Secondary Logo

Journal Logo

Clinical Science

Phase 3 Randomized Double-Masked Study of Efficacy and Safety of Once-Daily 0.77% Olopatadine Hydrochloride Ophthalmic Solution in Subjects With Allergic Conjunctivitis Using the Conjunctival Allergen Challenge Model

McLaurin, Eugene MD; Narvekar, Abhijit MS; Gomes, Paul MS; Adewale, Adeniyi PhD; Torkildsen, Gail MD

Author Information
doi: 10.1097/ICO.0000000000000562

Abstract

The ocular symptoms of allergy are considerable and represent a recurrent burden for sufferers.1 Furthermore, impaired emotional well-being may accompany the allergic reaction in addition to typical eye and nasal symptoms.2 Up to 40% of the US population is affected by ocular allergy symptoms,3 including itchy eyes, puffiness, and watering.2

The initial mechanism of a conjunctival allergic response is the production of immunoglobulin E (IgE) by plasma cells when exposed to an allergen, resulting in sensitization. On reexposure, the same allergen binds to IgE molecules attached to mast cell membranes. This cross-bridging of IgE molecules initiates mast cell degranulation resulting in release of histamine and other preformed proallergic and proinflammatory mediators,4 stimulating itching and vasodilatory responses that may last from minutes to hours. Additionally, chemokines drive late-phase inflammation in the conjunctiva because of inflammatory cell infiltration. Cumulative effects of allergen exposure and leukocyte responses in local tissues can lead to chronic inflammation and changes in adaptive immunity. Hallmark signs of ocular inflammation in allergic conjunctivitis (AC) include ocular itching, redness, tearing, chemosis, and eyelid swelling.4

To effectively alleviate symptoms of AC, there is a need to target multiple pathways,5,6 including mast cell degranulation. One such agent is olopatadine, which shows diverse mechanisms of action, including selective histamine H1 receptor antagonism, mast cell stabilization, and prevention of histamine-induced inflammatory cytokine production by human conjunctival epithelial cells.7 Previously, olopatadine hydrochloride ophthalmic solution 0.1% twice daily (Patanol) and 0.2% once daily (Pataday) have demonstrated symptom relief efficacy and safety for AC in clinical trials.8–11

However, where patients experience incomplete relief of symptoms, there is a need for a product that is effective over 24 hours without necessitating a second dose. A new preparation of olopatadine hydrochloride ophthalmic solution, containing olopatadine hydrochloride at a concentration of 0.77% (7.76 mg/mL), which is equivalent to 0.7% (7 mg/mL) olopatadine as free base,12 has been developed with the objective of expanding the benefit offered by olopatadine 0.2% while maintaining its safety profile. This new formulation has been recently approved by the US Food and Drug Administration for the treatment of ocular itching associated with AC.

This study aimed to assess the efficacy and safety of a novel once-daily 0.77% olopatadine solution compared with olopatadine 0.2%, olopatadine 0.1%, or the vehicle in subjects with AC using a conjunctival allergen challenge (CAC) model.13

METHODS

Study Design

This was a phase 3, multicenter, double-masked, randomized trial assessing efficacy and safety of olopatadine 0.77%. The study used the Ora Conjunctival Allergen Challenge (Ora-CAC) Model System (Ora, Inc, Andover, MA),13 which involves instillation of allergens directly into the eye to allow observations of acute allergic responses under controlled conditions.

All subjects enrolled in the study were required to attend 5 study visits:

  1. Visit 1, screening and titration CAC on day −21 (±2 days),
  2. Visit 2, confirmatory CAC on day −14 (±3 days),
  3. Visit 3A, randomization and treatment administration on day 0,
  4. Visit 3B, CAC 24-hour posttreatment administration on day 1,
  5. Visit 4 (exit visit), CAC 27 minutes (±1 minute) posttreatment administration [onset of action] on day 14 (±2 days).

A positive bilateral CAC response at visits 1 and 2 was essential for study eligibility. At visit 1, a positive bilateral CAC response was defined as scores, for each eye, of itching ≥2 and redness ≥2 in 2 of 3 vessel beds within 10 minutes of the last titration challenge. At visit 2, the required positive bilateral CAC response was defined as scores, for each eye, of itching ≥2 and redness ≥2 in 2 of 3 vessel beds for at least 2 of 3 post-CAC time points.

