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Abstract
Introduction Dry eye (DE) is a multifactorial ocular surface disease causing considerable medical, social and financial implications. Currently, there is no recognised long-term, effective treatment to alleviate DE. Clinical evidence shows that electroacupuncture (EA) can improve DE symptoms, tear secretion and tear film stability, but it remains controversial whether it is just a placebo effect. We aim to provide solid clinical evidence for the EA treatment of DE.
Methods and analysis This is a multicentre, randomised, sham-controlled trial. A total of 168 patients with DE will be enrolled and randomly assigned to EA or sham EA groups to receive 4-week consecutive treatments and follow-up for 24 weeks. The primary outcome is the change in the non-invasive tear break-up time (NIBUT) from baseline to week 4. The secondary outcomes include tear meniscus height, the Schirmer I test, corneal and conjunctival sensation, the ocular surface disease index, corneal fluorescein staining, the numerical rating scale and the Chinese DE-related quality of life scale.
Ethics and dissemination The trial protocol and informed consent were approved by the Ethics Committee of Yueyang Hospital of Integrated Traditional Chinese and Western Medicine Affiliated to Shanghai University of Traditional Chinese Medicine (identifier: 2021–119), Shanghai Eye Disease Prevention and Treatment Center (identifier: 2022SQ003) and Eye and ENT Hospital of Fudan University (identifier: 2022014).
Trial registration number NCT05552820.
- OPHTHALMOLOGY
- Corneal and external diseases
- COMPLEMENTARY MEDICINE
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STRENGTHS AND LIMITATIONS OF THIS STUDY
This is the first multicentre, randomised, sham-controlled trial evaluating the efficacy of electroacupuncture (EA) for dry eye.
The sham EA method is performed using non-penetration acupuncture and non-acupuncture points without electrical stimulation to blind the subjects and maximally circumvent therapeutic and non-specific effects.
The acupuncturists are not blinded due to the particularity of the EA intervention modality.
Introduction
Dry eye (DE) is a multifactorial ocular surface disease pathologically characterised by tear film instability, elevated tear osmolarity, ocular surface inflammation and injury and neurosensory abnormalities. DE has become a common health concern worldwide in recent years, with its global prevalence estimated as 5%–50%.1 In China, the prevalence is 6.1%–59.1%, higher than the global average and increasing yearly.2 A UK cross-sectional web-based survey showed that as DE symptoms worsened, patients were more affected in terms of social-emotional functioning, vision-related quality of life, daily activities and productivity.3 Therefore, interventions in the early stages of DE are crucial to delay its progression and reducing social and economic stress.4
There is no gold standard for the treatment of DE yet. In clinical practice, first-line treatment usually focuses on adequately relieving DE symptoms, routinely with tear supplementation with ocular surface lubricants.5 However, their effects can be relatively transient, partly because reflux tearing and drainage via the nasolacrimal duct clear ≥80% of the instilled drug very quickly after application.6 Besides, the long-term daily use and the high cost of eye drops hinder patients’ treatment adherence and efficacy. Therefore, it is necessary to find a treatment method that treats DE and is also characterised by high safety, good compliance, tolerance and cost-efficiency.
Acupuncture has been widely used as a complementary and alternative therapy. Substantial clinical evidence shows that acupuncture can improve DE symptoms, tear secretion and tear film stability with more significant efficacy than artificial tears.7–10 Its long-term effects are also satisfactory.11 The mechanism of acupuncture for treating DE has not yet been fully elucidated. However, existing studies have shown that its action is multitargeted, including improving structural and functional abnormalities of the ocular surface, regulating apoptosis and autophagy of ocular surface cells, inhibiting immune-inflammatory responses and promoting neurotransmitter secretion.12 In addition, recent experimental studies have demonstrated the potential of electroacupuncture (EA) as a critical modulator of immune-inflammatory reactions by inhibiting the reactive oxygen species/thioredoxin-interacting protein/NOD-like receptor pyrin domain containing-3 signalling cascade or the modulation of the alpha 7 nicotinic acetylcholine receptor/nuclear factor-kappa B signalling pathway.13 14 Currently, it remains controversial whether it is just a placebo effect.15 16 Our preliminary study found that, compared with 0.1% sodium hyaluronate eye drops, EA exerted more beneficial and long-lasting effects after 4 weeks of treatment.17 To rule out the placebo effect of EA, we propose conducting a multicentre, randomised, subject-blind and sham EA-controlled trial to provide high-quality clinical evidence to support using EA to treat DE.
