Two Multicenter, Randomized Studies of
`the Efficacy and Safety of Cyclosporine
`Ophthalmic Emulsion in Moderate to Severe
`Dry Eye Disease
`
`Kenneth Sall, MD,1 Onex Dara Stevenson, MD,2 Thomas K. Mundorf, MD,3 Brenda L. Reis, PhD4 and
`the CsA Phase 3 Study Group
`
`Objective: To compare the efficacy and safety of cyclosporin A ([CsA] 0.05% and 0.1% ophthalmic
`emulsions) to vehicle in patients with moderate to severe dry eye disease.
`Design: Multicenter, randomized, double-masked, parallel-group, 6-month, vehicle-controlled.
`Participants: A total of 877 patients with defined moderate to severe dry eye disease (292 to 293 in each
`treatment group).
`Methods: Two identical clinical trials; patients were treated twice daily with either CsA, 0.05% or 0.1%, or
`vehicle. The results of these two trials were combined for analysis.
`Main Outcome Measures: Efficacy: corneal and interpalpebral dye staining, Schirmer tear test (with and
`without anesthesia), tear break-up time, Ocular Surface Disease Index (OSDI), facial expression, patient subjec-
`tive rating scale, symptoms of dry eye, investigator’s evaluation of global response to treatment, treatment
`success, and daily use of artificial tears. Safety: occurrence of adverse events, best-corrected visual acuity,
`intraocular pressure, biomicroscopy, and blood trough CsA concentrations.
`Results: Treatment with CsA, 0.05% or 0.1%, gave significantly (P # 0.05) greater improvements than
`vehicle in two objective signs of dry eye disease (corneal staining and categorized Schirmer values). CsA 0.05%
`treatment also gave significantly greater improvements (P , 0.05) in three subjective measures of dry eye disease
`(blurred vision, need for concomitant artificial tears, and the physician’s evaluation of global response to
`treatment). There was no dose-response effect. Both CsA treatments exhibited an excellent safety profile, and
`there were no significant topical or systemic adverse safety findings.
`Conclusions: The novel ophthalmic formulations CsA 0.05% and 0.1% were safe and effective in the
`treatment of moderate to severe dry eye disease yielding improvements in both objective and subjective
`measures. Topical CsA represents a new pharmacologically based treatment for dry eye disease that may
`provide significant patient benefits. Ophthalmology 2000;107:631– 639 © 2000 by the American Academy of
`Ophthalmology.
`
`Despite the millions of individuals who have dry eye dis-
`ease,1– 4 there is currently no therapeutic treatment for this
`condition. Individuals plagued by the discomfort, burning,
`irritation, photophobia, and other symptoms of dry eye
`disease may also have blurred vision, gradual contact lens
`intolerance, and the inability to produce emotional tears, as
`
`Manuscript no. 99316.
`
`Originally received June 16, 1999.
`Accepted: December 8, 1999.
`1 Sall Eye Surgery Center, Bellflower, California.
`2 Stevenson Medical and Surgical Eye Center, New Orleans, Louisiana.
`3 Charlotte, North Carolina.
`4 Allergan, Inc., Irvine, California.
`Reprint requests to: Linda Lewis, 575 Anton Blvd, Suite 900, Costa Mesa,
`CA 92626.
`Supported by a grant from Allergan Inc.
`Dr. Reis is an employee of Allergan, Inc. None of the other authors has a
`financial interest in any of the products mentioned in this paper.
`
`well as an increased risk of ocular surface damage and
`ocular infection.5–9 Yet, at this time, the only treatments
`available are palliative in nature, consisting of lubricating
`eyedrops or punctal occlusion procedures that attempt to
`supplement the patient’s natural tears or improve the resi-
`dence time of the limited quantity of tears that the patient
`can produce.
