Clinical trial NCT03865160: Low-dose Atropine for Myopia Control in Children
Official title: Low-dose Atropine for Myopia Control in Children, a Prospective, Double-blind, Placebo-controlled, Multicentric, Randomized Clinical Trial
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
PHASE3
Conditions: Myopia, Progressive
Keywords: Myopia
Children
Atropine
Low-dose
0.01
0.02
Lead sponsor: University Eye Hospital, Freiburg
Sponsor class: OTHER
First posted: 2019-03-06
Enrollment: 302
Sex: ALL
Minimum age (years): 8
Maximum age (years): 12
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Year one: arm A atropine 0.02% / arm B placebo Year two: arm A atropine 0.02% / arm B atropine 0.01% Year three: arm A placebo/ arm B atropine 0.01%
Primary purpose: TREATMENT

Brief summary: Myopia (nearsightedness) is the most common eye disorder. Only second to age, it is the main risk factor for major degenerative eye diseases such as glaucoma, macular degeneration or retinal detachment. Their risk increases with the degree of myopia. Hence, prevention of myopia and slowing its progression is of high relevance. Almost all clinical studies, including two large randomised clinical trials (RCT) were performed in Asia with Asian study participants. The results indicate that atropine eye drops can attenuate myopic progression in children, even in low concentrations thus minimizing unwanted side effects. However, the cumulative evidence is yet not strong enough to recommend their unrestricted use, especially in a Non-Asian population. We therefore intend to set up an adequately powered RCT comparing atropine 0.02% eye drops with placebo to validate previous findings and to test whether this therapeutic concept holds its promise in a European population.

Detailed description: Myopia (nearsightedness) is the most common developmental eye disorder in the first decades of life. It is the biggest risk factor for sight threatening degenerative eye diseases later in life, second only to age. Its prevalence is increasing worldwide in pandemic dimensions affecting now \> 80% in Asian and \> 40% in Caucasian populations. Myopia is one of the five eye diseases identified as immediate priorities by the WHO's global initiative for the elimination of avoidable blindness. It usually develops during primary school and its onset and progression are related to environmental factors such as near work and lack of day light exposure, to a lesser degree to genetic factors. Therefore, retardation of myopia progression is a major therapeutic goal. Clinical trials from Asia have shown that 0.01% atropine eye drops can attenuate progression of myopia while inducing only little side effects such as light sensitivity and reduced accommodation. Subsequent data also from Asia have suggested that a concentration of 0.05% atropine is slightly more effective with a still acceptable level of adverse effects. However, it is unclear whether this therapy is equally and sufficiently efficacious in a Caucasian population. It is also unclear which concentration of atropine represents the best compromise between efficacy and safety. Our own uncontrolled pilot data suggest that 0.01% delays progression by about 50% with negligible side effects, but that 0.05% induces a pupil dilation of \> 3 mm, which is considered unacceptable. Due to the increasing prevalence also in Europe and an increasing demand from parents for means to retard myopia progression, the trial is the first European large scale randomized clinical trial investigating the safety and efficacy of 0.01% and 0.02% atropine eye drops in comparison to placebo drops. Such a trial is mandatory to substantiate the increasing off-label prescriptions of low-dose atropine in children and to develop clinical guidelines.

Eligibility criteria: Inclusion Criteria:

1. Male or female patients aged 8 to 12 years (up to the day before the 13th birthday)
2. Myopia of -1 D to -6 D with reported or documented annual progression ≥ 0.5 D of myopia
3. Written informed consent obtained from patient (if applicable) and parents or legal guardians according to international guidelines and local laws
4. Ability to understand the nature of the trial and the trial related procedures and to comply with them

Exclusion Criteria:

1. Asian or African origin
2. Abnormal binocularity
3. Strabismus
4. Astigmatism \>1.5 D
5. Anisometropia \>1.5 D
6. History of amblyopia
7. Corrected visual acuity in any eye \<0.63
8. Any acquired or developmental organic eye disease
9. Premature birth
10. Any known systemic metabolic disease or chromosomal anomaly
11. Previous use of any kind of contact lenses
12. Previous use of atropine eye drops
13. Epilepsy
14. Known hypersensitivity to the active substances or any of the excipients
15. Participation in any other interventional clinical trial within the last 30 days before the start of this trial
16. Simultaneous participation in other interventional trials which could interfere with this trial; simultaneous participation in registries and diagnostic trials is allowed
17. Contraindications according to the Summary of Product Characteristics (SmPC): Increased intraocular pressure (primary forms of glaucoma or narrow angle glaucoma), chronic rhinitis sicca
18. Caution and pediatric counselling shall be assured if any of the following conditions are present according to the Summary of Product Characteristics (SmPC): Cardiac insufficiency, arrhythmia, coronary stenosis, hyperthyroidism, stomach or bowel stenosis, bowel paralysis, megacolon, muscle weakness, lung edema, hypersensitivity to atropine, spastic paralysis
19. Parents or children with poor understanding of the German language
20. Person who is in a relationship of dependence/employment with the sponsor or the investigator

