The main objectives of this study are twofold: (1) to observe the clinical efficacy of press-needle therapy in patients with GPCI and provide feasible and affordable press-needle treatment for them and (2) to investigate whether press-needle therapy improves the visual function of patients with GPCI by regulating eye blood circulation.

This multicenter, sham-controlled, blinded, randomized trial of press-needle therapy (Seilini Ltd) for GPCI will be executed in the Mianyang Central Hospital (Sichuan, China), the Mianyang Hospital of Traditional Chinese Medicine (Sichuan, China), and the Mianyang Wanjiang Eye Hospital (Sichuan, China). The study time schedule is presented in Table S1 in Multimedia Appendix 1.

The trial protocol was approved by the Science and Technology Department of Sichuan Province (approval no: 2021YJ0443), the National Natural Science Foundation of China for the Youth (approval no: 82305324), Mianyang Central Hospital Incubation Subjects (approval no: 2020FH07), and the Medical Ethics Committee of the Mianyang Central Hospital (approval no: S2021046 (02)). It has been registered with an identifier (ChiCTR2300067862) with ClinicalTrials. The study will be strictly conducted according to the principles of the Declaration of Helsinki, as well as Good Clinical Practice (GCP) guidelines. The trial will be performed in accordance with the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) checklist [10]. Signed informed consent will be obtained from all patients or their legal guardians by specific researchers prior to beginning the trial. If there are changes to the eligibility criteria, outcomes, or analyses, a new version of the protocol will be submitted to the Medical Ethics Committee of the Mianyang Central Hospital for approval.

In total, 192 patients with GPCI recruited from the Mianyang Central Hospital, (Sichuan, China), the Mianyang Hospital of Traditional Chinese Medicine (Sichuan, China), and the Mianyang Wanjiang Eye Hospital (Sichuan, China) will participate in this study. All patients will be screened by specialists and acupuncturists according to the diagnostic criteria in the European Glaucoma Society Terminology and Guidelines for Glaucoma [11]. The TCM syndrome of kidney deficiency and blood stasis will be diagnosed based on guidelines delineated in the Clinical Research Guideline of New Investigational Drugs in Traditional Chinese Medicine [12].

Participants who meet the following inclusion criteria will be eligible for the study:

Participants who have any of the following conditions will not be eligible to participate:

The TCM syndrome of kidney deficiency and blood stasis will be based on guidelines delineated in the Clinical Research Guideline of New Investigational Drugs in Traditional Chinese Medicine [12]: primary signs and symptoms include blurry visual acuity, narrow visual field, and eye distension, while secondary signs and symptoms include dry eye, limp aching lumbus, and knees.

The conditions for a diagnosis of kidney deficiency and blood stasis are the presence of at least 2 or more primary signs/symptoms and at least 2 or more secondary signs/symptoms. The necessary condition is a dark-purple tongue and a thready deep, stringy, or unsmooth pulse. The investigators must receive training in standard operating procedures (SOPs) for examining TCM symptoms. They will then conduct a symptom assessment survey using the TCM Symptom Score Scale (Figure 1) for each participant.

Potential participants with GPCI were recruited from the Mianyang Central Hospital (Sichuan, China), the Mianyang Hospital of Traditional Chinese Medicine (Sichuan, China), and the Mianyang Wanjiang Eye Hospital (Sichuan, China). We used the internet, hospital announcements, and posters to provide a hotline calling for potential volunteers. If patients were interested in our study, researchers informed them in detail of the purpose and content of the research and the benefits and risks of participating.

After screening, participants meeting the inclusion criteria will be enrolled. Frequent follow-up phone calls are an important aspect of adherence monitoring. Every participant will have the right to withdraw from the trial at any time. Furthermore, it will be obligatory for all subjects to sign an informed consent document prior to commencement of the trial.

Baseline evaluation will be conducted for eligible subjects. All eligible patients will be stratified according to early, moderate, and advanced stages of glaucoma [14]. Patients with early glaucoma exhibit early glaucomatous visual field impairment, as characterized by a mean deviation (MD) of >–6 dB. Conversely, patients with moderate glaucoma present a moderate glaucomatous visual field loss, defined as MD≤–6 to ≥–12 dB. Patients with advanced glaucoma experience advanced glaucomatous visual field loss, defined as MD<–12 dB. SAS software will be used to automatically generate a set of random numbers ranging from 001 to 192. These numbers will be further classified into 3 ranges based on the disease stage. The early stage will incorporate random numbers from 001 to 064, the moderate stage will encompass numbers from 065 to 128, and the advanced stage will comprise numbers from 129 to 192. Following stratification, the participants will be assigned randomly to either an experimental group or a control group in a 1:1 ratio. Random numbers will be inserted into identical envelopes of equal dimensions, which will then be sealed to ensure concealment of group allocation and minimize the risk of selection bias. The random sequence allocation will be preserved and withheld from the investigators, statisticians, and outcome assessors to avoid detection bias.

Safety assessments using 3 routine tests (blood, urine, and stool), electrocardiography, liver function tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP], gamma-glutamyl transferase [GGT], and serum total bilirubin [TBIL]) and kidney function tests (blood urea nitrogen [BUN], serum creatinine [SCr], uric acid [UA], and β 2-microglobulin) will be measured at baseline and 4 weeks thereafter.

A research assistant will monitor and record data regarding adverse events (AEs) associated with interventions, which may include infection, hematoma, severe pain, needle breakage, bleeding, heart palpitations, fainting, and headaches, in case report forms (CRFs). Severe AEs will be managed by emergency medicine physicians or acupuncturists. Additionally, any significant AEs will be reported to the Ethics Committee of the Mianyang Central Hospital.

