Highlights
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Allergic conjunctivitis has an inflammatory late-stage allergic response.
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Corticosteroids can treat this response, but serious side effects are a concern.
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A dexamethasone intracanalicular insert reduced itching and conjunctival redness.
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This benefit can last up to 30 days while maintaining a favorable safety profile.
Purpose
The purpose of this study was to evaluate the efficacy and safety of a dexamethasone intracanalicular ocular insert for the treatment of allergic conjunctivitis.
Design
Multicenter, randomized, double-masked, placebo-controlled, Phase 3 clinical trial.
Methods
Subjects with allergic conjunctivitis were randomized 1:1 to receive a dexamethasone insert or a placebo insert in both eyes and were evaluated using a modified version of the conjunctival allergen challenge (CAC) model. After inserts were placed in office, a series of 4 closely spaced post-insertion CACs were conducted at weeks 1, 2, and 4 across approximately 30 days. Primary efficacy endpoints, assessed at week-1 CAC-day 8, were reported by subjects of ocular itching at 3, 5, and 7 minutes post CAC and investigator-evaluated conjunctival redness at 7, 15, and 20 minutes post CAC.
Results
For the primary endpoints, dexamethasone inserts showed statistically significantly lower mean ocular itching scores than placebo at all time points ( P <.001), with differences favoring dexamethasone inserts over placebo (0.86, 0.98, and 0.96 units at 3, 5, and 7 minutes, respectively) and statistically significantly lower conjunctival redness scores at 20 minutes ( P <.05) but not at 7 or 15 minutes ( P ≥.05). Results also showed statistically significantly less itching and conjunctival redness at 31 and 29 of 33 other time points, respectively ( P <.05). There were no serious adverse events; 1 subject had elevated intraocular pressure in both eyes.
Conclusions
Data presented in this study demonstrate the potential for a single, physician-administered dexamethasone intracanalicular insert to provide relief of ocular itching for up to 4 weeks in subjects with allergic conjunctivitis, while maintaining a favorable safety profile.
Allergic conjunctivitis is reported in up to 40% of the general population, and it is associated with a reduction in patients’ quality of life. Allergens can be seasonal (such as airborne pollen) or perennial (such as dust mites and pet dander), but the symptoms of allergic conjunctivitis include ocular itching, tearing, burning, stinging, photophobia, redness, swelling of the conjunctiva, , and nasal symptoms. Allergic conjunctivitis is caused by an inflammatory response to an allergen which binds to immunoglobulin E on the surface of mast cells. This binding induces mast cell activation and subsequent cellular release of histamine, tryptase, prostaglandins, and leukotrienes, which are responsible for the early phase of the allergic response (20-30 minutes after exposure). In addition, mast cell degranulation also induces the activation of vascular endothelial cells, which ultimately recruit inflammatory cells to the conjunctival mucosa, leading to the late phase of the allergic response approximately 4-8 hours after allergen exposure.
Topical antihistamines, which competitively and reversibly block histamine receptors, are commonly used to treat allergic conjunctivitis and have a rapid onset but short duration of action, which requires multiple instillations throughout the day. Because of their mechanism of action, antihistamines are typically effective against the early phase of the allergic response. Side effects of antihistamines include dizziness, sedation, blurred vision, impaired cognition, ocular burning, and ocular dryness. Topical mast cell stabilizers are another type of pharmacologic agent used to treat allergic conjunctivitis; they act by inhibiting the degranulation of mast cells, thereby potentially preventing the release of histamine and other allergic mediators, but they require a long loading period, meaning they must be routinely used for weeks before expected exposure to the allergen. ,
Most eye drops, including all antihistamines and mast cell stabilizers approved in the United States, contain preservatives which can cause ocular discomfort, corneal toxicity, and damage to the ocular surface.