Primary outcomes:
measure: Demonstration of superiority of low-dose atropine 0.02% eye drops compared to placebo for myopia control
timeFrame: Baseline - 12 months
Secondary outcomes:
measure: Assessment of axial eye length growth under low-dose atropine 0.02% in comparison to placebo
timeFrame: Baseline - 12 months
measure: Assessment of the categorized rate of change in refraction of low-dose atropine 0.02% compared to placebo
timeFrame: Baseline - 12 months
Other outcomes:
measure: Assessment of rebound of myopia progression (refraction) after cessation of atropine 0.02% treatment
timeFrame: 24-months - 36-months
measure: Assessment of rebound of myopia progression (axial length) after cessation of atropine 0.02% treatment
timeFrame: 24-months - 36-months
measure: Change in refraction [D/year]
timeFrame: intervention group: baseline - 24-months, control group: 12-months - 36-months
measure: Change in axial length [mm/year]
timeFrame: intervention group: baseline - 24-months, control group: 12-months - 36-months
measure: Assessment of safety of topical preservative free atropine in comparison to placebo with regard to pupil size
timeFrame: Baseline - 36-months
measure: Assessment of safety of topical preservative free atropine in comparison to placebo with regard to near vision
timeFrame: Baseline - 36-months
measure: Assessment of safety of topical preservative free atropine in comparison to placebo with regard to accomodation
timeFrame: Baseline - 36-months
measure: Assessment of safety of topical preservative free atropine in comparison to placebo with regard to pulse rate
timeFrame: Baseline - 36-months
measure: Number of participants with treatment-related adverse events as assessed by the current CTCAE v4.0
timeFrame: Baseline - 36-months
Locations:
city: Ahaus
country: Germany
facility: Augen-Zentrum-Nordwest, Augenpraxis Ahaus
city: Bonn
country: Germany
facility: Universitäts-Augenklinik Bonn
city: Erlangen
country: Germany
facility: Universitätsklinikum Erlangen, Augenklinik
city: Essen
country: Germany
facility: Universitätsklinikum Essen, Klinik für Augenheilkunde
city: Freiburg
country: Germany
facility: Medical Center - University of Freiburg, Eye Hospital
city: Göttingen
country: Germany
facility: Universitätsmedizin Göttingen, Augenklinik
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf, Klinik und Poliklinik für Augenheilkunde
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover, Klinik für Augenheilkunde
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg, Augenklinik
city: Kiel
country: Germany
facility: Universitätsklinikum Schleswig-Holstein
city: Köln
country: Germany
facility: Uniklinik Köln, Zentrum für Augenheilkunde
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig, Klinik und Poliklinik für Augenheilkunde
city: Magdeburg
country: Germany
facility: Universitätsklinikum Magdeburg A.ö.R., Universitätsaugenklinik
city: Mainz
country: Germany
facility: Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Augenklinik und Poliklinik
city: München
country: Germany
facility: Ludwig-Maximilians-Universität München, Augenklinik und Poliklinik
city: Münster
country: Germany
facility: Klinik für Augenheilkunde des UKM, Gebäude D15
city: Oldenburg
country: Germany
facility: Pius-Hospital Oldenburg, Medizinischer Campus Universität Oldenburg, Universitätsklinik für Augenheilkunde
city: Rosenheim
country: Germany
facility: AugenCentrum Rosenheim
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm, Klinik für Augenheilkunde
Study officials:
affiliation: Eye Center, Medical Center, University Hospital Freiburg
name: Wolf Lagrèze, Prof.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Farassat N, Bohringer D, Kuchlin S, Molnar FE, Schwietering A, Seger D, Hug MJ, Knobel AB, Schneider-Fuchs S, Ihorst G, Wabbels B, Beisse C, Ziemssen F, Schuettauf F, Hedergott A, Ring-Mangold T, Schuart C, Wolf A, Schmickler S, Biermann J, Eberwein P, Hufendiek K, Eckstein A, Gusek-Schneider G, Schittkowski M, Lischka T, Lagreze WA. Low-dose AtropIne for Myopia Control in Children (AIM): protocol for a randomised, controlled, double-blind, multicentre, clinical trial with two parallel arms. BMJ Open. 2023 Apr 20;13(4):e068822. doi: 10.1136/bmjopen-2022-068822.