Microvolume eyedrop delivery using a patient-operated adaptor improved IOP control, reduced adverse effects and bottle exhaustion, and enhanced usability compared with conventional drops in outpatient glaucoma therapy.
Abstract
Purpose:
Comparing the intraocular pressure lowering (IOP-L) of microdrops (MD) dispensed with the Nanodropper with conventional drops (CD) in patients on IOP-L monotherapy.
Setting:
Outpatient clinic.
Design:
Prospective, crossover, examiner-masked, active-controlled, randomized trial conducted at a single center.
Methods:
We enrolled adults with stable primary glaucoma or ocular hypertension on monotherapy with either latanoprost 0.005% or timolol maleate 0.5%. Participants self-administered either CD or MD for 12 weeks, then crossed over to the alternate treatment for an additional 12 weeks. The primary outcome was IOP at 12 weeks compared with baseline at enrollment. Secondary outcomes included running out of drops (premature bottle exhaustion or PBE), adverse effects (AEs), and subjective evaluations of the device's usability.
Results:
29 participants completed the study. MD significantly decreased IOP from baseline by 1.6 mm Hg (95% CI 0.88-2.29), compared with a CD (0.13 mm Hg, 95% CI −0.26 to 0.52). Incidence of PBE decreased from 83% with CD to 17% with MD. AEs were reduced from 83% of participants reporting at least 1 AE with CD vs 62% with MD. Most found MD easy to administer and believed it helped prevent eyedrop waste.
Conclusions:
MD delivered with the Nanodropper adaptor provided additional IOP-L, significantly reduced PBE, and decreased the occurrence and severity of nonsystemic AEs compared with CD in this cohort of stable primary open-angle glaucoma/ocular hypertension participants. MD use among glaucoma participants may enhance tolerability, and improve adherence and long-term IOP control.
Globally, glaucoma is the leading cause of permanent blindness in adults. Even in the United States, more than 26% of patients with primary open-angle glaucoma (POAG) or ocular hypertension (OHT) may experience eventual blindness in at least 1 eye.1,2 In the United States, medications such as prostaglandin analogs and topical beta-blockers are often used as once-daily first-line therapies to minimize visual disability, with beta-blockers also commonly used as a second-line or adjunctive therapy.3
The human eye can only retain 7 to 10 μL of instilled fluid, yet most glaucoma medication bottles dispense conventional drops (CD) ranging in volume from 25 to 60 μL.4,5 Furthermore, videographic studies have demonstrated that many patients with glaucoma struggle with self-administration, often unintentionally instilling multiple drops (or even producing a stream) in a single attempt.6–8 Unsurprisingly, a previous report found that 25% of patients with glaucoma ran out of their medications before insurance covered their next refill on at least 1 occasion annually, a phenomenon we refer to as premature bottle exhaustion (PBE).9 Legislative support to address coverage gaps for PBE events is currently limited because only 29 states have adopted legislation mandating insurer coverage of early refills at the time of writing.10 A recent study found that compared with a U.S. state with these protections, patients with glaucoma in a state without this legislation were 9 times more likely to go without their medication because of the increased cost of an early refill.11
One potential solution is to reduce eyedrop and glaucoma medication wastage with the use of microdrops (MD), which are typically 20 µL or less. Microvolume delivery devices, such as the Nanodropper adaptor (Nanodropper, Inc.), have the potential to mitigate PBE by effectively reducing eyedrop volume and increasing the number of potential doses available per bottle.12
We previously reported that MD of timolol maleate delivered through the Nanodropper device produces less bradycardia and noninferior intraocular pressure–lowering (IOP-L) efficacy in comparison with CD when delivering timolol maleate 0.5% to OAG/OHT participants in a 1-day trial.13 A number of studies, using both the Nanodropper and other microvolume delivery devices, have also shown MD to exhibit comparable mydriatic efficacy and improved tolerability in pediatric populations.14,15 However, most studies on MD have been conducted in controlled clinical environments, possibly limiting the generalizability of findings to real-world patient use. In addition, previous research has predominantly assessed relatively short-term outcomes.
To advance this area of research, we designed a study to evaluate MD delivery of IOP-L medications using the Nanodropper when compared with CD in outpatients with OAG/OHT over sequential 12-week periods. We hypothesized that MD would provide noninferior IOP-L efficacy compared with CD while potentially reducing PBE, minimizing adverse effects (AEs), and improving participant-reported usability.
METHODS
Study Design and Participants
We designed a prospective, randomized, crossover, investigator-masked, active-controlled, noninferiority crossover trial to compare the effects of IOP-L medications delivered using a conventional eyedrop bottle with MD administered using the Nanodropper adaptor on a conventional bottle.
