Clinical Trials Register

Summary
EudraCT Number:	2021-004884-29
Sponsor's Protocol Code Number:	PSt012021
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2022-01-03
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Germany - BfArM

A.2

EudraCT number

2021-004884-29

A.3

Full title of the trial

A Randomized, Double-Blind, Placebo-Controlled Dose Finding Study of 0.05%, 0.025%, 0.01% and 0.005% Atropine Eye Drops to inhibit myopia progression in children in a European population

Eine randomisierte, doppelblinde, placebokontrollierte Dosisfindungsstudie von 0,05%, 0,025%, 0,01% und 0,005% Atropin-Augentropfen zur Hemmung der Myopieprogression bei Kindern in einer europäischen Population

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A study of 0.05%, 0.025%, 0.01% and 0.005% Atropine Eye Drops compared to eye drops without any efficient ingredients in European children suffering from progredient shortsightness, where neither the doctors nor the children or their parents know about the applied substance.

Eine Studie über 0,05%, 0,025%, 0,01% und 0,005% Atropin-Augentropfen im Vergleich zu Augentropfen ohne wirksame Inhaltsstoffe bei europäischen Kindern, die an progredienter Kurzsichtigkeit leiden, wobei weder die Ärzte noch die Kinder oder ihre Eltern über die angewandte Substanz Bescheid wissen.

A.4.1

Sponsor's protocol code number

PSt012021

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Pharma Stulln GmbH
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Pharma Stulln GmbH
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Winicker Norimed GmbH
B.5.2	Functional name of contact point	Johanna Nikulka-Stark
B.5.3	Address:
B.5.3.1	Street Address	Deutschherrnstraße 15-19
B.5.3.2	Town/ city	Nürnberg
B.5.3.3	Post code	90429
B.5.3.4	Country	Germany
B.5.4	Telephone number	0049911926808704
B.5.5	Fax number	0049911926808840
B.5.6	E-mail	johanna.nikulka-stark@winicker-norimed.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Atropine 0.005% eye drops, solution in single-dose container
D.3.2	Product code	AT005
D.3.4	Pharmaceutical form	Eye drops, solution in single-dose container
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Ocular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ATROPINE SULFATE
D.3.9.1	CAS number	55-48-1
D.3.9.2	Current sponsor code	AT005
D.3.9.3	Other descriptive name	Atropine0.005
D.3.9.4	EV Substance Code	SUB00625MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.05
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Atropine 0.01% eye drops, solution in single-dose container
D.3.2	Product code	AT01
D.3.4	Pharmaceutical form	Eye drops, solution in single-dose container
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Ocular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ATROPINE SULFATE
D.3.9.1	CAS number	55-48-1
D.3.9.2	Current sponsor code	AT01
D.3.9.3	Other descriptive name	Atropine01
D.3.9.4	EV Substance Code	SUB00625MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.1
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 3
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Atropine 0.025% eye drops, solution in single-dose container
D.3.2	Product code	AT025
D.3.4	Pharmaceutical form	Eye drops, solution in single-dose container
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Ocular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ATROPINE SULFATE
D.3.9.1	CAS number	55-48-1
D.3.9.2	Current sponsor code	AT025
D.3.9.3	Other descriptive name	Atropine025
D.3.9.4	EV Substance Code	SUB00625MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.25
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 4
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Atropine 0.05% eye drops, solution in single-dose container
D.3.2	Product code	AT05
D.3.4	Pharmaceutical form	Eye drops, solution in single-dose container
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Ocular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ATROPINE SULFATE
D.3.9.1	CAS number	55-48-1
D.3.9.2	Current sponsor code	AT05
D.3.9.3	Other descriptive name	Atropine05
D.3.9.4	EV Substance Code	SUB00625MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Eye drops, solution in single-dose container
D.8.4	Route of administration of the placebo	Ocular use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Myopia progression in children

E.1.1.1

Medical condition in easily understood language

Progredient shortsightness in children

E.1.1.2

Therapeutic area

Diseases [C] - Eye Diseases [C11]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the optimal dose of low-dose atropine eye drops compared to placebo for the inhibition of myopia progression in children

E.2.2

Secondary objectives of the trial

To evaluate anatomical and functional effects of low-dose atropine eye drops compared to placebo

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male subjects and female subjects from 6 to 12 years of age. (female subjects who cannot become pregnant and female subjects of child bearing potential (after menarche) who use an highly effective contraceptive method or strategy (failure rate per year < 1%) according to the CTFG Guidance “Recommendations related to contraception and pregnancy testing in clinical trials, version 1.1, updated”; see Section 11.3).

2. Subjects showing myopia between ≥-1.0 and ≤-4.0 D (spherical equivalent as assessed by autorefraction under cycloplegia) and a progression of myopia within the past 12 months in at least one eye.

