Clinical Trial Details
— Status: Enrolling by invitation
Administrative data
| NCT number |
NCT03949101 |
| Other study ID # |
YFZX2019001 |
| Secondary ID |
|
| Status |
Enrolling by invitation |
| Phase |
Phase 4
|
| First received |
|
| Last updated |
|
| Start date |
May 8, 2019 |
| Est. completion date |
September 1, 2021 |
Study information
| Verified date |
May 2019 |
| Source |
Shanghai Eye Disease Prevention and Treatment Center |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Investigators are going to conduct a randomized controlled trial that myopic children are
randomly allocated into two groups: combined use of 1% atropine and 0.01% atropine
(experimental group) and 0.01% atropine (control group) in order to explore a better way to
control myopia progression and eliminate adverse effects at the same time, provide reliably
evidence for clinical guideline of atropine use in children, and investigate the mechanism of
atropine on eyes.
Description:
1. Introduction:
1.1 Myopia is a major public health problem around the world At present, myopia has
become a major public health problem. World Health Organization (WHO) statistics show
that there are about 75 million visual impairment patients in China, 2010, and
uncorrected myopia is the first cause (42%). Over the past 50-60 years, the prevalence
of myopia in East Asia such as China has risen rapidly, and the incidence of myopia
shows a progressive trend after the onset of early age. In cities, the prevalence of
myopia among middle school students is over 70%, and among high school graduates, 80-90%
are myopia, of which 10-20% are high myopia. According to the degree of myopia, myopia
above - 6D is defined as high myopia. The harm of high myopia mainly lies in its
complications, some blinding eye diseases, such as macular degeneration and retinal
detachment, are caused by corresponding changes of other tissues in the eye, and the
quality of life of patients with high myopia is seriously affected. Morgan et al.
pointed out in the comments of myopia experts published in Lancet in 2012 that the risk
of complications such as posterior scleral staphyloma, choroidal neovascularization,
retinal splitting and choroidal atrophy, which may cause blindness, has increased
dramatically in a large number of new-onset high myopic people in Asia in the past 100
years. WHO has considered the prevention and treatment of myopia as part of the global
blindness prevention plan, especially in East Asia. Recent epidemiological studies on
ophthalmopathy show that with the improvement of the national ophthalmological service
level, the rate of cataract surgery has increased rapidly, and the proportion of
cataract-curable blindness in the population has continued to decline, while high
myopia-Related retinopathy has gradually become the first irreversible blinding eye
disease in China.
1.2 The overview of high myopia From the occurrence of high myopia to pathological
myopia and the final occurrence of blindness and visual impairment is a long-term
process. First, myopia occurs in early childhood (the age of initial myopia is often
before school age). The growth rate of myopia is significantly higher than that of most
people. It often exceeds - 6D at the age of 15 (graduation from junior middle school).
Secondly, unlike myopia in general children, myopia degree and axis length continue to
progress in adulthood. With the extension of eye axis, posterior choroid and sclera
continue to develop and become thinner. When pathological changes such as chorioretinal
atrophy and choroidal neovascularization occur, they are generally over 50 years old. In
order to avoid blindness and visual impairment caused by complications of high myopia,
it is necessary to start myopia screening and intervention from childhood and
adolescence.
1.3 Studies about atropine for controlling myopia progression In order to reduce the
incidence of high myopia, many myopia control interventions have been carried out in
children and adolescents at home and abroad. Among them, atropine, an M-receptor
antagonist, has been shown to be effective in myopia control in many experimental and
clinical trials in recent years. In ATOM2 study in Singapore, a randomized controlled
clinical trial was conducted. Two years after the use of 1% atropine eye drops,
children's myopia decreased by 0.92D and eye axis increased by 0.4mm compared with the
control group. After 2 years of treatment with 0.5%, 0.1% and 0.01% respectively, the
myopia of children increased by 0.30D, 0.38D and 0.49D, respectively, which were
significantly lower than that of the control group (1.20D). Although 1% atropine eye
drops had myopic rebound effect after discontinuation, the rebound effect disappeared
when the concentration of atropine was reduced to 0.1% and 0.01%.
In the LAMP study in Hong Kong, after one year of treatment with 0.05%, 0.025% and 0.01%
respectively, the myopia of children increased by 0.27D, 0.46D and 0.59D, which were
significantly lower than that of the control group (0.81D), and the ocular axis
increased by 0.20mm, 0.29mm and 0.36mm, respectively, which were lower than that of the
control group (0.41mm). Similar studies at home and abroad have also confirmed that the
use of low-concentration atropine has a good effect on myopia control. At present, in
Taiwan, Hong Kong, Singapore and other Chinese areas, children with high myopia risk and
rapid growth of myopia have been more commonly treated with low-concentration atropine
eye drops for intervention.
