Table 3.

Summary of uncontrolled trials evaluating the use of reduced eyedrop volume

Author, year	Design	Population (sample size)	Regimen(s)	Instilled drop volumes (level of comparison, i.e., eyes or subjects)	Method of instilling microdrops	Efficacy outcome(s)	Safety outcome(s)
a1-adrenergic agonists and muscarinic antagonists
Kremer 2021 [143]	Pilot randomized uncontrolled trial	Preterm infants (16)	Group A: PHE 1% & CYCLO 0.2% in a mixture (1 drop) Group B: PHE 0.5% & CYCLO 0.1% in a mixture (1 drop)	Only microdrops – exact volume ΝR (subjects)	24-gauge cannula attached to a 3 mL syringe after removal of the needle	No difference in pupil diameter at T45 and T90	No difference in the level of respiratory support up to day 2 No difference in gastrointestinal AE
Kremer 2023 [144]	Multi-center, non-inferiority, uncontrolled, randomized trial	Preterm infants (150)	Group A: PHE 1% & CYCLO 0.2% in a mixture (1 drop, up to 3 doses, 20 min interval) Group B: PHE 0.5% & CYCLO 0.1% in a mixture (1 drop, up to 3 doses, 20 min interval)	7 µl (subjects)	24-gauge cannula attached to the end of a syringe after removal of the needle	Successful ROP eye examination in both groups Smaller pupil dilation occurred in group B compared with group A (p = 0.01)	No difference in cardiovascular, respiratory (up to day 2), and gastrointestinal (up to day 7) AE
beta-blockers
Filippi 2017 [145]	Multicenter, open-label, pilot uncontrolled trial	Infants with stage 2 ROP in zone II without plus disease (23)	Propranolol 0.1% (3 drops every 8 h in each eye, as soon as stage 1 ROP was diagnosed and until complete retinal vascularization, but for no longer than 90 days)	6 µl	Variable volume pipette	1/23 progressed to ROP stage 2 with plus 5/23 progressed to ROP stage 3 with plus	None of the severe AE usually related to propranolol was observed No extended hospital stays Plasma propranolol during days 1–3 and on day 10 was about 10 times lower than that reported after oral propranolol administration of 1 mg/kg/d
Filippi 2019 [146]	Multi-center, open-label, single arm, phase IIB clinical trial	Preterm infants with GA ≤ 32 weeks and birthweight ≤ 1500 g, diagnosed with stage 1 ROP in zone II or III (98)	Propranolol 0.2% (3 drops every 6 h in each eye, as soon as stage 1 ROP was diagnosed and until complete retinal vascularization, but for no longer than 90 days)	6 µl	Micropipette	12/98 progressed to ROP stage 2 or 3 with plus Reduced number of treatments with laser or anti-VEGF compared with historical controls (p = 0.107)	None of the severe AEs usually related to propranolol was observed No extended hospital stays Large inter-individual differences in plasma concentrations were observed between the patients
Scaramuzzo 2023 [147]	Single arm, phase II clinical trial	Preterm infants (25)	Propranolol 0.2% (3 drops every 6 h in each eye, as soon as stage 1 or stage 2 ROP was diagnosed and until complete retinal vascularisation had been achieved, but for no longer than 90 days)	6 µl	Micropipette	A fourfold reduction in the number of infants who reached stage 3 ROP compared with historical controls (p = 0.013)	No reported AEs
prostaglandin analogues
Pasquale 2018 [148]	Uncontrolled trial	Adults (30)	Latanoprost 0.005% (1 drop every morning for 2 days)	8 µl	High-precision, piezo-print horizontal delivery system	Reduced levels of diurnal IOP at 1st and 2nd day post-instillation (p < 0.0001)	No cases of unintentional overdosing, tear fluid overflow, or dispenser tip/nozzle touching the eye None reported ocular discomfort No reported AEs

BP blood pressure, HR heart rate, NR not reported, IOP intraocular pressure, ROP retinopathy of prematurity, PHE phenylephrine, CYCLO cyclopentolate, AE adverse event