Mydriasis with micro-array print touch-free tropicamide-phenylephrine fixed combination MIST: pooled randomized Phase III trials

Mydriasis is necessary for approximately 80 million comprehensive and diabetic eye examinations [1] and over 3.8 million cataract surgeries annually in the USA [2]. Mydriasis is often achieved using parasympathetic antagonists, for example, tropicamide (TR), that block acetylcholine activation of muscarinic receptors, thereby, paralyzing the iris sphincter and ciliary muscles. Blockage of the iris sphincter muscle prevents pupil constriction. Paralysis of the ciliary muscle disrupts visual accommodation resulting in blurry near vision that may persist for hours. Rare but serious systemic side effects have been observed after ocular administration of anticholinergics, particularly in infants and children [3,4].

Pupil dilation is also achieved by sympathetic agonists, such as phenylephrine (PH), by stimulating the iris dilator muscle. While PH does not impact the ciliary body or decrease accommodation, the lower concentration (2.5%) generally does not dilate the pupil as well as parasympathetic antagonists. When full mydriasis is required, 10% PH is used. However, higher concentrations of PH are known to cause cardiovascular effects after systemic absorption, including hypertension, tachycardia, and, more rarely, arrhythmia and stroke, especially in patients with pre-existing heart conditions [4]. The standard of care is to incorporate both drug classes of mydriatics using 1.0% TR with 2.5% PH. Since eye drops containing a combination of PH and TR are only marketed outside the USA, most eye care providers administer sequentially a combination of both classes of mydriatic agents via conventional eye drop bottles to maximize mydriasis and minimize side effects.

Topical anesthesia has been recommended prior to the use of mydriatics. 0.5% proparacaine is often used to reduce the discomfort or stinging experienced as a side effect of subsequent mydriatics. Anesthetics disrupt the cornea increasing penetration and may enhance both the onset and magnitude of dilation. A typical mode of practice is to insert three separate drugs, igtt of 0.5% proparacaine, igtt of 1.0% TR and igtt of 2.5% PH to achieve mydriasis. The common practice of using three separate drugs for the purpose of dilation frequently reduces efficiency and impedes patient flow [5–7].

The average tear volume of an adult eye is 6–7 μl [8,9]. The estimated maximum volume that the inferior cul de sac of the eye can momentarily contain is approximately 30 μl which is rapidly reduced to 10 μl with normal blinking [10]. Typical bottle dispensers provide eye drops that range from 25 μl to more than 50 μl depending on the angle of the bottle, the amount of ophthalmic solution remaining, and the manufacturer [11]. Eye drops may lead to overflow where the excess drop spills beyond the lid margin and down the cheeks. When administering eye drops, even when completely correctly applied, several routes of absorption are possible and excess amounts can sometimes cause an unwanted systemic bioavailability of the drops when not completely absorbed into the eye [4]. The lack of fixed dosing with conventional eye drops to achieve mydriasis may negatively affect efficacy and efficiency. Specifically, instillation of 2 drops without adequate wait time will exceed the capacity of inferior cul de sac and dilute the therapeutic effect, while increasing the wait between administration of multiple drops substantially increases the time required to achieve maximal mydriasis. Therefore, there is a clinical benefit for microdose administration of the combined mydriatic agents to achieve dilation.

The Optejet^® uses Microdose Array Print (MAP) technology with horizontal delivery and columnar mist to administer a medication directly onto the cornea in less than the average involuntary blink response time of 100 milliseconds [12]. In particular, the Optejet was designed to deliver approximately 200 μg of PH and 80 μg of TR in a single application of approximately 8 μl to achieve reduced exposure to drug and preservatives. In contrast, a conventional eye drop dose, which is approximately 40 μl in volume, contains approximately 1000 μg PH and 400 μg of TR. The recessed nozzle and shutter of the Optejet enable no-touch columnar mist application, minimizing the risk of cross contamination by touch.

