A Study Protocol for a Randomised Pilot Clinical Trial

BMJ Open: first published as 10.1136/bmjopen-2017-016269 on 11 August 2017. Downloaded from

PEER REVIEW HISTORY

BMJ Open publishes all reviews undertaken for accepted manuscripts. Reviewers are asked to complete a checklist review form (http://bmjopen.bmj.com/site/about/resources/checklist.pdf) and are provided with free text boxes to elaborate on their assessment. These free text comments are reproduced below.

ARTICLE DETAILS

TITLE (PROVISIONAL) Electroacupuncture for treating insomnia in cancer patients: a study protocol for a randomised pilot clinical trial AUTHORS Kim, Mikyung; Kim, Jung Eun; Lee, Hye-Yoon; Kim, Ae-Ran; Park, Hyo-Ju; Kwon, O-Jin; Kim, Bo-Kyung; Cho, Jung Hyo; Kim, Joo-Hee

VERSION 1 - REVIEW

REVIEWER Simon Hayhoe NHS Pain Management Department Colchester University Hospital UK REVIEW RETURNED 19-Mar-2017

GENERAL COMMENTS This is a very well designed protocol for a randomised controlled trial that should be a useful addition to the current evidence concerning the use of acupuncture for insomnia. There are just a few points that need further clarification: 1. I appreciate that the Streitberger needle is marketed as a non- penetrating “placebo-needle”. However, as you note in the

Discussion, there has been controversy concerning possible http://bmjopen.bmj.com/ physiological effect of these needles: there seems to be skin sensation of pressure and tingling, akin to acupressure, which is what makes the sham needle believable. Its use in the treatment of insomnia is even more likely to demonstrate active benefit than its use in other problems, since acupressure (as opposed to acupuncture) is popularly considered effective for insomnia. The Cochrane review (your reference 16)

noted that trials of acupressure showed improvement and a review on September 24, 2021 by guest. Protected copyright. of acupressure RCTs (Yeung WF, Chung KF, Poon MM, et al. Sleep Medicine 2012;13(8):971-84.) found acupressure to be efficacious. I think you should include this information in your discussion. 2. Despite the marketing as a placebo, it might be wise to refer to the Streitberger as a “sham-needle” throughout, rather than a placebo (which it probably isn’t!). Similarly, the sham control group is in places (e.g. Page 22) referred to as a placebo control group. This is unsuitable, and sham should be the default. 3. There needs to be explanation of the rationale for the selection of the points and electro-frequency used. 4. The time of day that treatment is given should be recorded. I’m not sure what the Korean tradition is, but according to traditional Chinese medicine, acupuncture treatment should be applied in the early evening, and Western night sedation medication is usually given an hour or so before bedtime. So the timing could be of importance. Also, the proposed frequency of treatment may be regarded as insufficient as the popular PC6 self-treatment regimes advise treatment every evening. BMJ Open: first published as 10.1136/bmjopen-2017-016269 on 11 August 2017. Downloaded from

5. I note that “intention to treat” analysis is intended. However, it would be helpful to add a sentence at the bottom of page 13 (Prohibited … treatment section) emphasising that recordings and treatment would continue if already randomised, despite withdrawal from the trial, and that intention to treat analysis would be carried out and recorded in the results. 6. For patients failing to attend for follow-up or treatment sessions, there should be a phone call and/or letter to discover the reason and to encourage compliance. This should be recorded.

Overall This has been a well planned and presented protocol, and I wish the authors every success in the clinical trial.

REVIEWER Nguyen Thuy Ly Queensland University of Technology REVIEW RETURNED 30-Mar-2017

GENERAL COMMENTS The author should clarify the Korean version of the questionnaires used to measure symptom outcomes. Whether the questionnaires were used among people in Korea in previous studies and if yes, which type of population. If the Korean version is not available, how the translation and validation of the questionnaire were obtained.

VERSION 1 – AUTHOR RESPONSE

Reviewer: 1 This is a very well designed protocol for a randomised controlled trial that should be a useful addition http://bmjopen.bmj.com/ to the current evidence concerning the use of acupuncture for insomnia. There are just a few points that need further clarification: 1. I appreciate that the Streitberger needle is marketed as a non-penetrating “placebo-needle”. However, as you note in the Discussion, there has been controversy concerning possible physiological effect of these needles: there seems to be skin sensation of pressure and tingling, akin to acupressure, which is what makes the sham needle believable. Its use in the treatment of insomnia is even more likely to demonstrate active benefit than its use in other problems, since acupressure (as opposed to acupuncture) is popularly considered effective for on September 24, 2021 by guest. Protected copyright. insomnia. The Cochrane review (your reference 16) noted that trials of acupressure showed improvement and a review of acupressure RCTs (Yeung WF, Chung KF, Poon MM, et al. Sleep Medicine 2012;13(8):971-84.) found acupressure to be efficacious. I think you should include this information in your discussion. => Thank you for providing your professional opinion. Accepting your advice, we have added a sentence to explain the similarity between responses to sham acupuncture and to acupuressure (line 3-5, 3rd paragraph, page 22)

2. Despite the marketing as a placebo, it might be wise to refer to the Streitberger as a “sham-needle” throughout, rather than a placebo (which it probably isn’t!). Similarly, the sham control group is in places (e.g. Page 22) referred to as a placebo control group. This is unsuitable, and sham should be the default. => We have replaced the term “placebo” with “sham”, in the appropriate places, reflecting your advice.

