Current Eye Research
`
`ISSN: 0271-3683 (Print) 1460-2202 (Online) Journal homepage: http://www.tandfonline.com/loi/icey20
`
`Efficacy of Once-Daily Olopatadine 0.2%
`Ophthalmic Solution Compared to Twice-Daily
`Olopatadine 0.1% Ophthalmic Solution for
`the Treatment of Ocular Itching Induced by
`Conjunctival Allergen Challenge
`
`Mark B. Abelson, Dennis L. Spangler, Arthur B. Epstein, Francis S. Mah & H.
`Jerome Crampton
`
`To cite this article: Mark B. Abelson, Dennis L. Spangler, Arthur B. Epstein, Francis S. Mah
`& H. Jerome Crampton (2007) Efficacy of Once-Daily Olopatadine 0.2% Ophthalmic Solution
`Compared to Twice-Daily Olopatadine 0.1% Ophthalmic Solution for the Treatment of Ocular
`Itching Induced by Conjunctival Allergen Challenge, Current Eye Research, 32:12, 1017-1022, DOI:
`10.1080/02713680701736558
`To link to this article: https://doi.org/10.1080/02713680701736558
`
`Published online: 02 Jul 2009.
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`IPR2018-01020 and IPR2018-01021, Exhibit 1027, Page 1
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`

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`Current Eye Research, 32:1017–1022, 2007
`Copyright (cid:1)c Informa Healthcare USA, Inc.
`ISSN: 0271-3683 print / 1460-2202 online
`DOI: 10.1080/02713680701736558
`
`Efficacy of Once-Daily Olopatadine 0.2%
`Ophthalmic Solution Compared to
`Twice-Daily Olopatadine 0.1% Ophthalmic
`Solution for the Treatment of Ocular Itching
`Induced by Conjunctival Allergen Challenge
`
`Mark B. Abelson
`Schepens Eye Research Institute
`and Department of
`Ophthalmology, Harvard
`Medical School, Boston,
`Massachusetts, USA;
`Ophthalmic Research
`Associates, North Andover,
`Massachusetts, USA
`
`Dennis L. Spangler
`The Atlanta Allergy & Asthma
`Clinic, Atlanta, Georgia, USA
`
`Arthur B. Epstein
`North Shore Contact Lens &
`Vision Consultants, Long
`Island, New York, USA
`
`Francis S. Mah
`University of Pittsburgh School
`of Medicine, Pittsburgh,
`Pennsylvania, USA
`
`H. Jerome Crampton
`Ophthalmic Research
`Associates, North Andover,
`Massachusetts, USA
`
`Received 3 August 2007
`Accepted 20 September 2007
`Correspondence: H. Jerome Crampton,
`M.D., 863 Turnpike Street, North
`Andover, Massachusetts 01845, USA.
`E-mail: Cram3528@hotmail.com
`
`ABSTRACT Olopatadine 0.1% (Patanol(cid:1)R ) and olopatadine 0.2% (PatadayTM)
`
`ophthalmic solutions are topical ocular anti-allergic agents with antihistaminic
`and mast cell stabilizing properties. The efficacy of two doses of olopatadine
`0.1% was compared to one dose of olopatadine 0.2% in the prevention of ocular
`itching associated with allergic conjunctivitis over 24 hours. This double-masked
`conjunctival allergen challenge (CAC) study found no significant difference in
`the mean itching scores between two drops of olopatadine 0.1% and one drop
`of olopatadine 0.2%. Both showed significant activity at the 24-hour time point
`and were statistically superior to placebo. No adverse events occurred while on
`drug therapy.
`
`KEYWORDS olopatadine; conjunctival allergen challenge; ophthalmic; allergic conjunc-
`tivitis; rhinoconjunctivitis; allergy; Pataday; Patanol
`
`INTRODUCTION
`The allergic response occurs secondary to crosslinking of allergens to IgE
`molecules on sensitized mast cells. This triggers degranulation of the mast cell
`and subsequent release of various allergic and inflammatory mediators. All of
`these mediators contribute to the allergic reaction; however, histamine plays the
`primary role, particularly in initiating ocular itching.1−4
`Treatment options are available to help ease these symptoms by stabilizing
`mast cells as well as blocking histamine binding to ocular H1 receptors. Olopata-
`(cid:1)R Alcon), for example, is a potent H1 antihistamine5 and
`dine 0.1% (Patanol,
`(cid:1)R is indicated for the
`a proven human conjunctival mast cell stabilizer.6Patanol
`twice-daily treatment of all signs and symptoms of allergic conjunctivitis. It has
`consistently been shown to be comfortable and well tolerated; its safety has
`been investigated extensively in both adults and children.7–11
`
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`Olopatadine 0.2% (Pataday,TM Alcon) is a new for-
`mulation of olopatadine that was developed to enhance
`clinical efficacy by extending the duration of action.