`Until recently, attempts to develop therapeutic treatments
`for dry eye disease were hampered by a limited understand-
`ing of the underlying pathophysiologic processes. Although
`the exact mechanism is still not completely understood,
`there is now sufficient evidence to suggest that dry eye
`disease is the result of an underlying cytokine and receptor-
`mediated inflammatory process affecting both the lacrimal
`gland and the ocular surface.2,10 –14 This hypothesis is fur-
`ther supported by results from animal15–18 and human 20 –21
`(Foulks et al, Invest Ophthalmol Vis Sci 1996;37:S646;
`Helms et al, Invest Ophthalmol Vis Sci 1996;37; S646;
`Kunert et al, Invest Ophthalmol Vis Sci 1999;40(4):S771;
`
`© 2000 by the American Academy of Ophthalmology
`Published by Elsevier Science Inc.
`
`ISSN 0161-6420/00/$–see front matter
`PII S0161-6420(99)00176-1
`
`631
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`Ophthalmology Volume 107, Number 4, April 2000
`
`Turner et al, Invest Ophthalmol Vis Sci 1999;40[4]:S558)
`studies that demonstrate that topical treatment with the
`immunomodulatory agent cyclosporin A (CsA) can have
`beneficial effects on the underlying inflammatory patho-
`logic condition of dry eye disease, as well as improve the
`signs and symptoms of this condition.
`Evidence of the inflammatory nature of dry eye disease
`and the success of preliminary investigations into the effects
`of topical CsA treatment led to a large-scale multicenter,
`vehicle-controlled, dose-ranging (phase 2) clinical trial of
`the efficacy and safety of CsA treatment in moderate to
`severe dry eye disease. This study demonstrated that such
`treatment was safe and resulted in significant improvements
`in the signs and symptoms of the disease.21
`The objective of the studies described here was to com-
`pare the efficacy and safety of twice daily CsA, 0.05% and
`0.1%, ophthalmic emulsions to vehicle in the treatment of
`moderate to severe dry eye disease in patients with or
`without Sjo¨gren’s syndrome. In addition, specialized assays
`were performed on conjunctival biopsy specimens from a
`subset of patients to investigate the levels of several inflam-
`matory markers and the density of conjunctival goblet cells
`before and after treatment. The results of these specialized
`studies will be reported separately; preliminary reports have
`been presented (Kunert et al, Invest Ophthalmol Vis Sci
`1999;40[4]:S771; Turner et al, Invest Ophthalmol Vis Sci
`1999;40[4]:S558).
`
`Materials and Methods
`
`Study Design
`
`Two identical multicenter, randomized, double-masked, parallel-
`group clinical trials were conducted to compare two concentrations
`of CsA ophthalmic emulsion to its vehicle. The 6-month treatment
`phase was preceded by a 2-week run-in phase to standardize all
`patients to a common regimen of artificial tear use. The results of
`these two trials were combined for analysis.
`Both trials were conducted in compliance with Good Clinical
`Practices, investigational site Institutional Review Board Regula-
`tions, Sponsor and Investigator Obligations, Informed Consent
`Regulations, and the Declaration of Helsinki. Potential patients
`signed a prescreening informed consent. A second written in-
`formed consent was obtained from all patients before actual en-
`rollment, and a separate informed consent was obtained for the
`subset of patients who participated in the pharmacokinetic evalu-
`ations.
`Patients. Adult patients of either sex were eligible for partic-
`ipation if they had a diagnosis of moderate to severe dry eye
`disease as defined by the following criteria (detailed descriptions
`of each parameter are given under “Outcome Measures”): (1)
`Schirmer test without anesthesia of # 5 mm/5 min in at least one
`eye (if Schirmer test without anesthesia of 5 0 mm/5 min, then
`Schirmer with nasal stimulation had to be . 3 mm/5 min in the
`same eye); (2) sum of corneal and interpalpebral conjunctival
`staining of $ 15 in the same eye where corneal staining was $
`12; (3) a baseline Ocular Surface Disease Index ([OSDI]; see
`later) score of 0.1 with no more than three responses of “not
`applicable”; and (4) a score of $ 3 on the Subjective Facial
`Expression Scale (see later). Signs and symptoms must have been
`present despite conventional management, which may have in-
`cluded artificial tear drops, gels and ointments, sympathomimetic
`
`632
`
`agents, parasympathomimetic agents, and punctal occlusion. Eli-
`gible patients were enrolled if they were deemed capable of
`following the study protocol and considered likely to complete the
`treatment period and return for all scheduled visits; if they had
`normal lid position and closure, and a best-corrected ETDRS
`visual acuity score of 10.7 LogMar or better in each eye.