Previously, MAP technology evaluated in Phase II trials [13,14] in humans administered PH 2.5 and 10%, and TR 1% ophthalmic solutions individually, resulted in peak mydriasis that was at least comparable to eye dropper delivery. Compared with conventional eye dropper use, microdosing significantly reduced eye irritation, reduced plasma PK levels, and minimized discomfort. These microdosed mydriatics were well tolerated without the prior use of anesthetics. These initial clinical study results demonstrated that MAP technology may enhance drug bioavailability to target tissues and efficacy while minimizing exposure to nontarget tissues, systemic absorption, associated side effects, drug dilution and spillage.

To further validate these Phase II clinical results, the safety and efficacy of fixed-combination tropicamide-phenylephrine (TR-PH) for mydriasis was compared with its individual components and to placebo in two Phase III trials. In the MIST trials, TR-PH was specifically evaluated for efficacy in pupil dilation and for ocular tolerability.

Materials & methods

Study design

The MIST-1 and MIST-2 Phase III pivotal studies were prospective, double-masked, controlled, cross-over superiority studies. Eligible subjects were scheduled for three treatment visits occurring at least 2 days but no more than 7 days apart.

Randomization

In the MIST-1 study, each eligible subject was randomly assigned to receive one of six sequences of drug administration. At each of the three treatment visits one of the three study treatments (TR-PH, PH alone and TR alone) was administered in both eyes. Each study subject was treated with all three study medications over the course of this three-period crossover design. In the MIST-2 study each eligible subject was randomly assigned to receive one of two sequences (ABB or BAA) of study drug administration. At each of the three treatment visits one of the two study treatments (TR-PH or placebo) was administered in both eyes. Each study subject received one of these study treatments twice over the course of this 3-period crossover design. For both MIST-1 and MIST-2 the study drug administration schedule was equally distributed. In both studies subject drug administration assignments were prepared using a computer-generated randomization scheme by an independent statistician not involved in day-to-day study conduct. In MIST-1 and MIST-2 the drug assignment sequence was provided in paper format contained in a sealed envelope for each randomized subject.

Purpose

The two Phase III MIST (microdosed mydriasis therapy) pivotal trials were conducted to evaluate the safety and efficacy of a fixed-combination of TR-PH for mydriasis compared with each individual component and placebo with all treatment arms using the Optejet dispenser.

Procedures

The Optejet was used to deliver a microdroplet mist (~8 μl in volume). While sitting upright, the Optejet was positioned approximately 2–3 inches anterior to the cornea, and the subject was instructed to look directly at the Optejet target without blinking. No anesthesia was used for mydriasis prior to study drug administration.

Examinations performed

Efficacy and safety assessments were performed at specific time intervals. Specifically, pupil diameter was measured at baseline (predosing) and 20, 35, 50, 65, 80, 120 and 180 min following study drug administration. Pupil diameter was measured by digital pupillometry in highly photopic conditions that were established using a fully-charged transilluminator at the brightest setting. Pupil diameter was measured using the Neuroptics VIP 300 pupillometer. For all study subjects, the same pupillometer was used for each evaluation on any study visit day. Subjects were asked to focus straight ahead at a target 3 m distant to avoid accommodation. A fully-charged transilluminator was shone into one eye while the pupillometer was used to measure the pupil diameter in the fellow eye. After a brief rest period, the process was repeated to measure pupil diameter in the other eye. Another efficacy outcome measured was pupillary light reflex (PLR) to determine response to light after administration of study drug. A dilated pupil following administration of mydriatics is less responsive to light therefore an indication of efficacy. PLR evaluations were made using a fully-charged transilluminator that was shone into the eye and the pupil response (speed of pupil constriction) was noted using a scale. The response was recorded on a scale ranging from 0 to 3 where 0 = nonresponsive, 1 = minimally responsive, 2 = moderately responsive and 3 = brisk response. Baseline PLR was obtained prior to dose administration. Following dosing, PLR was again evaluated at 35 ± 5 min, 65 ± 5 min and 180 ± 5 min. Safety assessments included occurrence of adverse events (AEs).