`Olopatadine 0.2% contains twice the active molecule as
`olopatadine 0.1%. The excipients of the two formula-
`tions are similar, with the addition of edetate disodium
`(EDTA) and povidone to olopatadine 0.2%. EDTA is a
`common chelating agent that was added to enhance the
`preservative efficacy of the new formulation. Povidone,
`a common ingredient in many ophthalmic products, is
`an FDA-classified demulcent. Olopatadine 0.2% is in-
`dicated once daily for the treatment of ocular itching
`associated with allergic conjunctivitis. In clinical trials
`it has been shown to significantly reduce ocular itching
`and redness associated with allergic conjunctivitis.12,13
`It has also demonstrated an extended duration of ac-
`tion of up to 24 hours.13 Olopatadine 0.2% has been
`shown to be safe in both adults and children as young as
`three years of age,14 and its once-daily dosing regimen
`increases convenience and compliance for all ocular al-
`lergy patients.
`This study used the conjunctival allergen challenge
`(CAC) model to compare the efficacy after 24 hours of
`one dose of olopatadine 0.2% to two doses (separated
`by 8 hours) of olopatadine 0.1% in the prevention of oc-
`ular itching associated with allergic conjunctivitis. The
`CAC model employed in this study used titrated quan-
`tities of allergen to induce the signs and symptoms of
`allergic conjunctivitis in a standardized, precise, and re-
`producible manner. Pre-determinded concentrations of
`allergen are used to elicit an allergic response, elimi-
`nating much of the variability associated with environ-
`mental models.15 The method allows for evaluation of
`safety, comfort, and efficacy using standardized grading
`scales.
`
`METHODS
`Design
`This was a 3-week, double-masked, randomized, con-
`tralateral eye, placebo-controlled CAC study. The study
`visits were conducted in a clinic setting (Ophthalmic Re-
`search Associates, North Andover, MA), and all study-
`related procedures and ophthalmic examinations were
`conducted by examiners who were qualified through
`medical training and experience with the CAC method-
`ology. The study protocol, informed consent form,
`investigator qualifications, and all recruiting materials
`
`were approved by an independent institutional review
`board (IntegReview, Austin, TX) prior to initiation of
`the study. The study was conducted in accordance with
`current Good Clinical Practice guidelines and the Dec-
`laration of Helsinki.
`
`Visit 1: Baseline Screening
`(Day-14 ± 3)
`
`Written informed consent was obtained from each
`subject. The study followed a standardized allergen chal-
`lenge protocol.15 Demographic data, along with med-
`ical and medication histories were recorded, and vi-
`sual acuity was measured using the Early Treatment
`of Diabetic Retinopathy Study (ETDRS) eye chart. A
`urine pregnancy test was administered to women of
`childbearing potential. Subjects were not allowed to
`use any topical ocular medication (other than study
`medication) for the duration of the study, have any
`active ocular disease, or use any systemic medication
`that could have affected the outcome of the study (e.g.,
`topical or systemic antihistamines, mast cell stabilizers,
`corticosteroids).
`A biomicroscopic (slit lamp) examination was per-
`formed to exclude all subjects with disallowed ocular
`conditions, including erythema (redness), defined as a
`redness score of >1 inany ocular vessel bed (ciliary,
`conjunctival, episcleral). In addition, any subject who
`experienced any itching in either eye at baseline was ex-
`cluded. A CAC was performed bilaterally with an aller-
`gen to which the subject tested positive in a skin prick
`test (e.g., cat dander, trees, ragweed, or grasses). Skin
`prick tests were performed within 24 months of study
`initiation, and were used as inclusion criteria. Increas-
`ing antigen concentrations were instilled bilaterally at
`10-min intervals until a positive reaction was elicited.
`Ocular itching was assessed using a scale that ranged
`from 0 to 4, where 0 = no itch and 4 = incapacitating
`itch; redness was assessed using a 0 to 4 scale, where
`0 = no redness and 4 = “extremely severe” redness. A
`positive CAC reaction was defined as a score of ≥2 for
`redness in at least one of the three vessel beds of each
`eye and ≥2 for ocular itching in both eyes within 10
`min of receiving that dose of allergen. Any subject who
`failed to test positively was excluded from the study.