The mechanism of atropine controlling myopia has not been fully elucidated. Early
studies suggested that atropine could control myopia by regulating mechanism. However,
McBrien found that atropine could still control the development of myopia after cutting
off the regulating pathway through animal experiments. Therefore, the mainstream view is
that atropine controls myopia by non-regulating mechanism. It may be through the
antagonism of M receptor signaling pathway on the retina or scleral surface to slow down
the development of myopia, but the specific mechanism has not yet been fully elucidated.
Atropine eye drops belong to mydriasis and ciliary paralysis drugs. Long-term use of
atropine eye drops can lead to symptoms such as dilatation of pupils, photophobia and
blurring of close-range objects. These symptoms are closely related to drug
concentration and frequency of use.
1.4 The objectives of our study From previous studies, investigators can find that 1%
atropine has good effect in early myopia control, but its side effects are great,
long-term use compliance is poor, and there is a rebound effect; 0.01% atropine has poor
effect in early myopia control, and the effect of follow-up for one year is not as good
as 0.05%, but the effect of follow-up for two years is equal to 1%, that is, long-term
use effect is good, and there are few side effects. Considering that only 1% or 0.01%
atropine eyedrops (gels) are available in atropine eyedrops approved by the drug
administration, investigators consider whether 1% atropine can be used for six months,
and 0.01% atropine for one and a half years to achieve better early myopia control, late
consolidation efficacy and side effects. In addition, the current clinical studies
mainly focus on diopter and ocular axis. This project will explore the changes of lens
and fundus after atropine treatment, whether there are indicators that reflect the
effect of atropine control earlier and more accurately than diopter and ocular axis, and
explore the target of atropine for myopia control.
2. Research Objectives:
to explore a better way to control myopia progression and eliminate adverse effects at
the same time; to provide reliably evidence for clinical guideline of atropine use in
children; to investigate the mechanism of atropine on eyes.
3. Trail Design a randomized controlled, prospective cohort study, no mask. 3.1 Groups and
Sample size Myopic children aged from 7-12 years old are randomly allocated into two
groups: combined use of atropine sulfate 1% ophthalmic ointment and atropine sulfate
0.01% eye drop (experimental group) and atropine sulfate 0.01% eye drop (control group).
Each group includes 111 participants.
3.2 Medications and usage: 3.2.1 control group: atropine sulfate 0.01% eye drop, once a
day, once a drop, for two years; 3.2.2 Combined application group: atropine sulfate 1%
ophthalmic ointment, once a day for the first week, once a drop for both eyes; and then
once a week, once a drop for both eyes for half a year. Half a year later, atropine
sulfate 0.01% eye drop is used once a day, one drop each time, with both eyes for one
and a half years. Usage: Drop it into conjunctival sac, about the size of a rice grain,
press the nasal root with thumb and index finger for 2 minutes after dripping, and use
it before going to bed. Patients once a week are advised to use it before going to bed
on Friday night.
3.3 Examination 3.1. Examination process: The brief process is as follows: Identity
information registration > height, weight > naked eye vision & wearing vision >
intraocular pressure > accommodation, near vison acuity > mesopic pupil size > slit lamp
anterior segment examination > cycloplegia > Autorefraction and subjective refraction >
IOL-Master, Pentacam, Swept-source optical coherence tomography（SS-OCT，Topcon),
wide-angle optical coherence tomography angiography(OCTA,Zeiss-9000)> fill out the
questionnaire.
3.2 Ophthalmology inspection project operation rules 3.2.1 Vision test: The eyesight
examination used the ETDRS visual acuity chart (LCD backlit lamp, WH0701), the test
distance was 4 meters, and the visual target at 20/20 was the same height as the eye of
the examinee. The recognition time of each visual target is 2~3s; the eye of the subject
is required to be opened normally for examination, and the blinking, hoeing, neck
stretching and peeking are strictly prevented. Vision is converted to a decimal count
record. Visual acuity examination includes two parts: uncorrected visual acuity (UCVA)
and corrected visual acuity (CVA). Children who are not wearing glasses are only
examined by UCVA, and children who wear glasses are required to check CVA after
completing the UCVA test.
3.2.2 Intraocular pressure measurement Intraocular pressure was measured using a
non-contact tonometer (NT-4000, Nidek, USA). Each eye was repeatedly measured 3 times
and averaged, and the difference between each two was less than 5 mmHg. Those with an
intraocular pressure higher than 24 mmHg should be recorded and added for visual field
examination.