Corticosteroids broadly respond to an allergic reaction through multiple mechanisms of action, including suppression of mast cell proliferation, reduction of inflammatory cell infiltration, and inhibition of the production of inflammatory mediators, such as prostaglandins and leukotrienes. These pleiotropic effects permit corticosteroids to positively impact both the early and the late phases of the allergic response. Topical corticosteroids are therefore often used for those patients more likely to experience the late-phase inflammatory response, including patients with moderate-to-severe symptoms, those with prolonged or repeated exposure to allergens, and those with persistent allergic conjunctivitis symptoms that are not adequately controlled by antihistamines and/or mast cell stabilizers. , However, serious potential side effects are possible due to long-term steroid use, including elevated intraocular pressure (IOP) and glaucoma, cataracts, and susceptibility to infections.
Despite the widespread use of topical therapies for the management of allergic conjunctivitis, a number of unmet needs remain. Because currently available treatment options for allergic conjunctivitis have suboptimal treatment characteristics (inconsistent efficacy, short duration of action, slow onset of action) and safety issues due to side effects, both steroid-induced and preservative-induced, there is a continued unmet need for long-acting therapy with consistent efficacy, a reduced dosing burden, and an improved ability to inhibit the late-phase inflammatory response without inducing any serious side effects.
To exploit the benefits of corticosteroids while avoiding their serious side effects, an intracanalicular dexamethasone insert has been developed (DEXTENZA [dexamethasone ophthalmic insert, 0.4 mg] Ocular Therapeutix, Inc., Bedford, Massachusetts, USA) ( Figure 1 ). Designed to replace traditional corticosteroid eye drops, this hydrogel-based dexamethasone insert is a hands-free, preservative-free alternative. It is placed by the physician through the lacrimal punctum into the canaliculus of the eyelid, and it is conjugated with fluorescein to aid in visualization, assuring compliance with the corticosteroid. The insert delivers a tapered release of 0.4 mg of dexamethasone to the ocular surface in a sustained manner for up to 30 days. The insert is resorbable and is cleared through the nasolacrimal duct, obviating the need for physician removal of the insert, although it can be removed if necessary. This dexamethasone insert was recently approved by the US Food and Drug Administration for the treatment of postoperative ocular pain and inflammation based on a favorable efficacy and safety profile among subjects undergoing cataract surgery. , ,
Evaluation of potential therapies for the treatment of allergic conjunctivitis can be difficult. Because of the wide variability in allergens and individuals’ responses to these allergens, environmental studies can introduce bias in the evaluation of potential ocular therapies. The standard Ora-CAC (conjunctival allergen challenge) (Ora Inc., Andover, Massachusetts, USA) model, on the other hand, reproducibly induces an acute moderate-to-severe ocular allergic reaction so that potential therapies can be studied for their impact on relieving signs and symptoms associated with the early phase of the allergic response. Using this approach, numerous antihistamines and mast cell stabilizers have been approved by regulatory agencies for this indication, including alcaftadine 0.25% (Lastacaft), cetirizine 0.24% (Zerviate), and bepotastine besilate 1.5% (Bepreve). However, to evaluate the impact of corticosteroid therapies on the late-phase inflammatory response to ocular allergens, multiple, repeated doses of allergen exposures are needed to provoke this late-phase response. Thus, a modified Ora-CAC model has been developed in which a series of repeated allergen challenge (using 4 challenges over a 2-day interval) induces the inflammatory component of allergic conjunctivitis, including an increase in the level of cellular infiltrates.
The objective of this study was to evaluate the efficacy and safety of a dexamethasone intracanalicular insert for the treatment of allergic conjunctivitis.
METHODS
This was a multicenter, randomized, double-masked (included subjects and study staff/investigators), parallel, placebo-controlled, Phase 3 study of a sustained-release dexamethasone intracanalicular insert (Investigational New Drug number: 114720) using a modified Ora-CAC model in subjects with allergic conjunctivitis. The study was conducted in accordance with tenets of the Declaration of Helsinki and complied with the Health Insurance Portability and Accountability Act. One central Institutional Review Board (Alpha IRB, San Clemente, CA) was used for all participating sites and IRB approval was obtained before study initiation for both the protocol and the informed consent form. Subjects provided written informed consent and signed the Health Insurance Portability and Accountability Act of 1996 form. This trial is registered in ClinicalTrials.gov (A Phase 3 Study Evaluating the Safety and Efficacy of OTX-DP for the Treatment of Chronic Allergic Conjunctivitis [OTX-14-007]; NCT02445326).
