Randomized Controlled Trial Comparing the Efficacy and Safety of Mydriatic Microdrops Over Standard Dose Mydriatics for Pupil Dilation in Retinopathy of Prematurity Examination
Phase: EARLY_PHASE1
Conditions: Retinopathy of Prematurity
Sponsor: The University of Hong Kong

Date: 14th July, 2022  
 1 
Study Protocol 
 
Project title: Randomized controlled trial comparing the efficacy and safety of mydriatic 
microdrops over standard dose mydriatics for pupil dilation in retinopathy of prematurity 
examination.  
 
Background and purpose:  
Preterm and very low birth weight infants are at risk of developing retinopathy of 
prematurity (ROP) hence they require regular screening for early detection and timely 
treatment for ROP. Mydriatics are applied before ROP exam to dilate the pupils for fundal 
examination. In our unit, we are using Mydrin-P (0.5% tropicamide / 0.5% phenylephrine 
HCl) given thrice at 15 minutes intervals. This total dosage is the same as is being used for 
adult patients. Mydriatics are well known to have systemic side effects such as hypertension 
or hypotension, tachycardia or bradycardia, apnoea, cardiopulmonary arrest, seizures, 
necrotizing enterocolitis, and sepsis as they can bypass hepatic first pass metabolism and be 
directly absorbed into the systemic circulation. Preterm infants are more prone to suffer 
from these side effects due to smaller blood volume and immature drug metabolism. 10 13 14 
The smallest efficacious dose and combination of mydriatics for use in preterm infants has 
yet to be documented.  
 
Reduction in mydriatics dose for ROP exam emerges as a promising method to minimize 
systemic side effect without compromising the efficacy of mydriatics. 1 2 3  Several pilot 
studies in non-Asian countries were able to show that lower doses of mydriatics can achieve 
adequate pupil dilation 16 17. A systemic review evaluated 47 publications from 1986 to 2017 
on different mydriatics preparation used for ROP exam. It was shown that the lower doses 
mydriatics are effective compared to current high dose mydriatics being used following 
international guidelines. 14 However, most published data are underpowered and the 
population group in those studies are mostly non-Asians. It is known that that darker irides 
in Asians or Africans are more difficult and slower to dilate.20 The study on Asians by Luo et 
al. mentioned in the systemic review only compared the commercial Mydrin-P over locally 
compounded eye drops with the same concentration. 14, 19 There have been no studies or 
trials attempting to reduce the dose of Mydrin-P for use in ROP eye exams. Hence, we hope 
to be the pioneer in this area to conduct a non-inferiority trial comparing the efficacy and 
safety of microdrops over standard dose Mydrin-P in ROP screening.  
 
Aim of the study:  
To investigate  
1. If microdrops Mydrin-P can be used in ROP exam with similar efficacy compared to 
our current standard dose Mydrin-P, potentially with the advantage of fewer 
adverse effects.  
2. To ascertain the optimal time for eye examination after administration of mydriatics. 
3. To assess whether the cardiovascular, respiratory and gastrointestinal adverse 
effects differ between low dose mydriatics compared to standard dose. 
 
Inclusion and exclusion criteria:  
All preterm infants eligible for ROP screening will be recruited including those with 
estimated gestational age (EGA) at birth ≤32 weeks and/or birth weight ≤1500g. Neonates 

Date: 14th July, 2022  
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with severe clinical condition with unstable vital signs, congenital anomalies, syndromic 
disease, ophthalmological conditions such as eye infections, congenital eye anomalies, 
trauma, or with conditions that are contraindication to mydriatics will be excluded from the 
trial.  
 
Methods: 
This is a prospective, single centre, double blinded randomized controlled trial to be 
conducted on a group of preterm infants undergoing retinopathy of prematurity (ROP) 
examination.  The study will be conducted from around third quarter of 2022 (July-
September) to end of 2023. Inpatient infants will be recruited from Queen Mary Hospital in 
the neonatal intensive care unit and special baby care unit. Informed consent will be 
obtained from parents. Participants will be randomly assigned to either the study group or 
control group through computer generated algorithm for each episode of ROP exam. 
Randomization ratio is assigned to be 1:1. Each patient may have more than 1 episode of 
ROP examination so each episode of ROP exam will be randomly allocated into study or 
control group.  The randomization result will be concealed to principal investigator and 
ophthalmologist who will conduct the ROP exam. The control group will receive the 
standard Mydrin-P eyedrops which contain 0.5% phenylephrine HCl and 0.5% tropicamide. 
The study group will receive mydriatic microdrops which contain around one-third of the 
standard Mydrin-P dosage.  
 
