Efficacy and Safety of Mydriatic Microdrops for Retinopathy Of Prematurity Screening

Study Overview
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Brief Summary
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The purpose is to test the hypothesis that microdrop instillation of combined phenylephrine 1.67% and tropicamide 0.33% eyedrops causes at least equal mydriasis compared with standard drop instillation of the same mydriatic regimen, which constitutes routine care for pupil dilation during retinopathy of prematurity (ROP) screening in our neonatal intensive care unit. Comparison, also, will be made to the subsequent adverse events and the drug concentration in peripheral blood samples.

Detailed Description
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A non-inferiority, crossover, randomized controlled trial will be conducted for this purpose. Participants will be randomly assigned to receive either a) microdrops on their first and standard drops on their second screening examination a week later (M/S group), or b) standard drops first and microdrops a week later (S/M group). Microdrops (6.5 μL) will be instilled using a calibrated micropipette, while standard drops (28-34 μL) will be instilled directly through the commercially available plastic multi-dose mydriatic dropper bottle.

Official Title
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Efficacy and Safety of Mydriatic Microdrops for Retinopathy Of Prematurity Screening: a Non-inferiority Crossover Randomized Controlled Trial (MyMiROPS Trial)

Conditions
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Retinopathy of Prematurity

Intervention / Treatment
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* Drug: Microdrop administration of phenylephrine 1.67% and tropicamide 0.33%
* Drug: Standard drop administration of phenylephrine 1.67% and tropicamide 0.33%


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Preterm infants undergoing screening for ROP, i.e. infants with GA < 32 weeks and/or BW < 1501 grams infants of greater GA and BW with comorbidities, e.g. sepsis, prolonged need for oxygen supplementation etc., as recommended by the attending neonatologist Exclusion Criteria: Unstable clinical condition Severe cardiovascular disease Congenital anomalies Clinical syndromes Inotropes' intake during the week prior to enrollment Traumatic apoptosis of the corneal epithelium Corneal ulcer Anatomical variations of the anterior segment Infants that are outpatients at the commencement of ROP screening

Ages Eligible for Study
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Minimum Age: 30 Weeks
Maximum Age: 36 Weeks

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Screening
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Study Group<br>Mydriasis with microdrops | Drug: Microdrop administration of phenylephrine 1.67% and tropicamide 0.33%<br>* 1 drop (6.5 μL) for 3 doses with 5-minute intervals<br>|
| Active Comparator: Control Group<br>Mydriasis with standard drops | Drug: Standard drop administration of phenylephrine 1.67% and tropicamide 0.33%<br>* 1 drop (28-34 μL) for 3 doses with 5-minute intervals<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mydriatic efficacy: millimeters of horizontal pupil diameter. |  | 45 minutes after the first drop instillation. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mydriasis sustainability: millimeters of horizontal pupil diameter. |  | 90 minutes after the first drop instillation. | 
| Mydriasis sustainability: millimeters of horizontal pupil diameter. |  | 120 minutes after the first drop instillation. | 
| Pharmacokinetic profile of phenylephrine: area under the whole blood concentration versus time curve (AUC). | Each participant will be sampled once (random allocation to one time-point). Blood sampling will be combined with peripheral blood collection for routine examinations. | Blood sampling at 15, 20, 25, 30, 40, 50, 60, 120, and 180 minutes after the first drop instillation. | 
| Pharmacokinetic profile of phenylephrine: maximum (peak) whole blood concentration (Cmax). | Each participant will be sampled once (random allocation to one time-point). Blood sampling will be combined with peripheral blood collection for routine examinations. | Blood sampling at 15, 20, 25, 30, 40, 50, 60, 120, and 180 minutes after the first drop instillation. | 
| Pharmacokinetic profile of phenylephrine: time to reach maximum (peak) whole blood concentration (Tmax). | Each participant will be sampled once (random allocation to one time-point). Blood sampling will be combined with peripheral blood collection for routine examinations. | Blood sampling at 15, 20, 25, 30, 40, 50, 60, 120, and 180 minutes after the first drop instillation. | 
| Pharmacokinetic profile of phenylephrine: elimination half-life (T1/2). | Each participant will be sampled once (random allocation to one time-point). Blood sampling will be combined with peripheral blood collection for routine examinations. | Blood sampling at 15, 20, 25, 30, 40, 50, 60, 120, and 180 minutes after the first drop instillation. | 
| Heart rate values (beats per minute). |  | 45, 90 and 120 minutes after the first drop instillation. | 
| Oxygen saturation (SpO2) values (%). |  | 45, 90 and 120 minutes after the first drop instillation. | 
| Systolic, diastolic, and mean blood pressure values (mmHg). |  | 45, 90 and 120 minutes after the first drop instillation. Hourly blood pressure measurements for the first 24 hours after mydriasis. | 
| Number of participants with systemic adverse events. | Apnea, increased gastric residuals, inhibited duodenal motor activity, delayed gastric emptying, feeding intolerance, abdominal distension, vomiting, paralytic ileus, acute gastric dilatation, necrotizing enterocolitis (NEC). | During the 48 hours after mydriasis. | 
| Number of participants with local adverse events. | Periorbital pallor, eyelid swelling, flushing. | 45 minutes after the first drop instillation. | 
| Adequacy of judging the presence or absence of treatment-requiring ROP. |  | At the end of the eye examination (fundoscopy). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ROP, microdrops, mydriasis, dilating drops, phenylephrine, tropicamide, retinopathy of prematurity, screening