3. Parents or legal guardians who have been informed about the clinical study and have signed the informed consent form.

E.4

Principal exclusion criteria

Medical Conditions
1. Anisometropia (SE) > |1.0| D
2. Corneal astigmatism (ΔTK) > |1.5| D
3. Best corrected visual acuity VADecimal< 1.0 (VAlogMAR > 0.0)
4. Pathological findings in the eyes, i.e. pathological myopia, corneal scars and pathologies in the
anterior or posterior segments of the eye
5. Known intolerances to atropine eye drops or known hypersensitivity to any of the other components
of the investigational product, allergies against eye drops
6. Presence of a contraindication for the treatment with atropine:
- Hypersensitivity to the active substance or to any of the excipients.
- Primary forms of glaucoma
- narrow-angle glaucoma
- rhinitis sicca
- Narrow-angel of anterior chamber
- Tachycardia, congestive heart failure, coronary stenoses
- Thyrotoxicosis, hyperthyroidism
- Mechanical obstruction of the gastrointestinal tract
- Paralytic ileus
- Megacolon
- Obstructive urinary tract diseases, e.g. prostatic hypertrophy with residual urine formation
- Myasthenia gravis
- Acute pulmonary edema
- Pregnancy toxicosis
- Spastic paralysis
7. Down syndrome

Concomitant Therapy within the last 3 Months prior to Enrollment
8. Any ocular therapy other than the IMP, except for antibiotic or anti-allergic eye drops
9. Treatments with
- Monoamine oxidase (MAO) inhibitor therapy
- Antidepressants which affect noradrenergic transmission (e.g. tricyclic antidepressants and
mianserine)
10. Treatment with sympathomimetics
11. Treatment with drugs that may increase the anticholinergic effect of atropine:
- Amantadine
- Anti-arrhymics such as chinidine, procainamide and disopyramide
- Dopamine-antagonists such as metoclopramide
- Antihistaminics
- Certain anti-Parkinsonian drugs (except dopamine receptor agonists)
- Neuroleptics
12. Treatment with pilocarpin and physostigmine containing drugs
13. Treatment with digoxine and nitrofurantoin
14. Treatment with phenothiazine
15. Treatment with levodopa

Prior/Concurrent Clinical Study Experience
16. Enrolment in another clinical study within the last 4 weeks or during enrolment in this study

Other Exclusion Criteria
17. East Asian or African origin
18. Previous or current alcohol or drug abuse
19. Mental or emotional instability of the subject, parents or legal guardians that might jeopardize the
validity of the informed consent or the compliance with the study procedures.
20. Unreliability or lack of cooperation
21. History of any myopia treatment within 3 months before inclusion: e.g. DIMS glasses,
Orthokeratology contact lenses, multifocal contact lenses, atropine eye drops
22. Pregnancy
23. Other reasons why, in the opinion of the investigator, the subjects should not participate in the
study.

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint is the change of myopia determined by the spherical equivalent measured by autorefractor measurement with cycloplegia in the following 12 months after the beginning of low dose atropine treatment.

Primary efficacy variable is the difference of the spherical equivalent measured by autorefraction with cycloplegia after 12 months of low dose Atropine treatment and of autorefraction with cycloplegia at start of study.

E.5.1.1

Timepoint(s) of evaluation of this end point

Days 1, 15, 183, 365

E.5.2

Secondary end point(s)

The secondary efficacy endpoints are the changes in
- Axial eye growth
- Anterior chamber depth
- IOL-power for Spheris 209
- Lens thickness
- Pupil size under photopic and scotopic conditions
- Accommodation
- Best corrected visual acuity and distance corrected near visual acuity
- Atropine effects as a function of iris pigmentation
in the course of 12 months of low dose Atropine treatment.
The secondary efficacy variables are the
differences (measurement after 12 months of low dose Atropine treatment minus measurement at start of study) of
- Axial eye growth
- Anterior chamber depth
- IOL-power for Spheris 209
- Lens thickness
- Pupil size under photopic and scotopic conditions
- Accommodation
- Best corrected visual acuity and distance corrected near visual acuity
- Atropine effects as a function of iris pigmentation

Safety:
Change from Baseline to Day 365 in:
- IOP
- Appearance of the macula
Incidence of
- Local adverse drug reactions
- Systemic adverse drug reactions
as assessed by the subject/caregiver.
Incidence of adverse events assessed by investigator

E.5.2.1

Timepoint(s) of evaluation of this end point

Days 1, 15, 183, 365

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

135

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

105

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

Yes

F.3.3.7.1

Details of other specific vulnerable populations

Children, 6 - 12 years old

Kinder, 6 - 12 Jahre alt

F.4 Planned number of subjects to be included

F.4.1

In the member state

135

F.4.2

For a multinational trial

F.4.2.2

In the whole clinical trial

135

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

Keine außer der üblichen Behandlung

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2022-03-16

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-03-08

P. End of Trial
P.	End of Trial Status	Ongoing

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