`
`Visit 2: Confirmatory (Day-7 ± 3)
`
`Medical and medication histories were updated
`and visual acuity was recorded. A biomicroscopic
`
`M. B. Abelson et al.
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`examination was performed to exclude subjects with ac-
`tive allergic conjunctivitis (a score of >1 for redness in
`any vessel bed or any itching in either eye) at baseline. A
`second CAC was administered to each subject using the
`same antigen/concentration combination that elicited
`the positive reaction at Visit 1. The subject made as-
`sessments of ocular itching at 3, 5, and 7 min following
`allergen challenge. The investigator made assessments
`of redness at 7, 15, and 20 min post-challenge. If the
`subject failed to react positively (i.e., ≥2 for redness in
`at least one vessel bed and ≥2 for itching) in both eyes
`in at least one out of the three time points within this
`20-min interval, the subject was discontinued from the
`study.
`
`Test Visit: Drug Evaluation (Day 0,
`one Week After Visit 2)
`Medical and medication histories were updated and
`visual acuity was recorded. A biomicroscopic exami-
`nation was performed to exclude subjects with active
`allergic conjunctivitis (a score of >1 for redness in any
`vessel bed or any itching in either eye) at baseline. Base-
`line allergic signs and symptoms were assessed.
`Subjects who continued to qualify for the study were
`assigned treatment numbers in sequential order and
`had one drop of masked study medication instilled in
`the conjunctival sac of the appropriate eye according
`to a prescribed randomization schedule. Prior to com-
`mencement of all study procedures, an independent
`
`TABLE 1 Patients were randomized by eye to receive olopata-
`dine 0.2%, olopatadine 0.1%, or placebo at the first and second
`dose
`
`First dose
`
`Olopatadine 0.2% in
`one eye and placebo
`in the other
`Olopatadine 0.1% in
`one eye and placebo
`in the other
`Olopatadine 0.2% in
`one eye and
`olopatadine 0.1% in
`the other
`
`Olopatadine 0.2% in
`both eyes
`Olopatadine 0.1%in
`both eyes
`Placebo in both eyes
`
`1019
`
`Second dose
`
`Placebo in both eyes
`
`Olopatadine 0.1% in
`same eye and
`placebo in the other
`Placebo in the eye that
`had olopatadine
`0.2% and
`olopatadine 0.1% in
`the other eye
`Placebo in both eyes
`
`Olopatadine 0.1%in
`both eyes
`Placebo in both eyes
`
`statistician who was not involved in any other aspect of
`the study developed the randomization schedule. Sub-
`jects were randomized by eye into treatment groups in a
`1:1:1 pattern to receive olopatadine 0.2%, olopatadine
`(cid:1)R ) (Table 1). Given
`0.1%, or placebo (Tears Naturale II
`the bilateral symmetry of the ocular allergic response
`during the CAC, contralateral, placebo-controlled treat-
`ment arms were used in this study, allowing the sub-
`ject to act as an internal control.15–17 A similar study
`design was used for the pivotal study of olopatadine
`0.1%.18 For patient distribution into study groups, see
`Table 2.
`All subjects received a second dose of masked study
`medication 8 hours after the first (Table 1). Twenty-four
`hours after the first dose, a conjunctival allergen chal-
`lenge was performed bilaterally using the same concen-
`tration of allergen that had elicited a positive response
`at Visits 1 and 2. Ocular assessments of itching were per-
`formed in the same manner and at the identical time
`points as described for Visit 2. Adverse events were col-
`lected for all subjects post-instillation of study drug. A
`final visual acuity and slit lamp exam was conducted
`for all subjects.
`
`Statistical Analyses
`Statistics & Data Corporation of Mesa, Arizona, per-
`formed statistical analyses. Non-parametric Wilcoxon
`rank sum tests were performed on the mean scores
`per eye at each time point to assess statistical signifi-
`cance in the differences between treatments. The pri-
`mary efficacy variable in this study was ocular itch-
`ing. Statistical significance was defined as α = 0.05.
