PONE-D-20-34179

Providing Open-Label Placebos Remotely – A Randomized Controlled Trial in Allergic Rhinitis

PLOS ONE

Dear Dr. Kube,

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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We look forward to receiving your revised manuscript.

Kind regards,

Zheng Liu, M.D., Ph.D.

Academic 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: Partly

Reviewer #2: Yes

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: Yes

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 authors investigated the placebo effect in an allergic rhinitis randomized controlled trial by providing placebo remotely and virtual clinical encounter. They concluded it was possible to provide open-label placebo and enhance the encounter remotely, but the effectiveness might be lower than physical patient-provider interaction. In general, this is a well-designed study, the authors described their findings with details. The study is of novelty, especially in the COVID-19 pandemic period. My major concern is the small sample size of this study, as only 54 patients were enrolled in this 4-arm clinical trial and an average of 14 cases in each arm. I’m not sure if it is qualified to discriminate the potential differences among the 4 subgroups, although the authors have acknowledged it as a limitation in the discussion. Meanwhile, the manuscript can be shortened and avoid narrating repeatedly.

Reviewer #2: The authors presented the interaction between OLP (with and without TAU) and encounter (augmented and limited) during COVID-19 pandemic, and found that the remote provision of OLP is feasible, but their effectiveness might be lower than those found in previous research for OLP provided within a physical encounter. There are several questions,

1.Augmented and limited encounters may have some impact on patients’ psychology, do you think there are some impact on the effects, especially in control & limited groups?

2.Previous studies have showed that network may help patients to use medicine regularly, and benefit to symptoms control. However, in this study, the authors have different results. I want to know that in no treatment subgroup, did the patients have the TAU or OLP regularly? If they took the medicine (OLP or TAU) as other subgroups, changes of symptom score may origin from the higher score in no treatment group and the lower score in regular treatment group.

3.What’s the frequency of regular treatment, treatment on demand and no treatment in four subgroups of OLP-augmented, OLP-limited, TAU-augmented, and TAU-limited? Do you think there are some impact on the results of the four subgroups respectively?

Reviewer #3: A two-arm placebo controlled randomized clinical trial was conducted to compare TAU alone to OLP+TAU and clinical encounter (augmented vs. limited). Primarily ANOVA models were used to test for differences in outcomes between treatments and clinical encounters. Participants from all treatment groups showed significant symptom reduction from baseline to two weeks later, but OLP had no incremental effect over TAU.

Minor revision:

1- Indicate the statistical testing method used in G*Power to justify the sample size.

2- Indicate if the following procedure was followed when testing main and interaction effects. If the interaction effect is significant, provide an interpretation of the results, but do not test main effects because the tests for main effects are uninteresting in light of significant interactions. If interaction effects are non-significant, drop the interaction effects from the model and test the main effects. Determining which results to present when testing interactions is often a multi-step process.

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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

Reviewer #3: No

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Providing Open-Label Placebos Remotely – A Randomized Controlled Trial in Allergic Rhinitis

PONE-D-20-34179R1

Dear Dr. Kube,

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,

Zheng Liu, M.D., 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: (No Response)

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

Reviewer #1: Yes

Reviewer #3: (No Response)

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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: (No Response)

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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: (No Response)

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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: Although the sample size is relatively small in this study, the authors discussed this issue thoroughly and noted it as the major limitation in the revision manuscript. I have no further comments.

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: No

Reviewer #3: No