Modified Conjunctival Allergen Challenge Model
In the standard Ora-CAC model, allergens are applied directly to the eye under controlled conditions to allow observations of acute allergic changes. This model included a titration visit, to determine the specific allergen and the dose that elicited a positive clinical response, and a confirmation visit, to confirm the reproducibility of the response to the chosen dose. The efficacy of the study drug was then tested by performing a CAC at 1 week later in the presence of the drug and by measuring the signs and symptoms of allergic conjunctivitis at multiple post-CAC time points. In this study, a modified Ora-CAC model was used to induce the underlying inflammatory component of allergic conjunctivitis rather than induce only the early phase of the allergic response ( Figure 2 ). As opposed to a standard Ora-CAC model in which only 1 post-baseline CAC was performed, this modified Ora-CAC model included 3 sets of 4 post-baseline CACs, with each set performed during successive days (the first visit was day 1, followed by the second and third visits on the next day [8 hours apart], and the fourth visit held 24 hours after the third visit). The week-1 CAC was conducted on days 6-8, the week-2 CAC on days 13-15, and the week-4 CAC on days 26-29 through 28-31. Conducting successive, closely spaced CACs induced late-phase inflammation by the second CAC of each set. Thus, this study was conducted to assess the impact of the inserts on the acute allergic response in the presence of late-phase inflammation, as occurs with allergic conjunctivitis.
Study Participants
Inclusion criteria included subjects ≥18 years old; a positive history of ocular allergies; a positive skin test reaction to both a perennial allergen (cat or dog dander, dust mites, cockroaches) and a seasonal allergen (trees, grasses, and/or ragweed), as confirmed by the allergic skin test given at the subject’s initial screening visit. Inclusion criteria also included a positive bilateral CAC reaction (ie, ocular itching score ≥2 as measured on the Ora Calibra itching scale [Ora Inc., Andover, Massachusetts, USA]), which measures ocular itching on a scale of 0-4, where a score of 0 = none and a score of 4 = severe, and a conjunctival redness score ≥2, as measured on the Ora Calibra conjunctival redness scale, which measures conjunctival redness on a scale of 0-4 where a score of 0 = none and a score of 4 = severe) to a perennial allergen within 10 ± 2 minutes of instillation of the last titration of the allergen during the CAC titration. Inclusion criteria also included a positive bilateral CAC reaction for at least 2 of the 3 time points following the challenge during the first confirmatory CAC (on both visits); as well as an average itching score ≥3 and a conjunctival redness score of ≥2.5 for both eyes at post-CAC assessments during the second confirmatory CAC and a visual acuity of 0.7 logMAR or better in each eye.
Key exclusion criteria included a history of an IOP response to steroid treatment and a punctum that was too small to allow transient dilation to 0.7 mm prior to insertion of either the dexamethasone or placebo insert. Other exclusion criteria included but were not limited to IOP >22 mm Hg, narrow-angle glaucoma, retinal detachment, diabetic retinopathy, active retinal disease, presence of an active ocular infection, congenital or ocular anomaly or anomalies of the punctum, current diagnosis or history of herpes simplex keratitis, and any significant illness or condition. No antihistamines or corticosteroids (other than the dexamethasone insert) were permitted during the study.
