This trial is designed in accordance with "Ethical Review of Biomedical Research Involving Human Subjects" issued by the Ministry of Health of the People's Republic of China. The implementation of this project has been reviewed and approved by the Ethical Review Committee of Beijing University of Chinese Medicine(4 June 2020, Approval Number: 2020 BZYLL0306). Written informed consent will be obtained from each subject and his/her guardian.
This study will be a prospective, multicenter, randomized controlled clinical trial. The included subjects (n=1140) will be randomly assigned to the experimental (n=760) and control (n=380) groups in a 2:1 ratio. The aim of this study is to objectively evaluate the clinical efficacy of the guided meditation of vision training for adolescent myopia. This report will be compiled according to the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) 2013 Statement ‘Defining Standard Protocol Items for Clinical Trials’ (Fig. 1).
In this trial, 1140 primary and secondary school students with simple myopia will be recruited from 27 schools in Sichuan and Hunan provinces or other cities with relatively uniform schooling conditions. The main points for the diagnosis of simple myopia in China's “Myopia Prevention and Treatment Guidelines”  will be used as a reference standard for recruitment: near visual acuity is normal , distance visual acuity is less than 1.0 (5.0 by the Mucosal method), there are no pathological changes in the fundus, the progression is slow, vision can be corrected to normal with appropriate lenses, while other visual function indicators are mostly normal; and the subject recruited meet the quantitative criteria for myopia according to the “White Paper on Myopia Prevention and Control” of the International Myopia Institute (IMI)  : myopia diopter ≤ -0.50D.
(1) ≥8 years old，and≤18 years old;
(2) Meeting the diagnostic criteria for simple myopia, with -6.00 D ≤refractive state ≤ -0.50 D, astigmatism ≤ 1.50 D, and having a normal vision after optically corrected.
(3) Able to cooperate to complete the study.
(4) The subjects and their guardians must both voluntarily sign an informed consent form.
(1) Those who have comorbidities or complications of other eye diseases, such as glaucoma, amblyopia, eye infections, etc.
(2) Those who have comorbidities of very severe heart, brain, liver, kidneys, hematopoietic system diseases and neuropsychiatric diseases, or systemic diseases that may affect the progression of myopia.
(3) Those who have had eye surgery or a history of eye trauma;
(4) Those who have comorbidities of hearing abnormalities;
(5) Those who are unable to cooperate with the study for personal or family reasons;
(6) Those who refuse to sign an informed consent form by himself/herself or any of his/her guardians.
Subjects have the right to withdraw from the study, as defined in the informed consent document, or to "drop out" if they do not explicitly withdraw from the study but are no longer undergoing training and testing. The reason for withdrawal should be understood as far as possible, and recorded. For example, (1) perceiving lack of efficacy; (2) intolerance of certain adverse effects; (3) inability to continue the clinical study; (4) or lost to follow-up without explanation. Case record forms for withdrawn subjects will be kept and the results of the last trial will be considered final. The data on the clinical efficacy and adverse effects of the focused vision-guided meditation training will be fully analyzed.
The investigator will decide to terminate the study of a subject who has been enrolled in the study that the subject is unfit to proceed the study. For example, (1) the subject develops certain comorbidities and complications under study; (2) the subject is unfit to continue the study due to unexpected events or specific physio-pathological changes during the study. (3) The subject meets the criteria for cure in less than 30 days, the study may be discontinued early if the subject so desires.
Those who with any of the following should be excluded: (1) subjects with incomplete case information that affects the analysis of the trial results; (2) subjects with poor compliance during the trial due to subjective or objective factors of their own or family members; (3) subjects who uses other interventions for myopia outside the protocol.
The random sequence will be designed and processed by the research team of Beijing University of Chinese Medicine. SPSS 20.0 (SPSS Inc., Chicago, Illinois, United States) software will be used to generate serial numbers for the subjects; the 1140 random numbers and the allocation sequence table with the unit are saved as blind codes. Subjects will be assigned to the experimental (n=760) and control groups (n=380) at a ratio of 2:1.
The randomization lists will be kept in opaque envelopes by the non-investigator on the team which are ordered, identical, and sealed with adhesive.
The participants will be consecutively enrolled and distributed into experimental and control groups by researchers according to the randomized sequences generated who will not participate in assessing outcomes. Another group of researchers responsible for analyzing results will be blind to the grouping of subjects and will not participate in the treatment. The executors of this trial and subjects will not be blinded to the treatment assignment.
Explanation for the choice of comparators
The choice of the comparator is based on the current treatment of myopia in clinical.
