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  • The protocol for this trial and supporting CONSORT checklist are available as supporting information; see Checklist S1 and Protocol S1. This was a randomised, active controlled, parallel designed trial. The study protocol has been previously published [10]. This multicentre trial was conducted in three clinical research centres of South Korea from June to November 2010: Korea Institute of Oriental Medicine (Daejeon University Hospital), DongGuk University Ilsan Oriental Hospital and Dongshin University Gwangju Oriental Hospital. The research protocol was approved before study onset by the institutional review board (IRB) of each participating hospital. Participants were independently recruited by each centre through advertisements in local newspapers. The protocol was registered with ClinicalTrials.gov (Identifier: NCT01105221) before participant enrolment. Written informed consent was obtained from all of the participants. Patients aged nineteen to sixty five years old with aggravating dry eye symptoms in a single eye or in both eyes were recruited [1]. Physicians and ophthalmologists assessed participant eligibility [11]. Inclusion criteria were based on the following ophthalmologic tests: a tear film break-up time (TFBUT) below 10 seconds and a Schirmer Ι test (with application of alcaine, a local anaesthetic) value below 10 mm/5 minutes [12]. These ophthalmologic tests were performed by the ophthalmologists who did not know the allocation results. Participants with several conditions were excluded: pathological changes of the eye, Stevens-Johnson syndrome, external injuries and eye-surgery history affecting dry eye. Participants who had been taking or needed active treatment for dry eyes were also excluded, as were patients with punctal occlusion history or current usage of anti-inflammatory eye drops. Contact lens use was prohibited throughout the participation period. Participants were allocated into either acupuncture or artificial tears evenly. Random numbers were generated through computerised block-randomisation with the SAS package (SAS® Version 9.1, SAS Institute, Inc., Cary, NC) by separate statistician. Opaque assignment envelopes with consecutive numbers for each centre were used for allocation concealment. The necessary sample size was calculated from the results of previous studies regarding the effects of acupuncture [11], [13] and artificial tears [14]. The mean difference (standard deviation) of ocular surface disease index (OSDI) after acupuncture treatment was 17.61 (15.61), and after artificial tears (sodium carboxymethylcellulose), it was 11.3 (6.3) [13], [14]. Anticipating a 20% dropout rate, a total of 150 participants was recruited and was evenly assigned to each centre (50 participants in each centre). Acupuncture was administered according to the theory of traditional Korean medicine (TKM) without using lubricants. An expert committee composed of clinical experts and researchers working on acupuncture research or ophthalmologic practice of TKM decided on acupuncture points and needling methods based on published literature and textbooks about acupuncture for ophthalmologic diseases or dry eye syndrome [9], [15]. Certified practitioners with at least 7 years of TKM education and 3 years of clinical experience performed the acupuncture treatment. To reduce non-specific effects originating from the close relationship between patients and practitioners, interactions were strictly limited [16]. Seventeen acupuncture points (bilateral BL2, GB14, TE 23, Ex1, ST1, GB20, LI4, and LI11 and single GV23), located according to the WHO Standard Acupuncture Point Locations in the Western Pacific Region, were treated with 0.20×30-mm disposable acupuncture needles (Dongbang Co., Korea) [17]. The depths of inserted needles differed but were approximately 0.6 to 3 cm for the acupuncture points at the face and head (BL2∶1.5 to 3 cm; GB14∶0.9 to 1.5 cm; TE23∶1.5 to 3 cm; Ex1∶1.5 to 3 cm; ST1∶0.6 to 0.9 cm; GV 16∶0.9 to 1.5 cm) and 3 to 4.5 cm for points of hand (LI4) and arm (LI11). Each acupuncture needle was twisted until patient felt a ‘deqi’ sensation and retained for 20 minutes before removal. Participants had acupuncture treatments three times per week for four weeks (a total of 12 treatments). Preservative-free single-use artificial teardrops (0.5% sodium carboxymethylcellulose) were provided, and participants were advised to use them as needed (at least once per day) for four weeks. A diary of both the frequency and quantity of drops used was collected at every visit. In both groups, other treatments for dry eyes were forbidden during the four weeks of treatment. However, during the follow-up period, participants were allowed to use any kind of treatment for dry eyes, and participant reports on treatment usage were requested at every visit. Outcome assessment included two aspects, subjective ophthalmologic tests and objective questionnaires for both ocular symptoms