BMJ Open: first published as 10.1136/bmjopen-2017-016269 on 11 August 2017. Downloaded from

3. There needs to be explanation of the rationale for the selection of the points and electro-frequency used. => The regimen, including the selection of the points and the frequency of the electric stimulation, was decided by expert consensus based on previous research. This information has been clarified in the Methods and analysis-Interventions-EA group section (line 9-11, EA group paragraph, page 12) in the manuscript and the STRICTA table (1b).

4. The time of day that treatment is given should be recorded. I’m not sure what the Korean tradition is, but according to traditional Chinese medicine, acupuncture treatment should be applied in the early evening, and Western night sedation medication is usually given an hour or so before bedtime. So the timing could be of importance. Also, the proposed frequency of treatment may be regarded as insufficient as the popular PC6 self-treatment regimes advise treatment every evening. => I agree with your opinion that the timing could be important and that the frequency of this trial could be insufficient. However, as you know, the mechanism of EA for treating insomnia has not yet been clearly investigated. Therefore, no one can be sure of which timing and which frequency of EA regimen is most effective for treating insomnia. In this situation, we chose the regimen according to previous research (references 12, 19, 28, 29, 54, etc.) that provided the intervention without considering any specific timepoint, with a frequency similar to ours. In addition, most of the clinics of Korean traditional medicine including our clinical trial centres provide treatment during business hours (which usually ends before evening). Therefore, in real-world clinical practice in Korea, it is not possible to perform the EA to outpatients in the evening or bedtime. In addition, it is very difficult to get non-inpatients to visit the centres more than 2-3 times a week at a similar time of day for every visit. If the results of relevant studies in the future show that a certain time point and a certain frequency must be promising variables that can contribute to insomnia therapy, we will design and conduct a new clinical trial with an improved regimen reflecting those new discoveries. However, please understand that the current design is the best choice we can make to increase the feasibility of the study within the conditions and evidences available to us as of now. http://bmjopen.bmj.com/ 5. I note that “intention to treat” analysis is intended. However, it would be helpful to add a sentence at the bottom of page 13 (Prohibited … treatment section) emphasising that recordings and treatment would continue if already randomised, despite withdrawal from the trial, and that intention to treat analysis would be carried out and recorded in the results. => We have added sentences reflecting your comment at the end of the prohibited and permitted concomitant treatment section (last line, page 13 to page 14)

on September 24, 2021 by guest. Protected copyright. 6. For patients failing to attend for follow-up or treatment sessions, there should be a phone call and/or letter to discover the reason and to encourage compliance. This should be recorded. => We have added a sentence at the end of the Data collection and management section, page 17.

Overall This has been a well planned and presented protocol, and I wish the authors every success in the clinical trial.

*************************** Reviewer: 2 The author should clarify the Korean version of the questionnaires used to measure symptom outcomes. Whether the questionnaires were used among people in Korea in previous studies and if yes, which type of population. If the Korean version is not available, how the translation and validation of the questionnaire were obtained. => We will use the Korean versions of the questionnaires, which have already been developed and BMJ Open: first published as 10.1136/bmjopen-2017-016269 on 11 August 2017. Downloaded from verified. Based on your comment, this information is clarified in the manuscript (Outcomes section, page 14-15).

VERSION 2 – REVIEW

REVIEWER Simon Hayhoe Pain Management Department, University Hospital, Turner Road, Colchester, Essex UK REVIEW RETURNED 20-Apr-2017

GENERAL COMMENTS Thank you, all my concerns have been satisfactorily addressed in this revised version.

REVIEWER Nguyen Thuy Ly Queensland University of Technology REVIEW RETURNED 05-May-2017

GENERAL COMMENTS This is a well design pilot RCT. However, as the pilot study with small sample size (15 participants each arm), the main objectives of the study should mainly focus on testing the feasibility. The pilot study is underpowered to make definitive conclusion of the effectiveness of the intervention. As such, I recommend the research team to make the objectives clearer: (1) feasibility of the study and (2) preprimary effectiveness of the intervention. In the outcome section, study feasibility should be firstly mentioned as the primary outcome.

In limitation section, the author should consider the small sample http://bmjopen.bmj.com/ size. I wish the research team all the best for conducting this important study.

VERSION 2 – AUTHOR RESPONSE

Thank you very much for your advice. on September 24, 2021 by guest. Protected copyright. Accepting your comment, I have revised the 'abstract, strengths and limitations of this study, introduction, outcomes, and discussion' parts of the manuscript to more clearly show that this study is a small-sized pilot study. I hope this modified version has reflected your opinion well.