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Trial registered on ANZCTR

Registration number

ACTRN12619000795190

Ethics application status

Approved

Date submitted

16/05/2019

Date registered

30/05/2019

Date last updated

4/07/2022

Date data sharing statement initially provided

30/05/2019

Type of registration

Prospectively registered

Titles & IDs

Public title

The Little Eye Drop Study: a randomised controlled non-inferiority trial on the microdrop administration of phenylephrine and cyclopentolate eye drops in neonates

Scientific title

Randomised Controlled Non-Inferiority Trial: Microdrop Administration of Phenylephrine and Cyclopentolate Eye Drops in Neonates

Secondary ID [1]

n/a

Universal Trial Number (UTN)

U1111-1233-2494

Trial acronym

n/a

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Retinopathy of Prematurity

Condition category

Condition code

Eye

Diseases / disorders of the eye

Reproductive Health and Childbirth

Complications of newborn

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Participants will be randomised to receive either a combination of;
1. Reference treatment: one combination microdrop of both phenylephrine 1% and cyclopentolate 0.2% to both eyes, or
2. Low dose treatment: one combination microdrop of both phenylephrine 0.5% and cyclopentolate 0.1% to both eyes.

Eye drops will be instilled by the nurse caring for the infant, approximately 30 minutes prior to eye examination. Eye examination will be carried out by the Paediatric Ophthalmologist, and will usually occur fortnightly, and up to weekly if there is retinopathy.

If the pupil is insufficiently dilated with one drop, two further administrations can occur, 20 minutes apart.

Intervention code [1]

Early detection / Screening

Comparator / control treatment

Reference treatment: one combination microdrop of both phenylephrine 1% and cyclopentolate 0.2% to both eyes

Control group

Active

Outcomes

Primary outcome [1]

Ease of dilation, using a study specific verbal survey of the Ophthalmologist.

Timepoint [1]

The research staff or nurse caring for the infant at the time of the retinopathy of prematurity eye examination (ROPEE) will verbally survey the ophthalmologist immediately after the ROPEE to ascertain the success of ROPEE/ease of ROPEE for the Ophthalmologist (easy vs difficult) immediately after the ROPEE.

Secondary outcome [1]

Adverse effects associated with the eye drops will be measured; 1) blood pressure, 2) heart rate, 3) feed intolerance and 4) respiratory function. Blood pressure and heart rate will be assessed with a Phillips monitor. Feed intolerance will be assessed by a review of medical notes. Feed volumes and spills, on the observation chart, for 24 hours prior and 24 hours post eye drop installation. Medical notes will be reviewed retrospectively for any documentation of Necrotising Enterocolitis (NEC) for 7 days post mydriatic eye drop installation. Respiratory function will be assessed by reviewing medical notes. Any change in overall daily level of respiratory support for 24 hours prior, day of and day after ROPEE to identify any changes in support, e.g. changes in level of PEEP, change in mode of support, or persistent change in oxygen requirement.

Timepoint [1]

Baseline blood pressure and heart rate measurements will be recorded. Subsequent measurements will be taken 20 min after eye drop instillation and then immediately before ROPEE. Medical notes will be reviewed for any change in the overall daily level of respiratory support for 24 hours prior, day of, and day after ROPEE. Feed intolerance will be reviewed by retrospectively reviewing feed volumes and spills, on the observation chart, for 24 hours prior and 24 hours post eye drop installation. Any associated or causative treatment emergent adverse events (TEAE), up to 7 days following eye drop instillation, will be recorded on the Case Report Form.

Secondary outcome [2]

Sufficient pupil dilation, determined by pupil diameter.

Timepoint [2]

Secondary efficacy outcome: research staff will take a photo of both eyes at the time of ROPEE (approx. 30 - 45 min after eye drop instillation).