Masking

The MIST-1 and MIST-2 studies were double-masked. The study drug administered was masked to the study subject, the investigator and study staff administering performing clinical assessments. The Sponsor (or designee) involved in day-to-day study management was also masked to study drug assignments. There were no differences in study drug presentation of the solutions tested. In accordance all study solutions were administered as a microdroplet mist (~8 μl in volume) using the Optejet. Study drug administration was performed by clinicians and technicians who had been trained on administration technique. In both studies, the Optejet (Figure 1) containing each study medication was used for medication administration to multiple subjects on each treatment day. To maintain masking of treatment assignments for study staff administering investigational product and/or performing clinical evaluations a pharmacy associated with the study site prepared, stored and managed the study solutions. In addition, clinicians who administered study drug were not allowed to perform post-treatment ophthalmic assessments. Therefore, different masked clinicians performed the ophthalmic assessments that were taken post study drug administration. Multiple clinicians performed the post study drug administration assessments and all measurements were taken following the procedures outlined in the approved protocol.

The MIST-1 study was conducted at a single site to assess the safety and efficacy of fixed-combination TR-PH in comparison with the individual drug components. The MIST-2 study was conducted as a multicenter study at two sites to assess the safety and efficacy of TR-PH in comparison with placebo. Both the MIST-1 and MIST-2 studies were conducted in compliance with the Declaration of Helsinki, Good Clinical Practice, Health Insurance Portability and Accountability Act (HIPAA) regulations and other applicable local and federal regulations including prospective Institutional Review Board (IRB) approval, and prospective, written informed consent provided by all participating subjects. The trials were registered at ClinicalTrials.gov (identifiers NCT03751631 and NCT03751098).

Subjects

Eligible subjects were male or female volunteers of any age with a photopic pupil diameter ≤3.5 mm in each eye at screening. Participants were required to be able and willing to provide signed written informed consent; those under the age of adulthood were required to provide written assent and/or parental consent as specified by the reviewing IRB.

Excluded from the study were individuals with an allergy to PH or TR, irregularly shaped pupil(s), history of neurogenic pupil disorder or closed angle glaucoma, anatomically narrow anterior chamber angles (Van Herrick grade ≤2 in either eye) as well as women of childbearing potential who were pregnant, nursing or not using a medically acceptable form of birth control. Other exclusions involved use or anticipated use of a benzodiazepine, monoamine oxidase inhibitor, tricyclic antidepressant, anticonvulsant or cholinergic drug, and current active eye disease requiring topical or systemic ophthalmic medication, except for artificial tears which had to be discontinued on the day of each treatment visit.

Statistics

Results from the pooled analyses of the Phase III MIST-1 and MIST-2 studies are presented. The primary efficacy end point is the mean change in pupil diameter at 35 min versus baseline at combined visits determined in the per-protocol (PP) population. The PP population consists of all randomized subjects who received all doses of medication and underwent all planned study assessments without a major protocol deviation.

The balanced crossover design used in MIST-1 allows for within-subject (i.e., within-eye) estimates of all treatment effects (A, B, and C for MIST-1) and all cross-treatment first-order carryover effects (AB, AC, BA, BC, CA, CB). The ABB/BAA crossover design used in MIST-2 allows for within-subject (i.e., within-eye) estimates of both treatment effects (A and B) and carryover effects (AA, AB, BA, BB). Thus, there is no need to include random effects for subject or eye in the analysis model. The fixed-effects ANOVA was used to analyze the data (Jones and Kenward, 2015, section 5.2) and tests were based on within-eye variances. A SAS REPEATED statement was used to adjust for correlation between fellow eyes. Hypothesis tests were based on confidence intervals produced by the SAS LSMEANS option for the pairwise differences between treatment.

Assessment of systemic and ocular safety and tolerability is based on AEs and findings from ophthalmic exams. The safety population consists of all randomized subjects who received a dose of study medication.

Exploratory efficacy outcomes include the proportion of eyes achieving 35-min postdosing clinically meaningful pupil diameters ≥6.0 and ≥7.0 mm, mean change in pupil diameter at 20, 50, 65, 80, 120 and 180 min postdose, and PLR at 35, 65 and 180 min postdose. PLR was graded on a scale ranging from 0 to 3 and the evaluation included the proportion of eyes for each grading on the scale 0 (nonresponsive), 1 (minimally responsive), 2 (moderately responsive) or 3 (brisk response).