The subjects were randomized 2:2:2:1 to receive olopatadine hydrochloride 0.77%, olopatadine hydrochloride 0.2%, olopatadine hydrochloride 0.1%, or the vehicle, respectively. The subjects received 1 dose (defined as 1 drop of the study product administered topically to each eye by a designated site staff member) at visits 3A and 4.

The study (clinicaltrials.gov; NCT01743027) was performed in accordance with the ethical principles of the Declaration of Helsinki and Good Clinical Practice guidelines, and all subjects gave informed consent before participation. The study protocol and consent form were reviewed and approved by all relevant Independent Ethics Committees or Institutional Review Boards.

Subjects

Subjects were eligible for study if they were ≥18 years old; could have eye drops administered to both eyes; and had a positive diagnostic skin test indicative of allergy to cat hair, cat dander, grasses, ragweed, dust mite, dog dander, cockroach, or trees within 24 months of visit 1. Eligible subjects needed to have a history of seasonal or perennial AC for at least 1 year before visit 1 and a best-corrected visual acuity (BCVA) of ≥55 letters in each eye as measured by the Early Treatment Diabetic Retinopathy Study Chart, a positive bilateral CAC response at visits 1 and 2, and willingness to discontinue wearing contact lenses ≥72 hours before visit 1 and throughout the duration of the study.

Exclusion criteria were a known history or presence of persistent dry eye syndrome or current treatment for dry eyes; any clinically significant ophthalmic abnormality that may affect study outcomes; presence of ocular infection (bacterial, viral, or fungal) or history of ocular herpes within 30 days; any chronic ocular degenerative condition or active intraocular inflammation that could worsen during the study; intraocular pressure (IOP) <8 or >21 mm Hg or a history or diagnosis of glaucoma; history of ocular surgery within 6 months; signs or symptoms of active AC; history of an anaphylactic reaction to any study allergens; evidence or recent history of severe, unstable, or uncontrolled systemic disease; use of any disallowed medications during the period indicated in the protocol; any contraindications or hypersensitivities to the use of the study medications; or participation in another investigational agent trial within 30 days or in any previous trial with olopatadine 0.77%.

Study Objectives

The primary objectives were to demonstrate superiority of olopatadine 0.77% over the vehicle for the treatment of patient-assessed ocular itching (assessed 3, 5, and 7 minutes after CAC) at the onset of action and at 24-hour duration of action, and over olopatadine 0.2% and olopatadine 0.1% at 24-hour duration of action.

The secondary objectives were to demonstrate superiority of olopatadine 0.77% over olopatadine 0.2%, olopatadine 0.1%, and the vehicle at onset and at 24-hour duration of action visits for investigator-assessed conjunctival redness and total redness. Additional secondary objectives were to demonstrate the superiority of olopatadine 0.77% over olopatadine 0.2% and olopatadine 0.1% at onset and 24 hours for the proportion of ocular itching responders. Supportive end points included chemosis and tearing scores at postchallenge time points at onset and 24-hour duration of action visits.

Efficacy Variables

Subject-evaluated symptoms included ocular itching (0–4 scale with 0.5-unit increments: 0 = none and 4 = incapacitating itch) and tearing (0–4 scale: 0 = none and 4 = very severe). Investigator-evaluated signs consisted of conjunctival redness, ciliary redness, episcleral redness (all assessed on a 0–4 scale with 0.5-unit increments: 0 = none and 4 = extremely severe), and chemosis (0–4 scale with 0.5-unit increments: 0 = none and 4 = severe). An ocular itching responder was defined as any subject scoring zero on ocular itching for both eyes or having at least a reduction of 2 units in ocular itching relative to the baseline confirmatory CAC score (assessed at visit 2); scores were averaged across both eyes and over the 3 post-CAC time points. Total redness was the sum of conjunctival, ciliary, and episcleral redness scores (0–12 scale).

Ocular itching was assessed before CAC (visit 3A) and at 3, 5, and 7 minutes after challenge for 24-hour duration of action (visit 3B), and before CAC and at 3, 5, and 7 minutes after challenge for the onset of action (visit 4). Conjunctival redness, ciliary redness, episcleral redness, chemosis, and tearing were assessed before CAC and at 7, 15, and 20 minutes after CAC for the onset of action and 24-hour duration of action.