`Patients were excluded from the study if they had participated
`in an earlier clinical trial with CsA ophthalmic emulsion or had
`used systemic or topical ophthalmic cyclosporine within 90 days
`before the study. Other exclusion criteria included the presence or
`history of any systemic or ocular disorder or condition (including
`ocular surgery, trauma, and disease) that could possibly interfere
`with the interpretation of the study results; current or recent use of
`topical ophthalmic or systemic medications that could affect a dry
`eye condition; known hypersensitivity to any component of the
`study or procedural medications; required contact lens wear during
`the study; recent (within 1 month) or anticipated use of temporary
`punctal plugs during the study; permanent occlusion of lacrimal
`puncta within 3 months of the study; or if they were pregnant,
`lactating, or planning a pregnancy. Patients were also excluded if
`they appeared to have end-stage lacrimal gland disease (Schirmer
`reading with nasal stimulation of , 3 mm/5 min) or if their dry eye
`disease was the result of destruction of conjunctival goblet cells or
`scarring. Any patient who no longer met the criteria for moderate
`to severe dry eye (as defined previously) after completing the
`2-week run-in phase was excluded from enrollment in the treat-
`ment phase of the study.
`Patients could be discontinued before the completion of the
`study because of adverse events, pregnancy, protocol violations,
`lack of efficacy, or administrative or personal reasons.
`Study Medications. CsA, 0.05% and 0.1%, ophthalmic emul-
`sions and the vehicle of CsA ophthalmic emulsion were the study
`medications, with individually packaged preservative-free artificial
`tears (REFRESH Lubricant Eye Drops, Allergan, Inc.) provided as
`an adjunctive treatment to be used as frequently as needed. The
`doses of CsA used were based on the results of an earlier dose-
`ranging study.21 Both the CsA emulsions and vehicle were sterile,
`nonpreserved castor oil in water emulsions whose precise formu-
`lation is proprietary. All the study medications were supplied in
`unit dose vials.
`Concomitant Medications. Any therapy considered necessary
`for the maintenance of patient welfare was given at the discretion
`of the investigator and noted on the case report form. If the
`medication would not interfere with the response to study medi-
`cation, the patient was kept in the study. During the study, all
`concomitant medication treatment regimens were kept as constant
`as permitted by accepted medical practice. Systemic and topical
`ophthalmic medications that could interfere with the response to
`study medications or the interpretation of the study results were
`prohibited during the study. This included cyclosporine, other
`immunomodulatory agents, general anesthetics, antihistamines,
`cholinergic agents, antimuscarinics, b-blocking agents, tricyclic
`antidepressants, phenothiazines, topical ophthalmic steroids, estro-
`gen-progesterone (or other estrogen derivatives), or any topical
`ocular medications other than the assigned study medication and
`assigned artificial tears.
`Study Protocol. During the 2-week run-in phase, all patients
`were instructed to use the assigned artificial tears only (as needed).
`During the treatment phase, patients were instructed to instill 1
`drop of study medication twice daily in each eye for 6 months;
`once on waking in the morning and once at bedtime. Patients were
`allowed to use the assigned artificial tears as needed up to month
`4. To avoid dilution of the study medication, patients were in-
`structed not to use artificial tears within 30 minutes before or after
`use of the study medication. To minimize the habitual concomitant
`use of artificial tears, patients were asked to stop using artificial
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`z CsA in Dry Eye Disease
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`tears 1 week before their month 4 study visit. At this visit, patients
`were encouraged to use artificial tears less than eight times a day
`for the rest of the study period.
`During the treatment phase, patients returned for evaluation
`after 1, 3, 4, and 6 months of treatment.
`
`Outcome Measures
`Efficacy. The objective signs monitored were corneal and inter-
`palpebral conjunctival staining, Schirmer tear test (with and with-
`out anesthesia), and tear break-up time. The subjective endpoints
`used were the OSDI, the facial expression subjective rating scale,
`symptoms of dry eye, investigator’s evaluation of global response
`to treatment, treatment success, and artificial tears use. All these
`variables were evaluated at baseline and at each study visit, except
`for tear break-up time, which was not evaluated at the 1-month
`visit; the investigator’s evaluation of global response to treatment,
`which could not be meaningfully assessed at baseline; and the
`Schirmer tear test with anesthesia, which was only evaluated at
`baseline, month 3, and month 6.
