Please be advised that due to the high volume of submissions, the ANZCTR is currently experiencing delays in processing submissions from those outside of Australia and New Zealand. As the ANZCTR is funded by Australia and New Zealand, we must prioritise submissions from these countries first. International submissions should allow additional time for registration. Apologies for any inconvenience caused.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial registered on ANZCTR


Registration number
ACTRN12619000795190p
Ethics application status
Not yet submitted
Date submitted
16/05/2019
Date registered
30/05/2019
Date last updated
30/05/2019
Date data sharing statement initially provided
30/05/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Randomised Controlled Non-Inferiority Trial: 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] 298257 0
n/a
Universal Trial Number (UTN)
U1111-1233-2494
Trial acronym
RCT: MAPC-N
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Retinopathy of Prematurity 312861 0
Condition category
Condition code
Eye 311361 311361 0 0
Diseases / disorders of the eye
Reproductive Health and Childbirth 311444 311444 0 0
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] 314501 0
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] 320087 0
Ease of dilation, using a study specific verbal survey of the Ophthalmologist.
Timepoint [1] 320087 0
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.

Primary outcome [2] 320210 0
Sufficient pupil dilation, determined by pupil diameter.
Timepoint [2] 320210 0
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).
Secondary outcome [1] 370495 0
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] 370495 0
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.

Eligibility
Key inclusion criteria
Premature neonates admitted to Invercargill, Dunedin, Christchurch or Wellington 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
Gender
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
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 21487 0
New Zealand
State/province [1] 21487 0
Otago
Country [2] 21488 0
New Zealand
State/province [2] 21488 0
Southland
Country [3] 21489 0
New Zealand
State/province [3] 21489 0
Canterbury
Country [4] 21490 0
New Zealand
State/province [4] 21490 0
Capital and Coast

Funding & Sponsors
Funding source category [1] 302798 0
Charities/Societies/Foundations
Name [1] 302798 0
CureKids
Address [1] 302798 0
96 New North Road, Eden Terrace, Auckland 1021
Country [1] 302798 0
New Zealand
Funding source category [2] 302799 0
University
Name [2] 302799 0
University of Otago, School of Pharmacy and Dunedin School of Medicine
Address [2] 302799 0
18 Frederick St
Dunedin
9054
Country [2] 302799 0
New Zealand
Primary sponsor type
University
Name
University of Otago
Address
18 Frederick St
Dunedin
9054
Country
New Zealand
Secondary sponsor category [1] 302747 0
None
Name [1] 302747 0
Address [1] 302747 0
Country [1] 302747 0
Other collaborator category [1] 280705 0
Hospital
Name [1] 280705 0
Southern District Health Board
Address [1] 280705 0
201 Great King St
Dunedin
9054
Country [1] 280705 0
New Zealand
Other collaborator category [2] 280706 0
Hospital
Name [2] 280706 0
Christchurch Womens Hospital
Address [2] 280706 0
2 Riccarton Ave, Christchurch Central, Christchurch 8011
Country [2] 280706 0
New Zealand
Other collaborator category [3] 280707 0
Hospital
Name [3] 280707 0
Wellington Regional Hospital
Address [3] 280707 0
Riddiford St, Newtown, Wellington 6021
Country [3] 280707 0
New Zealand

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 303387 0
Health and Disability Ethics Committees (HDECs)
Ethics committee address [1] 303387 0
133 Molesworth Street
Thorndon
Wellington 6011
Ethics committee country [1] 303387 0
New Zealand
Date submitted for ethics approval [1] 303387 0
03/06/2019
Approval date [1] 303387 0
Ethics approval number [1] 303387 0

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 93498 0
Ms Lisa Kremer
Address 93498 0
University of Otago
School of Pharmacy
Adams Building
18 Frederick St
Dunedin
9054
Country 93498 0
New Zealand
Phone 93498 0
+64 34797275
Fax 93498 0
Email 93498 0
lisa.kremer@otago.ac.nz
Contact person for public queries
Name 93499 0
Ms Lisa Kremer
Address 93499 0
University of Otago
School of Pharmacy
Adams Building
18 Frederick St
Dunedin
9054
Country 93499 0
New Zealand
Phone 93499 0
+64 34797275
Fax 93499 0
Email 93499 0
lisa.kremer@otago.ac.nz
Contact person for scientific queries
Name 93500 0
Ms Lisa Kremer
Address 93500 0
University of Otago
School of Pharmacy
Adams Building
18 Frederick St
Dunedin
9054
Country 93500 0
New Zealand
Phone 93500 0
+64 34797275
Fax 93500 0
Email 93500 0
lisa.kremer@otago.ac.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
All non-identifiable data; individual participant data underlying published results only.
When will data be available (start and end dates)?
Immediately following publication and until 31/12/2021
Available to whom?
Only researchers who provide a methodologically sound proposal, on a case-by-case basis at the discretion of this studies PI.
Available for what types of analyses?
Any purpose, only to achieve the aims in the approved proposal, for IPD meta-analyses, as deemed fit by this studies PI.
How or where can data be obtained?
Access subject to approvals by this studies Principal Investigator, requirement to sign data access agreement.
What supporting documents are/will be available?
Study protocol
Informed consent form
Clinical study report
Ethical approval
Summary results
No Results