Safety Variables

Safety assessments performed for both eyes were BCVA, measured at each visit using the Early Treatment Diabetic Retinopathy Study Visual Acuity Chart at 3 or 4 m; slit-lamp biomicroscopy for the cornea, lens, iris, and anterior chamber; IOP with a Goldmann applanation tonometer; and dilated fundus examination, including ophthalmoscopic assessments of the vitreous, peripheral retina, macula, choroid, and optic nerve. All treatment-emergent adverse events were coded using the Medical Dictionary for Regulatory Activities (MedDRA), version 15.0.

Statistical Analysis

All randomized subjects who received study medication were included in the intent-to-treat population as used for all analyses. The safety population included all patients who were exposed to the test article.

The primary efficacy variable was analyzed using a mixed-model repeated measures analysis of variance with fixed effects for the investigator, treatment, eye type (right or left eye), time, and treatment-by-time interaction. Sensitivity analyses were conducted using a 2-sample t test for each post-CAC time point comparison.

The same model specified for the primary analyses was also applied for the secondary and supportive analyses. The only exception was for analysis of ocular itching responder end points, which were based on proportions and analyzed using a χ2 test.

For an end point assessed at 3 time points, the 3 comparisons over the time points were regarded as a family of hypotheses. Overall statistical significance could be demonstrated only on that family of comparisons by the attainment of statistical significance at 2 of 3 time points in the family. To ensure that type 1 error was controlled over all sets of study hypotheses at a desired (0.05 two sided) level, a gate-keeping strategy was used.

RESULTS

Study Population

A total of 345 subjects were randomized (olopatadine 0.77%, n = 98; olopatadine 0.2%, n = 99; olopatadine 0.1%, n = 99; or vehicle, n = 49), and 325 (94.2%) subjects completed the study. All 345 randomized subjects were included in the safety and intent-to-treat analyses. Demographics and baseline characteristics were similar across treatment groups (Table 1).

TABLE 1
TABLE 1:
Demographic and Baseline Characteristics (Intent-to-Treat Population)

Efficacy Analysis

Olopatadine 0.77% was superior to the vehicle for alleviating ocular itching at all 3 post-CAC time points at onset and 24 hours (difference in means: −0.9 to –1.5; P < 0.0001 for all comparisons Fig. 1). A difference in means ≥1 unit compared with the vehicle is considered clinically relevant by the Food and Drug Administration in a CAC study. The difference in means was greater than 1 unit at majority of post-CAC time points (at all 3 time points for onset and at 2 of 3 time points for 24-hour). Furthermore, at the 24-hour visit, olopatadine 0.77% was superior for ocular itching to olopatadine 0.2% at 3 and 5 minutes after CAC (difference in means: −0.3 to –0.3; P < 0.05; Fig. 2), and to olopatadine 0.1% at all 3 post-CAC time points (difference in means: −0.4 to –0.5; P < 0.05).

FIGURE 1
FIGURE 1:
Ocular itching examined at 3, 5, and 7 minutes after CAC for olopatadine 0.77% versus vehicle at the onset of action and at 24-hour duration of action. *P < 0.0001. The differences in means for ocular itching scores between olopatadine 0.77% and the vehicle were significant at all 3 post-CAC time points at onset and 24-hour duration of action. Ocular itching scores were assessed on a 0 to 4 scale with 0.5-unit increments (0 = none and 4 = incapacitating itch); data are presented as least square means. Olopatadine 0.77% refers to the olopatadine HCl 0.77% (equivalent to 0.7% olopatadine free base) treatment group.
FIGURE 2
FIGURE 2:
Ocular itching examined at 3, 5, and 7 minutes after CAC for olopatadine 0.77% versus olopatadine 0.2% (A) and olopatadine 0.1% (B) at 24-hour duration of action. *P < 0.0001 and †P < 0.05. The differences in means for ocular itching scores at 24 hours between olopatadine 0.77% and olopatadine 0.2% were significant at 2 post-CAC time points (3 and 5 minutes). The differences in means for ocular itching at 24 hours between olopatadine 0.77% and olopatadine 0.1% were significant at all 3 post-CAC time points. Ocular itching scores were assessed on a 0 to 4 scale with 0.5-unit increments (0 = none and 4 = incapacitating itch); data are presented as least square means. Olopatadine 0.77% refers to the olopatadine HCl 0.77% (equivalent to 0.7% olopatadine free base) treatment group.