`For corneal fluorescein staining, the entire cornea was exam-
`ined using slit-lamp evaluation with a yellow barrier filter and
`cobalt blue illumination. Staining was graded using the Oxford
`Scheme 6-point scale (from 0 to 5), with each investigator using
`the same set of photographs (provided by the study sponsor) as a
`guide. Lissamine green was then instilled, and interpalpebral con-
`junctival staining was evaluated more than 30 seconds, but less
`than 2 minutes, later. Using white light of moderate intensity, the
`interpalpebral regions of the temporal and nasal conjunctiva were
`graded using the same Oxford Scheme. The sum of corneal and
`interpalpebral staining was therefore on a 0 to 15point scale. On
`all scales, a negative change from baseline indicated an improve-
`ment.
`The Schirmer tear test was performed both with and without
`anesthesia and graded on a 5-point scale as follows: 1 (, 3 mm/5
`min), 2 (3– 6 mm/5 min), 3 (7–10 mm/5 min), 4 (11–14 mm/5
`min), and 5 (.14 mm/5 min) using the worse eye. A positive
`change from baseline indicated improvement. Categorized values
`were used to reduce overall within-patient variability known to
`occur for Schirmer wetting scores. The categories were chosen a
`priori on the basis of cutoff points suggested by a review of the
`medical literature and consultation with clinical investigators.
`Time until random location tear break-up between blinks was
`measured only up to 10 seconds and recorded only if the value was
`less than 10 seconds.
`The OSDI questionnaire was used to evaluate the impact of a
`patient’s dry eye disease on vision-related functioning.22 It con-
`sisted of 12 questions that were each rated from 0 5 none of the
`time to 4 5 all of the time. An overall score was calculated by
`dividing the sum of the responses for all questions answered by the
`total possible score. Thus, overall scores ranged from 0 5 no
`disability to 1 5 complete disability. A negative change from
`baseline indicated an improvement in vision-related functioning.
`The Subjective Facial Expression Rating Scale23 consisted of
`nine facial schematics ranging from 1 (the happiest face) to 9 (the
`unhappiest face) analyzed in five grades from 1 (pictures 1 and 2)
`to 5 (pictures 8 and 9). A negative change from baseline indicated
`an improvement.
`Symptoms of ocular discomfort, such as stinging/burning, itch-
`ing, sandiness/grittiness, blurred vision, dryness, light sensitivity,
`pain or soreness, were graded using a 5-point scale ranging from
`0 5 do not have this symptom to 14 5 always notice this
`symptom). A negative change from baseline indicated an improve-
`ment.
`The investigator completed a global evaluation of the overall
`effect of the study medication relative to the qualification visit
`
`using a 7-point scale in which 0 5 completely cleared, 1 5 ’90%
`improvement, 2 5 ’75% improvement, 3 5 ’50% improvement,
`4 5 ’25% improvement, 5 5 condition unchanged, and 6 5
`condition worsened. Treatment success was defined as a global
`evaluation of ’90% improvement or better.
`Patient use of concomitant artificial tears was also monitored.
`At each study visit, patients were queried about the average num-
`ber of times they used artificial tears each day during the past week
`and the number of days during the past week when they did not use
`any artificial tears.
`Safety. The primary safety variable monitored was the occur-
`rence of adverse events. The severity of each adverse event ob-
`served was rated from mild (awareness of sign or symptom, but
`easily tolerated) to severe (incapacitating with inability to work or
`do usual activity). The relationship of the event to the study
`medication was assessed by the investigator as none, unlikely,
`possible, probable, or definite.
`Other safety variables monitored included best-corrected visual
`acuity (using the ETDRS chart), intraocular pressure (using Gold-
`man applanation tonometry), and biomicroscopy (using slit-lamp
`examination without pupil dilation). Pharmacokinetic testing was
`also done on a subset of patients to determine blood trough CsA
`concentrations during treatment.
