Clinical Trials in Pediatric Ophthalmology

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Early Treatment for Retinopathy of Prematurity (ETROP)

Arch Ophthalmol 2003;121:1684 | Trans Am Ophthalmol Soc 2004;102:233 | Arch Ophthalmol 2006;124:24 | Br J Ophthalmol 2006;128:663 | Arch Ophthalmol 2010;128:663.

Objectives

The goal was to determine if early treatment with laser in retinopathy of prematurity (ROP) in high-risk eyes improves visual and anatomical outcomes and the grades most likely to benefit.

Design

Prospective clinical trial including infants with bilateral high‐risk pre threshold ROP (birth weight less than 1251 grams). The infants had one eye randomly assigned to laser treatment with peripheral retinal ablation. The fellow eye was managed conventionally, and either treated at threshold ROP or observed if the threshold was never reached. In patients with asymmetrical disease, the high‐risk, prethreshold eye was randomised to earlier treatment or to conventional management. These infants were examined every fortnight, beginning at four to six weeks of age.

Inclusion criteria were pre-threshold ROP defined as 1) Zone 1, any stage (when less than threshold) 2) Zone 2, stage 2 with plus disease 3) Zone 2, stage 3 (when less than threshold).

Main outcome measures

Failure of treatment, defined as unfavourable structural outcome (1) a posterior retinal fold involving the macula, (2) a retinal detachment involving the macula or (3) retrolental tissue or “mass” obscuring the view of the posterior pole.

Results

From 2000 to 2002, Data were available on 339 of 374 (90.6%) surviving children. Unfavourable structural outcomes were reduced from 15.4% in conventionally managed eyes to 9.1% in earlier laser-treated eyes. There were no side effects.

Conclusions

The benefit of earlier laser treatment of high‐risk prethreshold ROP on retinal structure, and has no side effects. Furthermore, earlier treatment improves the chance for long‐term favourable retinal structural outcomes in eyes with high‐risk prethreshold ROP.

Pearls for clinical practice

Earlier laser treatment is beneficial on high‐risk prethreshold ROP.


Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity (BEATROP) 2008

Arch Ophthalmol 2008;126:1161 | N Engl J Med 2011;364:603.

Objectives

The goal was to determine if anti-VEGF would help retinopathy of prematurity and which grades would most likely benefit.

A randomised clinical trial was performed to compare intravitreal anti-VEGF to conventional laser therapy for ROP.

Design

Prospective, controlled, randomized, stratified, multicenter trial. Infants with a birth weight less than 1500 grams or a gestational age of less than 30 weeks were recruited and randomised to receive bilateral bevacizumab monotherapy (0.625 mg in 0.025 ml) vs. conventional laser therapy. These infants were examined beginning at four weeks or 31 weeks of post-menstrual age (whichever was later).

The inclusion criteria were stage 3+ disease in zone 1 or posterior zone 2, and bilateral involvement.

Main outcome measures

Failure of treatment, defined as recurrence of neovascularisation in one or both eyes arising from the retinal vessels requiring re-treatment by 54 weeks age.

Results

From 2008 to 2010, 150 infants were randomised to receive bilateral bevacizumab monotherapy (0.625 mg in 0.025 ml) vs. conventional laser therapy. Bevacizumab injection could be repeated based on the ophthalmologist’s discretion. Retinopathy of prematurity recurred in 4 infants in the bevacizumab group (4%) and 19 infants in the laser group (22%). In the bevacizumab group, a significant treatment effect was found for zone I retinopathy of prematurity but not for zone II disease

Limitations

The failure rate of laser treatment in this study was higher than in the ETROP study. If a similar success rate with laser had been achieved, it is less likely that the results for Zone 1 disease would have been significant. The study was not powered to assess safety outcomes, but 71% of the infant deaths in this study occurred in the bevacizumab group.

Conclusions

Bevacizumab is effective in the treatment of stage 3+ ROP in Zone 1 and posterior Zone 2. 2. Bevacizumab is no better than laser for reducing the recurrence rate of posterior Zone 2 disease but was shown to be superior for Zone 1 disease. The development of peripheral retinal vessels continued after treatment with intravitreal bevacizumab; however, conventional laser therapy permanently destroyed the peripheral retina avoiding the appearance of vessels.