Methods and design
Trial design and setting
This will be a 28-week multicentre, randomised, subject-blind, sham-controlled trial carried out at three clinical centres, including Shanghai Research Institute of Acupuncture and Meridian, Shanghai Eye Disease Prevention and Treatment Centre and Eye and ENT Hospital of Fudan University. The trial flow chart is illustrated in figure 1, and the schedule of treatment assessments and data collection is shown in table 1. The trial will be conducted according to the Standard Protocol Items: Recommendations for Intervention Trials guidelines18 (Additional file 1) and adhere to the principles of the Consolidated Standards of Reporting Trials19 and the Standards for Reporting Interventions in Clinical Trial of Acupuncture.20 The trial protocol and informed consent were approved by the Ethics Committee of Yueyang Hospital of Integrated Traditional Chinese and Western Medicine of Shanghai University of Traditional Chinese Medicine (identifier: 2021–119), Shanghai Eye Disease Prevention and Treatment Center (identifier: 2022SQ003) and Eye and ENT Hospital of Fudan University (identifier: 2022014) and registered with ClinicalTrials.gov (identifier: NCT05552820).
Schedule of treatment assessments and data collection
Flow diagram of the trial procedure.
Subjects
We will post on official social media and posters in hospitals and communities. People with intentions can contact the researchers by telephone or in person. We will inform the subjects of the study protocol and obtain written informed consent before screening them according to the inclusion and exclusion criteria. The included subjects will be randomly allocated at 1:1 to receive 4-week EA or sham EA treatments. We will then conduct a 24-week follow-up for further observation. All procedures will rigorously adhere to the Declaration of Helsinki.
Eligibility
Inclusion criteria
Patients meeting the diagnostic criteria for mild-to-moderate DE according to the Tear Film and Ocular Surface Society Dry Eye Workshop II21: Ocular surface disease index (OSDI) ≥ 13, < 33 and NIBUT <10 s.
Age 18–65 years, no gender limit.
Exclusion criteria
Combined with other eye diseases (eg, severe blepharitis, blepharospasm, conjunctival laxity, strabismus, amblyopia, glaucoma, cataract, fundus disease and ocular trauma).
With active eye diseases or a history of eye surgery within 3 months.
Received acupuncture treatment or other DE treatment within 1 month that may influence the assessment of efficacy.
Previously experienced EA intervention.
Pregnant or breastfeeding women.
With serious systemic diseases such as cardiovascular, cerebrovascular, hepatic, renal and haematopoietic system and psychiatric disorders.
With autoimmune diseases such as Sjögren’s syndrome, rheumatoid arthritis, systemic lupus erythematosus or ankylosing spondylitis.
With damaged, ulcerated, infected or scarred skin at the selected acupuncture points.
Allergic to metal or tape.
Randomisation and blinding
Eligible subjects will be randomly assigned to either the EA group or the sham EA group evenly via a central randomisation system. A randomisation sequence will be produced by third-party personnel not involved in the trial using SAS V.9.4. Permuted blocks with block sizes of 2 and 4 and centre-stratified randomisation are implemented to ensure allocation concealment. Numbered, sealed, opaque envelopes will be delivered to the research assistant at each centre. Subjects, examiners, data collectors and statisticians are unaware of the grouping, but only acupuncturists can access it. Researchers will only break the mask to take action in case a serious adverse event happens. After the first and last treatment sessions, subjects’ blindness to treatment modalities will be validated by the Treatment Credibility Scale, where they will be asked whether the treatment is logical, whether it is considered successful and how confident it can help patients with DE.22 23 If the subjects of both groups hold equal expectations of efficacy, the potential psychological placebo effect produced by EA can be ruled out; if not equal, this means that the difference in results between groups is not solely due to the specific therapeutic effect of EA, and then the results should be interpreted with caution.