`Safety variables were evaluated at baseline and at all study
`visits, except for intraocular pressure, which was only evaluated at
`baseline and month 6, and CsA blood levels, which were evaluated
`at baseline and months 1 and 6.
`
`Other Measures
`Blood was collected from all patients for autoantibody testing to
`aid in the prospective identification of individuals with Sjo¨gren’s
`syndrome. Frozen samples were sent to a central laboratory (Co-
`vance Central Laboratories Inc, Indianapolis, IN) for log in and
`inventory before shipment to the Scripps Reference Laboratory
`(San Diego, CA) for the actual tests. Blood samples were evalu-
`ated for the presence of antinuclear antibodies, rheumatoid factor,
`and class SS-A and class SS-B Sjo¨gren’s antibodies.
`Blood was also collected from a subset of patients for deter-
`mination of mean blood CsA trough concentration. Frozen samples
`were sent to the sponsor (Allergan, Inc.) for analysis, under Good
`Laboratory Practices regulations, using liquid chromatography-
`mass spectrometry mass/mass spectrometry (LC-MS/MS) with a
`quantitation limit of 0.1 ng/ml.
`
`Statistical Methods
`All analyses presented in this report were conducted on the intent-
`to-treat patient population (all patients randomized). A last-obser-
`vation carried-forward method was used to input missing data,
`although baseline data (before study treatment) were not carried
`forward. For efficacy variables collected on both eyes, only the
`data from the “worse” eye were included in the analyses. The
`“worse” eye was defined as the eye with the worse Schirmer tear
`test value (without anesthesia) and the worse sum of corneal and
`interpalpebral conjunctival staining. If both eyes were comparable,
`then the right eye was used. The “worse” eye was defined on the
`basis of the baseline measurements, and data from this eye were
`used for all subsequent analyses. However, it should be noted that
`data were collected on both eyes throughout the study. All safety
`analyses included data from both eyes.
`Descriptive statistics were used to summarize all continuous
`variables (such as all staining variables and the OSDI score) and
`categorical variables (such as the Subjective Facial Expression
`Rating Scale, symptoms of dry eye disease, and categorized
`Schirmer values). A two-way analysis of variance (ANOVA), with
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`Ophthalmology Volume 107, Number 4, April 2000
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`Table 1. Patient Disposition
`
`Enrolled
`Completed
`Discontinued
`Lack of efficacy
`Adverse events
`Lost to follow-up
`Personal reasons
`Protocol or enrollment violations*
`Other†
`
`CsA 0.05%
`
`293
`235 (80.2%)
`
`1 (0.3%)
`19 (6.5%)
`4 (1.4%)
`9 (3.1%)
`19 (6.5%)
`6 (2.0%)
`
`CsA 0.1%
`
`292
`218 (74.7%)
`
`3 (1.0%)
`29 (9.9%)
`3 (1.0%)
`14 (4.8%)
`21 (7.2%)
`4 (1.4%)
`
`Vehicle
`
`292
`218 (74.7%)
`
`3 (1.0%)
`13 (4.5%)
`11 (3.8%)
`9 (3.1%)
`30 (10.3%)
`8 (2.7%)
`
`CsA 5 cyclosporin A.
`* Protocol or enrollment violations included improper entry, non-compliance, and use of prohibited medications.
`† Other included pregnancy, relocation, and removal from the study by the sponsor.
`
`group and investigator effects and interaction, was used to test for
`among-group differences in continuous variables. The Cochran-
`Mantel-Haenszel24 procedure with modified ridits, stratified by
`site, was used to test for differences in change from baseline
`among treatment groups in categorical variables and for among-
`group differences in global response distributions. The paired t test
`method was used to analyze within-group changes from baseline in
`continuous variables, whereas the Wilcoxon signed rank test was
`used to analyze within-group changes from baseline in categorical
`variables.