`Safety was evaluated through a review of all reported
`adverse events. Changes from baseline in visual acuity
`and slit lamp biomicroscopy were reviewed for clinical
`
`TABLE 2 Patients (N = 23) were distributed among nine possi-
`ble treatment combinations
`
`Number of
`subjects
`
`3
`3
`3
`2
`2
`3
`3
`2
`2
`
`OD Treatment
`
`Olopatadine 0.2%
`Olopatadine 0.1%
`Placebo
`Placebo
`Placebo
`Olopatadine 0.2%
`Olopatadine 0.1%
`Olopatadine 0.2%
`Olopatadine 0.1%
`
`OS
`Treatment
`
`Placebo
`Placebo
`Olopatadine 0.2%
`Olopatadine 0.1%
`Placebo
`Olopatadine 0.1%
`Olopatadine 0.2%
`Olopatadine 0.2%
`Olopatadine 0.1%
`
`Pataday vs. Patanol for Treating Ocular Itching
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`significance. No statistical analyses were performed to
`evaluate safety.
`
`RESULTS
`Subject Disposition
`Of the 37 screened subjects, 23 were enrolled based
`on the inclusion/exclusion criteria. All 23 enrolled sub-
`jects completed the study. Subject demographics are
`shown in Table 3.
`
`Efficacy
`At the 24-hour time point, two doses of olopatadine
`0.1% significantly reduced itching scores in compar-
`ison to placebo (p = 0.002). Similarly, one dose of
`olopatadine 0.2% significantly reduced itching scores
`in comparison to placebo (p = 0.0007). Both treat-
`ments demonstrated 1-score unit differences from base-
`line. There were no statistically significant differences
`(Fig. 1) in the mean itching reduction scores between
`olopatadine 0.1% dosed twice daily (BID) and olopata-
`dine 0.2% dosed once daily (QD) (p = 0.081) at 24 hr.
`
`Safety
`No adverse advents occurred while on drug ther-
`apy. Olopatadine 0.2% and olopatadine 0.1% were both
`found to be safe and well tolerated as used in this study.
`No clinically significant changes from baseline for vi-
`sual acuity or slit-lamp biomicroscopy safety measure-
`ments occurred for either drug formulation. Slit-lamp
`biomicroscopy examinations included lids, tear menis-
`cus, conjunctiva, cornea, lens, and anterior chamber.
`Any abnormalities or changes from baseline would have
`been noted as adverse events.
`
`TABLE 3 Demographics of the 23 subjects enrolled in the study
`
`Sex, N (%)
`Female
`Male
`Age (years), mean
`Race, N (%)
`Caucasian
`Hispanic
`Iris color, N (%)
`Brown
`Hazel
`Blue
`Green
`
`13 (56.5)
`10 (43.5)
`41
`
`22 (95.7)
`1 (4.3)
`
`9 (39.1)
`7 (30.4)
`5 (21.7)
`2 (8.7)
`
`DISCUSSION
`Ocular itching associated with allergic conjunctivi-
`tis is a constant source of irritation for many people.
`Olopatadine 0.1% has been prescribed as an effective
`twice-daily antihistamine/mast cell stabilizer for treat-
`ing allergic conjunctivitis.11,16–17 The increasing preva-
`lence of allergies combined with patient attitudes to-
`wards usage has prompted an increased need for once-
`daily treatments.19 Olopatadine 0.2% is an ocular anti-
`allergy agent indicated for once-daily dosing. A one-
`drop dose has a rapid onset of action and provides quick
`relief from allergy symptoms—relief that is sustained for
`24 hours.
`Using the CAC model, this study showed that over
`24 hours, one drop of olopatadine 0.2% has an effi-
`cacy profile comparable to two drops of the original
`formulation. Since the two formulations share the in-
`dication for the relief of ocular itching, this was the
`variable analyzed. These results are consistent with pre-
`vious studies performed with the olopatadine molecule,
`
`FIGURE 1 Comparison of mean ocular itching scores between olopatadine 0.2%, olopatadine 0.1%, and placebo following conjunctival
`allergen challenge performed 24 hours after medication instillation (N = 23).
`
`M. B. Abelson et al.