The vision acuity training of this study is conducted in the schools, and school leaders are fully aware of this project, support and cooperate with the research work. Relevant teachers will be designated by the schools to be responsible for this project with respect to the specific matters concerned. The study will be conducted in two phases over a period of 8 months, with a training period of 30 days in each phase and a follow-up of 3 months. No interventions will be conducted during the treatment period and follow-up period. One visual acuity examination will be performed in each of the two phases at months 1, 2, and 3 of the follow-up.
Two sets of vision acuity training movement verbal commands will be applied in the experimental group. In order to facilitate the subjects to follow the verbal commands in a uniform, standardized way, the related audio and standard movements will be recorded.
The first set of audio and video content are relatively rich, lasting about 1 hour, and the audio and video will be projected in the classroom on the first and eighth day of training, with the subjects following the verbal commands and the movement demonstrations in the video. Visual training tutors (trained in procedures and methods) will be responsible for audio and video presentations.
The second set of audio and video content are relatively concise, approximately 15-20 minutes in length, and the subjects will be trained under the schools’ uniform deployment for the remaining 28 days.
Due to the uninterrupted daily vision acuity training for 30 days, it is recommended to use the last self-study class at the schools to ensure that the students’ normal studies are not interrupted; students will still be required to come to get trained at their school or a designated location confirmed with the schools on Saturday.
The first set of audio and video training exercises will be projected in the classroom by the vision acuity training tutor, and the students will be guided by the audio-visual movements and verbal commands to perform the following exercises.
(1) Abdominal breathing: Inhale through the nose, exhale through the mouth, bulge abdomen while inhaling, tighten abdomen while exhaling; start doing abdominal breathing when hearing the words of “adjust your breath and inhale.
(2) Eye-warning exercise: Rub your hands more than 30 times, cover your eyes with the palms, place thumbs on the temples, clasp four fingers on your forehead, and leverage the temperature of your palms to warm eyes; after the temperature gradually dissipates, use Yuji acupoints of the palms to gently press your eyes 5 times, with moderate intensity; start eye-warning exercise when you hear the words "get ready to press "and" quickly rub your hands" during training.
(3) Healthy vision exercise: Press both hands palms on your ears, place fingers on the back of your head; do not move the palms, and use fingers to gently tap the back of your head. During the training, when you hear "healthy vision exercise", start doing it.
(4) Activate Shixuan acupuncture point: Tap your fingers on your palm, shake your palm, and make an arrow shape.
(5) Play the "1-Audio", turn off the lights in the classroom, close the curtains, and try to create a dark environment. Remain quiet the entire time. Close your eyes until the audio says to open them. Follow the audio to imagine and do movements, e.g., "Use the fingertips of one hand to gently touch the center of the palm of the other, and then shake your hand vigorously.
(6) Play the "C-video", a video about lotus flowers to stimulate the imagination and match the 2-Audio with the images that appear in the video. For example, "On a calm lake, you can definitely see the vivid color of the lotus flowers and the greenish-blue leaves of the lotus ......."
(7) Demonstration and correction. Make a hollow bowl shape with your hands (thumbs on the second knuckle of your index finger) and clasp them over your eyes, with palms facing your eyes.
(8) Play "2-Audio" and do the eye stretches: Close your eyes and move them from front to back as if a train is moving back and forth in a tunnel.
(9) Play "3-Audio" and listen to the audio with your hands in a hollow bowl shape over your eyes the whole time. When the audio says "in", put pressure on your eyes for one second, and when it says "out", relax your eyes and perform the related imagery and actions. When the audio say "pull" in future exercises, let your eyes enter a state just like going into a tunnel, hold for 1 second, and then relax.
(10) Play "D-Video (Ball of Light)" to stimulate imagination and introduce natural light.
(11) Play "4-Audio" to build up the confidence of myopia sufferers to restore their eyesight.
The above training will be repeated on the 8th day to intensify the effect, for 1 hour.
Daily vision acuity training
Guided by the second set of audio and video movement verbal commands, the subjects perform self-rehabilitation exercises.
(1) Ocular exercises: keep body and head still, torso upright, move only eyes, four 8-tempos per part.
In the first part, both eyes look up and down to the left. In the second part, both eyes look up and down to the right. In the third part, both eyes look to the left to the right. In the fourth part, both eyes turn clockwise. In the fifth part, turn both eyes counterclockwise. In the sixth part, close your eyes hard and then open them to look up. In the seventh part, close your eyes for a moment to control the time.
(2) Eye-warming exercises: same movements as before, 12 movements per day.
(3) Vision acuity exercise: same movements as before, 24 movements per day.