Eligible participants were 18 years or older with a diagnosis of POAG or OHT. All were on daily topical IOP-L therapy and were deemed to be stable (no apparent need to change IOP-L medications, no progression in IOP, disc cupping, retinal nerve fiber layer changes, or visual field changes within the preceding year). All participants were active or retired U.S. Air Force personnel, or family members thereof. Exclusion criteria included a diagnosis of secondary glaucoma, other retinal disease(s), use of more than 1 IOP-L medication, and history of IOP-L surgical interventions or laser procedures—with the exception of selective laser trabeculoplasty, as long as the procedure had not been performed within 6 months of enrollment. The study was conducted at the Wilford Hall Eye Center on Lackland Air Force Base in San Antonio, TX. The study was approved by the San Antonio Institutional Review Board, research protocols adhered to the tenets of the Declaration of Helsinki and HIPAA, and informed consent was obtained from all participants. The study was registered at ClinicalTrials.gov as NCT05844384.
Study Procedure and Assessments
Before enrollment, prospective participants underwent a prestudy evaluation where clinical histories were reviewed to assess eligibility. Eligible participants then provided informed consent and were randomized by a computer in a 1:1 ratio to 1 of 2 crossover treatment sequences: Sequence 1 consisted of CD for weeks 1 to 12 followed by MD for weeks 13 to 24, and sequence 2 consisted of MD for weeks 1 to 12 followed by CD for weeks 13 to 24 (Figure 1). After randomization, participants were scheduled for 4 study visits: baseline, safety, crossover, and final visits.
Figure 1.
Schematic of the crossover study design. CD = conventional drops; MD = microdrops
At the baseline visit, participants underwent IOP measurement using the Tono-Pen AVIA Tonometer (Reichert, Inc.), as well as a comprehensive slitlamp examination including both gonioscopy and dilated fundus examinations by an experienced optometrist. Investigators responsible for data collection were masked to treatment allocation. Participants also completed a baseline survey assessing medication utilization and AEs (Supplemental Material 1, available at http://links.lww.com/JRS/B515). Data were collected on local AEs as assessed with the Comparison of Ophthalmic Medications for Tolerability survey, and custom surveys were designed to record self-reported PBE, medications used and exhausted early, and perceived factors contributing to PBE.16
All participants returned for a safety visit during their MD treatment period (at week 4 in sequence 1 or week 16 in sequence 2) during which IOP measurements were repeated. The safety visit was to ensure that MD use did not cause IOP to change by more than 5 mm Hg from the preceding measurement.
At week 12, participants returned for a crossover visit, where they transitioned to the alternate treatment period (CD to MD for sequence 1, MD to CD for sequence 2) and received treatment-specific education corresponding to their new regimen. IOP was measured, and participants were surveyed again about medication utilization, AEs, and solicited factors supporting Nanodropper and CD usability using treatment-specific surveys (Supplemental Materials 2 and 3, available at http://links.lww.com/JRS/B516 and http://links.lww.com/JRS/B517).
At the final study visit (week 24), all study assessments were repeated, including IOP measurement, comprehensive slitlamp examination, and a final survey.
Intervention and Treatment Administration
All participants remained on their prescribed topical therapy regimen and were advised to use a single drop per eye of latanoprost 0.005% (2.5 mL, Sandoz Group AG) once daily or timolol maleate 0.5% (5 mL, Sandoz Group AG) twice daily throughout the study. No medication washout was implemented before enrollment, allowing for a continuous interval of therapy that would reflect real-world clinical usage. At the visit preceding the CD treatment period, participants were instructed on a proper eyedrop instillation technique using a conventional bottle. At the visit preceding the MD treatment period, participants were trained on how to install and use the Nanodropper with their respective medication. Participants were also supplied with new bottles of their medication and Nanodropper adaptors.
Study Outcomes and Statistical Considerations
The primary study outcome was IOP after 12 weeks of treatment. IOP was measured in both eyes, but only the eye with higher baseline IOP was included for analysis. If both eyes had the same baseline IOP, data from the right eye were used. Secondary planned outcomes included absolute and relative change in 12-week IOP compared with baseline, incidence of PBE, incidence and severity of nonsystemic AEs, and measures of device usability.
To assess whether Nanodropper-mediated MD were noninferior to CD in IOP-L efficacy, the required sample size was 24 participants (12 per sequence), calculated using 95% power, a 2-sided type I error rate of 0.05, a noninferiority margin of 3 mm Hg, and a within-participant SD in IOP-L difference of 2.7 mm Hg (determined from a pilot study; data not shown).17 To account for potential loss to follow-up, we recruited 30 participants.
The primary noninferiority analysis was conducted on the per-protocol population, defined as randomized participants with measurements from both posttreatment study visits. The primary superiority analysis and all secondary endpoint analyses were conducted on the intention-to-treat (ITT) population, which included all randomized participants with at least 1 posttreatment study visit.
The primary end point was deemed noninferior if the upper limit of the standard Wald-type 95% CI for the paired mean difference in 12-week IOP (MD IOP − CD IOP) did not exceed 3 mm Hg. If noninferior was established, superiority was tested using a longitudinal linear regression model for 12-week IOP (up to 2 observations per participant). Superiority was concluded if the upper limit of the 95% CI did not exceed zero.
