Author's response to reviews

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1 Author's response to reviews Title:Efficacy of 1% carboxymethylcellulose sodium for treating dry eye after phacoemulsification: results from a multicenter, open-label, randomized, controlled study Authors: Ke Yao MD (xlren@zju.edu.cn) Yongzhen Bao MD, PhD (drbaoyz@sina.com) Jian Ye MD (yejian1979@163.com) Yi Lu MD (luyiox@163.com) Hongsheng Bi MD (bihongsheng@126.com) Xin Tang MD (tangprofessor@yahoo.com.cn) Yune Zhao MD ( @qq.com) Jinsong Zhang MD (cmu4h-zjs@126.com) Jinling Yang MD (yang_jinlin@allergan.com) Version:4Date:16 December 2014 Author's response to reviews: see over

2 Sunil Chauhan, MD Associate Editor, Cornea and External Eye Diseases BMC Ophthalmology Re: BMC Ophthalmology - MS: Dear Dr. Chauhan, On behalf of all co-authors, thank you and the reviewers for your interest in our manuscript, Efficacy of 1% carboxymethylcellulose sodium for treating dry eye after phacoemulsification: results from a multicenter, open-label, randomized, controlled study. We have addressed each comment point-by-point in italics below and have amended the manuscript accordingly (highlighted in yellow). Reviewer: Ahmad Kheirkhah 1. Although this study is a multicenter RCT, the patients and researchers were not masked to the treatment regimen. This may significantly affect the findings. This is especially true as the patients in the control group were possibly aware that they are not being treated for dry eye. The open-label design was described as a potential limitation of the study in the discussion, but we have modified the discussion as follows to further emphasize the point (p. 12, lines ): Since neither patients nor investigators were masked to treatment, patients in the control group were likely aware of their treatment status, which could explain the above findings. However, despite this potential limitation of the study, the difference in the percentage of patients with dry eye between the treatment and control groups was not significant by day 30 after surgery, arguing against this possibility. One possible, alternative explanation 2. It is not clear why the authors did not have a control group with placebo or the vehicle of CMC without active ingredient. The study objective was to compare the efficacy and safety of anti-inflammatory + CMC eye drop therapy with anti-inflammatory therapy alone. Use of vehicle as a control tear solution may have had some impact on the symptoms of dry eye and may thus have confounded the results in the control group. 3. In Introduction, the statement on the effects of various factors on ocular surface health after cataract surgery needs to have references. We apologize for the oversight; the following references have been added to support the statement in question (p. 3, line 71). 1

3 1. The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf 2007, 5(2): Movahedan A, Djalilian AR. Cataract surgery in the face of ocular surface disease. Curr Opin Ophthalmol 2012, 23(1): There is no data to show whether all surgical procedures were standardized regarding, for example, the location and size of incision, intraoperative medications, type of anesthesia. At the reviewer s request, we have added the following information to the manuscript: Overall, 52.3% and 47.7% of patients in the treatment group had surgery in the right and left eye, compared with 55.5% and 44.4% in the control group, respectively. The percentage of patients who had a superior (12 o clock), temporal (9 o clock), tempo-superior (10-11 or o clock), or nasal superior (10-11 or o clock) incision was also similar between groups. The mean incision length (± SD) was 2.8 ± 0.3 cm vs 2.8 ± 0.4 cm in the treatment and control groups, respectively. (p. 8, lines ) We have also added the following information regarding the type of anesthetics used for the surgical procedure: Topical anesthesia with oxybuprocaine hydrochloride 0.4% eye drops (Benoxil, Santen Pharmaceutical Co, Ltd, Osaka, Japan) or proparacaine hydrochloride 0.5% eye drops (Alcaine, Alcon Laboratories, Inc, Ft Worth, TX) was administered before the surgical procedure. (p.5, lines ) No other intraoperative medications were used. 5. It is not clear whether cases with intraoperative or postoperative complications have been excluded from the study. Patients were withdrawn from the study if they experienced complications during surgery, or post-surgical ocular hypertension, endophthalmitis, infectious keratitis, or conjunctivitis. This information has been added to the Methods section (p. 4, lines ). 6. It is not clear whether cases with preop dry eye have been under any treatment for dry eye and whether they have continued it during the course of study. If not, as it seems to be the case, there is a question of ethical issues. Similarly, based on the literature it is obvious that ocular surface will be compromised after the surgery. Therefore, not treating the patients with pre-existing dry eye seems to be unethical. The use of any topical ophthalmologic agents that might have affected the efficacy assessment of the study treatment was prohibited during the study (added to p. 5, lines ). Almost all patients with dry eye at baseline were reported to have mild dry eye symptoms by the clinician using non-standardized criteria. Since there are no usual treatment recommendations for dry eye in these patients, ethics were not in question. Patients undergoing cataract surgery would naturally have tear film instability from the surgery resulting in dry eye syndrome and in this study all patients including those in the 2