(4) Character card stretching: 10 minutes of training, with results recorded on an observation chart. Character cards (Chinese characters of different sizes) are placed on a well-lit wall at the subject's eye level. Find the farthest place where you can see the card clearly, that is, about 10-15cm back where you cannot see the card clearly. Let your eyes stretch 6 times for 1.5 seconds each (eye movement, stretching backwards), without blinking, stare at the characters for 10 seconds, step back 15cm, and repeat the above movements until you are unable to see the location of the character card after stretching. If the training time is less than 10 minutes, switch to a second character and repeat the above steps; if it has reached 10 minutes, end the exercise and take notes.
The control group will be given Chinese eye exercises in the first stage of the trial. On the first day and the eighth day of the trial, the school teachers who has received training in Chinese eye exercises will give instructions on finding the positions of acupoints, massage intensity, direction and frequency according to the standard Chinese eye exercises Assessment Form to ensure that the students can perform the eye exercises independently and with high quality. For the remaining 28 days, subjects will be in a uniform classroom for 15-20 minutes of daily Chinese eye exercises. Acupoints: Jingming, Zanzhu, Yuyao, Tongziliao, Sizhukong, Taiyang, Chengqi, Sibai.
After the completion of the first phase of the randomized controlled study, data will be collected and compared between the vision acuity training group and the Chinese eye exercises group. If the data show that the vision acuity training is not significantly better than the Chinese eye exercises, the trial will be terminated; if the data show that the vision acuity training is significantly better than the eye exercises, the trial will enter the second phase, and the 3-month follow-up period of the first phase will be used as an elution period before the second phase. In the second phase, the experimental group will end the trial, and the control group will switch to a 30-day vision acuity training method based on meditation and concentration, with a follow-up period of 3 months.
The subjects in this study are adolescent students with simple myopia and no other comorbidities of chronic diseases. If the subjects need to combine medication due to cold or other reasons, they should be recorded promptly.
Basic Information Collection
Information will be collected from the subjects before the start and after the trial is completed, and the main information is as follows.
a. Basic information: age, nation, grade, height, weight, family history of myopia, parents' high myopia, etc.
b. Myopia: duration of myopia, possible causes of myopia, naked eye visual acuity, corrected visual acuity, diopter of both eyes, astigmatism and so on.
c. Time allocation for daily activities: including close range activities (<50 cm): such as drawing, homework, reading and using electronic screen terminals such as mobile phones; outdoor activities: including playing outdoors, cycling, hiking, etc.
Primary observation indexes
vision acuity training aims to improve the visual acuity of the naked eye that affects life and work, so this study will use distance visual acuity as the primary observation index. After the start of the training, visual acuity tests will be performed before and after daily training for the first 7 days; after 7 days of training, visual acuity tests are performed once a week; and the tests will be performed at the 1st, 2nd, and 3rd months of follow-up.
The specification for visual acuity testing is based on the “Expert Consensus on Workflow of Myopia Screening in Children and Adolescents (2019)” . Measurements are taken under adequate lighting conditions and the subjects are measured 5 meters away from the visual acuity meter. All visual acuity examinations in this study will be performed by a regular person who will not undergo vision acuity training or clinical examinations. Specific details of subjects will be not disclosed to this measurer.
Secondary observation indexes
Ocular symptoms, diopter and astigmatism are secondary indexes. Ocular symptoms will be evaluated before and after 30 days of training, respectively. Diopter will be obtained from the subjects after testing at the same hospital before and after the training.
a. Ocular symptom scores are developed based on the “Visual Fatigue Test and Evaluation Method (VFTEM)” and principally cover eye fatigue, dryness, pain, visual double vision, neck pain, thought disorders, and lags in response.
b. Collective Insufficient Symptoms Survey (CISS): the CISS is a valid tool in quantifying near visual acuity symptoms in adolescents  and consists of 15 items, each with five options of varying degrees, scored as follows: never (0), rarely (1), sometimes (2), often (3) and always (4). The sum of the 15 items’ scores (ranging from 0 to 60) is the total score.
All of the above information and scales need to be completed with the help of the subject student's parents and professional staff.
Diopter and astigmatism
The diopter (after pupil dilation by tropicamide) and astigmatism will be obtained from the students after examination at a local first-tier public hospital or public eye hospital accompanied by their family members, and the data will be recorded in the entry of "Information Collection - Visual Acuity".
Data Entry and Statistical Analysis
A paper version of the Case Report Form will be developed for data collection. The data will be collected using standardized entry terms and structured registration contents as much as possible, which will facilitate post-processing and analysis of the data and minimize the burden on the researcher. According to the original observation records of the subjects, the data manager will load the data into the case report form in a timely, complete, correct and clear manner. When amending a case, the original record should be clearly visible, and corrections should be signed and dated by the investigator.