Considering secondary end points, at onset, olopatadine 0.77% was superior to the vehicle for reduction of conjunctival redness at all 3 post-CAC time points (difference in means: −0.4 to –0.6; P < 0.05; Table 2). Olopatadine 0.77% was also superior to olopatadine 0.2% and 0.1% for conjunctival redness at all 3 post-CAC time points (differences in means: −0.3 to –0.3 and −0.3 to –0.3; both P < 0.05). At the 24-hour visit, olopatadine 0.77% had lower mean values for conjunctival redness scores compared with the vehicle, olopatadine 0.2% and 0.1% at all or majority of post-CAC time points; however, these differences were not statistically significant.

TABLE 2
TABLE 2:
Mean Treatment Differences After CAC: Secondary and Supportive End Points (Intent-to-Treat Population)

For total redness, at onset, olopatadine 0.77% was superior to olopatadine 0.2% and 0.1% at all 3 post-CAC time points (differences in means: −0.8 to –0.9 and −0.9 to –1.1; both P < 0.05; Table 2). At the 24-hour visit, olopatadine 0.77% had lower mean values for total redness scores compared with olopatadine 0.2% and 0.1%, but the mean differences were not statistically significant.

Observed proportions of ocular itching responders, at onset, were 71.4%, 73.7%, 59.6%, and 10.2% for olopatadine 0.77%, 0.2%, 0.1%, and vehicle, respectively (see Table, Supplemental Digital Content 1, http://links.lww.com/ICO/A299). Comparisons at onset between olopatadine 0.77% versus 0.2% and 0.1% were not statistically significant. The observed proportions of ocular itching responders at the 24-hour visit were 40.8%, 30.3%, 26.3%, and 4.1% for olopatadine 0.77%, 0.2%, 0.1%, and vehicle, respectively. The proportion of ocular itching responders at 24 hours for olopatadine 0.77% was significantly higher than that of olopatadine 0.1% (difference: 14.6%; P < 0.05), but not of olopatadine 0.2%.

A lower mean chemosis score was observed with olopatadine 0.77% relative to the vehicle at all 3 post-CAC time points at onset and 24 hours (P < 0.05; Table 2). At onset, olopatadine 0.77% showed a lower chemosis mean score at 15 and 20 minutes after CAC compared with olopatadine 0.2% (P < 0.05), and at all 3 post-CAC time points compared with olopatadine 0.1% (P < 0.05).

At the onset of action, olopatadine 0.77% reduced tearing compared with the vehicle (P < 0.05) at all 3 post-CAC time points. At 24 hours, olopatadine 0.77% reduced tearing compared with olopatadine 0.1% (P < 0.05) and the vehicle (P < 0.05) at 7 and 15 minutes after CAC (Table 2).

Safety Analysis

At least 1 treatment-emergent adverse event was experienced by 10.2%, 2.0%, 7.1%, and 6.1% included in the safety population (345 subjects) for olopatadine 0.77%, 0.2%, 0.1%, and the vehicle, respectively. Two subjects treated with olopatadine 0.77% experienced a transient decrease in the visual acuity. Both events were mild, resolving without treatment within 10 minutes, and were assessed as unrelated to the treatment.

Review of adverse drug reactions (adverse events having a causal relationship with exposure to the test drug) also showed no clinically relevant differences between treatment groups. However, 2 subjects treated with olopatadine 0.77% experienced mild dysgeusia, and both were resolved without treatment. Additionally, no clinically relevant differences were observed from baseline across treatment groups for safety parameters evaluated using BCVA, slit-lamp examination, IOP, or dilated fundus examination.

DISCUSSION

This study is the first double-masked randomized controlled trial to compare olopatadine hydrochloride 0.77% ophthalmic solution with its vehicle solution and with both olopatadine 0.2% and olopatadine 0.1% ophthalmic solutions for the treatment of AC using the CAC model.

This study met its primary objectives, showing that olopatadine 0.77% is superior to the vehicle, olopatadine 0.2%, and olopatadine 0.1% for the reduction of ocular itching 24 hours after dosing and is also superior to the vehicle at onset. This clinical finding was supported by the statistical significance achieved for itching responders treated with olopatadine 0.77% compared with olopatadine 0.1% at 24 hours. We believe that the observed 10.5% difference between olopatadine 0.77% and olopatadine 0.2% at 24 hours is also of clinical relevance.