Intervention
In a previous study, we developed a standardised DE treatment protocol based on traditional Chinese medicine theory.24 At each centre, one certified acupuncturist with over 3 years of clinical experience will be in charge of the treatment. DE treatments other than artificial tears are not permitted. Those who use artificial tears regularly before enrollment will continue their original medication regimen; those who do not use artificial tears before recruitment will remain off the regimen during the treatment and follow-up. The researcher will keep a complete record of the duration and dosage of the use of artificial tears. Each subject will receive treatment in a separate space, with medical tape to help close their eyes. They will also be asked to keep quiet to avoid communication and speculating about treatment assignments.
Electroacupuncture
In this study, Cuanzhu (BL2), Taiyang (EX-HN5), Sibai (ST2), Sizhukong (TE23), Baihui (GV20), Fengchi (GB20), Hegu (LI4), Zusanli (ST36), Guangming (GB37), Sanyinjiao (SP6) and Taichong (LR3) are used. All points are taken bilaterally, except GV20. The points are positioned according to the WHO Standard Acupuncture Point Locations in the Western Pacific Region25 (table 2, figure 2).
Location of the acupoints
Acupuncture point diagram.
To receive the treatment, patients are supine with their eyes closed. After routine disinfection of the points, a sterile polyethylene cylindrical needle pad will be put on each point. Sterile acupuncture needles (0.25 mm×0.40 mm, Hwato brand, Suzhou Medical Supplies Factory Co., China) are inserted into the points through the needle pads. The acupuncturist will then perform twisting and lifting operations at the points until the subject reports Deqi (acupuncture sensations such as soreness, numbness, distension and heaviness). The needle handles of each side of BL2 and EX-HN5 will attach to a pair of electrodes from an EA apparatus (SDZ-III type, Hwato brand, Suzhou Medical Supplies Factory Co., China) to receive electrical stimulation with a continuous wave at 2 Hz and a current of 1–2 mA. Each treatment session lasts for 30 min. The subjects will receive the treatment three times a week for four consecutive weeks (a total of 12 sessions), with at least 1 day off between treatments. The EA procedure follows a standardised method of operation.26
Sham EA
Sham points are used for sham EA here, selected near the points used in the EA group but away from meridians (table 3, figure 2). We chose Streitberger sham acupuncture needles (Asia-med GmbH, Germany) for the procedure, producing some tingling sensations when fixing the needles on the skin to convince the subject of needle insertion. However, the needle does not penetrate the skin but is only pressed against the skin and withdraws back.27 The needles are kept upright by foam needle pads at the sham points, with the same appearance as the EA settings. Sham points SA1 and SA3 are connected to electrodes from the EA apparatus. The acupuncturist will turn on the machine to give the same external display and beeps and set the same parameters as in the EA group but disconnect the internal wires to disrupt electrical stimulation. The sham EA intervention’s duration, frequency and number of sessions are the same as in the EA group.
Location of the sham points
Subjects who attend at least 10 sessions are considered to have completed the whole course of treatment.