`Statistical adjustment of P values for multiple comparisons
`have been addressed by use of the Fisher’s least significant differ-
`ence protected tests to ensure that the experimental-wise error rate
`was 0.05. Specifically, a pair wise comparison between either
`cyclosporine group and vehicle groups is considered statistically
`significant if and only if (1) the overall comparison among the
`three groups is significant at the 0.05 level, and (2) the pair wise
`comparison between cyclosporine and vehicle is significant at the
`0.05 level. In addition, although patients were evaluated at multi-
`ple time points throughout the study, the primary endpoint is on the
`last observation while on treatment during the 6-month study
`period, and no further adjustments need to be made.
`Each trial was powered separately, whereby given an expected
`sample size of 100 per group, the power to detect a three-grade
`difference between treatment groups in the change from baseline
`for the sum of corneal and interpalpebral conjunctival staining was
`greater than 0.86, using a two-sided Wilcoxon rank sum test with
`an estimated standard deviation of 6.49.
`A two-sided test with a P value # 0.05 was considered statis-
`tically significant.
`
`Patient Treatment Assignment
`
`Qualified patients were randomly assigned to receive one of the
`three study medications in a 1:1:1 ratio using a block size of 3.
`Only a single randomization was used per trial. There was no
`stratification by either site or baseline factors.
`
`Study Masking
`
`Results
`
`Participant Flow and Follow-up
`
`A total of 877 patients was enrolled in approximately equal num-
`bers in the three treatment groups and more than 76% (671/877)
`completed the study (Table 1). The first patient was enrolled in
`July 1997 and the last patient completed the 6-month treatment
`period and evaluation in September 1998. Most of the patients who
`exited the study prematurely did so as a result of protocol or
`enrollment violations, personal reasons, lost to follow-up, or other
`nontreatment-related reasons. Only 0.8% of patients (7/877) were
`discontinued because of lack of efficacy; 1 of 293 (0.3%) in the
`CsA 0.05% group, 3 of 292 (1.0%) in the CsA 0.1% group, and 3
`of 292 (1.0%) in the vehicle group. Only 7.0% (61/877) were
`discontinued because of adverse events; 19 of 293 (6.5%) in the
`CsA 0.05% group, 29 of 292 (9.9%) in the CsA 0.1% group, and
`13 of 292 (4.5%) in the vehicle group.
`
`Patient Demographics
`The demographic characteristics of the study population are listed
`in Table 2. Overall, most of the patients were women (82%;
`715/877) and Caucasian (84%; 740/847). There were no statisti-
`cally significant differences between the treatment groups in any of
`the demographic variables measured. The use of prior therapy, or
`the types of concomitant medications used during the study for
`other medical conditions, were similar among the treatment
`groups.
`Sjo¨gren’s syndrome was defined as the presence of ocular
`symptoms, oral symptoms, and a Schirmer test # 5 mm, as well as
`the presence of at
`least one of the following autoantibodies:
`antinuclear antibodies, rheumatoid factor, and Sjo¨gren’s antibodies
`class SS-A and SS-B. Of the 877 enrolled patients, 270 (30.8%)
`were determined to have Sjo¨gren’s syndrome on the basis of these
`criteria. The number of patients with Sjo¨gren’s syndrome identi-
`fied may underestimate the number in the study population be-
`cause some patients left the studies without having autoantibody
`data collected and therefore could not meet
`the criteria for
`Sjo¨gren’s syndrome.
`
`The study medication was packaged, labeled, and masked in a
`manner consistent with Good Manufacturing Practices for inves-
`tigational supplies. Identical unit-dose vials were used to hold the
`study treatments, which were each of an identical milky color.