Pearls for clinical practice

Bevacizumab is effective in the treatment of stage 3+ ROP in Zone 1 and posterior Zone 2.


Pediatric Eye Disease Investigators Group Study (PEDIG) –or– Amblyopia Treatment Study

Arch Ophthalmol 2002;120:268 | Arch Ophthalmol 2003;121:603 | Ophthalmol 2003;110:2075 | J AAPOS 2004;8:420 | Arch Ophthalmol 2005;123:437 | Ophthalmol 2006;113:895 | Ophthalmol 2006;113:904.

Objectives

The goal was to determine if correcting the refractive error alone can treat amblyopia, the benefits of patching, and the risks of recurrence after suspension of treatment. In addition, it wanted to know until what age can amblyopia be treated and the management with atropine and occlusion.

This trial tried to facilitate an evidence-based approach to the treatment of amblyopia.

Design

Clinical trials involving

  1. Observational study of spectacles alone for anisometropic amblyopia.
  2. Amblyopia treatment randomized to daily atropine to the fellow eye or at least 6 hours of patching per day.
  3. 2 concurrent randomized trials of patching, prescribed 2 hours/day versus 6 hours/day for moderate amblyopia and prescribed 6 hours/day versus full-time for severe amblyopia.
  4. Patching in older children: children randomised to receive optical correction ± patching for near activities.
  5. Recurrence of amblyopia: children treated with patching or atropine for at least three months with at least three lines of improvement were brought off therapy, and followed up for one year.

Moderate amblyopia was defined as 20/40 to 20/80. Severe amblyopia was defined as 20/100 to 20/400. Successful treatment was defined as the improvement of VA to within one line of the non-amblyopic eye. Recurrence of amblyopia was defined as a reduction in at least two lines after cessation of amblyopia therapy or when treatment was restarted at an investigator’s discretion.

Inclusion criteria were children less than seven years, BCVA in the better eye better than 20/40, and the amblyopic eye less than 20/40. Previous refractive error corrected for at least four weeks before the study.

Main outcome measures

Primary endpoint: BCVA.

Results

More than 4000 subjects have participated in 19 Amblyopia Treatment Studies (ATS). The main ones were:

  1. Observational study of spectacles alone for anisometropic amblyopia: 84 children, 3 to 6 years of age and VA from 20/40 to 20/250 at enrollment. 77% of the children improved at least 2 lines, and 27% showed resolution within 1 line of the fellow eye. Maximum improvement was achieved by 83% of subjects by 10 weeks, but some children improved for 30 weeks. Improvement was found in children with moderate and severe amblyopia. The key lesson was that spectacles are an effective initial tool in managing amblyopia.
  2. Amblyopia treatment randomized to daily atropine to the fellow eye or at least 6 hours of patching per day. 419 children, 3 to 6 years of age with amblyopia 20/40 to 20/100. VA improved in both groups at 6 months; during the initial treatment phase, the patching group did improve more quickly, but the atropine group caught up by 6 months. Thus, atropine and patching are effective in the treatment of amblyopia. Parental questionnaires found atropine to be better tolerated in terms of social stigma and compliance. The amblyopia treatment benefit persisted through age 10 years without a mean VA loss, but residual amblyopia remains in a large proportion of children. The mean amblyopic eye VA at 10 years was approximately 20/32, with 46% of amblyopic eyes 20/25 or better. After the initial 6-months, children were treated at the investigator's discretion with occlusion or atropine, and more than 85% of children continued to be prescribed treatment. So, amblyopia treatment is not a short-term task; it represents a long-term effort.
  3. 2 concurrent randomized trials of patching, prescribed 2 hours/day versus 6 hours/day for moderate amblyopia and prescribed 6 hours/day versus full-time for severe amblyopia in 3 to 6-year-olds children. 175 severe amblyopes were randomised to receive full-time patching vs. six hours/day patching for four months. 189 moderate amblyopes were randomised to receive either two or six hours a day of patching for four months. VA improved with both patching regimens without differences. Therefore, it is reasonable to initiate therapy with a lower dose and increase treatment intensity if the response is not good.
  4. Patching in older children: 507 children with amblyopia aged 7 to 18 were recruited and randomised to receive optical correction ± patching for near activities. There was a significant improvement in BCVA in those treated with patching in the 7-12 age group but not in the 13 -17 age group. When only the 13-17-year olds with no previous treatment for amblyopia were considered, there was an improvement in the patched group.
  5. Recurrence of amblyopia: 156 children who had been treated with patching or atropine for at least three months with at least three lines of improvement were brought off therapy at the investigator's discretion and followed up for one year. The average age was 5.9 years, and no child was older than eight. 21% of children experienced amblyopia recurrence, with 40% occurring within the first five weeks.