Secondary analyses of the primary end point compared absolute and relative changes in IOP from baseline to 12 weeks. Additional secondary endpoint analyses included comparisons of incidence of both PBE and AE, as well as comparisons of the average AE severity (defined as the total severity on a scale of 1 to 5 divided by total number of AEs). Owing to the low prevalence of specific AEs, exact McNemar tests were used to compare the prevalence of specific AEs associated with each treatment. Exploratory analyses summarized device usability measures using descriptive statistics.
Subgroup analyses included assessment of the primary end point within groups defined by medication (latanoprost 0.005% vs timolol maleate 0.5%). All models included a main term for MD vs CD and robust standard errors to account for within-participant correlation. All hypothesis tests are 2-sided with a type I error rate set at 0.05 unless otherwise specified.
RESULTS
Participant Demographics and Baseline Characteristics
Between March, 2022, and November, 2023, 72 eligible participants were identified, and 30 consented to be enrolled and were randomized to treatment sequences. All 30 participants completed treatment with CD, and 29 participants completed treatment with MD; 1 participant was lost to follow-up before initiating MD treatment (Figure 2). Participant demographics and baseline characteristics for the ITT population are given in Table 1. All participants were on a single IOP-L medication.
Figure 2.
CONSORT diagram illustrating participant flow through each stage of the randomized controlled trial. CD = conventional drops; CONSORT = Consolidated Standards of Reporting Trials; MD = microdrops
Table 1.
Study participant demographics and baseline clinical characteristics
| Parameter | Sequence 1: CD → MD (n = 15) | Sequence 2: MD → CD (n = 15) | All (n = 30) |
| Age (y)a | 62.53 ± 7.66 | 60 ± 10.54 | 61.27 ± 9.15 |
| Sex, n (%) | |||
| Female | 5 (33.33) | 6 (40) | 11 (36.67) |
| Male | 10 (66.67) | 9 (60) | 19 (63.33) |
| IOP (mm Hg) | 15.8 ± 3.1 | 16.93 ± 2.55 | 16.37 ± 2.85 |
| VA (logMAR) | 0.01 ± 0.05 | 0.02 ± 0.07 | 0.02 ± 0.06 |
| Diagnosis, n (%) | |||
| POAG | 10 (66.67) | 9 (60) | 19 (63.33) |
| OHT | 5 (33.33) | 6 (40) | 11 (36.67) |
| Medication, n (%) | |||
| Latanoprost 0.005% | 12 (80) | 9 (60) | 21 (70) |
| Timolol 0.5% | 3 (20) | 6 (40) | 9 (30) |
CD = conventional drops; MD = microdrops; OHT = ocular hypertension; POAG = primary open-angle glaucoma
Values are expressed as mean ± SD unless otherwise indicated
Intraocular Pressure
In the ITT population, the mean baseline IOP (measured at the pretreatment visit) was 16.4 mm Hg. After 12 weeks of treatment, IOP was 16.2 mm Hg with CD and 14.9 mm Hg with MD (Figure 3, A). MD significantly reduced IOP by 1.6 mm Hg (9.4%) from baseline, whereas CD did not provide a significant reduction (0.1 mm Hg, 0.6%) (Figure 3, B and C). Treatment sequence (i.e. order of MD and CD administration) did not affect IOP.
Figure 3.
The effect of conventional drops and microdrops of IOP-lowering medications on IOP in patients with OAG/OHT. A: Mean IOP at baseline, 12 weeks, and 24 weeks in the 2 treatment sequences. The vertical line in the figure key signifies different sample sizes for the CD and MD treatments. Data graphed are mean ± SD. B: Mean IOP at baseline and after 12 weeks of treatment with MD or CD. Data graphed are mean ± SD. C: Mean IOP represented as percent of IOP at baseline (set to 100%) and after 12 weeks of treatment with MD or CD. Data graphed are mean ± SD. D: IOP point estimates (mean difference of MD IOP − CD IOP) and 95% CIs after 12 weeks of treatment. The magenta point estimate for the PP population was used to assess noninferiority, and the turquoise point estimate for the ITT population was used to assess superiority. The dotted magenta line and solid turquoise line represent the noninferiority (3 mm Hg) and superiority (0 mm Hg) margins, respectively. To establish noninferiority and superiority of MD compared with CD, the upper limit of the 95% CI for the point estimate must be less than the prespecified margins. Data graphed are mean ± SD. CD = conventional drops; ITT = intention-to-treat; MD = microdrops; OAG = open-angle glaucoma; OHT = ocular hypertension; PP = per-protocol
MD met the noninferiority criterion, with a mean IOP difference (MD − CD) of −1.4 mm Hg (95% CI −2.09 to −0.73) in the per-protocol population, which remained below the predetermined 3 mm Hg noninferiority margin (Figure 3, D). Furthermore, MD demonstrated superiority over CD, exhibiting a mean IOP difference of −1.30 mm Hg (95% CI −1.97 to −0.64) in the ITT population, which was significantly below the superiority margin of 0 mm Hg. Subgroup analyses for latanoprost 0.005% and timolol 0.5% are also summarized in Supplemental Table 1 (available at http://links.lww.com/JRS/B512), reflecting that both medications resulted in significantly greater IOP reductions with MD compared with CD.