Statistical programming and analyses were performed using SAS^® Version 9.4 or higher, or R version 3.5 or higher. Descriptive statistics were used to summarize continuous outcomes (e.g., mean, SD or standard error of the mean, median, maximum and minimum) and categorical variables (frequency and percentage). All primary analyses were performed using data from both eyes. All statistical tests were two-sided with a significance level of 0.05 (α = 0.05). CI for differences between treatment groups were two-sided at 95% confidence. Firth logistic regression [15] was used to compare the proportion of eyes achieving 35-min postdose pupil diameters ≥6.0 mm for TR-PH versus TR, PH and placebo (due to the absence of responders to placebo), while a clustered bootstrap provided CIs that account for correlation within subjects.

Results

Demographics & disposition

A total of 146 subjects from the combined MIST studies were screened for study participation, with 134 subjects randomized to treatment. After their first treatment visit three subjects withdrew from the study. Therefore, 131 subjects completed the two MIST studies. Demographics for the intent-to-treat (ITT) population are shown in Table 1. Mean age was 37.3 years with a SD of 13.5 years. Therefore, age ranged from 12 to 66 years. Slightly more subjects were male. The majority of subjects were white, and the majority of irides were dark.

Pupil dilation

As shown in Table 2, for primary efficacy the mean change in pupil diameter (mm) at 35 min postdosing with TR-PH in the pooled pp population recorded as mean (SE) was 4.72 (0.04) versus 4.11 (0.06) with TR, 0.85 (0.08) with PH and 0.05 (0.03) with placebo. The treatment group differences between TR-PH and each of its two components and placebo were statistically significant (p < 0.0001). The primary efficacy analysis for each individual study of MIST-1 and MIST-2 was similarly statistically significant. In MIST-1 treatment with TR-PH resulted in a statistically significantly greater change in pupil diameter than with either TR or PH alone and in MIST-2 the treatment with TR-PH resulted in a statistically significant greater change in pupil diameter than placebo.

The mean at baseline was similar across treatment groups noted as TR-PH 2.59 (0.03), TR 2.61 (0.05), PH 2.62 (0.05) and Placebo 2.59 (0.04) and is shown in Table 2. Of note in Table 2, was the mean at 35 min postdose for TR-PH 7.31 (0.05), TR 6.73 (0.08), PH 3.47 (0.08) and Placebo 2.63 (0.04).

The proportion of eyes achieving pupil diameter ≥6.0 mm at 35 min postdose in the pooled PP population by treatment is depicted in Figure 2. The actual proportion of eyes that achieved a pupil diameter of ≥6.0 mm at 35 min postdose was 93.3% with TR-PH compared with 78.2% with TR and 1.6% with PH. As expected, none of the placebo-treated eyes achieved a pupil diameter of ≥6.0 mm. The odds-ratio comparing TR-PH versus TR was 1.42 (two-sided bootstrap 95% CI [0.61, 2.40]), and 8.62 (two-sided bootstrap 95% CI [6.69, 12.52]) comparing TR-PH versus PH. The 95% CIs for the log odds ratios did not include 0, indicating significant differences between TR-PH and each of the other active treatments in the odds of achieving a ≥6.0 mm pupil diameter at 35 min postdose. Note, the proportion of eyes that achieved a pupil diameter of ≥6.0 mm at 20 min postdosing with TR-PH was 60.6%. A pupil diameter of ≥7.0 mm at 35 min postdose was achieved in 67.8% of eyes with TR-PH, 42.7% of eyes with TR, while no PH-treated eyes achieved a pupil diameter ≥7.0 mm.

