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Trial registered on ANZCTR


Registration number
ACTRN12616001266459
Ethics application status
Approved
Date submitted
5/09/2016
Date registered
9/09/2016
Date last updated
16/05/2019
Date data sharing statement initially provided
16/05/2019
Date results information initially provided
16/05/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Microdrop administration of phenylephrine and cyclopentolate in neonates (MAPC-N)
Scientific title
Testing a lower than standard dose of phenylephrine and cyclopentolate in neonates requiring pupil dilation for routine retinopathy of prematurity screening and red reflex testing.
Secondary ID [1] 290092 0
None
Universal Trial Number (UTN)
U1111-1187-0769
Trial acronym
MAPC-N
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Retinopathy of prematurity 300180 0
Condition category
Condition code
Eye 300064 300064 0 0
Diseases / disorders of the eye

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants will be randomised to receive either a combination of;
1. One combination microdrop (7 microlitre) of both phenylephrine 1% and cyclopentolate 0.2% to both eyes. Participants will have one to three doses administered depending on pupil dilation.
2. One combination microdrop (7 microlitre) of both phenylephrine 0.5% and cyclopentolate 0.1% to both eyes. Participants will have one to two doses administered depending on pupil dilation. If a third dose is required, it will be one combination microdrop (7 microlitre) of both phenylephrine 1% and cyclopentolate 0.2%

To develop an eye colour chart to determine light iris vs dark iris.

Intervention code [1] 295829 0
Early detection / Screening
Comparator / control treatment
Control treatment is one combination microdrop (7 microlitre) of both phenylephrine 1% and cyclopentolate 0.2% to both eyes.
Control group
Active

Outcomes
Primary outcome [1] 299532 0
To identify whether phenylephrine 1% or 0.5% and cyclopentolate 0.2% or 0.1% in a 7 microlitre volume will achieve adequate pupil dilation (>5 mm) for retinal examination in premature neonates. Pupil dilation will be measured using two pupilometers; Colvard pupilometer and a Neuroptics pupilometer.
Timepoint [1] 299532 0
Pupil measurements will be taken from both eyes at baseline, 20 minute, 45 minute, 90 minute and 120 minute intervals.
Secondary outcome [1] 327467 0
To describe the time-course of physiological markers of systemic absorption following eye drop administration (blood pressure).

Timepoint [1] 327467 0
Blood pressure will be taken at baseline, then six hourly post mydriatic dosing for 24 hours. Manual blood pressure will be measured using a Phillips monitor.
Secondary outcome [2] 327468 0
To determine if eye pigmentation (light or dark) is a potential covariate for phenylephrine and cyclopentolate induced pupil dilation.

Timepoint [2] 327468 0
Pupil measurements will be taken from both eyes at baseline, 20 minute, 45 minute, 90 minute and 120 minute intervals. Pupil measurement will be measured with both a Colvard pupilometer and a Neuroptics pupilometer.

Eye pigmentation will be determined by comparing neonatal eye colour to a colour chart (dark eye colour vs light eye colour).
Secondary outcome [3] 327538 0
To describe the time-course of physiological markers of systemic absorption following eye drop administration (heart rate).
Timepoint [3] 327538 0
Heart rate will be continuously measured for 24 hours prior and 24 hours post eye drop installation. Heart rate will be measured using a Phillips monitor.
Secondary outcome [4] 327539 0
To describe the time-course of physiological markers of systemic absorption following eye drop administration (feed intolerance).
Timepoint [4] 327539 0
Feed intolerance will be reviewed by retrospectively reviewing feed volumes and spills, on either the category 4 or 5 observation chart, for 24 hours prior and 24 hours post eye drop installation. Medical notes will be reviewed for 7 days post eye drop installation to monitor for diagnosis of necrotising enterocolitis.

Eligibility
Key inclusion criteria
All neonates that meet the Dunedin Hospital, Neonatal Intensive Care Unit (NICU) retinopathy of prematurity (ROP) screening criteria.

All infants who require pupil dilation for red reflex testing.
Minimum age
6 Weeks
Maximum age
4 Months
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Any neonate with ROP greater than stage 2.
Any neonate with an ocular medical condition.
If the staff member who administered the eye drop was unsure if the microdrop reached the eye, then the neonate will be excluded from the trial, in accordance with the per-protocol study design.
Any neonate whom phenylephrine and/or cyclopentolate is contraindicated.