Premature Bottle Exhaustion
At the baseline visit, we surveyed participants about factors contributing to PBE (Supplemental Table 2, available at http://links.lww.com/JRS/B513). In the ITT population, 25 participants (83.3%) reported running out of their medication prematurely at least once annually before the study, citing the following reasons (multiple responses allowed): 21 (84%) reported that more than 1 drop is dispensed from their medication bottle, 14 (56%) reported difficulty seeing the bottle tip clearly, 5 (20%) reported difficulty holding the bottle steady, and 3 (12%) reported that the drops are too large.
During the 12-week CD treatment period, 25 participants (83.3%) reported at least 1 PBE event (Table 2). Among these, 12 participants (48%) had 1 event, 9 (36%) had 2 events, 3 (12%) had 3 events, and 1 (4%) could not recall the exact number of PBE events. By contrast, PBE was only reported by 5 participants (17.2%) during the MD treatment period, and all cases involved only a single event. Overall, PBE prevalence was 66% lower with MD compared with CD (Table 2).
Table 2.
Premature bottle exhaustion events reported at the 12-week timepoint
| Parameter | CD (n = 30) | MD (n = 29) |
| Experienced PBE during 12-wk treatment perioda | 25 (83.33) | 5 (17.24) |
| Difference in PBE prevalence, % (MD − CD) (95% CI) | −66 (−100 to −8)* | |
| No. of PBE events | Participants reporting PBE (n = 25) | Participants reporting PBE (n = 5) |
| 1 | 12 (48) | 5 (100) |
| 2 | 9 (36) | 0 (0) |
| 3 | 3 (12) | 0 (0) |
| Don't remember | 1 (4) | 0 (0) |
CD = conventional drops; MD = microdrops; PBE = premature bottle exhaustion
Statistically significant
Values are expressed as n (%) unless otherwise indicated
Adverse Effects
A total of 14 unique AEs were reported by study participants. At least 1 AE was reported by 25 participants (83.3%) during the CD treatment period and 18 participants (62.1%) during the MD treatment period, although this difference did not reach significance (Table 3). Among AEs for which statistical significance could be calculated, the prevalence of bitter taste, burning, itchy eyes, eye redness, and tearing was significantly lower with MD than CD (Table 3).
Table 3.
Adverse effects reported at the 12-week timepoint
| Parameter | CD (n = 30) | MD (n = 29) | Difference in AE prevalence, % (MD − CD) | Significance (P value)a |
| Experienced ≥1 AEb | 25 (83.33) | 18 (62.07) | −21 | ns (.0703) |
| AE experienced | ||||
| Bitter taste | 21 (70) | 1 (3.45) | −66.55 | * (<.001) |
| Dry eyes | 20 (66.67) | 13 (44.83) | −21.84 | ns (.070) |
| Unusual taste | 19 (63.33) | 0 (0) | −66.33 | n/a |
| Burning | 18 (60) | 6 (20.69) | −39.31 | * (.004) |
| Itchy eyes | 16 (53.33) | 6 (20.69) | −32.64 | * (.002) |
| Eye redness | 13 (43.33) | 5 (17.24) | −26.09 | * (.021) |
| Tearing | 13 (43.33) | 4 (13.79) | −29.54 | * (.012) |
| Difficulty reading | 9 (30) | 5 (17.24) | −12.76 | ns (.125) |
| Blurred vision | 8 (26.67) | 4 (13.79) | −12.87 | ns (.125) |
| Difficulty focusing | 4 (13.33) | 4 (13.79) | 0.46 | ns (>.99) |
| Trouble seeing at night | 3 (10) | 2 (6.9) | −3.1 | ns (>.99) |
| Discharge from eyes | 2 (6.67) | 0 (0) | −6.67 | n/a |
| Swelling of eyelids | 2 (6.67) | 0 (0) | −6.67 | n/a |
| Dimming of vision | 1 (3.33) | 0 (0) | −3.33 | n/a |
| Brow ache | 0 (0) | 0 (0) | n/a | n/a |
AE = adverse effect; CD = conventional drops; MD = microdrops; n/a = not assessed; ns = nonsignificant
Statistically significant
P values derived from exact McNemars test for paired binary data
Values are expressed as n (%) unless otherwise noted
Nanodropper Usability
Participants were also surveyed about their opinions of various solicited features and potential benefits of the Nanodropper adaptor. The bright-colored tip was favored by 25 of the surveyed participants (86.2%), while 16 (55.2%) valued that the Nanodropper made eyedrops smaller, and 12 (41.4%) liked the softness of the tip (Supplemental Table 3, available at http://links.lww.com/JRS/B514). Regarding potential benefits, 23 participants (79.3%) valued the extended duration of their eyedrop medications, 15 (51.7%) experienced less discomfort during instillation, and 12 (41.4%) appreciated that MD reduced their AEs. Finally, 27 participants (93.1%) reported that using the Nanodropper to administer MD did not present any difficulties, and 24 (82.8%) believed that using the adaptor prevented them from wasting eyedrops.