`
`Efficacy Analysis
`Corneal Staining. At baseline, the mean values for corneal stain-
`ing in the different treatment groups ranged between 2.61 and 2.77
`(using the Oxford scale from 0 to 5), with no statistically signif-
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`Table 2. Patient Demographics
`
`CsA 0.05%
`(n 5 293)
`58.7 6 13.9
`
`49 (16.7%)
`244 (83.3%)
`
`253 (86.3%)
`8 (2.7%)
`8 (2.7%)
`23 (7.8%)
`1 (0.3%)
`
`97 (33.1%)
`126 (43.0%)
`20 (6.8%)
`0 (0.0%)
`48 (16.4%)
`2 (0.7%)
`96 (32.8%)
`
`CsA 0.1%
`(n 5 292)
`60.1 6 13.3
`
`54 (18.5%)
`238 (81.5%)
`
`243 (83.2%)
`16 (5.5%)
`6 (2.1%)
`26 (8.9%)
`1 (0.3%)
`
`95 (32.5%)
`127 (43.5%)
`26 (8.9%)
`2 (0.7%)
`38 (13.0%)
`4 (1.4%)
`83 (28.4%)
`
`Vehicle
`(n 5 292)
`59.9 6 14.3
`
`59 (20.2%)
`233 (79.8%)
`
`244 (83.6%)
`15 (5.1%)
`6 (2.1%)
`26 (8.9%)
`1 (0.3%)
`
`109 (37.3%)
`116 (39.7%)
`18 (6.2%)
`0 (0.0%)
`46 (15.8%)
`3 (1.0%)
`91 (31.2%)
`
`Age (mean 6 SD)
`Sex
`Male
`Female
`Race
`Caucasian
`African-American
`Asian
`Hispanic
`Other
`Iris color
`Blue
`Brown
`Green
`Black
`Hazel
`Other
`Sjo¨gren’s syndrome patients
`
`CsA 5 cyclosporin A.
`
`icant differences among the groups. There was a statistically
`significant improvement from baseline in corneal staining (de-
`crease in mean score) within all treatment groups at all follow-up
`visits (P , 0.001). The improvement in corneal staining was
`significantly greater in both CsA groups than the vehicle group (P
`# 0.044) at month 4, and in the CsA 0.05% group at month 6 (P
`5 0.008). There was also a trend (P 5 0.062) toward a signifi-
`cantly greater improvement in the CsA 0.1% group than the
`vehicle group at month 6 (Fig 1).
`Conjunctival staining. At baseline, the mean values for tem-
`poral interpalpebral conjunctival staining ranged between 2.22 and
`2.26 (using the Oxford scale from 0 to 5), with no statistically
`significant differences among the groups. Similarly, the mean
`baseline values for nasal
`interpalpebral conjunctival staining
`ranged between 2.42 and 2.45, with no statistically significant
`differences among the groups. Statistically significant improve-
`ments from baseline were seen in both temporal and nasal con-
`junctival staining within all study groups at all follow-up visits
`(P , 0.001), but there were no statistically significant among-
`group differences.
`
`Schirmer Tear Test. At baseline,
`the mean categorized
`Schirmer values (obtained with anesthesia) in the different treat-
`ment groups ranged between 1.94 and 2.11 (on a scale from 0 to
`5 with 1 , 3 mm/5 min, 2 5 3– 6 mm/5 min, 3 5 7–10 mm/5 min,
`4 5 11–14 mm/5 min, and 5 .14 mm/5 min), with no statistically
`significant differences among the groups. At month 3, there was a
`significant worsening with the vehicle group (P 5 0.014) and a
`significant difference among the treatment groups, with the CsA
`0.05% group significantly greater than the vehicle group (P 5
`0.009). At month 6, there was a statistically significant improve-
`ment from baseline within both CsA groups. Moreover,
`the
`changes in Schirmer values in each of the CsA groups was signif-
`icantly better than in the vehicle group (P , -0.007; Fig 2).
`Schirmer tear tests were also conducted without anesthesia. At
`baseline, the mean categorized Schirmer values (obtained without
`anesthesia) in the different treatment groups ranged between 1.47
`and 1.50 (on the same scale as was used for the Schirmer test with
`anesthesia), with no statistically significant differences among the
`
`Figure 1. Change from baseline in corneal staining. Mean value 6
`standard error. Graded on a scale from 0 to 5.
`
`Figure 2. Change from baseline in categorized Schirmer values (measured
`with anesthesia). Mean value 6 standard error. Categorized Schirmer
`values were graded on a 5-point scale as follows: 1 (, 3 mm/5 min), 2 (3– 6
`mm/5 min), 3 (7–10 mm/5 min), 4 (11–14 mm/5 min), and 5 (.14 mm/5
`min) using the worse eye.
