Safety and efficacy of combined acupuncture (body and intradermal acupuncture) for dry eye disease: study protocol for a pilot, single-centre, assessor-blinded, randomised, artificial tear drop-controlled trial at Naju Dongshin University Korean Medicine Hospital

Abstract

Introduction

The prevalence of dry eye disease (DED) has been consistently increasing yearly. However, the radical therapy has not yet been established. This study is to confirm the superiority of acupuncture over artificial tear drops (ATDs) in patients with DED.

Methods and analysis

This study is a single-centre, investigator-initiated, assessor-blinded, parallel randomised controlled trial. 30 participants will be enrolled. Over a period of 4 weeks, the experimental group would receive two kinds of acupuncture three times a week. First, body acupuncture would be performed on bilateral BL2, GB14, TE23, EX-HN5 and ST1 for 15 min. Thereafter, intradermal acupuncture would be performed on the same acupoints for 4 hours. On the other hand, the control group would apply the provided ATD at least four times a day. As a rescue medication for severe DED symptoms, both groups can additionally apply ATD. The frequency of ATD use would be recorded during the trial. The primary outcomes are the Ocular Surface Disease Index and tear film break-up time. The secondary outcomes are subjective symptom Visual Analogue Scale, quality of life, Schirmer I test, tear lactoferrin level, treatment satisfaction and safety. The outcomes would be mostly assessed at visits 1, 13 and 14.

Ethics and dissemination

This study was approved by the institutional review board of Naju Dongshin University Korean Medicine Hospital (Approval No. NJ-IRB-23-5). The obtained results will be disseminated through publication in a peer-reviewed journal.

Trial registration number

KCT0008563.

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• In addition to assessing patients’ subjective symptoms, this study also uses objective outcomes, including the Schirmer I test, tear film break-up time and tear lactoferrin level, to evaluate the effectiveness of acupuncture for dry eye disease (DED).

• Allowing the experimental group to use artificial tear drops (ATDs) may reflect the lives of numerous patients with DED who routinely use ATDs.

• Although tear lactoferrin levels are adopted as a molecular outcome in this study, similar to other recent studies, further in-depth studies may be necessary to fully understand the beneficial effects of lactoferrin on DED.

• The sample size of 30 patients and the relatively young participants may not adequately represent the true effectiveness of acupuncture in patients with DED, especially considering that the elderly constitute the majority of DED worldwide.

• Differences in the visit count between the experimental and control groups could affect the attention of the participants, potentially impacting the trial results.

Introduction

Dry eye disease (DED) is a condition of the tear film caused by the short or overevaporation of tears, resulting in superficial eye damage and eye-irritating symptoms.¹ In 2018, the prevalence of DED in Korea had known for increasing by 2.1% yearly over the past 5 years.² Recent environmental factors, such as increased use of electronic devices, prolonged indoor stay time, increased particulate matter and widespread use of contact lenses, can exacerbate DED.^3–5 Western medicine has attempted to treat DED with various therapies, including artificial tear drops (ATDs), but their numerous side effects have been reported.^6–9 Thus, the radical therapy for DED has not yet been established in Western medicine.

To treat DED, Korean medicine uses acupuncture or herbal medicine to cool pathological heat or replenish qi, yin, blood and fluid.¹⁰ Acupuncture is a primary therapy for DED in clinical practice. Consequently, studies investigating the effect of acupuncture for DED have been steadily published.^11–14 However, randomised controlled trials (RCTs) are necessary to establish the evidence of acupuncture for DED, as domestic studies primarily consist of case reports.