Our results also demonstrate that a rapid response was elicited by olopatadine 0.77% in alleviating redness symptoms of AC, and a similarly swift effect was also seen for chemosis. Conjunctival redness and total redness relief at 24 hours numerically favored olopatadine 0.77% compared with olopatadine 0.2% and 0.1%, whereas olopatadine 0.77% was significantly superior to its comparators at onset. The lack of a significant difference at 24 hours for both redness parameters may be due to the specific mechanism of action of olopatadine, whereby efficacy seems more pronounced in alleviating itching rather than redness as measured in the CAC model. Ocular itching is driven by histamine H1 receptor activation of conjunctival neuronal cells, whereas redness involves both histamine H1 and H2 receptors and other vasoactive amines that cause dilation of conjunctival blood vessels.14 The selectivity of olopatadine for histamine H1 receptors may, therefore, explain its more pronounced effect against itching compared with redness at 24 hours.15,16

The CAC model accurately replicates an IgE-mediated allergic reaction that results in mast cell degranulation.17 The CAC model works independently of the allergy season, reducing the effect of environmental variables. Other advantages of this approach include its clinical reproducibility, increased sensitivity, and the ability to monitor effects at onset and duration of action, which are otherwise difficult to assess in an environmental study.17 Furthermore, compliance is ensured with the instillation of the study treatments in a controlled setting by trained staff. The strengths of this model support the favorable efficacy results associated with olopatadine 0.77%.

As ocular itching is considered a principal symptom of AC,18 24-hour relief resulting in consistent symptom relief until the next day after administration could offer significant benefits. This is clinically pertinent as environmental allergen concentrations vary throughout the 24-hour day–night cycle, for example, a patient's allergen exposure to dust mites and pet dander is likely to be higher as they sleep, whereas many plants release pollen around dawn.19 This study shows that olopatadine 0.77% provides relief from ocular itching symptoms of AC over a 24-hour period regardless of causal allergen, prolonging duration of antiitch efficacy and translating as clinically meaningful benefit for patients. Prolonged activity of olopatadine 0.77% up to 24 hours is also supported by preclinical data.20 Furthermore, once-daily dosing of olopatadine 0.77% provides ocular allergy sufferers with a convenient dosing regimen that may enhance patient compliance. Indeed, studies have shown that less-frequent dosing can result in better adherence, and once-daily regimens demonstrate the highest compliance.21,22

Based on the review of adverse events and ocular safety parameters, no safety concerns were identified for olopatadine 0.77% after dosing once daily for 2 nonconsecutive days in adult subjects with AC. Dysgeusia was the only adverse drug reaction uniquely reported in the olopatadine 0.77% treatment group. Dysgeusia is not an uncommon occurrence after instillation of eye drops and does not represent a safety concern for this treatment. Thus, increasing the concentration of olopatadine by almost 4-fold compared with the olopatadine 0.2% commercial formulation does not seem to compromise safety.

A similar phase 3, multicenter, randomized trial has also been conducted, which showed positive effects of olopatadine 0.77% compared with olopatadine 0.2% and the vehicle for ocular itching and conjunctival redness symptoms of AC at onset and 24 hours, without safety concerns, supporting the findings of this study (Torkildsen et al, in preparation). Two further unpublished trials have been completed to date for olopatadine 0.77%, a safety trial in subjects ≥2 years and a pharmacokinetics study (data on file).

The rapid onset of action and prolonged duration of action (≥24 hours) of olopatadine 0.77%, coupled with a safety profile similar to the marketed olopatadine 0.2% product, support the potential for this solution to be used as a once-daily dosing regimen in treatment of AC. By minimizing proinflammatory vascular permeability7 and allergic inflammation, combined with subjective relief of itching on a clinically meaningful scale, olopatadine 0.77% afforded significant additional benefits to olopatadine 0.2% at 24-hour duration of action in this study. This suggests advantages of a longer duration of symptom control with olopatadine 0.77% and may translate to improved long-term management of AC, subject satisfaction, and, consequently, adherence to therapy.

ACKNOWLEDGMENTS

The authors thank Stacey Ackerman, Robert Rice, and Steven Silverstein for their contributions to the study as principal investigators. Medical writing support, which was funded by Alcon Research, was provided by Tamara Hirsch from DJE Science.

