Clinical

Topical Low-Dose Atropine: A Global Perspective

June 24, 2020

By Dwight Akerman, OD, MBA, FAAO, FBCLA
Chief Medical Editor, Review of Myopia Management

The use of atropine to treat pediatric myopia dates back over 150 years, yet our understanding of its exact mechanism of action remains incomplete. Franciscus Donders, a Dutch ophthalmologist, described using atropine to treat myopia in his 1864 book, On the Anomalies of Accommodation and Refraction of the Eye. In the book, he theorized myopia was due to excessive accommodation.1 In 1916, Inglis Pollack, an ophthalmologist from the Glasgow Eye Infirmary, was the first to describe its prolonged use in treating progressive high myopia in Scottish school-aged children.2 However, its widespread and consistent use has been limited, mostly due to the unacceptable side effects of photophobia and blurred near vision as well as concerns about long-term safety.

Atropine is a non-selective antimuscarinic agent. The exact mechanism whereby atropine slows myopic progression is not entirely understood. The initial theory that it is mediated by impairing accommodation has been disproven in animal models. In chicks, for example, atropine slows progression even though they possess striated ciliary muscles comprised of nicotinic receptors rather than muscarinic receptors.3 The leading theories are that atropine affects signaling at the retinal photoreceptor level to impair axial elongation or that it acts directly on scleral fibroblasts to reduce scleral growth.4

Whatever the mechanism, it is clear from over a century of laboratory and clinical studies that atropine significantly slows myopic progression. Today, over a dozen randomized controlled trials (RCTs) are being conducted in the U.S. and around the world to understand better how atropine works with different ethnic populations, optimal dosage to maximize efficacy and minimize side effects, as well as to gain regulatory approval.

This white paper will summarize the atropine RCTs currently being conducted around the world, with emphasis on those being undertaken in the U.S. to gain FDA regulatory clearance.

FDA Pivotal Phase III Clinical Studies

CHAMP: NVK-002 in Children With Myopia

Nevakar is currently conducting a pivotal Phase III randomized, multicenter, double-masked, placebo-controlled, three-arm study in two parts. Part I is a safety and efficacy phase of three years in duration, during which subjects will be allocated to one of three study medications. Part II is a randomized crossover phase of one year in duration, during which subjects will be re-randomized to receive one of the three study medications, with subjects initially randomized to Vehicle only eligible for randomization to low or high-dose NVK-002. The treatment arms are NVK-002 preservative-free low-dose concentration, NVK-002 preservative-free high-dose concentration, and preservative-free Vehicle (placebo). This pivotal Phase III clinical trial is evaluating a new formulation of commercially prepared low-dose atropine made using proprietary technology designed for maximum stability, tolerability, and accurate dosing.

The CHAMP study is being conducted at 26 locations in the U.S. and Europe with 483 children ages 3 to  ≤ 17 years at the time of enrollment with myopic SER of at least -0.50D and ≤ -6.00D in each eye as measured by cycloplegic autorefraction.

The primary outcomes measure is:

  • The overall between-group difference in the proportion of subjects who show < -0.50D myopia progression (SER) at the 36-month visit.

The secondary outcome measures are:

  • The between-group difference in mean progression rates at month 12, month 24, and month 36.
  • The between-group difference in the proportion of subjects who show <-0.75D progression and the between-group median time to a change in myopia of <-0.75D at month 36.

The CHAMP study began enrollment in November 2017, and the completion date is estimated to be August 2023.

The official title of the study: A 3-Arm Randomized, Double-Masked, Placebo-Controlled, Phase 3 Study of NVK-002 in Children With Myopia. ClinicalTrials.gov Identifier: NCT03350620.

 

CHAPERONE: Microdosed Atropine 0.1% and 0.01% Ophthalmic Solutions for Reduction of Pediatric Myopia Progression

Eyenovia is conducting a pivotal Phase III clinical trial that evaluates the progression of myopia in participants using microdosed atropine 0.01 percent, atropine 0.1 percent, or placebo ophthalmic solution. Eligible subjects will administer study medication daily in each eye for 48 months. Efficacy and safety assessments will be performed at visits scheduled for 1, 6, 12, 18, 24, 30, and 36 months after initiation of medication use. Subjects will be re-randomized at the 36-month visit then followed at six-month intervals for an additional year.

Randomization will be stratified by iris color (e.g., dark and light) and study site. Study enrollment will be limited to a maximum of 50 percent of subjects who self-identify as East Asian ethnicity. Subjects will use their assigned study medication daily in both eyes and return for efficacy and safety assessments at 1, 6, 12, 18, 24, 30, and 36 months.