4 control group received the usual post-surgical topical corticosteroids and anti-infective care for corneal damage and post-operative inflammation. 7. It is not clear which grading system has been used for nucleus hardness. To address this comment, the following information was added to the Methods (Patients) section: Patients were scheduled to undergo phacoemulsification and IOL implantation and had a lens nucleus hardness of grade 3 or less (based on nucleus color per the standard Lens Opacities Classification System III [12]). (p. 4, lines 96-97) 8. The criteria used in this study for the definition of dry eye needs to have a reference. Otherwise, it is not clear why the authors have used a symptom score of 3 or more and TBUT#5 or Schirmer #3 as their criteria. We apologize for the oversight and have added references to the following sentence (p. 7, lines ): Patients were diagnosed as having dry eye symptoms if they met one of the following conditions: TBUT 5 s, plus a subjective symptom score of 3 or greater,[14, 15] or Schirmer test 3 mm in 5 min, plus a subjective symptom score of 3 or greater. [14, 16] 14. Z Wang, HY Wang, et al. The changes of tear film after phacoemulsification combining with intraocular lens implantation. J Tongji Univer (Medi Sci) 2007, 4: H Li, F Yuan, et al. Chin J Optom Ophthalmol Vis Sci. Effects of phacoemulsification on tear film and eye surface. 2005, 3: Methodologies to diagnose and monitor dry eye disease: report of the Diagnostic Methodology Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf 2007;5(2): It is not clear how the normality of the data has been tested. To address this comment, the text was modified to include the following: Quantitative data were compared between the two groups using the t-test (normal distribution) and the Wilcoxon rank sum test (non-normal distribution). Similarly, differences before and after surgery within the treatment and control groups were assessed using paired t-tests (normal distribution) or Wilcoxon signed rank test (non-normal distribution). (p. 7, lines ) 10. Although based on sample size calculation the authors needed to have a 31 cases per group, it is not clear why they have included 90 per group. Sample size for the study was determined based on results from an early study, in which the value of TBUT was determined at day 7 after cataract surgery. One-tailed test was conducted with α=0.05 and β=0.2, and it was determined that at least 31 patients per group were required to detect superiority between the treatment groups. However, taking patient discontinuation into consideration, as well as post-surgery follow-up visits at both day 7 and 3

5 day 30, it was estimated that a sample size of 90 patients in each group was required for the intent-to-treat (ITT) population. The underlined portion was added to the text to clarify this point (p. 8, line 185). 11. The authors should mention the exact values for P and avoid stating the P values as >0.05 or <0.05. At the reviewer s request, we have replaced all generic P values with the actual values. 12. In Table 1, the patients with other disease have not been defined. In addition, the duration of cataract should be deleted as there is no precise value for that. The test used for comparison of Schirmer between the two groups in this Table is not clear. We apologize for the apparent oversight. The other diseases were concomitant systemic diseases and information regarding their nature are not available. For clarity, however, other disease has been replaced with concomitant systemic diseases in Table 1. (p. 19) In addition, we have deleted the duration of cataract from Table 1 and have added a footnote to indicate that the results of the Schirmer test were compared between groups using the Wilcoxon rank sum test (p. 19). 13. It is not clear why the authors have used 7-day as a time point for evaluation of dry eye. As at this time point, the patient is still recovering from the surgery with its usual symptoms of postop ocular discomfort, the validity of symptom questionnaire is questionable. Because damage to the ocular surface usually occurs early after phacoemulsification, the day-7 time point was used to assess whether early intervention with carboxymethylcellulose 1% was beneficial for treating post-surgical dry eye. Information was added to the manuscript to clarify this point (p. 6, lines ). 14. The findings have been repeated in text, tables and graphs. The authors should avoid repeating the findings. At the reviewer s request, the Results section has been amended to avoid repetition (p. 8-11). 15. It is not clear why corneal fluorescein staining and conjunctival lissamine green staining have been significantly positive in the patient population at the baseline. As mentioned in the discussion, Aging is an established risk factor for dry eye, [3] and androgen deficiency associated with aging has also been reported to be a contributing factor to dry eye. [20, 21] The patient population enrolled in this study, ages 60 to 80 years with age-related cataract, was high risk of dry eye disease (p. 12, lines ). Moreover, 38.9% and 36.7% of patients in the treatment and control groups were diagnosed with dry 4

