Efficacy and Safety of Mydriatic Microdrops for Retinopathy Of Prematurity Screening (MyMiROPS)

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

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.

Study Overview

• Status: Completed
• Conditions: Retinopathy of Prematurity
• Intervention / Treatment: Drug: Microdrop administration of phenylephrine 1.67% and tropicamide 0.33%; Drug: Standard drop administration of phenylephrine 1.67% and tropicamide 0.33%

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 83
• Phase: Phase 4

Contacts and Locations

Study Locations

• Greece
  • Thessaloníki, Greece, 56429
    • Papageorgiou General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 8 months (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: SCREENING
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Study Group; Mydriasis with microdrops	Drug: Microdrop administration of phenylephrine 1.67% and tropicamide 0.33%; 1 drop (6.5 μL) for 3 doses with 5-minute intervals
ACTIVE_COMPARATOR: Control Group; Mydriasis with standard drops	Drug: Standard drop administration of phenylephrine 1.67% and tropicamide 0.33%; 1 drop (28-34 μL) for 3 doses with 5-minute intervals

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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).

Collaborators and Investigators

• Sponsor: Aristotle University Of Thessaloniki
• Collaborators: National and Kapodistrian University of Athens

Publications and helpful links

General Publications

• Lynch MG, Brown RH, Goode SM, Schoenwald RD, Chien DS. Reduction of phenylephrine drop size in infants achieves equal dilation with decreased systemic absorption. Arch Ophthalmol. 1987 Oct;105(10):1364-5. doi: 10.1001/archopht.1987.01060100066027.
• Elibol O, Alcelik T, Yuksel N, Caglar Y. The influence of drop size of cyclopentolate, phenylephrine and tropicamide on pupil dilatation and systemic side effects in infants. Acta Ophthalmol Scand. 1997 Apr;75(2):178-80. doi: 10.1111/j.1600-0420.1997.tb00119.x.
• Seliniotaki AK, Prousali E, Lithoxopoulou M, Kokkali S, Ziakas N, Soubasi V, Mataftsi A. Alternative mydriasis techniques for retinopathy of prematurity screening. Int Ophthalmol. 2020 Dec;40(12):3613-3619. doi: 10.1007/s10792-020-01542-x. Epub 2020 Aug 9.
• Seliniotaki AK, Haidich AB, Lithoxopoulou M, Gika H, Boutou E, Virgiliou C, Nikolaidou M, Dokoumetzidis A, Raikos N, Diamanti E, Ziakas N, Mataftsi A. Efficacy and safety of Mydriatic Microdrops for Retinopathy Of Prematurity Screening (MyMiROPS): study protocol for a non-inferiority crossover randomized controlled trial. Trials. 2022 Apr 15;23(1):322. doi: 10.1186/s13063-022-06243-7.

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 7, 2021
• Primary Completion (ACTUAL): January 20, 2023
• Study Completion (ACTUAL): January 23, 2023

Study Registration Dates

• First Submitted: September 2, 2021
• First Submitted That Met QC Criteria: September 9, 2021
• First Posted (ACTUAL): September 13, 2021

Study Record Updates

• Last Update Posted (ACTUAL): February 10, 2023
• Last Update Submitted That Met QC Criteria: February 9, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: ROP; retinopathy of prematurity; screening; phenylephrine; mydriasis; tropicamide; microdrops; dilating drops
• Additional Relevant MeSH Terms: Eye Diseases; Infant, Newborn, Diseases; Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Infant, Premature, Diseases; Retinal Diseases; Premature Birth; Retinopathy of Prematurity; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Muscarinic Antagonists; Cholinergic Antagonists; Cholinergic Agents; Protective Agents; Adrenergic alpha-Agonists; Adrenergic Agonists; Cardiotonic Agents; Respiratory System Agents; Sympathomimetics; Vasoconstrictor Agents; Mydriatics; Nasal Decongestants; Adrenergic alpha-1 Receptor Agonists; Phenylephrine; Oxymetazoline; Tropicamide
• Other Study ID Numbers: 23265/14-07-2021

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Deidentified Individual Participant Data (IPD) that underline published results, along with related data dictionaries, will be available from 3 months to 36 months following article publication, only to researchers who will provide a methodologically sound proposal, for types of analyses to achieve aims in the approved proposal or for individual participant data meta-analysis, and only after acceptance of the proposed protocol by our Institution's IRB. Proposals should be directed to the corresponding author (AM, amatafts@auth.gr) and data requestors will need to sign a data access agreement. The study protocol and statistical analysis plan will also be available, if needed.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No