PONE-D-23-33264Neuromuscular electrical stimulation for physical function maintenance during hematopoietic stem cell transplant: Study ProtocolPLOS ONE

Dear Dr. Anderson,

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Academic Editor

PLOS ONE

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When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for your study in the ‘Funding Information’ section.

3. Thank you for stating the following financial disclosure: 

"This study was funded by a grant from the U.S. Dept. of VA (grant number RX003245)"

  

Please state what role the funders took in the study.  If the funders had no role, please state: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript." 

If this statement is not correct you must amend it as needed. 

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4. Thank you for stating the following in the Acknowledgments Section of your manuscript: 

'This study was supported by resources and facilities at the VAPSHCS Geriatric Research, Education and Clinical Center and JMG receives research support from the VA (BX002807), the Congressionally Directed Medical Research Program (PC170059), and the National Institutes of Health (NIH; R01CA239208, R01AG061558). LJA receives research support from the University of Washington (DK007247) and the VA (RX003245). RS Medical contributed the RS-4i Plus Sequential Stimulators, were involved in design of the NMES and sham parameters, and provided technical support throughout the study."

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6. We note that the original protocol file you uploaded contains a confidentiality notice indicating that the protocol may not be shared publicly or be published. Please note, however, that the PLOS Editorial Policy requires that the original protocol be published alongside your manuscript in the event of acceptance. Please note that should your paper be accepted, all content including the protocol will be published under the Creative Commons Attribution (CC BY) 4.0 license, which means that it will be freely available online, and any third party is permitted to access, download, copy, distribute, and use these materials in any way, even commercially, with proper attribution.

Therefore, we ask that you please seek permission from the study sponsor or body imposing the restriction on sharing this document to publish this protocol under CC BY 4.0 if your work is accepted. We kindly ask that you upload a formal statement signed by an institutional representative clarifying whether you will be able to comply with this policy. Additionally, please upload a clean copy of the protocol with the confidentiality notice (and any copyrighted institutional logos or signatures) removed.

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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: Partly

Reviewer #2: Yes

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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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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: 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 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: In this study protocol, the authors investigated the efficacy of NMES for mitigating the detrimental effect of hematopoietic stem cell transplant in patients with cancer. The application of NMES is patients with cancer is emerging and with a promising evidence. Therefore, new studies are welcome to have a comprehensive understanding of the efficacy and drawbacks of this strategy. I have included some comments for authors’ consideration as follows:

1. Line 71-74; The sentence needs correction.

2. Line 66-79 (Paragraph 2); In order to shorten the introduction, the information provided in the second paragraph could be summarized. Moreover, the structure and the information provided in the second paragraph of the introduction are as if exercise is the main intervention in this study while the authors just want to justify the use of NMES instead of exercise training. So, I recommend to re-structure the second paragraph and remove unnecessary information.

3. In the introduction, the authors have appropriately presented the current knowledge and understanding concerning the application of NMES in clinical populations such as cancer, however, it would be more interesting if the authors briefly highlight which specific gaps in the literature are covered in this study and what is the main novelty of this project.

4. I congratulate the authors for providing the detailed information in the “Participants and study design” section.

5. Line 173; No information regarding the randomization and blinding procedure have been provided. How did the author evaluate the efficacy of the blinding strategy used in this study?

6. Line 174; Since the replication of a study protocol by other researchers is important, I recommend the authors to provide more information regarding the “stratification by diagnosis”.

7. Could the authors elaborate more on their choice of the NMES parameters? Considering the fact that the main outcome measure of this study is 6MWT and that low frequency-NMES is more likely to induce aerobic adaptations while high frequency-NMES is proven to have strengthening effect on target muscles.

8. Line 255, Please provide a reference for using one-minute rest between MVICs.

9. Line 261; Instead of providing justifications for the choice of instruments used for “Patient-Reported Outcomes”, I recommend the authors to provide detailed information regarding the scoring and interpretation of these measures.

10. Line 304; Please provide more information regarding the incremental test on the ergometer for measuring peak aerobic capacity. What was the initial workload? How much load was added at each stage and what was the duration of each stage? Was the verbal encouragement provided? When the participants reported their RPE and by which Borg scale?

11. Line 402; Did the authors have any control on nutritional status of the participants during the project (in particular between FU1 and FU2)? If so, please provide the related information, if not, it could be another limitation of the study.

12. Line 403-407; I addressed this issue in my 5th comment. I think it is necessary that the author provide more information regarding any strategies used for blinding in the related section of the manuscript. Nevertheless, I agree that the nature of NMES makes it difficult to blind the participants.

Reviewer #2: As the statistical reviewer I will focus on methods and reporting. This is a well planned and reported study. However, I have some comments to make.

1) the term pilot is used at times. As far as I understand, this relates to very small trials that obtain an effect estimate to be used for a power calculations towards designing a larger trial. Some clarification is needed, as to whether that is the case here, or the term trial needs to be dropped.

2) the authors estimate an attrition rate of 50% and they need 30 participants, but they aim to recruit 46 rather than 60 - is there a mistake somewhere?

3) power may be inadequate for other outcomes, so this needs to be discussed as a limitation and needs to be reported when the authors conduct their analyses.

4) randomisation may not work that well for a sample this small, so maybe the authors could consider more deterministic approaches, for example please see https://www.jstatsoft.org/article/view/v055c01. They may want to ignore this advice, but this would be my preferred approach. Randomisation may work fine, by chance.

5) and regression models will not work well with 30 subjects, so you may want to control for numerous covariates where imbalances exist, but in practice you will struggle to include more than a handful of covariates, especially if categorical. So it's better to strive for balance, for at least a few key covariates using a deterministic algorithm in my view, although the size of the sample means some imbalances will definitely exist.

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Reviewer #1: Yes: Ehsan Amiri

Reviewer #2: No

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Neuromuscular electrical stimulation for physical function maintenance during hematopoietic stem cell transplantation: Study protocol

PONE-D-23-33264R1

Dear Dr. Anderson,

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.

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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,

Masoud Rahmati

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

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: Yes

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: The authors have implemented all my comments appropriately. I have no further comments. The manuscript is acceptable for publication in the current format.

Reviewer #2: I am satisfied with the authors' responses and the resulting changes to the paper...................

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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: Yes: Ehsan Amiri

Reviewer #2: No

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