Intradermal acupuncture (IA), which will be used alongside body acupuncture (BA) in the experimental group, is also commonly used to treat DED. IA stimulates acupoints with a low-intensity, long-term stimulus by embedding a small needle into the skin. Its strengths are minimal pain and free physical activity. Hence, IA has been widely used to treat various chronic diseases that require continuous acupuncture stimulation.^15–18 However, there are few prior studies on IA. As preliminary steps, the authors analysed previous RCTs that used IA for DED.¹⁹ Thereafter, the authors compared IA with BA by performing each acupuncture on patients with DED in an RCT (not published). As the results, both acupuncture treatments were effective for DED, had similar therapeutic effects and were safe. In addition, a recent study suggested that thread-embedding acupuncture effectively improves symptoms of DED and increases lactoferrin levels in tears.²⁰ Therefore, this study has included tear lactoferrin levels as a new outcome.

To confirm the superior efficacy of acupuncture compared with ATD, this study is to compare the BA–IA complex acupuncture with ATD in patients with DED.

Method and analysis

Study design

This study is a single-centre, investigator-initiated, assessor-blinded, parallel RCT. Participants would be recruited at the Naju Dongshin University Korean Medicine Hospital. Participants who voluntarily sign the informed consent (online supplemental material 1) will be screened based on the eligibility criteria and necessary tests. The eligible participants would be randomly allocated to one of the two groups at visit 1. Over a period of 4 weeks, the experimental group would receive BA–IA complex acupuncture three times a week. Meanwhile, the control group would use ATDs at least four times daily. Thereafter, both groups would undergo outcome assessments 4 and 6 weeks later from visit 1.

Patients and public involvement

This study does not involve the intervention of patients or the public in its design, implementation or assessment of the outcomes. The participant recruitment began once all the preparations for this study were completed. The results of this study would be disseminated through an article in a peer-reviewed journal.

Eligibility

Inclusion criteria

Only patients fitting all of the following criteria would be recruited:

1. Male or female patients aged 19–65 years at the screening visit.

2. Those who exhibit typical symptoms of DED, including itch, a sensation of a foreign body in the eye, irritation, pain, dryness, blear eyes, glare, hyperaemia and lacrimation, and have the Ocular Surface Disease Index (OSDI) Score of ≥13.

3. Those with the Schirmer I test (SIT) result of ≤10 mm/5 min.

4. Those with tear film break-up time (TFBUT) of ≤10 s.

5. Those who voluntarily signed the informed consent.

The age range of participants was determined based on the prevalence of DED by age in the 2020 domestic statistics and potential practical issues for elderly participants.^{21 22} The limit of TFBUT was set at 10 s, based on the time generally diagnosed as DED in other literature.^{23 24}

Exclusion criteria

Patients who satisfy any of the following criteria would be ineligible for inclusion:

1. Those who have DED due to issues with the eyelid or eyelashes.

2. Those who experience eye irritation caused by acute inflammatory responses in the eyelid, eyeball and ocular appendage.

3. Those who have secondary DED due to scarring, including irradiation, alkali burn, Stevens-Johnson syndrome and cicatricial pemphigoid.

4. Those who were diagnosed with vitamin A deficiency.

5. Those who have traumatic injury to the eyeball and ocular appendage.

6. Those who received surgeries on the anterior segment, including cataract surgery and laser assisted in situ keratomileusis, within the past 3 months.

7. Those who are unable to blink due to Bell’s palsy.

8. Those who received a plug or occlusion to the punctum lacrimale.

9. Those who applied anti-inflammatory eye drops containing ciclosporin, corticosteroids and autoserum within the past 2 weeks.

10. Those with active infections in the eye, for example, anterior uveitis and anterior palpebritis.

11. Those who have ocular allergies or are receiving treatments for allergic ocular diseases.

12. Those who are suffering from or receiving treatments for viral conjunctivitis.

13. Those who have an intraocular pressure of ≥25 mm Hg or have been diagnosed with glaucoma in any eye.

14. Those who have worn contact lenses within recent 2 weeks or have to wear contact lenses during the trial period.

15. Those who are taking systemic corticosteroids or immunosuppressants.

16. Women who are pregnant, lactating or planning for pregnancy.

17. Those who were considered inappropriate by the investigators.

Sample size

Due to the limited number of similar prior studies, this study will follow Julious’ recommendation that a pilot study should recruit a minimum of 12 people in each group.²⁵ A dropout rate is calculated as 20%, taking into account the 12 treatments over a period of 4 weeks. Thus, each group needs 15 participants, totalling 30 participants.