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`which have indicated its strong antihistaminic and mast
`cell stabilizing capabilities.20
`Although concern is often expressed about the po-
`tential for additional adverse events when the concen-
`tration of a drug is increased, no adverse events were
`observed in this study for either the 0.1% or 0.2% for-
`mulations. The safety of olopatadine 0.2% has been in-
`vestigated in previously published clinical trials; these
`studies indicate that the frequency and severity of ad-
`verse events in patients dosed with olopatadine 0.2%
`is comparable to that of placebo.21,22 Furthermore, the
`efficacy and safety of once-daily formulations has been
`established with nasal sprays (previously twice-daily
`dosing) for the treatment of allergic and non-allergic
`chronic allergic rhinitis.23
`The potential clinical significance of once-daily
`dosing includes enhanced compliance and increased
`convenience for ocular allergy sufferers, particularly
`contact lens wearers, children, and others who have dif-
`ficulties with dosing more than once per day.24 Non-
`compliance is a well-known issue in clinical practice,
`and the reduction of twice- to once-daily dosing has
`repeatedly been shown in studies that involve vari-
`ous conditions and administration routes to signifi-
`cantly enhance patient compliance.25–30 One study
`that electronically measured compliance within mul-
`tiple indications found that patients on once-daily reg-
`imens had the highest compliance (79%) of all in-
`vestigated dosing regimens.23 Once-daily dosing de-
`creases the risk of missed doses, thereby enhancing
`the efficacy of
`the drug and the comfort of
`the
`patient.
`
`CONCLUSIONS
`This study demonstrated that at the end of a 24-hour
`period, one dose of olopatadine 0.2% was compara-
`ble to two doses (separated by 8 hours) of olopatadine
`0.1% in the prevention of ocular itching. Olopatadine
`0.2% has therefore demonstrated once-daily efficacy in
`the prevention of ocular itching associated with allergic
`conjunctivitis.
`
`ACKNOWLEDGMENTS
`This study was funded by an unrestricted grant from
`Alcon Laboratories. Dr. Crampton has no personal or
`financial interest in any of the products discussed.
`
`REFERENCES
`[1] Abelson MB, Smith L, and Chapin M. Ocular allergic disease: Mech-
`anisms, disease sub-types, treatment. Ocular Surface. 2003;1:127–
`149.
`[2] Phipatanakul W. Allergic rhinoconjunctivitis: Epidemiology. Immunol
`Allergy Clin North Am. 2005;25:263–281.
`[3] Abelson MB, George M, and Garafalo C. Differential diagnosis of
`ocular allergic disorders [published correction appears in Ann Allergy
`1993;70:192]. Ann Allergy. 1993;70:95–109.
`[4] Abelson MB, Allansmith MR. Histamine in the eye. In: Silverstein A,
`O’Connor G, eds. Immunology and Immunopathology of the Eye.
`New York: Masson Publishing, 1979:362–364.
`[5] Yanni J, Stephens D, Miller S, et al. The in vitro and in vivo oc-
`ular pharmacology of olopatadine (al-4943a), an effective anti-
`allergic/antihistaminic agent. J Ocul Pharmacol Ther. 1996;12:389–
`400.
`[6] Brockman HL, Momsen MM, Knudtson JR, et al. Interactions of
`olopatadine and selected antihistamines with model and natural
`membranes. Ocul Immunol Inflamm. 2003;11:247–268.
`[7] Artal MN, Luna JD, Discepola M. A forced choice comfort study of
`olopatadine hydrochloride 0.1% versus ketotifen fumarate 0.05%.
`Acta Ophthalmol Scan. 2000;78:63–65.
`[8] Katelaris CH, Cipriandi G, Missotten L, et al. A comparison of
`the efficacy and tolerability of olopatadine hydrochloride 0.1%
`ophthalmic solution and cromolyn sodidum 2% ophthalmic solu-
`tion in seasonal allergic conjunctivitis. Clin Ther. 2002;24:1561–
`1575.
`[9] Leonardi A, Zafirakis P. Efficacy and comfort of olopatadine ver-
`sus ketotifen ophthalmic solutions: A double-masked environmen-
`tal study of patient preference. Curr Med Res Opin. 2004;20:1167–
`1173.
`[10] Ciprandi G, Turner D, Gross RD. Double-masked, randomized,
`parallel-group study comparing olopatadine 0.1% ophthalmic so-
`lution with cromolyn sodium 2% and levocabastine 0.05% oph-
`thalmic preparations in children with seasonal allergic conjunctivitis.
`Curr Ther Res. 2004;65:186–199.
`[11] Abelson MB. Evaluation of olopatadine, a new ophthalmic antialler-
`gic agent with dual activity, using the conjunctival allergen challenge
`model. Ann Allergy Asthma Immunol. 1998;81:211–218.
`[12] 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 rhinocon-
`junctivitis: A randomized, double-masked environmental study. Clin
`Ther., 2004;26:1237–1248.
`[13] Vogelson C, Abelson M, Pasquine T, et al. Preclinical and clinical an-
`tiallergic effect of olopatadine 0.2% solution 24 hours after topical
`ocular administration. Allergy Asthma Proc, 2004;25:69–75.