DISCUSSION
In this randomized controlled trial, we compared MD delivery of 2 common IOP-L medications—latanoprost 0.005% and timolol maleate 0.5%—using the Nanodropper adaptor vs CD over a longer-term, 12-week study period. To the authors' knowledge, this is the first trial to evaluate at-home MD use by participants rather than administration by eyecare professionals in a clinical setting, and the first to evaluate its usability, along with its effects on PBE, and nonsystemic AEs. Compared with CD, MD demonstrated noninferior and superior IOP-L efficacy. Notably, these reductions in IOP were achieved while also producing more favorable AE profiles and significantly reduced rates of PBE.
Overall, treatment with MD resulted in a significant mean IOP reduction of 1.6 mm Hg from baseline, which was 1.4 mm Hg greater than with CD. Although participants in our study were already within their target IOP range, even a seemingly incremental reduction in IOP may influence clinical outcomes and the need for future interventions. For example, the VOYAGER study showed latanoprostene bunod 0.024% to produce a 1.2 mm Hg greater IOP reduction compared with latanoprost 0.005%, translating to a nearly 60% increase in the proportion of participants achieving their goal IOP within 1 month.18 These findings suggest that IOP reductions in the range observed with MD may be clinically impactful and that MD may be particularly useful for patients who are close to, but have failed to reach, their target IOP on a given therapy. In this way, MD may enable patients to remain on the same agent, mitigating the need to add or switch to other glaucoma medications, which could complicate adherence.
A number of factors may explain how MD enabled greater reductions in IOP relative to CD. A main physiologic consideration is decreased medication washout from reductions in reflex tearing associated with MD, which may have pharmacokinetic implications such as enabling longer precorneal residence time and increasing bioavailability.19,20
Lower rates of PBE may have also improved participant adherence to medication because premature eyedrop depletion can directly affect adherence if patients are unable to obtain early refills. In this study, MD decreased the prevalence of PBE by 79% compared with CD. Notably, 83% of participants in our study experienced PBE at least once during the CD treatment period, which is higher than previous studies with CD, which reported PBE rates between 25% and 46%.9,11 Potential explanations include differences in follow-up periods, proactively asking about PBE on the baseline survey, or increased awareness of PBE among eligible participants who chose to enroll.
AEs are also a known predictor of nonadherence.21 Previous studies found that up to 65% of patients with glaucoma experience at least 1 local AE, with AEs cited as the second-most common reason for switching IOP-L medications.22,23 These findings align with our results because 83% of participants experienced at least 1 AE during CD treatment. MD use significantly decreased multiple key AEs, such as eye redness, burning, and tearing. Given this moderate AE profile reduction—even with prostaglandin analogs, generally the most well-tolerated class of IOP-L medications—we posit that microvolume delivery adaptors may also improve tolerability across many other classes of topical ophthalmic medications.
Participants reported generally favorable perceptions of the Nanodropper adaptor. Key-endorsed features included the device's soft tip and smaller drop size, with perceived benefits such as eyedrop bottles lasting longer, reduced AEs, and improved instillation comfort. Although these impressions were subjective and solicited from survey response options, these perceptions may be broadly applicable to use of the Nanodropper adaptor with any compatible topical ophthalmic medication.
Our results agree with previously cited studies finding MD at least as effective as CE. This may help physicians to learn about the potential cost saving, efficacy, safety, and environmental impact of MD. Hopefully our study might influence the FDA to not only market the lowest comparably effective concentration of a medication but also the lowest volume drops with the most efficacy and least adverse events.
Our study may have had different results had we had a complete washout between study arms. The results of the efficacy data may have been more pronounced had we used a formal washout. Likewise, we might also have seen differences in the adverse events data.
During the conduct of our study, all participants received standardized counseling on the eyedrop instillation technique and adherence before both the CD and MD treatment phases; however, as is typical in outpatient settings, we were unable to directly verify adherence to eyedrops, which may have affected IOP outcomes. Our study also has several design limitations. We used a crossover rather than a parallel design, which assumes that responses by a specific participant in the first-treatment period would be comparable with those in the second. In addition, in an effort to reflect real-world clinical practice settings where patients with glaucoma typically continue IOP-L therapy without interruption, we did not include washout periods before treatment initiation or crossover. Although this precluded formal assessment of carryover effects, it aligns with previous studies and allowed for evaluation of medication utilization and adherence patterns.24–30 To mitigate concerns, IOP-L efficacy was assessed after 12 weeks of treatment, exceeding the typical 4-week washout period, and an IOP post hoc analysis confirmed the absence of a carryover effect (data not shown).