Study Design
The study was conducted at 4 sites throughout the United States from April 2015 through August 2015 and included study visits on 13 days over a period of up to 11 weeks (approximately 30 days post insertion) ( Figure 2 ). After the final of 4 screening CACs (considered the baseline CAC), post-CAC ocular and nonocular allergic signs and symptoms were assessed. Visual acuity, slit lamp biomicroscopy, and punctum examination were also conducted as part of the baseline assessment. Investigators then scheduled qualified subjects to return in 2 to 3 days for randomization in a 1:1 ratio to receive either a 0.4 mg dexamethasone insert or placebo (vehicle) insert and insertion of the test article by the physician or optometrist into the canaliculus of both eyes (day 1). The placebo insert was manufactured in a process identical to the commercially available dexamethasone insert and was identical to it except for the absence of the dexamethasone. A computer-generated randomization schedule was produced prior to study enrollment by an unmasked statistician who was not otherwise involved in the study. Identical study drug packages were labeled with a unique number based on the randomization scheme such that the identity of the study drug (dexamethasone insert or placebo insert) could not be identified by the study site or the subject. Study staff randomly assigned each subject by using the lowest randomization number available at the site to obtain the subject’s study drug package.
After in-office placement of the insert as described in the dexamethasone insert instructions for use, subjects returned for 12 additional visits over 9 discrete days across approximately 30 days to conduct post-insertion CACs at weeks 1, 2, and 4. During those visits, the following assessments were performed: medical history and medication history update, visual acuity examination, slit lamp biomicroscopy, punctum examination (using a slit lamp with a blue light and yellow filter), visualization of the ophthalmic insert, IOP (selected visits), collection of adverse events (AE), CAC results, post-CAC subject-evaluated ocular and nonocular symptoms, and post-CAC investigator-evaluated signs.
Study Endpoints
The primary efficacy endpoints of the study, assessed at week-1 CAC-day 8 were 1) ocular itching reported by the subject at 3, 5, and 7 minutes post CAC; and 2) conjunctival redness evaluated by the investigator at 7, 15, and 20 minutes post CAC.
Key secondary efficacy endpoints included ocular itching and conjunctival redness at all visits other than the primary endpoint visit (day 8). Other secondary efficacy endpoints to be evaluated at 7, 15, and 20 minutes after each of the 4 visits for all 3 post-insertion CACs (weeks 1, 2, and 4), were 1) ciliary redness; 2) episcleral redness; 3) eyelid swelling; 4) tearing and watery eyes; 5) chemosis; 6) rhinorrhea; 7) nasal pruritus; 8) ear or palate pruritus; and 9) nasal congestion. All study endpoints were graded using Ora Calibra scales (all 0-4 scales except for eyelid swelling, which used a 0-3 scale).
Safety assessments at each post-insertion visit consisted of a collection of AE, visual acuity, slit lamp biomicroscopy, IOP, and dilated fundus examination (performed only at week-4 CAC days 28-31).
Statistical Methods
All efficacy analyses were performed on an intent-to-treat (ITT) population (all randomized subjects), and the primary efficacy analyses used Markov chain Monte Carlo multiple imputation methodology. All safety analyses were performed using the safety population (all subjects who received an ophthalmic insert). The statistical analyses of the data obtained from this study were performed using SAS version 9.2 software (Cary, North Carolina, USA).
The average of each subject’s eyes at each post-CAC time point was used as the unit of analysis for the primary endpoints. Each primary endpoint analysis was analyzed using an analysis of covariance (ANCOVA) for each post-CAC time point at week-1 CAC-day 8, with the time-appropriate post-CAC scores at the baseline visit as a covariate and treatment arm as the sole factor. At each post-CAC time point, treatment differences were considered statistically significant for each primary endpoint if they were significant at a 2-sided significance level of α = .05. Sample size was derived by calculating >90% power to demonstrate statistically significant differences.
A total of 36 subjects per treatment arm provided 91.4% and 98.6% power to demonstrate a statistically significant difference in ocular itching between dexamethasone insert and placebo insert arms at the first and each of the last 2 post-CAC time points of week-1 CAC-day 8, respectively, assuming a difference of 0.8 units at the first time point and 1.0 unit at the last 2 time points, an SD of ±1.0 unit, and a 2-sided Type I error of 0.05.