Eligibility

Key inclusion criteria

Premature neonates admitted to Invercargill, Dunedin, Christchurch, Wellington or Auckland City hospital’s neonatal intensive care units, who are undergoing routine ROPEE in accordance with the National Guidelines (e.g. infants born less than 31 weeks gestational age and/or less than 1250g birthweight).

Minimum age

6 Weeks

Maximum age

4 Months

Sex

Both males and females

Can healthy volunteers participate?

Yes

Key exclusion criteria

Neonates with, a) retinopathy of prematurity (ROP) greater than stage 2, b) current eye infection, c) not able to use phenylephrine or cyclopentolate eye drops.

Study design

Purpose of the study

Diagnosis

Allocation to intervention

Randomised controlled trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

Participants will be randomised to treatment or control, by Optimus Healthcare, who are manufacturing the eye drops (off-site), and then Optimus Healthcare will courier the eye drops to the various Neonatal Units.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation)

Masking / blinding

Blinded (masking used)

Who is / are masked / blinded?

The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data

Intervention assignment

Parallel

Other design features

non-inferiority study design

Phase

Phase 4

Type of endpoint/s

Safety/efficacy

Statistical methods / analysis

The primary efficacy outcome measures are nominal variables, and the data set is less than 1,000, therefore the Fisher’s exact test of independence will be used. The null hypothesis is that the relative proportions of the reference treatment are independent of group B.
The secondary efficacy outcome measures and secondary safety outcome measures include one measurement variable and one nominal variable, therefore a paired Student’s t-test will be used. It is assumed that both groups will be normally distributed and homoscedasticity. The null hypothesis is that the means of the measurement variable are equal for the two groups.

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

8/07/2019

Actual

7/10/2019

Date of last participant enrolment

Anticipated

23/11/2020

Actual

12/07/2021

Date of last data collection

Anticipated

30/11/2020

Actual

12/09/2021

Sample size

Target

150

Accrual to date

Final

150

Recruitment outside Australia

Country [1]

New Zealand

State/province [1]

Otago

Country [2]

New Zealand

State/province [2]

Southland

Country [3]

New Zealand

State/province [3]

Canterbury

Country [4]

New Zealand

State/province [4]

Capital and Coast

Country [5]

New Zealand

State/province [5]

Auckland City Hospital

Funding & Sponsors

Funding source category [1]

Charities/Societies/Foundations

Name [1]

CureKids

Address [1]

96 New North Road, Eden Terrace, Auckland 1021

Country [1]

New Zealand

Funding source category [2]

University

Name [2]

University of Otago, School of Pharmacy and Dunedin School of Medicine

Address [2]

18 Frederick St Dunedin 9054

Country [2]

New Zealand

Primary sponsor type

University

Name

University of Otago

Address

18 Frederick St
Dunedin
9054

Country

New Zealand

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Other collaborator category [1]

Hospital

Name [1]

Southern District Health Board

Address [1]

201 Great King St Dunedin 9054

Country [1]

New Zealand

Other collaborator category [2]

Hospital

Name [2]

Christchurch Womens Hospital

Address [2]

2 Riccarton Ave, Christchurch Central, Christchurch 8011

Country [2]

New Zealand

Other collaborator category [3]

Hospital

Name [3]

Wellington Regional Hospital

Address [3]

Riddiford St, Newtown, Wellington 6021

Country [3]

New Zealand

Other collaborator category [4]

Hospital

Name [4]

Auckland City Hospital

Address [4]

Research Coordinator Room 92057 9th Floor/ Support building 1 Newborn Services Auckland City hospital 2 Park road Grafton Auckland 1023

Country [4]

New Zealand

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Health and Disability Ethics Committees (HDECs)

Ethics committee address [1]

133 Molesworth Street
Thorndon
Wellington 6011

Ethics committee country [1]

New Zealand

Date submitted for ethics approval [1]

03/06/2019

Approval date [1]

20/06/2019

Ethics approval number [1]

19/STH/114

Summary

Brief summary

Our study aims to find out if low dose vs very low dose pupil dilating eye microdrops are effective in premature infants, and if the eye drops are associated with a low risk of harm.