The multicenter, double-masked CHAPERONE study will evaluate MicroPine, a proprietary microdose atropine formulation delivered with Optejet, the company’s piezo-print delivery technology. The Optejet is also designed with Bluetooth technology, which means patient use can be monitored.

This study is being conducted at 14 locations in the U.S., and 420 children with myopia between -1.00D to ≤ -6.00D who are between the ages of 3 and 12 years old at the time of enrollment are being recruited.

The primary outcome measure is:

  • The proportion of primary study eyes showing less than -0.50D (spherical equivalent) myopia progression compared to baseline measured using cycloplegic autorefraction at the 36-month visit.

The CHAPERONE study began in June 2019, and the estimated study completion date is December 2024.

The official title of the study: A Multicenter, Double-Masked, Randomized, Placebo-Controlled Phase 3 Study of the Safety and Efficacy of Atropine 0.1 percent and 0.01 percent Ophthalmic Solutions Administered With a Microdose Dispenser for the Reduction of Pediatric Myopia Progression (The CHAPERONE Study). ClinicalTrials.gov Identifier: NCT03942419

 

STAAR: The Safety and Efficacy of SYD-101 in Children With Myopia

Sydnexis is conducting a pivotal Phase III multicenter, randomized, double-masked, Vehicle-controlled study to assess the safety and efficacy of SYD-101 ophthalmic solution for the treatment of myopia in children. This Phase III clinical trial is evaluating a new formulation of commercially prepared low-dose atropine made using proprietary technology designed for maximum stability, tolerability, and accurate dosing.

This is a five-arm, multicentered, randomized, double-masked, Vehicle-controlled study conducted in two parts. Part 1 is the primary treatment period of three years, during which participants will receive one of three masked medications (SYD-101 Dose 1, SYD-101 Dose 2, or Vehicle.) Part 2 is the randomized withdrawal period of one year, during which participants originally receiving Vehicle will receive SYD-101, and participants originally receiving SYD-101 will receive either Vehicle or SYD-101.

This STAAR study is being conducted at 47 locations in the U.S. and Europe, and 840 children with myopia of -0.50D to ≤ -6.00D who are between the ages of 3 and 14 years old at the time of enrollment will be recruited to participate in this study.

The primary outcome measure is:

  • Proportion of participants with confirmed myopic progression > 0.75D (diopters), based on spherical equivalent (SE) as measured by cycloplegic autorefraction at the 36-month visit compared to baseline.

The secondary outcome measures are:

  • Mean annual progression rate of myopia measured in diopters: SE as measured by cycloplegic autorefraction at the 36-month visit.
  • Time to progression of myopia > 0.75D measured as SE via cycloplegic autorefraction. The time frame is up to 36 months (from the date of randomization until date myopia progresses > 0.75D)
  • Mean change in axial length from baseline to the 36-month visit as measured by cycloplegic biometry.

The STAAR study began in April 2019, and the completion date is estimated to be July 2024.

The official title of the study: A Multicenter, Randomized, Double-masked, Vehicle-controlled Study to Assess the Safety and Efficacy of SYD-101 Ophthalmic Solution for the Treatment of Myopia in Children. ClinicalTrials.gov Identifier: NCT03918915

 

Academic and Global Atropine Clinical Trials

BAM: Bifocal & Atropine in Myopia Study

The Bifocal & Atropine in Myopia (BAM) study being conducted at The Ohio State University College of Optometry aims to determine whether combining 0.01 percent atropine (compounded by a local pharmacy) and +2.50D add center-distance soft bifocal contact lenses (Biofinity Multifocal D +2.50D ADD is a monthly disposable contact lens) slows myopia progression more than soft bifocal contact lenses alone in children 7 to 11 years old. The results could provide important information on the myopia control effect of combining optical and pharmacological treatments.

Both atropine and soft bifocal contact lenses have been shown to slow myopia progression, and both can cause changes in choroidal thickness. But the relationship between these mechanisms is unclear. The central hypothesis to be tested in the BAM Study is that atropine and soft bifocal contact lenses each exert their anti-progression actions through a common pathway that involves the choroid. If this is correct, then adding atropine treatment to soft bifocal contact lens wear will lead to a more effective slowing of myopia progression than prescribing soft bifocal contact lenses alone due to the additive effects in the common pathway.