Blinding

This study only blinds the examiner. Thus, the investigators would divide their roles into three categories: the examiner, clinical research coordinator and practitioner. The examiner would assess the outcomes before and after the intervention. The clinical research coordinator would manage the visit schedule and treatment of the participants. The practitioner would perform acupuncture on the experimental group.

The examiner would assess outcomes, including OSDI, TFBUT, subject symptom Visual Analogue Scale (VAS), quality of life (QoL) and SIT at the screening visit, visits 1, 13 and 14. During the trial, the examiner would be prevented from contacting the participants in order to maintain the confidentiality of each participant’s assigned intervention. The examiner can only meet the participants when assessing the outcomes. An additional worksheet, without any identifiable information, will be provided to the examiner to record the results. In addition, the examiner would not be able to read the case report form containing the participants’ records until this study is terminated.

Random allocation

To allocate the participants, block randomisation would be performed by SPSS Statistics V.21. The block size would be set as 4. In total, 30 participants would be randomised into 2 groups with an equal probability of 1:1. Randomisation codes assigned to each participant will be kept sealed in opaque envelopes sequentially numbered, which will be stored in a separate double-lock cabinet.

Investigators would determine the intervention by opening the envelope that contains the randomisation code in the presence of the eligible participant. Subsequently, the used envelope would be kept in a distinct location.

Interventions

The experimental group

Participants in the experimental group will receive combined acupuncture treatment of BA and IA. The treatment is based on standard needling of BA and IA using periocular acupoints. Initially, the participants would receive BA treatment. A total of 0.20 mm × 30 mm disposable sterile stainless steel filiform needles (Dong Bang acupuncture needle DB108C, Dongbang Medical, Seongnam, Republic of Korea) will be inserted with a fine tube into 10 acupoints, including bilateral BL2, GB14, TE23, EX-HN5 and ST1. During needling, the insertion depth is approximately 0.6–3 cm (0.2–1 cun), depending on the insertion angle or participant’s dermal thickness, and de qi sensation would be induced locally or toward the orbit. The inserted needles will be retained for 15 min and will be removed by medical staff.

Immediately thereafter, the participants will be treated with IA. A total of 0.18 mm × 1.0 mm disposable sterile thumbtack needles (T-press needle DB130A, Dongbang Medical, Seongnam, Republic of Korea) will be completely inserted into the aforementioned 10 acupoints until the fixing plaster of the needle firmly adheres to the skin. The inserted IA needles would be retained for 4 hours and will be removed by the participants themselves. The removed IA needles will be returned to the investigators for compliance assessment.

The treatment will be performed three times a week over a 4-week period, a total of 12 visits. All acupuncture treatments will be performed by Korean medicine specialists or residents who possess at least 3 years of clinical experience. The selected acupoints are frequently used for treating ocular disorders, as indicated by prior studies.^{10 26 27} The treatment session was determined based on the results from the authors’ unpublished prior RCTs and other prior studies.^{10 26 27}

The control group

For 4 weeks, participants in the control group will apply ATD (Q-tess Eye Drop, Hanlim Pharm, Seoul, Republic of Korea) daily. The participants should apply the provided ATDs at least four times a day, and they should record the number of use in the application diary.

Concurrent treatments

During the trial period, it will be strictly forbidden for all participants to receive any concurrent treatments for DED, including Korean medical treatments. Prohibited medications include anti-inflammatory eye drops, containing ciclosporin, corticosteroids or autoserum, oral corticosteroids and immunosuppressants.

However, some treatments would be restrictively permitted under the decision of the investigators. The treatments would be permitted if the participant had been receiving them prior to participating in this study and if they are not expected to affect the results. The medications temporarily used to treat other diseases would be permitted if the investigators have determined that they are not expected to affect the results. For both groups, ATD is permitted as rescue medication in cases of severe DED symptoms. Both groups can freely apply ATDs if the symptoms are severe and should record the frequency and time of ATD use in the application diary.