Retinopathy of prematurity (ROP) is a major cause of blindness in children who were born before 31 weeks gestational age or with a birth weight less than 1250 g.  Because of the risk of permanent blindness, this group of premature infants have routine ROP eye examinations (ROPEE).  

The eye examination involves a two-step process; 1) administration of mydriatic (pupil dilating) eye drops, and 2) the eye examination.  The eye drops are administered approximately 30 to 60 minutes prior to the ROPEE, and the eye exam occurs fortnightly, however if there are signs of retinopathy, the infant is likely to need weekly eye checks.  
Sufficient pupil dilation is needed to view of the retina.  Phenylephrine with cyclopentolate or tropicamide are the eye drop regimens that are used to dilate the pupil.  We know from our recent survey of neonatal units in Australia and New Zealand, that there is a wide variety of these regimens in use.  Regimens varied in concentration, drop volume and frequency of administration, and within this variation, 5 of the 11 centres were using adult doses, 2 were using more than an adult dose, and only 4 were using less than adult doses.  Results from a systematic review of the literature suggested that low dose mydriatics are effective at sufficiently dilating the neonatal pupil for ROPEEs.1   

Mydriatics have been associated with clinically significant cardiovascular, respiratory, and gastrointestinal adverse effects.1  Therefore, guidance on clinical practice is required to help reduce the exposure of excessive doses that some premature infants are receiving, especially when there is evidence that low doses are effective.  


References
1. Kremer LJ RD, Medlicott N, Broadbenr R. Systematic review of mydriatics used for screening of retinopathy in premature infants. BMJ Paediatrics Open 2019 doi: doi:10.1136/bmjpo-2019-000448

Trial website

none

Trial related presentations / publications

none

Public notes

none

Contacts

Principal investigator

Name

A/Prof David Reith

Address

University of Otago, Deans Department, Dunedin School of Medicine, 201 Great King St, Dunedin,9016

Country

New Zealand

Phone

+64 34797275

Fax

[email protected]

Contact person for public queries

Name

Lisa Kremer

Address

University of Otago School of Pharmacy Adams Building 18 Frederick St Dunedin 9054

Country

New Zealand

Phone

+64 34797275

Fax

[email protected]

Contact person for scientific queries

Name

Lisa Kremer

Address

University of Otago School of Pharmacy Adams Building 18 Frederick St Dunedin 9054

Country

New Zealand

Phone

+64 34797275

Fax

[email protected]

Data sharing statement

Will the study consider sharing individual participant data?

Yes

Will there be any conditions when requesting access to individual participant data?

Persons/groups eligible to request access:
• Only researchers who provide a methodologically sound proposal, on a case-by-case basis at the discretion of this studies PI.

Conditions for requesting access:
• -

What individual participant data might be shared?

• All non-identifiable data; individual participant data underlying published results only.

What types of analyses could be done with individual participant data?

• Any purpose, only to achieve the aims in the approved proposal, for IPD meta-analyses, as deemed fit by this studies PI.

When can requests for individual participant data be made (start and end dates)?

From:
Immediately following publication and until 31/12/2022

To:
-

Where can requests to access individual participant data be made, or data be obtained directly?

• Access subject to approvals by this studies Principal Investigator, requirement to sign data access agreement.

Are there extra considerations when requesting access to individual participant data?

What supporting documents are/will be available?

Doc. No.	Type	Email	Attachment
5830	Ethical approval	[email protected]	Study-related document.pdf
5831	Study protocol		Study-related document.pdf
5832	Informed consent form		Study-related document.pdf

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	Low dose or very low dose phenylephrine and cyclopentolate microdrops for retinopathy of prematurity eye examinations (The Little Eye Drop Study): A randomised controlled non-inferiority trial.	2023	https://dx.doi.org/10.1136/archdischild-2022-324929

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Documents added manually

Documents added automatically