Assessments and outcomes
Subjects will be assessed at baseline and at weeks 4, 8, 16 and 28. Both eyes will receive DE measurements. The primary outcome measure is the NIBUT change from baseline to week 4. The secondary outcomes include tear meniscus height (TMH), Schirmer I test (SIT), corneal and conjunctival sensation, OSDI (0 (best)−100 (worst)), corneal fluorescein staining (CFS) (0 (best)−5 (worst)), ocular pain assessed by the numerical rating scale (NRS) (0 (best)−10 (worst)) and Chinese DE-related quality of life scale (CDERQOL) (five domains containing 45 items rated on a five-point Likert scale ranging from 1 (completely disagree) to 5 (completely agree)).28 29
The researcher will perform the objective ocular tests in the sequence of increasing invasiveness to minimise interferences.30 The order will be NIBUT, TMH, CFS, corneal perception, conjunctival perception, SIT and NRS for ocular pain. First, the tear film rupture video is taken using MODI2 (CSO, Italy).31 The subject is seated with the lower jaw on the jaw rest and the forehead firmly attached to the frontal band to fix the head. The subject will then be asked to blink naturally 3–4 times and keep looking at the central light source of the Placido disc until the examiner observes the breaking and deformation of the Placido rings, which is recorded as NIBUT. The measurement repeats three times, and the average value will be taken. After the NIBUT measurement, a digital slit lamp (SL990N, CSO, Italy) is applied to take images of the lower tear meniscus in a dark room. The system’s built-in calliper measures the TMH directly below the pupil’s centre.29 Next, the CFS is performed to observe corneal epithelial integrity. The Cochet-Bonnet perception metre (Luneau Chartres, France) is used to evaluate the corneal perception (including central, superior, inferior, nasal and temporal corneas, all 2 mm from the corneal rim) and conjunctival perception (including temporal and nasal bulbar conjunctivae, both 3 mm from the corneal rim; superior and inferior conjunctivae, at the centre of the eyelid). The measured fibre lengths will be converted into pressure (g/mm2) using a specifically calibrated curve, with a higher threshold indicating a more insensitive perception.32 Then, tear secretion will be measured using SIT. The intensity of ocular pain will be evaluated using the NRS once before and 30 s after using 0.4% oxybuprocaine hydrochloride eye drops (Santen Pharmaceutical Co., Japan).33 This scale is usually used to assess pain intensity with numbers ranging from 0 to 10; the higher the number, the greater the pain. In recent years, there has been an increasing interest in the relationship between DE and mental health.34 Therefore, we will additionally apply the patient health questionnaire-9 (0 (no)−27 (severe))35 and the generalised anxiety disorder (0 (no)−21 (severe))36 to understand the mental health status of patients before and after treatment.37
Neurosensory abnormalities are one of DE’s core pathological mechanisms.38 Corneal nerves have an essential role in the tear secretion reflex and the maintenance of ocular surface health.39 Corneal nerve fibres are shorter in length and less dense in patients with DE than in normal subjects,40–42 and corneal nerve morphology is closely related to DE symptoms and visual quality.43 44 Therefore, at baseline and week 4, we will perform in vivo confocal microscopy (IVCM) to take a primary look at the morphological changes of corneal subbasal nerves. IVCM is a non-invasive technique that examines the morphology of corneal subbasal nerves at the microstructural level. An experienced examiner will perform this test using the Heidelberg Retina Tomograph III (Heidelberg Engineering, Germany).45 Before the examination, the ocular surface of each eye is anaesthetised with 0.4% oxybuprocaine hydrochloride eye drops. The focus is located at the corneal subbasal nerve plexus layer, with the sequence mode selected to scan 6–8 different spots of the cornea. A masked observer will pick up three clear and typical images of the corneal subbasal nerve. The ACC Metrics analysis software (M.A. Dabbah, Imaging Science Biomedical Engineering, Manchester, UK) is used to calculate the neuromorphological parameters of the selected images, namely corneal nerve fibre density, corneal nerve branch density, corneal nerve fibre length and corneal nerve fibre width. The average values are taken for statistical analyses.41
Adverse events
Any adverse events will be recorded. EA-related adverse events include local bleeding, subcutaneous hematoma, pain, itch, infection and generalised symptoms such as dizziness and palpitation during the treatment.
Data monitoring and management
All subjects’ data will be managed using printed case report forms with double entry and validation by the EpiData 4.6 password-protected database. All investigators will receive training on data management. Paper and electronic data will all be kept for at least 3 years after publication. In addition, an independent Data Safety Monitoring Committee (DSMC) consisting of three experts with backgrounds in ophthalmology, acupuncture and statistics will be established prior to the trial. The DSMC will hold an online conference every 4 months to oversee the trial progress and review the safety and quality of the data. At the stage of 1/2 enrollment, an interim analysis will be conducted, and the DSMC will decide whether it is necessary to terminate the trial in advance. Information involving personal privacy (eg, name, age, telephone number) will be concealed within DSMC reports.