Limitations

Children younger than three were not included

Conclusions

Refractive correction alone may be effective in the treatment of amblyopia. There is no benefit in patching moderate amblyopes for longer than two hours and severe amblyopes for more than six hours per day. Children need close follow-up after discontinuation of occlusion therapy. There may be a benefit in treating amblyopia until 12 years of age. Teenagers with amblyopia who have never before received treatment may benefit from a trial of patching. There is no clinical difference in using atropine vs. patching in moderate amblyopes.

Pearls for clinical practice

Refraction helps amblyopia.

Moderate amblyopes can be treated using atropine or patching.


Infant Aphakia Treatment Study (IATS)

Arch Ophthalmol 2010;128:810 | Ophthalmol 2011;118:2330 | Arch Ophthalmol 2012;130:293 | JAMA Ophthalmol 2014;132:676.

Objectives

The goal was to determine the visual outcomes of using contact lenses (CL) or intraocular lenses (IOL) to correct monocular aphakia during infancy, and the adverse events.

Design

Randomized, multicenter clinical trial, patients with unilateral congenital cataract were assigned to undergo cataract surgery either with or without IOL implantation. Children randomized to IOL treatment had their residual refractive error corrected with spectacles. Children randomized to no IOL had their aphakia treated with a contact lens.

Refractive aim was 6D under-correction in those older than six weeks.

Additional refractive correction was achieved with spectacles. The CL group was prescribed soft or gas permeable CLs to overcorrect refractive error by 2 D. Both groups underwent the same patching regime.

Inclusion criteria were infants with unilateral congenital cataracts undergoing surgery between 28 days to six months of age.

Main outcome measures

Primary endpoints: VA, Grating acuity at 12 months of age, and HOTV visual acuity at 4.5 years of age. Secondary endpoints: Intraocular complications, adverse events, operations required, ocular alignment.

Results

From 2004 to 2009, 114 eyes of 114 infants randomized to each treatment group with either IOL placement (n= 57) or aphakia (n= 57). The median age at the time of cataract surgery 1.8 months. The eyes with cataracts had shorter axial lengths and steeper corneas on average than the fellow eyes.

VA was not significantly different in the two groups at one and five years. Still, at five years, more patients with VA better than 20/40 corresponded to the CL group (23% CL vs. 11% IOL).

There were no differences in the development of glaucoma (35% CL vs. 28% IOL). There were more intraoperative complications in the IOL group (28% IOL vs. 11% CL), mainly because of a higher incidence of iris prolapse. There were more post-operative adverse events in the IOL group (77% IOL vs. 25% CL), mainly because of lens re-proliferation (42%), pupillary membrane (30%), and corectopia (11%). There was one case of keratitis and one case of endophthalmitis in the CL group.

There were more additional intraocular surgeries in the IOL group (63% IOL vs. 12% CL), mainly because of clearing the visual axis.

There was a trend for increased strabismus in the CL group at one year (62% CL vs. 42% IOL).

At five years, there was a higher incidence of further surgeries in the IOL group (72% IOL vs. 28% CL).

Limitations

Presenting the incidence of glaucoma, the study did not consider the IOL location in the capsular bag or the sulcus. Contact lenses, spectacles and patching were free in this study, different from real life. The costs of treatment may affect compliance. The study provides no information on the time to implant secondary IOL in the CL group.

Conclusions

The optimal optical treatment of aphakia in infants is unknown. IATS was designed to provide empirical evidence whether optical treatment with an IOL or a contact lens following unilateral cataract surgery during infancy is associated with a better VA.

Pearls for clinical practice

There is no significant difference in VA at one year or five years in congenital cataract patients undergoing Primary IOL implantation or CL use. Primary IOL implantation is associated with a higher incidence of intraoperative and post-operative complications, requiring further surgery. IOL implantation may have advantages in cases of low compliance using CL.


