MAD Trial: Myopia Atropine Dose (MAD)

Investigator Led, Double-masked, Multicenter, Randomized Clinical Trial for the Comparison of Atropine 0.5% Versus Atropine 0.05% Eye Drops for the Prevention of Myopia Progression in Dutch Children

The goal of this interventional study is to compare the efficacy of Atropine 0.05% to Atropine 0.5% treatment against progression of axial length in European children with progressive myopia, and to evaluate the safety, adherence, and reasons for nonresponse. Subjects will use Atropine eye drops for a period of 3 years, followed by a 2 year observational period.

Study Overview

• Status: Recruiting
• Conditions: Progressive Myopia
• Intervention / Treatment: Drug: Atropine Ophthalmic 0.05%; Drug: Atropine Ophthalmic 0.5%

Detailed Description

With the current worldwide myopia boom the frequency of high myopia will also increase, and potentially blinding complications such as myopic macular degeneration, retinal detachment, and glaucoma will occur more often. In the Netherlands high myopia will become the most important cause of low vision and blindness by 2050. As treatment options are limited once the eye is fully grown, prevention of a long axial length at childhood is the only way to counteract this prospect. Pharmacological interventions have shown a high efficacy in stopping eye growth, in particular eye drops with high dose Atropine (0.5%, 1%). Nevertheless, the high frequency of side effects (photophobia, reading problems) of these Atropine concentrations has favoured the use of low dose Atropine. Atropine 0.01% is the most commonly used and lowest dosage; it has shown stability of refractive error, but not of axial length. Recent studies have shown that Atropine 0.05% has low risk of side effects, but a higher efficacy than 0.01%. Many ongoing trials are now comparing various low dose Atropine to placebo, but none are comparing the highest low dose to the lowest high dose Atropine.

• Study Type: Interventional
• Enrollment (Estimated): 550
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Jan Roelof Polling, Dr.; Phone Number: +31628449254; Email: j.polling@erasmusmc.nl
• Study Contact Backup: Name: Trialbureau Oogheelkunde; Phone Number: +31107039740; Email: research.oogheelkunde@erasmusmc.nl

Study Locations

• Netherlands
  • Almere, Netherlands
    • Recruiting
    • Flevoziekenhuis
    • Contact: D. Laan
  • Amsterdam, Netherlands
    • Recruiting
    • OLVG, locatie Oost
    • Contact: van Zijderveld
  • Delft, Netherlands
    • Recruiting
    • Reinier de Graaf Gasthuis
    • Contact: E. Abma-Bustraan
  • Delft, Netherlands
    • Recruiting
    • Ophthalmologistenpraktijk Delfland
    • Contact: A. van der Schans
  • Den Haag, Netherlands
    • Recruiting
    • Haga ziekenhuis
    • Contact: M.T. de Jong
  • Den Haag, Netherlands
    • Recruiting
    • Oogkliniek Den Haag
    • Contact: M.H.L. Vermeulen-Jongen
  • Deventer, Netherlands
    • Recruiting
    • Deventer Ziekenhuis
    • Contact: M. Bartels
  • Dordrecht, Netherlands
    • Recruiting
    • Albert Schweitzer Ziekenhuis
    • Contact: S. Boekhoorn
  • Ede, Netherlands
    • Recruiting
    • Bergman Clinics - Ede
    • Contact: C. Scholten
  • Goes, Netherlands
    • Recruiting
    • Admiraal De Ruyter Ziekenhuis
    • Contact: J. Kieviet- de Geus
  • Heerenveen, Netherlands
    • Recruiting
    • Frisius MC
    • Contact: J. Fonk
  • Heerhugowaard, Netherlands
    • Recruiting
    • Oogcentrum Noordholland
    • Contact: A. Heemskerk
  • Leiden, Netherlands
    • Recruiting
    • Leiden University Medical Center
    • Contact: N.E Schalij-Delfos
  • Lelystad, Netherlands
    • Recruiting
    • Bergman Clinics - Lelystad
    • Contact: L. Boon
  • Maastricht, Netherlands
    • Recruiting
    • Maastricht UMC+
    • Contact: N. Bauer; Phone Number: +31433876543; Email: poli.oogheelkunde@mumc.nl
  • Nieuwegein, Netherlands
    • Recruiting
    • St. Antonius
    • Contact: L.K. v.d. Jong- van Beek
  • Nijmegen, Netherlands
    • Recruiting
    • Radboudumc
    • Contact: C.C.W. Klaver
  • Rotterdam, Netherlands
    • Recruiting
    • Erasmus Medical Center
    • Contact: Jan Roelof Polling, Dr.; Phone Number: +31628449254; Email: j.polling@erasmusmc.nl
  • Tiel, Netherlands
    • Recruiting
    • Ziekenhuis Rivierenland Tiel
    • Contact: L. Hazeleger-van Zetten
  • Tilburg, Netherlands
    • Recruiting
    • Elisabeth-TweeSteden Ziekenhuis
    • Contact: I. Donkers