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`635
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`FAMY CARE - EXHIBIT 1007-0005
`
`

`
`Ophthalmology Volume 107, Number 4, April 2000
`
`Figure 3. Change from baseline in blurred vision. Mean value 6 standard
`error. Graded on a scale from 0 to 4.
`
`Figure 4. Change from baseline in assigned lubricating eyedrop use. Mean
`value 6 standard error.
`
`groups. Statistically significant improvements from baseline were
`seen in these Schirmer values within all treatment groups at all
`follow-up visits, but there were no significant among-group dif-
`ferences.
`Symptoms of Dry Eye Disease. Of the subjective ocular
`symptoms monitored, the most notable changes were seen in
`blurred vision. At baseline, the mean score for blurred vision in the
`different treatment groups ranged between 1.83 and 2.04 (on a
`scale from 0 to 4), with no statistically significant differences
`among the groups. The decrease from baseline in blurred vision
`was statistically significant within both CsA groups at all fol-
`low-up visits (P # 0.012) but only at month 6 within the vehicle
`group (P 5 0.039). Moreover, the improvement in blurred vision
`was significantly greater in the CsA 0.05% group than the vehicle
`group at all follow-up visits (P # 0.014; Fig 3).
`Statistically significant changes from baseline were observed
`within all treatment groups at all time points in dryness (P ,
`0.001), sandy/gritty feeling (P , 0.001), and itching (P # 0.038).
`Statistically significant improvements from baseline were seen in
`photophobia within both CsA groups at all follow-up visits (P #
`0.028) and within the vehicle group at months 3, 4, and 6 (P #
`0.023). Statistically significant improvements from baseline were
`also seen in burning and stinging within both CsA groups at
`months 4 and 6 (P # 0.024) and within the vehicle group at
`months 3, 4, and 6 (P # 0.019). There was also a statistically
`significant improvement from baseline in pain within the CsA
`0.1% group at all follow-up visits (P # 0.012) and the CsA 0.05%
`group and vehicle group at month 6 (P # 0.012). There were no
`statistically significant among-group differences in any of these
`variables.
`Physician’s Subjective Assessment of Global Response to
`Treatment. According to the physician’s subjective assessment of
`global response to treatment, most patients in all treatment groups
`demonstrated a response to treatment at all follow-up visits. At
`months 3 and 4, the distribution of global responses was signifi-
`cantly better in the CsA 0.1% group than the vehicle group (P #
`0.006). At month 4,
`the percentage of patients exhibiting an
`improvement (i.e., slight response or better) was 63.3% in the CsA
`0.05% group, 65.4% in the CsA 0.1% group, and 53.1% in the
`vehicle group. These percentages improved to 68.5%, 67.3%, and
`63.0%, respectively, at month 6. At month 6, the percentage of
`patients with at least a moderate response to treatment was 35.5%
`in the CsA 0.05% group, 39.3% in the CsA 0.1% group, and 31.9%
`in the vehicle group.
`Concomitant Use of Artificial Tears. The average daily use
`of artificial tears at baseline was 4.86 units in the vehicle group,
`
`636
`
`6.25 units in the CsA 0.05% group, and 5.56 units in the CsA 0.1%
`group; these between-group differences at baseline were statisti-
`cally significant (P # 0.019) (Fig 4). Within both CsA groups,
`there were statistically significant decreases in artificial tear use at
`months 3, 4, and 6 (P # 0.002), whereas within the vehicle group
`the decrease in artificial tear use was only statistically significant at
`month 4 (P , 0.001). At month 6, the decrease in artificial tear use
`was significantly greater in the CsA 0.05% group than the vehicle
`group (P # 0.006). In addition, there was a statistically significant
`increase from baseline in the number of days without artificial tear
`use within all treatment groups at all follow up visits (P , 0.001),
`but there were no statistically significant among-group differences.
`Other Efficacy Analyses. Within all treatment groups at all
`follow-up visits, there were statistically significant improvements
`from baseline in both the OSDI and the Subjective Facial Expres-
`sion Rating Scale (P , 0.001). However, there were no statisti-
`cally significant among-group differences.
`
`Safety Analysis
`Adverse Events. Treatment-related adverse events were defined
`as those adverse events that the in