PONE-D-21-27340"Let's See What Happens:" - Women's experiences of open-label placebo treatment for menopausal hot flushes in a randomized-controlled trialPLOS ONE

Dear Dr. Pan,

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.

The manuscript has been evaluated by two reviewers, and their comments are available below.

The reviewers have raised a number of major concerns. They feel the manuscript they request improvements to the reporting of methodological aspects of the study. The reviewers also note concerns about the statistical analyses presented.

Could you please carefully revise the manuscript to address all comments raised?

Please submit your revised manuscript by Jun 11 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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We look forward to receiving your revised manuscript.

Kind regards,

Thomas Phillips, PhD

Staff Editor

PLOS 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: Partly

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

Reviewer #1: N/A

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: No

Reviewer #2: No

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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: 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 manuscript is very well written, appears thoroughly prepared and contains crucial contribution to the field of OLP and placebo research. The methods are precisely described and the results are very interesting.

I have some remarks:

- There are references lacking in the introduction (e.g., 34, 37, ff).

- Line 50: I would not write „recently“. It is not so recent anymore.

- You might think about omitting the p values of your study in the intro for better readability

- It would be helpful to have the verbal script of the OLP treatment rationale in the appendix or a link

- Please provide also the a priori defined questions for the two blocks. It would be interesting to know, how many of these questions were asked in the interviews.

- Further, original comments in German might be added to the supplement.

- You could omit to mention the RCT results again in the methods section.

- Regarding the potential bias for only interviewing women who showed improvement: You may make this transparent already in the abstract: “women who benefited…”

- Table 1 might be adapted: Substitute the changed names with the N of participants who mentioned the theme. This would give a better overview and enable more focus on the themes. The themes could also be highlighted (e.g., in bold) and the letters A-D in a first, separate column.

- Sociodemographic data of the qualitative sample is missing. Please add descriptive information.

- Did you correct the verbatim grammatically? The statements seem very structured.

Small correction suggestions:

. line 52 e.g., 13 RCTs

. , at least not part of the study

. line 422 placebos being “better than nothing” treatments

Reviewer #2: Abstract

line 21: It is not true that no study investigated patients’ experiences undergoing treatment. There are now at least two studies who did so:

Bernstein MH, Magill M, Weiss A-P, et al. Are conditioned open placebos feasible as an adjunctive treatment to opioids? results from a single-group dose-extender pilot study with acute pain patients. Psychother Psychosom 2019;88:380–2.

Locher, C., Buergler, S., Nascimento, A. F., Kost, L., Blease, C., & Gaab, J. (2021). Lay perspectives of the open-label placebo rationale: a qualitative study of participants in an experimental trial. BMJ open, 11(8), e053346.

line 28: the summary of the abstract seems very optimistic, considering that many patients had low expectations about the placebo treatment. I would urge that the authors list pro and cons of the approach

Introduction

line 38: the authors state that recent research into the neurobiological underpinnings of placebo effects have been conducted. I would prefer a list of references after this sentence.

line 58: again, it is not true that no study has yet assessed participants’ experiences taking OLP (Bernstein et al.; Locher et al; see abstract comment). I would recommend that the authors briefly discuss the findings of these qualitative studies and outline how their approached differed from them.

Methods

lines 76: the original RCT included 100 women suffering from hot flushes. The nested qualitative study only conducted interviews with a total of 8 patients. This is a very small sample size, also for a qualitative approach.

line 99: I am also very worried that the authors only included patients with an experience of relief in the RCT (i.e., a score of 5 or higher on the overall improvement scale [range from 1-7] was mandatory in order to take part in the qualitative study). I think it would have been much more representative if participants with and without symptom relief would have been eligible. This would allow researchers to learn from both subgroups and to have an in-depth insight about chances and hurdles of the OLP approach.

line 11: the authors designed two blocks for the unstructured interviews, whereby the first block focused on symptom history. The authors state that the second block, which concentrated on placebos, was the focus of the current analysis. Why did the authors create two blocks and then only focused on one of them? I would advise that both blocks are considered equally important for the results, especially with the claim that these two blocks interact (line 116).

Results

Table 1: all themes listed in table 1 are positive attitudes towards the OLP approach. This is surprising since the authors also state that “almost all women reported that they had little expectations”. I would urge that the authors build an independent category for this statement and also list it in table 1. A statement like “I approached it without too much thinking. It also wouldn’t seem logical to me, that I’d come out all healed” was listed under the main category “openness and hope”. This is not at all intuitive to me.

line 252: in one of the citations, linguistic reinforcement was underlined by the authors. I would recommend to do this consistently throughout all citations (especially because the authors did not apply a content/thematic analysis that only concentrates on the content of the quotations but rather more a phenomenological approach that is interested in the lived experiences of participants)

Discussion

line 392: the authors state that participants were hopeful, curious, fascinated, and at ease. Again, I think that low expectations should also be discussed. The finding that all women had a relatively positive view of placebos when entering the trial could be associated with the fact that they all experienced symptom relief (i.e., which could have been the cause of a positive attitude).

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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: Antje Frey Nascimento

Reviewer #2: Yes: Cosima Locher

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

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PONE-D-21-27340R1"Let's See What Happens:" - Women's experiences of open-label placebo treatment for menopausal hot flushes in a randomized-controlled trialPLOS ONE

Dear Dr. Pan,

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.

Please submit your revised manuscript by Oct 27 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Walid Kamal Abdelbasset, Ph.D.

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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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 #3: (No Response)

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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 #3: Partly

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

Reviewer #1: N/A

Reviewer #3: I Don't Know

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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: Yes

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: 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: I thank the authors for considering my suggestions and addressing my concerns.

The authors may consider excluding a remaining opening bracket in line 94 and change: „Was“ instead of „What“ in Table 1 in Q2.

Reviewer #3: TITLE: This particular study where 8 women where interviewed after administering a placebo is supposed to be a randomized control trial however, it is not clear when the randomization was done hence the title seems to contradict the study design.

I9NTRODUCTION: The 1st sentence in page 4 is not clear, did the placebos significantly reduce or increase menopause related quality of life?

METHODS: The 1st sentence which states states that the study is the second part of a design is not clear and this is not referenced? In line 77, the quantitative study referred to is not referenced and no information or synopsis is given for better understanding . In line 78, what do the authors mean by -- moderate subjective burden? In line 79, what do the authors mean by --- one week run in to access base line symptoms and what are these symptoms? In line 88, COREQ should 1st be written in full. Line 89, which protocol are the authors referring to and how is it related to this study?

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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: Antje Frey Nascimento

Reviewer #3: No

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[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

"Let's See What Happens:" - Women's experiences of open-label placebo treatment for menopausal hot flushes in a randomized-controlled trial

PONE-D-21-27340R2

Dear Dr. Pan,

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.

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,

Walid Kamal Abdelbasset, Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

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 #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: Yes

Reviewer #3: Yes

**********

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

Reviewer #1: N/A

Reviewer #3: I Don't Know

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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

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: Yes

Reviewer #3: Yes

**********

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: I have nothing to add. This is a very interesting study and it is valuable to see the subjective explanations of the women who underwent the OLP intervention in addition to the results of the RCT!

Reviewer #3: (No Response)

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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: Antje Frey Nascimento

Reviewer #3: No

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