Study schedule

This study consists of 15 visits, which are divided into the screening period and the treatment period. The trial schedule is summarised in online supplemental material 2.

Screening visit

After being provided with sufficient information for this study, the patient would voluntarily sign the informed consent. The patients who have submitted the informed consent will undergo screening tests to determine their eligibility. The screening tests include a sociodemographic survey, general medical history taking, treatment history for DED, vital signs measurement, blood test, vision test, tonometry, anterior segment examination with a slit lamp, OSDI, TFBUT, subjective symptom VAS, QoL and SIT. Based on the eligibility criteria and screening tests, identification codes would be granted to eligible participants.

Visit 1

Visit 1 will be arranged within a week from the screening visit. The participants who have successfully completed the screening visit can proceed to visit 1 on the same day. The participant’s changes in medical history and medication taking since the screening visit will be surveyed. Randomisation will be performed on the eligible participants. Before implementing each intervention, examinations would be conducted to measure outcomes, including vision test, OSDI, SIT, subjective symptom VAS, QoL, TFBUT, anterior segment examination and tear lactoferrin analysis. The participants would be educated according to the assigned intervention, and they would receive ATDs and an application diary to record ATD use. The experimental group would receive acupuncture treatment, and any discomfort or adverse events (AEs) before and after the treatment would be surveyed.

Some observation items, including vital signs, vision test, medical history, medication taking, participant’s compliance, discomfort before and after the treatment and AEs, will be examined every visit. Participant teaching would also be conducted during every visit.

Visits 2–12

During visits 2–12, the observation items will be examined including visual acuity, medical history, medication taking, discomfort before and after the treatment and AEs since the last visit. The experimental group would visit three times a week for 4 weeks. At each visit, the experimental group would receive the acupuncture treatment, and discomfort before and after the treatment would be surveyed. Both groups would submit the ATD application diary to the investigators at visits 7 and 13.

Visit 13

Visit 13 will be arranged within 3 days, after a 4-week period has elapsed since visit 1. If 4 hours have elapsed since the treatment of visit 12, visit 13 could be arranged on the same day as visit 12. For the experimental group, a survey would be conducted to check any changes related to medical history, medication taking and AEs since visit 12. For the control group, the changes since visit 7 will be surveyed. The following assessments would be conducted: vision test, OSDI, SIT, subjective symptom VAS, QoL, TFBUT, anterior segment examination and tear lactoferrin analysis. When the assessments have finished, treatment satisfaction will be evaluated.

Visit 14

Visit 14 will be arranged within 3 days, after a 6-week period has elapsed since visit 1. Any changes in medical history, medication taking and AEs since visit 13 will be surveyed. Final assessments for vision test, OSDI, subjective symptom VAS, QoL, SIT, anterior segment examination and TFBUT will be conducted. Lastly, the participants’ final compliance will be investigated.

Additional visits

Additional visits can be arranged on the participants’ request or if the investigators deem them necessary. Additional follow-ups for the appeared AEs could also be arranged. They would be permitted if the AEs continue until the trial is fully completed or stopped early, or if the investigators or the participants request additional follow-ups after finishing the treatment.

Primary outcomes

The primary objective of this study is to compare whether the experimental group exhibits a greater average change in OSDI and TFBUT in comparison to the control group.