The demographics including sex, gestational age and corrected age, current weight, 
ethnicity, level of respiratory support, eye color, other comorbidities such as 
bronchopulmonary dysplasia, necrotizing enterocolitis, renal failure, patent ductus 
arteriosus, sepsis etc. will be obtained prior to ROP examination.  
 
Following the randomization, those allocated to the control group will receive standard 
Mydrin P eyedrops (0.5% tropicamide / 0.5% phenylephrine HCl). Those allocated to the 
study group will receive Mydrin-P microdrops. The microdrop administration is through 
attaching a 16 gauge needle to a 1ml syringe.  Drop volume measurement was performed. A 
precision weight scale (Sartorius) with accuracy up to 0.001g was used to measure the drop 
volume. Standard Mydrin-P volume is around 45microlitre. Microdrop volume is around 
16microlitre which is around one-third of the standard Mydrin-P drop size.  
 
The eyedrops will be applied to the patients by nurses through a standardized method. All 
nurses will be taught on the methods of eyedrop application in order to reduce variations. 
Each dose of eyedrop should be applied from the medial corner of the eye directed to the 
lateral corner. Drug spilling around the eyes will be wiped off. Then a slight pressure should 
be applied to the medial corner of the eye for 3 minutes to prevent nasal mucosal 
absorption. For both groups of babies, one drop will be administered every 15 minutes for 
three administrations in total as per current practice prior to ROP screening by the 
ophthalmologist.   
 
Sample size calculation 
The sample size calculation was based on mean and standard deviation. Referring to the 
study published by Luo et al.19, mean pupil diameter was 7.22mm with 0.4mm standard 
deviation. The sample size was calculated based on the margin of error of this effect. With a 

Date: 14th July, 2022  
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sample size of 30, 95% of the confidence interval will be from 7.067 to 7.36mm with a 
margin of error of 0.15mm. Moreover, our pre-set cut off for minimal pupil diameter 
adequate for ROP exam is 7mm which was agreed by our ophthalmologist, with this sample 
size, it is estimated that 95% of the subject will have greater than or equal to a pupil size of 
7.067mm for ROP exam.  
 
Statistical analysis: 
IBM SPSS statistics version 26 software will be used for all statistical analysis. 
Demographic data are expressed in mean, standard deviation, number, and percentage 
when appropriate.  
Outcome including mean pupil diameter, vital signs such as heart rate, blood pressure, 
oxygen saturation, FiO2 requirement, episode of vomiting, volume of gastric residuals, 
episode of apnoea and the presence of periorbital blanching will be measured and 
compared between the study and the control group. Fisher's exact test will be used for 
categorical variables, independent samples T test will be used for continuous data. A paired 
sample t-test will be used to compare the related two means between paired observations. 
Significance level was set at 5%. All ethical considerations will be ensured throughout the 
study.  
Study outcomes:   
A trained masked observer will assess pupil size by using a pupillometer and visual 
assessment to capture 2 readings from each eye for each patient at four timepoints. Pupil 
diameter (in millimetres, mm) will be documented at baseline (before eyedrops are applied, 
T0), 30 minutes later (T30), 60 minutes later (T60) and 120 minutes later (T120). An eye 
speculum may need to be inserted by a registered trained doctor to open up the eyelids 
during pupillometer measurements to obtain the readings if spontaneous eye opening is not 
possible. Ophthalmologist will perform the ROP exam after the 3 doses of mydriatics. If 
there is inadequate pupil dilation as determined by the ophthalmologist, additional doses of 
standard dose Mydrin-P will be given in order to facilitate completion of the exam. And 
these patients would be considered as failure for exam and the data will not be included in 
the final analysis. Time of fundoscopy, the number of additional doses of mydriatics given 
will be documented.  
 
The primary outcome is whether the pupil size has attained equal or more than 7mm for 
ROP exam. 7mm will be the cutoff we use for an adequate pupil diameter for ROP exam.  
  
The secondary outcomes are the pupil diameters at T0, T30, T60 and T120, cardiovascular, 
respiratory, gastrointestinal side effects followed by the mydriatics administration. Vital 
signs such as heart rate, blood pressure (systolic and diastolic blood pressure taken at the 
same body part), oxygen saturation, FiO2 requirement will be documented at baseline (T0, 
just before eyedrop application), 30 minutes later (T30), 60 minutes later (T60) and 120 
minutes (T120). The following data will also be documented in the 24 hours after eyedrops 
administration and compared to the baseline which is the past 24 hours prior to the 
eyedrops exposure: episodes of vomiting, volume of gastric residuals, episodes of apnoea 
and the presence of periorbital blanching. Any other adverse event will also be recorded.  
 

Date: 14th July, 2022  
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