The BAM Study is an ancillary study of an NIH-sponsored, multicenter, randomized clinical trial, the Bifocal Lenses In Nearsighted Kids (BLINK) Study. The BLINK Study compares myopia progression between subjects who wear single vision contact lenses and those wearing soft bifocal contact lenses. The BAM Study enrolls an additional 49 children who are age-matched with the participants who are wearing +2.50D ADD soft bifocal contact lenses in the BLINK Study. The subjects in the BAM Study wear +2.50D ADD soft bifocal contact lenses in combination with daily administration of one drop of 0.01 percent atropine in each eye for three years. The rates of myopia progression and axial elongation will be compared to the rates in participants who are receiving treatment with +2.50D ADD soft bifocal contact lenses alone in the BLINK Study.

The primary outcome measure is:

  • Refractive error, as measured by cycloplegic autorefraction in both eyes, will be measured yearly over 36 months to assess the difference in progression between the combination treatment (+2.50D ADD soft bifocal lens and 0.01% atropine) group and the historical control group (+2.50D ADD soft bifocal lens only) in the BLINK Study.

The secondary outcome measure is:

  • Axial length progression, as measured by Lenstar in both eyes, will be measured yearly over 36 months to assess the difference in progression between the combination treatment (+2.50D ADD soft bifocal lens and 0.01 percent atropine) group and the historical control group (+2.50D ADD soft bifocal lens only) in the BLINK Study.

The BAM study began in July 2016, and the completion date is estimated to be June 2020.

The official title of the study: Myopia Control in Children With Low-dose Atropine and Soft Bifocal Contact Lenses. ClinicalTrials.gov Identifier: NCT03312257

 

CHAMP-UK: Low-dose Atropine Eye Drops to Reduce Progression of Myopia in Children in the United Kingdom

The CHAMP study hypothesis is that low-dose (0.01 percent) atropine eye drops will reduce the progression of myopia in children compared with placebo eye drops. This is a randomized controlled trial that will be conducted across four clinical research facilities associated with higher education institutions in the U.K. It is a double-masked trial involving 289 children ages 6 to 12 years old with myopia. They will be randomly chosen to receive either atropine eye drops or placebo eye drops on a 2:1 basis. Therefore, 193 participants will receive atropine eye drops, and 96 participants will receive placebo eye drops.

The primary outcome measure is:

  • Spherical equivalent refractive error (i.e., myopia severity) of both eyes measured by autorefractor under cycloplegia at 24 months compared to baseline.

The secondary outcome measures include:

  • Central axial length measured using a laser biometer at central fixation conditions at 24 months compared to baseline.
  • Eye drop tolerability assessed using a four-point scale to quantify, from the point of view of the participant, (1) local irritation/stinging associated with eye drop instillation; (2) photophobia; and (3) difficulties reading and writing at 24 months.
  • Quality of life using the EQ-5D-Y at 24 months.

The CHAMP-UK study began in April 2019, and the completion date is estimated to be December 2024.

The official title of the study: Low-dose Atropine Eye Drops to Reduce Progression of Myopia in Children: a Multi-centre Placebo Controlled Randomised Trial in the United Kingdom.

ClinicalTrials.gov Identifier: NCT03690089

 

APPLE: A Study Assessing the Efficacy and Safety of DE-127 Ophthalmic Solution in Subjects With Mild or Moderate Myopia

Santen recently conducted a Phase II clinical trial to investigate the efficacy and safety of three concentrations of DE-127 atropine ophthalmic solution (low, medium, and high dose) when compared to placebo in subjects diagnosed with mild or moderate myopia.

The twelve-month dose-response study was conducted at the Singapore National Eye Centre. A group of 100 children between the ages of 6 and 11 at baseline was included in the study.

This 12-month study was conducted at the Singapore National Eye Centre, and 100 Singaporean children between the ages of 3 and 11 years old at the time of enrollment with myopia between -1.00D to ≤ -6.00D were included in the study.

The primary outcome measure is:

  • Change from baseline in spherical equivalent determined by cycloplegic autorefraction at month 12 in the study eye.

The APPLE study began in October 2017 and was completed in December 2019. The results have not been published yet.

The official title of the study: A Phase II, Randomized, Double-Masked, Placebo-Controlled, Parallel-Group Study Assessing the Efficacy and Safety of DE-127 Ophthalmic Solution Compared With Placebo in Subjects With Mild or Moderate Myopia (APPLE)

ClinicalTrials.gov Identifier: NCT03329638

 

MOSAIC: The Myopia Outcome Study of Atropine in Children

The Myopia Outcome Study of Atropine in Children (MOSAIC) aims to explore the efficacy, safety, acceptability, and mechanisms of action of 0.01 percent atropine for myopia control in a Caucasian population.