For the IOP noninferiority assessment, our study used a margin of 3 mm Hg, which is broader than the typical 1.5 mm Hg margin used in single IOP-L drug trials. Notably, our results also met the more rigorous superiority criterion of 0 mm Hg margin. In assessing secondary outcomes, one limitation is that treatment adherence was not directly measured. In addition, PBE prevalence was assessed using a binary yes/no inquiry, rather than direct enumeration of doses missed. Collecting these numerical data may help further elucidate the relationship between PBE, medication adherence, and IOP control, as well as the role of MD in mitigating missed doses and potentially impacting long-term vision outcomes.
Other study limitations include the inability to mask participants, limited power to detect small IOP differences for each drug individually, and the difference in dosing frequency between timolol (twice daily) and latanoprost (once daily). Finally, the trial was conducted within a U.S. Air Force clinic, where participants received medications exclusively at military pharmacies with no out-of-pocket costs. As a result, financial and accessibility factors that influence medication adherence among civilians may not have been fully represented.
Despite these limitations, this study provides clinically relevant information regarding MD delivery vs CD in patients with glaucoma. It demonstrates that MD delivery with the Nanodropper adaptor provides superior IOP-L efficacy compared with CD over a 12-week period in stable patients with glaucoma and that this efficacy can be achieved while simultaneously decreasing PBE and AE burden relative to CD. These findings support MD as a strategy to optimize IOP-L medication delivery, with the potential to improve vision outcomes and reduce barriers to adherence in outpatient glaucoma therapy.
WHAT WAS KNOWN
Achieving effective IOP-lowering (IOP-L) with topical ophthalmic medications is essential for glaucoma management, yet conventional-sized drops are associated with premature bottle exhaustion and adverse effects, which may adversely affect medication adherence and treatment efficacy.
Microvolume eyedrop delivery devices have the potential to optimize medication dosing, reduce medication waste, and mitigate adverse effects, although evidence for these in the glaucoma outpatient setting is lacking.
WHAT THIS PAPER ADDS
To the authors' knowledge, this study is the first randomized controlled trial to evaluate at-home microdrop use vs conventional drops for delivering topical IOP-L medications in stable patients with glaucoma.
Microdrops produce noninferior and superior IOP-L efficacy compared with conventional drops, with evidence suggesting potential advantages in mitigating premature bottle exhaustion, reducing adverse effects, and improving patient adherence to therapy.
Footnotes
Funding was provided by Nanodropper, Inc. (Rochester, Minnesota) and the U.S. Air Force Small Business Innovation Research (SBIR) Phase 2 Contract #FA864920C0054. The views expressed are those of the authors and do not reflect the official views or policy of the Department of Defense or its Components. The voluntary, fully informed consent of the participants used in this research was obtained as required by 32 CFR 219 and DODI 3216.02. The views of the companies/materials discussed in this presentation are not necessarily the official views of, or endorsed by, the U.S. Government, the Department of Defense, or the Department of the Air Force. No federal endorsement is intended.
Presented at the American Glaucoma Society Annual Meeting, Washington, District of Columbia, February 2025; and the American Academy of Ophthalmology Annual Meeting, Chicago, Illinois, October 2024.
Disclosures: J.S. Steger, E.P. Grewal, and A.J. Song are employees of Nanodropper, Inc. A.L. Robin is a consultant to Nanodropper, Inc. None of the other authors have any financial or proprietary interest in any material or method mentioned.
First author:
Jennifer S. Steger, PhD
Nanodropper, Inc., Rochester, Minnesota
Contributor Information
Jennifer S. Steger, Email: jsteger719@gmail.com.
José E. Capó-Aponte, Email: Jose.E.CapoAponte.ctr@health.mil.
Alexandra Papp, Email: axiepapp@gmail.com.
Alexandra J. Schulte, Email: alex.j.schulte2@gmail.com.
Eric P. Grewal, Email: eric@nanodropper.com.
Allisa J. Song, Email: allisa@nanodropper.com.
Elizabeth Colantuoni, Email: ejohnso2@jh.edu.
Jared C. Kelstrom, Email: jared.c.kelstrom.mil@health.mil.
