Author s response to reviews

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1 Author s response to reviews Title: A comparative study of three conservative treatments in patients with lumbar spinal stenosis: Lumbar Spinal Stenosis with Acupuncture and Physical Therapy study (LAP study) Authors: Hiroyuki OKa (okah-tky@umin.ac.jp) Ko Matsudaira (kohart801@gmail.com) Yuichi Takano (luigi.igiul1030@gmail.com) Daichi Kasuya (kasuya-daichi@umin.ac.jp) Masaki Niiya (reha@iwai.com) Juichi Tonosu (juichitohnosu@yahoo.co.jp) Masayoshi Fukushima (masamasayoshi21@gmail.com) Tomoko Fujii (ort4771@gmail.com) Yasushi Oshima (yoo-tky@umin.ac.jp) Sakae Tanaka (tanakas-ort@h.u-tokyo.ac.jp) Hirohiko Inanami (ina@iwai.com) Version: 1 Date: 16 Aug 2017 Author s response to reviews: (Responses to Reviewer 1) Carlo Ammendolia (Reviewer 1): Manuscript Number: BCAM-D Full Title: A comparative study of three conservative treatments in patients with lumbar spinal stenosis: Lumbar Spinal Stenosis with Acupuncture and Physical Therapy study (LAP study) Abstract No Comments Thank you very much for your suggestions. We provided a reply to each of your comments below.

2 Q-1: Background, Authors should provide additional information on the use of acetaminophen for LSS. Have there been any RCT or clinical study evaluating their effectiveness. Is there data to support that acetaminophen is commonly used to treat LSS? A-1: Thank you for your comment. There is no RCT on which acetaminophen is used for LSS. However, there are papers describing the possibility that it may be effective for neuropathic pain. Compared with NSAIDs, acetaminophen is superior in safety. Since this drug acts centrally, it is suggested that it may also be effective for neuropathic pain. We added the sentences in the Discussion section (lines ). Q-2: Please state your hypothesis. A-2: Thank you very much for this question. We hypothesized that all three conservative treatments improve the symptoms of LSS, but they are superior or inferior. We added the sentence to the Background section (lines ). Q-3: Methods, Explain rationale for selecting only patients with L5 radiculopathy? A-3: Thank you very much for this question. Among radiculopathy of LSS, L5 root disorders have been reported to the highest prevalence. In clinical study, it is necessary for quick recruitment and subjects to be homogeneous. Thus the subject was limited to L5 radiculopathy. We have added the sentence to the Methods sections (lines ). Q-4: Explain and provide more details on patients were assigned based on visit date? A-4: Thank you very much for this question. On the statistical analysis section, we described that one group of sample size is about 40 cases. We recruited patients who met inclusion and exclusion criteria in order of medication, exercise, acupuncture until each group reaches approximately 40. The duration of the recruitment was medication, exercise, acupuncture, which were December 2011 to August 2012, September 2012 to March 2013, and April 2013 to December 2013, respectively. We added the sentence to the Methods section (lines ).

3 Q-5: Line 138. Can it be confirmed that patients took their medication as prescribed? If not rephrase state to patients were recommended 900 mg of acetaminophen. A-5: Thank you very much for this question. As a result of confirming compliance concerning oral administration, all the patients were taken throughout the examination period without those of drop out. We added the sentence to the Results section (lines ). Q-6: Line 144. Same as above regarding exercise. If we were to replicate this study we would need more details on this intervention with respect to what self-management strategies and education provided. A-6: Thank you for this comment. We added the detail of exercise to the Methods section and Figure 2 (lines ). Q-7: What was the duration of time the acupuncture needles were applied and was there any other treatment provided? A-7: Thank you very much for this question. Not only in acupuncture group but in all groups, loxoprofen [up to 3 times a day] or celecoxib [up to twice a day] can be used as needed when pain is present. The drug must not be taken on the day of visit for efficacy evaluation and the day before that. We added the sentence to the Methods section (lines ). Q-8: Who assessed the outcomes and was the assessor blinded? A-8: Thank you very much for this question. At study end, an investigator (HO) blinded to individual patient treatment regimens assessed the outcomes. We added the sentence to the Methods section (lines ). Q-9: Results: Provide details on the dropouts and did this bias the results?