Ocular Surface Disease Index (OSDI)

The Asia Dry Eye Society considers both subjective symptoms and TFBUT as important criteria in diagnosing DED.²⁸ Due to its high reliability and validity, the OSDI is recommended as an endpoint in clinical trials on DED for assessing subjective symptoms in patients.^{29 30}

The OSDI is examined at the screening visit, visits 1, 13 and 14. This questionnaire surveys visual acuity, eye symptoms and the environment that causes symptoms.³¹ The severity of each question is rated on a scale of 0–4. For unanswered questions, the answers are rated as ‘not applicable’ and are not included in the final scoring. The total score is computed using the following formula: ‘total score = (sum of scores for all questions answered) × 100/(total number of questions answered) × 4’.²⁹ The total score ranges 0–100, and the severity increases in a score-dependent manner. The score ranges of 0–12, 13–22, 23–32 and 33–100 refer to normal, mild, moderate and severe DED, respectively.^{31 32}

Tear film break-up time (TFBUT)

The TFBUT will be examined at the screening visit, visits 1, 13 and 14. The dye on the fluorescein paper (Haag-Streit Diagnostics, Switzerland) is dissolved in a small amount of normal saline and then applied to the upper and lower palpebral conjunctivae. After blinking, the time until dry spots appear is measured using a slit lamp (HS-7000 and HIS-5000, Huvitz, Anyang, Republic of Korea). The observation is performed at a magnification of ×25, using cobalt blue and yellow filters. Generally, the time of ≤10 s in either one or both eyes is diagnosed as DED.^{23 24}

Secondary outcomes

For the secondary objectives, one is to compare the efficacy of the two groups in terms of secondary outcomes. These outcomes include subjective symptom VAS, QoL, SIT and tear lactoferrin levels. The other is to confirm the safety of each intervention.

Subjective symptom VAS

The VAS is examined at visits 1, 13 and 14. The severity of DED during the last week is scored by indicating it on a 100 mm line. The scale of 0 mm refers to ‘no symptoms’, while 100 mm refers to ‘the worst discomfort’. The score is determined by quantifying the distance between the 0 mm to the indicator where the participant marked.

Quality of life (QoL)

The QoL is examined at visits 1, 13 and 14. Each participant would score the QoL affected by DED during the last week on a scale of 0–6. Score 0 refers to ‘the worst’ and score 6 refers to ‘the best’. The question is ‘During the last week, how was your overall QoL related to DED?’

Schirmer I test (SIT)

The SIT measures lacrimation. It will be examined at the screening visit, visits 1, 13 and 14. The end of the Schirmer strip (BIO Color Tear Test, Bio Optics, Seongnam, Republic of Korea) is folded and then hung on the lateral third of the lower palpebrae. Thereafter, the participants look upwards and keep their eyes closed for a duration of 5 min. When the time is up, the length stained by the tears is measured.

Lactoferrin level in tears

Lactoferrin is an antimicrobial tear protein that represents lacrimal function.³³ It has a robust correlation with clinical symptoms, slit lamp examination, SIT, Rose Bengal stain and TFBUT in patients with severe DED.³⁴ Furthermore, tear lactoferrin analysis is considered to be a more accurate diagnostic method for DED than SIT.³⁵ Recent studies on DED have included tear lactoferrin levels as an outcome, reflecting these features.^{20 36 37}

Tear samples for analysis will be collected at visits 1 and 13. Schirmer strips (BIO Color Tear Test, Bio Optics, Seongnam, Republic of Korea) will be used to collect tears.^{38 39} The collection procedure will be conducted simultaneously with SIT at 21°C and 40%–60% humidity. Throughout the procedure, the investigators will handle the strips with gloves. The procedure that collects tears from the participants is the same as that of the SIT. A total of four strips will be collected as the tear samples from each participant. The collection is performed twice in both eyes of the participant, with a 2 min break between each collection. Thereafter, the strips will be stored in a 1.5 mL Eppendorf tube at 4°C until analysis. The College of Korean Medicine at Dongshin University would conduct a quantitative analysis of tear lactoferrin levels.

Treatment satisfaction

At visit 13, the participants will assess their improvements in DED compared with visit 1. The improvements are scored between 1 and 5. Score 1 refers to a severe aggravation, while score 5 refers to significant improvement.