Sample size
In the previous sham-controlled study,46 the tear break-up time (BUT) increased from 3.29±1.01 s to 4.24±1.26 s in the acupuncture group versus 3.71±1.38 s to 4.00±1.34 s in the sham acupuncture group. Based on the formulas in the Cochrane Handbook47 and the imputed correlation coefficient between the pretreatment and post-treatment values of BUT of 0.5,16 the means and SD for changes in the BUT were calculated to be 0.95±1.16 s and 0.29±1.36 s in the acupuncture group and the sham acupuncture group, respectively. Thus, we estimated a sample size of 134 (67 subjects per group) to provide a power of 85% and a two-sided significance level of 5%. Assuming a 20% attrition rate, we increased the sample size to 168 (84 subjects per group).
Data analysis
An independent statistician will analyse the data using SAS software V.9.4 (SAS Institute). Analyses will be performed according to the intention-to-treat principle. The study will employ linear regression for continuous variables and the χ2 test for categorical variables to compare subject-level characteristics at baseline and specific visits. Similarly, eye-level characteristics at baseline and typical visits will be compared using linear regression for continuous variables with generalised estimating equations to account for the correlation between eyes and logistic regression for categorical variables with generalised estimating equations.48–50 Missing data for NIBUT will be addressed using propensity scores and multiple imputation regression methods. A mean change analysis of the NIBUT with adjustments for baseline values will be performed, followed by additional longitudinal data analyses to fully characterise the relation of the NIBUT change to the treatment group over time. A mixed-effects model with a random intercept for each subject will account for the correlation between repeated measurements. Time will be modelled as a categorical variable for a non-linear relationship between the NIBUT and time. An interaction term between time and treatment group will be included in the model and dropped if it is not statistically significant. These models will evaluate the correlation between the change in NIBUT from baseline to follow-up and the influence of possibly prognostic factors. All statistical tests are two-sided, and the statistical significance level will be 0.05.
Quality control
Before starting the trial, we developed an investigator’s manual to standardise the assessment procedure, performance of EA and sham EA, DE measurements and data collection and entry. All the involved researchers will receive centralised and unified training to ensure strict adherence to the trial protocol and the standardisation and uniformity of the study. The true and sham EA interventions will be provided by licenced acupuncturists with at least 3 years of clinical experience. The acupuncturists at each site will be trained face-to-face by the senior acupuncturist from the lead site to standardise the intervention procedures, including greetings, preparations, the locations of points and sham points and the needling manipulations of both true and sham EA. Those who pass the quality assessment are qualified to take part in the trial.
Discussion
This trial is designed to reveal the non-placebo and long-lasting efficacy of EA for mild-to-moderate DE and provide a feasible therapeutic strategy for treating DE. In addition, we will further investigate the association between EA’s treatment efficacy and changes in the corneal nerve.
We have established a standardised EA procedure for DE treatment with high reproducibility.24 The prescribed points include periocular and body points, known as the distal–proximal point combination. In light of the theory of traditional Chinese acupuncture, the distal–proximal point combination is a classic point prescription method widely used in the acupuncture treatment of DE, and it has been proven superior to selecting periocular points alone.51 All the points on the head and face can be considered as proximal points near the eyes. Among them, BL2, TE23, EX-HN5 and ST2 are the most commonly used periocular points in treating DE.51 52 At the local points, a mass of nerve endings and blood vessels are distributed in the hypodermis and muscles, interlacing with the collagen fibres.53 Benefiting from this microanatomical structure, EA at BL2 and EX-HN5 can effectively stimulate the periocular nerves. In terms of body points, ST36, LI4 and LR3 are frequently prescribed for all sorts of diagnosis patterns based on network analysis.53 The association rules analysis also shows that TE23 and LI4 can be used as the core point groups in treating DE.52 The latest meta-analysis also suggested that 2–3 times of acupuncture per week for 21–30 days might be the most appropriate option for managing DE.8 Thus, the EA intervention performed in this trial should be both theoretically and practically reasonable and beneficial.