REFERENCES
- 1.Susanna R, Jr, De Moraes CG, Cioffi GA, Ritch R. Why do people (still) go blind from glaucoma? Transl Vis Sci Technol. 2015;4(2):1. doi: 10.1167/tvst.4.2.1 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Malihi M, Moura Filho ER, Hodge DO, Sit AJ. Long-term trends in glaucoma-related blindness in Olmsted County, Minnesota. Ophthalmology. 2014;121(1):134–141. doi: 10.1016/j.ophtha.2013.09.003 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Wang T, Cao L, Jiang Q, Zhang T. Topical medication therapy for glaucoma and ocular hypertension. Front Pharmacol. 2021;12:749858. doi: 10.3389/fphar.2021.749858 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Mishima S, Gasset A, Klyce SD, Jr, Baum JL. Determination of tear volume and tear flow. Invest Ophthalmol. 1966;5(3):264–276 [PubMed] [Google Scholar]
- 5.Lederer CM, Harold RE. Drop size of commercial glaucoma medications. Am J Ophthalmol. 1986;101(6):691–694 [DOI] [PubMed] [Google Scholar]
- 6.Stone JL, Robin AL, Novack GD, Covert DW, Cagle GD. An objective evaluation of eyedrop instillation in patients with glaucoma. Arch Ophthalmol. 2009;127(6):732–736 [DOI] [PubMed] [Google Scholar]
- 7.Hennessy AL, Katz J, Covert D, Kelly CA, Suan EP, Speicher MA, Sund NJ, Robin AL. A video study of drop instillation in both glaucoma and retina patients with visual impairment. Am J Ophthalmol. 2011;152(6):982–988. doi: 10.1016/J.AJO.2011.05.015 [DOI] [PubMed] [Google Scholar]
- 8.Hennessy AL, Katz J, Covert D, Protzko C, Robin AL. Videotaped evaluation of eyedrop instillation in glaucoma patients with visual impairment or moderate to severe visual field loss. Ophthalmology. 2010;117(12):2345–2352. doi: 10.1016/J.OPHTHA.2010.03.040 [DOI] [PubMed] [Google Scholar]
- 9.Moore DB, Walton C, Moeller KL, Slabaugh MA, Mudumbai RC, Chen PP. Prevalence of self-reported early glaucoma eye drop bottle exhaustion and associated risk factors: a patient survey. BMC Ophthalmol. 2014;14(1):79. doi: 10.1186/1471-2415-14-79 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Early Eye Drop Prescription Refill Legislation. American Academy of Ophthalmology. Accessed October 10, 2025. https://www.aao.org/advocacy/eyedrop-refills/eyedrop-prescription-refill-map [Google Scholar]
- 11.Hehr N, Barlow PB, Najdawi W, Reyes AG, Boese E, Fingert JH, Pouw AE. The effect of insurance coverage laws on glaucoma eyedrop medication usage. Ophthalmology. 2024;131(4):507–509. doi: 10.1016/J.OPHTHA.2023.12.022 [DOI] [PubMed] [Google Scholar]
- 12.St Peter DM, Steger JS, Patnaik JL, Davis N, Kahook MY, Seibold LK. Reduction of eyedrop volume for topical ophthalmic medications with the Nanodropper bottle adaptor. Med Devices (Auckl). 2023;16:71–79. doi: 10.2147/MDER.S397654 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Steger JS, Durai I, Odayappan A, Raman R, Sruthi T, Song AJ, Puthuran G, Venkatesh R, Colantuoni E, Robin AL. An evaluation of the efficacy and safety of timolol maleate 0.5% microdrops administered with the Nanodropper. Ophthalmology. 2024;131(9):1045–1055. doi: 10.1016/j.ophtha.2024.03.012 [DOI] [PubMed] [Google Scholar]
- 14.Hoppe CB, Yonamine S, Kao BW, Turner ML, Ou Y, Han Y, Keenan JD, Oatts JT. Randomized trial to evaluate the efficacy of the Nanodropper device for pupillary dilation and cycloplegia in children. Ophthalmology. 2023;130(3):324–330. doi: 10.1016/j.ophtha.2022.10.016 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Seliniotaki AK, Lithoxopoulou M, Virgiliou C, Gika H, Dokoumetzidis A, Bougioukas KI, Raikos N, Diamanti E, Ziakas N, Haidich AB, Mataftsi A. Efficacy and safety of mydriatic microdrops for retinopathy of prematurity screening: the MyMiROPS randomized clinical trial. JAMA Ophthalmol. 2025;143(2):110–116. doi: 10.1001/jamaophthalmol.2024.5462 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Barber BL, Strahlman ER, Laibovitz R, Guess HA, Reines SA. Validation of a questionnaire for comparing the tolerability of ophthalmic medications. Ophthalmology. 1997;104(2):334–342. doi: 10.1016/S0161-6420(97)30314-5 [DOI] [PubMed] [Google Scholar]
- 17.Schoenfeld D. Statistical Considerations for a Cross-Over Study Where the Outcome Is a Measurement. MGH Mallinckrodt General Clinical Research Center. Accessed October 10, 2025. http://hedwig.mgh.harvard.edu/sample_size/js/js_crossover_quant.html [Google Scholar]
