PONE-D-20-23822

Topical Diclofenac vs Placebo for the Treatment of Chronic Achilles Tendinopathy: A Randomized Controlled Clinical Trial

PLOS ONE

Dear Dr. Scott,

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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

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: A two-arm randomized clinical trial was conducted to test the effectiveness of topical diclofenac. Effectiveness was measured as change in achilles tendinopathy (VISA-A score) at 4 and 12 weeks. No statistically or clinically significant differences were observed between the treatment and placebo arms for any of the outcomes.

Minor revisions:

1- Indicate if the distribution of the data was checked for normality prior to applying the ANOVA or t-tests.

2- Table 2: Indicate the percentages which correspond to the frequencies in Table 2.

Reviewer #2: Thank you for the opportunity to review this paper. On the whole it is well written, but I think there are some further points for consideration. Please see below.

The participants are not representative of the wider Achilles tendinopathy population; they are recruited from running clubs and sports clubs and were excluded if they had any commonly associated disease, such as a metabolic disorder. Not surprisingly they were all very active with low pain scores and high VISA-A scores. I think the title would benefit from changing to reflect this. This should also be considered in the discussion and conclusion.

The reporting of participant characteristics should be in line with recent recommendations: https://bjsm.bmj.com/content/54/11/627. Missing characteristics should be considered in the limitations section

Method used to generate random allocation sequence would benefit from justification. Why was this process used and not a more usual approach e.g block randomisation.

How sample size was determined would benefit from justification. Why a repeated Anova is used when the primary outcome is between group differences is not clear. This could leave the study under-powered and thus not able to detect a difference – 32 per group is a small number.

Clinical trials should include a measure for each of the nine core domains at a minimum, so that future meta-analyses will be able to better estimate treatment effects. https://bjsm.bmj.com/content/54/8/444. Missing domains should be discussed and considered in the limitations section

The clinometric limitations of the VISA-A should be discussed. https://journals.sagepub.com/doi/pdf/10.1177/1071100718816953?casa_token=QBSv-wQQ9h8AAAAA:I5KUyJK4cGnFG-CQytrhvpbc4faxF2gHs1qg2j8aobFpGmhIIQ16HO8y5uDERpaqBrItufDt0K7KoyI

https://bjsm.bmj.com/content/52/19/1221.abstract

Given the high levels of scoring, could the tool be no be sensitive enough to change?

Line 145 is repeated and should be deleted

There are two full stops at the end of the last sentence on p.6.

Reviewer #3: Thank you for the opportunity to review this interesting and important paper examining the efficacy of topical diclofenac in the management of Achilles tendinopathy (AT). The paper has been well-written and has simple but solid methods, appropriate to answer the research question. Whilst I have a few comments to make, most are minor and/or cosmetic, which I expect the authors to be able to address with relative ease. Likewise, I trust the authors will receive these comments with the constructive and collegial nature of their intention.

INTRODUCTION: No comments

METHODS:

L90. One inclusion criterion is that the patient must be "currently or previously engaged in a rehabilitation programme". I don't see the relevance of this to the research question. Furthermore, as you point out in the discussion, the nature of the involvement (or not) in a rehabilitation programme served as a confounding factor for the findings. I think the paper would benefit from a clearer justification for this issue, as well as further commentary in the discussion.

L120. Concerning the "potential side-effects of diclofenac", as a non-medical practitioner I would value a summary of the key side-effects that might be relevant to this drug and as a science-reader, would like to know which side-effects the participants were informed of and by what basis participants were excluded should they occur (as was the case on occasion).

L133. Table 1; NPRS is included within the Table title. I think it belongs as a table footnote (where you have placed the VISA-A abbreviation (L134)). Furthermore, you haven't provided an expansion for the abbreviation NPRS. This should be rectified.

L137. I don't understand this statement. We are in the methods section, and I read this as you describing results, yet with no detail. Please address this to allay confusion.

L145. The VISA-A was completed in person and then via email at a later date. My understanding of the VISA-A literature is that its validity across these different media has not been established. This may seem a little pedantic but in addition to that, my personal experience in executing this questionnaire leads me to believe that it might be possible that potentially significant sampling error may be introduced by this. I don't know if it would be sufficient to change the overall study findings, but I feel compelled to point this out and recommend you mention it in the discussion.

L145. This sentence effectively repeats the sentiment of Lines 142-4. Suggest removal.

L151. As per L145.

L194. I am curious regarding the genesis of the "unplanned analyses". Can you please provide a more thorough justification for this? As you describe and then discuss these findings they seem reasonable, but in order not to appear as though you were fishing, the nature of unplanned/post-hoc analyses should be described with more clarity.

RESULTS:

L213. Table 2; can you confirm that there was no difference in symptom duration between the diclofenac and placebo groups?

L222 (& L239, L249, L250, L256). I would like to see evidence from you statistical testing articulated here (eg p values). It would be best approached I think as a Table.

L249. "...non-significant trend for PPT to be higher at 4 weeks." Given significance testing (for all its faults), provides a binary outcome. I don't think it is appropriate to articulate such findings in this manner; it speaks of bias. Please remove.

DISCUSSION:

L305. In your opening discussion paragraph I think value would be added by summarising your key findings, including p-values.

L338. You describe the Fredberg study, but have not provided any relevance to the inclusion of it in your discussion. ie you do not allude to their findings and certainly do not describe them in the context of your study. Recommend revising this or removing altogether.

L358. Can you provide reference(s) for the estimates of MCID. To my knowledge there is less validation of MCID than you imply here. Please clarify.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes: James Debenham

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Attachments

Attachment

Submitted filename: PLOS article.docx

Topical Diclofenac vs Placebo for the Treatment of Chronic Achilles Tendinopathy: A Randomized Controlled Clinical Trial

PONE-D-20-23822R1

Dear Dr. Scott,

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,

Johannes Fleckenstein

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 #2: 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: (No Response)

Reviewer #2: Yes

Reviewer #3: Yes

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

Reviewer #1: (No Response)

Reviewer #2: Yes

Reviewer #3: Yes

**********

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 Response)

Reviewer #2: 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: (No Response)

Reviewer #2: 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: (No Response)

Reviewer #2: (No Response)

Reviewer #3: All of the comments from my review have been attended to and meet my satisfaction. Thanks and well done.

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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: Yes: Adrian Mallows

Reviewer #3: Yes: James Debenham