures should also be discussed in the methods.

I am very excited to see the results of your study. Keep it up, and I wish you all the best,

Reviewer #2: The primary objective of this single-blinded, parallel two-armed pilot randomized trial is to determine preliminary efficacy of improving physical capacity of prehabilitation for people undergoing autologous stem cell transplant. The primary outcome is to assess changes in physical capacity using the 6-minute walk test. The secondary otucomes are (1) time to engraftment, (2) C-reactive protein, (3) physical activity (accelerometer), (4) grip strength, (5) health-related quality of life (EORTC QLQ-C30 and HDC29 supplement), (6) self-efficacy, and (7) recording of adverse events. Although this protocol has covered key components, there are several major concerns about the experimental design and data analysis plan of the trial.

Major critiques:

1. The overall goal of this pilot study should be the hypothesis generating instead of hypothesis testing.

2. The permuted block randomization method was proposed; however, it is unclear if the randomization process includes any stratification factors.

3. The power analysis is based on the effect size method, which is not very informative. The authors should perform the precision analysis, i.e., the estimated width of the 95% CI, to reassure the proposed study sample size is sufficient. In addition, please specify the statistical test that was used for the power analysis, and clearly specify if the power analysis was based on the one- or two-sided type I error.

4. The trial has one primary endpoint, but there are almost 10 secondary outcomes in this very small trial. The authors may need to apply the multiple comparison method for the secondary outcomes when reporting the results.

5. The discussion of the patients’ compliance measurement is superficial.

6. The authors should clearly discuss the statistical test that will be used for each secondary outcome.

7. The authors should clearly specify the methods that will be used to estimate the 95% Confidence Intervals (CIs).

8. The authors should discuss the statistical software that will be used to analyze the data.

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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.

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Reviewer #1: Yes: Alhadi M. Jahan

Reviewer #2: No

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Prehabilitation to Improve outcomes afteR Autologous sTem cEll transplantation (PIRATE): A pilot randomised controlled trial protocol

PONE-D-21-32897R1

Dear Dr. Dennett,

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. Please note that I've asked my colleagues in the editorial office to request the original trial protocol submitted to your IRB, as this is required for all clinical trials and clinical trial study protocols. 

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,

Dario

Dario Ummarino, PhD

Senior Editor

PLOS ONE

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

Reviewer #2: Yes

**********

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: Yes

**********

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

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. 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

**********

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

**********

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.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Dear authors,

Thank you for carefully addressing my comments. I am happy with the revisions and I do not have anything else to add.

I wish you all the best,

Reviewer #2: The authors have responded well to the statistical issues raised in the previous review. There is no further statistical concern about this revised manuscript.

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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: No

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