3.2.3 Accommodation, near visual acuity: Accommodation is measured using a Royal Air
Force (RAF) near point rule (Harlow, Essex, UK) with best-corrected distance spectacle
correction. Near visual acuity is assessed using best-corrected distance spectacle
correction with a reduced logMAR reading chart placed at 40 cm under well-lit conditions
3.2.4 Mesopic pupil size: measured by automated computer refractometer (KR-8900, Topcon,
Japan) after staying in a dark room for 5 minutes at least. At least 5 pupil size
readings were recorded and averaged.
3.2.5 Ophthalmologist examination Ophthalmologist examinations included anterior segment
slit lamp examination (66 Vision. Tech, Suzhou,China) and ophthalmoscopy examination(66
Vision. Tech, Suzhou,China). To exclude those children with cycloplegia contradictions.
3.2.6 Cycloplegia The cycloplegia procedure is as follows: 1 drop of 0.5% proparacaine
(Alcaine, Alcon) is added to the conjunctival sac of each eye, and 2 drops of 1%
cyclopentolate are added to each eye after 15 seconds. (Cyclogyl, Alcon), 5 minutes
apart. After each drip, ask the participant to press the inner canthus for a few seconds
gently and try to take the head back posture. The last drop of cyclopentolate was
instilled into the conjunctival sac for 30 minutes to check for light reflection. If the
light reflection disappeared and the pupil diameter was greater than 6 mm, cycloplegia
was considered complete. If the light reflection still exists, add a third drop of
cyclopentolate, and re-examine the light reflection and pupil diameter after 20 minutes.
If there was still light reflection, the inspector needs to record this. During
cycloplegia, if the participant has symptoms of ocular discomfort, the ophthalmologist
should carefully examine it and give an appropriate treatment.
3.2.7 Axis measurement The axial measurement was performed using an IOL Master (version
5.02, Carl Zeiss Meditec, Germany). Simulated eye calibration was needed before
measurement. Each eye was measured repeatedly for 3 times, and the difference was less
than 0.02 mm each time. For those who still have large fluctuations in multiple
measurements, the examiner needs to record it.
3.2.8 Measurement of refractive state and corneal radius of curvature (CR) The
refractive status and CR measurements were performed using an automated computer
refractometer (KR-8900, Topcon, Japan), which was performed after ciliary muscle
paralysis. Simulated eye calibration needed before measurement. Each eye was repeatedly
measured three times to average, and if any two results differ by more than 0.5 D, the
measurement needed to be repeated. If there were still significant differences in the
results of multiple measurements, the examiner needed to record it.
3.2.9 Subjective optometry Children who do not wear glasses have a UCVA of less than 0.8
(less than 0.63 for children 6 years of age and younger) or children with glasses have a
CVA of less than 0.8 (children under 6 years of age and below 0.63) need to finish a
subjective optometry after cycloplegia in order to measure the best corrected visual
acuity (BCVA). If the BCVA is less than 0.8 (less than 0.63 for children aged 6 and
under), or the degree of compliance during the examination is poor, the examiner should
record it. If the BCVA is less than 0.8 (children under 6 years of age and below is less
than 0.63), further examination by an ophthalmologist is required to determine whether
the inclusion conditions are still met.
3.2.10 Pentacam (OCULUS Optikgeratic Gmbh, Germany) was examined after cycloplegia.
Measurements include corneal diameter and curvature, anterior chamber depth and volume,
anterior chamber angle, pupil diameter, crystal thickness, etc. Shooting requirements:
Image quality display "OK", crystal thickness value is available. This item is optional
for children under 6 years old.
3.2.11 SS-OCT （Topcon） SS-OCT (DRI OCT Triton, Topcon, Tokyo, Japan) was examined after
cycloplegia. OCT location: Macular + optic disc area. Shooting mode: 12*9 mm 3D scan
mode (4 overlap) / Line scan (64 overlap) + 9 mm radial scan mode (16 overlap, follow up
mode) + optic disc area 9 Mm radial scan mode (16 overlap, follow up mode) + macular
area 7*7 mm 3D scan mode (4 overlap) + optic disc area 6*6 mm 3D scan mode (4 overlap).
Shooting requirements: input spherical error, cylinder, axis length, corneal curvature
radius correction magnification before shooting; image signal of strength 3D scan mode
is not less than 50, radial scan mode is not lower than 60, peripheral image avoids
mirror flip as much as possible. When shooting the disc area, investigators need to
manually adjust the shooting center to the center of the disc. If the image quality is
affected by blinking or eye movement during shooting, participants need to re-shoot. If
participants still can't meet the requirements, participants need to record it. SS-OCT
comes with a fundus color photograph. The shooting position is required to be consistent
with the SS-OCT scanning position and to avoid eyelids, eyelashes and hair occlusion.