Atropine for the Treatment of Myopia I (ATOM I) 2006

Ophthalmol 2006;113:2285 | Ophthalmol 2009;116:572 | Ophthalmol 2012;119:347.

Objectives

The goal was to determine if atropine can affect the progression of myopia in myopic Asian children and the effect after the cessation of the treatment.

Design

Double-masked, randomised, placebo-controlled trial, where children received 1% atropine or placebo to one of their eyes every night for two years, with a followed-up for 1 and 3 years.

Inclusion criteria were 6-12 years, refractive error of spherical equivalent between -1 D and -6 D, BCVA in both eyes of logMAR 0.2 or better, astigmatism of less than 1.50 D, anisometropia of less than 1.50 D.

Main outcome measures

Spherical equivalent (by cycloplegic autorefraction) and axial length (by A-scan ultrasonography).

Results

346 children completed the 2-year study. Myopia progression and axial elongation in placebo was -1.20+/-0.69 D and in atropine was 0.38+/-0.38 mm. The differences in myopia progression and axial elongation between the 2 groups were -0.92 D in placebo and 0.40 mm in atropine. In the atropine group, the myopia progression was only -0.28+/-0.92 D, and the axial length remained essentially unchanged compared with baseline (-0.02+/-0.35 mm). No serious adverse events related to atropine were reported. The differences were statistically significant. The fellow eye of the atropine treated eye progressed in its myopia that was not statistically different from either of the placebo eyes.

Despite the success of atropine in reducing myopia progression in the treated eye when given for two years, there was a rebound phenomenon observed over the following 12 months once atropine was stopped. The spherical equivalent of the atropine treated eye progressed by -1.14D ± 0.80 over the third year compared to -0.38D ± 0.39 in the placebo group. However, overall, after the third year, the eyes treated with atropine were less myopic than the eyes in the placebo group: Mean total spherical equivalent was -4.29 D ± 1.67 in atropine compared to -5.22 D ± 1.38 in placebo.

Limitations

This study was conducted at a single centre in Singapore with a high prevalence of myopia.

The mechanism for atropine is incompletely understood.

Conclusions

Atropine may limit the progression of low/moderate myopia in children. There is a rebound effect after cessation of treatment. Overall despite the rebound effect, the total spherical equivalent may be less in eyes treated with atropine.

Pearls for clinical practice

Atropine is a treatment to stop the progression of low/moderate myopia in children.


Atropine for the Treatment of Myopia II (ATOM II) 2014

Ophthalmol 2012;119:347 | Am J Ophthalmol 2014;157:451 | Ophthalmol 2016;123:391.

Objectives

The goal was to determine if atropine can slow the progression of myopia without causing side effects from cycloplegia and mydriasis in different concentrations and the results after the cessation of the atropine treatment.

Design

Double-masked, randomized study of children aged 6-12 years with myopia of at least -2.0 diopters (D) and astigmatism of -1.50 D or less, were randomly assigned in a 2:2:1 ratio to 0.5%, 0.1%, and 0.01% atropine to be administered once nightly to both eyes for 2 years. Cycloplegic refraction, axial length, accommodation amplitude, pupil diameter, and visual acuity were noted at baseline, 2 weeks, and then every 4 months for 2 years.

Inclusion criteria were 6-12 years, refractive error of spherical equivalent of at least -2 D in both eyes, astigmatism of less than 1.50 D, progression of at least 0.5 D over the last 12 months.

Main outcome measures

Myopia progression at 2 years. VA while wearing best corrected distance spectacle correction, the near point of accommodation (by RAF rule), spherical equivalent (by cycloplegic auto-refraction) and axial length (by coherence interferometry).

Results

400 children were randomised to 2:2:1 ratio to 0.5%, 0.1%, and 0.01% atropine. The mean myopia progression at 2 years was -0.30±0.60, -0.38±0.60, and -0.49±0.63 D in the atropine 0.5%, 0.1%, and 0.01% groups, respectively (P=0.02 between the 0.01% and 0.5% groups; between other concentrations P > 0.05). The mean increase in axial length was 0.27±0.25, 0.28±0.28, and 0.41±0.32 mm in the 0.5%, 0.1%, and 0.01% groups, respectively (P < 0.01 between the 0.01% and 0.1% groups and between the 0.01% and 0.5% groups). However, differences in myopia progression (0.19 D) and axial length change (0.14 mm) between groups were small and clinically insignificant. Atropine 0.01% had a negligible effect on accommodation and pupil size, and no effect on near visual acuity. Allergic conjunctivitis and dermatitis were the most common adverse effect noted, with 16 cases in the 0.1% and 0.5% atropine groups, and no cases in the 0.01% group.