The distribution of pupil diameters over each study-evaluated time point (20, 35, 50, 65, 80, 120 and 180 min) by treatment for the pooled PP population is presented in Figure 3. Mydriatic effect by timepoint showed treatment differences in mean pupil diameter as early as 20 min and remained present at 180 min postdose. Pupil dilation with TR-PH was rapid, with approximately 90% of the effect achieved at the 35-min evaluation. The observed mean pupil diameters at each time point for TR-PH in the pooled PP population were 2.59 mm (baseline), 6.22 mm (20 min), 7.31 mm (35 min), 7.66 mm (50 min), 7.75 mm (65 min), 7.78 mm (80 min), 7.59 mm (120 min) and 7.00 mm (180 min). Pupil dilation with TR was also rapid, with nearly all effect achieved at the 35-min evaluation. The onset effect of PH was slower, with very modest mydriasis at the 35-min evaluation. No meaningful change in pupil diameter was observed in the placebo group. For each of the active study medications, the mydriatic effect began to dissipate at the 120-min postdose evaluation and continued to decline at the 180-min time point.

Pupillary light reflex

As shown in Table 3, there was significantly less PLR after dosing with TR-PH than with either TR, PH or placebo at the prespecified 35, 65 and 180-min postdose evaluations. At 35 min postdose, the proportion of fully nonresponsive pupils (grade 0) was 97.5% with TR-PH, 75.8% with TR and 4.8% with PH. At 65 min postdose, the proportion of fully nonresponsive pupils (grade 0) was 93.3% with TR-PH, 82.3% with TR and 4.8% with PH. At 180 min postdose, the proportion of fully nonresponsive pupils (grade 0) was to 66.0% with TR-PH, 8.9% with TR and 0.8% with PH.

Study drug administration

After each dose was administered, subjects were asked if they felt wetness in the eye, which is an indication of successful dosing. If a negative response was registered, an additional dose of medication was administered. Successful dosing (administration of at least 1 mist) was achieved in all eyes at all treatment visits. The proportion of doses that were successfully administered on the first attempt with the Optejet was 83%. Unsuccessful dosing on initial attempt occurred when the patient moved or had eyes closed when drug was dispensed. There were no reports of ocular overflow and no reports of touch between the Optejet and the eye for any subject.

Adverse events

All subjects that received any study medication were included in the safety population. The rate of AEs was low (Table 4), and no systemic or serious AEs were reported. There were four ocular AEs reported with the use of each of the active treatments involving four subjects. The frequency of Any AE reported is represented in Table 4 by treatment arm as number of subjects (proportion of treatment group) or n (%). The frequency of Any AE reported across treatments was TR-PH 4 (3.1%), TR 4 (6.2%), PH 4 (6.5%) and placebo 0 (0.0%). While a single AE of moderate photophobia was reported with use of TR-PH, all other ocular AEs were mild in severity. All ocular AEs were transient and resolved prior to study exit. The types of ocular AEs reported were blurred vision, reduced visual acuity, photophobia, instillation site pain, eye pain and corneal staining. The frequency of each type of ocular AE with the use of TR-PH was blurred vision 1 (0.8%), reduced visual acuity 1 (0.8%), photophobia 1 (0.8%) and instillation site pain 1 (0.8%). These types of ocular AEs are consistent with the most common AEs reported with commercially available mydriatic eye drops.

Discussion

Over 80 million office-based and 3.8 million presurgery related instances of pupil dilation are performed annually in the USA. Current standard of care for most eye care providers is to employ a combination of TR and PH eye drops administered sequentially. Approximately 80% of a medication instilled as a conventional eye drop is lost to drainage during the first 15–30 s [16]. Eye drops stimulate lacrimation and can increase tear turnover rate more than fourfold, which additionally dilutes the drug product administered [17]. Eye drops often cause overflow over the lid and down the cheek causing waste and minimizing efficacy.

The inherent design problems with eye droppers can also impact safety and the potential for undesirable effects. Conventional eye drop volume overage drains into the nasolacrimal canal and is absorbed through the nasal mucosal vessels where the active drug product becomes available systemically and avoids first pass metabolism. Ocular medication in swallowed nasolacrimal secretions is theoretically available for absorption in the gastrointestinal tract. Only a small fraction of the applied medication is absorbed directly into the eye, while there remain multiple opportunities for systemic absorption [18]. Additionally, excess drug in the eye may cause ocular surface toxicity and tolerability issues. If eye drops cause discomfort, the loss rate can be even higher [19]. Therefore, a transition to microdosing from conventional eye drops would represent an advancement in the delivery of topical ophthalmic medication.