Dark areas are avoided in the image, and the image quality is not less than 90. This
item is optional for children under 6 years old.
3.2.12 Wide angle OCT/OCTA (Zeiss-9000) Wide-angle OCT/OCTA examinations were performed
after cycloplegia. OCT/OCTA location：macular + optic disc area. Shooting mode: 12*12mm,
15*9mm angio mode; 16mm loop sweep mode (horizontal and vertical directions) a total of
8 scans. Shooting requirements: communicate more with the subject; the forehead and chin
must be close to the instrument. If the image quality is affected by blinking or eye
movement during shooting, participants need to re-shoot. This item is optional for
children under 6 years old.
3.3 Questionnaire The questionnaire is about the time children spend on outdoor
activities and near work.
4. Follow up 4.1 Frequency Combined use of 1% atropine and 0.01% atropine group is followed
up after first week, then every three months. 0.01% atropine group is followed up every
three months.
4.2 Examinations: 4.2.1 First week follow up for combined use group: accommodation, near
vison acuity > mesopic pupil size > Autorefraction and subjective refraction >
IOL-Master, Pentacam, Swept-source optical coherence tomography（SS-OCT，Topcon),
wide-angle optical coherence tomography angiography(OCTA,Zeiss-9000 4.2.2 Every three
months: accommodation, near vison acuity > mesopic pupil size > slit lamp anterior
segment examination > cycloplegia > Autorefraction and subjective refraction >
IOL-Master, Pentacam, Swept-source optical coherence tomography（SS-OCT，Topcon),
wide-angle optical coherence tomography angiography(OCTA,Zeiss-9000
5. Statistical Analysis 5.1 Descriptive statistics A． Continuity variables: sample size,
mean, standard deviation, minimum, maximum, quartile B． Classification variable or grade
variable: frequency distribution 5.2 statistical methods A. Continuous variables: The
normality test uses the Kolmogorov-Smirnov test. If the normal distribution is
satisfied, the t test or one-way ANOVA is used; if the normal distribution is not
satisfied, the Mann-Whitney U test or the Kruskal Wallis test is used. The two-two
comparison between groups was performed using the Bonferroni method.
B. Categorical variable: chi-square test. C. Correlation analysis: simple linear
regression and stepwise multiple linear regression, using nonlinear regression if
necessary.
5.3 Statistical significance All differences were statistically defined as P < 0.05
(bilateral) 5.4 Subgroup analysis Subjects will be assigned to different subgroups for
subgroup analysis based on age, gender, diopter, axial length, fundus structure, and
functional changes.
5.5 Interim analysis Baseline data (2019) and follow-up data are used for analysis and
reporting.
6. Ethical issues 6.1 Ethics committee The study will be carried out after the approval of
the Shanghai General Hospital Ethics Committee and strictly abide by the Helsinki
Declaration.
6.2 Protect the privacy of participants In order to protect the privacy of the children
and adolescents in the test, when the research materials are provided to other
organizations, the subject code or initials should be used instead of their ID number or
real name. In addition, the researcher and the relevant staff involved in the research
must keep the privacy information of the children and adolescents in the test
confidential.
6.3 Informed consent The informed consent form will be distributed to the children and
adolescents participating in the study and their parents or guardians after approval by
the ethics committee. For children and adolescents and their parents or guardians who
voluntarily agree to participate in the study, parents or guardians are required to sign
an informed consent form prior to the baseline study. Before signing the informed
consent form, the researcher should fully introduce the content of the study, the
benefit of the subject and the potential risks, and confirm that the children and
adolescents and their parents or guardians fully understand and voluntarily sign the
informed consent form. When signing the informed consent form, the parent or guardian
has sufficient time to consider and has the right to ask questions. For questions from
parents or guardians, the researcher needs to provide adequate answers. For parents or
guardians who agree to sign an informed consent form, the investigator signs the
informed consent form after the informed consent is fully explained and states the
relationship with the child and adolescent. Informed consent is in duplicate, one of
which is kept by the parent or guardian and the other is kept by the researcher. During
the research process, if there is a major change in the research content, the revised
informed consent form should be sent to the ethics committee for approval. After the
approval, the researcher must fully communicate with the children and adolescents and
their parents or guardians, and confirm that they agree to continue to participate in
the study and re-sign the informed consent form.
7. Funds and insurance funds Before the start of the study, funds were raised by the
Shanghai Eye Disease Prevention and Treatment Center.