RESULTS
Participant Flow
A total of 73 subjects were randomly assigned in this study, 35 to the dexamethasone insert arm and 38 to the placebo insert arm. Of the 73 subjects enrolled in the ITT population and analyzed for the primary outcome ( Table 1 ), 70 completed the study, whereas 2 subjects discontinued due to withdrawn consent (1 subject in each treatment arm), and 1 subject (in the dexamethasone insert arm) discontinued due to unsuccessful placement of the insert. Thus, 72 subjects received intended treatment. Safety population constituted 72 subjects (excluding the subject with the unsuccessful dexamethasone insert placement) ( Table 1 ).
| Population | Dexamethasone Insert | Placebo Insert |
|---|---|---|
| ITT | 35 | 38 |
| Safety | 34 | 38 |
| Characteristic (ITT population) | (n = 35) | (n = 38) |
| Age, years | ||
| Mean ± SD | 38.2 ± 11.60 | 36.3 ± 12.01 |
| Median | 39 | 35 |
| Min, max | 19.0, 66.0 | 18.0, 62.0 |
| Sex | ||
| Males | 18 (51.4) | 24 (63.2) |
| Females | 17 (48.6) | 14 (36.8) |
| Ethnicity | ||
| Hispanic or Latino | 3 (8.6) | 6 (15.8) |
| Not Hispanic or Latino | 31 (88.6) | 31 (81.6) |
| NR/unknown | 1 (2.9) | 1 (2.6) |
| Race | ||
| Asian | 13 (37.1) | 11 (28.9) |
| White | 10 (28.6) | 12 (31.6) |
| Black or African American | 10 (28.6) | 9 (23.7) |
| Multiple | 0 (0.0) | 2 (5.3) |
| Unknown | 2 (5.7) | 4 (10.5) |
Demographics and Baseline Characteristics
The demographics and baseline characteristics of the ITT population are presented in Table 1 . The population of subjects receiving the dexamethasone insert had a mean age of 38.2 years and was similarly divided among Asians (n = 13 [37.1%]; Whites (n = 10 [28.6%]); and Blacks (n = 10 [28.6%]). All demographic and baseline characteristics were similar between arms except for distribution of sex; although male:female distribution was balanced in the dexamethasone insert arm (18:17; 51.4%:48.6%, respectively), substantially more males than females were present in the placebo insert arm (24:14; 63.2%:36.8%, respectively).
Efficacy
Ocular itching
At the week-1 CAC-day 8 visit, the dexamethasone insert arm had significantly lower scores for subject-reported ocular itching (using a 0 [none]-4 [severe] scale) compared with the placebo insert arm, with a 0.91-point difference at 3 minutes (1.71 vs. 2.62, respectively), a 0.87-point difference at 5 minutes (1.90 vs. 2.77, respectively), and a 1.00-point difference at 7 minutes (1.78 vs. 2.78, respectively; all P < .001) ( Figure 3 ). The dexamethasone insert arm showed significant reduction in ocular itching compared with the placebo insert arm at nearly every time point (3, 5, and 7 minutes post CAC) at each visit (week-1 CAC-day 6 through week-4 CAC-days 28-31), for a total of 34 of 36 distinct time points ( Figure 4 ).
Conjunctival redness
The dexamethasone insert arm had significantly lower investigator-assessed conjunctival redness scores (scale: 0 [none]-4 [severe]) compared with placebo insert arm at 20 minutes (1.38 vs 1.77; P = .0322) post CAC at the week-1 CAC-day 8 visit ( Figure 5 ). However, at 7 minutes and 15 minutes post CAC, the differences between arms were not statistically significant (1.58 vs. 1.78, respectively; P = .2983 and 1.50 vs 1.82, respectively; P = .0534). The dexamethasone insert arm showed significant conjunctival relief from redness compared with the placebo insert arm at most time points (7, 15, and 20 minutes post CAC), with exceptions at week-1 CAC-day 8 (7- and 15-minute time points), week-2 CAC-day 14 (7-minute time point), and week-4 CAC-days 28-31 (7-, 15-, and 20-minute time points) ( Figure 6 ).