Safety

The safety of acupuncture and ATD will be monitored. Side effects are any unintended results despite normal use of the interventions. AEs are any undesirable and unintended signs, symptoms or diseases that manifest after the intervention during the trial. Pre-existing medical conditions or diseases will only be considered AE if they worsened after the intervention began. The severity of AE will be evaluated using Spilker and Revicki’s three-level classification: mild, moderate and severe.⁴⁰ The causality will be evaluated using the following six grades: definitely, probably, possibly, probably not, definitely not related and unknown.

Expected AEs

Acupuncture

The expected local AEs of the BA are subcutaneous haemorrhage or ecchymosis lasting more than 2 weeks, peripheral neuritis, pain persisting for more than 2 weeks in the treated area and swelling, redness or itch lasting more than 3 days after treatment. The expected systemic AEs of the BA are circulatory symptoms, including dizziness and tachycardia. The expected psychiatric AEs are headache lasting more than 3 days, anxiety or fear lasting more than 60 hours per event and hyperaesthesia with tingling lasting more than 3 days.^{41 42}

For the IA, the expected AEs include headache, dizziness, nausea, vomiting, visual disturbance due to nerve injury, local infection (redness, swelling, local pain or haematoma with local fever) and local skin irritation (redness, skin inflammation or erosion).^{41 42}

Artificial tear drop (ATD)

For the ATD, the expected AEs are palpebral itch, eye irritation, conjunctivitis, hyperaemia, corneal disorders such as diffuse superficial keratitis, foreign body feeling, eye discharge, ocular pain, blepharitis and palpebral dermatitis.

Statistical analysis

The results would be suggested as descriptive statistics. The changes before and after each intervention in all outcomes will be assessed with the Student’s paired t-test or the Wilcoxon signed-rank test. The results will be presented with 95% CIs. The differences between the two groups would be analysed using either the two-sample t-test or the Mann-Whitney test, depending on the normality.

All AEs would be thoroughly described. The frequency of AEs would be recorded. The incidence of AEs in the two groups would be compared with the χ² test or Fisher’s exact test. Furthermore, a descriptive analysis will be conducted to compare the variations in the severity and types of AEs between the two groups. For other variables, other appropriate analysis methods would be used.

Exclusion from analysis

In the event of a severe breach of protocol, the participant would be disqualified from the analysis. The participant’s results would be evaluated with an intention-to-treat method. The following are examples of severe protocol violations:

1. Infringement of the eligibility criteria.

2. Concurrent use of prohibited medications during the trial.

3. Omission of the primary outcome assessment, either at the beginning or termination of the trial.

4. The intervention was not performed at least 80% of the planned frequency.

Other minor violations will be recorded, along with their severity and reasons. They would be analysed with a per-protocol method when writing the clinical trial report.

Dropout

The trial would be suspended if the following cases occur.

1. Infringement of the eligibility criteria.

2. Serious AEs or challenges in maintaining trial participation as the result of AEs.

3. The participants or their legal representatives request to stop the trial due to dissatisfaction with the treatments.

4. Low compliance of less than 80%.

5. Protocol violation by the investigators or the participants.

6. Cancellation of participants’ consent for this study.

7. Failure to follow-up.

8. Taking unauthorised medications, which can affect the results during the treatment and follow-up periods.

9. Others were determined to be inappropriate to continue the trial by the investigators.

The completion of each participant will be checked. If the intervention is suspended, its reason will be recorded. Although the participant has dropped out, a close-out visit will still be conducted. However, the close-out visit could be skipped if no interventions are performed.

Ethics and dissemination

This study was approved by the institutional review board of Naju Dongshin University Korean Medicine Hospital (Approval No. NJ-IRB-23-5). This study was registered with the Clinical Research Information Service (Registration No. KCT0008563). This study will adhere to the tenets of the Declaration of Helsinki. The investigators will provide detailed information about this study to the patients who are willing to participate and obtain informed consent from them. The study results will be disseminated through publication in a peer-reviewed journal.

Trial status

Ongoing. This study was registered in the registry on 27 June 2023. The first participant was enrolled on 5 July 2023. Recruiting participants is almost complete, but is not yet fulfilled.

Ethics statements

Patient consent for publication

Not applicable.