In this trial, we employ a sham EA group as a control. Establishing an inert and concealable sham EA control is quite a challenge in acupuncture studies because of methodological difficulties.54 In the previous DE studies,11 15 shallow needling at non-meridian non-acupuncture points was designed as a sham acupuncture control, whereas an unintended treatment effect on DE was still found, indicating that even superficial stimulation of sham acupuncture could lead to physiologic changes beyond a placebo effect.55 We take the essence and make some adjustments to the published sham methods. So, the same number of non-meridian non-acupuncture points are used, located minimally 1 cm away from the standard acupuncture points. For needle insertion, non-skin-penetration sham acupuncture is performed, different from the penetration acupuncture adopted in the previous DE studies.11 15 Some researchers reported that penetration acupuncture, even the shallow needling at non-acupuncture points, could induce a therapeutic effect,56 57 which may explain the lack of a significant difference in some sham-controlled DE studies. Hence, the non-penetration sham method seems to be a better choice.58 59 However, the controversy remains regarding whether a non-penetration sham acupuncture is physiologically inert on account that a slight mechanical stimulation with no skin penetration might evoke brain responses and physiological activities.59 60 The sham EA control conducted here uses a device combining a blunt-tipped needle and a foam pad placed at the sham points. The needle will retract after touching the skin to give the patient the illusion that it has pierced the skin but actually has not. Besides, the foam pad helps to imitate the real acupuncture setting, increasing the patient’s confidence in the treatment. In order to avoid electrical stimulation, the sham EA device is used with its internal electrodes disconnected. The exterior appearance, indicator light and prompt tone of the sham device are all indistinguishable from the normal one. To ensure concealment, subjects with real EA interventions will be excluded. Currently, this type of sham EA procedure is believed to be optimal enough to blind the subjects and maximally circumvent therapeutic and non-specific effects.54
Recruitment for this trial started on 12 October 2022 and is planned to be completed on 31 December 2023. The last follow-up assessment is planned to be finished in August 2024.
We should note several limitations in this protocol. First, the acupuncturists are not blinded due to the particularity of the EA intervention modality, but we will use standardised operations and avoid communication to reduce the influence. Second, the sham EA operation is not entirely inert. Nevertheless, the study is still deemed to provide high-quality evidence for the effectiveness of EA in treating DE and unveil the potential neuroregulatory mechanisms of EA.
Ethics and dissemination
The trial protocol (V.3.0, 11 November 2021) and informed consent were approved by the Ethics Committee of Yueyang Hospital of Integrated Traditional Chinese and Western Medicine of Shanghai University of Traditional Chinese Medicine (identifier: 2021–119), Shanghai Eye Disease Prevention and Treatment Center (identifier: 2022SQ003) and Eye and ENT Hospital of Fudan University (identifier: 2022014) and registered with ClinicalTrials.gov (identifier: NCT05552820).
Ethics statements
Patient consent for publication
References
Footnotes
Contributors LYQ, YG and LMY have contributed equally to this work and shared first authorship. Conception and design: ZXT, MXP, LYQ, YG and KXH. Administrative support: MZ and HXY. Provision of study materials or patients: ZYL and ZY. Collection and assembly of data: LYQ, YG, LMY and WXJ. Statistical method design: YG and KXH. Manuscript writing: LYQ, YG, HJ and YYT. All authors conceived or refined the trial design and approved the final manuscript.
Funding The study is supported by the National Science Foundation of China (81904302), the Scientific Research Project of Shanghai Municipal Health Commission (20214Y0116, 202040249, 201940130) and the Shanghai Sailing Programme (19YF1445000, 23YF1442000). The funding has no role in the design of the study, the collection, analysis and interpretation of data, or in writing the manuscript.
Competing interests None declared.
Patient and public involvement Patients were not involved in the design, conduct or reporting of this trial. They will be evaluated about the availability to complete study treatment based on their time and the degree of mobility difficulty.