Presently, eyedroppers are the primary delivery method for topical ocular medications. This method of ocular drug delivery is hampered by the physiological barriers presented by the eyes [20]. While these barriers are intended to offer protection from ocular disease through lid blinking, glandular reflex tearing, nasolacrimal drainage and an impermeable cornea, they present challenges to topical ocular drug administration and related pharmacokinetic/pharmacodynamic profiles of medications. Furthermore, the challenges encountered by eyedropper drug delivery more specifically limit ocular drug bioavailability and drug retention. This presents a major need for new forms of topical ocular drug administration aimed at advancing the pharmacodynamic and pharmacokinetic profiles of ocular therapeutics. A recent area of focus for scientific advancement in ocular drug pharmacokinetics/pharmacodynamics has been to reduce the current drug volume of conventional eyedrops. Dropper bottles deliver a volume between 25 and 70 μl [21]. The average capacity of the conjunctival fornix is reported to be approximately 7 μl [8,9]. As the eyedropper volume exceeds the tear volume capacity of the eye, the excess medication may spill over to the inferior lid and cheek as overflow, may be absorbed into collateral tissue through the conjunctival vessels introducing ocular surface toxicity and/or exit the ocular surface through the nasolacrimal drainage system introducing unnecessary exposure to the systemic circulation. All these disadvantages due to administering excess medication ultimately results in a clearance of 90% of the eye drops within 2 min and only 5% of the administered dose permeates to the eye [22]. To improve upon this limited standard of care, the development program of the MAP technology was aimed at overcoming both eyedrop clearance and bioavailability hurdles. The novel approach to drug delivery with MAP technology administers 80% less medication and preservatives to avoid the pitfalls of ocular and systemic routes of clearance. In addition, the main objective of ocular therapeutics is to provide and maintain adequate concentration of the drug at the target site [23]. To foster an adequate concentration of drug at the target site and enhance pharmacodynamic profiles, the Optejet with MAP technology utilizes advanced electronically metered technologies for precision delivery of single-digit microliter volumes of ocular medications [13]. The Optejet’s single digit microliter drug volume administration falls below the reflex tearing threshold volume of 14 μl [8,13,24] allowing further potential to markedly increase the bioavailability of topical ocular medications.

The design of the Optejet allows for high precision targeted administration of TR-PH (∼8 μl/dose) without any use of prior anesthesia, resulting in improved patient comfort, lower drug exposure and significantly reduced overflow risk than with eye drops. Additionally, in clinical practice, eye dropper bottles of mydriatic agents are often used to treat multiple patients, increasing the risk of touch cross-contamination. The Optejet dispenser has no protruding parts to touch the ocular surface, thus minimizing cross-contamination risk.

The outlook of eyecare is acutely focused on improving patient outcomes and experience while increasing the efficiency of delivering care. The patient centric approach is evidenced by rapid advancements in diagnostic testing precision, as well as the emergence of well-targeted therapeutics aimed at maximizing the overall benefit/risk profile. All pharmaceutical agents whether diagnostic or therapeutic should be administered at the minimal required dose allowing immediate interaction with the target tissue in order to achieve the most efficient desired response within the broadest base of individual patients. The Optejet’s MAP technology is designed to closely align with this vision, offering an elegant, low-volume delivery of pharmaceuticals thus modernizing the current dilation process. The two Phase III MIST trials have evaluated the efficacy and safety of microdosed fixed-combination TR 1%/PH 2.5% for mydriasis and effectively demonstrated functional dilation is achieved without an anesthetic and with far less exposure to TR and PH, resulting in an improved patient experience.