REFERENCES

1. Katelaris CH, Bielory L. Evidence-based study design in ocular allergy trials. Curr Opin Allergy Clin Immunol. 2008;8:484–488.
2. Blaiss MS. Allergic rhinoconjunctivitis: burden of disease. Allergy Asthma Proc. 2007;28:393–397.
3. Singh K, Axelrod S, Bielory L. The epidemiology of ocular and nasal allergy in the United States, 1988–1994. J Allergy Clin Immunol. 2010;126:778–783 e6.
4. Chigbu DI. The pathophysiology of ocular allergy: a review. Cont Lens Anterior Eye. 2009;32:3–15;43–14.
5. Azari AA, Barney NP. Conjunctivitis: a systematic review of diagnosis and treatment. JAMA. 2013;310:1721–1729.
6. Ridolo E, Montagni M, Caminati M, et al.. Emerging drugs for allergic conjunctivitis. Expert Opin Emerg Drugs. 2014;19:291–302.
7. Yanni JM, Stephens DJ, Miller ST, et al.. The in vitro and in vivo ocular pharmacology of olopatadine (AL-4943A), an effective anti-allergic/antihistaminic agent. J Ocul Pharmacol Ther. 1996;12:389–400.
8. Abelson MB, Gomes PJ, Vogelson CT, et al.. Clinical efficacy of olopatadine hydrochloride ophthalmic solution 0.2% compared with placebo in patients with allergic conjunctivitis or rhinoconjunctivitis: a randomized, double-masked environmental study. Clin Ther. 2004;26:1237–1248.
9. Berdy GJ, Spangler DL, Bensch G, et al.. A comparison of the relative efficacy and clinical performance of olopatadine hydrochloride 0.1% ophthalmic solution and ketotifen fumarate 0.025% ophthalmic solution in the conjunctival antigen challenge model. Clin Ther. 2000;22:826–833.
10. Spangler DL, Bensch G, Berdy GJ. Evaluation of the efficacy of olopatadine hydrochloride 0.1% ophthalmic solution and azelastine hydrochloride 0.05% ophthalmic solution in the conjunctival allergen challenge model. Clin Ther. 2001;23:1272–1280.
11. Vogelson CT, Abelson MB, Pasquine T, et al.. Preclinical and clinical antiallergic effect of olopatadine 0.2% solution 24 hours after topical ocular administration. Allergy Asthma Proc. 2004;25:69–75.
12. Patentscope. WO2012159064 high concentration olopatadine ophthalmic compostion. Available at: http://patentscope.wipo.int/search/en/WO2012159064. Accessed December 19, 2014.
13. Abelson MB, Chambers WA, Smith LM. Conjunctival allergen challenge. A clinical approach to studying allergic conjunctivitis. Arch Ophthalmol. 1990;108:84–88.
14. Leonardi A. Role of histamine in allergic conjunctivitis. Acta Ophthalmol Scan Suppl. 2000;230:18–21.
15. Kaliner MA, Oppenheimer J, Farrar JR. Comprehensive review of olopatadine: the molecule and its clinical entities. Allergy Asthma Proc. 2010;31:112–119.
16. Uchio E. Treatment of allergic conjunctivitis with olopatadine hydrochloride eye drops. Clin Ophthalmol. 2008;2:525–531.
17. Abelson MB, Loeffler O. Conjunctival allergen challenge: models in the investigation of ocular allergy. Curr Allergy Asthma Rep. 2003;3:363–368.
18. del Cuvillo A, Sastre J, Montoro J, et al.. Allergic conjunctivitis and H1 antihistamines. J Invest Allerg Clin. 2009;19(suppl 1):11–18.
19. Ribeiro H, Oliveira M, Abreu I. Intradiurnal variation of allergenic pollen in the city of Porto (Portugal). Aerobiologia. 2008;24:173–177.
20. Iyer GR, Yanez JAW, Womble S, et al.. Ocular pharmacokinetics comparison between Pataday® versus 0.77% newly developed olopatadine to male NZW rabbits. Paper presented at: International Society for Eye Research 2014; July 20–24, 2014; San Francisco, CA.
21. Giger R, Pasche P, Cheseaux C, et al.. Comparison of once- versus twice-daily use of beclomethasone dipropionate aqueous nasal spray in the treatment of allergic and non-allergic chronic rhinosinusitis. Eur Arch Otorhinolaryngol. 2003;260:135–140.
22. van Dulmen S, Sluijs E, van Dijk L, et al.. Patient adherence to medical treatment: a review of reviews. BMC Health Serv Res. 2007;7:55.
Keywords:

antihistamine; allergic conjunctivitis; conjunctival allergen challenge model; once-daily olopatadine; ocular itching

Supplemental Digital Content

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.