`[14] Lichtenstein S, Vogelson C, Wells D, et al. Olopatadine is safe and
`well-tolerated in adults and children as young as three years of age.
`Presented at Western Society of Allergy, Asthma & Immunology
`Annual Meeting; Jan 19–23, 2003; Wailea, HI.
`[15] Abelson M, Chambers W, Smith L. Conjunctival allergen challenge:
`A clinical approach to studying allergic conjunctivitis. Arch Ophthal-
`mol. 1990;108:84–88.
`[16] Lanier R, Finegold I, D’Arienzo P, Granet D, Epstein AB, Ledgerwood
`G. Clinical efficacy of olopatadine vs epinastine ophthalmic solution
`in the conjunctival allergen challenge model. Curr Med Res Opin.
`2004;20:2644–2651.
`[17] Abelson MB, Spitalny L. Combined analysis of two studies using the
`conjunctival allergen challenge model to evaluate olopatadine hy-
`drochloride, a new ophthalmic antiallergic agent with dual activity.
`Am J Ophthal. 1998;125:797–804.
`[18] Olopatadine HCl 0.1% Summary Basis of Approval. FDA NDA
`020688. April 11, 1997.
`[19] Richter A, Anton SE, Koch P, Dennett SL. The impact of reduc-
`ing dose frequency on health outcomes. Clin Ther. 2003;25:2307–
`2335.
`
`1021
`
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`
`

`

`[20] Yanni JM, Miller ST, Gamache DA, Spellman JM, Xu S, Sharif
`NA. Comparative effects of topical ocular anti-allergy drugs on
`human conjunctival mast cells. Annal Allergy Asthma Immunol.
`1997;79:541–545.
`[21] Edwards MR, Pasquine T, Gross RD, Robertson SM. Frequency of
`treatment-related ocular adverse events associated with olopatadine
`0.2% (PatadayTM) in clinical trials. Presented at Western Society
`of Allergy, Asthma & Immunology Annual Meeting; Jan 23, 2007;
`Wailea, HI
`[22] Lichtenstein SJ, Pasquine TA, Edwards MR, et al. Safety and toler-
`ability of olopatadine 0.2% in children and adolescents. J Ocular
`Pharmcol Ther. 2007;23:366–371.
`[23] Giger R, Pasche P, Cheseauz C, et al. Comparison of once- ver-
`sus twice-daily use of beclomethasone dipropionate aqueous nasal
`spray in the treatment of allergic and non-allergic chronic rhinosi-
`nusitis. Eur Arch Otorhinolaryngol. 2003;260:135–140.
`[24] Scoper SV, Berdy GJ, Lichtenstein SJ, et al. Physician assessment,
`patient perception, and safety of once-a-day olopatadine in treat-
`ing allergic conjunctivitis. Presented at American College of Allergy,
`Asthma & Immunology; Nov. 11–12, 2006; Philadelphia, PA.
`
`[25] Claxton AJ, Cramer J, Pierce C. A systematic review of the asso-
`ciations between dose regimens and medication compliance. Clin
`Ther. 2001;23:1296–1310.
`[26] Kardas P. The DIACOM study (effect of dosing frequency of oral
`antidiabetic agents on the compliance and biochemical control of
`type 2 diabetes). Diabetes Obes Metab. 2005;7:722–728.
`[27] Granger AL, Fehnel SE, Hogue SL, Bennett L, Edin HM. An assess-
`ment of patient preference and adherence to treatment with Well-
`butrin SR: A web-based survey. J Affect Disord. 2006;90:217–221.
`[28] McDonald HP, Garg AX, Haynes RB. Interventions to enhance pa-
`tient adherence to medication prescriptions: scientific review. JAMA.
`2002;288:2868–2879.
`[29] Guest JF, Davie AM, Ruiz FJ, Greener MJ. Switching asthma patients
`to a once-daily inhaled steroid improves compliance and reduces
`healthcare costs. Prim Care Respir J. 2005;14:88–98.
`[30] Schenker H, Maloney S, Liss C, Gormley G, Hartenbaum D. Pa-
`tient preference, efficacy, and compliance with timolol maleate oph-
`thalmic gel-forming solution versus timolol maleate ophthalmic so-
`lution in patients with ocular hypertension or open-angle glaucoma.
`Clin Ther. 1999;21:138–147.
`
`M. B. Abelson et al.
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`1022
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`IPR2018-01020 and IPR2018-01021, Exhibit 1027, Page 7
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