Another movement to look toward is increasing the efficiency of the delivery of care. The fixed combination microdose of 1% TR/2.5% PH administered by the Optejet dispenser will allow eyecare practitioners to advance their practice with touch-free mydriasis, delivered with the push of a button in a precise, fast, microdroplet mist. Fixed combination 1% TR/2.5% PH microdroplet mist achieves effective mydriasis using the Optejet dispenser to hygienically administer a lower dose while eliminating the prolonged waiting time between conventional drops. Ultimately, during this period of upgrading sanitizing procedures across the healthcare field the portable Optejet is designed without protruding parts that can contribute to cross-contamination so it will meet the critical needs of modern eye care professionals when used on multiple patients.

Microdosed TR-PH with the Optejet dispenser moves essential mydriasis beyond the use of individual eye drop bottles, eliminates the need for topical anesthesia and reduces the dose of PH and TR. The safety and efficacy of TR-PH Optejet (delivery of ~80 μg of TR 1% and ~200 μg of PH 2.5% in a single application) was assessed in two prospective, double-masked, controlled, cross-over superiority studies with a favorable benefit to risk profile.

All study arms were limited to the use of the novel Optejet MAP technology for drug administration. The study did not include the conventional method of drug administration by eyedroppers. Previous studies have evaluated pupil dilation with common topical mydriatics in the form of traditional drops. In one study of 30 adult subjects administered a commercial eye drop of 1% TR, the mean pupillary diameter, measured by a millimeter ruler under the illumination of a direct ophthalmoscope, was initially 2.4 mm and increased to 5.5 mm at 30 min postadministration [25]. Another study compared the efficacy in pupil dilatation between a mixture containing 0.75% TR/2.5% PH and the alternate application of 1% TR/10% PH eye drops. At 40 min after drug application, mean pupil diameter was 6.6 (SD 0.8) mm in the mixture group and 6.0 (SD 0.9) mm in the alternate drug group (p = 0.05) [26]. There have been two studies that compared microdose to macrodose mydriatic drug delivery. The first study involving 26 premature infants compared mydriasis using 5 versus 26 μl cyclopentolate 0.5%/PH 2.5% showed no statistical difference in pupil dilation [27]. The other study was smaller with 12 healthy adults and specifically used the Optejet to dispense an 8 μl microdose of 10% PH compared with two different concentrations of 2.5% PH and 10% PH delivered by a 32-μl eyedropper. Microdosing with 10% PH achieved comparable peak dilation as 10% PH eyedropper-delivery and superior dilation to 2.5% PH eyedropper-delivery (p = 0.009) at 75 min. At 75 min after administration of 10% PH, the mean change in pupil size from baseline was similar using eyedropper-delivery and microdosing, in other words, 1.78 (SD 0.73) mm versus 1.55 (0.71) mm; p = 0.318. The mean change in pupil size from baseline with microdosed 10% PH was 47.6% greater compared with eyes treated with 2.5% PH eyedropper-delivery (1.55 vs 1.05 mm; p = 0.009) at 75 min [14].

Conclusion

The pooled results of these studies demonstrate that TR-PH produced clinically relevant and statistically superior pupil dilation compared with PH, TR and placebo. A statistically larger proportion of eyes achieved ≥6 mm pupil diameter with TR-PH than eyes treated PH, TR, and placebo at 35 min postdose. Mydriasis following TR-PH was rapid and sustained, which will provide ample time to perform ophthalmic assessments during dilated fundus exams or to perform routine cataract surgery. Moreover, the magnitude and sustainability of the mydriatic effect were confirmed by the pupillary nonresponsiveness results of PLR testing after administration of TR-PH.

TR-PH was safe and well-tolerated, with infrequent and generally mild, transient AEs consistent with existing mydriatic drugs. The outcomes of these MIST Phase III pivotal trials validate the efficacy and excellent safety profile of TR-PH. Microdosed TR-PH with the Optejet introduces an ‘anesthetic-free’ dilation to reduce exposure to unnecessary agents and streamline routine ophthalmic care for patients, technicians and physicians. Furthermore, use of TR-PH may enhance office efficiency, practice flow and patient experience.