and quality of life related to dry eyes. The primary outcome was the difference in OSDI changes between the two groups. The secondary outcomes were the differences in 100 mm VAS for the ocular discomfort, quality of life questionnaire using the Measure Yourself Medical Outcome Profile-2 (MYMOP-2), TFBUT, Schirmer Ι test (with anaesthesia) score and adverse event rate of acupuncture treatment and artificial tears usage. Both eyes were assessed for the evaluation of TFBUT and Schirmer Ι test, respectively. Outcomes were assessed 13 weeks after the first visit. OSDI is a validated questionnaire consisting of twelve questions for evaluating ocular symptoms and worsening conditions related to dry eyes [18]. Each question has a score between zero and four, where zero indicates “none of the time” and four indicates “all of the time”. The OSDI score was calculated according to the following formula: OSDI = [(sum of scores for all questions answered)*100]/[(total number of questions answered)*4]. The score ranges from 0 to 100, and higher scores represent a more severe dry eye state. The minimal clinically important difference (MCID) of OSDI for dry eye syndrome is suggested to be 7.3 to 13.4 points in severe dry-eye patients [19]. A version translated into the Korean language was used [20]. A 100 mm VAS for self-assessment of ocular discomfort was reported by participants. Ocular symptoms related to dry eye (e.g., ocular itching, foreign body sensation, burning, pain and dryness, blurred vision, sensation of photophobia, ocular redness, and sensations of tearing) were quantified and summarised in a standard 100 mm VAS scale. The QOL section of the MYMOP-2 was adopted for assessing dry eye-related QOL [21], [22]. A seven-point Likert scale (from zero as ‘excellent’ to six as ‘worst’) was used for the assessment of QOL grade. The question was “During last week, how would you express your quality of life related to dry eyes, overall?”. Tear film break-up time (TFBUT) is a test for assessing tear film stability [23], [24]. Sodium fluorescein (2.5%) was applied to both eyes, and the interval between the blink of eyes and the first appearance of a dry spot or disruption in the tear film was measured. If TFBUT is below 10 sec, it suggests at least a moderate severity of dry eyes [1], [12]. The Schirmer Ι test (with anaesthesia) is a diagnostic method to measure the basic quantity of tear secretion [12]. After application of local anaesthesia, Schirmer test paper (Color Bar, Eagle Vision, USA) was placed in the lateral third of the lower eyelids for 5 minutes with closed eyes. If the Schirmer test result is below 10 mm/5 min, it also suggests at least a moderate severity of dry eyes [1], [12]. General improvements of dry eye-related symptoms were assessed by practitioners and participants using a five-grade Likert scale: excellent, good, fair, poor and aggravation. For the evaluation of safety issues, we assessed adverse events rates of acupuncture and artificial tears. If unexpected responses happened, the type and frequency were collected. The type and frequency of adverse events were reported for each group. According to the criteria of the WHO Toxicity Grading Scale for Determining The Severity of Adverse Events, the severity of the adverse event was evaluated by practitioners as grade 1 (mild) to grade 4 (life threatening) [25]. OSDI, VAS and quality of life were assessed by separate outcome assessors who did not perform acupuncture treatment. TFBUT and Schrmir Ι test were evaluated by ophthalmologists. To determine the differences between the acupuncture and artificial tears groups, the changes in values from baseline were compared at each visit on an intention-to-treat basis at a 95% significant level. Missing data of dropped-out participants were assigned by the last observation carried forward (LOCF) method. Participant expectations of acupuncture treatment for dry eye symptoms were collected with a nine-point Likert scale and were compared between the two groups [26]. Key baseline characteristics including risk factors for dry eyes such as computer use, age, occupational environment, contact lens usage, etc. were evaluated for the difference between two groups. ANCOVA (Analysis of Covariance) were used for continuous outcomes such as OSDI score, TFBUT, Schirmer test result, QOL and VAS for self-assessment of ocular discomfort, adjusted for baseline values and research centres as covariates. Adjusted differences, which were calculated from the ANCOVA model, were reported at each visit to estimate the effect size. Chi-squared tests were used for dichotomous outcomes such as general improvements of dry eye-related symptoms and differences in the usage of additional treatment during follow-up period. As suggested in the study protocol, repeated measures of analysis of variance for OSDI were performed to show trend changes. Statistical analyses were conducted using the SAS statistical package.
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