- 18.Weinreb RN, Ong T, Scassellati Sforzolini B, Vittitow JL, Singh K, Kaufman PL; VOYAGER study group. A randomised, controlled comparison of latanoprostene bunod and latanoprost 0.005% in the treatment of ocular hypertension and open angle glaucoma: the VOYAGER study. Br J Ophthalmol. 2015;99(6):738–745. doi: 10.1136/bjophthalmol-2014-305908 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Song AJ, Steger JS, Robin AL. Redefining ocular drug delivery. Ocul Surf. 2022;26:197–199. doi: 10.1016/j.jtos.2022.09.001 [DOI] [PubMed] [Google Scholar]
- 20.Kelly JA, Molyneux PD, Smith SA, Smith SE. Relative bioavailability of pilocarpine from a novel ophthalmic delivery system and conventional eyedrop formulations. Br J Ophthalmol. 1989;73(5):360–362. doi: 10.1136/bjo.73.5.360 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Kahook MY. Developments in dosing aids and adherence devices for glaucoma therapy: current and future perspectives. Expert Rev Med Devices. 2007;4(2):261–266. doi: 10.1586/17434440.4.2.261 [DOI] [PubMed] [Google Scholar]
- 22.Nordmann JP, Auzanneau N, Ricard S, Berdeaux G. Vision related quality of life and topical glaucoma treatment side effects. Health Qual Life Outcomes. 2003;1:75. doi: 10.1186/1477-7525-1-75 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Zimmerman TJ, Hahn SR, Gelb L, Tan H, Kim EE. The impact of ocular adverse effects in patients treated with topical prostaglandin analogs: changes in prescription patterns and patient persistence. J Ocul Pharmacol Ther. 2009;25(2):145–152. doi: 10.1089/jop.2008.0072 [DOI] [PubMed] [Google Scholar]
- 24.Rossi GCM, Pasinetti GM, Bracchino M, Bucarelli M, Franchin S, Cerqueti P, Bellini R, Caravati C, Celesia L, Clemente A, Tinelli C. Switching from concomitant latanoprost 0.005% and timolol 0.5% to a fixed combination of travoprost 0.004%/timolol 0.5% in patients with primary open-angle glaucoma and ocular hypertension: a 6-month, multicenter, cohort study. Expert Opin Pharmacother. 2009;10(11):1705–1711. doi: 10.1517/14656560903061283 [DOI] [PubMed] [Google Scholar]
- 25.Centofanti M, Oddone F, Gandolfi S, Hommer A, Boehm A, Tanga L, Sangermani C, Sportelli V, Haustein M, Manni G, Rossetti L. Comparison of travoprost and bimatoprost plus timolol fixed combinations in open-angle glaucoma patients previously treated with latanoprost plus timolol fixed combination. Am J Ophthalmol. 2010;150(4):575–580. doi: 10.1016/j.ajo.2010.05.003 [DOI] [PubMed] [Google Scholar]
- 26.Wang CY, Chen YY, Liu CJL. Assessing the safety and efficacy of switching to brinzolamide/timolol fixed combination as a replacement therapy in patients with uncontrolled intraocular pressure in Taiwan. Taiwan J Ophthalmol. 2012;2(3):85–88. doi: 10.1016/j.tjo.2012.08.001 [DOI] [Google Scholar]
- 27.Shoji T, Sato H, Mizukawa A, Hirota N, Enoki T, Kojima T, Kanda T, Takeuchi M. Hypotensive effect of latanoprost/timolol versus travoprost/timolol fixed combinations in NTG patients: a randomized, multicenter, crossover clinical trial. Invest Ophthalmol Vis Sci. 2013;54(9):6242–6247. doi: 10.1167/iovs.13-11942 [DOI] [PubMed] [Google Scholar]
- 28.Özyol E, Özyol P. The efficacy of a latanoprost/timolol fixed combination versus latanoprost and timolol gel-forming solution unfixed combination on daytime intraocular pressure. J Glaucoma. 2016;25(2):135–139. doi: 10.1097/IJG.0000000000000170 [DOI] [PubMed] [Google Scholar]
- 29.Aptel F, Choudhry R, Stalmans I. Preservative-free versus preserved latanoprost eye drops in patients with open-angle glaucoma or ocular hypertension. Curr Med Res Opin. 2016;32(8):1457–1463. doi: 10.1080/03007995.2016.1202818 [DOI] [PubMed] [Google Scholar]
- 30.Gómez-Aguayo F, Paczka JA, Leñero-Córdova R, Jiménez-Román J, Davila-Villarreal J, Hartleben C, Baiza-Durán L, Olvera-Montaño O, García-Velez F, Muñoz-Villegas P. A phase III randomized clinical trial of a 0.5% timolol + 0.2% brimonidine + 2.0% dorzolamide fixed combination, preservative-free ophthalmic solution vs. 0.5% timolol + 0.2% brimonidine + 2.0% dorzolamide fixed combination in patients with controlled primary open-angle glaucoma. Ophthalmol Ther. 2018;7(1):145–156. doi: 10.1007/s40123-018-0128-8 [DOI] [PMC free article] [PubMed] [Google Scholar]