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)
Sealed opaque envelopes
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Descriptive statistics for use in sample size calculations
Mean (SD) within-person dilation pre-treatment between eyes.
For those that have repeat measures: Mean (SD) within-person dilation pre-treatment, between visits for each eye.
Mean (SD) post-treatment dilation for each treatment
Mean (SD) within-person dilation post-treatment (difference between treatments). (calculated for: (a) only first visit data and (b) all data including repeats).
Pearson’s correlation coefficients for all within-person comparisons.
Proportion that sufficiently dilated for each treatment.
Range of dilation (mm) measured for “sufficient” and “not sufficient”.
Proportion of eyes/infants that had to be excluded because drop application was not successful.
Inter-observer reliability:
Inter-observer reliability assessed with intraclass correlation coefficient.
Mean (SD) difference between two measures by different observers (within-person mean. calculated, including repeats; then calculate the mean (SD) of the within-person means).
Data will be displayed visually where appropriate (histograms, scatter-plots, bar-graphs).
Statistical Analysis
Due to sample size, statistical tests in a pilot study are to be applied and interpreted with caution.
Was dilation different between treatments?
Paired and unpaired t-test for difference between treatments.
Was the proportion with sufficient dilation different between treatments?
McNemar’s test and Fishers exact test for analysis of sufficient dilation between treatments.
Was dilation different by demographics?
Using control data (current treatment) determine if pre- and post-treatment dilations are different by: gender; ethnicity; and iris colour, grade of ROP and level of respiratory support. Use unpaired t-tests for dilation measures and Fisher’s Exact test for sufficient dilation. Descriptive statistics (mean, SD and proportions) will be calculated for each of the groups.
Pupil diameter measurements
Correlations will be used for test-retest reliability of pupil diameter measurements and relative validity between measurement methods.
Ambient light measurements
Correlation between pre treatment dilation and ambient light. Difference in ambient light between those that sufficiently dilate and those that didn’t. Use unpaired t-test for analysis.
Describe the time course physiological markers
Systolic and diastolic blood pressure and heart rate results will be anaylsed using summary measures of hourly mean and peak results.
Feed intolerance will be commented on using summary measures and descriptive statements.
TEAE results will be commented on using descriptive statements.

Recruitment
Recruitment status
Completed
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] 8190 0
New Zealand
State/province [1] 8190 0
Dunedin

Funding & Sponsors
Funding source category [1] 294461 0
University
Name [1] 294461 0
University of Otago
Address [1] 294461 0
School of Pharmacy and Department of Medicine (Womens and Childrens)
18 Frederick St
Dunedin
9054
Country [1] 294461 0
New Zealand
Primary sponsor type
University
Name
University of Otago
Address
School of Pharmacy and Department of Medicine (Womens and Childrens)
18 Frederick St
Dunedin
9054
Country
New Zealand
Secondary sponsor category [1] 293327 0
None
Name [1] 293327 0
Address [1] 293327 0
Country [1] 293327 0
Other collaborator category [1] 279203 0
Hospital
Name [1] 279203 0
Dunedin Hospital
Address [1] 279203 0
201 Great King St
Dunedin
9054
Country [1] 279203 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295901 0
Health and Disability Ethics Committee
Ethics committee address [1] 295901 0
Ministry of Health
Ethics Department
Freyberg Building
Reception – Ground Floor
20 Aitken Street
Wellington
6011
Ethics committee country [1] 295901 0
New Zealand
Date submitted for ethics approval [1] 295901 0
12/09/2016
Approval date [1] 295901 0
28/11/2016
Ethics approval number [1] 295901 0
16/CEN/135
Ethics committee name [2] 295902 0
Health Research South
Ethics committee address [2] 295902 0
Dunedin Hospital
201 Great King St
Dunedin
9054
Ethics committee country [2] 295902 0
New Zealand
Date submitted for ethics approval [2] 295902 0
12/09/2016
Approval date [2] 295902 0
Ethics approval number [2] 295902 0

Summary
Brief summary
Phenylephrine and cyclopentolate are two medicines that are currently used at Dunedin Hospital during retinopathy of prematurity screening (eye checks). The two medicines are used to dilate the pupil so the retina can be viewed. Both of these medicines have been associated with harmful side effects such as necrotising enterocolitis, can cause reflux, feed intolerance, increase in blood pressure (which can increase the risk of intraventricular haemorrhage), increase in heart rate and there are case reports of seizures. One of the ways side effects can be reduced, is to reduce the amount of medication administered (i.e. reduce the dose).

It is known from published papers that small doses of these two medicines are likely to be effective in dilating pupils. What is unknown is if even smaller doses are effective, and this is what this study will compare – standard eye drop doses to half the usual dose.

The hope of the researchers, is that results from this study will suggest if using an even lower dose of phenylephrine and cyclopentolate will be effective in dilating neonatal pupils, with minimal side effects.
Trial website
n/a
Trial related presentations / publications
n/a
Public notes
n/a
Attachments [1] 1091 1091 0 0
Attachments [2] 1093 1093 0 0
Attachments [3] 1094 1094 0 0

Contacts
Principal investigator
Name 68826 0
Miss Lisa Kremer
Address 68826 0
University of Otago
School of Pharmacy
Adams Building
18 Frederick St
Dunedin
9054
Country 68826 0
New Zealand
Phone 68826 0
+6421973255
Fax 68826 0
Email 68826 0
lisa.kremer@otago.ac.nz
Contact person for public queries
Name 68827 0
Miss Lisa Kremer
Address 68827 0
University of Otago
School of Pharmacy
Adams Building
18 Frederick St
Dunedin
9054
Country 68827 0
New Zealand
Phone 68827 0
+6421973255
Fax 68827 0
Email 68827 0
lisa.kremer@otago.ac.nz
Contact person for scientific queries
Name 68828 0
Miss Lisa Kremer
Address 68828 0
University of Otago
School of Pharmacy
Adams Building
18 Frederick St
Dunedin
9054
Country 68828 0
New Zealand
Phone 68828 0
+6421973255
Fax 68828 0
Email 68828 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
Ethical approval
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
No
Results – basic reporting
Results – plain English summary
All infants had a successful retinopathy of prematurity eye examination following the administration of both eye drop regimens. Preliminary data analysis suggests that low dose and very low dose microdrop administration of cyclopentolate and phenylephrine is effective at dilating the neonatal pupil for retinopathy of prematurity eye examinations. Preliminary analysis of the safety data suggests no clinically or statistically significant difference in cardiovascular, respiratory or gastrointestinal effects.