6 eye at baseline (p. 19, Table 1), which is consistent with findings of corneal and conjunctival staining in the overall study population at baseline. 16. OSDI at baseline has been very high, probably due to effect of the cataract on the visual part of OSDI. The authors are encouraged to use the non-visual part of OSDI for the study. The presence of cataract can indeed affect the results of the OSDI questionnaire. However, using only the non-visual part of the questionnaire would leave at best- 5 out of 12 questions to be analyzed, which may negate its clinical and statistical value. To circumvent the issue, we instead evaluated 11 additional subjective symptoms to assess dry eye, as described in the Clinical assessments section of the manuscript (p. 6-7, lines ). 17. The methods used for evaluation of the drug safety as well as the definition for adverse events are not clear. For example, the authors have used the symptoms of tearing, foreign body sensation, and photophobia as adverse events (Table 5) while the same items have been used as symptoms of dry eye. To clarify this point, we have modified the last paragraph of the Clinical assessments section as follows: The clinical investigator was responsible for monitoring adverse events (eg, eye swelling, ocular hypertension) and reporting incidents to the study sponsor. Any worsening of pre-existing dry eye symptoms (eg, tearing, foreign body sensation, or photophobia) or new occurrence of such symptoms was also considered an adverse event. (p. 7, lines ) 18. The authors have failed to discuss many of the findings. For example, why patients with preop dry eye had similar TBUT in both treatment and control groups after the surgery; why fluorescein and lissamine staining decreased postop in the control group, why symptoms decreased postop in the control group, etc. It is unclear why post-surgical TBUT values were similar in the treatment and control groups of patients who had dry eye prior to surgery, or why fluorescein staining, lissamine staining and symptoms decreased in the control group after surgery. However, since corticosteroids can reduce inflammation in the injured ocular surface epithelium of patients with dry eye, and prednisolone was part of the post-surgical therapy administered to the entire study population, it is possible that prednisolone prevented the detection of a difference between the treatment and control groups for those parameters. The post-surgical decrease in symptoms observed in the two groups may also be attributable to the enhanced vision due to the phacoemulsification itself. It is also possible that the questionnaires used are not optimally designed to assess dry eye following cataract surgery. This information has been added where appropriate in the Discussion section (p. 12, lines ; p. 13, lines and ). 5

7 In fact, most patients who develop dry eye post-cataract surgery have a mild form of the disease due to the period of tear film instability which usually improves as the eye recovers. This factor may have impacted in the small treatment differences. 19. Discussion has over-emphasized on the efficacy of CMC on postop dry eye while it is not supported with the findings of this study. We understand the reviewer s concern and have revised the discussion and conclusions to avoid over-interpreting and/or over-emphasizing the findings (p ). Reviewer: Tae-im Kim 1. Page 5 line 124 anesthesia (Tianjin Jingming New Technological Development Co, Ltd, Tianjin, 125 China), what is the name of anesthetic medication? It is unclear what is related with Tianjin Jingming New Technological Development Co, Ltd. Does it mean Schirmer strip? Although information regarding the anesthetics used for the Schirmer test had been provided in the second paragraph of the Clinical assessments section, it was not easily recognizable. The description is now included earlier in the first paragraph of the section. In addition, the role of Tianjin Jingming New Technological Development Co, Ltd as the vendor of the test strips has been added. The sentence now reads as follows: At each of the three visits, the following assessments were conducted serially and prior to instillation of eye drops: TBUT, fluorescein and lissamine green ocular staining, and Schirmer test with oxybuprocaine hydrochloride 0.4% eye drops (Benoxil, Santen Pharmaceutical Co, Ltd) or proparacaine hydrochloride 0.5% eye drops (Alcaine, Alcon Laboratories, Inc) as anesthetics (and test strips from Tianjin Jingming New Technological (p. 6, lines ) 2. Schirmer I test usually means the test without anesthesia, Schirmer II test is the test with anesthesia. I recommend use the term Schirmer test and define it as Schirmer test with anesthesia one time. As recommended by the reviewer, the type of Schirmer test used was amended to designate with anesthesia once in the abstract and once in the main text. 3. When do you analyze the patient clinical outcome after artificial tear instillation? Too close application of eye drops may influence on data of TBUT and Schirmer test. To address this comment, the second sentence of the Clinical assessments section was modified as follows: On the day of each of the three visits, administration of CMC was withheld prior to and immediately after study assessments. The following were conducted in sequence: TBUT, fluorescein and lissamine green ocular staining, and Schirmer test with (p. 6, lines ) 4. What is the order of the test was done? Please describe it serially. 6

8 The tests were completed in the following order: Symptom questionnaire, TBUT, fluorescein and lissamine green ocular staining, Schirmer test with anesthesia. The text has been modified to reflect this important point. (p. 6, lines ) 5. In Results session, line 184 Based on the criteria for diagnosis of dry eye. What is the criteria for diagnosis of dry eye in this study? It would be better to describe it. Because this is multicenter study, standardized criteria for diagnosis is critical. This comment is similar to comment #8 from Reviewer 1 and was addressed by adding references to support the statement found on p. 7 (lines ): Patients were diagnosed as having dry eye symptoms if they met one of the following conditions: TBUT 5 s, plus a subjective symptom score of 3 or greater,[14, 15] or Schirmer test 3 mm in 5 min, plus a subjective symptom score of 3 or greater. [14, 16] 14. Discussion and conclusion do not describe separately The discussion and conclusion sections were separated as specified in the instructions to authors provided on the BMC Ophthalmology website. We will, however, gladly combine them if the editor advises so. Thank you for your kind attention. We look forward to hearing from you. Sincerely, Ke Yao, MD Eye Center, Second Affiliated Hospital Zhejiang University School of Medicine Phone: xlren@zju.edu.cn 7