Limitations

The axial lengths of all groups were approximately the same at 36 months which suggests that the mechanism of action is not directly associated with axial length. The authors compared axial lengths of ATOM I and II even that the methods to calculate it were different.

Conclusions

The progression of myopia and cycloplegic effects show a dose-related response to atropine. Atropine 0.01% may slow the progression of myopia with minimal side effects from cycloplegia. The rebound change in spherical equivalent at three years after stopping atropine was greater in higher concentrations of atropine.

Pearls for clinical practice

Atropine 0.01% is the best concentration because it has minimal side effects and has comparable efficacy in controlling myopia progression.


LAMP study 2019

Yam JC, Jiang Y, Tang SM, Law AKP, Chan JJ, Wong E, Ko ST, Young AL, Tham CC, Chen LJ, Pang CP. Low-Concentration Atropine for Myopia Progression (LAMP) Study: A Randomized, Double-Blinded, Placebo-Controlled Trial of 0.05%, 0.025%, and 0.01% Atropine Eye Drops in Myopia Control. Ophthalmology. 2019 Jan;126(1):113-124.

Objectives

The goal was to evaluate the efficacy and safety of low-concentration atropine eye drops at 0.05%, 0.025%, and 0.01% compared with placebo over a 1-year period.

Design

Randomized, placebo-controlled, double-masked trial of children aged 4 to 12 years, with myopia of at least −1.0 diopter (D), were randomised to 1:1:1:1 ratio to receive 0.05%, 0.025%, and 0.01% atropine eye drops, or placebo eye drop, respectively, once nightly to both eyes for 1 year. Cycloplegic refraction, axial length (AL), accommodation amplitude, pupil diameter, and BCVA were measured at baseline, 2 weeks, 4 months, 8 months, and 12 months.

Inclusion criteria were children aged 4 to 12 years with myopic refraction of at least 1.0 D in both eyes, astigmatism of less than 2.5 D, and documented myopic progression of at least 0.5 D in the past 1 year.

Main Outcome Measures

Changes in spherical equivalent (SE) and AL.

Results

From 2016 to 2017, 438 children were randomised to 1:1:1:1 ratio to receive 0.05%, 0.025%, and 0.01% atropine eye drops, or placebo eye drop. After 1 year, the mean SE change was −0.27±0.61 D, −0.46±0.45 D, −0.59±0.61 D, and −0.81±0.53 D in the 0.05%, 0.025%, and 0.01% atropine groups, and placebo groups, respectively (P < 0.001), with a respective mean increase in AL of 0.20±0.25 mm, 0.29±0.20 mm, 0.36±0.29 mm, and 0.41±0.22 mm (P < 0.001). The accommodation amplitude was reduced by 1.98±2.82 D, 1.61±2.61 D, 0.26±3.04 D, and 0.32±2.91 D, respectively (P < 0.001). The pupil sizes under photopic and mesopic conditions were increased respectively by 1.03±1.02 mm and 0.58±0.63 mm in the 0.05% atropine group, 0.76±0.90 mm and 0.43±0.61 mm in the 0.025% atropine group, 0.49±0.80 mm and 0.23±0.46 mm in the 0.01% atropine group, and 0.13±1.07 mm and 0.02±0.55 mm in the placebo group (P < 0.001). VA and vision-related quality of life were not affected.

Limitations

Placebo-compared efficacy was determined at 1-year, but not at 2-years, because it was considered unethical.

Conclusions

The 0.05%, 0.025%, and 0.01% atropine eye drops reduced myopia progression along with a concentration-dependent response, 0.05% atropine was most effective in controlling SE progression and AL elongation over 1 year. All concentrations were well tolerated without any adverse effects.

Pearls for clinical practice

Atropine eye drops reduce myopia progression safely.

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