Data entry and storage
The paper-based data should be entered by a dedicated data manager using a dual-track entry to reduce the error rate, and any problems or unexpected matters found in the entry process should be registered and reported promptly so that problems can be dealt with quickly. Observation forms should be subject to random inspections at the end of data entry to understand the quality of the entry and to analyze and address any problems. Once data entry is completed, all original case report information should be kept. The original case report forms, after completion of data entry and verification as required, should be filed in a numbered order, and a dedicated person should be assigned to manage the files and complete the search directory, etc. Also, the entered data should be backed up regularly to prevent loss of data and other unexpected occurrences. Particular attention should be paid to the security of data storage and the protection of the privacy of the subjects and related personnel. All research documents will be stored in special filing cabinets that are locked to ensure the security of the stored documents. In any case, only authorized staff will have access to the data.
The sample size of this superiority trial will be estimated based on the past research and early observations. According to the references and professional judgment, it is assumed that the effective rates of the control group and the experimental group will be 40% and 51%, respectively. Under 20% dropout rate, if the two-tailed α=0.05 and β=0.1（test efficacy of 0.9）, experimental group: control group = 2:1, and the dropout rate is 20%, then it will be calculated through the following formula:
It’s finally confirmed there will be 1140 cases in total, with 760 cases in the experimental group and 380 cases in the control group.
Statistical analysis using SPSS 20.0 will be performed, and data management software will be used to construct the database. Dedicated staff will be assigned to oversee the management of electronic data, and a clinical research team will be deployed for data entry, validation, reporting, and answering questions. Measurement data will be described statistically using mean ± standard deviation and counts will be described statistically using frequency. Measurement data conforming to a normal distribution will be compared between groups using two independent samples t-test in randomized controlled study and paired samples t-test in pre-post controlled study. P ≤ 0.05 will be considered a statistically significant difference.
Primary and secondary observation indexes will be analyzed by the superiority test depending on the treatment, using Per Protocol Set (PPS) and Full Analysis Set (FAS) datasets. The indices of safety evaluation will be analyzed using the Save Set (SS) dataset.
A Data Monitoring Committee（DMC）will be instituted during the study, which is consisted of project researchers, ethics committee members, statistical analysis personnel, and implementation teachers. Who have no competing interests. It is the responsibility of the DMC to review the trial design and trial documentations prior to the commencement of the study to identify issues that may affect data analysis or patient safety. And identify problems during project implementation and take timely intervention measures. The collected data will be checked again at the end of the study.
In case of any adverse event, subjective discomfort (dizziness, nausea, etc.) or abnormal laboratory parameters of subjects should be treated seriously, the cause should be carefully analyzed, and immediate measures should be taken to maintain the safety of the subject's life. Procedures: Detailed records should be made on the case report form, and retesting should be performed within 24 hours, 7 days, and 14 days as appropriate. Records of persistence, prognosis and disappearance should be kept.
Treatment of serious adverse events: If there is any serious adverse event in the course of the study, it must be reported immediately to the ethics committee of the organization, and the sponsor, and the "Serious Adverse Event Report Form" must be filled; if there is a serious adverse reaction, it should be reported to the National Medical Products Administration within 24 hours, and the contact person should be notified according to the telephone number and home address listed in the case report form.
(1) Treatment measures: When the subject has an accident or emergency, the investigator should make corresponding treatment according to the experimental therapy and its symptoms, and pass the treatment results to the clinical examiner. The institute should record the treatment and results on the case report form and sign it.
(2) Follow-up of unmitigated adverse events: all adverse events should be tracked for their cause until they can be appropriately resolved.
Frequency and plans for auditing trial conduct
The DMC and the ethics committee will meet annually during the trial to review the conduct of the study, Good Clinical Practice(GCP), compliance with the protocol standard operating procedures and applicable regulatory requirements.
Quality control is crucial to the reliability and accuracy of the research results, mainly conducted over the implementation process and data management aspects to achieve quality assurance. Quality control principally covers the following aspects: 1. investigator training: before the implementation of the study, a detailed research protocol and the SOPs should be developed, participants of the study should be trained and documented; 2. data quality control: investigators should be trained, and the way in which data are collected, the list of all data elements and definitions, and the treatment methods for missing values, invalid entries, incorrect entries, and logically inconsistent data should be clarified during training. To prevent data bias, data entry and statisticians should be masked during the trial.
This study will fully comply with the relevant provisions of the data protection legislation. All appropriate and necessary precautions will be taken to keep medical data and personal information permanently confidential.