Thorough recording of all data will be performed on CRFs subsequent to in-person visits or telephonic communications with participants. The same examiner will assume responsibility for conducting the examination of every patient during each assessment. Baseline measurements, demographics, medical history, and prior medications will only be gathered during the initial visit. Primary outcomes, secondary outcomes, and safety indicators will be gathered at baseline and 4 weeks thereafter. Following adequate training and successful completion of a test, 2 data entry clerks will thoroughly review the CRFs and subsequently enter the collected data independently. Participants’ personal information will be kept confidential the same way as their medical histories in the hospitals before, during, and after the trial. The absence of a data monitoring committee in this study is justified by the anticipated low incidence of AEs and the limited participant numbers at each center. The Epidata 3.1 statistical application will be used for data entry. Subsequently, the collected data will be transferred to IBM SPSS 22.0 statistical software for the purpose of analysis.

The sample size calculation was based on previous studies. The basis of optic nerve protection effectiveness is 70% [16,17]. We hypothesized an 80% effective rate of the basis of optic nerve protection + press needles for GPCI in a larger sample size. According to the sample size of the estimation formula [18], α=.05 and β=0.10 in a 2-sided test, P₁=.67 and P₂=.87, 2-sided u_α/2=u_0.05/2=1.96, and 1-tailed u_β=u_0.1=1.282. We substituted these values into the following formula:

This resulted in n¹=n²=79.02, that is, approximately 80 cases each in the experimental and the control group, or 160 cases in both groups. To account for a 20% dropout rate, the calculation 160 + (160 × 20%) = 192 suggested that 192 patients be recruited.

Statistical analysis will be conducted independently by statisticians. The data will be presented as means (SDs). IBM SPSS 22.0 statistical software will be used. All statistical tests will be 2-sided tests, and the limit for statistical significance will be set at P<.05. The chi-square test will be performed for categorical variables, the independent Student t test will be used for measurement data, and the rank-sum test will be used for grade data. To evaluate the covariate balance, baseline characteristics will be summarized and compared between the experimental group and the control group using simple descriptive statistics.

Due to the expected low number of missing data, we will deal with missing data by transferring the last data item to the final dataset. This participant's data will be invalidated in the full analysis set (FAS), and this case will not be included in the per protocol set (PPS). Finally, the statistical significance of the FAS and PPS will be analyzed. A consistent statistical significance will indicate a significant difference.

Acupuncture is a major treatment in TCM, and studies have shown that acupuncture can protect the optic nerve in patients with glaucoma [20]. The press needle is a new kind of acupuncture device that can create a more lasting stimulus and simpler operation, while resulting in less pain, with the therapeutic effect of cumulative treatment characteristics. At present, press-needle therapy is widely used in various clinical diseases and has achieved satisfactory therapeutic effects [9,21]. Acupuncture is effective in protecting visual function in glaucoma [22]. Press-needle embedding can improve the deteriorating vision and shrinking visual field of patients with optic nerve atrophy and increase clinical efficacy [23]. Abnormal blood flow is an important factor in optic nerve damage in glaucoma [24], and acupuncture can modify the blood flow parameters in glaucoma [7]. Clinically, we have widely used press-needle therapy for glaucoma visual function protection and achieved good clinical efficacy, and we have further found that press-needle therapy can improve ocular circulation in patients with glaucoma. However, the quality of evidence supporting the use of press-needle therapy for GPCI is limited due to methodological limitations. Therefore, it is necessary to explore the effect of press-needle therapy on visual function and eye blood circulation in patients with GPCI. The double-blind method reduces the differential assessment of outcome events and improves subject adherence. Previous studies have shown that press needles and sham press needles (lacking the needle element) enable effective double-blind settings for acupuncture clinical studies [25]. Therefore, sham press needles were chosen as the control intervention for this study.

Due to the unique nature of glaucoma, patients experience progressive optic nerve damage as the disease progresses. To avoid violating medical ethics and reduce the rate of patient detachment, methylcobalamin has been chosen as the basic optic neuroprotective drug for the experimental and control groups in this study. In addition, to observe the effect of press-needle therapy on GPCI of different disease severities, participants will be classified as early, moderate, and advanced based on their visual field defects.

This study is designed as a double-blind, placebo-controlled trial. To guarantee the quality of the study, its design and execution will be strictly performed with proper quality control. A training session for each center will be held to explain the detailed study protocol, the diagnosis of the TCM syndrome pattern, and the SOPs. The same investigator will be responsible for the examination of each patient at different times. All indicators will be assessed by independent assessors. The principal investigators, statisticians, and outcome assessors will be blinded to the treatment assignments until the database is locked.

This is the inaugural clinical trial protocol devised by our team to investigate the potential mechanisms of acupuncture for patients diagnosed with GPCI. We have selected eye blood circulation as the entry point for this study. The trial will be conducted in accordance with rigorous methodology. For example, patients with GPCI will be randomly assigned to 2 groups. For the control group, a nonpenetrating sham apparatus, similar in appearance to acupuncture needles, will be used to achieve blinding. Furthermore, each participant will be requested to provide feedback on their experience following the acupuncture session, with a view to evaluating the efficacy of the blinding process. The data will be subjected to statistical analysis in a blinded trial, with the intervener, efficacy assessor, and statistician all acting independently. However, it is not possible to eliminate gender bias in the randomization process. Consequently, to guarantee the reliability of the data, it is necessary to expand the sample size further.

In conclusion, the purpose of this research is to verify that press-needle therapy can effectively improve visual function and eye blood circulation in patients with GPCI. The outcome of this study will provide evidence-based data for the use of press-needle therapy to treat GPCI accompanied by liver-kidney deficiency, blood stasis, and fluid retention syndrome, thereby providing a new avenue for the treatment of GPCI.