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years to 11 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Children aged 6 to ≤ 11 years with bilateral myopia
• Onset of myopia ≥ 4 years of age
• History of progression
• SER of at least -1.00D and no greater than -6.00D in each eye measured using cycloplegic auto refraction
• Intraocular pressure < 21 mm Hg in each eye
• Distance vision correctable to at least 0.1 Log MAR (logarithm of the minimum angle of resolution) in each eye

Exclusion Criteria:

• Allergy to atropine or other excipients of the eye drops
• History of amblyopia or strabismus
• History of retinal dystrophy or systemic disorder
• Abnormal ocular biometry aside from axial length
• History of glaucoma
• Chronic use of topical or systemic antimuscarinic/anticholinergic medications in the 21 days prior to screening, and/or anticipated need for chronic use over the duration of the study (i.e., more than 7 consecutive days in 1 month or more than a total of 30 days in 1 year).
• Chronic use (more than 3 days a week) of topical ophthalmological medication (prescribed or over the counter) other than the assigned study medication. The use of artificial tears is allowed but not in the 1 hour before or after the administration of the study medication.
• The anticipated need to use chronic ophthalmic or systemic oral corticosteroids during the study. (i.e., < 2 weeks)
• Prior myopia treatments.
• Employees of the study center and their family members.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Low dose atropine; Atropine 0.05% sulphate ophthalmic solution should be administered, one drop in each eye, once daily, at bedtime, for 3 years.	Drug: Atropine Ophthalmic 0.05%; Atropine 0.05% sulphate ophthalmic solution
Active Comparator: High dose atropine; Atropine 0.5% sulphate ophthalmic solution should be administered, one drop in each eye, once daily, at bedtime, for 3 years.	Drug: Atropine Ophthalmic 0.5%; Atropine 0.5% sulphate ophthalmic solution

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Progression of axial length in mm from baseline to t = 36 months.	3 years

Secondary Outcome Measures

Outcome Measure	Time Frame
Progression of axial length in mm from baseline to t = 60 months.	5 years
Progression of spherical equivalent of refraction in dioptres from baseline to t = 36 months. compared to atropine 0.5% treatment.	3 years
Progression of spherical equivalent of refraction in dioptres from baseline to t = 60	5 years
Proportion of subjects who show ≤ 0.20 mm (good response); 0.2 - 0.3 mm (acceptable response), and > 3 mm (nonresponse)	3 years
Proportion of subjects who progressed to high myopia (AL 26+ mm)	3 years
Change in visual function (BCVA, contrast sensitivity, and glare)	3 years
Frequency and type of treatment-related (serious) adverse events as assessed by CTCAE v5.0 (=safety)	3 years
Proportion of non-adherence	3 years
Difference in health related quality of life	5 years

Collaborators and Investigators

• Sponsor: Erasmus Medical Center
• Collaborators: ZonMw: The Netherlands Organisation for Health Research and Development
• Investigators: Principal Investigator: C.C.W. Klaver, Prof. Dr., EMC

Study record dates

Study Major Dates

• Study Start (Actual): December 19, 2022
• Primary Completion (Estimated): March 1, 2029
• Study Completion (Estimated): April 1, 2029

Study Registration Dates

• First Submitted: November 21, 2022
• First Submitted That Met QC Criteria: December 19, 2022
• First Posted (Actual): December 28, 2022

Study Record Updates

• Last Update Posted (Actual): April 27, 2025
• Last Update Submitted That Met QC Criteria: April 24, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Keywords: Child; Myopia; Atropine; Axial length
• Additional Relevant MeSH Terms: Eye Diseases; Refractive Errors; Myopia; Myopia, Degenerative; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Neurotransmitter Agents; Anti-Arrhythmia Agents; Adjuvants, Anesthesia; Respiratory System Agents; Anti-Asthmatic Agents; Bronchodilator Agents; Muscarinic Antagonists; Cholinergic Antagonists; Cholinergic Agents; Parasympatholytics; Mydriatics; Atropine
• Other Study ID Numbers: NL78526.078.21; MEC-2021-0814 (Other Identifier: METC Erasmus MC); 2021-004015-11 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No