MOSAIC is an investigator-led, double-masked, placebo-controlled, randomized clinical trial investigating the efficacy, safety, and mechanisms of action of 0.01 percent atropine eye drops in myopic progression management. During Phase I of the trial, 250 children ages 6 to 16 years with progressive myopia apply eye drops once nightly in both eyes from randomization to month 24. No treatment is given during Phase II from month 24 to 36 (washout period) for those participants initially randomized to the intervention arm (n=167), during which any potential rebound effects on termination of treatment will be monitored. All participants initially assigned to the placebo (n=83) crossover to the intervention arm of the study for Phase II, and from month 24 to 36, instill 0.01 percent atropine eye drops once nightly. Further treatment and monitoring beyond 36 months are planned (Phase III) and will be designed dependent on the outcomes of Phase I.

The primary outcome measure is:

  • Spherical equivalent refractive error progression at the 24-month visit compared to baseline.

The secondary outcome measures include:

  • Axial length change as well as the rebound, safety, and acceptability profile of 0.01 percent atropine in a Caucasian population.
  • Additional analyses will address questions of the mechanism of action of atropine.

The MOSAIC study began in October 2017, and the completion date is estimated to be May 2023.

The trial registration: ISRCTN: ISRCTN36732601 and EudraCT database 2016-003340-37

 

MTS1: Low-Dose Atropine for Treatment of Myopia

The Myopia Treatment Study is being conducted in the U.S. by the Pediatric Eye Disease Investigator Group (PEDIG). This Phase III study is designed as an efficacy study. After a run-in phase during which all participants are treated with daily artificial tear eye drops for two to four weeks (and glasses are updated if required) to assess their ability to adhere to daily eye drops, participants are randomly assigned to daily 0.01% atropine or placebo for 24 months, followed by six months off treatment.

For this multi-site study, 187 American children ages 5 to 13 years, -1.00D to -6.00D spherical equivalent in both eyes, have been allocated to either atropine 0.01% or a placebo for two years. The outcomes for six months post-cessation will also be measured.

The objectives for this RCT are:

  1. To determine the efficacy of daily low-dose atropine (0.01%) for slowing myopia progression over a two-year treatment period in children aged 5 to less than 13 years (Primary Outcome On-Treatment).
  2. To determine the efficacy of atropine treatment on myopia progression six months following cessation of low-dose atropine treatment (Secondary Outcome Off-Treatment).

The MTS1 study began in June 2018, and the completion date is estimated to be November 2022.

The official title of the study: Low-Dose Atropine for Treatment of Myopia (Myopia Treatment Study)

ClinicalTrials.gov Identifier: NCT03334253

 

LAMP: Two-Year Clinical Trial of the Low-Concentration Atropine for Myopia Progression Study: Phase 2 Report

Yam and co-researchers from The Chinese University of Hong Kong Department of Ophthalmology and Visual Sciences have recently published the results of the LAMP Study phase 2. This study is a randomized, double-masked clinical trial that looked at the efficacy and safety of 0.05%, 0.025%, and 0.01% atropine eye drops over two years. The LAMP study phase 1 results were published in 2018.

The aim of phase 2 of the LAMP study was to answer the following questions: 1) Which concentration of atropine confers the best efficacy in myopia control over two years? 2) Are the efficacies of low-concentration atropine better in the second year than the first year? 3) Are the side effects of low concentration atropine similar in the first and second year, and remained tolerable? 4) What is the efficacy after administration of 0.05% atropine to the placebo self-control group for a year?

The authors concluded that over two years, the efficacy of topical 0.05% atropine was double that of 0.01% atropine, and it remained the optimal concentration among the studied atropine concentrations in slowing myopia progression. The generalizability of results from this clinical trial is limited by the predominantly Asian ethnicity of the study populations

Yam, J. C., Li, F. F., Zhang, X., Tang, S. M., Yip, B. H. K., Kam, K. W., … & Pang, C. P. (2019). Two-Year Clinical Trial of the Low-concentration Atropine for Myopia Progression (LAMP) Study: Phase 2 Report. Ophthalmology. https://doi.org/10.1016/j.ophtha.2019.12.011

1 Donders, F. C., & Moore, W. D. (1864). On the anomalies of accommodation and refraction of the eye: With a preliminary essay on physiological dioptrics (Vol. 22). New Sydenham Society.

2 Pollock, W. I. (1916). The reduction of myopia in children of school age. Glasgow Medical Journal, 86(4), 214.

3 McBrien, N. A., Moghaddam, H. O., & Reeder, A. P. (1993). Atropine reduces experimental myopia and eye enlargement via a nonaccommodative mechanism. Investigative ophthalmology & visual science, 34(1), 205-215.

4 McBrien, Neville A., William K. Stell, and Brittany Carr. “How does atropine exert its anti‐myopia effects?.” Ophthalmic and Physiological Optics 33, no. 3 (2013): 373-378.

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