4 A-9: Thank you for this comment. Patients who dropped out (medication=8, exercises=5, acupuncture=7) had not been visited since the first visit. These patients can only collect data at the first visit. We added the sentence to the Results section (lines ). Q-10: Can you provide data on compliance, co-interventions or adverse events (other than liver assessment)? A-10: Thank you for this comment. In the questionnaire at the time of the final follow up, each group was observed to comply with the assigned treatment, and no serious adverse events occurred. Regarding the co-intervention of loxoprofen and celecoxib with regard to pain exacerbation, more than half of the data are missing and cannot be analyzed. We added the sentence to the Results section (lines ). Q-11: Provide dates defining period of recruitment and follow-up. A-11: Thank you for this comment. As mentioned in the responses A4 above, we added the duration of the recruitment. Intervention was done from the day of assignment and follow-up was done for 1 month from the first visit. We added the sentence to the Methods section (lines and ). Q-12: Can you provide comparison of the duration of symptoms among participants in each group? A-12: Thank you for this comment. The data of the duration of symptoms has not been collected in this study. About this limitation, we mentioned in the Discussion section (lines ). Q-13: What are the minimally clinically important differences for the outcomes? What was the timing of the follow-up assessment relative to the last treatment between groups?

5 A-13: Thank you very much for this question. In previous report, minimally clinically important difference was 0.5 for both ZCQ Physical Function and ZCQ Symptom Severity. The followup assessment was done for 1 month from the first visit. We added the sentence to the Methods section (lines ). Q-14: Discussion, Provide possible explanation for the potential mechanism of action of acupuncture on neurogenic claudication (neuro-ischemia)? A-14: Thank you for this comment. Improvement of clinical symptoms and blood flow improvement are related. It was reported that acupuncture affected the blood flow improvement, and one possible mechanism was associated with regulation of systemic vascular resistance via modulation of sympathetic tone. We have added the sentences in the Discussion section (lines ).. Q-15: Limiations.include not blinding of assessors. Thank you for this comment. As mentioned in the responses A8, an investigator blinded to individual patient treatment regimens assessed the outcomes. (Responses to Reviewer 2) Koji Otani (Reviewer 2): This manuscript describes the comparative trial of conservative treatment (medication, exercise and acupuncture). The reviewer enjoys reading it. This has some worth of publication in BMC Complementary and Alternative Medicine. However, there is problem to resolve before publication. Revision should be needed. Thank you for taking the time to review our manuscript; we appreciate your encouraging comments regarding our study. We revised our manuscript based on your comments, and we hope you find the revised version acceptable. Q-1: Page 7 line 115: What is mixed type LSS?

6 A-1: Thank you very much for this question. We added information to Methods section regarding mixed type LSS. Mixed type LSS has both radicular and caudal type symptoms (lines ). Q-2: 8 line 128: What is "according to the visit time"? Please describe the detail how to divide three groups. A-2: Thank you very much for this question. We got similar comments on reviewer 1. As mentioned in the responses A4 of reviewer 1 above, we added the detail how to divide three groups. We added the sentence to the Methods section (lines ). Q-3: Page 8-9: How do authors confirm patients take pills or do exercise? Please describe the detail how to confirm. A-3: Thank you very much for this question. Details on the allocation of interventions are described in the Materials and Methods section. We added the sentence to the Methods section (lines ). Q-4: Page 10 line : Why do authors decide 0.8 point to detect a difference between groups? For each participant, point 1 is the least change. A-4: Thank you very much for this question. We got similar comments on reviewer 1. As mentioned in the responses A13 of reviewer 1 above, we have added the minimally clinically important difference of ZCQ. We applied a strict set of criteria ( 0.8 points) for the purpose of adjustment of multiple comparison of 3 groups. We added the sentence to the Methods section (lines ). Q-5: Table 3: Reviewer cannot judge if the suitable methods or not to assess the difference between two groups in three groups. If author's analysis is suitable, is this change meaningful clinically?

7 A-5: Thank you for this question. As mentioned in the responses A4 above, we have added the explanation of stricter criteria on ZCQ. Furthermore, we corrected the p value of multiple comparisons between the three groups. Therefore we think that our analysis is suitable. Q-6: Table 3 Please remove "CI= Confidence Interval". A-6: Thank you for this comment. We have deleted the sentence "CI= Confidence Interval" from Table 3.